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Medicographia
Vol 36, No. 2, 2014
119
A
Ser vier
publication
Osteoporosis:
the fracture cascade
must be stopped
E DITORIAL
139
Don’t drop the guard: osteoporosis is still a fatal disease!
L’ostéoporose demeure une maladie fatale : la vigilance reste de mise
J. Y. Reginster, Belgique
T HEMED
143
ARTICLES
Epidemiology of secondary fractures
B. Cortet, France
150
Osteoporotic fragility fractures: why the care gap?
L. M. March, Australia
156
Fracture consolidation and osteoporosis
J. M. Féron, France
163
Growing in age and numbers: how can we best manage the elderly
with osteoporosis?
F. C. Santos, Brazil
170
“Ossa sanus in corpore sano”—A sound bone in a sound body:
the importance of nutrition, physical activity, and nonpharmacological
management in osteoporosis
A. Gómez-Cabello, I. Ara, A. González-Agüero, J. A. Casajús,
G. Vicente-Rodríguez, Spain
176
Osteoporosis is also a male disease
J. M. Kaufman, S. Goemaere, Belgique
184
Capture the Fracture: an IOF initiative to break the cycle of fragility fracture
K. Åkesson , Sweden
192
Secondary fracture prevention is good, avoiding the first fracture, better still
M. L. Brandi, Italy
197
How can we convince osteoporotic patients to take their treatment?
S. Lipschitz, South Africa
Contents continued on next page
Medicographia
Vol 36, No. 2, 2014
119
A
C ONTROVERSIAL
Ser vier
publication
QUESTION
205 Is there any difference between primary and secondary prevention for
patients with osteoporosis?
J. R. Caeiro Rey, Spain - H. Canhão, Portugal - A. El Garf, Egypt O. Ershova, Russia - T. S. Fu, Taiwan - D. Grigorie, Romania J. Li-Yu, Philippines - M. O’Brien, Ireland - V. Povoroznyuk, Ukraine S. Rojanasthien, Thailand - E. Rudenka, Belarus - G. Singh, Malaysia B. Stolnicki, Brazil
I NTERVIEW
219 Fracture liaison services and secondary fracture prevention
R. Rizzoli, T. Chevalley, Switzerland
F OCUS
225 Complicated fractures: how should one deal with them?
D. N. Alegre, Portugal
U PDATE
230 The bone-fat connection: A Very Bad Trip
G. Duque, Australia
A
TOUCH OF
F RANCE
238 Lascaux: preserving a 20 000-year old legacy of Paleolithic art
M. Mauriac, France
253 Abbé Henri Breuil and the rediscovery of prehistoric humans
A. Hurel, France
‘‘
EDITORIAL
It is of prime importance to
concentrate on the early diagnosis
of osteoporosis, on the identification of incident vertebral fractures,
and on providing osteoporotic patients with appropriate management. Key elements of any strategy
must also include a better implementation of national guidelines,
the establishment of facture liaison services to identify high-risk
patients, and a better adherence
to treatment to improve the cost/
effectiveness of treatments.”
Don’t drop the guard:
osteoporosis is still
a fatal disease!
b y J . Y. R e g i n s t e r, B e l g i u m
his editorial highlights the recent report prepared by Hernlund et al in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industries and Associations (EFPIA).
In 1984, the World Health Organization (WHO) issued a report on fracture
risk assessment and screening for postmenopausal osteoporosis. It also provided
diagnostic criteria for osteoporosis based on the measurement of bone mineral density (BMD) and recognized osteoporosis as an established and well-defined disease
affecting more than 75 million people in the United States, Europe, and Japan.
T
Jean-Yves REGINSTER
MD, PhD
President, European Society
for Clinical and Economic
Aspects of Osteoporosis and
Osteoarthritis (ESCEO)
Co-Founder and Board Member
International Osteoporosis
Foundation (IOF)
Department of Public Health
and Health Economics
University of Liège
Liège, BELGIUM
Address for correspondence:
Professor Jean-Yves Reginster,
Department of Public Health and
Health Economics, University of
Liege, 4020 Liege, Belgium
(e-mail: jyreginster@ulg.ac.be)
Medicographia. 2014;36:139-142
www.medicographia.com
More than 8.9 million fractures occur annually worldwide due to osteoporosis. Moreover, because of changes in population demography, the number of men and women
with osteoporosis will increase by 23% between 2010 and 2025, and the number
of fractures by 28%. The most common osteoporotic fractures are those at the hip,
spine, forearm, and humerus but many other fractures after the age of 50 years are
related, at least in part, to low BMD and should be regarded as osteoporotic. These
include fractures of the ribs, tibia, pelvis and other femoral fractures. However, when
we talk about osteoporosis, most people think about hip fractures, the most wellknown and most debilitating fractures linked to the disease. As a consequence,
incidence rates of hip fractures are available for most countries, at least in the EU,
whereas information on country-specific incidence rates of forearm fractures, clinical
vertebral fractures, and other osteoporotic fractures are scarce. However, these fractures are at least as important as hip fractures as they are generally the first sign of
osteoporosis and mark the beginning of the fracture cascade. Indeed, it has been
shown that a wrist fracture doubles the risk of vertebral fracture, which itself increases the risk of hip fracture 5-fold.
In 2010 in the EU, the number of new fractures was estimated at 3.5 million, comprising approximately 620 000 hip fractures, 520 000 vertebral fractures, 560 000
forearm fractures and 1 800 000 other fractures (ie, pelvis, rib, humerus, tibia, fibula,
clavicle, scapula, sternum, and other femoral fractures). This corresponds to 9556
new fractures per day (390 per hour). Due to the 4:1 women-to-men ratio in those
affected by osteoporosis, around two-thirds of all these incident fractures occurred
in women.
Approximately 20% of individuals suffering a fracture will require long-term care due
to decreased mobility, and it is estimated that only 40% of those individuals will
regain their before-fracture level of independence. Moreover, 20% of patients who
suffer a hip fracture will die in the following 6 months. Additional data on osteoporo-
Don’t drop the guard: osteoporosis is still a fatal disease! – Reginster
MEDICOGRAPHIA, Vol 36, No. 2, 2014
139
EDITORIAL
sis-related deaths have shown that in the EU the number of
deaths causally related to fractures was estimated at 43 000.
In women, approximately 50% of these deaths were related
to hip fractures, 28% to clinical vertebral fractures, and 22%
to other fractures. In men, the corresponding proportions
were 47%, 39%, and 14%, respectively.
The cost of osteoporosis, including pharmacological intervention, is very high with an annual cost estimated at €32
billion per year in the EU, and €20 billion per year in the US.
Costs of treating incident fractures represented 66% of this
cost, while pharmacological prevention represented 5%, and
long-term fracture care 29%. Excluding the cost of pharmacological prevention, hip fractures remain the most expensive
with 54% of the costs, while “other fractures” represent 39%,
and vertebral and forearm fractures represent 5% and 1%, respectively. Moreover, the older the population gets, the more
the economic weight of the disease will increase. This is especially true for Asia, South America, or the Middle East.
For fractured osteoporotic patients and their families, the impact on quality of life can be devastating and the psychological impact severe. A life of chronic pain and reduced mobility
can lead to loss of independence, social restrictions and isolation, as well as depression and loss of self-esteem. The burden of osteoporosis can also be measured from a health point
of view by measuring the number of quality-adjusted life years
(QALYs) lost. The QALY is a multi-dimensional outcome measure frequently employed in health economic analysis that incorporates both the quality (health-related) and quantity (length)
of life. QALYs are derived by multiplying the duration of life
(years) with a health utility index ranging from 0 (death) to 1
(perfect health). For example, a person who lives for 5 years
with a health utility index of 0.8 would accrue 4 QALYs during
those 5 years.
In the EU in 2010, the total health burden—measured in terms
of lost QALYs—was estimated at 1 180 000 QALYs. Twice as
many QALYs were lost in women compared with men. Moreover, the majority of the QALYs lost were a consequence of
prior fractures. This is another strong argument in favor of increasing the management of osteoporosis after a first fracture.
In the EU, the annual number of fractures will rise from 3.5
million in 2010 to 4.5 million in 2025, which corresponds to an
increase of 28%. Hence, the number of QALYs lost annually
due to fractures will increase from 1.2 million in 2010 to 1.4
million in 2025, corresponding to an increase of 20%, and the
total cost including values of QALYs lost will rise by 22%.
The treatment uptake of osteoporosis drugs has increased
considerably during the last decade, although uptake of individual treatments differs between regions. Globally, however,
the proportion of treated patients has decreased, suggesting
a decreased interest for the disease and its consequences.
Hence, there is still a too large gap between the number of men
(59%) and women (57%) that are being treated compared
with the proportion of the population that could be considered eligible for treatment based on their fracture risk. As mentioned above, a wrist fracture multiplies by 2 the risk of vertebral fracture, which itself multiplies by 5 the risk of hip fracture;
as the risk of these new fractures remains elevated for at least
10 years, it should be mandatory to increase secondary prevention.
Conclusion
Although the management of osteoporosis has dramatically
improved over the last decade, osteoporosis will continue to
be a growing burden as the population keeps getting older, all
the more so as the fastest-growing segment of the population
is the over-80-year-olds.
Due to the major increase in the risk of subsequent fractures
among patients who have had a first osteoporotic fracture, it
is of prime importance to concentrate on the early diagnosis
of osteoporosis, on the identification of incident vertebral fractures, and on providing osteoporotic patients—and especially those at high risk of incident fractures—with appropriate
management. Key elements of any strategy must also include
a better implementation of national guidelines, the establishment of facture liaison services to identify high-risk patients,
and a better adherence to treatment to improve the cost/effectiveness of treatments. ■
Reference
E. Hernlund, A. Svedbom, M. Ivergård, et al. Osteoporosis in the European Union:
Medical Management, Epidemiology and Economic Burden. A report prepared in
collaboration with the International Osteoporosis Foundation (IOF) and the European
Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporosis.
2013;8:136.
Keywords: cost; fracture; health burden; osteoporosis; quality-adjusted life year
140
Don’t drop the guard: osteoporosis is still a fatal disease! – Reginster
ÉDITORIAL
‘‘
Il est extrêmement important
de se concentrer sur le diagnostic
précoce de l’ostéoporose, la mise
en évidence des fractures vertébrales incidentes et la prise en
charge appropriée des patients atteints d’ostéoporose. Les stratégies adoptées doivent également
reposer sur une meilleure mise en
œuvre des directives nationales,
sur l’établissement de services de
liaison pour fractures (SLF) afin
d’identifier les patients présentant
un risque élevé, ainsi que sur une
meilleure observance du traitement pour améliorer le rapport
coût/efficacité des traitements. »
L’ostéoporose demeure
une maladie fatale :
la vigilance reste de mise
p a r J . Y. R e g i n s t e r, B e l g i q u e
C
et éditorial met en avant le récent rapport élaboré par Hernlund et al en
collaboration avec la Fondation Internationale Contre l’Ostéoporose (IOF)
et la Fédération Européenne des Associations et Industries pharmaceutiques (EFPIA). En 1984, l’Organisation Mondiale de la Santé (OMS) a publié un rapport portant sur l'évaluation du risque de fracture et le dépistage de l’ostéoporose post-ménopausique. Ce rapport fournissait également des critères pour
le diagnostic de l’ostéoporose en se basant sur la mesure de la densité minérale osseuse (DMO) et reconnaissait l’ostéoporose comme une maladie établie et bien définie touchant plus de 75 millions de personnes aux États-Unis, en Europe et au Japon.
On dénombre plus de 8,9 millions de fractures dues à l’ostéoporose chaque année
dans le monde. Par ailleurs, en raison de l’évolution démographique de la population, le nombre d'hommes et de femmes souffrant d’ostéoporose augmentera de
23 % entre 2010 et 2025, et le nombre de fractures, de 28 %. Les fractures ostéoporotiques les plus fréquentes sont celles de la hanche, de la colonne vertébrale,
de l’avant-bras et de l'humérus, mais de nombreuses autres fractures survenant
après 50 ans sont associées, du moins en partie, à une faible DMO et doivent être
considérées comme ostéoporotiques. Il s’agit notamment des fractures des côtes,
du tibia, du bassin et d'autres fractures fémorales. Cependant, lorsque l’on parle
d’ostéoporose, on pense généralement aux fractures de la hanche, qui sont les
fractures les plus connues et invalidantes associées à cette maladie. De ce fait, les
taux d’incidence des fractures de la hanche sont disponibles dans la plupart des
pays, du moins en Europe, alors qu’il n’existe que peu d’informations sur les taux
d’incidence spécifiques à chaque pays des fractures de l’avant-bras, des fractures
cliniques vertébrales et des autres fractures ostéoporotiques. Pourtant, ces fractures
sont au moins tout aussi importantes que les fractures de la hanche puisqu’elles
constituent généralement la première manifestation de l’ostéoporose, et marquent
le début de la cascade fracturaire. Il a en effet été prouvé qu'une fracture du poignet multiplie par 2 le risque de fracture vertébrale, qui elle-même multiplie par 5 le
risque de fracture de la hanche.
En 2010 dans l’Union Européenne, le nombre de nouvelles fractures a été estimé
à 3,5 millions, dont environ 620 000 fractures de la hanche, 520 000 fractures vertébrales, 560 000 fractures de l’avant-bras et 1 800 000 autres fractures (à savoir,
bassin, côtes, humérus, tibia, péroné, clavicule, omoplate, sternum et autres fractures
fémorales). Cela représente 9 556 nouvelles fractures par jour (390 par heure). En raison d’un ratio femme/homme de 4:1 chez les personnes souffrant d’ostéoporose,
environ deux tiers de l’ensemble de ces fractures incidentes ont concerné des femmes.
L’ostéoporose demeure une maladie fatale : la vigilance reste de mise – Reginster
141
ÉDITORIAL
Environ 20 % des individus souffrant d'une fracture auront besoin de traitements de longue durée en raison d’une mobilité
réduite, et on estime que 40 % seulement de ces individus récupéreront le niveau d’indépendance dont ils bénéficiaient
avant la fracture. Par ailleurs, 20 % des patients présentant
une fracture de la hanche décéderont dans les 6 mois qui
suivent. Des données complémentaires sur les décès associés à l’ostéoporose ont montré que dans l’UE, le nombre
de décès liés à ces fractures était estimé à 43 000. Chez les
femmes, environ 50 % de ces décès étaient associés à des
fractures de la hanche, 28 % à des fractures vertébrales cliniques et 22 % à d’autres fractures. Chez les hommes, les
proportions correspondantes étaient de 47 %, 39 % et 14 %,
respectivement.
Le coût de l’ostéoporose, y compris son traitement pharmacologique, est très élevé, avec un coût annuel estimé à 32 milliards d’euros par an dans l'UE et 20 milliards d’euros par an
aux États-Unis. Les dépenses liées au traitement des fractures incidentes représentent 66 % de ce coût, alors que la
prévention pharmacologique en représente 5 % et les traitements de longue durée associés aux fractures, 29 %.
En dehors des dépenses liées à la prévention pharmacologique, les fractures de la hanche demeurent les fractures les
plus onéreuses puisqu’elles représentent 54 % des coûts,
alors que les « autres fractures » y contribuent à hauteur de
39 % et les fractures vertébrales et de l’avant-bras représentent 5 % et 1 % des coûts, respectivement. Par ailleurs, plus
la population ira en vieillissant, plus lourd sera le poids économique de la maladie. Cela est particulièrement vrai en ce qui
concerne l'Asie, l’Amérique du Sud ou le Moyen-Orient.
Pour les patients souffrant de fractures ostéoporotiques et
leurs familles, l’impact sur la qualité de vie peut être dévastateur et l’impact psychologique, grave. Les douleurs chroniques
et la mobilité réduite qui sont le lot quotidien de ces patients
peuvent conduire à une perte d'indépendance, à des restrictions sociales et à un isolement, ainsi qu’à une dépression et
à une perte d'estime de soi. Le fardeau de l’ostéoporose peut
également être évalué du point de vue de la santé en mesurant le nombre d'années de vie ajustées sur la qualité (QALY)
perdues. Ce paramètre multi-dimensionel est fréquemment
employé pour les analyses économiques de santé et intègre
la qualité de vie (liée à la santé) et sa quantité (durée). Les QALY
sont obtenues en multipliant la durée de vie (années) par un
indice de l’état de santé allant de 0 (décès) à 1 (parfaite santé).
Par exemple, une personne qui vit pendant 5 ans avec un
indice d’état de santé de 0,8 cumulerait 4 QALY pendant ces
5 ans. Dans l’UE, en 2010, le fardeau sanitaire total, a été es-
142
timé à 1 180 000 QALY perdues. Pour les femmes, la perte
en QALY était deux fois plus élevée que chez les hommes.
Par ailleurs, la majorité des QALY perdues étaient la conséquence de fractures antérieures. Il s’agit là d'un autre argument de poids en faveur d’une meilleure prise en charge de
l’ostéoporose après une première fracture. Dans l’UE, le nombre annuel de fractures passera de 3,5 millions en 2010 à
4,5 millions en 2025, soit une augmentation de 28 %. Ainsi, le
nombre de QALY perdues chaque année pour cause de fractures passera de 1,2 million en 2010 à 1,4 million en 2025,
soit une hausse de 20 %, et le coût total incluant les valeurs
des QALY perdues augmentera de 22 %.
L’utilisation de médicaments pour traiter l’ostéoporose a considérablement augmenté au cours de la dernière décennie, bien
qu’il existe des variations en fonction des régions. Cependant,
la proportion des patients traités a globalement diminué, ce
qui suggère une perte d’intérêt pour la maladie et ses conséquences. Ainsi, on constate encore une trop grande différence entre le nombre d’hommes (59 %) et de femmes (57 %)
recevant un traitement par rapport à la population théoriquement éligible à un traitement sur la base de son risque de
fracture. Comme indiqué plus haut, une fracture du poignet
multiplie par 2 le risque de fracture vertébrale, qui elle-même
multiplie par 5 le risque de fracture de la hanche ; le risque de
ces nouvelles fractures demeurant élevé pendant au moins
10 ans, une amélioration de la prévention secondaire est indispensable.
Conclusion
Bien que la prise en charge de l’ostéoporose ait été considérablement améliorée au cours de la dernière décennie, l’ostéoporose continuera d'être un fardeau croissant puisque la
population ne cesse de vieillir, d’autant plus que les personnes
qui composent le segment de la population qui augmente le
plus rapidement concerne les plus de 80 ans.
En raison de l’importante augmentation du risque de nouvelles
fractures chez les patients ayant subi une première fracture
ostéoporotique, il est extrêmement important de se concentrer sur le diagnostic précoce de l’ostéoporose, la mise en
évidence des fractures vertébrales incidentes et la prise en
charge appropriée des patients atteints d’ostéoporose, notamment ceux présentant un risque élevé de fractures incidentes. Les stratégies adoptées doivent également reposer
sur une meilleure mise en œuvre des directives nationales, sur
l’établissement de services de liaison pour fractures (SLF) afin
d’identifier les patients présentant un risque élevé, ainsi que
sur une meilleure observance du traitement pour améliorer le
rapport coût/efficacité des traitements. ■
L’ostéoporose demeure une maladie fatale : la vigilance reste de mise – Reginster
‘‘
OSTEOPOROSIS:
Vertebral fractures are among
the major fragility fractures and
occur in 16% of postmenopausal
women. Vertebral fractures are emblematic of osteoporosis. However, their frequency is difficult to determine since only 1 in 4 comes to
clinical attention… A prevalent
vertebral fracture dramatically increases the risk of future fracture,
particularly in the spine, and the
concept of the fracture cascade
seems to be particularly relevant
for vertebral fractures.”
THE
FRACTURE
CASCADE
MUST
BE
STOPPED
Epidemiology of
secondary fractures
b y B . C o r t e t , Fra n c e
T
Bernard CORTET, MD, PhD
Department of Rheumatology
and EA 4490
University-Hospital of Lille
Lille, FRANCE
he term fracture cascade has been coined to describe the fact that the
occurrence of a first fracture dramatically increases the risk of subsequent fractures. Although the etiopathogenesis of this phenomenon is
not fully understood, it seems that the mechanisms are not identical for the
vertebral and nonvertebral fracture cascades. For the vertebral fracture cascade, the main risk factors are low bone mineral density and impaired bone
quality (which is also true for the nonvertebral fracture cascade); however, several non-bone parameters also characterize the vertebral fracture cascade:
changes in local properties, alterations in bone macroarchitecture, spinal curvature and spinal loading abnormalities, and impaired intervertebral disc integrity. A past history of at least one vertebral fracture leads to a 4-fold increased risk of vertebral fracture. Moreover, it has been shown that the higher
the number of prevalent vertebral fractures, the higher the risk of new vertebral fractures will be. In addition, a prevalent vertebral fracture also increases
the risk of subsequent nonvertebral fracture. The risk is highest in the first year
following a vertebral fracture and greater in men than in women. Similarly, for
the nonvertebral fracture cascade, the occurrence of a nonvertebral fracture
also increases both the risk of subsequent vertebral fractures — to varying
degrees, according to the site of the prevalent nonvertebral fracture — and
the risk of subsequent nonvertebral fractures. All of these findings are important since some fractures (both prevalent and incident) are associated with
an excess in mortality (particularly those of the hip and vertebrae).
Medicographia. 2014;36:143-149 (see French abstract on page 149)
umerous risk factors have been associated with the occurrence of fragility
fractures. Among them, a prevalent fragility fracture is a major risk factor for
future fractures. Whatever the site of the prevalent fracture, the risk of subsequent fracture is increased. The subsequent fracture can occur either at the same
site or another site; however, the level of risk varies depending on the site of the
prevalent fracture and whether it is a vertebral or nonvertebral fracture. A simple
example can illustrate the weight of a prevalent fracture when assessing the risk
of fracture and the FRAX® tool (Fracture Risk Assessment tool)1 is a simple tool with
a clear educational value in this context. The 10-year major osteoporotic fracture
risk of a 74-year-old woman (weight, 60 kg; height, 160 cm) whose only risk factor
for fracture is a smoking history (10 packs per year) is 12%. However, if this patient
had a past history of fragility fracture, her 10-year risk for major osteoporotic fracture would almost double (22%).
N
Prof Bernard Cortet, Centre de
Consultation et d’Imagerie de
l’Appareil Locomoteur, Hôpital Roger
Salengro, Rue Emile Laine, 59037
Lille Cedex, France
(e-mail: bernard.cortet@chru-lille.fr)
Epidemiology of secondary fractures – Cortet
143
OSTEOPOROSIS:
THE
FRACTURE
CASCADE
MUST
The term fracture cascade has been coined to illustrate the
fact that once a first fracture has occurred, the risk of a second fracture increases greatly, and that once a second fracture occurs the risk of a third fracture increases even further.
In this article we will review the burden of the fracture cascade according to the site of prevalent fracture.
Prevalent vertebral fracture and risk of subsequent
vertebral fracture
Vertebral fractures are among the major fragility fractures and
occur in 16% of postmenopausal women.2 Vertebral fractures are emblematic of osteoporosis. However, their frequency is difficult to determine since only 1 in 4 comes to clinical
attention for various reasons such as the low diagnostic performance of radiography or the absence of recognized classic symptoms of vertebral fractures.3
A prevalent vertebral fracture dramatically increases the risk
of future fracture, particularly in the spine, and the concept
of the fracture cascade seems to be particularly relevant for
vertebral fractures.
u Etiopathogenesis
Although the etiopathogenesis of the fracture cascade is
complex and not fully understood, there are several hypotheses.4 First, let’s consider bone properties. In clinical practice,
bone properties are assessed by measuring bone mineral
density (BMD) by dual-energy x-ray absorptiometry (DXA).
However, although BMD measured by DXA is lower for patients with vertebral fractures compared with controls, the
mean difference in terms of BMD is modest.4 Comparing
measurements of subregional BMD in patients with and without vertebral fractures would be more relevant; yet, this approach is not used in clinical practice.4 These data suggest
that other factors may explain the vertebral fracture cascade,
in particular bone quality, spine properties, and neurophysiological properties. As previously mentioned, measurement
of bone quality is a relevant factor when evaluating bone
strength.5 However, in studies performed in patients with vertebral fractures, bone quality—and particularly bone microarchitecture—is usually measured using transiliac bone biopsies. Therefore, the conclusions of these studies may not be
relevant to the concept of the fracture cascade. That’s because the skeleton is quite heterogeneous and the measurement of bone microarchitecture at the ilium does not necessarily reflect the situation at the vertebral level. In contrast,
spine properties seem to play a major role. The first reason for
this is that the fracture cascade is more marked in the spine
than in other bone sites. The vertebral fracture cascade may
be the consequence of changes in local properties and several studies have indicated that women with vertebral fractures have smaller vertebrae than control patients.6 It has also
been shown that women with vertebral fractures have smaller lever arms (the distance between the erector spinae and
vertebral centroids). These abnormalities (reduced vertebral
144
BE
STOPPED
cross-sectional areas and shorter lever arms) lead to increased mechanical loading. Therefore, in order to maintain
the moment of equilibrium, the muscle force must increase.
This is not a problem in normal situations4; however, in case
of bone fragility, the vertebral body is not able to sustain the
resultant increase in compressive and shear load and this
leads to vertebral failure. Changes in load distribution may
also be involved. Indeed, these changes are influenced by
intervertebral disc integrity, and owing to the age of the osteoporotic population, disc degeneration is very common.
Moreover, it has been shown that intervertebral disc narrowing is associated with an increased risk of vertebral fracture.7
The characteristics of the fracture should also be considered,
and particularly its location, type, and severity.8 The risk of
incident vertebral facture is dramatically increased when the
prevalent fracture occurs between the T5 and T7 vertebrae
for thoracic fractures, and between the L1 and L3 vertebrae
for lumbar fractures.8 The risk is also increased when the deformation occurs in the anterior and middle parts of a vertebra. Finally, the greater the prevalent deformation, the greater
the risk of incident fracture. Due to increased compression
and shear loads in the vicinity of the vertebral fracture, the
risk of subsequent vertebral fracture is particularly high on
the vertebrae directly adjacent to the fracture.4
Global spine properties may also be involved in the etiopathogenesis of the vertebral fracture cascade. Although there
are conflicting data on this issue, one can speculate that osteoporotic vertebral fractures are associated with increases in
thoracic curvature. More than 10 years ago, Cortet et al found
a correlation between thoracic curvature and the vertebral
deformity index (r=0.6, P<0.001) using a curviscope (a tool
composed of angular potentiometers placed on the skin over
the thoracolumbar area).9 The longitudinal part of the study
also demonstrated a relationship between the occurrence of
vertebral fracture at year 1 and 3 and an increase in spinal
curvature at the thoracic level. However, other authors have
not been able to confirm this relationship.10 Nevertheless, thoracic kyphosis is an independent and significant predictor of
SELECTED
BMD
CI
DXA
FIT
FRAX
GLOW
GPRD
HR
KI
MORE
SQ
ABBREVIATIONS AND ACRONYMS
bone mineral density
confidence interval
dual-energy x-ray absorptiometry
Fracture Intervention Trial
Fracture Risk Assessment tool
Global Longitudinal study of Osteoporosis in Women
General Practice Research Database
hazard ratio
kyphosis index
Multiple Outcomes of Raloxifene Evaluation trial
semi-quantitative (score)
OSTEOPOROSIS:
vertebral fracture. In a large prospective cohort of postmenopausal women with at least one vertebral fracture at
baseline, Roux et al measured the kyphosis index (KI), which
is defined as the percentage ratio between the maximum
depth of thoracic curvature and the height measured from
the T4 to the T12 vertebrae.11 Patients with the highest KI experienced significantly more new vertebral fractures over the
3-year study period (incidence, 27.36%) than those in the
medium tertile (fracture incidence, 19.07%; relative risk [RR],
1.5; 95% confidence interval [CI], 1.19-1.96; P<0.001) or
those in the lowest tertile (incidence, 17.31%; RR, 1.70; 95%
CI, 1.32-2.21; P<0.001).
Finally, neurophysiological properties may also be involved in
the fracture cascade. Although studies are scarce on this issue, it seems that vertebral fractures have a negative effect
on balance control, with an increased risk of falling and, therefore, an increased risk of subsequent
fracture.4 Muscle abnormalities characterized by a reliance on trunk muscle co-contraction have been identified in patients with vertebral fractures.
Co-contraction of the trunk muscuBone properties
lature is defined by a simultaneous
Bone density
contraction of agonist and antagoBone quality
nist muscles and causes an increase
Intravertebral
in spinal loading. In addition, elecdistribution of
bone mass
tromyographic abnormalities in the
Microarchitectural
thoracic erector spinae in patients
deterioration
with vertebral fracture have also been
observed.4
The different factors involved in the
vertebral fracture cascade are summarized in Figure 1.
THE
FRACTURE
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MUST
BE
STOPPED
These two types of patient recruitment did not seem to influence the magnitude of the association. Overall, the risk of
subsequent fractures was shown to dramatically increase
with the number of prevalent vertebral fractures. For example, women with at least 5 prevalent vertebral fractures (an
unusual situation, fortunately) had a 35-fold higher risk of
subsequent vertebral fracture than women with no vertebral
fracture at baseline.13 More recently, Siris et al studied 2651
postmenopausal women from the placebo groups of both
the FIT (Fracture Intervention Trial) and MORE trials (Multiple
Outcomes of Raloxifene Evaluation).14 They confirmed the
findings from Klotzbuecher et al12 and found that women with
a semi-quantitative score (SQ) of 1 at baseline had a 3-fold
higher risk of subsequent vertebral fracture after 2 years of
follow-up than women with a SQ score of 0. A SQ score of 2
led to an approximately 5-fold increased risk and a SQ score
of 3 led to an approximately 10-fold increased risk. Kanis et
Vertebral fracture
Neurophysiological
properties
Trunk muscle control
Balance
Fear and pain
Functional mobility
Spine properties
Local spine properties
Global spine properties
Vertebral macrostructure
Intervertebral disc integrity
Baseline fracture
charasteristics
Spinal curvature
Spine loading
Muscle weakness
u Relationship between prevalent
and incident vertebral fractures
Several studies have focused on the
relationship between a prior verte- Figure 1. Etiopathogenesis of the vertebral fracture cascade.
reference 4: Briggs et al. Osteoporos Int. 2007;18:575-584. © 2007, International Osteoporosis Foundation
bral fracture and the occurrence of After
and National Osteoporosis Foundation.
a new vertebral fracture. In a metaanalysis (the first published on this issue), Klotzbuecher et al
al published another meta-analysis including a large cohort
demonstrated that a prevalent vertebral fracture dramatically (44 902 women and 15 259 men) and studied the relationincreases the risk of new vertebral fracture with an odds ratio
ship between a previous fracture and the subsequent risk of
of 4.4 (95% CI, 3.6-5.4).12 In this meta-analysis (see below), fracture.15 Unfortunately, in this meta-analysis there was no
all types of prevalent fractures increased the risk of a new fracseparate analysis focusing on vertebral fractures.
ture but the strongest association was observed between
prevalent vertebral fractures and incident vertebral fractures.
Johnell et al studied a large cohort of patients (both men and
women) with different types of prevalent fractures (hip, foreIn this meta-analysis, about 50% of the patients were in- arm, spine, and shoulder).16 They confirmed the association
cluded on the basis of systematic spine radiographs (mor- between the presence of a vertebral fracture at baseline and
phometric diagnosis). The remaining 50% patients were in- the risk of subsequent vertebral fracture. However, whereas
cluded on the basis of prior clinical vertebral fracture. Most the overall risk of subsequent fracture seemed to decrease
of the studies selected included postmenopausal women. over time, it was not the case for vertebral fractures. By con-
145
THE
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STOPPED
A
B
➤
T9
C
T9
➤
OSTEOPOROSIS:
➤
T11
➤
➤
➤
trast, in a previous study, Johnell et al had showed a decreasing risk of fracture over time in a subpopulation of patients with vertebral fracture requiring hospitalization.17
Roux et al focused their study on women with mild vertebral
fractures.18 This is a particularly interesting population since,
as previously mentioned, mild vertebral fractures are often underdiagnosed. Data were extracted from the placebo group
of two phase 3 studies of strontium ranelate. After 4 years of
follow-up, they found a 1.8-fold (95% CI, 1.3-2.4) increased
risk of subsequent vertebral fracture in women with mild vertebral fractures at baseline. Obviously, the association was
stronger in women with at least one grade ⱖ2 fracture at
baseline (odds ratio, 2.7; 95% CI, 2.3-3.3).
Lindsay et al studied the risk of new vertebral fracture in the
year following a fracture.19 Data were extracted from the placebo groups of four large clinical trials that assessed the efficacy
of risedronate. A total of 2725 postmenopausal women were
included. First, the authors confirmed previous findings and
found that women with at least one vertebral fracture at baseline had a 5-fold increased risk of subsequent vertebral fracture compared with women with no vertebral fracture. In total,
381 women developed an incident vertebral fracture. Among
them, 19.2% (95% CI, 13.6%-24.8%) had a new vertebral fracture in the subsequent year. A few years later, Lindsay et al
evaluated the probability of vertebral fracture in a population
of postmenopausal women with osteoporosis but without
vertebral fracture at baseline.20 The population studied was
the same as the one described previously and a Markov mod-
146
Figure 2.
Progression of
the vertebral fracture cascade over
time.
A. Fracture
of the T6
vertebra at
baseline.
B. Fractures
of the T6
and T9 vertebrae at the
12-month
evaluation.
C. Fractures
of the T6,
T9, and
T11 vertebrae at the
24-month
evaluation.
el was used to show the distribution of fracture prevalence
over time. Lindsay et al found that an osteoporotic woman
with no existing vertebral fractures had a 7.7% probability of
having a vertebral fracture within 1 year. After 5 years, the percentage was 33%, and after 10 years, 55%.
Finally, in the recent GLOW study (Global Longitudinal study
of Osteoporosis in Women) Gehlbach et al evaluated the association between a past history of fracture and the incidence
of subsequent fractures.21 The strengths of the GLOW study
were the high number of women recruited (n=51 762) and
the high number of sites assessed for both prevalent and subsequent fractures. Vertebral fractures were clinically diagnosed
and the diagnosis was confirmed by radiography. The association between a past history of vertebral fracture and the
occurrence of a subsequent vertebral fracture was found to
be very strong, with an odds ratio of 7.34 (95% CI, 5.42-9.92).
Figure 2 illustrates the progression of the vertebral fracture
cascade over time.
Prevalent vertebral fracture and risk of subsequent
nonvertebral fracture
A prevalent vertebral fracture also increases the risk of nonvertebral fracture. The etiopathogenesis of this phenomenon
is not fully understood—as in the case of vertebral fractures—
although bone properties seem to play a major role. Bone
properties reflect both bone quantity and bone quality, but in
clinical practice only bone quantity can be measured using
DXA. Even if BMD is usually lower in women with vertebral
fractures, BMD alone cannot explain the increased risk of non-
OSTEOPOROSIS:
vertebral fracture in women with a prevalent vertebral fracture. Indeed, after adjustment for BMD, the increased risk is
attenuated (by about 20%) but remains significant.12 This is
also true for women with nonvertebral fractures at baseline
(see below). In their meta-analysis, Klotzbuecher et al showed
that among peri-/postmenopausal women the association
with subsequent hip fracture was stronger than with all subsequent fractures combined, with corresponding odds ratios
of 2.3 (95% CI, 2-2.8) and 1.8 (95% CI, 1.7-1.9), respectively.12 However, the association seems to be weaker for wrist
fractures than for other subsequent fractures, with an odds
ratio of 1.4 (95% CI, 1.3-2.4). The association between prevalent vertebral fracture and subsequent fractures was later
demonstrated in several studies.16,19,22,23 Moreover, Johnell et
al showed that the risk of nonvertebral fracture is highest the
first year and decreases over time, although it remains significant after 5 years of follow-up.16 Van Staa et al showed that the
risk is lower in elderly women (>85 years).22 They also demonstrated that the association was stronger in men than in women, whatever their age. These findings were confirmed in the
Dubbo Osteoporosis Epidemiology Study, with odds ratio of
6.18 (95% CI, 4.17-9.14) for fractures of any type in men with
a past history of vertebral fracture, and 2.52 (95% CI, 1.993.19) in women.23
Prevalent nonvertebral fracture and the risk of
subsequent fracture
There is also convincing data regarding the risk of subsequent
fracture (both in the spine and at other sites) in women (but
also in men) with prevalent nonvertebral fracture. The mechanisms underlying this association are probably similar to those
previously described for the association between prevalent
vertebral fracture and the occurrence of a subsequent nonvertebral fracture.
u Prevalent nonvertebral fracture and risk of subsequent
vertebral fracture
In the meta-analysis of Klotzbuecher et al, the odds ratio for a
vertebral fracture in those with a prevalent wrist fracture was
1.7 (95% CI, 1.4-2.1).12 For those with a prevalent hip fracture the odds ratio was 2.5 (95% CI, 1.8-3.5). Johnell et al
studied 1918 patients with fractures at various sites who
were diagnosed and followed for 5 years in the department
of radiology in Malmö University Hospital (Sweden).16 They
found that the risk of vertebral fracture was higher in both men
and women with a past history of hip fracture than in the general population. However, the risk was significant in younger
people only. Interestingly, the findings were similar for those
with a past history of shoulder fracture. Using the GPRD database (General Practice Research Database), van Staa et al had
the opportunity to study 222 369 subjects (119 317 women
and 103 052 men) who had sustained at least one fracture
during follow-up.22 Whatever the site of the prevalent fracture
(tibia/fibula/ankle, femur/hip, radius/ulna, ribs, and humerus),
the odds ratios for a subsequent vertebral fracture were always
THE
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CASCADE
MUST
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STOPPED
increased. They ranged from 1.5 (95% CI, 1.3-1.8) for radius/
ulna to 4.3 (95% CI, 3.7-5.2) for ribs. The association was significant in both women and men but was stronger in men than
in women. More recently, Gehlbach et al also studied the association between a past history of nonvertebral fracture and
the occurrence of subsequent vertebral fractures in the GLOW
cohort (n=51 762).21 As previously mentioned, one of the
strengths of the GLOW study was the high number of fracture sites evaluated for both prevalent and incident fractures.
The association was significant for prevalent nonvertebral fracture located at the rib and wrist, with respective odds ratios
of 2.28 (95% CI, 1.64-3.17) and 1.37 (95% CI, 1.01-1.85).
For the other sites of prevalent nonvertebral fracture (ie, hip,
upper arm, ankle, lower leg, upper leg, clavicle, and pelvis) the
associations were not significant.
u Prevalent nonvertebral fracture and risk of subsequent
nonvertebral fracture
Numerous studies have found an association between prevalent nonvertebral fracture and the risk of subsequent nonvertebral fracture. In the meta-analysis of Klotzbuecher et al,
the authors found that a past history of wrist fracture increased
not only the risk of subsequent wrist fracture, but also the risk
of hip fracture.12 The odds ratios were 3.3 (95% CI, 2.0-5.3)
and 1.9 (95% CI, 1.6-2.2), respectively. Similarly, a past history of hip fracture was shown to increase the risk of subsequent hip fracture, with an odds ratio of 2.3 (95% CI, 1.5-3.7)
in peri- or postmenopausal women. In this meta-analysis, a
prevalent fracture, regardless of its site, was shown to increase the risk of subsequent fracture (pooled vertebral and
nonvertebral fractures) with an odds ratio of 2 (95% CI, 1.82.1) in peri- and postmenopausal women. The conclusion of
the meta-analysis of Kanis et al was quite similar, with an odds
ratio of 1.86 (95% CI, 1.75-1.98).15 Moreover, adjustment for
BMD did not modify the association, and the strength of the
association was similar regardless of age. Johnell et al found
that the risk of hip fracture was higher in women and men with
a past history of both shoulder and hip fracture than in the
general population.16 However, for those with a previous history of shoulder fracture, the risk was significant for younger
people only. In addition, a past history of both shoulder and
hip fractures increased the risk of wrist fracture. However,
the association between a prevalent hip fracture and a subsequent forearm fracture was significant in men only. In the
GPRD cohort, Van Staa et al confirmed these findings.22 They
demonstrated that a previous fracture of the tibia/fibula/ankle, femur/hip, radius/ulna, ribs, and humerus increased the
risk of subsequent fracture at these sites, with corresponding odds ratios ranging from 2 to 3. The strongest association was observed for a past history of radius/ulna fracture
and the risk of humerus fracture, with an odds ratio of 5.8
(95% CI, 5.5-6.1). In addition, the association was stronger in
men than in women, whereas, findings were quite similar overall whatever the age of the selected population. In the GLOW
study, Gehlbach et al demonstrated that a prevalent fracture
147
OSTEOPOROSIS:
THE
FRACTURE
CASCADE
MUST
(whatever its site) multiplied the risk of subsequent fracture
(of any bone) by 2.19 (95% CI, 2.03-2.35).21 The association
was quite similar for the risk of incident hip fracture, where the
odds ratio was 2.02 (95% CI, 1.55-2.63). Similarly, Gehlbach
et al demonstrated that a past history of fracture increased
the risk of fracture in other weight-bearing bones (ie, pelvis,
upper leg, lower leg, ankle, foot, and knee, but not spine or
hip) but also non–weight-bearing bones (ie, rib, wrist, upper
arm, clavicle, hand, elbow, and shoulder).21 The corresponding odds ratios were 2.21 (95% CI, 1.96-2.49) and 2.15 (95%
CI, 1.93-2.39), respectively. However, the association with a
prevalent nonvertebral fracture (ie, either rib, hip, wrist, upper arm, ankle, lower leg, upper leg, clavicle, or pelvis) and
the risk of subsequent hip fracture was significant for hip, upper leg, and pelvis only. The corresponding odds ratios were
3.50 (95% CI, 2.30-5.32), 2.15 (95% CI, 1.12-4.14), and 2.62
(95% CI, 1.44-4.77), respectively. The association between
a previous nonvertebral fracture and the risk of subsequent
other weight-bearing bone fracture was significant for nearly
all the sites evaluated, except for the hip and clavicle. By contrast, the association between a prevalent nonvertebral fracture and the risk of subsequent non–weight-bearing bone was
significant for rib, hip, wrist, and upper arm. Recently, Omsland et al studied the association between a prevalent hip
fracture and the risk of a second hip fracture over a 10-year
period.24 They collected data on prevalent hip fractures in
Norwegian hospitals between 1999 and 2008. Among the
81 867 people who suffered from a first hip fracture, 6161
women (15%) and 1782 men (11%) suffered from a second
hip fracture. The overall age-adjusted hazard ratio did not differ according to sex. However, by taking into account the higher risk of death in men than in women after a hip fracture, the
corresponding age-adjusted hazard ratio was higher in men
than in women: 1.40 (95% CI, 1.33-1.47).
Conclusion
In conclusion, a previous fracture dramatically increases the
risk of subsequent fracture, whatever the site of the prevalent fracture (vertebral or nonvertebral), and this is the case
BE
STOPPED
for both vertebral and nonvertebral fractures. The concept
of fracture cascade is particularly relevant since some of these
fractures—which Bliuc et al25 call “major fractures” (vertebral,
hip, pelvis, distal femur, proximal tibia, 3 or more simultaneous ribs, and proximal humerus)—are associated with an increased risk of death. This association was demonstrated for
both prevalent major fractures and incident major fractures.
Finally, let’s consider the cost related to the fractures occurring as a result of the fracture cascade. In France, Maravic
et al showed that in 2008, a total of 67 807 hospitalizations
were related to osteoporotic hip fractures in women.26 The
cost associated with these hospitalizations was €415.4 million and the cost of rehabilitation was €331.8 million. In Canada, Leslie et al analyzed the direct health care costs for 5
years post-fracture.27 They showed that the incremental median costs were highest the first year after a hip fracture. They
were Can$25 306 in women, and Can$21 396 in men (in 2009
constant Canadian dollars). In addition, they also showed that
—unsurprisingly—the costs decreased over time. However,
in women and men who survived a hip fracture, the costs at 5
years remained above the prefracture costs. The figures were
similar for vertebral fractures; however the costs at 1 year (and
thereafter) were lower. For vertebral fractures, the costs were
Can$15 392 in women and Can$11 309 in men at 1 year.
Fractures caused by osteoporosis represent a major health
concern comparable to that posed by other severe diseases.
Piscitelli et al studied the costs of hip fractures, acute myocardial infarctions, and strokes (both hemorrhagic and ischemic) between 2001 and 2005 in Italy.28 Overall, the number of hospitalizations related to these diseases increased
between 2001 and 2005. In 2005, the costs related to hip
fractures were similar to those associated with strokes (both
hemorrhagic and ischemic) and were higher than those associated with acute myocardial infarctions. Rehabilitations
costs associated with hip fractures and acute myocardial
infarctions were comparable but lower than those associated
with strokes. ■
References
1. Kanis JA; World Health Organization Scientific Group. Assessment of osteoporosis at the primary health care level. Sheffield, UK: WHO Collaborating Centre,
University of Sheffield. 2008. Accessed March 21, 2011. Available at: http://www.
shef.ac.uk/FRAX/.
2. Melton LJ 3rd, Chrischilles EA, Cooper C, Lane AW, Riggs BL. Perspective.
How many women have osteoporosis? J Bone Miner Res. 1992;7:1005-1010.
3. Delmas PD, van de Langerijt L, Watts NB, et al. Underdiagnosis of vertebral fracture is a worldwide problem: the IMPACT study. J Bone Miner Res. 2005;20:
557-563.
4. Briggs AM, Greig AM, Wark JD. The vertebral fracture cascade in osteoporosis:
a review of aetiopathogenesis. Osteoporos Int. 2007;18:575-584.
5. Aaron JE, Shore PA, Shore RC, Beneton M, Kanis JA. Trabecular architecture
in women and men of similar bone mass with and without vertebral fracture:
II. Three-dimensional histology. Bone. 2000;27:277-282.
6. Gilsanz V, Loro ML, Roe TF, Sayre J, Gilsanz R, Schulz EE. Vertebral size in
elderly women with osteoporosis. Mechanical implications and relationship to
fractures. J Clin Invest. 1995;95:2332-2337.
7. Sornay-Rendu E, Munoz F, Duboeuf F, Delmas PD; OFELY Study. Disc space
148
narrowing is associated with an increased vertebral fracture risk in postmenopausal women: the OFELY Study. J Bone Miner Res. 2004;19:1994-1999.
8. Lunt M, O'Neill TW, Felsenberg D, et al; European Prospective Osteoporosis
Study Group. Characteristics of a prevalent vertebral deformity predict subsequent vertebral fracture: results from the European Prospective Osteoporosis
Study (EPOS). Bone. 2003;33:505-513.
9. Cortet B, Roches E, Logier R, et al. Evaluation of spinal curvatures after a recent
osteoporotic vertebral fracture. Joint Bone Spine. 2002;69:201-208.
10. Schneider DL, von Mühlen D, Barrett-Connor E, Sartoris DJ. Kyphosis does not
equal vertebral fractures: the Rancho Bernardo study. J Rheumatol. 2004;31:
747-752.
11. Roux C, Fechtenbaum J, Kolta S, Said-Nahal R, Briot K, Benhamou CL. Prospective assessment of thoracic kyphosis in postmenopausal women with osteoporosis. J Bone Miner Res. 2010;25:362-368.
12. Klotzbuecher CM, Ross PD, Landsman PB, Abbott TA 3rd, Berger M. Patients
with prior fractures have an increased risk of future fractures: a summary of
the literature and statistical synthesis. J Bone Miner Res. 2000;15:721-739.
13. Ross PD, Genant HK, Davis JW, Miller PD, Wasnich RD. Predicting vertebral
OSTEOPOROSIS:
fracture incidence from prevalent fractures and bone density among nonblack, osteoporotic women. Osteoporos Int. 1993;3:120-126.
14. Siris ES, Genant HK, Laster AJ, Chen P, Misurski DA, Krege JH. Enhanced
prediction of fracture risk combining vertebral fracture status and BMD. Osteoporos Int. 2007;18:761-770.
15. Kanis JA, Johnell O, De Laet C, et al. A meta-analysis of previous fracture and
subsequent fracture risk. Bone. 2004;35:375-382.
16. Johnell O, Kanis JA, Odén A, et al. Fracture risk following an osteoporotic fracture. Osteoporos Int. 2004;15:175-179.
17. Johnell O, Oden A, Caulin F, Kanis JA. Acute and long-term increase in fracture risk after hospitalization for vertebral fracture. Osteoporos Int. 2001;12:207214.
18. Roux C, Fechtenbaum J, Kolta S, Briot K, Girard M. Mild prevalent and incident
vertebral fractures are risk factors for new fractures. Osteoporos Int. 2007;18:
1617-1624.
19. Lindsay R, Silverman SL, Cooper C. Risk of new vertebral fracture in the year
following a fracture. JAMA. 2001;285:320-323.
20. Lindsay R, Pack S, Li Z. Longitudinal progression of fracture prevalence through
a population of postmenopausal women with osteoporosis. Osteoporos Int.
2005;16:306-312.
21. Gehlbach S, Saag KG, Adachi JD, et al. Previous fractures at multiple sites in-
THE
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CASCADE
MUST
BE
STOPPED
crease the risk for subsequent fractures: the Global Longitudinal Study of Osteoporosis in Women. J Bone Miner Res. 2012;27:645-653.
22. van Staa TP, Leufkens HG, Cooper C. Does a fracture at one site predict later
fractures at other sites? A British cohort study. Osteoporos Int. 2002;13:624629.
23. Center JR, Bliuc D, Nguyen TV, Eisman JA. Risk of subsequent fracture after lowtrauma fracture in men and women. JAMA. 2007;297:387-394.
24. Omsland TK, Emaus N, Tell GS, et al. Ten-year risk of second hip fracture. A
NOREPOS study. Bone. 2013;52:493-497.
25. Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR. Mortality
risk associated with low-trauma osteoporotic fracture and subsequent fracture
in men and women. JAMA. 2009;301:513-521.
26. Maravic M, Jouaneton B, Vainchtock A, Tochon V. Economic burden of osteoporosis in women: data from the 2008 French hospital database (PMSI). Clin
Exp Rheumatol. 2012;30:222-227.
27. Leslie WD, Lix LM, Finlayson GS, Metge CJ, Morin SN, Majumdar SR. Direct
healthcare costs for 5 years post-fracture in Canada: a long-term populationbased assessment. Osteoporos Int. 2013;24:1697-1705.
28. Piscitelli P, Iolascon G, Argentiero A. Incidence and costs of hip fractures vs
strokes and acute myocardial infarction in Italy: comparative analysis based
on national hospitalization records. Clin Interv Aging. 2012;7:575-583.
Keywords: etiopathogenesis; fracture cascade; nonvertebral fracture; osteoporosis; risk factor; vertebral fracture
ÉPIDÉMIOLOGIE
DES FRACTURES SECONDAIRES
Le terme « cascade fracturaire » a été proposé pour décrire le fait que la survenue d’une première fracture augmente
considérablement le risque de fractures ultérieures. Bien que l’étiopathogénie de ce phénomène ne soit pas complètement comprise, les mécanismes des cascades fracturaires vertébrales et non vertébrales semblent différents.
Pour la cascade fracturaire vertébrale, les principaux facteurs de risque sont une densité minérale osseuse basse et
une dégradation de la qualité osseuse (ce qui est vrai aussi pour la cascade fracturaire non vertébrale) ; cependant,
plusieurs paramètres non osseux caractérisent aussi la cascade fracturaire vertébrale : modifications des propriétés
locales, altérations de la macroarchitecture osseuse, anomalies de la courbure et de la charge rachidiennes et détérioration de l’intégrité du disque intervertébral. Un antécédent d’au moins une fracture vertébrale multiplie par 4 le
risque de fracture vertébrale. D’autre part, il a été démontré que le risque de nouvelles fractures vertébrales augmente avec le nombre de fractures vertébrales prévalentes. De plus, une fracture vertébrale prévalente augmente aussi
le risque de fracture non vertébrale ultérieure. Le risque est plus important l’année qui suit une fracture vertébrale et
plus élevé chez les hommes que chez les femmes. De même, pour la cascade fracturaire non vertébrale, la survenue
d’une fracture non vertébrale augmente aussi le risque de fracture vertébrale ultérieure (plus ou moins selon le site
de la fracture non vertébrale prévalente) et le risque de fracture non vertébrale ultérieure. Toutes ces données sont
importantes à prendre en considération puisque certaines fractures (prévalentes et incidentes) s’associent à un surcroît de mortalité (en particulier celles de la hanche et des vertèbres).
149
‘‘
OSTEOPOROSIS:
There is an osteoporosis
“care gap” and we are failing in our
duty by providing suboptimal care
to more than 75% of the fragility
fracture patients coming through
our hospital systems. It is a global problem; wherever it has been
audited at local and national levels, whether the sites are in the primary care and community setting
or in university teaching hospitals
and centers of excellence, the care
gap is there.”
THE
FRACTURE
CASCADE
MUST
BE
STOPPED
Osteoporotic fragility
fractures: why the care gap?
b y L . M . M a rc h , A u s t ra l i a
F
Lyn M. MARCH, MD, PhD
Liggins Professor of
Rheumatology and Musculoskeletal Epidemiology
Sydney Medical School
University of Sydney
Senior Staff Specialist in
Rheumatology
Royal North Shore Hospital
Sydney, AUSTRALIA
ollowing an initial fracture, patients are at increased risk of another fracture. While the peer-reviewed literature and numerous Cochrane reviews have outlined the benefits and cost-effectiveness of numerous antiresorptive and bone-active medications in reducing the risk of subsequent
fractures, a multitude of papers and reports have documented the lack of implementation of this knowledge and evidence. There is an osteoporosis “caregap” whereby individuals who have had one fracture are not being assessed
and treated to prevent the next fracture. The barriers contributing to the osteoporosis refracture prevention care gap are multifactorial and include patient,
clinician, societal, and health system factors. Yet, the main reason appears to
be the lack of clarity as to whose responsibility it is to provide secondary prevention. The reason for this ambiguity is that there is currently no single group
that manages all aspects of a fracture. Many different professional groups are
involved, including general practitioners, orthopedic surgeons, and osteoporosis specialists. The urgency of the problem calls for a dedicated coordinated strategy for secondary fracture prevention. Fully coordinated, intensive
models of care such as fracture liaison services with dedicated fracture coordinators are the key to identifying the patients requiring secondary prevention and providing them with the care that they need to reduce their risk of subsequent fracture.
ny adult man or woman sustaining a fracture, whether low trauma or not,
is placed at higher risk for another fracture. Research from around the world
has shown that at least half of hip fracture patients have suffered a fragility
fracture—eg, at the wrist, the humerus, spine, and even the other hip—prior to breaking their hip. So, to quote from many other reports and presentations, these patients
have in essence “told us they were coming.”
A
Professor Lyn M. March,
Department of Rheumatology, Royal
North Shore Hospital, St Leonards,
NSW 2065, Australia
(e-mail: lyn.march@sydney.edu.au)
150
Yet, multiple national and international surveys have repeatedly shown that we are
not listening to them.1 Less than a quarter of fragility fracture patients are being
connected with the proven treatments that can reduce the risk of their next fracture despite the fact that the peer-reviewed literature and numerous Cochrane reviews have outlined the benefits and cost-effectiveness of numerous antiresorptive
and bone-active medications in reducing the risk of subsequent fractures.2-5 There
is an osteoporosis “care gap” and we are failing in our duty by providing suboptimal care to more than 75% of the fragility fracture patients coming through our hos-
Osteoporotic fragility fractures: why the care gap? – March
OSTEOPOROSIS:
pital systems. It is a global problem; wherever it has been audited at local and national levels, whether the sites are in the
primary care and community setting or in university teaching
hospitals and centers of excellence, the care gap is there. So
why is it so? The barriers are multifactorial and include patient,
clinician, and system factors, but it would appear the main reason is the lack of clarity as to whose responsibility it should be.
There is a general consensus that it should be the role of the
primary care doctor to provide the long-term preventive treatment that is required. But they need to be told about the fracture episode and most say they would not initiate treatment
without a recommendation from a specialist. Most orthopedic surgeons agree that they should be the ones to refer the
patient for assessment for osteoporosis, yet most also report
that they do not do it.
The gap grows as there is a disconnect in the system, where
orthopedic surgeons rely on primary care doctors to manage
osteoporosis; primary care doctors routinely only do so if so
advised by the orthopedic surgeon; and osteoporosis experts—usually endocrinologists or rheumatologists—have no
cause to interact with the patient during the fracture episode.
A recent review of the literature evaluating a range of possible
solutions and implementation strategies has confirmed that
a dedicated coordinated strategy is the key to identifying the
patients and connecting them with the tests and care that they
need to reduce their risk of future fractures.6 The urgency of the
problem calls for the implementation of a systems-based solution such as the one advocated by the Capture the Fracture
campaign.7
The osteoporotic refracture cascade
While numerous epidemiological studies have documented
the high prevalence of osteoporotic fractures and the ensuing fracture cascade with its increased risk of subsequent fractures, there have been very few studies that described the refracture incidence and readmission rates for new fractures per
se. In the report and osteoporotic refracture prevention model of care from the New South Wales Agency for Clinical Innovation8 an historical cohort was drawn from 2002 and then
tracked forward through the state-wide Hospitals Admission/
Separation In-patient Statistics collection for the next seven
years. It was found that 35% of people came into hospital
with another fracture (~5% refracture/readmission rate per annum), with 19% having 3 or more admissions with new fractures. Scottish data suggests a refracture rate of 4% per annum, while in the Lih et al paper from the successful Fracture
Liaison Service established at Concord Hospital in Sydney,
the refracture rate in the control (untreated) population was
~5% per annum over 5 years.9
Why the care gap?
The epidemiological and economic data show that osteoporotic fractures are everyone’s problem in terms of the unnecessary and growing burden that they place on our health care
THE
FRACTURE
CASCADE
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STOPPED
systems and society in general; yet, the care-gap shows us
that no-one is taking ownership and responsibility. The lack of
clarity surrounding the clinical “ownership” of the patient prevention pathway following a fracture may be the primary problem but it is most certainly coupled with a lack of awareness
or acknowledgment that intervention can lead to prevention
of the next fracture. Fragility fractures are seen as inevitable
and not preventable. They are not seen as a priority for treatment or funding. They appear to be a nuisance to be ignored
rather than a trigger to take action to help them go away.
There is no single group who currently manages all aspects
of a fracture. Many different professional groups are involved.
The orthopedic surgeons manage the acute event, giving
guidance and providing the necessary acute treatment—the
open or closed reduction, the type of fixation, etc. They will
usually also follow up the patients at intervals up to the 6- or
8-week mark, when the x-ray shows bony union. They will
then usually discharge the patients from their care. It is a rare
occurrence for orthopedic surgeons to order testing for bone
density or secondary causes of osteoporosis such as vitamin D
testing. They will usually reassure the patients that their bones
are strong again once the fracture is healed. Patients will return to their general practitioner or primary care physician and
both will be unlikely to request or recommend any investigation or treatment for osteoporosis if the specialist has not also
recommended it. Older patients may sustain fractures of the
pelvis and spine that are treated nonoperatively and not cared
for by surgical or medical specialists. They may even be managed at home. On the other hand, patients sustaining a hip
fracture will generally be in hospital or rehabilitation for a sufficient duration of time to be seen by a geriatrician or clinicians
other than orthopedic surgeons and will usually have a greater
chance of getting onto preventive medications.
International and national audits and surveys abound confirming and reconfirming the care gap—ie, the lack of preventive care offered to patients sustaining a fragility fracture.1 In its
Capture the Fracture program, the International Osteoporosis
Federation (IOF) provides some of the key references.8,10-12 In
2012, in their large prospective observational study of 60 393
women aged 55 years and over recruited from 723 primary
physician practices across 10 countries, Greenspan et al reported that less than 20% of women who sustained a new fracture were prescribed osteoporosis treatment.10 These Canadian patients were more likely to receive treatment if they had,
in descending magnitude of association, sustained a spinal
fracture (odds ratio [OR], 6.6), multiple fractures (OR, 3.8), a
hip fracture (OR, 2.6), or had a prior diagnosis of osteoporosis (OR, 2.6).
The wide variability in the availability of facilities for testing for
bone density or providing osteoporosis medication has been
documented between—and even within—countries and was
summarized following a 2004 survey of more than 3000 or-
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OSTEOPOROSIS:
THE
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MUST
thopedic surgeons jointly organized by the IOF and the Bone
and Joint Decade (BJD).11 Surgeons from France, Germany,
Italy, Spain, the United Kingdom, and New Zealand were surveyed, and while the majority believed that it was their role
to identify and initiate the assessment of osteoporosis in patients with fragility fractures, only 10% of the orthopedic surgeons reported that they made sure that a surgically treated
patient with a fragility fracture was referred for a bone mineral density (BMD) test, and approximately 20% reported that
they never referred a patient for BMD testing after such a fracture. Almost 75% of those surveyed felt they were not sufficiently knowledgeable in the treatment of osteoporosis, and
less than 50% reported receiving any formal training.
In another systematic literature review12 the barriers to implementation of osteoporosis assessment and treatment postfracture included the cost of therapies, the time and cost of
resources required for diagnosis, the lack of access to BMD
testing facilities, concerns about medications, and the lack of
clarity regarding the responsibility to undertake this care.
The range of factors that have been identified as contributing
to the care gap are outlined in Table I.1,8,10-12
◆ Patient factors
Patient factors include lack of awareness and knowledge of
the increased risk; lack of self-perceived risk for osteoporosis
or fracture; concerns about the time and cost of investigations
and treatment; concerns about treatment side effects, particularly following media attention to serious—yet rare—adverse
events; lack of knowledge regarding the benefits of treatment;
and patient reluctance to take long-term medication for prevention.
◆ Clinician factors
All of the patient-related factors may be operating among
clinicians too, such as concerns over costs and side effects
and constraints of managed care; some clinicians have concerns about the unproven effectiveness of medication in some
fracture subpopulations; and concerns regarding polypharmacy and lack of adherence to long-term preventive therapy.
However, the overriding barrier appears to be lack of ownership of the problem. No responsibility will generally follow if
there is lack of ownership. This leads to various quotes likening the fracture patients to ships that disappear without trace
in the “Bermuda triangle” between the orthopedic surgeon, the
primary care clinician, and the osteoporosis specialist. Dreinhoffer et al nicely summarized the issues and pointed out that
orthopedic surgeons manage the majority of the fragility fractures and in many instances may be the only physician that
the fracture patient sees; yet the paper reported that many
orthopedic surgeons still neglect to identify, assess, and treat
such patients for osteoporosis.11 The majority of orthopedic
surgeons focus on acute fracture management and say that
they lack the time to address secondary prevention. Lack of
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Clinician factors
◆ Lack of ownership of the problem
◆ Lack of awareness of increased risk
◆ Lack of knowledge of treatments and prevention strategies
◆ Concern about costs of investigation and treatment
◆ Concern about treatment side effects
◆ Lack of awareness of male osteoporotic fracture risk
◆ Lack of priority to treat this issue in older patients
Patient factors
◆ Lack of awareness of risk
◆ Lack of knowledge of possible treatments
◆ Concern about costs of tests and treatments
◆ Concern about side effects
Health system and societal factors
◆ Lack of integrated health systems
◆ Lack of communication between clinical services
◆ Lack of ICD (International Classification of Diseases)
coding to identify fragility fractures
◆ Lack of prioritization and recognition of the fragility
fracture burden
◆ Lack of funding and foresight to invest in fragility fracture
coordinators
Table I. Barriers contributing to the osteoporosis refracture prevention care gap.
knowledge of the harms of preventive treatments was reported as an issue, and in one survey 100% of surgeons and 91%
of family physicians said that ‘‘they would be more likely to
treat elderly patients with a fracture if they had a safe medication shown to reduce patients’ risk of a recurrent fracture.’’12
Investigators in the UK sought to understand the disconnect
between orthopedic surgeons and primary care doctors.13 The
majority of respondents recognized that fragility fracture patients should in principle be investigated for osteoporosis (81%
of orthopedic surgeons, 96% of general practitioners). However, this was not consistently followed and considerable variability was associated with the different fracture types. For
example, in the case of the Colles fracture the majority of orthopedic surgeons (56%) would discharge the patient without requesting investigation for osteoporosis, and when faced
with this scenario, the majority of general practitioners would
take no action, having assumed that the orthopedic surgeon
would have conducted investigations if appropriate (45%),
or would instigate investigations only if prompted by the orthopedic surgeon to do so (19%). Only 7% of orthopedic surgeons and 32% of general practitioners would assess and/
or start treatment themselves. The hip fracture scenario generated similar responses; however, both orthopedic surgeons
and general practitioners were more likely to assess and or
start treatment themselves for vertebral compression fracture
cases.
OSTEOPOROSIS:
◆ Health system and societal factors
Health system issues include lack of integrated health services and information technology (IT) linking patients with ongoing care in the community following their admission into hospital; lack of communication between treating doctors; lack
of medical record and ICD (International Classification of Diseases) coding that directly captures the fragility fracture; lack
of electronic data systems to track the patients to facilitate follow-up; lack of funding to cover the costs of the investigations
and treatment; and lack of foresight to invest in the fracture
liaison coordinator role—despite it having been proven to lead
to greater implementation of best practice and reduction in
expenditure related to unnecessary refractures.
Societal barriers include lack of prioritization of preventive services in the elderly; lack of concern for osteoporosis as a health
issue; lack of awareness of the high cost of doing nothing; and
lack of awareness of the significant benefits of having fracture
coordinators and fracture liaison services.
Solutions to the care gap
Given the wide array of possible barriers, it is clear that a range
of solutions and identification strategies may be required. There
is a growing movement toward recommending that orthopedic surgeons be a leading part of the solution to increase
identification and treatment rates in fragility fracture patients.
The World Orthopaedic Osteoporosis Organization (WOOO)
strongly advocates a leading role for orthopedic surgeons in
the management of osteoporosis in their fragility fracture patients. However, some orthopedic surgeons continue to have
strong reservations about this clinical activity and feel that it
is not their responsibility. Nevertheless, orthopedic organizations are participating in efforts to increase osteoporosis identification and treatment rates in fragility fracture patients.14 The
American Academy of Orthopedic Surgeons’ ‘‘Bone up on
bone loss’’ program recommends that osteoporosis should
become a national public health priority. They have also joined
the National Bone Health Alliance, which has recently launched
its “20:20 vision” campaign to reduce refractures by 20% by
2020 in the USA.15
The British Orthopaedic Association has made an important
contribution through the publication of “The Blue Book” for
the care of fragility fracture patients and management of osteoporosis,16 and these guidelines—together with the data
derived from the National Hip Fracture Database—have culminated in government funding reimbursement to health services that offer osteoporotic refracture prevention treatment to
patients suffering a fragility fracture.
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tients plus primary care physicians; and type D: patient education only. Meta-regression analysis revealed a trend toward increased BMD testing (P = 0.06) and treatment initiation
(P = 0.03) with increasing intensity of intervention. One type
A service with a valid control group showed a significant decrease in refractures. Type A and B services were cost-effective, although the definition of cost-effectiveness varied between
studies. Fully coordinated, intensive models of care for secondary fracture prevention are more effective in improving patient outcomes than approaches involving alerts and/or education only.
Way forward
Implementing the following suggestions should help bridge
the care gap:
◆ Set up multidisciplinary and system-based approach-
es to identify and implement practice change, both in
tertiary centers and in general practice.
◆ Increase role for IT solutions.
◆ Increase uptake of management guidelines for osteoporosis.
◆ Set up integrated fracture liaison services with fracture
prevention coordinators.
◆ Lobby health providers for additional funding to create
fracture prevention officer positions.
◆ Lobby for better integration of falls and fracture prevention strategies.
◆ Ensure that education of all stakeholders:
– Is targeted (with a specific aim to reduce fractures).
– Promotes a consistent message.
– Is funded (for coordinators).
– Promotes recognition of osteoporosis.
– Promotes a multidisciplinary approach and continuity of care.
– Addresses patients’ fear of taking medications and
their side effects.
– Promotes recognition and treatment of osteoporosis.
– Promotes osteoporosis as a chronic disease.
– Promotes medication compliance.
◆ Address issues specific to rural and remote communi-
ties, including:
– Access to skilled staff.
– Availability of diagnostic testing within manageable
reach.
– Resourcing constraints.
◆ Address the lack of systems, including the need for:
Ganda et al6 recently conducted a systematic review of published implementation strategies The studies were grouped
into four general models of care; type A: identification, assessment, and treatment of patients as part of the service; type B:
similar to A, without treatment initiation; type C: alerting pa-
– Allocation of appropriate staffing and funding to
support identification and next fracture prevention.
– For routine follow-up fracture is a precipitator for:
diagnosis and investigation, treatment, and contin-
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uing care by general practitioners
– A multidisciplinary approach that addresses the
fragmentation of services, including a chronic care
plan.
– Flexibility in care delivery model.
– Easy access to services.
– Guidelines and protocols.
– IT support for coordination of identification, treatment, and follow up.
– Ownership and definition of roles in diagnosis/treatment/follow-up.
Bridging the care gap – why not fracture liaison
services for all?
A growing number of reports are showing that fracture liaison services with dedicated fracture coordinators are the solution and lead to a reduction in the risk of refractures. Meanwhile, multiple studies continue to be published showing this
disconnect—or care gap—between the patients and the treatment they need.
When confronted with the size of the problem, the pain and
suffering inflicted on the patients, and the enormous burden
on health care systems, governments and payers do not need
much convincing about the figures. As it is so obviously a big
problem, for which cost-effective interventions exist, most
think the solution should be simple. It is clearly the right thing
to treat these patients, so why doesn’t everyone get on with
it and just do it? Most cannot understand why it isn’t being
done automatically, when the evidence of its benefit is so clear.
BE
STOPPED
Many think it is one simple “fix.” But it has been shown repeatedly that no single strategy can identify all the relevant patients, no simple awareness or education program can make
much difference alone.
Multiple case-finding strategies are needed and a dedicated
person is crucial to bridging the care gap to coordinate it all.
In the current climate no health care provider or government
wants to hear that the solution is a person, and therefore, a
salary. Even within the much acclaimed Kaiser-Permanente
model of a totally integrated health care system the patients
are identified from multiple sources, including radiology reports,
hospital admissions, and attendance at emergency centers;
compliance is also tracked from multiple sources and thus
dedicated personnel are required to coordinate the report writing and the reminder calls and to track data in order to achieve
the goal of reducing future fractures.
Conclusion
Governments are unsure whether they can afford to pay for
the set-up of fracture liaison services/refracture prevention
programs and the fracture prevention coordinators; but clinicians and consumer organizations are now asking how we
can afford NOT to invest in these services given the overwhelming current and looming burden coupled with the convincing evidence of refracture reduction when these services are
implemented. Failure of health systems and governments to
provide these services when there is overwhelming evidence
of their benefit and potential for saving lives and reducing pain
and suffering is negligent, regardless of what the perceived
barriers may be. What overcomes the barriers is the coordinated fracture liaison service! n
References
1. Giangregorio L, Papaioannou A, Cranney A, Zytaruk N, Adachi JD. Fragility
fractures and the osteoporosis care gap: an international phenomenon. Semin Arthritis Rheum. 2006;35(5):293-305.
2. Stevenson M, Jones ML, De Nigris E, Brewer N, Davis S, Oakley J. A systematic review and economic evaluation of alendronate, etidronate, risedronate, and
teriparatide for the prevention and treatment of postmenopausal osteoporosis.
Health Technol Assess. 2005;9(22):1-160.
3. Stevenson M, Davis S, Lloyd-Jones M, Beverley C. The clinical effectiveness
and cost-effectiveness of strontium ranelate for the prevention of osteoporotic
fragility fractures in postmenopausal women. Health Technol Assess. 2007;11
(4):1-134.
4. Levis S, Theodore G. Summary of AHRQ's comparative effectiveness review
of treatment to prevent fractures in men and women with low bone density or
osteoporosis: update of the 2007 report. J Manag Care Pharm. 2012;18(4 suppl
B):S1-S15; discussion S13.
5. Hiligsmann M, Kanis JA, Compston J, et al Health technology assessment in
osteoporosis. Calcif Tissue Int. 2013;93(1):1-14.
6. Ganda K, Puech M, Chen JS, et al. Models of care for the secondary prevention of osteoporotic fractures: a systematic review and meta-analysis. Osteoporos Int. 2013;24(2):393-406.
7. Capture the Fracture. International Osteoporosis Foundation Web site. http:
//www.iofbonehealth.org/capture-fracture‎. Accessed December 11, 2013.
8. NSW Model Of Care for Osteoporotic Refrature Prevention. NSW Agency for
Clinical Innovation Web site. http://www.aci.health.nsw.gov.au/__data/assets/
pdf_file/0003/153543/aci_osteoporotic_refractu.pdf. Accessed December 11,
2013.
9. Lih A, Nandapalan H, Kim M, et al. Targeted intervention reduces refracture
rates in patients with incident non-vertebral osteoporotic fractures: a 4-year
prospective controlled study. Osteoporos Int. 2011 Mar;22(3):849-858.
10. Greenspan SL, Wyman A, Hooven FH, et al. Predictors of treatment with osteoporosis medications after recent fragility fractures in a multinational cohort
of postmenopausal women. J Am Geriatr Soc. 2012;60(3):455-461.
11. Dreinhöfer KE, Anderson M, Féron JM, et al. Multinational survey of osteoporotic fracture management. Osteoporos Int. 2005;16(suppl 2):S44-S53.
12. Elliot-Gibson V, Bogoch ER, Jamal SA, Beaton DE. Practice patterns in the diagnosis and treatment of osteoporosis after a fragility fracture: a systematic review. Osteoporos Int. 2004;15(10):767-778.
13. Chami G, Jeys L, Freudmann M, Connor L, Siddiqi M. Are osteoporotic fractures
being adequately investigated? A questionnaire of GP & orthopaedic surgeons.
BMC Fam Pract. 2006;7:7.
14. American Orthopaedic Association. Own the Bone Web site. http://www.own
thebone.org. Accessed December 11, 2013.
15. National Bone Health Alliance Web site. htttp://www.nbha.org. Accessed December 11, 2013.
16. British Geriatrics Society. The care of patients with fragility fractures. Available
at: http://www.bgs.org.uk/index.php?option=com_content&view=article&id=
338:bluebookfragilityfracture&catid=47:fallsandbones&Itemid=307. Accessed
December 11, 2013.
Keywords: barrier; care-gap; clinician ownership; fracture liaison coordinator; fragility fracture; refracture rate
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LES FRACTURES OSTÉOPOROTIQUES DE FRAGILITÉ :
POURQUOI UNE TELLE LACUNE DANS LES SOINS DE SANTÉ
MUST
BE
STOPPED
?
Après une première fracture, le risque de nouvelle fracture est augmenté. Tandis que la littérature médicale indexée
et les nombreuses analyses Cochrane mettent en avant les bénéfices et le rapport coût-efficacité favorable de nombreux médicaments antirésorptifs et ostéoactifs pour réduire le risque de futures fractures, une multitude d’autres
articles et de rapports font état du manque de mise en pratique de ces connaissances et de ces données. Il existe une
véritable « lacune de soins de santé » concernant l’ostéoporose : les patients qui ont eu une fracture ne sont pas évalués ni traités en vue de prévenir une nouvelle fracture. Les obstacles contribuant à cette lacune sont multifactoriels
et impliquent des facteurs liés au patient, au médecin, à la société et au système de santé. La principale raison semble encore être l’incertitude quant à savoir à qui incombe la responsabilité de la prévention secondaire. La raison de
cette ambiguïté est l’absence actuelle de prise en charge de tous les aspects des fractures par un seul groupe. De
nombreux groupes professionnels différents sont impliqués, comme les médecins généralistes, les chirurgiens orthopédiques et les spécialistes de l’ostéoporose. L’urgence du problème nécessite une stratégie coordonnée dédiée
à la prévention des fractures secondaires. Parfaitement coordonnés, les modèles intensifs de soin comme « les services de liaison pour fractures » avec des coordonnateurs dédiés sont la clé de l’identification des patients ayant
besoin d’une prévention secondaire et de l’apport des soins dont ils ont besoin pour réduire leur risque de fracture
ultérieure.
155
‘‘
OSTEOPOROSIS:
Osteoporotic bone differs
from normal bone in its reduced
bone mass and deterioration of
its architecture, leading to bone
fragility and an increased fracture risk. This is a consequence of
the imbalance in bone formation
vs bone remodeling. Osteoporosis
is potentially harmful for fracture
treatment: the compromised bone
strength affects anchorage of the
implants and, at the fracture site,
the impaired bone ingrowths and
late remodeling could impair the
strength of the callus and bony
union.”
THE
FRACTURE
CASCADE
MUST
BE
STOPPED
Fracture consolidation
and osteoporosis
b y J . M . Fé ro n , Fra n c e
B
Jean-Marc FÉRON, MD, PhD
Head of the Orthopedic and
Trauma Department
Saint Antoine Academic Hospital
Université Pierre et Marie Curie
(UPMC), Sorbonne University
Paris, FrAnCe
one differs from other tissues in its capacity to self-repair after a fracture. The role of the orthopedic surgeon is to reduce the bone fragments
anatomically, stabilize the fracture to allow healing without malunion,
and thus restore function. The healing process is a cascade of events, mainly influenced by the mechanical fracture fixation stability and the biological
environment, summarized as the “diamond concept.” Depending on various
factors, bony union occurs either by primary or secondary healing. Basic knowledge of fracture healing is a prerequisite to understanding how the repair of
fragility fractures can be improved. The osteoporotic elderly population presents a higher risk of nonunion or delayed union, which leads to increased morbidity and economic burden. Antiosteoporotic drugs target either reduced
bone remodeling or stimulate bone construction in order to increase bone
strength and prevent fractures. It is important to know their potential interactions on the fracture healing process and to assess their ability to promote
bone healing. Most preclinical studies, largely involving osteoporotic rodent
models, have demonstrated a stimulation of fracture healing by bone-forming agents; there is no evidence of any deleterious effect on the early stage
of fracture healing by antiresorptive drugs. In humans, several case reports
and well-designed clinical trials seem to confirm the potential beneficial effects of bone-forming agents on fracture repair. More studies are needed to
evaluate this systemic approach of enhancing fracture repair, especially in
people diagnosed with osteoporosis.
one differs from other tissues in its capacity to self-repair after a fracture. The
role of the orthopedic surgeon is to stabilize the fracture with bone contact and
restore the normal anatomy. The fracture healing process is under the control
of mechanical and biological factors summarized in the “diamond concept.” Basic
knowledge of the healing process is a prerequisite to understanding how the repair
of fragility fractures in older osteoporotic patients can be improved.
B
Prof Jean-Marc Féron, Orthopaedic
and Trauma Surgery Department,
Saint Antoine Hospital,
184 rue du Faubourg Saint Antoine,
75571 Paris Cedex, France.
(e-mail: jean-marc.feron@sat.aphp.fr)
156
Antiosteoporotic drugs have been shown either to reduce bone remodeling or stimulate bone construction, thus increasing bone strength and preventing fractures.
Their interactions in the fracture healing process have mainly been studied in animal
models. Despite there being few clinical studies, there exists some encouraging evidence for systemic stimulation of bone repair in the future, either by shortening the
healing time of fractures or preventing nonunion in high-risk populations.
Fracture consolidation and osteoporosis – Féron
OSTEOPOROSIS:
Mechanisms of normal fracture repair
Bone, unlike other tissues, has the capacity to self-repair after a fracture without leaving a scar.1 Once the continuity of the
bone and its mechanical properties are restored, the bone
structure recovers its pre-injury state. Fracture healing is a
complex process involving biological factors and mechanical principles. The stability of the fracture, depending on the
method of fixation chosen by the surgeon, determines the type
of bony union.2 Bone union occurs either by primary or secondary healing.3
Primary fracture healing, or direct bony union, occurs when
there is no motion at the fracture site, and is usually achieved
after a surgical procedure: open anatomical reduction with
very rigid internal fixation.4 Direct contact of compact bone is
required and the fracture gap should be less than 200 mm,
so that cutting cones are formed at the end of the osteons
closest to the fracture site. This “contact healing” involves osteoclasts, which cross the fracture line and create small cavities. These cavities are filled by new bone generated by osteoblasts from the surrounding mesenchymal cells. Bony union
and haversian remodeling occur simultaneously. This is a slow
process, quite similar to intramembranous ossification during
fetal skeletogenesis and to normal bone remodeling. The fracture heals directly without the formation of
a periosteal callus (Figure 1). In the same
A
mechanical and anatomical conditions, the
process differs when the gap is wider, but
still less than 1 mm. In this “gap healing”
process, the gap is primarily filled with lamellar bone, which is mechanically weak after
4 to 8 weeks and is followed by remodeling, which starts as the “contact healing”
cascade takes place.
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bone biology over the last decades has increased the knowledge of the molecular control of cellular events.7 The healing
process involves a combination of intramembranous ossification and endochondral ossification, similar to bone formation
during osteogenesis. The healing process has been characterized by four successive phases, while in reality it appears
that they may occur at different rates, at different sites, and
sometimes simultaneously.
Fracture repair follows a characteristic course, which can be
divided into three partially overlapping phases: the inflammatory, repair, and remodeling phases.8 The first two phases last
10 to 18 weeks and correspond to the restoration of bone
continuity and mechanical properties to allow full weight bearing. The last phase takes months to years and can be considered a gradual adaptation of the restored bone to the usual
strains of life.
u Inflammatory phase
Hematoma and inflammation are the immediate reactions to
fracture: bleeding occurs from the bone and the surrounding
soft tissues and the microvascular disruption leads to hypoxia
and bone necrosis. The hematoma coagulates around the
bone extremities and within the medulla, forming a template
B
Secondary fracture healing, or indirect bony
union, is the most common process through
which bone union occurs after a fracture.
This indirect healing does not require an
anatomical reduction of the fracture or highly rigid mechanical conditions. The biological response under loading is the formation
of an external callus bridging the fracture
Figure 1. Rigid plate fixation and primary healing of a combined tibia and fibula fracture.
gap, with the fracture considered healed A. Preoperative x-ray. B. X-ray 1 year postsurgery: rigid plate fixation and primary healing.
when bone continuity is visible on x-ray. Indirect bone healing is characteristic in nonoperative fracture for callus formation. The fracture hematoma houses blood-detreatment and in elastic fixation, preserving some micromo- rived inflammatory cells, which release cytokines and initiate
tion at the fracture level, such as intramedullary nailing, ex- the inflammatory response: increased blood flow, increased
ternal fixation, or plate fixation in complex and comminuted vessel permeability, and increased cell migration.9 Osteoclasts
fractures. The process recapitulates the steps of the endo- are activated to resorb bone debris, and vascular proliferation
chondral ossification during the fetal period.5
provides stem cells, which differentiate into cells with osteogenic potential based upon the mechanical environment and
The histological morphology of bone after fracture was first signaling molecules. This inflammatory response peaks within 24 hours and is complete after 7 days. A tissue, called caldescribed in 1930 by Ham and the cellular mechanism later
emphasized by McKibbin.6 The improved understanding of lus, forms at the fracture site and stiffens as it calcifies.
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A
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B
BE
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The “diamond concept” of normal
fracture healing
The “diamond concept,” described by Giannoudis, is a requirement for successful bone
healing.11 The fundamental constituents of
bone healing are: the osteogenic cells that
initiate repair, an osteoconductive scaffold
upon which new bone can be created, and
osteoinductive growth factors, like bone morphogenetic protein, that differentiate the stem
cells along the bone repair pathway. Mechanical stability is a fourth crucial element
which must be given the same importance.
This conceptual framework is completed by
two of the most significant parameters for
the healing process: vascularity at the site
of the fracture and the biology of the host
Figure 2. Locked nail fixation of a tibial fracture.
(Figure 3).12 The progression of fracture healA. Postoperative x-ray. B. Secondary bone healing at 4 months with a callus formation.
ing can be compromised by many physiological, pathological, or environmental factors. A recent large
u Repair phase
The nature of the repair phase is dependent on mechanical case-control study has shown that factors like diabetes, nonsteroidal anti-inflammatory use, or high-energy trauma are
and anatomical conditions in the fracture healing zone (primary or secondary healing). In the secondary healing process, more likely to results in fracture-healing complications, regardthe fracture repair has been classically divided into the forma- less of fracture site.13 Aging, smoking, and inflammatory contion of soft callus, which subsequently calcifies to form the hard ditions also increase the risk of delayed union or nonunion (Ficallus. During the soft callus formation (3-4 weeks) the clot is gure 4).14,15
invaded by a fibrin-rich granulation tissue. Within this tissue,
an endochondral formation develops between the bone extremities and external to the periosteum. This chondroid carVascularity
tilaginous matrix rich in proteoglycans and type 2 collagen is
replaced by an osteoid matrix rich in type 1 collagen. The ossified cartilage is replaced progressively by woven bone. The
soft callus enveloping the bone extremities becomes more
Mechanical
Growth
environment
factors
solid and mechanically rigid. The hard callus formation (3-4
months) is characterized by an intramembranous ossification occurring in the subperiosteal area adjacent to the disHost
tal and proximal ends of the fracture forming the peripheral
hard callus (Figure 2). The inner layer of the periosteum contains osteoblasts, which synthesize a matrix rich in type 1 collagen and directly generates calcified tissue.10 This final central
bridging by woven bone provides the fracture with a semiHost
rigid structure, allowing weight bearing and restoring the function of the limb. At this stage the woven bone is identical to
the secondary spongiosa of the growth plate, and the fracture
Osteogenic
Osteoconductive
is considered healed.
cells
scaffold
u Remodeling phase
Once the fracture has been bridged by the callus, the process
of fracture repair slowly replacing the new woven bone with
lamellar bone continues. The remodeling results in a balanced
resorption of the hard callus by osteoclasts and lamellar bone
deposition by the osteoblasts. This last phase is initiated as
early as the first month, and it takes years to achieve the reconstruction of the original bone structure.
158
Vascularity
Figure 3. The “diamond concept” of bone fracture healing interactions.
Adapted from reference 12: Giannoudis et al. Injury. 2008;39(suppl 2):S5-S8.
© 2008, Elsevier Ltd.
OSTEOPOROSIS:
Fracture healing, osteoporosis, and aging
Osteoporotic bone differs from normal bone in its reduced
bone mass and deterioration of its architecture, leading to
bone fragility and an increased fracture risk. This is a consequence of the imbalance between bone formation and bone
remodeling. Osteoporosis is potentially harmful for fracture
treatment: the compromised bone strength affects anchorage of the implants and, at the fracture site, the impaired bone
ingrowths and late remodeling could impair the strength of
the callus and bony union.16 Few studies have investigated
the effects of osteoporosis itself on the bone healing process. Fracture healing has been assumed
to be the same in osteoporotic bone and normal
bone.
THE
Clinical data are even more controversial. The failure rates of fixation in patients with osteoporosis
range from 10% to 25%.19 Despite significant effects
in several clinical studies, there is so far no high level of evidence that osteoporosis, per se, increases
the incidence of fracture nonunion.20,21 Cohorts of
patients are heterogeneous, and randomized studies comparing osteoporotic patients with non-osteoporotic patients are missing.
MUST
BE
STOPPED
Bone mineral
density
Bone quality
Potential
of bone
regeneration
Choice of
implant
Successful
fracture
healing
Bone loss
Mechanical
stability
Fracture
comminution
Fracture
reduction
Biological factors
Figure 4. Factors for successful fracture healing.
Osteoporosis is closely linked with aging. Fracture healing in
the elderly is compromised by the decline in capacity of bone
formation.14 The loss of osteoblasts in the aging skeleton has
been attributed to a decrease in the number of mesenchymal
stem cells and their ability to differentiate in progenitors toward the osteoblastic lineage.22 Due to the augmentation of
life expectancy, the absolute number of fragility fractures and
its corollary, the absolute number of delayed union or nonunion, increase and the consequences are an augmentation
of the mortality and morbidity in this population. The main
determinants for deficient fracture healing can be divided into
biological and surgical factors (Figure 4).19
The treatment of fragility fractures in the elderly remains challenging for the orthopedic surgeon. The poor quality of bone
and frequent fracture comminution make fixation of osteoporotic fractures difficult, despite the development of new fixation devices like locked plating or locked intramedullary nail-
CASCADE
ing, both having revolutionized fracture fixation in weak bone.23
Augmentation with cement or bone substitutes may fill the
bone void or enhance the strength of the fixation. As in hip
fractures, where the indications of arthroplasty have been well
described for a long time, some complex epiphyseal fractures
(shoulder, elbow, knee), may benefit from primary prosthetic
replacement. This option of replacement, instead of fixation, in
comminuted articular fractures of the shoulder, the knee, or the
elbow, has faster and better functional results in very elderly
people, compared with a mechanically poor fracture fixation.24
Surgical factors
Animal studies have been conducted on ovariectomized rodent animal models with a tibia or femur
osteotomy.17 Despite some contradictory results,
more studies support a delay in ossification, a decrease of 20% to 40% in callus area, and a reduction of around 20% in bone mineral density. Mechanical properties of the callus were also disrupted,
with decreased strength, decreased peak failure
load, and decreased bending stiffness. The architecture was modified with thinning and disruption
of the trabeculae and a decrease in connectivity.18
FRACTURE
Local stimulation of fracture healing
The mechanical stability of fixation and preservation of the
environment, without adding injury to soft tissues (muscles,
vessels) are minimal requirements for successful fracture healing. nevertheless, 5% to 10% of all fractures are complicated
by delayed union or nonunion healing. Autogenous bone grafting, as an optimization of the biological milieu, was for years
the “gold standard” in the treatment for healing complications
(Figure 5, page 160).
Over the past decades, new local interventions have been developed to stimulate or accelerate bone union. Most physical
stimulation therapies, such as ultrasound, electrical or electromagnetic fields, and extra corporeal shockwave, seem to
stimulate the healing process25 despite the heterogeneity of
the clinical studies. Different local biological stimulations have
demonstrated their potential to augment the bone regeneration process: autologous mesenchymal stem cell injections
159
OSTEOPOROSIS:
A
THE
FRACTURE
CASCADE
MUST
B
BE
STOPPED
C
D
Figure 5. Complicated intertrochanteric hip fracture in an osteoporotic postmenopausal woman.
A. Postoperative x-ray. B. Nonunion at 9 months and mechanical plate failure. C. Revision surgery with locked nail and autogenous bone graft. D. Healing 3 months later.
from bone marrow aspiration and centrifugation26 or applications of osteoinductive proteins27,28; the next step will be local
delivery by gene therapy.29
Systemic stimulation of fracture healing
Antiosteoporotic drugs have been shown either to reduce
bone remodeling or stimulate bone construction in order to
prevent fractures and to increase bone strength. The different classes of drugs, antiresorptive, bone-forming, or dualeffect agents, have been investigated in preclinical and clinical studies to evaluate how they could influence the early
stages of fracture healing. So far, there is no evidence that
any antiosteoporosis treatment has negative effects on initial
union of fractures in animal models30,31; however, these investigations were conducted in the setting of an indirect healing process. recently in a rodent model of rigid compression
plate fixation of a tibial osteotomy, an inhibitory effect of bisphosphonates has been shown on primary healing.32 The clinical evidence of the current and new osteoporosis treatment
are reviewed below.
u Antiresorptive agents
Bisphosphonates are the most widely used medications to
treat osteoporosis. Various studies have demonstrated no increased risk of nonunion or of deleterious effect on fracture
healing compared with a control group, independent of the
postfracture timing of administration of zoledronic acid or risedronate in intertrochanteric hip fracture or risedronate in distal
radius fractures.33 The same results were observed with denosumab, a receptor activator of nuclear factor kappa-B ligand
(rAnKL) inhibitor, in the posthoc analysis of a phase 2 clinical trial.34
160
u Bone-forming agents
The impact of parathyroid hormone (PTH) peptides on bone
repair has strong evidence in preclinical studies and there is
a growing number of cases reporting off-label use in complex
situations of impaired healing, suggesting a positive stimulation of bone repair.35 Two recent clinical randomized control
trials have investigated the potential of accelerated healing of
osteoporotic fractures. In postmenopausal women sustaining a distal radius fracture treated nonoperatively, the median time to radiological healing of the fracture was significantly shortened with 20 mg daily of PTH (1-34) compared with the
placebo group.36 Another study compared elderly osteoporotic patients with a pubic fracture: the group treated with 100 mg
daily of PTH (1-84) had a shorter radiological healing time as
well as a better functional improvement compared with the
control group.37
u Dual-effect agents
Strontium ranelate was found to stimulate bone formation and
inhibit bone resorption.38 Most preclinical data support the
concept of improved fracture healing and better osseointegration of implants with strontium ranelate.30 evidence from
case reports suggest that strontium ranelate has a potentially direct benefit on the fracture healing process. Bone union
has been reported in different cases of delayed union or nonunion.39,40
Strontium ranelate has been reported to have a positive bone
anabolic effect on unhealed atypical femoral fractures associated with chronic bisphosphonate use, with a quick increase
in bone-formation markers observed following treatment initiation and a cure of the fracture within a few months.41,42
OSTEOPOROSIS:
THE
FRACTURE
CASCADE
MUST
BE
STOPPED
u Future anabolic agents
Inhibitors of Wnt signaling proteins, sclerostin and Dikkopf-1
(DKK1), present potential therapeutic options to enhance osteoblastic bone formation.43 To date, only preclinical studies
have demonstrated the effects of these antibodies in accelerating bone healing. A clinical phase 2 trial is ongoing with
sclerostin antibodies in patients with a tibia fracture or an intertrochanteric hip fracture.
due to weak bones, and the biological consequences of aging and comorbidities on the bone repair process. To date, impaired healing is treated by mechanical improvement in bone
fixation and local biological stimulation by autogenous bone
graft, or more recently, “osteobiologics.” With the growing
number of antiosteoporotic drugs to prevent fracture and increase bone quality, it was a priority to investigate their impact
on the fracture healing process.
Calcilytic drugs represent a new class of bone-forming drugs.
Acting as antagonists of a calcium-sensing receptor (CaSr)
in the parathyroid cells, they stimulate the endogenous release of PTH and increase bone formation markers. A study in
a phase 2 clinical trial of distal radius fractures has not demonstrated any significant radiological or clinical effect of ronacaleret, a CaSr antagonist, on fracture healing.44
The evidence for the effects of antiosteoporotic drugs on fracture healing is rather positive. The concerns for potentially detrimental consequences of such therapeutics on the fracture
repair process seem to be overwhelmed by preclinical and
clinical data. Following a fragility fracture, there is no reason to
delay a preventive antiosteoporotic treatment till the union of
the fracture, except perhaps in the case of a very rigidly fixed
fracture requiring direct bone union. There is promising experimental and clinical evidence for possible enhancement of
the bone repair process via a systemic agent. Further well-designed studies in humans are necessary to accumulate more
evidence on the positive effects of such agents and to translate this knowledge into valid therapeutic applications. n
Conclusion
The number of osteoporotic fractures is increasing, especially among the elderly population. Fracture treatment in elderly
osteoporotic patients remains challenging. Fracture healing
is often compromised, both by a high rate of fixation failure,
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2. Aro HT, Chao eY. Bone-healing patterns affected by loading, fracture fragment
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3. Marsell r, einhorn TA. The biology of fracture healing. Injury. 2011;42:551-555.
4. Isaksson H. recent advances in mechanobiological modeling of bone regeneration. Mechanics Research Com. 2012;42:22-31.
5. Deschaseaux F, Sensebe L, Heymann D. Mechanisms of bone repair and regeneration. Trends Mol Med. 2009;15:417-429.
6. McKibbin B. The biology of fracture healing in long bones. J Bone Joint Surg
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10. Ball MD, Bonzani IC, Bovis MJ, Williams A, Stevens MM. Human periosteum
is a source of cells for orthopaedic tissue engineering: a pilot study. Clin Orthop Relat Res. 2011;469:3085-3093.
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Injury. 2007;38(suppl 4):S3-S6.
12. Giannoudis PV, einhorn TA, Schmidmaier G, Marsh D. The diamond concept—
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13. Hernandez rK, Do TP, Critchlow CW, Dent re, Jick SS. Patient-related risk factors for fracture-healing complications in the United Kingdom General Practice research Database. Acta Orthop. 2012;83:653-660.
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15. Castillo rC, Bosse MJ, MacKenzie eJ, Patterson BM. Impact of smoking on
fracture healing and risk of complications in limb-threatening open tibia fractures. J Orthop Trauma. 2005;19:151-157.
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17. namkung-Matthai H, Appleyard r, Jansen J, et al. Osteoporosis influences the
early period of fracture healing in a rat osteoporotic model. Bone. 2001;28:80-86.
18. Cortet B. Bone repair in osteoporotic bone: postmenopausal and cortisone-
induced osteoporosis. Osteoporosis Int. 2011;22:2007-2010.
19. Cornell Cn. Internal fracture fixation in patients with osteoporosis. J Am Acad
Orthop Surg. 2003;11:109-119.
20. nikolaou VS, efstathopoulos n, Kontakis G, Kanakaris nK, Giannoudis PV. The
influence of osteoporosis in femoral fracture healing time. Injury. 2009;40:663668.
21. van Wunnik BPW, Weijers PHe, van Helden SH, Brink PrG, Poeze M. Osteoporosis is not a risk factor for the development of nonunion: a cohort nested
case-control study. Injury. 2011;42:1491-1494.
22. Almeida M, O’Brien CA. Basic biology of skeletal aging: role of stress response
pathways. J Gerontol A Biol Sci Med Sci. 2013;68:1197-1208.
23. Bogunovic L, Cherney SM, rothermich MA, Gardner MJ. Biomechanical considerations for surgical stabilization of osteoporotic fractures. Orthop Clin North
Am. 2013;44:183-200.
24. Johanson nA, Litrenta J, Zampini JM, Kleinbart F, Goldman HM. Surgical treatment options in patients with impaired bone quality. Clin Orthop Relat Res.
2011;469:2237-2247.
25. Marsell r, einhorn TA. emerging bone healing therapies. J Orthop Trauma.
2010;24(suppl 1):S4-S8.
26. Hernigou P, Poignard A, Beaujean F, rouard H. Percutaneous autologous bonemarrow grafting for nonunions. Influence of the number and concentration of
progenitor cells. J Bone Joint Surg Am. 2005;87:1430-1437.
27. Jones AL, Bucholz rW, Bosse MJ, et al. recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal
tibial fractures with cortical defects. A randomized, controlled trial. J Bone Joint
Surg Am. 2006;88:1431-1441.
28. Kanakaris nK, Calori GM, Verdonk r, et al. Application of BMP-7 to tibial nonunions: a 3-year multicenter experience. Injury. 2008;39(suppl 2):S83-S90.
29. Marie PJ. Cell and gene therapy for bone repair. Osteoporos Int. 2011;22:20232026.
30. Goldhahn J, Féron J-M, Kanis J, et al. Implications for fracture healing of current and new osteoporosis treatments: an eSCeO consensus paper. Calcif
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32. Savaridas T, Wallace rJ, Salter DM, Simpson AH. Do bisphosphonates inhibit direct fracture healing?: A laboratory investigation using an animal model.
Bone Joint J. 2013;95-B(9):1263-1268.
33. Lyles KW, Colon-emeric CS, Magaziner JS, et al. Zoledronic acid in reducing clinical fracture and mortality after hip fracture. N Engl J Med. 2007;357:nihpa40967.
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THE
FRACTURE
CASCADE
MUST
34. Adami S, Libanati C, Boonen S, et al. Denosumab treatment in postmenopausal
women with osteoporosis does not interfere with fracture healing. J Bone Joint
Surg Am. 2012;94:1-7.
35. Pietrogrande L, raimondo e. Teriparatide in the treatment of non-unions: scientific and clinical evidences. Injury. 2013;44(suppl 1):S54-S57.
36. Aspenberg P, Genant HK, Johansson T, et al. Teriparatide for acceleration of
fracture repair in humans: a prospective, randomized, double-blind study of
102 postmenopausal women with distal radial fractures. J Bone Miner Res.
2010;25:404-414.
37. Peichl P, La H, Maier r, Holzer G. Parathyroid hormone 1-84 accelerates fractures healing in pubic bones of elderly osteoporotic women. J Bone Joint Surg
Am. 2011;93:1583-1587.
38. Marie PJ, Felsenberg D, Brandi ML. How strontium ranelate, via opposite effects
on bone resorption and formation, prevents osteoporosis. Osteoporosis Int.
2011;22:1659-1667.
39. Alegre Dn, ribeiro C, Sousa C, Correia J, Silva L, de Almeida L. Possible ben-
BE
STOPPED
efits of strontium ranelate in complicated long bone fractures. Rheumatology
Int. 2012;32:439-443.
40. Tarantino U, Celi M, Saturnino L, al. Strontium ranelate and bone healing: report
of 2 cases. Clin Cases Miner Bone Metab. 2010;7:65-68.
41. Carvalho nnC, Voss La, Almeida MOP, Salgado CL, Bandeira F. Atypical femoral
fractures during prolonged use of bisphosphonates: short-term responses to
strontium ranelate and teriparatide. J Clin Endocrinol Metab. 2011;96:26752680.
42. negri AL, Spivacow Fr. Healing of subtrochanteric atypical fractures after
strontium ranelate treatment. Clin Cases Miner Bone Metab. 2012;9:166-169.
43. Ke HZ, richards WG, Li X, Ominsky MS. Sclerostin and dickkopf-1 as therapeutic targets in bone diseases. Endocr Rev. 2012;33:747-783.
44. Fitzpatrick LA, Smith PL, McBride TA, et al. ronacaleret, a calcium-sensing receptor antagonist, has no significant effect on radial fracture healing time: results of a randomized, double-blinded, placebo-controlled phase II clinical trial.
Bone. 2011;49:845-852.
Keywords: antiosteoporotic drug; bone repair; delayed union; fracture; fracture healing; nonunion; osteoporosis
CONSOLIDATION
FRACTURAIRE ET OSTÉOPOROSE
L’os diffère des autres tissus par ses capacités d’autoréparation après une fracture. Le rôle du chirurgien orthopédique est de réduire anatomiquement les fragments osseux, de stabiliser la fracture pour permettre la consolidation sans cal vicieux afin de rétablir une fonction normale. Le processus de consolidation est une cascade d’événements, principalement contrôlés par la stabilité mécanique de la fixation et par l’environnement biologique de la
fracture, résumé par Giannoudis selon le « concept du diamant ». Modulée par ces différents facteurs, la formation
du cal osseux se fait sur un mode primaire ou secondaire. Connaître les bases de la consolidation fracturaire est un
prérequis pour comprendre comment améliorer le traitement des fractures de fragilité. Dans la population âgée ostéoporotique, le risque de pseudarthrose ou de retard de consolidation est plus élevé, entraînant une augmentation
de la morbidité et du coût financier. Les médicaments anti-ostéoporotiques agissent soit en freinant le remodelage
osseux soit en stimulant la construction osseuse afin de renforcer la résistance osseuse et de prévenir les fractures.
Il est important de connaître leurs interactions potentielles sur la consolidation fracturaire et d’évaluer leurs capacités
à stimuler la réparation du tissu osseux. La plupart des études précliniques, utilisant principalement des modèles murins ostéoporotiques, ont démontré une stimulation de la consolidation des fractures avec des médicaments ostéoformateurs. Il n’existe aucune donnée rapportant des effets indésirables avec des médicaments antirésorptifs aux
stades précoces de la consolidation osseuse. Chez l’homme, plusieurs observations de cas et quelques études cliniques confirment les effets bénéfiques potentiels des médicaments ostéoformateurs sur la réparation fracturaire.
D’autres études sont cependant nécessaires pour évaluer cette approche systémique de stimulation de la consolidation osseuse, en particulier dans les fractures ostéoporotiques.
162
‘‘
OSTEOPOROSIS:
The best management of the
elderly population with osteoporosis includes exercise training, optimal dietary calcium intake, vitamin D supplementation, and use
of antiosteoporotic drugs. There is
good evidence for the benefits of
bisphosphonates (alendronate,
risedronate, and zolendronic acid),
denosumab, teriparatide, and strontium ranelate in vertebral fracture
reduction, but there are limited data
regarding the reduction of nonvertebral and hip fracture for some of
these drugs.”
THE
FRACTURE
CASCADE
MUST
BE
STOPPED
Growing in age and numbers:
how can we best manage
the elderly with osteoporosis?
b y F. C . S a n t o s , B ra z i l
T
Fânia Cristina SANTOS
MD, MSc, PhD
Osteoarticular Disease and
Pain Sector, Department of
Geriatrics and Gerontology
Federal University of Sao Paulo
Sao Paulo, BRAZIL
he number of elderly people is fast increasing and their average age is
simultaneously rising, thus the prevalence of osteoporosis is expected
to grow, along with its medical and socioeconomic impact. Management of the elderly is no easy task and requires a different approach to that in
younger patients. Osteoporosis therapies appear safe and efficacious in the
elderly, and appropriate management of osteoporosis will reduce the associated morbidity, mortality, and economic costs. All older seniors should be
educated about a bone-healthy lifestyle, which includes age-appropriate
weight-bearing exercise and smoking and alcohol cessation. It is important
to remember that falls play a very important role in the risk for osteoporotic
fracture; thus, strategies should be implemented to reduce the occurrence
of falls. The risk for vitamin D insufficiency and deficiency is high in the older
senior and can contribute to falls and fractures, so deficiencies need to be
treated through supplementation. Calcium intake is also important, and if inadequate, calcium supplementation is necessary. Current clinical data in older seniors have shown a benefit regarding vertebral fracture reduction with
bisphosphonates (alendronate, risedronate, and zolendronic acid), denosumab, teriparatide, and strontium ranelate. However, limited data exist for some
of these drugs regarding nonvertebral and hip fracture reduction. Strontium
ranelate has been shown to reduce nonvertebral and hip fracture events in
the high-risk elderly female population and has been found to be cost effective in preventing fractures in this population. Moreover, its antifracture efficacy is maintained over the long term.
he number of old people is growing very rapidly and is projected to more
than triple globally in the next half century, from 593 million to 1.97 billion.
With increasing life expectancy the prevalence of osteoporosis is expected
to increase, along with its medical and socioeconomic impact.
T
Prof Fânia Cristina Santos,
Department of Geriatrics and
Gerontology, Federal University
of Sao Paulo, Professor Francisco
de Castro, 105 – Vila Clementino,
Sao Paulo, CEP 04020-050, Brazil
(e-mail: faniacs@uol.com.br)
Osteoporosis and associated fractures place significant demands on health resources—particularly hip fractures, which are a major source of morbidity and mortality among those aged over 65 years.1 Osteoporotic fractures of the hip and spine
carry a mortality rate of up to 20% in one year; this is because they require hospitalization and consequently increase the risk of developing other medical complications due to chronic immobilization, such as thromboembolic disease.1 The incidence of hip fracture rises exponentially with advancing age in men and women
Growing in age & numbers: how can we best manage the elderly with osteoporosis? – Santos
163
OSTEOPOROSIS:
THE
FRACTURE
CASCADE
MUST
over 75 years old.2 A review of hip fractures found that femoral
neck and intertrochanteric fractures occur with approximately the same frequency in individuals between the ages of 65
and 99 years.3 Hip fractures cause acute pain and loss of
function; the recovery is slow and rehabilitation is often incomplete, with many elderly people becoming permanently
institutionalized in nursing homes. After a hip fracture, only half
of patients return to their prefracture ability level.4
Vertebral fractures also have a major impact on a patient’s
life. The SOF study (Study of Osteoporotic Fractures) assessed
the effect of vertebral fractures in 7723 women aged >65
years. The impact on their quality of life was assessed according to changes in disability, pain, and fear for the future, and
with every additional fracture, further deterioration in their quality of life.5 Often, vertebral fractures recur, and the consequent
disability increases with increasing number of these fractures.
Fragility fractures at other sites, including the forearm, upper
arm, pelvis, ribs, and clavicle, also contribute to the overall
morbidity of osteoporosis.
Important issues surrounding the elderly with
osteoporosis
One of the issues surrounding osteoporosis management is
the diagnosis of at-risk patients before they develop a fracture;
ie, identification of clinical factors that improve the detection
of older adults at risk for fractures as well as disability and falls.
Many elderly people at very high risk of fracture are currently
not being identified.
Osteoporotic fracture risk in the geriatric patient is multifactorial, and often involves having osteoporotic bone with poor
biomechanical characteristics and a higher likelihood of falls
due to poorer balance, medication side effects, and difficulty
maneuvering around environmental hazards.6-8 Risk factors
for fracture include inherent, nonmodifiable factors, as well as
those that individuals can address to prevent or slow down
fracture occurrence.
It has been suggested that elderly individuals have a reduced
ability to control their posture, which may predispose them to
increased risk of falling.8 The risk for falls increases with advanced age,6,7 and it is estimated that 50% of senior citizens
aged 85 years and older will fall at least once per year, and
half of those who fall will do so more than once.8 Approximately 5% of these falls will result in a fracture.9
The senior population often has multiple comorbid conditions—such as stroke, Alzheimer’s dementia, and Parkinson’s
disease—that may pose a high risk for fracture.9 Cognitive
and functional changes associated with aging may make it
difficult for the elderly to adhere to treatment regimens. In addition, the presence of comorbid medical conditions may be
a risk factor for falls9 and thus present another barrier regard-
164
BE
STOPPED
ing osteoporosis care. Frailty, a common geriatric syndrome
that embodies an increased vulnerability to stressors, is an
independent predictor of hip fractures, hospitalization, disability, and death in the elderly and is receiving increasing attention as a risk factor for falls.10
The parallels between osteoporosis and sarcopenia are striking. Findings from a sample of oldest old women living in one
community suggested a concomitant impact of severe osteopenia/osteoporosis plus sarcopenia on frailty status.11 Sarcopenia—the age-related decline in muscle mass and function—and severe osteopenia/osteoporosis are prevalent in
cases of frailty and in the prefrail elderly.11 It seems likely that
sarcopenia is a substantial contributor to the increased falls
and fracture risk seen with advancing age.
The use of multiple medications—which occurs very often in
the elderly—particularly psychoactive medications such as
benzodiazepines, antidepressants, and antipsychotics, has
also been strongly associated with falls and fractures.12-14 Furthermore, the increased risk of side effects from medications
in the elderly contributes to nonadherence to antifracture treatments.
Management of the elderly with osteoporosis
Osteoporosis treatment is aimed at reducing the risk of fracture, thereby reducing morbidity and mortality associated with
the first fracture and preventing subsequent fractures. There
is sufficient evidence to merit the treatment of osteoporosis
in the elderly; however, only a small proportion of older senior citizens with osteoporosis receive treatment, particularly
among those aged over 80 years.15 Moreover, many elderly
individuals who start treatment do not take their treatment correctly or for long enough to lower their risk of fracture.
Management of the elderly with osteoporosis is no easy task,
and requires a different approach to that in younger patients.
Viable preventative and therapeutic approaches are the key
to managing this problem within the aging population, and
nonpharmacological and pharmacological strategies should
be adopted.
SELECTED
European Society for Clinical and Economic Aspects
of Osteoporosis and Osteoarthritis
FREEDOM Fracture REduction Evaluation of Denosumab in
Osteoporosis every 6 Months
HIP
Hip Intervention Program
HORIZON Health Outcomes and Reduced Incidence with
Zoledronic acid ONce yearly
SOF
Study of Osteoporotic Fractures
SOTI
Spinal Osteoporosis Therapeutic Intervention
TROPOS TReatment Of Peripheral Osteoporosis Study
ESCEO
OSTEOPOROSIS:
◆ Nonpharmacological strategies
Nonpharmacological strategies must be viewed as an essential part of the prevention of fractures in the elderly, but
should also be employed from childhood through to adulthood. Preventive programs to address falling, as well as nutrition, hip protection, and exercise, are important nonpharmacological approaches to preventing fractures.
◆ Interventions for falls and immobility
There are a number of different management strategies aimed
at reducing the risk of falls and osteoporotic fractures in the
elderly.16 All older senior citizens should be evaluated annually for falls, and strategies should be implemented to reduce
the risk of falls in this population. Any patient that reports a
single fall should undergo a basic evaluation of gait and balance. Questioning the individual about fear of falling is important, because not only is fear of falling a consequence of
falling, but it is also a psychological risk factor for falls. Important interventions for fall prevention in the older senior citizen are outlined in Table I.16
◆ Physical activity
◆ Home environment modification
◆ Vision assessment
◆ Use of ambulation-assistive devices
◆ Treatment of cardiovascular causes of falls
◆ Elimination of unnecessary medication
◆ Vitamin D supplementation
Table I. Recommendations for fall prevention in the elderly.
Based on reference 16: Vondracek and Linnebur. Clin Interv Aging. 2009;4:
121-136. © 2009, Vondracek and Linnebur, publisher and licensee Dove Medical Press Ltd.
Disease or disability requiring complete bed rest or severely
limiting activity will cause immobility, and immobility should,
wherever possible, be avoided. The reason for this is that immobilized patients may lose as much bone in a week when
confined to bed as they would otherwise lose in a year. It is
ideal for individuals to get some form of physical activity16 since
this contributes to increased bone mass density.
◆ Nutrition recommendations
It is necessary to ensure that elderly individuals with osteoporosis receive adequately balanced nutrition. The role of protein intake remains controversial in osteoporosis. Excessive
protein intake can be responsible for a metabolic increase in
acid production and acid renal excretion, with increased calciuria favoring bone loss and hip fracture.17,18 One study observed that the risk of hip fracture was not associated with
calcium or vitamin D intake, but was negatively related to total protein intake (the decrease in relative risk for hip fracture
paralleling the intake in animal protein).19 Another study reported that the negative effects of protein intake were related
to a high ratio in the diet of dietary proteins of animal origin
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over vegetable proteins, which could induce a higher rate of
bone loss at the femoral neck and an increased risk for hip
fractures in women aged more than 65 years.20 However, this
apparent deleterious effect of animal protein intake can be
counteracted by dietary or supplemental calcium and vitamin D (500 mg as calcium citrate malate and 700 IU vitamin D
per day).21 Inadequate dietary protein intake in the presence
of adequate total calcium intake does not seem to confer any
protection against fractures.22
Adequate intake of calcium is important. Encouraging consumption of foods rich in calcium is one of the best ways to
preserve body calcium economy, and when dairy consumption is low, a calcium supplement should be considered.
Additionally, adequate intake of vitamin D should be recommended.23 However, hypovitaminosis D principally results from
insufficient skin exposure to sunlight and the reduced efficacy of vitamin D synthesis in the skin of elderly individuals. Low
sun exposure in the elderly is related to an indoors style of
living and/or wearing clothing that leaves little skin exposed.
If there is inadequate sun exposure as well as a diet with inadequate levels of vitamin D, supplements of this vitamin may
need to be taken.23 Vitamin D also plays an important role in
falls,24 in addition to bone strength.
◆ Exercise
A systematic review found that in individuals with an increased
risk of fracture, bone strength was improved by weight-bearing aerobic exercise with or without muscle strengthening
exercise when the duration of the intervention was at least 1
year.25 Programs of resistance exercise for the elderly need to
be evaluated carefully. Strength-training programs and the
intensity of the training should be carefully planned and progressively adapted to suit the body.
The major benefit of exercise in patients with osteoporosis
may be an improvement in muscle strength and coordination,
which, in turn, decreases the frequency of falls.26 Exercise interventions have mainly been reported to reduce risk factors
for fracture; ie, produce a decrease in the propensity to fall and/
or an increase in bone mass density. A Cochrane meta-analysis showed that multifactorial interventions and single, supervised exercise interventions can both reduce the risk of
falling, with multifactorial interventions also reducing the rate
of falls (relative risk [RR], 0.69; 95% confidence interval [CI],
0.49-0.96).27 The general recommendation is that exercise
should be performed two to three times per week and must include 15 to 60 minutes of aerobic exercise and a set of strength
training. Exercise intensity should be at 70% to 80% of functional capacity or maximum strength.26
◆ Smoking and alcohol cessation
Current smoking and excessive alcohol consumption are associated with an increased risk of fracture,23 and smoking cessation and reduction in alcohol consumption can slow the rate
165
OSTEOPOROSIS:
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of bone loss. Despite a lack of data in older seniors and the
fact that the benefits of smoking cessation for osteoporosis
may be delayed, the other health benefits of smoking cessation make it important for all older seniors.26 Alcohol may interfere with bone metabolism through direct toxic effects on
osteoblasts, as well as indirectly through adverse skeletal effects caused by nutritional deficiencies in calcium, vitamin D,
and proteins, which are prevalent in heavy drinkers.26
cium supplementation.31 In this meta-analysis, calcium/vitamin D supplements (1200 mg of calcium and 800 UI of vitamin D/day) significantly reduced fracture risk by 12%, and they
also reduced bone loss (by 0.54% at the hip and 1.19% in
the spine). In a subgroup analysis based on age, fracture risk
reduction was 11% in those aged 70 to 79 years and 24%
in those aged 80 years, while in those aged 50 to 69 years it
was 3%.
◆ Hip protectors
Use of external hip protectors is aimed at reducing the impact of falls onto the hip. A meta-analysis of randomized controlled trials demonstrated no benefit from hip protectors in
community-dwelling seniors.28 By contrast, a pooled analysis
suggested that two-sided devices may potentially reduce the
risk of hip fracture, at least in institutionalized elderly individuals.29 Although the available evidence is insufficient to allow
firm and final conclusions or recommendations, it would seem
that it may not be appropriate to discount the potential benefit of this intervention in a long-term care setting. Poor compliance is the main drawback with these devices, as patients
tend to find them uncomfortable and cosmetically unappealing.
Moreover, among older individuals, vitamin D supplementation has been found to reduce the risk of falling by 19%, and
to a similar degree as active forms of vitamin D (700-1000 IU/
day).24
◆ Pharmacological strategies
In all older seniors a diagnosis of osteoporosis will in theory
warrant drug therapy. However, several factors need to be
taken into consideration before instituting drug therapy for the
management of osteoporosis in the elderly population to determine whether there is evidence to support a benefit of osteoporosis therapy.
◆ Vitamin D and calcium supplementation
The European Society for Clinical and Economic Aspects of
Osteoporosis and Osteoarthritis (ESCEO)30 provides clinical
practice recommendations to ensure the optimal management
of elderly and postmenopausal women with regard to vitamin D supplementation: patients with serum 25-hydroxyvitamin D (25[OH]D) levels of <50 nmol/L have increased bone
turnover, bone loss, and possibly mineralization defects compared with patients with 25[OH]D levels of >50 nmol/L. Similar relationships have been reported for frailty, nonvertebral
and hip fracture, and all-cause mortality, with poorer outcomes
among those with 25[OH]D levels at <50 nmol/L. Thus, the
ESCEO recommends that 50 nmol/L (ie, 20 ng/mL) should
be the minimum serum 25(OH)D concentration at the population level and in patients with osteoporosis to ensure optimal bone health. Below this threshold, vitamin D supplementation is recommended at 800 to 1000 IU/day. The ESCEO
recommends that fragile elderly subjects should have a minimum serum 25(OH)D concentration of 75 nmol/L (ie, 30 ng/
mL) for the greatest impact on fracture risk reduction.30
A meta-analysis of calcium and calcium/vitamin D supplementation concluded that oral vitamin D appears to reduce the
risk of hip fractures, but only when it is combined with cal-
166
There have been suggestions that calcium supplementation,
either as monotherapy or combined with vitamin D, increases cardiovascular risk. However, the trials that have reported
this were not valid in the sense that they were not primarily
designed to assess cardiovascular events. When it is necessary to supplement calcium intake, either calcium carbonate
or calcium citrate can be used.16 The calcium citrate form may
be advantageous for older seniors, since calcium citrate absorption does not rely on gastric acid (unlike calcium carbonate), and older seniors may suffer from achlorhydria. Moreover, patients taking proton pump inhibitors may benefit more
from supplementation with calcium citrate.16
◆ Bisphosphonates
Data from one clinical trial showed that in a subgroup of women
aged 75 years or above, alendronate reduced the risk of new
vertebral fractures by 38% during an average follow-up of
2.9 years.32 The absolute risk reduction with alendronate for
combined clinical hip, spine, and wrist fractures was greatest
in the 75- to 85-year age group: there were 65, 80, 111, and
161 women with fractures per 10 000 person-years in the age
groups 55 to <65 years, 65 to <70 years, 70 to <75 years,
and 75 to 85 years, respectively.33 For risedronate, a 44% reduction was observed in the risk of vertebral fractures in women
aged 80 years or above, but there was no significant difference in the incidence of nonvertebral fractures.34 In a post
hoc analysis of the HIP study (Hip Intervention Program), risedronate significantly reduced the risk of hip fracture by 46% in
women aged up to 100 years with established osteoporosis.35
A study with zoledronic acid taken intravenously once a year
demonstrated the efficacy of the treatment in reducing the
risk of hip fracture in older postmenopausal women aged 65
to 89 years.36 Over 3 years, hip fracture incidence was significantly reduced by 41%. In a post hoc subgroup analysis of
pooled data from the HORIZON trials (Health Outcomes and
Reduced Incidence with Zoledronic acid ONce yearly), which
assessed the effect of zoledronic acid treatment in postmenopausal women aged 75 years and older, significant reductions were observed in the risk of any clinical fracture (35%),
clinical vertebral fractures (66%), and nonvertebral fractures
(27%).37 Common adverse events were flu-like symptoms.
OSTEOPOROSIS:
◆ Denosumab
In a post-hoc analysis of the 3-year FREEDOM trial (Fracture
REduction Evaluation of Denosumab in Osteoporosis every
6 Months), in the subgroup of postmenopausal women aged
75 years or above, denosumab treatment reduced the relative risk of new vertebral and hip fractures by 69% and
47%, respectively.38 There was a possible increased rate of
eczema and cellulitis.
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nonvertebral fracture in such an elderly population (aged ≥80
years).40 Additionally, in patients with a mean age of 72 years,
vertebral and nonvertebral fracture incidence was lower over
a period of 5 to 10 years than in a matched placebo group,
thus showing that the anti-fracture efficacy of strontium ranelate is maintained over the long term.41
◆ Raloxifene
Although older women have been included in some studies
of raloxifene, the numbers have been small and there are no
published data on older cohorts or subgroups.
In TROPOS, strontium ranelate significantly reduced the risk
of hip fracture by 36% in a high-risk subgroup (those aged
≥74 years with a femoral neck bone mineral density T-score
of ≤–3, corresponding to a T-score of –2.4 when using data
from NHANES III [the Third National Health and Nutrition Examination Survey] as a reference).42
◆ Strontium ranelate
Strontium ranelate is the first agent of a new therapeutic class
in osteoporosis, capable of both promoting bone formation
and, to a lesser extent, inhibiting bone resorption. Pooled data
on strontium ranelate from the trials SOTI (Spinal Osteoporosis
Therapeutic Intervention; mean patient age, 70 years [range
50 to 96 years]) and TROPOS (TReatment Of Peripheral Osteoporosis Study; mean patient age, 77 years [range 70 to 100
years]) revealed risk reductions after 3 years of 32%, 31%, and
22% for vertebral, nonvertebral, and any clinical fracture, respectively, in the subgroup of women aged 80 years or above
with osteoporosis.39 Strontium ranelate is the only antiosteoporotic drug to have been shown to achieve an early and sustained reduction (up to 5 years) in the risk of vertebral and
With regard to cost effectiveness, a recent meta-analysis of
trials undertaken in different settings (Belgium, the UK, and
Sweden) confirmed that treatment with strontium ranelate is
cost-saving in women with osteoporosis aged 80 years and
older.43 Furthermore, for all ages, the cost per quality-adjusted life year gained with strontium ranelate compared with
no treatment, when assuming adherence similar to bisphosphonate therapy, was less than the cutoffs established in
countries like the UK and Sweden. In patients at risk of venous thromboembolism, strontium ranelate should be used
with caution and discontinued in the event of an illness or a
condition leading to immobilization.44 Patients with significant
risk factors for cardiovascular events should only be treated with strontium ranelate after careful consideration.
Drug
Dose
Fracture risk reduction
Comments
Alendronate
5-10 mg orally
once daily
VF: 38% (patients aged ≥75 years) No data for NVF or HF32
HF, VF, and WF: 40%
GI side effects (eg, nausea, dyspepsia, esophagitis, ulceration),
muscle pain; small risk of osteonecrosis of the jaw. Link
between prolonged bisphosphonate use and atypical fractures
Risedronate35
2.5-5 mg orally
once daily
HF: 46% (patients aged 70 to
100 years)
GI side effects (eg, nausea, dyspepsia, esophagitis, ulceration),
muscle pain; small risk of osteonecrosis of the jaw
Zoledronic
acid36,37
5 mg intravenous
infusion over
15 minutes once
yearly
HF: 41% (patients aged 65 to
89 years [mean age 73 years],
at 3 years)
ACF: 35%; VF: 66%; NVF: 27%
HF was lower, but did not reach statistical significance36
Common adverse events: flu-like symptoms (pyrexia, myalgia,
and bone and musculoskeletal pain). Risk of osteonecrosis
of the jaw
Strontium
ranelate39-41,42
2 g orally one daily
VF: 32% (women aged ≥80 years,
at 3 years)
NVF: 31%; ACF: 22%
NVF: 16% (women aged ≥74 years)
HF: 36%
VF: 59%; NVF: 41% at 1 year39
High-risk subgroup (age ≥74 years plus T score <– 3 to
femoral neck)41
Cost-saving in osteoporotic women aged 80 years or above42
Possible increased risk for VTE and MI
Denosumab38
60 mg subcutaneous
injection twice yearly
VF: 69% (women aged ≥75 years, High-risk subgroup (multiple and/or moderate or severe prevaat 3 years)
lent vertebral fractures and/or T score ≤2.5 to femoral neck)
HF: 47%
Increased rate of eczema and incidence of urinary infections
Teriparatide45
20 mcg subcutaneous
injection once daily
VF: 65%
HF: nonsignificant
NVF: 54%
32,33
Mild hypercalcemia, nausea, headache, dizziness, and leg
cramps. Contraindicated in those with history of prior radiation therapy to the skeleton and severe kidney dysfunction
Table II. Pharmacological therapy for osteoporosis in the elderly.
Abbreviations: ACF, any clinical fracture; GI, gastrointestinal; HF, hip fracture; MI, myocardial infarction; NVF, nonvertebral fracture; VF, new morphometric vertebral
fracture; VTE, venous thromboembolism; WF, wrist fracture.
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◆ Teriparatide
Teriparatide is an option for patients who are at high risk of
fracture or who cannot tolerate, or fail on, other therapies. Daily administration by injection in the older senior can be challenging. A study of the clinical fracture incidence, back pain,
and health-related quality of life in patients receiving teriparatide treatment over a period of 18 months and in the 18 months
following treatment reported a reduced clinical fracture incidence in the subgroup of 589 postmenopausal women with
osteoporosis who were aged ≥75 years.45 In addition, an improvement in quality of life was observed, and possibly also
an early and significant reduction in back pain, which lasted
for at least 18 months after teriparatide discontinuation when
patients were taking other osteoporosis medication.
Table II (page 167) summarizes data on the current pharmacological agents available for the treatment of osteoporosis in
the elderly.
Finally, there is limited data on the clinical efficacy and safety
of specific antiosteoporotic treatments for the reduction of
fracture risk in the elderly with osteoporosis, particularly in the
elderly aged ≥ 75 years.46 Given the positive impact of medications on fracture prevention, the low risk of drug-drug interactions, and low incidence of adverse effects, prescription
of antiosteoporotic drugs should not be considered “inappropriate” in older patients. However, it is necessary to adopt different strategies in this patient age group, as their fracture risks
and treatment strategies may be quite different from younger
populations. Extending strategies for fracture risk reduction
beyond osteoporosis, targeting several clinical conditions
BE
STOPPED
rather than focusing on a single condition, may be preferable.
Strategies focused on a combination of clinical conditions
would be interesting in the elderly; for example, osteoporosis
and sarcopenia or sarcopenic obesity, which has very recently been termed “dysmobility syndrome” and is characterized
by difficult or impaired mobility that leads to an increased
risk of adverse musculoskeletal outcomes such as falls and
fractures.47
Conclusion
It is important for health care providers to be fully aware of the
potential risks and benefits of treating osteoporosis in the elderly, a high-risk group for osteoporotic fracture as well as for
osteoporosis-related complications and treatment-related adverse events. Osteoporotic therapies appear safe and efficacious in the elderly population, and appropriate management
would reduce the morbidity, mortality, and economic costs associated with this disease. The best management of the elderly population with osteoporosis includes exercise training,
optimal dietary calcium intake, vitamin D supplementation,
and use of antiosteoporotic drugs. There is good evidence for
the benefits of bisphosphonates (alendronate, risedronate,
and zolendronic acid), denosumab, teriparatide, and strontium
ranelate in vertebral fracture reduction, but there are limited
data regarding the reduction of nonvertebral and hip fracture
for some of these drugs. Strontium ranelate has demonstrated an ability to reduce nonvertebral and hip fracture events in
the high-risk elderly female population. Furthermore, its cost
effectiveness has also been shown for fracture prevention in
this population, as well as its maintained antifracture efficacy
over the long term. n
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Keywords: antiosteoporotic treatment; elderly; fracture prevention; osteoporosis
PLUS
VIEUX ET PLUS NOMBREUX : COMMENT MIEUX PRENDRE EN CHARGE
LES SUJETS ÂGÉS OSTÉOPOROTIQUES ?
La croissance rapide du nombre de personnes âgées et simultanément de leur moyenne d’âge, devrait augmenter
la prévalence de l’ostéoporose et son impact médical et socio-économique. La prise en charge des personnes âgées
n’est pas chose facile et demande une approche différente de celle de patients plus jeunes. Les traitements de l’ostéoporose semblent sûrs et efficaces chez les sujets âgés, une bonne prise en charge de l’ostéoporose devant diminuer la mortalité, la morbidité et les coûts économiques associés. Tous les sujets plus âgés devraient être éduqués
pour adopter un mode de vie favorisant la santé osseuse, par exemple faire des exercices en charge adaptés à l’âge
et arrêter l’alcool et le tabac. Il est important de rappeler que les chutes jouent un rôle très important dans le risque
de fracture ostéoporotique et qu’il faut donc mettre en place des stratégies pour les prévenir. En cas d’insuffisance
ou de carence en vitamine D, dont le risque plus élevé chez les patients âgés peut participer aux chutes et aux fractures, un complément doit être apporté. La prise de calcium est également importante et un complément doit être
prescrit si c’est nécessaire. D’après les données cliniques actuelles chez les patients âgés, les bisphosphonates
(alendronate, risédronate et acide zolendronique), le dénosumab, le tériparatide et le ranélate de strontium diminuent les fractures vertébrales. Nous manquons cependant de données pour certains de ces médicaments en ce
qui concerne la diminution des fractures de hanche et non vertébrales. Le ranélate de strontium diminue ces fractures
chez les femmes âgées à haut risque et a un rapport coût-efficacité favorable dans cette population en termes de prévention. De plus, son efficacité antifracturaire se maintient au long cours.
169
‘‘
OSTEOPOROSIS:
…men and women who are
more active throughout life have
a higher bone mass and subsequently a reduced risk of osteoporosis later in life. Moreover,
physical activity appears to be a
powerful stimulus to prevent osteoporotic fractures during the
ageing process, especially at the
hip site, while an excessive time
spent in sedentary activities
seems to be a potential risk factor for developing an osteoporotic fracture.”
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“Ossa sanus in corpore sano”
A sound bone in a sound
body: the importance
of nutrition, physical activity,
and nonpharmacological
management in osteoporosis
b y A . G ó m e z - C a b e l l o , I . A ra ,
A . G o n z á l e z - A g ü e ro , J . A . C a s a j ú s
and G. Vicente-Rodríguez, Spain
T
▲
Alba GÓMEZ-CABELLO,a,b PhD
Ignacio ARA,b,c PhD
Alejandro GONZÁLEZ-AGÜERO b,d
PhD
José Antonio CASAJÚS,b,e MD, PhD
Germán VICENTE-RODRÍGUEZ b,e
PhD
a Centro Universitario de la Defensa,
Zaragoza, SPAIN
b GENUD
“Growth, Exercise, Nutrition
and Development” Research Group
University of Zaragoza, SPAIN
c GENUD Toledo Research Group
University of Castilla-La Mancha
Toledo, SPAIN
his review summarizes and updates the knowledge regarding the importance of nutrition and physical activity on bone mass and fracture risk.
Adequate nutrition is of great importance to guarantee optimal development and maintenance of bone structures. Use of calcium and vitamin D in
combination is effective in preventing osteoporosis as it helps to reduce the
bone loss that occurs during the ageing process. Moreover, proteins can also
impact skeletal mass and the risk of fractures, and other nutrients such as vitamins C and K or antioxidants are also associated with increased bone mass,
though more research is needed to fully understand these associations. In
addition to appropriate nutrition, physical activity and specific training programs represent another key factor in the prevention and/or treatment of osteoporosis. Bone mass seems to benefit from present and past physical activity. Sport practice at the time of bone development increases bone density,
and more recent sport training contributes to the preservation of bone-related variables. Therefore, those who are more active throughout life have a higher bone mass, and subsequently a reduced risk of osteoporosis later in life.
Moreover, physical activity appears to be a powerful stimulus to prevent the
risk of osteoporotic fractures, especially at the hip. Finally, specific training programs are useful to mitigate the decline in bone mass during senescence, especially in postmenopausal women.
d Department
of Sport and Exercise
Science, Aberystwyth University
Ceredigion, UNITED KINGDOM
e Faculty
of Health and Sport Science
(FCSD), Department of Physiatry
and Nursing, University of Zaragoza
SPAIN
Dr Alba Gómez-Cabello,
Centro Universitario de la Defensa,
Academia General Militar,
Ctra de Huesca s/n,
50090, Zaragoza, Spain
(email: agomez@unizar.es)
170
ne of the major demographic changes occurring in developed societies is
a significant ageing of the population. Currently, people over 65 represent
up to 20% of the total population in several countries, a proportion that is
expected to rise in the coming decades due to increased life expectancy.1
O
In older people, age-related bone loss in both sexes is usually in the range of 0.5% to
1.0% per year, with an apparent increased rate of bone loss at the femoral neck with
increasing age, especially in women. For this reason, the risk of fracture is higher in
women and increases with age. Therefore, as people are living longer, osteoporosis
and fracture risk are expected to increase. Osteoporosis is commonly referred to
as a “silent disease” as there are no symptoms until the first fracture occurs. The adverse outcomes of osteoporosis do not manifest themselves until later in life, when
Nonpharmacological management in osteoporosis – Gómez-Cabello and others
OSTEOPOROSIS:
the incidence of fractures increases. Osteoporotic fractures—
defined as those fractures associated with low-energy trauma
occurring at sites associated with low bone mineral density
(BMD)2—constitute a global and growing problem, especially
in postmenopausal women. The frequency of these fractures
increases by 1% to 3% per year in many areas worldwide,3
which has a deep impact on the quality of life4 and mortality5
of individuals. In the case of hip fracture, most deaths occur
in the first 3 to 6 months following the event, 20% to 30% of
which are causally related to the fracture event itself.6 In Europe in 2005 all osteoporotic fractures in men and women collectively accounted for 3.7 million fractures, representing a
direct cost of €36 billion.2 Moreover, health economists estimate that osteoporosis-related costs will double by 2050 in
Europe. This means an increase of up to €80 billion in 2050.7
Low BMD is a major risk factor for all types of fracture; however, other factors such as age over 75 years, self-reported
health, low body mass, weight loss, height, history of fractures, years since menopause, parental hip fracture, calcium intake, and physical inactivity may also contribute to the
development of this disease.8-10 These risk factors for low
BMD, osteoporosis, and osteoporotic fractures include both
unchangeable and modifiable factors. In fact, it is widely
known nowadays that diet and physical activity are two important modifiable lifestyle factors that can prevent—or at
least slow down—the rate of bone loss. Therefore, the aim of
this review is to summarize and update the knowledge regarding the importance of nutrition, physical activity, and nonpharmacological management on bone mass and fracture
risk in older adults and elderly people as a starting point for
developing future interventions to maintain a higher quality of
life in people throughout the ageing process.
u Nutrients, bone mass, and fracture risk
Adequate nutrition plays an important role in the development and maintenance of bone structures resistant to usual
mechanical stresses. Many nutrients play a role in optimizing
bone mass. In addition to calcium and vitamin D, other nutrients such as proteins, vitamin C, vitamin K, or other antioxidants can also impact skeletal mass and the risk of fractures.
u Calcium and vitamin D
Calcium and vitamin D are the most commonly studied nutrients in relation to bone mass and the risk of fractures. A
review has shown that interventions including food rich in
either calcium, vitamin D, or a combination of both improve
serum bone markers and BMD and reduce falls.11
Clearly, both calcium and vitamin D contribute to healthy bone
maintenance during ageing, although their relative contribution is still unclear. While most studies found that vitamin D
supplementation improves BMD and serum markers of bone
health; it seems that vitamin D given alone at doses of 10 to
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20 mg per day is not effective in preventing fractures if it is
not accompanied by adequate calcium intake. By contrast,
calcium and vitamin D given together seem to reduce hip fractures, total fractures, and probably vertebral fractures, irrespective of sex, age, or previous fractures.12 It therefore appears that while vitamin D supplementation combined with
coadministration of calcium reduces the rate of falls in older
people, vitamin D alone might not be effective in preventing
hip fracture, vertebral fractures, or any new fracture. For that
reason, it seems that an increase in dietary calcium is necessary to guarantee the effectiveness of vitamin D supplementation on the rate of falls and fractures.
The effect of combined calcium and vitamin D was specifically evaluated by Tang et al13 in a meta-analysis that showed
that calcium and vitamin D treatment was associated with
a 12% risk reduction in all types of fractures and a reduced
rate of bone loss of 0.5% at the hip and 1.29% at the spine.
Moreover, it was found that the fracture risk reduction was
significantly greater (up to 24%) in trials in which the compliance rate was high. The treatment effect was better with calcium doses of 1200 mg or more than with doses of less than
1200 mg and with vitamin D doses of 20 mg or more than with
doses of less than 20 µg per day.
In conclusion, calcium supplementation combined with vitamin D is effective in reducing osteoporosis and fracture risk in
older people. In contrast, vitamin D deficiency causes muscle
weakness, increasing the risk of falls and fractures. Therefore,
because sun exposure is generally reduced in the elderly and
cutaneous synthesis of vitamin D is reduced by ageing,14 patients being treated for osteoporosis should be adequately
supplemented with calcium and vitamin D to maximize the
benefit of treatment.15
u Proteins
In addition to an adequate intake of vitamin D and calcium,
dietary proteins represent key nutrients for bone health, and
thereby function, in the prevention or treatment of osteoporosis. Whereas a gradual decline in caloric intake with age can
be considered as an adequate adjustment to the usual progressive reduction in energy expenditure, the parallel reduction in protein intake is certainly detrimental in maintaining the
integrity and functioning of several systems or organs, including bone mass and skeletal muscle.
As mentioned above, dietary protein is crucial for bone and
muscle development.16 In a large number of studies, a positive relationship between protein intake and bone mineral content (BMC) or BMD has been found, while low protein intake
has been documented in elderly subjects at risk of fragility
fractures, and more so in those who have sustained a hip fracture. In particular, Munger et al17 found that between those in
the highest quartile of protein intake and those in the lowest
quartile, the reduction in the incidence of hip fractures was
171
OSTEOPOROSIS:
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67% and 79% for total and animal protein intake, respectively, representing 1.3 vs 1.0 g protein/kg of body weight per
day. Moreover, recent evidence suggests that increasing protein above the recommended dietary allowance may help to
prevent loss of bone and muscle mass in the elderly. Increased
essential amino acid or protein availability can enhance muscle protein synthesis and anabolism, as well as improve bone
homeostasis in older subjects.18 Thus, in primary or secondary prevention of osteoporosis, protein repletion, by positively influencing both bone and muscle mass and bone and
muscle strength, could contribute to the prevention of falls
and the subsequent occurrence of osteoporotic fractures.
u Vitamin K
The results of studies that focused on the relationship and effects of vitamin K on bone mass and fracture risk are controversial. Therefore, it is difficult to draw a definite conclusion
about the effectiveness of this micronutrient in the prevention
and/or treatment of osteoporosis and osteoporosis-associated fractures.
In observational studies, vitamin K insufficiency is generally associated with lower bone mass and an increased incidence
of hip fracture. Moreover, the findings of a number of crosssectional studies suggest that high vitamin K intake has benefits on bone. However, these findings are not supported by
the results of randomized controlled trials,19 as some important intervention studies have cast some doubts on the benefits of high vitamin K intake on bone health later in life. In fact,
based on the studies described in a review carried out by
Cashman et al,20 it would appear that vitamin K supplementation does not protect against loss of BMD in some skeletal sites such as lumbar spine, mid-distal radius and whole
body in older subjects. However, in other meta-analyses of
randomized controlled trials, vitamin K was shown to be effective in increasing BMD at the lumbar spine but not at the
femoral neck.21 In relation with combined supplementation
programs, it has been shown that those receiving the combination of calcium, vitamin D, and vitamin K had an increase
in BMC and BMD at the radius.11 In another study, the group
taking a supplementation of calcium, magnesium, zinc, vitamin D, and vitamin K showed decreased bone loss at the
femoral neck.22 However, it is difficult to know if this beneficial effect was due to vitamin K supplementation or due to the
well-reported positive influence of calcium and vitamin D on
bone mass. Specific randomized controlled trials are needed
to test the independent effect of vitamin K or the strengthening role of this vitamin.
u Vitamin C
Vitamin C has also been studied in relation to bone mass in
elderly people, although to a lesser extent. Sahni et al23 evaluated the associations of total, supplemental, and dietary
vitamin C intake with BMD at the hip, radius, and spine and
changes in BMD over 4 years. There was a possible protec-
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tive role of vitamin C on bone health among older men; however, null associations were observed in women. The same
authors also evaluated the associations of vitamin C with incident hip fracture and nonvertebral osteoporotic fracture
over a 15- to 17-year follow-up in a cohort of elderly men and
women.24 They found that subjects in the highest tertile of
total and supplemental vitamin C intake had significantly fewer hip fractures and nonvertebral fractures compared with
those in the lowest tertile.
u Other antioxidants
During the ageing process there is an increase in oxidative
stress, which impacts many age-related degenerative processes, such as bone and muscle loss. As the antioxidant defenses are significantly decreased in elderly people, oral supplementation with antioxidant agents may mitigate bone loss
in osteopenic or osteoporotic population,25 while at the same
time improving muscle mass, thereby reducing the risk of falls
and fractures. However, this conclusion is premature given
that the data is so limited.
u Physical activity, bone mass and fracture risk
The promotion of regular physical activity has been advocated as one of the main nonpharmaceutical measures proposed
to older subjects for successful ageing. In this regard, much research has been carried out in order to test the influence and
effects of physical activity and exercise on bone mass and
osteoporotic fractures.
u Physical activity and bone mass
Several cross-sectional studies have found that lifetime physical activity is positively related to bone mass later in life. It has
been shown that in healthy men and women, higher levels of
sporting activity during youth were associated with greater
lumbar spine BMD, and that femoral neck BMD was greater
in subjects who reported regular sports participation over the
previous 20 years and during their whole lifetime.26 On the
other hand, occupational physical activity in the past has also
been positively related to bone mass in senescence, showing that physical activity during adolescence and the young
adult years contributes to the preservation of BMD in adults
and older people.27,28
Not only does lifetime physical activity seem to have positive
associations with bone mass among elderly people, but so
does current physical activity. In a large cohort of elderly women
Bauer et al29 showed that weight-bearing physical activity was
associated with increased BMD. Furthermore, a 2000-kcal/
week increase in vigorous activity (approximately 20 minutes
of jogging per day) was associated with a 4% increase in calcaneal BMD and a 2% increase in distal radius BMD. Bone
geometry of the radius, tibia,30 and hip31 is positively associated with leisure time physical activity in postmenopausal women,
and metacarpal and ultradistal radius BMD correlates with
occupational activity in men.32,33
OSTEOPOROSIS:
AEROBIC TRAINING
FREQUENCY
u 3-4 days/week
DURATION
u 40-60 min
EXERCISE
u Walking + stair-climbing, walking
with loaded belts (10 min)
PROTOCOL TIME
INTENSITY
u 6-12 months
u 70%-85% Max heart rate
Table I. Aerobic-training protocol.
On the other hand, prospective studies have also been carried out to test the impact of maintaining an active lifestyle
throughout life on the bone mass of older adults and elderly
people. Morseth et al34 studied a cohort of adults to find out
whether leisure-time physical activity was associated with
BMD and risk of osteoporosis 22 years later. In both sexes,
those who participated in recreational sports at least 4 hours
per week or those who regularly participated in hard-training
or sports competitions had a higher BMD at both hip and forearm sites than their sedentary peers. Furthermore, the prevalence of osteoporosis decreased with increasing levels of physical activity by 8%, 6%, and 4% for sedentary, moderately
active, and active subjects, respectively.
u Physical activity and fracture risk
Because of the important implications that hip fractures have
in elderly people, most of the studies that evaluated the association between physical activity and fracture risk have focused on the hip. Several authors have tested the importance
of physical activity throughout life in prospective studies with
follow-ups ranging from 4 to 35 years; they found that past
and recent physical activity are important predictors of osteoporotic fractures.8,35,36 In a large cohort of elderly women
Gregg et al37 showed that an increase in total physical activity was associated with a reduced relative risk of hip fracture.
Specifically, very active women (>2201 kcal/week of physical
activity) had a 42% reduction in the risk of hip fractures compared with the least active women (<340 kcal/week).
In contrast, inactivity was associated with a higher risk of fracture; women who sat for at least 9 hours per day had a 43%
higher risk of hip fracture than those who sat for less than 6
hours per day.37 Finally, a recent review has shown that moderate-to-vigorous physical activity is associated with a hip
fracture risk reduction of 45% among men and 38% among
women.38,39
u Specific training programs
Bone-related variables can be increased—or at least the common decline in bone mass during ageing attenuated—by following specific training programs, especially in postmenopausal
women.40
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Because walking is a low-impact form of exercise, most of
the studies that investigated the relationships between BMD
and this type of activity reported no increase in bone parameters after a training program.41,42 However, the fact that aerobic exercise may maintain or slow down the loss of bone
mass in elderly people must be considered an important outcome of this kind of exercise (Table I).
Strength training is one of the most frequent types of exercise
programs applied in order to improve bone mass in elderly
people.40 The increased mechanical stress provided by this
type of training on the bone has been demonstrated as a causal
factor of osteogenesis. Therefore, strength training seems to
be a powerful stimulus for the improvement and maintenance
of bone mass during the ageing process (Table II).43,44 Whereas benefits for the femoral neck, lumbar spine, and radius
have been reported, whole-body BMD does not seem to be
affected by this kind of training program, since none of the
studies showed increments in this parameter.
STRENGTH TRAINING
FREQUENCY
EXERCISE
PROTOCOL TIME
INTENSITY
RESTING TIME
u 3 days/week
u Upper extremities: 4-5 exercises
u Lower extremities: 4-5 exercises
u Trunk: 3 exercises
u 6-12 months
u 3 sets x 5-15 repetitions maximum
u 1-2 min
Table II. Strength-training protocol.
Research shows that combined exercise programs can improve, or at least prevent, bone decline in postmenopausal
women.45,46 However, men seem to be less susceptible to
changes in bone mass, probably because of their higher initial BMD, or even because they may need exercise stimulus
of higher intensity.
Whole-body vibration, which is a type of exercise that uses
high-frequency mechanical stimuli generated by a vibrating
platform and transmitted through the body, seems to be effective in improving BMD at different sites in postmenopausal
women40; however, more research is needed to prove that this
is also the case in men and for bone structure and geometry.47 Moreover, whole-body vibration training appears to have
some extra benefits such as improved balance and a decrease in the number of falls, which are extremely important
in preventing osteoporotic fractures.48 However, the wide differences found between studies in the current literature makes
it difficult to make an in-depth comparison, and it is therefore
difficult to establish which protocol of vibration has a more beneficial effect on bone mass (Table III, page 174).
173
OSTEOPOROSIS:
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WHOLE-BODY VIBRATION
FREQUENCY
DURATION
TYPE OF VIBRATION
PROTOCOL TIME
TRAINING INTENSITY
u 1 days/week - 2 times/day
u 4-20 min
u Vertical vs rotational
u 6-18 months
u Frequency: 12.6-40 Hz
u Amplitude: 0.7-12 mm
Table III. Protocols of whole-body vibration found in the literature.
Summary of findings
Adequate nutrition is of great importance to guarantee optimal development and maintenance of bone structures. Combined calcium and vitamin D supplementation is effective at
preventing osteoporosis as both nutrients help to reduce bone
loss during the ageing process. For best therapeutic effect,
minimum doses of 1200 mg of calcium and 20 mg of vitamin D (for combined calcium plus vitamin D supplementation)
are recommended. In addition to calcium and vitamin D, proteins can also impact skeletal mass and the risk of fractures.
On the other hand, although intake of other nutrients such as
vitamin C, vitamin K, or antioxidants has been associated with
increased bone mass, more research is needed in order to
understand their independent associations with bone-related
variables and osteoporotic fractures.
As well as appropriate nutrition, physical activity and specific
training programs represent key factors for bone health, and
thereby function, in the prevention or treatment of osteoporosis.
Bone mass in older adults and elderly people seems to benefit from present and past physical activity. Sport practice at
the time of bone mass development increases subsequent
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BMD, and more recent sporting activity contributes to the
preservation of bone-related variables. There are two different ways by which physical activity may contribute to a higher bone mass during the ageing process; firstly, those who
were active during youth have a greater BMD later in life; secondly, men and women with high levels of physical activity
during adulthood and senescence experience less bone loss.
Therefore, those men and women who are more active throughout life have a higher bone mass and subsequently a reduced
risk of osteoporosis later in life. Moreover, physical activity appears to be a powerful stimulus to prevent osteoporotic fractures during the ageing process, especially at the hip site, while
an excessive time spent in sedentary activities seems to be a
potential risk factor for developing an osteoporotic fracture.
In addition, specific training programs are useful to ameliorate the decline in bone mass during senescence, especially
in postmenopausal women.
Finally, a combined effect and interaction between physical
exercise and calcium supplementation has been shown in
younger populations,49 and it seems to be more efficacious in
bone development than just exercise or calcium. However, to
our knowledge, the effect on bone mass acquisition of the
interaction between exercise and food intake or specific diets has not been deeply studied in the elderly population; new
studies are therefore needed to test this combined effect during the ageing process.
Conclusion
In conclusion, adequate nutrition and physical activity or specific training programs are good nonpharmacological treatments for preventing the decline in bone mass associated
with ageing and also for the amelioration of osteoporosis and
osteoporotic fractures. n
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increases bone mass in calcium-replete postmenopausal women. J Bone Miner Res. 2001;16:175-181.
44. de Matos O, Lopes da Silva DJ, Martinez de Oliveira J, Castelo-Branco C. Effect of specific exercise training on bone mineral density in women with postmenopausal osteopenia or osteoporosis. Gynecol Endocrinol. 2009;25:616-620.
45. Kemmler W, von Stengel S, Engelke K, Haberle L, Kalender WA. Exercise effects
on bone mineral density, falls, coronary risk factors, and health care costs in older women: the randomized controlled senior fitness and prevention (SEFIP) study.
Arch Intern Med. 2010;170:179-185.
46. Marques EA, Mota J, Machado L, et al. Multicomponent training program with
weight-bearing exercises elicits favorable bone density, muscle strength, and
balance adaptations in older women. Calcif Tissue Int. 2011;88:117-129.
47. Gomez-Cabello A, Gonzalez-Aguero A, Morales S, et al. Effects of a short-term
whole body vibration intervention on bone mass and structure in elderly people.
J Sci Med Sport. 2013 May 24. Epub ahead of print.
48. Gusi N, Raimundo A, Leal A. Low-frequency vibratory exercise reduces the
risk of bone fracture more than walking: a randomized controlled trial. BMC
Musculoskelet Disord. 2006;7:92.
49. Vicente-Rodriguez G, Ezquerra J, Mesana MI, et al. Independent and combined
effect of nutrition and exercise on bone mass development. J Bone Miner Metab. 2008;26:416-424.
Keywords: ageing; bone density; calcium; exercise; fracture; nutrients; osteoporosis; proteins; training; vitamin D
« UN OS SAIN DANS UN CORPS SAIN » : L’IMPORTANCE DE LA NUTRITION,
DE L’ACTIVITÉ PHYSIQUE ET DE LA PRISE EN CHARGE NON MÉDICAMENTEUSE DE L’ OSTÉOPOROSE
Cet article résume et actualise les connaissances concernant l’importance de la nutrition et de l’activité physique sur
la masse osseuse et le risque de fracture. Une bonne nutrition est importante pour garantir un développement optimal et le maintien des structures osseuses. L’association de calcium et de vitamine D est efficace pour prévenir
l’ostéoporose, car elle aide à diminuer la perte osseuse qui intervient au cours du vieillissement. De plus, les protéines
agissent aussi sur la masse squelettique et le risque de fractures, d’autres nutriments comme les vitamines C et K ou
les antioxydants étant aussi associés à l’augmentation de la masse osseuse. D’autres travaux sont cependant nécessaires pour comprendre complètement ces associations. En plus d’une nutrition adaptée, l’activité physique et des
programmes d’entraînement spécifiques sont un autre facteur clé dans la prévention et/ou le traitement de l’ostéoporose. L’activité physique, présente et passée est bonne pour la masse osseuse. La pratique du sport au moment
du développement osseux augmente la densité osseuse et un entraînement sportif plus tard au cours de la vie préserve les caractéristiques osseuses. Ceux qui sont plus actifs au cours de leur vie ont donc une masse osseuse plus
élevée et par conséquent un risque d’ostéoporose diminué plus tard dans leur vie. De plus, l’activité physique est un
stimulus puissant pour prévenir le risque des fractures ostéoporotiques, en particulier au niveau de la hanche. Enfin,
les programmes spécifiques d’entraînement sont utiles pour limiter la perte de la masse osseuse pendant la vieillesse,
en particulier chez les femmes ménopausées.
175
‘‘
OSTEOPOROSIS:
Although the fracture rate is
lower in men, the consequences of
a fracture tend to be more severe
in men than in women, in terms of
both morbidity and mortality, which
is explained only in part by a higher prevalence of comorbidities in
men. As much as one-third of the
burden of hip fractures worldwide, expressed in disability-adjusted life years, and one-third of
the cost of osteoporotic fractures
in Europe result from fractures in
men.”
THE
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MUST
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STOPPED
Osteoporosis is also
a male disease
by J. M. Kaufman and
S . G o e m ae re , B e l g i u m
O
▲
Jean-Marc KAUFMAN
MD, PhD
Stefan GOEMAERE, MD
Unit for Osteoporosis and
Metabolic Bone Diseases
Ghent University hospital
Ghent, BELGIUM
ne in three osteoporotic fractures occur in men; and the consequences
of a fracture in men tend to be more severe than in women. Yet, only
a small minority of men at high risk of fracture are identified and treated. Although there are sex differences in the pathophysiology of osteoporosis — such as in the pattern of bone loss — similarities predominate, which is
also the case for clinical risk factors. According to more traditional diagnostic
criteria, osteoporosis in men can be defined as a femoral neck T-score of –2.5
or less, calculated using the bone mineral density of women aged 20-29 years
from the database of NHANES III (Third National Health And Nutrition Examination Survey) as a reference. Calculation of the 10-year probability of osteoporotic fracture using the FRAX ® algorithm (Fracture Risk Assessment tool)
is a useful approach to identify men at high risk of osteoporotic fracture and
those who are thus most likely to benefit from treatment. Currently approved
drugs for the treatment of osteoporosis in men include the antiresorptive drugs
bisphosphonates and denosumab (only in men receiving androgen deprivation therapy for prostate cancer), the bone-forming agent teriparatide, and
strontium ranelate, a drug with opposite effects on bone resorption and formation. Although the evidence for the efficacy and safety of these drugs in
men is still relatively limited, available data indicate that treatment effects in
men are very similar to those observed in the treatment of postmenopausal
osteoporosis.
steoporosis in men carries a significant burden in terms of morbidity for patients and economic cost for society. Although osteoporosis is clearly more
prevalent in women, it has been estimated that up to one-third or more new
osteoporotic fractures occur in men.1 Nevertheless, although awareness of male
osteoporosis is increasing, osteoporosis remains a disease commonly considered
to be a disease of women. Male osteoporosis is largely underdiagnosed and undertreated, even in those men with a history of fracture, who are at high risk of new
fractures.2-4
O
Prof Jean-Marc Kaufman, Dienst
endocrinologie, Universitair
Ziekenhuis Gent, De Pintelaan 185,
B9000 Gent, Belgium
(e-mail: Jean.kaufman@ugent.be)
176
Epidemiology and burden of male osteoporosis
From adolescence through midlife, the fracture incidence is higher in men than in
women, a trend that is reversed in older age.5 Indeed, although relative bone fragility contributes to the occurrence of fractures in younger men, many fractures result from high-energy trauma related to sports, traffic accidents, or the workplace.
Osteoporosis is also a male disease – Kaufman and Goemaere
OSTEOPOROSIS:
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Progressive bone loss and deterioration of bone biomechanical properties, increased prevalence of comorbidities, and regression of neuromuscular function with an increased propensity to fall, all contribute to an exponential increase in the
incidence of fractures in elderly men, as is the case in elderly
women. However, the age-specific fracture risk in men over
the age of 50 years is lower than in women, and osteoporotic fractures tend to occur on average 5 to 10 years later than
in women, depending on the type of fracture. Men thus have
a similar absolute fracture risk at an older age. Estimates of
the lifetime risk of fracture after age 50 years in men range
between 13% and 25%. This is substantially lower than estimates in women, who have a lifetime risk of fracture of up to
50%. This can be explained by both a lower age-specific fracture incidence and shorter life expectancy in men.6-8
tries and Latin America. However, the hip fracture rate is lower in both women and men in Asian and Latin American populations than in Western populations, and sex differences are
also less marked.7,12-14
The major fractures associated with osteoporosis in men are
fractures of the vertebrae, hip, proximal humerus, and distal
forearm. Other fractures contributing to the burden of osteoporosis in men include fractures of the ribs, sternum, clavicle,
pelvis, and distal femur.6-9 The incidence of hip fractures increases exponentially with advancing age,6 but there are differences in reported fracture incidences between countries.10
In Europe, estimates of the 10-year probability of a hip fracture at age 50 range between 0.1% and 0.6% in men as compared with 0.2% to 1.1% in women. The fracture probability
increases with advancing age in men and women, although
the longer term 10-year probability ultimately decreases in the
oldest old because of limited life expectancy. Hip fractures
typically occur as a consequence of a fall after age 75 years.
Compared with cervical hip fractures, trochanteric fractures
tend to occur in somewhat older men and more often in men
with a history of other fragility fractures.9,10
The operational definition of osteoporosis relies on quantitative assessment of bone mineral density (BMD), usually by dualenergy x-ray absorptiometry (DXA). As initially proposed by
a working party of the WHO (World Health Organization) for
postmenopausal women, osteoporosis is defined as a BMD
that is 2.5 standard deviation or more below the mean BMD
of young women at age of peak bone mass, ie, a T-score
equal to or below –2.5. Since the T-score value is dependent
on the skeletal measurement site and the reference population considered, osteoporosis is now more precisely defined
as a T-score of –2.5 or less at the femoral neck as measured
by DXA, using the average BMD measured in women aged
20-29 years from the NHANES III database (the Third National Health and Nutrition Examination Survey; USA) as a reference.18 This approach was later broadened to also include
men.7,8,19
The incidence of vertebral fracture in men also increases with
age, although less steeply than in women.6,7 Similarly, in men
fracture rates for other fractures resulting from low-energy trauma, such as fractures of the proximal humerus, rib, or pelvis,
also increase with advancing age. The epidemiology of distal
forearm fractures in men differs more markedly from that in
women. Whereas in women the incidence of this type of fracture increases substantially between age 45 and 60 years, with
a plateau (or a limited increase) thereafter, in men the frequency of forearm fracture remains low with hardly any age-related
increase. Nevertheless, distal forearm fractures in men appear
to be associated with a considerable risk for the occurrence
of other osteoporotic fractures, in particular hip fractures.11
Temporal changes in the age-specific incidence of fractures
have been reported—particularly for hip fracture rates—and
there is geographical heterogeneity in these changes. While
the rate of hip fractures in Western populations—which was
increasing at the end of the past century—seems to have stabilized and may even have decreased, incidence rates appear
to be rising in other populations, in particular in Asian coun-
Although the fracture rate is lower in men, the consequences
of a fracture tend to be more severe in men than in women, in
terms of both morbidity and mortality, which is explained only
in part by a higher prevalence of comorbidities in men.9,15,16
As much as one-third of the burden of hip fractures worldwide, expressed in disability-adjusted life years, and onethird of the cost of osteoporotic fractures in Europe result
from fractures in men.17
Relationship of fracture incidence to BMD and
diagnosis of osteoporosis
The relationship between femoral neck BMD—as assessed by
DXA—and fracture risk appears similar in women and men,
with a consistent increase in the relative risk of fracture for each
standard deviation decrease in BMD. In both men and women
this gradient of risk is steeper for the risk of hip fracture than
for the risk of all osteoporotic fractures and is similarly dependent on age.20 Thus, women and men of the same age and with
a same absolute BMD, have a similar risk of fracture. Available
studies suggest that this is the case for both hip and vertebral
fractures.7 These findings constitute the rationale supporting
the use in men of the same operational definition as in women,
ie, a T-score of –2.5 or less, calculated using the mean BMD of
the women aged 20-29 years in NHANES III as a reference.19
SELECTED
BMD
DXA
FRAX®
NHANES III
Third National Health And Nutrition Examination
Survey
177
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Pathophysiology of low bone mass
Clinical risk factors
Adult bone mass is the resultant of the peak bone mass acquired during growth and maturation and the subsequent
bone loss in adulthood. Peak bone mass is largely genetically determined and its optimal acquisition is dependent on
the absence of interfering disease and on optimal exposure to
growth hormone and to estrogens and androgens during puberty.21-23 Trabecular bone loss begins before midlife, continues throughout life, and tends to accelerate in older men at
critical bone sites, ie, at the lumbar spine and femoral neck,
whereas it slows down at other sites such as the distal radius
and tibia. In men, trabecular bone loss results primarily from
trabecular thinning, with a relatively better preservation of trabecular numbers and connectivity than in women.24-26
Major risk factors for fracture in men include older age, a history of prior fracture after age 50 years, and a low BMD, with
further independent contribution provided by additional risk
factors. Many factors are related to impaired bone strength,
whether they directly contribute to bone fragility (eg, excess
glucocorticoids) or merely reflect existing bone fragility (eg,
history of prior low-energy trauma fracture). Other risk factors
contribute to increased exposure of the skeleton to excessive
biomechanical stresses (ie, primarily risk factors for falls). Obviously, some factors may be related to both bone fragility and
the risk of falls (eg, excessive alcohol consumption).
◆ Family history of fracture
Periosteal bone apposition is a continuous process throughout life. Cortical bone loss occurs mainly after age 60 years,
when periosteal apposition no longer compensates for increased endocortical bone resorption. Thus, with aging, the
cross-sectional area of bones tends to increase, while the
cortex becomes thinner as a result of endosteal bone resorption, which is characterized by a process of trabecularization
of the endosteal envelope of long bones. Data from longitudinal studies have consistently shown that the rates of cortical bone loss in elderly men may be considerably more rapid
(0.5% to 1% per year) than previous estimates from crosssectional studies (0.1% to 0.3% per year).7,24,26,27
In elderly men, increased trabecular and cortical bone loss is
accompanied by a modest-to-moderate increase in levels of
the biochemical markers of bone turnover, mostly evident after the age of 60 to 70 years.28 Acquired profound hypogonadism in men results in high bone turnover and accelerated
bone loss.29,30 Androgen effects, mediated through activation
of the androgen receptor, play an important role in the maintenance of adult bone health in men by preserving cancellous
bone and stimulating periosteal bone apposition.
There is, however, ample direct and indirect evidence in both
experimental animals and humans that aromatization of testosterone to estradiol plays a major role in the regulation of bone
homeostasis in males. Estrogen effects, mediated through
activation of estrogen receptor alpha, are required to effectively restrain bone turnover, and there is evidence that threshold levels of (free or bioavailable) estradiol might be required
to limit age-related bone loss in men.22,23,31,32
Other hormonal factors likely to contribute to senile bone loss
are decreased activity of the somatotropic axis, with possible
adverse effects on osteoblastic function, and secondary hyperparathyroidism.9,21,33 The latter increases bone resorption
and cortical porosity and is the consequence of the combined
effects of highly prevalent vitamin D insufficiency, age-related
decrease in the efficiency of intestinal calcium absorption, and
low dietary calcium intake in the elderly.
178
(parents; sibling)
◆ Prior fracture after age 50
years
◆ Anthropometrics and life-
style-related
– Low body weight; low
BMI
– >10% Weight decrease
– Decreased body height
– Smoking
– Excessive alcohol consumption
– Low level physical activity
– Low intake of dairy
products
– Low sun exposure
◆ Secondary osteoporosis*
◆ Medication-related*
◆ Fall-related
– Older age
– Increased incidence of
falls
– Fall in the past year
– Blindness
– Recent vertigo
– Premorbid dysfunction in
the lower limbs
– Decreased quadriceps
muscle strength
– Increased body sway
– Dementia; poor mental
score
– Parkinsonism
– Hemiplegia
Table I. Some clinical risk factors for fracture in men as identified
in epidemiological studies. * See Table II.
Adapted from reference 9: Kaufman and Goemaere. Best Pract Res Clin Endocrinol Metab. 2008;22:787-812. © 2008, Elsevier Ltd.
Epidemiological studies have identified a large number of risk
factors for fracture (Table I), although there is considerable
heterogeneity in reported risk factors among studies. A limited number of clinical risk factors have been validated in metaanalyses involving large numbers of subjects and shown to
contribute to fracture risk estimates independently of BMD.
These include age, history of previous fragility fracture, current glucocorticoid use, current smoking, excessive alcohol
consumption (≥3 units/day), parental history of hip fracture,
low BMI (≤19 kg/m2), and secondary causes of osteoporosis, in particular rheumatoid arthritis.17
FRAX® (Fracture Risk Assessment tool), a computer-based
algorithm, combines these risk factors and patient characteristics (sex, age, height, weight) with or without femoral neck
BMD to calculate the 10-year probability of a hip fracture and
of a major osteoporotic fracture.17
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Clinical presentation
Osteoporosis in men may be “primary,” which includes senile osteoporosis, osteoporosis linked to a specific monogenic
syndrome (eg, osteoporosis-pseudoglioma syndrome), and
“idiopathic” osteoporosis in young men. Osteoporosis may
also be “secondary,” ie, the consequence and epiphenomenon of another disease or its treatment (Table II). Some of the
more common secondary causes of osteoporosis in men include glucocorticoid treatment, alcohol abuse, obstructive
pulmonary disease, hypogonadism, posttransplantation, and
androgen ablation therapy in prostate cancer.7,9,33 The distinction between primary and secondary osteoporosis is not absolute. Indeed, it is not always clear whether an adverse environmental factor can be seen as a mere risk factor modulating
the expression of primary (senile) osteoporosis or rather one
that plays a decisive role in its pathogenesis and should thus
be considered as a secondary cause of osteoporosis.
It has been suggested that in men a larger proportion of patients present with secondary osteoporosis, than is the case
in women.34 Although this may well be the case in clinical practice—eg, in the practice of an endocrinologist or a rheumatologist—this has never been formally established in populationbased epidemiological studies. It is possible that the impression
that there is a larger proportion of secondary osteoporosis
cases in men is biased by the fact that in current clinical practice the rate of referral for bone densitometry is much lower
in asymptomatic men than in asymptomatic women.
In young men with idiopathic osteoporosis, genetically determined deficiency in the acquisition of peak bone mass and
size appears to be the dominant pathogenic presentation—
although increased cortical porosity in those presenting with
vertebral fracture has been reported.35-37 Deficient acquisition
of peak bone mass may also be a predominant presenting
feature in cases of secondary causes of osteoporosis already
present during childhood and adolescence.37 Bone loss with
its attendant deterioration of bone microarchitecture usually
plays a predominant role in secondary and senile osteoporosis. In terms of bone turnover, the picture in male osteoporosis is rather heterogeneous, but levels of the biochemical markers of bone turnover are often less markedly increased than
in postmenopausal osteoporosis.
Management of osteoporosis in men
◆ Strategies
Presently only a small proportion of men at high risk of fracture
are being treated. As is the case in women, there is no generally accepted algorithm for the management of osteoporosis
in men and no validated strategy for systematic osteoporosis
screening. Active case-finding (opportunistic screening) should
thus be encouraged, and focus primarily on the detection and
treatment of those men at high risk of fracture. Whereas treatment decisions in men have largely been based on BMD Tscores and/or occurrence of a prior fragility fracture, it is now
◆ Primary
– Diabetes mellitus
◆ Genetic
◆ Chronic obstructive
pulmonary disease
◆ Idiopathic
◆ Renal insufficiency
◆ Senile
◆ Posttransplantation
◆ Secondary
◆ Rheumatoid arthritis
◆ Immobilization
◆ Neoplastic diseases
◆ Alcoholism
◆ Hypercalciuria
◆ Gastro-intestinal
◆ Hemochromatosis
–
–
–
–
Post-gastrectomy
Post-bariatric surgery
Celiac disease
Primary biliary cirrhosis
◆ Endocrine
–
–
–
–
Hypogonadism
Hyperparathyroidism
Cushing’s syndrome
Hyperthyroidism
◆ Systemic mastocytosis
◆ Medication-related
– Glucocorticoids
– Gonadotropin-releasing
hormone analogues
– Anticonvulsants
– Glitazones
– Chemotherapy
– Antiretroviral therapy
Table II. Some causes of osteoporosis in men.
Adapted from reference 9: Kaufman and Goemaere. Best Pract Res Clin Endocrinol Metab. 2008;22:787-812. © 2008, Elsevier Ltd.
widely accepted that identification of those men most likely
to benefit from treatment can be refined by taking into account additional clinical risk factors.17 Using a stepwise approach, clinical risk factors can also be used to select men for
referral for bone densitometry.7 In this context, integration of
fracture risk probability calculation with the validated FRAX®
algorithm can represent a step forward toward a rational approach to case-finding and treatment decisions.7,17 Nevertheless, it should be noted that taking into account age, history
of fracture, and BMD will capture a substantial part of the fracture risk in men and that the risk of falls is not considered in
FRAX®. As for the latter, there is presently no generally accepted and applied measure of the propensity to fall.19
◆ General measures
Men at moderately increased risk of fracture should be given
lifestyle advice. A balanced diet and daily intake of 1200 mg
calcium, moderate sun exposure, and safe weight-bearing exercise should be encouraged. Excessive alcohol consumption and smoking should be discouraged. All necessary measures to reduce the risk of falls should be taken in elderly and
frail men. This includes a reappraisal of the indications for psychotropic and cardiovascular medication.
Evidence from available randomized trials does not support
systematic supplementation with calcium and/or vitamin D in
elderly men to reduce the fracture risk.38 Nevertheless, supplementation with 500 to 1000 mg calcium (depending on dietary
intake) and 800 to 1000 IU vitamin D (or higher in case of intestinal malabsorption) should be considered in men with deficiencies or at risk of deficiencies (eg, men who are house-
179
OSTEOPOROSIS:
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bound or residing in a home for the elderly, men avoiding milk
products, men on glucocorticoid treatment, men with secondary hyperparathyroidism…). Calcium supplementation,
usually with vitamin D, is an obligatory complement to other
specific pharmacological treatments of osteoporosis, because
these supplements were an inherent part of the treatment regimens validated in clinical trials.
Before initiating a pharmacological treatment for osteoporosis,
patients should be evaluated for secondary causes of osteoporosis as secondary osteoporosis might require a diseasespecific treatment (eg, surgery in primary hyperparathyroidism)
instead of, or in addition to, osteoporosis medication.
◆ Specific pharmacological interventions
It is only recently that the pharmacological armamentarium for
the treatment of osteoporosis in men has expanded considerably.7 All drugs registered for the treatment of osteoporosis
in men have previously been shown to effectively reduce vertebral fracture risk in postmenopausal women, and some of
them have also been shown to reduce the risk of nonvertebral
fractures. The approval of these drugs for use in men was
generally granted on the basis of so-called “bridging” studies,
which assessed the effects of these treatments on a surrogate
end point in men, ie, BMD changes; the data based on the effect of these treatments on fracture rate in men is very limited.7 The approval of these drugs for osteoporosis treatment in
men is based on the assumption that the fact that they have a
similar effect on BMD in men than in postmenopausal women
will also lead to a reduction in fracture risk similar to that previously documented in postmenopausal women. Although
some of the premises on which this assumption is based could
be argued, for a wide range of drugs the effects on BMD in
men were found to be remarkably similar to their effects in
postmenopausal women.7 Moreover, a recent study in osteoporotic men, with fractures as the primary end point, appears
to confirm that the similarity of effects between men and postmenopausal women also applies to the reduction of fracture
risk.39
Antiresorptive treatment with a bisphosphonate is the most
widely applied pharmacological treatment for osteoporosis in
men. Alendronate 10 mg/day was the first drug to be formally
validated for use in men with osteoporosis in a dedicated randomized trial.40 Alendronate-treated men showed an increase
in BMD similar to that previously observed in postmenopausal women. The radiographic vertebral, clinical vertebral, and
nonvertebral fracture risks were numerically reduced, without achieving statistical significance in this study, which was
not powered to assess antifracture efficacy. Risedronate 35
mg/day was also shown to significantly increase BMD in men
with osteoporosis in a dedicated randomized trial.41 Approval
of zoledronic acid for the treatment of osteoporosis in men
was granted on the basis of the findings of the HORIZON Recurrent Fracture Trial (Health Outcomes and Reduced Inci-
180
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dence with Zoledronic Acid ONce yearly Recurrent Fracture
Trial) in subjects with recent low-trauma hip fracture, of which
about one-third were men. In this study, an annual infusion of
5 mg zoledronic acid reduced the risk of clinical fractures by
35% in the overall population compared with placebo, and
there was no significant treatment-by-sex interaction.42 In a
subgroup analysis, the BMD increase in men was statistically
similar to that in women with hip fracture.43 Recently, in a trial
in which reduction of vertebral fracture risk was the primary
efficacy criterion, annual infusion of 5 mg zoledronic acid was
shown to significantly reduce the incidence of vertebral fracture in men with osteoporosis.39 The observed fracture reduction was of similar magnitude to that previously reported for
the treatment of postmenopausal osteoporosis with zoledronic acid.
Bone-forming treatment with daily subcutaneous injection of
teriparatide was approved for the treatment of osteoporosis
in men based on a bridging study in men with low BMD in
which changes in vertebral BMD was the primary efficacy criterion.44 Both the pattern of changes in biochemical markers
of bone turnover and the substantial increases in BMD following daily subcutaneous injection of 20 mg teriparatide compared with placebo were very similar to those observed with
this treatment in postmenopausal osteoporosis. A follow-up
study of 18 months including the majority of the patients from
the initial trial—which was terminated early (11 months of total treatment exposure)—showed that treatment withdrawal
resulted in rapid bone loss and that point estimates for the
reduction in vertebral fracture rates for the overall treatment
and posttreatment follow-up were similar to those observed
in postmenopausal women in the larger core trial.45 Given the
rapid decrease in BMD after termination of treatment with teriparatide, it seems advisable that treatment with teriparatide
should be followed by subsequent administration of an antiresorptive treatment so that the achieved BMD gains can be
maintained.45 However, concomitant treatment with alendronate and teriparatide was found to be less effective at increasing BMD than teriparatide alone.46
Strontium ranelate has opposite effects on bone resorption
and bone formation and thus a mode of action that differs
from that of both bisphosphonates and teriparatide. It was
granted an indication for use in men with severe osteoporosis
based on a bridging study with changes in BMD as the primary efficacy criterion.47 This study showed that the effect on
BMD of daily oral administration of 2 g strontium ranelate in
men with osteoporosis is similar to the effect of this treatment
on BMD in postmenopausal osteoporotic women, in whom
strontium ranelate treatment was shown to significantly reduce
the risk of vertebral and nonvertebral fractures.
◆ Hypogonadism and role of testosterone treatment
Hypogonadal men have a combined androgen and estrogen
deficiency and adult men with acquired profound hypogo-
OSTEOPOROSIS:
nadism have accelerated bone loss and are at increased fracture risk. As discussed above, it is now well documented that
estrogens are important for preservation of bone health in adult
men. In aging men, increased bone loss and fracture risk may
be more closely related to relative estrogen deficiency than to
the age-related decline in androgen levels.31,48
The beneficial effect on BMD of the pharmacological treatments of osteoporosis in men discussed above has been
shown to be largely independent of the prevailing serum (free)
testosterone levels. Moreover, it has been shown that bisphosphonates and the selective estrogen receptor modulator raloxifene can prevent bone loss in severe hypogonadism
induced by androgen deprivation therapy for prostate cancer.49 More recently, it has also been shown that treatment with
the antiresorptive drug denosumab, a monoclonal antibody
that binds and neutralizes receptor activator of nuclear factor kB ligand (RANKL) activity, increases BMD and reduces
fracture risk in men receiving androgen deprivation therapy for
nonmetastatic prostate cancer.50
For obvious reasons there have been no randomized controlled trials assessing the long-term effects on the skeleton
of testosterone substitution treatment in frankly hypogonadal
younger men, but available observational data suggest favorable effects on BMD.22,23 Nevertheless, the effect of testosterone treatment on fracture risk is unknown and the longterm risk-benefit ratio of prolonged treatment in elderly men
has not been established. In this context, hypogonadism in
elderly men requires a conservative approach. Testosterone
treatment in the elderly should be considered only if serum
testosterone—measured in the morning with a well validated
method—is found to be really low and the patient presents
with unequivocal signs and symptoms of hypogonadism.
Osteoporosis is neither a sufficient nor a specific indication
for testosterone treatment. In hypogonadal men with a high
fracture risk, one of the several validated treatments of osteoporosis in men should be initiated, and use of such a treatment
should be considered even in those men with a high fracture
risk who are also treated with testosterone for symptomatic
hypogonadism.19
Conclusions
One in three fragility fractures occur in men, and osteoporotic fractures in men represent a significant burden for public
health, both in terms of personal suffering and societal cost.
Because fractures in men tend to occur at an older age than
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in women, and because older men are more subject to comorbidity, fractures in men often affect frail individuals with potentially dramatic consequences.
Although awareness of osteoporosis in men among health
professionals has improved, only a small minority of men at
high risk of fracture are being treated. Therefore, active casefinding with a stepwise approach based on assessment of clinical risk factors complemented with bone densitometry when
appropriate should be encouraged. The FRAX® algorithm,
which is used to assess the 10-year probability of osteoporotic fracture, is a useful tool for case-finding and identification
of those men most likely to benefit from treatment. Men at
high risk of fracture should be investigated for possible secondary causes of osteoporosis, even though, contrary to common belief, it has not been established that, compared with
women, a larger proportion of osteoporosis cases in men are
secondary. Although there are sex differences in some aspects
of the pathophysiology of osteoporosis, such as in the pattern
of age-related bone loss, similarities between men and women
tend to predominate overall. In this regard, the major role of estrogens for maintenance of skeletal health in men deserves
to be mentioned. Also, the major clinical risk factors for fracture are the same in men and in women.
In men at high risk of fracture, general preventive measures—
including the prevention of falls—should be given the necessary attention. Calcium and vitamin D supplements are an integral part of all pharmacological treatment regimens aimed
at reducing fracture risk. The current level of evidence regarding the efficacy and safety of osteoporosis treatments in men
is lower than for the treatment of postmenopausal osteoporosis, with the evidence mainly based on BMD changes as a surrogate clinical efficacy criterion and little data on fracture reduction in men. Nevertheless, there are now several drugs
registered for use in men, ranging from antiresorptive treatment with bisphosphonates, bone-forming treatment with teriparatide, and strontium ranelate with its opposite effects on
bone resorption and formation. Antiresorptive treatment with
denosumab is indicated for treatment in men receiving androgen deprivation therapy treatment for prostate cancer. The
data available on the effects of this broad range of drugs indicate that treatment responses in men are very similar to the
treatment effects previously described in postmenopausal
women. Testosterone treatment should be reserved to symptomatic hypogonadal men with really low serum testosterone:
osteoporosis is neither a sufficient nor a specific indication for
testosterone treatment. n
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References
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Undertreatment of osteoporosis in men with hip fracture. Arch Intern Med.
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3. Papaioannou A, Kennedy CC, Ionnadis G, et al. The osteoporosis care gap in
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4. Curtis JR, McClure LA, Delzell E, et al. Population based fracture risk assessment and osteoporosis treatment disparities by race and gender. J Gen Intern
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6. Sambrook P, Cooper C. Osteoporosis. Lancet. 2006;367:2010-2018.
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8. Bilezikian JP. Osteoporosis in men. J Clin Endocrinol Metab.1999;84:3431-3434.
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skeletal fragility in Caucasian men. J Bone Miner Res. 2004;19:1933-1944.
12. Cooper C, Cole ZA, Holroyd CR, et al. Secular trends in the incidence of hip and
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fractures in Japan. J Orthop Sci. 2010;15:737-745.
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of hospitalised fractures in Sweden. Osteoporos Int. 2005;16:222-228.
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between men and women. Orthop Clin North Am. 2006;37:611-622.
17. Kanis JA; World Health Organization Scientific Group. Assessment of osteoporosis at the primary health care level. Sheffield, UK: WHO Collaborating Centre,
University of Sheffield. 2008. Available at: http://www.shef.ac.uk/FRAX/.
18. Kanis JA, McCloskey EV, Johansson H, Oden A, Melton LJ, Khaltaev N. A reference standard for the description of osteoporosis. Bone. 2008;42:467-475.
19. Kanis JA, Bianchi G, Bilezikian JP, et al. Towards a diagnostic and therapeutic consensus in male osteoporosis. Osteoporos Int. 2011;22:2789-2798.
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fractures. J Bone Miner Res. 2005;20:1185-1194.
21. Seeman E. The pathogenesis of bone fragility in women and men. Lancet.
2002;359:1841-1850.
22. Riggs BL, Khosla S, Melton LJ. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev. 2002;23:279-302.
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24. Riggs BL, Melton III LJ, Robb RA, et al. Population-based study of age and sex
differences in bone volumetric density, size, geometry, and structure at different
skeletal sites. J Bone Min Res. 2004;19:1945-1954.
25. Khosla S, Riggs BL, Atkinson EJ, et al. Effects of sex and age on bone microstructure at the ultradistal radius: a population-based non-invasive in vivo assessment. J Bone Min Res. 2006;21:124-131.
26. Riggs BL, Melton III LJ, Robb RA, et al. A population-based assessment of
rates of bone loss at multiple skeletal sites: evidence for substantial trabecular
bone loss in young adult women and men. J Bone Min Res. 2008;23:208-214.
27. Duan Y, Beck TJ, Wang XF, et al. Structural and biomechanical basis of sexual
dimorphism in femoral neck fragility has its origins in growth and aging. J Bone
Min Res. 2003;18:1766-1774.
28. Szulc P, Kaufman JM, Delmas P. Biochemical assessment of bone turnover
and bone fragility in men. Osteoporos Int. 2007;18:1451-1461.
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Endocrinol Metab. 1989;69:523-527.
30. Mittan D, Lee S, Miller E, et al. Bone loss following hypogonadism in men with
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31. Van Pottelbergh I, Goemaere S, Kaufman JM. Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes
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32. Gennari L, Nuti R, Bilezikian JP. Aromatase activity and bone homeostasis in
men. J Clin Endocrinol Metab. 2004;89:5898-5907.
33. Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors
and the skeleton. Endocrine Reviews. 2008;29:535-559.
34. Ebeling PR. Clinical practice. Osteoporosis in men. N Engl J Med. 2008;358:
1474-1482.
35. Van Pottelbergh I, Goemaere S, Zmierczak H, De Bacquer D, Kaufman JM.
Deficient acquisition of bone during maturation underlies idiopathic osteoporosis in men: evidence from a three-generation family study. J Bone Min Res.
2003;18:303-311.
36. Ostertag A, Cohen-Solal M, et al. Vertebral fractures are associated with increased cortical porosity in iliac crest bone biopsy of men with idiopathic osteoporosis. Bone. 2009;44:413-417.
37. Ferrari S, Bianchi ML, Eisman JA, et al. Osteoporosis in young adults: pathophysiology, diagnosis and management. Osteoporosis Int. 2012;23:2735-2748.
38. Moyer VA; U.S. Preventive Services Task Force. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force
recommendation statement. Ann Intern Med. 2013;158:691-696.
39. Boonen S, Reginster JY, Kaufman JM, et al. Fracture risk and zoledronic acid
therapy in men with osteoporosis. N Engl J Med. 2012;367:1714-1723.
40. Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med. 2000;343:604-610.
41. Boonen S, Orwoll ES,Wenderoth D, Stoner KJ, Eusebio R, Delmas PD. Onceweekly risedronate in men with osteoporosis: results of a 2-year, placebo-controlled, double-blind, multicenter study. J Bone Miner Res. 2009;24:719-725.
42. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical
fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809.
43. Boonen S, Orwoll E, Magaziner J, et al. Once-yearly zoledronic acid in older
men compared with women with recent hip fracture. J Am Geriatr Soc. 2011;
59:2084-2090.
44. Orwoll ES, ScheeleWH, Paul S, et al. The effect of teriparatide [human parathyroid hormone (1–34)] therapy on bone density in men with osteoporosis. J Bone
Miner Res. 2003;18:9-17.
45. Kaufman JM, Orwoll E, Goemaere S, et al. Teriparatide effects on vertebral fractures and bone mineral density in men with osteoporosis: treatment and discontinuation of therapy. Osteoporos Int. 2005;16:510-516.
46. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM. The effects
of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl
J Med. 2003;349:1216-1226.
47. Kaufman JM, Audran M, Bianchi G, et al. Efficacy and safety of strontium ranelate
in the treatment of osteoporosis in men. J Clin Endocrinol Metab. 2013;98:
592-601.
48. Mellstrom D, Vandenput L, Mallmim H et al. Older men with low serum estradiol and high serum SHBG have an increased risk of fractures. J Bone Miner
Res. 2008;23:1552-1560.
49. Body JJ, Bergmann P, Boonen S, et al. Management of cancer treatment-induced bone loss in early breast and prostate cancer: a consensus paper of
the Belgian Bone Club. Osteoporos Int. 2007;18:1439-1450.
50. Smith MR, Egerdie B, Hernandez Toriz N, et al. Denosumab in men receiving
androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361:
745-755.
Keywords: bone mineral density; epidemiology; fracture risk; male; osteoporosis; risk factor; therapy
182
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L’OSTÉOPOROSE
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FRACTURE
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EST AUSSI UNE MALADIE MASCULINE
Une fracture ostéoporotique sur trois survient chez l’homme et leurs conséquences tendent à être plus sévères que
chez la femme. Il n’y a encore qu’une petite minorité d’hommes à haut risque de fractures qui sont identifiés et
traités. Malgré les différences liées au sexe dans la physiopathologie de l’ostéoporose (comme dans le modèle de la
perte osseuse), les ressemblances prédominent, ce qui est aussi le cas pour les facteurs cliniques de risque. Selon
des critères diagnostiques plus traditionnels, l’ostéoporose chez l’homme peut être définie par un T-score au niveau
du col fémoral ≤ – 2,5, calculé d’après la densité minérale osseuse des femmes âgées de 20 à 29 ans comme référence [à partir de la base de données de la NHANES III (third National Health And Nutrition Examination Survey)].
Calculer la probabilité à 10 ans d’avoir une fracture ostéoporotique à l’aide de l’algorithme FRAX ® (Fracture Risk
Assessment tool) est utile pour identifier les hommes dont le risque de fracture ostéoporotique est élevé et ceux qui
ont donc le plus de chance de bénéficier d’un traitement. Dans les traitements actuellement mis sur le marché pour
le traitement de l’ostéoporose masculine, on trouve les antirésorptifs, bisphosphonates et denosumab (seulement
chez ceux traités par traitement anti-androgènes pour le cancer de la prostate), le tériparatide, ostéoformateur, et le
ranélate de strontium qui agit sur la formation et la résorption osseuses. Les données d’efficacité et de sécurité d’emploi pour ces médicaments sont encore relativement limitées chez l’homme mais celles disponibles montrent que les
effets thérapeutiques sont très proches de ceux observés dans le traitement de l’ostéoporose post-ménopausique.
183
‘‘
OSTEOPOROSIS:
IOF’s Capture the Fracture
campaign sets the standard for
best practice in FLSs, measures
performance, and engages the
health care community toward FLS
implementation. Providing the
opportunity for FLSs to benchmark their systems and showcase
achievements on the Capture the
Fracture Web-based map creates
a visual representation of progress
made and areas for development.
This, in turn, is a tool to influence
policy change in secondary fracture prevention.”
THE
FRACTURE
CASCADE
MUST
BE
STOPPED
Capture the Fracture:
an IOF initiative to break the
cycle of fragility fracture
b y K . Å ke s s o n , S w e d e n
on behalf of the IOF Capture the Fracture Steering
Committee and the IOF Fracture Working Group*
*IOF Capture the Fracture Steering Committee: Åkesson K (Sweden), Mitchell PJ (New
Zealand), McLellan AR (Glasgow, UK), Javaid MK (Oxford, UK), Stenmark J (Switzerland),
Pierroz DD (Switzerland), Kyer C (Switzerland), and Cooper C (Oxford, UK).
IOF Fracture Working Group: Åkesson K (chair), Boonen S† (Leuven, Belgium), Brandi
ML (Florence, Italy), Cooper C (Oxford, UK), Dell R (Downey, USA) co-opted, Goemaere S
(Gent, Belgium), Goldhahn J (Basel, Switzerland), Harvey N (Southampton, UK), Hough S
(Cape Town, South Africa), Javaid MK (Oxford, UK), Lewiecki M (Albuquerque, USA),
Lyritis G (Athens, Greece), Marsh D (London, UK), Napoli N (Rome, Italy), Obrant K (Malmo,
Sweden), Silverman S (Beverly Hills, USA), Siris E (New York, USA), and Sosa M (Las
Palmas de Gran Canaria, Spain).
Kristina Åkesson, MD, PhD
Chair, Capture the Fracture
Campaign, International
Osteoporosis Foundation
Department of Orthopaedics
Malmo, Skåne University
Hospital, Lund University
SWEDEN
Kristina Åkesson,
Jan Waldenströmsgata 35,
Skåne University Hospital,
20502 Malmö, Sweden
(email:kristina.akesson@med.lu.se)
I
ntroduction: There is a worldwide care gap in secondary fracture prevention. Up to 80% of fragility fracture patients are neither assessed nor treated for the likely underlying cause, osteoporosis. This is despite the widespread availability of diagnostic technology and effective medications that can
reduce fracture risk by as much as 30%-70%. However, there is reason for optimism: the coordinator-based model of care for secondary fracture prevention — known as FLS — has been proven to reduce fractures and is cost effective. The problem is that too few FLSs have been implemented worldwide.
Methods: Capture the Fracture aims to reduce secondary fractures by facilitating the implementation of FLSs on a global level. To set standards for FLSs,
the Best Practice Framework has been developed; it serves as a benchmark
for existing FLSs and as a guidance tool for developing FLSs. Engaging the
medical community, Capture the Fracture offers a Best Practice Recognition
program where FLSs can submit their service to The International Osteoporosis Foundation for evaluation against the Best Practice Framework. The FLS
is then included in the Showcase of Best Practice and plotted on Capture the
Fracture’s Web site map, which displays participating FLSs and their respective achievement level. To influence change, the map can be used as a visual representation of FLSs available worldwide, their achievements, as well as
the areas for opportunity and development in secondary fracture prevention.
Results: Capture the Fracture is successfully achieving its mission to generate interest in FLSs and to set effective, achievable benchmarks for FLS implementation worldwide. In less than a year, participation has grown from just
10 to over 65 FLSs, with the first 23 FLSs to have their results posted on the
map in early 2014.
184
Capture the Fracture: an IOF initiative to break the cycle of fragility fracture – Åkesson
OSTEOPOROSIS:
THE
FRACTURE
CASCADE
MUST
BE
STOPPED
etting standards in health care and being measured per year. These immense costs are the ‘tip of the iceberg’ as
against standards are powerful tools to improve patient they do not reflect the complete socioeconomic burden of
management. Unfortunately, worldwide standards of care fractures. This includes loss of quality of life and productivity,
to prevent secondary fractures are appallingly low. Studies the burden on family caregivers or the need for long-term nurshave shown that 80% of fragility fracture patients are neither ing care in many previously independent seniors, and, all too
assessed nor treated for osteoporosis or falls risk—even though often, premature death following hip fracture.
they are twice as likely to suffer additional fractures as compared with people who have not suffered a fracture. This is The situation is predicted to worsen as the population ages.
evidence of a serious care gap. Too often, vulnerable fragility In China, the US $1.6 billion spent on hip fracture care in
2006 is set to rise to US $12.5 billion by 2020 and US $265
fracture patients are sent home with a cast to treat their brobillion by 2050.1 Similar changes are projected across Asia,
ken bone, all-the-while remaining unaware that osteoporosis
may be the underlying cause. Statistics show that, if left un- Latin America, and the Middle East. In the EU the number of
treated, these patients are highly
men and women with osteoporolikely to fracture again. By missing
sis is expected to increase by 23%
The International Osteoporosis
the opportunity to respond to the
from 2010 to 2025, when an estiFoundation (IOF) has launched
first fracture, health care systems
mated 33.9 million people will have
Capture the Fracture: a global campaign
around the world are failing to preosteoporosis.
to facilitate the implementation of fracture
vent the second and subsequent
liaison services (FLSs) for secondary
fractures.1
u Fracture begets fracture
fracture prevention. IOF experts have comThe underlying cause of fragility
piled evidence that supports FLS implefractures is osteoporosis, a chronic
However, there is reason to be opmentation as the single most important
disorder that weakens bones and
timistic. Health care systems in many
leaves them easily susceptible to
countries have tackled this care gap
thing that can be done to directly improve
fracture, even after a minor bump or
and have created systems that propatient care and reduce spiraling fracturefall. Nature has provided us with an
vide a clinical pathway to “capture
related health care costs. IOF calls upon
opportunity to systematically identithe fracture” in efforts to prevent
those responsible for fracture patient care
fy a significant proportion of individsecondary fractures. These systems,
throughout the world to implement FLSs
uals that will suffer fragility fractures
often called fracture liaison servicas a means to “capture the fracture” and
in the future: the well-recognized
es (FLSs), have a dedicated posthelp millions of patients decrease their risk
phenomenon that fracture begets
fracture coordinator of care at their
of subsequent fractures.
fracture.
heart. Experts with the International
Osteoporosis Foundation (IOF) have
Those patients that suffer a fragility fracture today are much
compiled evidence that supports FLS implementation as the
single most important thing that can be done to directly im- more likely to suffer fractures in the future; in fact, they are
twice as likely to fracture as their peers who haven’t fractured.
prove patient care and reduce spiraling fracture-related health
From the obverse view, we have known for three decades that
care costs.
almost half of patients presenting with hip fractures have preTo this end, IOF has launched Capture the Fracture: a global viously broken another bone.
campaign to facilitate the implementation of FLSs for secondary fracture prevention. The campaign sets the standard for u The care gap
FLS implementation, provides a platform for successful FLSs There is a postfracture care gap in secondary prevention for
to showcase their successes on a global stage, and promotes
fragility fracture patients around the world. Consistently, studFLSs in developing systems. This article briefly highlights the
ies of health care systems indicate that fragility fracture paneed for FLS standards and provides the details of the Cap- tients fail to be tested for osteoporosis, remain untreated for
ture the Fracture campaign.
osteoporosis, are not given prescriptions for osteoporosisspecific medication, are not diagnosed nor documented, and
go on to break another bone.
Building the case
u Size of the problem
Worldwide, a fragility fracture is estimated to occur every 3
seconds. This amounts to almost 25 000 fractures per day or
SELECTED ABBREVIATIONS AND ACRONYMS
9 million per year.1 The human suffering associated with these
FLS
fracture liaison service
common, serious injuries is immense and the financial costs
IOF
International Osteoporosis Foundation
are staggering. The cost of fragility fractures to health care
BPF
Best Practice Framework
systems in the European Union is in excess of €37 billion each
2
year, and in the United States is approximately US $20 billion
S
185
OSTEOPOROSIS:
THE
FRACTURE
CASCADE
MUST
Over 80% of fracture patients are never offered screening for
future fracture risk and/or treatment for osteoporosis, despite
the fact that there is a broad spectrum of effective pharmacological agents that can reduce the risk of future fractures by
as much as 30% to 70%. These medicines have been shown
to reduce fracture rates among individuals with and without
fracture history, and even among those that have already suffered multiple fractures. Moreover, a large proportion of fractures are associated with a fall and interventions to reduce falls
are not commonly applied.
Regrettably, by missing the opportunity to respond to the first
fracture, health care systems around the world are failing to
prevent the second and subsequent fractures—leaving pa1. Lead clinician/local champion
2. Secondary care clinicians—consultant orthopedic surgeon,
consultant radiologist, consultant in care of the elderly
medicine
3. Nurse specialists/nurse practitioners (if appointed)
4. Primary care clinicians
5. Patient representatives
6. Allied health professionals—physiotherapists
7. Public health consultants
8. Service manager
9. Community pharmacists
10. Prescribing management team member
Table I. A typical multidisciplinary working group for osteoporosis
service development.
After reference 3: Marsh et al. Osteoporos Int. 2011;22:2051-2065. © 2011,
International Osteoporosis Foundation and National Osteoporosis Foundation.
Ortho
Osteoporosis
Exercise
COORDINATOR
Lab
Falls
DXA
GP
Figure 1. Coordinated model of care.
Abbreviations: DXA, dual-energy x-ray absorptiometry; GP, general practitioner;
ortho, orthopedic specialist.
© International Osteoporosis Foundation.
186
STOPPED
tients open to a future of suffering and debility. Numerous audits of secondary preventive care show that the majority of
fragility fracture patients never learn about the underlying cause
of their fracture, nor receive treatment to prevent it from happening again.
u Fracture liaison services
Some governments and health care providers have recognized the opportunity for secondary fracture prevention by
creating policies and reimbursement criteria that support treatment of osteoporosis for patients presenting with fragility fractures. They have done so to improve the quality of care for
those at risk of suffering future fractures and because such
strategies have been shown to be highly cost-effective by
many agencies responsible for resource allocation.
One such strategy is implementation of FLSs—coordinatorbased, postfracture models of care for secondary fracture prevention. An FLS is designed to (i) close the care gap for fracture patients, the majority of whom are never offered screening
and/or treatment for osteoporosis; (ii) enhance communication between health care providers by providing a care pathway for the treatment of fragility fracture patients.
An FLS is made up of a committed lead clinician, a multidisciplinary team of stakeholders—and at the core sits a dedicated coordinator (Table I, Figure 1).3 This person, often a nurse,
medical registrar, outpatient case manager, or in some cases a physician, is the key central figure who identifies and
connects the fragility fracture patient with the appropriate care
pathways for diagnosis and treatment of osteoporosis.
In a coordinated model most—if not all—patients presenting
to the health care system with a fragility fracture can be identified, linked with assessment protocols, and properly referred
on for appropriate treatment and follow-up care (Figure 2).
Communication is a key component of the coordinator’s job,3
as he/she should ensure the patient and the multidisciplinary
team of stakeholders are kept in the loop about diagnosis,
treatment, and follow-up.
Patient
Education
BE
u Cost savings
We know health care systems vary throughout the world; thus,
cost structures vary from country to country. For this reason
more analysis is needed to establish the cost-effectiveness
and cost-benefit of FLSs in the different health care systems.3
However, with this said, some of the more established FLSs
that have analyzed their systems have demonstrated cost savings, for example:
u An FLS in Canada managing 500 patients was able to prevent 3 fractures (1 hip) for every 100 patients seen, with a net
hospital cost saving of US $46 235 in the first year.1,3
u The cost-effectiveness demonstrated in a Glasgow (UK)
FLS found that for every 1000 patients assessed, 18 fractures
(11 hip) could be prevented with a net savings of US $34 700.3
OSTEOPOROSIS:
THE
FRACTURE
CASCADE
Osteoporosis
treatment
Orthopedic
trauma
New fracture
presentation
Orthopedics
in-patient ward
Emergency
department
and x-ray
Falls risk
assessment*
1. FLS identifies
fracture patients
2. FLS assessment
Emergency
department
Exercise
programme
Education
programme
Out-patient
fracture clinic
Comprehensive communication of management plan to
GP supported by fully integrated FLS database system
* Older patients, where approprate, are identified and referred for falls assessment
u In Australia, an FLS showed that the additional costs to operate the FLS were offset by a reduction in fractures, which
led to an overall discounted cost increase of US $1343 per
patient over 10 years.1
u The Kaiser Healthy Bones Program in the USA demonstrated that in 2006 there was a 37% reduction in the hip fracture rate of their patients resulting in an estimated savings
of US $30.8 million.
u Why Capture the Fracture?
All fragility fractures are sentinel events that should prompt
the health care system to “capture the fracture” and assess
these patients for treatment for secondary prevention of fractures.3 FLSs help to prevent patients from falling through the
care gap, as has been successfully demonstrated by exemplar
systems in Australia, Canada, Singapore, The Netherlands,
United Kingdom, and United States of America.1 The problem is that there are too few established FLSs.3 In the European Union, just 8 countries (30%) estimated the availability
of FLSs in just 10% or more of their hospitals.4 In the AsiaPacific region, just 4 of 16 countries estimated that FLSs were
available in only a minority of the hospitals in their countries.5
The case for FLS implementation is clear, and IOF strives to
make FLSs a common care model for secondary fracture prevention globally. Capture the Fracture does just this—it sets
the standard for FLS implementation, provides a platform for
successful FLSs to showcase successes on a global stage,
and promotes FLSs in developing systems.The next section
provides more detail about the Capture the Fracture campaign, its components, and how to get involved.
Capture the fracture campaign6
MUST
BE
STOPPED
Figure 2. The operational structure
of a UK-based fracture liaison service.
Abbreviations: FLS,
fracture liaison service;
GP, general practitioner.
After reference 1:
Akesson and Mitchell.
World Osteoporosis
Day Report. 2012.
Available at http:
//www.iofbonehealth.
org/capture-fracture-report-2012. ©2012, International Osteoporosis Foundation.
ing committee, led by Professor Kristina Åkesson (Sweden),
brought the campaign to life with an official launch at the IOF
European Congress on Osteoporosis and Osteoarthritis in
March 2012. A year later, at the Rome IOF/ESCEO congress
in April 2013, the campaign’s key initiatives commenced with
the publication of the Best Practice Framework in the second
position paper, Capture the Fracture: A Best Practice Framework and global campaign to break the fragility fracture cycle.6
Concurrently, IOF launched the Capture the Fracture Web
site and kicked off the campaign’s main program.
u Goals
Hosted on the online portal, www.capturethefracture.org,
Capture the Fracture is structured to cover three overarching goals:
Provide internationally endorsed standards for best
practice in secondary fracture prevention
u Best Practice Framework (for FLSs)
u Best Practice Recognition program
u Showcase of Best Practices
Facilitate change at a local and national level
u Implementation guides and toolkits
u Mentoring programs
u Facilitated grant support for developing systems
Raise awareness of FLSs for preventing secondary
fractures
u An on-going communications plan
u Anthology of literature, worldwide surveys and audits
u International coalition of partners and endorsers
u Background
Capture the Fracture was born from the IOF Position Paper
supporting FLS implementation, Coordinator-based systems
for secondary prevention in fragility fracture patients,3 and was
later the subject of World Osteoporosis Day 2012.1 A steer-
u Capture the Fracture’s main program
In order to raise awareness and influence change toward FLS
implementation, Capture the Fracture seeks to engage its
target audience: the medical community and policy makers.
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Essential
1) Patient
identification
Aspirational
Definition
Level 1
Level 2
Level 3
Fracture patients
are identified to
enable delivery of
secondary fracture
prevention
Patients
are identified but no
patient tracking
system exists
Patient tracking
system exists
Patient tracking
system exists
and is subject to
independent
review
Capture the Fracture’s main program does this through an
interactive process that evaluates and showcases FLSs on
a worldwide map that is hosted on the Capture the Fracture
Web site. First, to enable the evaluation of the effectiveness
of an FLS, standards for best practice were developed and
published as the Best Practice Framework. Second, FLSs are
encouraged to apply for evaluation through the Best Practice
Recognition program. Third, the FLS is plotted on the global
map as part of the Showcase of Best Practices. In the end,
this interactive process engages the FLSs globally, and creates a visual map of the services available as well as the areas
of opportunity for FLS development.
u Best Practice Framework
Setting the global standard of care for fracture patients, Capture the Fracture has developed the Best Practice Framework
(BPF), which is a tool that defines the essential and aspirational
building blocks necessary to implement a successful FLS. The
BPF can be found on the Capture the Fracture Web site at
http://www.capturethefracture.org/framework-breakdown.
Figure 3.
One of the 13
standards of the
Capture the
Fracture Best
Practice Framework.
© International
Osteoporosis
Foundation.
The BPF has been developed with cognizance that the scope
of an FLS—and the limits of its function and effectiveness—
may be constrained by the nature of health care infrastructure in the country of origin. To this end, the 13 standards were
built to be adaptable to the individual systems and procedures that are currently in place within the varying health care
systems.
“The Best Practice Framework will provide a basis for secondary prevention throughout Europe and worldwide.”
Professor Cyrus Cooper, United Kingdom
u Best Practice Recognition
Putting the BPF into action, FLSs are encouraged to apply for
Best Practice Recognition and have their system evaluated
against the BPF (Figure 4) and recognized on Capture the
Fracture’s interactive Web-based map (Figure 5).
Standard
Level 1
Level 2
Level 3
1. Patient identification
Presented as a set of 13 standards, the aims of the BPF are to:
u Empower change: the BPF empowers clinical champions
and health care administrators to evaluate their health system’s service of secondary fracture prevention in the context
of globally-endorsed standards.
u Provide recognition and fine-tuning: the BPF offers leaders of established FLSs an objective tool to identify where their
service delivers optimal care—and to be recognized internationally for excellence—and shows how the delivery and scope
of care could be refined to further improve outcomes.
u Provide guidance: for those health care systems that are
yet to establish an FLS, the BPF describes the essential and
aspirational elements of service delivery and so can inform the
business planning process for new FLSs in a very specific way.
2. Patient evaluation
3. Post fracture
assessment timing
4. Vertebral fracture
5. Assessment guidelines
6. Secondary causes of
osteoporosis
7. Fails prevention
services
8. Multifaceted health
risk-factors
9. Medication initiation
10. Medication review
The BPF is both achievable and ambitious. Some of the BPF
standards address aspects essential to an FLS, while others
are aspirational. Additionally, within each standard are three
achievement levels: bronze, silver, or gold (Figure 3). Structuring the BPF in this manner enables recognition of FLSs that
have achieved the most essential elements, while leaving room
for improvement toward implementing the aspirational elements. Additionally, it allows FLSs to be recognized, without
having to reach the highest level of care in each category.
188
11. Communication
strategy
12. Long-term
management
13. Database
Figure 4. Sample evaluation of a fracture liaison service against
the Best Practice Framework.
© International Osteoporosis Foundation.
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Step 1
Step 2
Step 3
Step 4
FLS submits
application
FLS is plotted on the map
while in review
Achievement level
is assigned
FLS is recognized on the
Capture the Fracture map
FLS submits
application through
Capture the Fracture
Web site
FLS is plotted on the map
with a green marker while the
application is reviewed
http://capturethefracture.
org/themes/capture/images/
2013-capturethefractureapplication-form.pdf
The Best Practice
Framework and
the application are
both used as guides
to assign an
achievement level
FLS is recognized on the
Capture the Fracture Web site
map with a gold, silver, or
bronze star
Unclassified
Bronze
Silver
Gold
Figure 5. Steps to achieve Capture the Fracture Best Practice Recognition. © International Osteoporosis Foundation.
Here is how it works: The FLS completes an online application through the Web-based questionnaire which gathers information about the FLS and the secondary fracture prevention services provided. IOF plots the FLS on the map with a
green star indicating that the FLS is under review; meanwhile,
IOF assesses the FLS services to determine if they correspond
to the Best Practice Framework. A level of recognition is then
assigned across four key fragility fracture patient groups—hip
fractures, other inpatient fractures, outpatient fractures, vertebral fractures—and organizational characteristics, and feedback is provided to the FLS in the form of a summary profile.
Applicants achieving Best Practice Recognition will be recognized on the Capture the Fracture Web site’s interactive map
with a gold, silver, or bronze star indicating their location, program showcase, and summary of performance against the BPF.
The Best Practice Recognition program accepts applications
from coordinator-based systems of care that are multidisciplinary in scope. The FLS can serve either inpatient or outpatient facilities, or both. FLSs at any stage of development
are encouraged to apply—be it a long-standing FLS looking
to showcase their services or a developing FLS looking for
guidance. As this is a global program, FLSs anywhere in the
world are encouraged to participate.
u Showcase of best practices
Recognizing excellence, FLS applicants are showcased on
Capture the Fracture’s Web site map. FLSs around the world
are demonstrating interest, and participation has grown from
10 to 65 sites from the program initiation in March 2013 through
to December 2013 (Figure 6, page 190). Early in 2014, the first
23 FLSs to complete the program will be recognized on the
map with their respective gold, silver, or bronze star and highlights about their achievements. The map is not only a venue
for FLSs to showcase achievements, but it is also a platform
to show support of, and create awareness about, FLS imple-
mentation worldwide. As the map becomes more and more
populated with FLS “stars” a visual message will be revealed
about the services available, as well as the gaps and opportunities for FLS development. This information will become invaluable to policy makers and health care systems alike when
considering secondary fracture prevention initiatives.
u Complimenting campaign initiatives
Supporting the Best Practice Framework, the Best Practice
Recognition program and the Showcase of Best Practices are
additional initiatives to achieve the Capture the Fracture aims
of facilitating change and raising awareness of FLSs.
u Facilitating change at a local and national level
The Capture the Fracture Web site provides links to resources
related to FLSs and secondary fracture prevention. These include FLS implementation guides, national toolkits and slide
kits which have been developed for some countries. As new
resources become available, the Web site will serve as a portal for the sharing of materials to support the growth of FLSs
in institutions and countries. Further supporting the establishment of FLSs, Capture the Fracture will organize a localityspecific mentoring program between sites that have achieved
Best Practice Recognition and those systems that are in early stage development. Additionally, IOF intends to develop a
grant program to aid clinical systems around the world that
require financial assistance to establish FLSs.
u Raising awareness of FLS for preventing
secondary fractures
A feature of the Capture the Fracture Web site is a Research
Library that organizes the world’s literature on secondary fracture prevention into an accessible format. This includes sections on care gaps and case finding; assessment, treatment
and adherence; and health economic analysis. To progress
the implementation of FLSs, IOF has undertaken to establish
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December 12, 2013
65
Figure 6. Screen shot of Capture the Fracture’s map of best practices. © International Osteoporosis Foundation.
an international coalition of partners who participate in and
endorse the campaign. Finally, IOF is actively communicating
and promoting Capture the Fracture to demonstrate how global FLS implementation is closing the care gap. As awareness
about FLSs spans the globe and more facilities adopt the
model, changes to policy and reimbursement systems can be
created to support establishment of new FLSs.
“Worldwide, there is a large care gap that is leaving millions
of fracture patients at serious risk of future fractures. Capture
the Fracture hopes to close this gap and make secondary fracture prevention a reality.”
John A. Kanis, President, IOF
Get involved/call to action
Approximately half of all people who have had one osteoporotic fracture will have another, yet 80% of fragility fracture patients are neither assessed nor treated for osteoporosis. This
gap in care is a missed opportunity to prevent future fractures—
including hip fractures, which can be reduced up to 25% with
prior osteoporosis treatment. Coordinator-based models of
care, or FLSs, are a proven and cost-effective solution to “capture the fracture” and offer patients diagnosis and treatment,
thus reducing the chance of future fractures. The problem is
that there are too few established FLSs. To change this on
190
a global level, IOF’s Capture the Fracture campaign sets the
standard for best practice in FLSs, measures performance,
and engages the health care community toward FLS implementation. Providing the opportunity for FLSs to benchmark
their systems and showcase achievements on the Capture the
Fracture Web-based map creates a visual representation of
progress made and areas for development. This, in turn, is a
tool to influence policy change in secondary fracture prevention. Providers, politicians, and patients drive change. n
IOF welcomes involvement in Capture the Fracture and
invites you to:
Visit www.capturethefracture.org to:
u Submit your FLS and get on the map
u Join the coalition of partners
u Endorse the campaign
Be active in your country:
u Advocate for FLS implementation
u Share your national guidelines with us
u Spread the word to scientific communities
u Encourage existing FLSs to participate in Capture the
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References
1. Åkesson K, Mitchell P. Capture the Fracture a global campaign to break the
fragility fracture cycle. International Osteoporosis Foundation World Osteoporosis Day Report. 2012. Available at http://www.iofbonehealth.org/capturefracture-report-2012. Accessed December 12, 2013.
2. Hernlund E, Svedbom A, Ivergard M, Compston J, et al. Osteoporosis in the
European Union: Medical Management, Epidemiology and Economic Burden
Arch Osteoporos 2013. A report prepared in collaboration with the International
Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical
Industry Associations (EFPIA). Arch Osteoporos. 2013;8:136. Epub Oct 11.
3. Marsh D, Åkesson K, Beaton DE, et al; IOF CSA Fracture Working Group. Co-
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ordinator-based systems for secondary prevention in fragility fracture patients.
Osteoporos Int. 2011;22:2051-2065.
4. Kanis JA, Borgstrom F, Compston J, et al. SCOPE: a scorecard for osteoporosis
in Europe. Arch Osteoporos. 2013;8:144. Epub Sep 13
5. Mithal A, Ebeling, P; International Osteoporosis Foundation. The Asian Pacific
Regional Audit: Epidemiology, costs & burden of osteoporosis in 2013. Available
at http://www.iofbonehealth.org/data-publications/regional-audits/asia-pacificregional-audit. Accessed December 12, 2013.
6. Åkesson K, Marsh D, Michell PJ, et al; IOF Fracture Working Group. Capture the
Fracture: a Best Practice Framework and global campaign to break the fragility
fracture cycle. Osteoporos Int. 2013;24(8):2135-2152.
Keywords: Best Practice Framework; Capture the Fracture; IOF; secondary fracture prevention
« CAPTURER LA FRACTURE » : UNE INITIATIVE DE L’IOF
(INTERNATIONAL OSTEOPOROSIS FOUNDATION) POUR BRISER LE CYCLE DE LA FRACTURE
DE FRAGILITÉ
Introduction : Il existe une insuffisance des soins de prévention secondaire des fractures sur le plan mondial. Chez
plus de 80 % des patients ayant eu une fracture de fragilité, la cause probable, l’ostéoporose, n’est ni évaluée, ni traitée, en dépit de la large disponibilité de technologies diagnostiques et de traitements efficaces qui pourraient réduire
le risque de fracture de plus de 30 à 70 %. L’optimisme reste cependant de mise : les FLS, définis comme un modèle
de soins pour la prévention secondaire des fractures reposant sur un coordonnateur, permettent de réduire le nombre
de fractures avec un rapport coût-efficacité favorable. Le problème, c’est qu’il y a trop peu de FLS dans le monde.
Méthodes : La campagne « Capture the Fracture » (Capturer la Fracture) a pour but de réduire l’incidence des fractures secondaires en facilitant la création de FLS au niveau mondial. Un « Best Practice Framework » (Cadre des Pratiques Exemplaires) a été instauré pour établir des standards pour les FLS ; il sert de référence aux FLS existants et
d’aide pour les améliorer. La campagne « Capture the Fracture » cherche à impliquer la communauté médicale via
un programme de « Best Practice Recognition » (Reconnaissance des Pratiques Exemplaires) grâce auquel les FLS
peuvent s’adresser à l’IOF (International Osteoporosis Foundation – Fondation Internationale contre l’Ostéoporose)
pour être évalués par rapport au « Best Practice Framework ». Les FLS sont ensuite inclus dans une « Vitrine de Pratiques Exemplaires » (Showcase of Best Practice) et reportés sur la carte du site Internet de « Capture the Fracture »,
qui montre les FLS participants et les niveaux respectifs atteints. Pour encourager le changement, la carte peut être
utilisée pour donner une représentation visuelle des FLS dans le monde, et montrer leurs réalisations ainsi que les
domaines susceptibles d’amélioration et de développement dans la prévention des fractures secondaires.
Résultats : La campagne « Capture the Fracture » a réussi à susciter l’intérêt pour les FLS et à mettre en place des
normes de qualité efficaces et réalisables pour leur mise en œuvre dans le monde. En moins d’1 an, la participation
s’est accrue de juste 10 à plus de 65 FLS, les 23 premiers ayant posté leurs résultats sur la carte début 2014.
191
‘‘
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…the current BMD screening
procedures do not identify the majority of younger postmenopausal
women who subsequently experience a fracture. These facts underscore the need for identification
of specific risk factors that should
be monitored in addition to BMD
for a more aggressive clinical management of osteoporosis in early
postmenopausal women. Early
intervention would enable these
women to maintain or increase
their bone mass and thereby reduce their fracture risk.”
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Secondary fracture
prevention is good, avoiding
the first fracture, better still
b y M . L . B ra n d i , I t a l y
O
Maria Luisa BRANDI, MD, PhD
Full Professor of Endocrinology
Department of Surgery and
Translational Medicine
University of Florence
Florence, ITALY
steoporosis will continue to be a growing burden as the population
keeps getting older. Although awareness of osteoporosis is increasing, osteoporosis remains largely underdiagnosed and undertreated.
In recent years, several guidelines have been developed for the diagnosis, prevention, and treatment of osteoporosis. Diagnostic tools, mainly based on densitometric measurement, are widely available and today efforts are being made
to design specific tools for risk assessment based on the specific characteristics of a given population. Also, the usefulness of physical activity, calcium
intake, and vitamin D administration as key players in preventing bone loss in
the elderly has been fully demonstrated. Several drugs with different mechanisms of action on bone remodeling have been developed in the past two
decades, all being able to prevent the risk of fracture. All of this, together with
the recognized burden of the “fracture cascade,” makes it imperative to put in
place interventions aiming to prevent the first fracture (primary prevention).
However, osteoporosis drug reimbursement is mostly limited to preventing
the fracture(s) that follow the first fracture (secondary prevention). But this
recommendation is not followed by doctors, as in the majority of fracture cases the corresponding best practices are not applied. This article looks at how
best to use diagnosis, risk assessment, prevention, and management of osteoporosis in primary prevention so as to avoid the first fracture.
steoporosis, literally “porous bone,” is a metabolic bone disorder characterized by fragile bone, with consequent fractures that occur spontaneously
or as a result of minor trauma. However, even though the disease has been
recognized for many years, the conceptual description of postmenopausal osteoporosis was formulated only less than 20 years ago by the World Health Organization (WHO), as a condition characterized by reduced bone mass, disruption of bone
architectural features, and an increased risk of fracture.1 The WHO Report made
it possible through the measurement of a quantifiable diagnostic measurement—
bone mineral density (BMD)—to screen for osteoporosis in postmenopausal women,
recognizing bone fragility as a defined condition affecting over 75 million people in
Europe, the United States, and Japan.1 The operational definition of osteoporosis
is based on the standard deviations (SDs) by which an individual’s femoral hip BMD,
measured by dual energy x-ray absorptiometry (DXA), differs from the mean value
expected in young healthy subject of the same sex (T-score). In men and women,
osteoporosis is diagnosed if the T-score is less than or equal to –2.5 SD.2 This does
O
Professor Maria Luisa Brandi,
Department of Surgery and
Translational Medicine, University
of Florence, Viale Pieraccini 6,
50139 Florence, Italy
(e-mail: marialuisa.brandi@unifi.it)
192
Secondary fracture prevention is good, avoiding the first fracture, better still – Brandi
OSTEOPOROSIS:
not preclude the use of measurements at other skeletal sites
by different technologies in clinical practice. Because the values of BMD in the young healthy population are normally distributed and bone loss occurs with advancing age, the prevalence of osteoporosis increases with age; this was shown in
Sweden, where approximately 6% of men and 21% of women
aged between 50 and 84 years were classified as having osteoporosis.3
Although the diagnosis of osteoporosis relies on the quantitative measurement of BMD, a variety of nonskeletal factors
contribute to the risk of low energy fracture.4 In analogy with
other multifactorial chronic diseases, such as hypertension,
a distinction needs to be made between the use of BMD for
diagnosis and for risk assessment. Thus, FRAX® (Fracture Risk
Assessment tool), a computer-based algorithm was developed to calculate the 10-year probability of major osteoporotic fracture (hip, clinical spine, humerus, or wrist fracture) and
the 10-year probability of hip fracture (http://www.shef.ac.
UK/FRAX).5,6 The use of clinical risk factors—age, body mass
index, prior fragility fracture, parental history of hip fracture, current tobacco smoking, ever use of long-term oral glucocorticoids, rheumatoid arthritis, other causes of secondary osteoporosis, and alcohol consumption—improves the sensitivity
of fracture prediction without having any adverse effects on
specificity.6 As fracture probability is characterized by marked
geographic differences, FRAX® is calibrated to those regions
where the epidemiology of fractures and death is known.7
Burden of disease
The worldwide estimated annual number of common osteoporotic fractures in men and women is of more than 8.9 million—approximately 1000 per hour.8 In Sweden, the remaining lifetime risk of sustaining a major osteoporotic fracture at
the age of 50 years is 46.4% in women and 22.4% in men,
with the vast majority of osteoporotic fractures occurring in elderly women.8 The worldwide incidence of hip fracture shows
large differences and this is probably true also for other fragility fractures, with a greater variation among regions than between sexes within a country.8
THE
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In 2010, the total monetary osteoporosis burden in the EU5
(France, Germany, Italy, Spain, UK) was estimated at €29.3
billion, with approximately 70% of the total costs incurring in
individuals older than 74 years.8 The burden of fractures, expressed as the sum of total costs and the value of Quality Ad-
MUST
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justed Life Years (QALYs), was estimated at €736 billion in the
EU5, with a financial burden for osteoporosis exceeding that
of migraine, stroke, multiple sclerosis, and Parkinson’s disease.8
Osteoporosis is a major noncommunicable disease and is set
to increase markedly in the future. The ultimate goal of osteoporosis management is to reduce the risk of future fractures;
but is every effort put in place to act against this epidemic? The
answer is no, as only a minority of patients at high fracture risk
are identified and treated.10,11 There is therefore an urgent need
to assess best practices in the prevention and treatment of
osteoporosis.
Levels of prevention of osteoporotic fractures
In the last twenty years, there have been enormous advances
in our understanding of the many factors that contribute to
fracture risk, and in elucidating the genetic, molecular, and cellular mechanisms that regulate bone metabolism, growth, and
involution during the course of life. Based on this knowledge,
we now have the ability to identify in a more efficient and timely manner those individuals that have a high fracture risk, and
thus be in the position to start them on preventive strategies
that have been proven to be effective in reducing the risk of
fracture.
The different levels of osteoporosis prevention are usually defined based on the reimbursement policy for antifracture drugs,
with primary and secondary prevention being the pharmacological intervention taking place before and after a fragility
fracture, respectively. However, when aiming to reduce the impact of bone fragility, we should consider factors other than
just pharmacological therapy, including a healthy lifestyle. It is
therefore urgent to define levels of intervention for bone fragility.
Primary prevention
Any intervention applied to the general population, independently of evaluation of the fracture risk
Secondary prevention Diagnosis in at-risk population through
BMD and/or fracture risk algorithms
Tertiary prevention
The global burden of osteoporosis can be quantified by disability-adjusted life years (DALYs). In the year 2000 the worldwide
DALYs lost for common osteoporotic fractures was 5.8 million,
accounting for 0.83% of the global burden of noncommunicable diseases.8 Due to the increased longevity in developed
and underdeveloped countries, the frequency of osteoporotic fractures is increasing in several regions and it is expected
that it will more than quadruple over the next 25 years.9
CASCADE
Treatment of patients who suffered
one or more fragility fracture(s)
Table I. Levels of prevention for fragility fractures.
In an attempt to redefine the prevention of low trauma fractures in absolute terms, we should consider three levels of
action: primary, secondary, and tertiary prevention (Table I).12
Primary prevention should encompass all the interventions
used in the general population in order to reduce the fracture
risk in an individual. These typically include adequate daily
calcium intake, regular physical activity, adequate circulating
concentrations of vitamin D, avoiding smoking, and limiting
alcohol intake. The aim of secondary prevention should be the
early recognition of an individual’s fracture risk in at-risk populations (ie, postmenopausal and secondary osteoporosis).
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Measurement of BMD and FRAX® risk calculation are classical approaches used to quantify the fracture risk. Tertiary prevention would be for patients who have already sustained one
or more fragility fractures. These patients should be assisted
with pharmacological, surgical, and rehabilitation measures.
While there are significant quantitative data available to indicate that primary prevention is possible for osteoporosis and
fragility fractures, as with other common chronic diseases, it
may not be easy—nor quick—to reach this goal. This should
not discourage us from taking a path that could lead to important results in the future by starting to educate the younger
population today (ie, it is estimated that a 5% increase in
bone at the end of bone development could translate into a
30% reduction of all fracture events in old age).13 However, despite the clear value of a healthier lifestyle in the primary prevention of osteoporosis, large population studies aiming to
show the efficacy and economic efficiency of this approach
are still lacking.
Considering the availability of both clinical and instrumental
diagnostic tools for the recognition of the risk of fragility fractures, it should be possible to apply this knowledge to secondary prevention measures. The measurement of BMD is the
only aspect of fracture risk that can be readily measured in
clinical practice, and forms the cornerstone for the general
management of osteoporosis, being used for diagnosis, risk
prediction, the selection of patients for treatment, and monitoring of patients on treatment.14 However, worldwide differences exist among different countries on the availability of DXA,
regarding its reimbursement and the practical use of densitometry measurements for drug reimbursement.8 Even though
the current version does not incorporate fall-related risk factors (fall being a well-recognized strong risk factor), FRAX®
is a well-validated tool that can be easily applied in clinical
practice, widening the access to the assessment of fracture
risk. Its application in clinical practice means that intervention thresholds should be based on fracture probability.8 It is
clear that primary medicine needs to have a key role in the
battle against fractures by contributing to the identification of
subjects at risk.
While tertiary prevention is considered a necessary intervention, only a small number of the patients that are hospitalized
for a fragility fracture are offered an appropriate diagnostic and
SELECTED
BMD
DXA
EPIC
FRAX®
DALY
QALY
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Early Postmenopausal Intervention Cohort study
disability-adjusted life year
quality-adjusted life year
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therapeutic path after discharge, in spite of the high risk of recurrence that is typical in these patients.15 On the other hand,
less than half of the patients that start a pharmacological treatment adhere to their medical and therapy regimen after one
year, thus generating unacceptable system inefficiency and
nullifying the chance of a cost-effective intervention.16 These
two issues may seem simple; however, they share the need for
a common approach from a cultural and organizational point
of view, through the development of true “Fracture Units” to
avoid the fragmentation of interventional measures. General
practitioners may be in the best position to plan a therapeutic
regimen and motivate their patients to adhere to the chosen
medication.
These are interesting observations because they present a
different perspective of osteoporosis prevention strategies.
However, as indicated in national and international guidelines,
pharmacological intervention is “primary” when treatment is
prescribed to patients before the first fragility fracture and
“secondary” when the patients have already experienced a
spontaneous or low-trauma fracture. The question is: would
it not be preferable to intervene prior to the occurrence of a
fragility fracture? Examples of early intervention will be discussed below.
Prevention and treatment of osteoporosis during
early postmenopause
One of the most important health issues for women entering
the menopause is the threat of the development of osteoporosis and the consequent fractures, as it has been estimated
that the average woman will lose up to 10% of her bone mass
during the first 5 years of the menopause. Women commonly
experience a phase of rapid bone loss that begins approximately 2 to 3 years before cessation of menses and continues for up to 3 or 4 years postmenopause.17 Although many
factors are known to be associated with osteoporotic fractures, a large number of women do not have their bone density tested and few are prescribed therapy. Consequently, several women do not receive a diagnosis of osteoporosis until a
fracture occurs.
To further complicate this scenario, a number of findings clearly suggest that the current BMD screening procedures do not
identify the majority of younger postmenopausal women who
subsequently experience a fracture.18 These facts underscore
the need for identification of specific risk factors that should be
monitored in addition to BMD for a more aggressive clinical
management of osteoporosis in early postmenopausal women.
Early intervention would enable these women to maintain or
increase their bone mass and thereby reduce their fracture
risk.
Nonpharmacological treatment options should be used as
first-line intervention in low-risk patients and in conjunction with
therapy in high-risk patients. For many years, hormone ther-
OSTEOPOROSIS:
apy was viewed as an appropriate strategy for the prevention
of postmenopausal bone loss. However, because the risks of
adverse events outweigh the potential benefits, prolonged
use of hormonal therapy is no longer recommended.19
In recent years, new treatment strategies have become available to prevent and treat osteoporosis.20 Subanalyses within controlled clinical trials have shown that all the antifracture
drugs are effective for the treatment of osteoporosis in postmenopausal women of all ages, with all drugs showing improvements in BMD and bone turnover markers.7 Moreover,
in the EPIC study (Early Postmenopausal Intervention Cohort
study), the largest and longest randomized controlled trial
examining the effects of an antifracture drug in the prevention of postmenopausal osteoporosis, alendronate effectively
normalized bone resorption and increased and maintained
BMD over 6 years.21 Using BMD scores, rates of bone turnover, and risk-based diagnostic criteria as part of the decision
to initiate therapy may allow for the identification of an early
postmenopausal patient population that would benefit from
preventive therapy.22,23
It is well recognized that it is never too late to initiate treatment to prevent fractures in postmenopausal women. Similarly, it is never too early in the postmenopause to evaluate
women for bone loss and advise them on the steps to take
to prevent the decline in bone mass and bone quality that
increases their risk of future osteoporosis and fragility fractures.
Prevention of fragility fractures in secondary
osteoporosis
Secondary osteoporosis represents an important area in the
clinical management of bone mass loss, as several conditions
are the cause of osteoporosis and fragility fractures (Table II).
Treatment with glucocorticoid therapy is a common cause of
osteoporosis and is associated with substantial morbidity. Although awareness of the condition has grown in recent years,
it remains underdiagnosed and undertreated. Glucocorticoidinduced osteoporosis is characterized by distinct features,
such as acute bone loss and early fracture risk, emphasizing
the importance of primary pharmacological intervention.24
Although a number of interventions for the management of
glucocorticoid-induced osteoporosis have been evaluated,
fracture reduction has not been a primary prevention end point
in any study and data are only available as secondary end
points or as safety data.25 Oral glucocorticoid use is one of the
clinical risk factors included in the FRAX® algorithm, since its
effect on fracture risk is partially independent of BMD.26 It is
foreseeable that the estimation of fracture probability in glucocorticoid-treated individuals will be performed using FRAX®.
Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition causing
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Disorders
◆ Endocrine disorders
◆ Osteoarticular disorders
◆ Kidney failure
◆ Hematologic disorders
◆ Cancer
◆ Gastrointestinal disorders
◆ Immobilization
◆ Neurological disorders
◆ Genetic disorders
MUST
BE
STOPPED
Drugs
◆ Glucocorticoids
◆ Calmodulin-calcineurin
phosphatase inhibitors
◆ Thyroid hormone
suppressive therapy
◆ LHRH agonists
◆ Aromatase inhibitors
◆ Heparin
◆ Neuroleptics
◆ Anticonvulsants
◆ Methotrexate
◆ Aluminum
◆ Antacids
◆ Lithium
◆ Exchange resins
◆ Saccharated ferric oxide
◆ Sodium fluoride
◆ PPAR agonists
(ie, rosiglitazone)
Table II. Causes of secondary osteoporosis.
Abbreviations: LHRH, luteinizing hormone–releasing hormone; PPAR, peroxisome
proliferator–activated receptor.
secondary osteoporosis. Estrogen and androgen deprivation
therapy in hormonal-responsive cancers, such as tumors of
the breast and prostate, are recognized causes of reduced
BMD and of increased fractures.27-30 These pharmacological
complications are associated with an important morbidity and
with a largely compromised quality of life. To preserve bone
and reduce this morbidity, effective therapies,31,32 with a highly favorable risk-benefits ratio are available. However, in contrast to what happened for the recognition of glucocorticoidinduced osteoporosis, reimbursement of the drugs used in
primary pharmacological prevention is not universally recommended for antihormonal therapies.
Conclusions
The development of FRAX® promises to change the manner
in which we target the treatment of osteoporosis from a BMDbased approach to a fracture probability–based one. Using
intervention thresholds based on absolute fracture probability
means that age will not limit evaluation. The trend toward a
risk-factor assessment approach to treating patients for osteoporosis is likely to draw attention to a cohort of subjects
with normal or osteopenic BMD values. Further research into
the efficacy of osteoporosis drugs for reducing the fracture risk
in these patients is needed to determine more precisely the
subset of patients in whom treatment will be most effective. n
Acknowledgements. This work was supported through an unrestricted
grant (to MLB) from F.I.R.M.O. Fondazione Raffaella Becagli.
195
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THE
FRACTURE
CASCADE
MUST
BE
STOPPED
References
1. World Health Organization. Assessment of fracture risk and its application to
screening for postmenopausal osteoporosis. Technical Report Series 843. Geneva, Switzerland: World Health Organization; 1994.
2. Kanis JA, McCloskey EV, Johansson H, Oden A, Melton LJ 3rd, Khaltaev N. A
reference standard for the description of osteoporosis. Bone. 2008;42:467-475.
3. Kanis JA, Johnell O, Oden A, Jonsson B, De Laet C, Dawson A. Risk of hip fracture according to the World Health Organization criteria for osteopenia and osteoporosis. Bone. 2000;27:585-590.
4. Kanis JA; WHO Scientific Group. Assessment of osteoporosis at the primary
health-care level. Technical Report. Sheffield, UK: WHO Collaborating Centre,
University of Sheffield and World Health Organization; 2008.
5. World Health Organization. Assessment of osteoporosis at the primary health
care level. Geneva, Switzerland: World Health Organization;2008. Available at:
www.who.int/chp/topics/rheumatic/en/index.html. Accessed December12, 2013.
6. Kanis JA, Oden A, Johnell O, et al. The use of clinical risk factors enhances the
performance of BMD in the prediction of hip and osteoporotic fractures in men
and women. Osteoporos Int. 2007;18:1033-1046.
7. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster J-Y. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2013;24:23-57.
8. Strom O, Borgstrom F, Kanis JA, et al. Osteoporosis: Burden, health care provision and opportunities in the EU. Arch Osteporos. 2011;6:59-155.
9. Cooper C, Cole Z, Holroyd C, et al. Secular trends in the incidence of hip and
other osteoporotic fractures. Osteoporos Int. 2011;22:1277-1288.
10. Giangregorio L, Papaioannou A, Cranney A, Zytaruk N, Adachi JD. Fragility fractures and the osteoporosis care gap: An international phenomenon. Semin
Arthritis Rheum. 2006;35:293-305.
11. Nayak S, Roberts MS, Greenspan SL. Factors associated with diagnosis and
treatment of osteoporosis in older adults. Osteoporos Int. 2009;20:1963-1967.
12. Ministero della Salute. Appropriatezza diagnostica e terapeutica nella prevenzione delle fratture da fragilità da osteoporosi. Quaderni del Ministero della Salute 4. Rome, Italy: Ministero della Salute; 2010.
13. Pampaloni B, Bartolini E, Barbieri M, et al. Validation of a food-frequency questionnaire in the assessment of calcium intake in schoolchildren aged 9-10 years.
Calcif Tissue Int. 2013;93:23-38.
14. Kanis JA, Gluer CC. An update on the diagnosis and assessment of osteoporosis with densitometry. Osteoporos Int. 2000;11:192-202.
15. Piscitelli P, Parri S, Brandi ML. Antifracture drugs consumption in Tuscany Region before the Target Project: A valuable model for the analysis of administrative database. Clin Cases Miner Bone Metab. 2012;9:76-79.
16. Compston JE, Seeman E. Compliance with osteoporosis therapy is the weakest link. Lancet. 2006;368:973-974.
17. Recker R, Lappe J, Davies K, Heaney R. Characterization of perimenopausal
bone loss: A prospective study. J Bone Miner Res. 2000;15:1965-1973.
18. Sanders KM, Nicholson GC, Watts JJ, et al. Half the burden of fragility fractures
in the community occur in women without osteoporosis. When is fracture prevention cost-effective? Bone. 2006;38:694-700.
19. Writing Group for the Women’s Health initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;
288:321-333.
20. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: Now and the future. Lancet.
2011;377:1276-1287.
21. McClung MR, Wasnich RD, Hosking DJ, et al. Prevention of postmenopausal
bone loss: Six-year results from the early postmenopausal intervention cohort
study. J Clin Endocrinol Metab. 2004;89:4879-4885.
22. Epstein S. Is treatment of early postmenopausal women with bisphosphonate
justified? Int J Clin Pract. 2007;61:963-971.
23. Delaney MF. Strategies for the prevention and treatment of osteoporosis during
early postmenopause. Am J Obstet Gynecol. 2006;194:S12-S23.
24. Rizzoli R, Adachi JD, Cooper C, et al. Management of glucocorticoid-induced
osteoporosis. Calcif Tissue Int. 2012;91:225-243.
25. Compston J, Reid DM, Boisdron J, et al. Recommendations for the registration
of agents for prevention and treatment of glucocorticoid-induced osteoporosis:
An update from the Group for the Respect of Ethics and Excellence in Science.
Osteoporos Int. 2008;19:1247-1250.
26. Lekamwasam S, Adachi JD, Agnusdei D, et al. An appendix to the 2012 IOFECTS guidelines for the management of glucocorticoid-induced osteoporosis.
Arch Osteoporos. 2012;7:25-30.
27. Chen Z, Maricic M, Bassford TL, et al. Fracture risk among breast cancer survivors: Results from the Women’s Health Initiative Observational Study. Arch
Intern Med. 2005;165:552-558.
28. Kanis JA, McCloskey EV, Powles T, Paterson AH, Ashley S, Spector T. A high
incidence of vertebral fracture in women with breast cancer. Br J Cancer.1999;
79:1179-1181.
29. Morote J, Morin JP, Orsola A, et al. Prevalence of osteoporosis during long-term
androgen deprivation therapy in patients with prostate cancer. Urology. 2007;69:
500-504.
30. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med. 2005;352:154-164.
31. Rizzoli R, Body JJ, De Censi A, Reginster JY, Piscitelli P, Brandi ML. Guidance
for the prevention of bone loss and fractures in postmenopausal women treated with aromatase inhibitors for breast cancer: An ESCEO position paper. Osteoporos Int. 2012;23:2567-2576.
32. Rizzoli R, Body JJ, Brandi ML, et al; International Osteoporosis Foundation
Committee of Scientific Advisors Working Group on Cancer-Induced Cancerassociated bone disease. Cancer-associated bone disease. Osteoporos Int.
2013;24:2929-2953.
Keywords: antifracture agent; fragility fracture; osteoporosis; primary prevention
PRÉVENIR
LES FRACTURES SECONDAIRES C’EST BIEN, ÉVITER LA PREMIÈRE FRACTURE, C’EST ENCORE MIEUX
La population allant en vieillissant, l’ostéoporose sera un fardeau de plus en plus lourd. Malgré la sensibilisation croissante à l’ostéoporose, celle-ci demeure sous-diagnostiquée et sous-traitée. Ces dernières années, son diagnostic,
sa prévention et son traitement ont fait l’objet de plusieurs recommandations. Des outils diagnostiques, principalement basés sur l’ostéodensitométrie, sont largement disponibles et les efforts actuels portent sur la conception d’outils spécifiques d’évaluation du risque adaptés aux caractéristiques particulières d’une population donnée. Le rôle clé
de l’activité physique, des apports calciques et de la prescription de vitamine D dans la prévention de la perte osseuse
chez le sujet âgé a été clairement démontré. Ces vingt dernières années, plusieurs médicaments aux mécanismes
d’action différents sur le remodelage osseux ont été développés et tous sont en mesure de prévenir le risque de fracture. Toutes ces données, associées aux implications économiques de la « cascade fracturaire », rendent impérative
la mise en place d’actions de prévention de la première fracture (prévention primaire). Cependant, le remboursement
des médicaments anti-ostéoporotiques est actuellement majoritairement limité à la prévention de nouvelles fractures
(prévention secondaire). Mais cette recommandation n’est pas suivie par les médecins puisque dans la majorité des
cas de fractures, les meilleures pratiques ne sont pas appliquées. Cet article se penche sur la meilleure façon d’utiliser le diagnostic, l’évaluation du risque, la prévention et la prise en charge de l’ostéoporose dans la prévention primaire afin d’éviter la survenue d’une première fracture.
196
‘‘
OSTEOPOROSIS:
A patient who is aware of the
potential complications of osteoporosis is more likely to be compliant. In practice, visual aids such
as macroscopic and microscopic
pictures/photographs of normal
and osteoporotic bone, x-rays of
wrist, hip, vertebral, and other osteoporotic fractures, and photographs of severe kyphosis can be
used to enhance full understanding. Microscopic pictures of bone
assist with the understanding of
the importance of bone mass and
bone quality.”
THE
FRACTURE
CASCADE
MUST
BE
STOPPED
How can we convince
osteoporotic patients
to take their treatment?
by S. Lipschitz, South Africa
O
Stanley LIPSCHITZ
MBBCh (Wits), FRACP (NZ)
Johannesburg
SOUTH AFRICA
steoporosis is a common disease with serious consequences as osteoporotic fractures are associated with increased morbidity and mortality. Although there are several treatment options available to reduce
the risk of fracture, there are barriers preventing ideal patient management,
which include lack of awareness of the disease and its consequences, underdiagnosis of those at risk of fracture, and lack of compliance and persistence
with therapy. This paper attempts to identify these barriers to ideal patient
management, in particular those causing poor compliance and persistence
with therapy in those patients at increased risk of fracture. A better understanding of the reasons for poor compliance allows the development of an intervention strategy to improve compliance. Better compliance and persistence
with therapy improve clinical outcomes. Various intervention strategies are
discussed in this paper, including improved diagnosis of osteoporosis in atrisk populations, improved patient education on the disease, the interpretation
of dual-energy x-ray absorptiometry (DXA) scans, the interpretation of fracture
risk, the consequences of fracture, and the benefits and risks related to specific drug treatments. Communication with patients is not ideal and many patients do not take their medication because they are not informed about osteoporosis, because they are not aware of their risk of fracture, and because
they are ill-informed of the risks associated with medication. It is ultimately the
responsibility of the doctor to improve compliance. Open and honest communication, sometimes assisted by specialized patient compliance programs,
has proven to be the most effective tool in improving patient compliance and
persistence with medication.
steoporosis is defined by the World Health Organization as “a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture.”1 It is estimated that 1 in 2 women and 1 in 5 men over the age
of 50 years will sustain a fragility fracture in her/his lifetime.2 The common sites of
osteoporotic fractures are the wrist, spine, and hip.
O
Dr Stanley Lipschitz, Postnet #252 P
Bag X31 Saxonwold 2132,
29 Jellicoe Avenue, Rosebank,
Johannesburg, South Africa
(e-mail: s.lipschitz@bonestan.co.za)
There are several treatment options available for fracture prevention, including hormone therapy, selective estrogen receptor modulators (SERMs), oral or intravenous
bisphosphonates, strontium ranelate, denosumab, and human parathyroid hormone
(hPTH). Despite this wealth of efficacious treatment, several problems have been
How can we convince osteoporotic patients to take their treatment? – Lipschitz
197
OSTEOPOROSIS:
THE
FRACTURE
CASCADE
identified which serve as major barriers to the
goal of achieving adequate fracture prevention in at-risk patients. These include lack of
awareness by doctors and patients, underdiagnosis even in patients who have had a
fracture, underestimation of fracture risk, and
fear by doctors and patients of the perceived
risks of treatment. The outcome is nonadherence to therapy and the consequences
thereof. Compliance is the extent to which a
patient’s behaviour coincides with medical advice. Good compliance is assumed when the
patient takes >80% of the prescribed medication. Adherence is defined as compliance
plus persistence, where compliance is the
percentage of pills taken over a prescribed
period, and persistence is the time from initiation to discontinuation of treatment.
Lack of awareness – lack of
diagnosis – lack of adequate
assessment of fracture risk
MUST
BE
STOPPED
Prevalence
Strength of
association
Calcitonin
Cancer risk
Very rare (<1/10 000)
+
Bisphosphonates
Gastrointestinal effects (oral formulations)
Musculoskeletal pain
Atrial fibrillation
Atypical fracture/delayed fracture healing
Osteonecrosis of the jaw
Hypersensitivity reactions
Renal impairment
Common (≥1/100)
Common (≥1/100)
Very rare (<1/10 000)
Very rare (<1/10 000)
Very rare (<1/10 000)
Very rare (<1/10 000)
Very rare (<1/10 000)
++
+
±
+
+
Denosumab
Severe infection
Osteonecrosis of the jaw
Atypical fracture/delayed fracture healing
Cancer
Common (≥1/100)
Very rare (<1/10 000)
Very rare (<1/10 000)
Very rare (<1/10 000)
+
±
-
Uncommon (≥1/1000 to
<1/100)
Very rare (<1/10 000)
Very rare (<1/10 000)
+
Selective estrogen receptor modulators
Venous thromboembolism
Stroke
Endometrial effects
+
In order to convince patients to take their
Strontium ranelate
treatment, it is first necessary to identify those
Myocardial infarction
Common (≥1/100)
+
at risk of fracture, and in this regard major
Venous thromboembolism
Very rare (<1/10 000)
+
problems persist, with a lack of awareness
Hypersensitivity
Very rare (<1/10 000)
+
from doctors and patients alike. The impor++ : strong evidence; + : evidence; ± : mixed evidence; - : no evidence
tance of clinical risk factors and prevalent
vertebral fractures as part of fracture risk assessment has been clearly established. Yet, Table I. Adverse reactions associated with antiosteoporotic medication.
After reference 10: Reginster et al. Expert Opin Drug Saf. 2013;12:507-522. © 2013, Informa UK
in clinical practice these risks are often ignored Limited.
and the focus is often only on the dual-energy
x-ray absorptiometry (DXA) scan. The reason for this may recase summary, 17% were mentioned in the medical record,
late to the fact that the DXA scan is often interpreted by nonand only 7% received treatment for osteoporosis.5 In a study
clinicians and this interpretation is often made without knowl- on 762 postmenopausal white women, the incidence of veredge of clinical risk factors.
tebral fracture was noted to increase with age, from 11.05%
at age 55 years, 14.65% at age 65 years, 31.5% at age 75
The IMPACT study (Improving the Measurements of Persistyears, 52.45% at 86 years, to 75% at age 95 years.6 Identience on ACtonel Treatment) identified newly diagnosed pa- fying vertebral fractures should, therefore, be an integral part
tients who underwent routine spinal radiography as part of of the initial patient assessment.
their initial assessment. Images were analyzed by local radiologists and subsequently by study radiologists. False nega- An incident fracture is clearly a major and independent risk
tive rates (missed fractures at local assessment) were 29.5%
factor for future fracture. The presence of a vertebral fracture
in Europe/South Africa/Australia, 45.2% in North America, is shown to increase the odds ratio of a future wrist fracture
and 46.5% in Central and South America.3 A Bone and Joint by 1.4, vertebral fracture by 4.4, and hip fracture by 2.3.7 The
Decade/International Osteoporosis Foundation (IOF) survey greater the number of incident fractures, the greater the risk,
of more than 3000 orthopedic surgeons in France, Germany, as was shown in the Study of Osteoporotic Fractures, where
Italy, Spain, the UK, and New Zealand found that orthopedic
the odds ratio of a new fracture rose from 3 for those with one
surgeons often failed to recognize osteoporosis as a cause of incident fracture to 5.2 and 10.5 for those with two and three
fracture and were inconsistent in providing appropriate treator more fractures, respectively.8 Incident vertebral fractures
4
ment and referral. A retrospective analysis of routine chest predict the risk of future fractures, independent of bone mineral density (BMD), and without a routine “vertebral fracture
x-rays in 934 women aged 60 years and older, hospitalized for
assessment” this risk factor is missed. Wainwright et al examvarious reasons, identified 132 (14.1%) patients with moderate-to-severe vertebral fractures. Of these, 52% were men- ined 8065 women and identified 243 fractures, 54% of whom
tioned in the radiology report, 23% were mentioned in the did not satisfy BMD criteria for the diagnosis of osteoporosis.9
198
OSTEOPOROSIS:
VTE
Bisphosphonates
Atypical
fractures
ONJ
GORD
RR, 1.70
Alendronate:
HR, 3.18
Common
(≥1/100)
Very rare
(<1/10 000)
*2 cases in
FREEDOM
Very rare
(<1/10,000)
THE
FRACTURE
Esophageal
Atrial
fibrillation
cancer
RR, 2.32
CASCADE
Skin
reactions
MUST
BE
DRESS
MI
Very rare
(<1/10 000)
RR, 1.6
STOPPED
Osteosarcoma
OR, 1.47
Raloxifene:
HR, 1.64
Bazedoxifene:
HR, 2.15
SERMs
Denosumab
Strontium
ranelate
Common
(≥1/100)
RR, 1.4
<1/10 000
patients
Teriparatide
Table II. Risks associated with antiosteoporotic medication.
Abbreviations: DRESS, drug rash with eosinophilia and systemic symptoms; FREEDOM, Fracture REduction Evaluation of Denosumb in Osteoporosis every 6 Months;
GORD, gastroesophageal reflux disease; HR, hazard ratio; MI, myocardial infarction; ONJ, osteonecrosis of the jaw; OR, odds ratio; SERM, selective estrogen
receptor modulator; RR, relative risk; VTE, venous thromboembolism.
After reference 10: Reginster et al. Expert Opin Drug Saf. 2013;12:507-522. © 2013, Informa UK Limited.
Fear by patients and doctors of perceived risks
of medication
The risks relating to treatment are often misunderstood and
overemphasized partly due to misinformation perpetrated by
the popular press and/or the internet. It is essential that these
risks be properly quantified and interpreted in relation to the
risk of not taking appropriate medication. A detailed overview
of the risks relating to the most common registered drugs used
in osteoporosis is beyond the scope of this paper but has
been extensively reviewed (Tables I and II).10
The antifracture efficacy of a variety of treatments has been
studied in multiple randomized placebo-controlled clinical
studies. All of them have been shown to reduce the risk of vertebral fracture (bisphosphonates, hormone therapy, teriparatide, SERMs, strontium ranelate, and denosumab), and some
of them have been shown to reduce the risk of nonvertebral
fracture (bisphosphonates, hormone therapy, teriparatide,
strontium ranelate, and denosumab) and the risk of hip fracture (bisphosphonates, strontium ranelate, and denosumab).11 In patients at risk of fracture, the risk of the disease is far
greater than any risk associated with medication.
SELECTED
BMD
DXA
FRAX®
IMPACT
Improving the Measurements of Persistence on
ACtonel Treatment
selective estrogen receptor modulator
IOF
SERM
The consequences of the failure of doctors to treat high-risk
patients and/or the failure of high-risk patients to adhere to
medication for whatever reason are clear. From the patients’
perspective there are many possible causes of nonadherence,
including side effects (real or perceived), complicated dosing
regimens, and a lack of knowledge and insight of the disease and its complications.12
Consequences of nonadherence – benefits of
adherence
Whatever the cause, nonadherence is common and the consequences of nonadherence cannot be underestimated. Complicated dosing regimens have been implicated as a cause of
nonadherence and some studies do show that patients find
weekly alendronate dosing preferable to daily dosing, with a
resulting concomitant improvement in adherence.13,14 However, even with weekly dosing, adherence remains poor.15 Data
from a large geographically diverse managed care plan shows
persistence curves for daily and weekly alendronate rapidly
declining over the first 3 months, followed by a slower, but consistent, decline over the rest of the 12-month period. The mean
time to discontinuation was 2.44 months and 2.55 months for
daily and weekly dosing, respectively.16 Weycker et al studied 18 822 women, 48% of whom initiated bisphosphonate
therapy.17 The risk of adherence failure was 47% at 3 months,
70% at 1 year, and 84% at 3 years, and the risk of persistence
failure was 47% and 77% at 1 and 3 years, respectively. Compliance with weekly bisphosphonate treatment was no better
that with daily dosing.
Compliance and persistence with medication are associated
with fracture prevention. Siris et al18 collected data on 35 537
women aged 45 years and older who received a bisphospho-
199
OSTEOPOROSIS:
THE
FRACTURE
CASCADE
MUST
nate prescription. Of these patients, 43% were refill compliant and 20% persisted with bisphosphonates throughout
the 24-month study period. Total vertebral, nonvertebral, and
hip fractures were significantly lower in the refill-compliant
and persistent patients, with relative risks of 20% and 45%,
respectively. A progressive relation was seen between refill
compliance and risk reduction, commencing at a compliance
of about 50% and becoming more significant at compliance
rates of 75% and over.
A study reviewing health data from the files of 11 249 women
with osteoporosis (mean age 68.4 years) from Saskatchewan
in Canada, with an average follow-up of 2 years between 1996
and 2001, showed an overall fracture rate of 4.5% per year.
At compliance rates of 80% or more, the fracture rate was
16% lower.19
A large study from 1999-2004 identified 14 760 new female
bisphosphonate users. A total of 387 fractures were recorded. Increased duration of compliant bisphosphonate use was
associated with a reduction in fracture risk. When compared
with less than 1 year of compliance, 1 to 2 years of compliance
was associated with a 12% reduction in fracture risk, and 3
to 4 years with a 46% reduction in risk. Paradoxically, 5 to 6
years of compliant bisphosphonate use was no longer associated with a reduction in fracture risk.20 This may strengthen
the case for discontinuing bisphosphonates after 4 or 5 years
of continued use.
Huybrechts et al studied more than 35 000 women with postmenopausal osteoporosis who received a prescription for a
bisphosphonate, and found that low compliance was associated with a 31% increase in fracture risk and 47% higher
hospitalization rates.21
Penning-van Beest et al showed, in 8822 female bisphosphonate users, that compliance of <20% was associated with
an 80% increase in the risk of fracture when compared with
subjects with >90% compliance.22
Practical approach to convince patients to adhere
to osteoporotic treatments
The problem of nonadherence is particularly evident in chronic and asymptomatic diseases—including osteoporosis—and
this poses a major problem to the treating practitioner. For the
asymptomatic patient the perceived threat (without full education) will not motivate adherence. Furthermore, the risk of
nonadherence increases with duration of therapy, a particular problem in diseases such as osteoporosis, where the actual threat to the patient may be several years down the line.23
In addition, for whatever reason, patients are often more fearful of the threat of the medication than the threat of the disease.
When attempting to define a strategy to reduce nonadherence, it is useful to try to understand the factors that are associated with nonadherence. In a large osteoporosis registry
200
BE
STOPPED
review study, the factors likely to improve adherence were increased age and the presence of an incidental nonvertebral
fracture, whereas the factors associated with reduced adherence were related to the use of alendronate as opposed
to etidronate.24 In a telesurvey of >950 women,25 the factors
associated with reduced adherence included having experienced an adverse event to a medication and perceptions regarding the bone densitometry result. Women who believed
that bone density did not show osteoporosis and women
who were unsure of the result were 1.6 times more likely to be
nonadherent. Women who were “somewhat bothered” by adverse events were 4 times more likely to be nonadherent, and
women who were “very or extremely bothered” by adverse
events were 25 times more likely to be nonadherent. Other
studies have identified predictors of poor adherence to be benzodiazepine use, use of gastroprotective medication, and unavailability of bone densitometry.26 Predictors of improved adherence were found to include early menopause, osteoporosis
on bone densitometry, family history of osteoporosis, presence
of a vertebral fracture, use of glucocorticoid medication, and
use of nonsteroidal anti-inflammatory medication,26 as well as
younger age, previous fracture, fracture after initiating treatment, fewer comorbidities, using fewer osteoporosis medication combinations, and nursing home residence.27 Applying
this information to the clinical setting, several strategies may
improve compliance and adherence:
u Improved diagnosis.
u Effective doctor/patient communication.
u Education on osteoporosis and fracture risk.
– How to interpret the bone densitometry reading.
– What a prevalent fracture means.
– Other risk factors (family history, eating disorder,
glucocorticoid use, smoking, alcohol, etc).
u Education on the outcomes of nontreatment.
– Fractures, pain, deformity, disability.
u Education to improve the patients’ knowledge and
belief in the medication.
u Education to improve the association between taking
the medication and the reduction in fracture risk.
u Education to improve the association between taking
the medication with fracture prevention and improved
quality of life.
u Honest communication on the true risks associated
with each medication.
– Attempt to limit adverse events by avoiding drug
use in susceptible patients (bisphosphonates in patients who have gastroesophageal reflux symptoms,
SERMs in patients with active menopausal symptoms, strontium ranelate in patients with active gastrointestinal pathology including malabsorption, inflammatory bowel disease, and diarrhea).
u Close monitoring to identify patients who are noncompliant.
OSTEOPOROSIS:
u Using the results of BMD follow-up and bone turnover
markers and explaining how these relate to risk reduction.
u Simple and user-friendly dosing.
u Several studies suggest that once-weekly bispho-
sphonate dosing improves adherence,26,28 and was
preferred by patients,29,30,31 and two studies have suggested that patients preferred once-monthly ibandronate to once-weekly alen-dronate.32,33 Once-yearly
zoledronate, or 6-monthly subcutaneous denosumab
potentially offer an even simpler dosing schedule and
100% adherence is guaranteed in patients who attend for their dosing.
u Other studies, however, suggest similarly poor compliance with daily and weekly alendronate dosing.15,16,17
u Data from phase 3 randomized controlled trials suggest that, at least in the clinical research setting, compliance and persistence is similar with oral bisphosphonates, SERMs, and strontium ranelate.
u User-friendly treatment programs.
u Patient education on dosing (oral bisphosphonates,
strontium ranelate, teriparatide), and patient reminders
for injectable medications (bisphosphonates, denosumab).
u Attention given to patients.
u A study by Clowes et al34 attempted to evaluate strategies to improve compliance. Patients were randomized into 3 groups: usual care (no monitoring), nurse
monitoring/attention, and bone turnover marker monitoring (attention and laboratory tests). Patients in the
two intervention groups showed increased adherence by 57%, but there was no difference between
these two groups, suggesting that the attention of
the provider is the most important intervention.
u Assess whether cognitive function is adequate,
whether there is financial restriction to purchasing the
medication and whether the patient’s lifestyle/work
allows the dosing schedule.
Improving the diagnosis of osteoporosis at population level
has been addressed with varying success by such bodies as
IOF, NOF (National Osteoporosis Foundation [USA]), NOFSA
(National Osteoporosis Foundation of South Africa), and various other national bodies. At the individual doctor/practitioner level, diagnosis can be improved using appropriate DXA
screening (European guidelines,11 South African guidelines35).
Assessment of fracture risk should be performed for each
patient. The NOFSA fracture risk algorithm,25 and the FRAX®
fracture risk assessment tool can easily and rapidly be applied in day-to-day practice. FRAX® was developed by the
World Health Organization, who recognized that clinical risk
factors increase the risk of fractures independently of BMD
and that the risk of fracture increased with the number of risk
factors.36 This tool integrates the risk associated with clinical
THE
FRACTURE
CASCADE
MUST
BE
STOPPED
risk factors (identified from meta-analyses of large epidemiological studies) as well as BMD at the femoral neck, to calculate the 10-year probability of fractures for men and women.
The FRAX® score improves the prediction of future fractures;
however, the intervention thresholds derived are dependent
on epidemiological and health economic data and are, therefore, country specific. FRAX® does, however, have a number of limitations, which should be taken into account when
assessing individual risk. These include: no assessment of
dose-response (number of incident fractures, severity of incident fractures, dose and duration of glucocorticoid exposure,
smoking, alcohol),11 as well as no assessment of falls risk,
vitamin D status, and bone turnover markers.
A patient who is aware of the potential complications of osteoporosis is more likely to be compliant. In practice, visual
aids such as macroscopic and microscopic pictures/photographs of normal and osteoporotic bone, x-rays of wrist,
hip, vertebral, and other osteoporotic fractures, and photographs of severe kyphosis can be used to enhance full understanding. Microscopic pictures of bone assist with the understanding of the importance of bone mass and bone quality.
The patient should be made aware that bone loss, as seen
in osteoporosis, is associated with qualitative and quantitative impairment of bone, and that the consequences of this
are fractures. The effects of fractures on morbidity37,38,39 and
mortality40,41 can be highlighted.
Specifically designed patient support programs may also be
of assistance in this regard. An unpublished analysis (done in
South Africa) of patient compliance with osteoporotic treatment, compared patients enrolled on a patient support program with patients not on any support program (control group).
The aim of the support program was to improve compliance
in patients taking osteoporotic treatment. The patient support program included education regarding the disease and
the treatment, with the aim of improving compliance and persistence. A total of 2791 patients completed the program
over a period of 13 months. In the control group, 40% of patients failed to fill their repeat prescription after month 1. This
noncompliance was reduced by 20% in the intervention group.
Patients enrolled on the patient support program achieved
compliance rates (measured from the day of enrolment on
the program until completion of the program) of >90% on a
month-to-month basis, compared with patients who were not
on a patient support program, where compliance rates averaged 55%. In this study, patient education and support was
shown to significantly improve compliance and persistence
to treatment.
Conclusion
Patient-doctor communication clearly affects patients’ acceptance of their disease and compliance and persistence with
their medication. Up to 51% of women do not recall anything
being said to them about osteoporosis at the time of diag-
201
OSTEOPOROSIS:
THE
FRACTURE
CASCADE
MUST
nosis, and 20% to 30% of patients cannot recall receiving
proper instructions on taking their osteoporosis medication.
So, what is communicated and how it is communicated will
clearly have a major effect on whether patients take their medication and whether they benefit from the process. There are
numerous challenges facing doctors attempting to educate
patients. These include not frightening them excessively,
while at the same time frightening them sufficiently to be appropriately concerned, empowering the patients to take control of, and accept responsibility for, their illness, and coping
with multiple sources of misinformation (magazines, internet,
and women’s groups).
At the time of diagnosis a considerable effort should be put
into educating patients as described above. Patients should
be encouraged to ask questions about the disease and the
treatment of the disease. They should be offered treatment
based on their specific profile. Where possible, more than one
option should be offered and the patients should be involved
in selecting the best option for themselves. Possible adverse
events should be explained in detail and put into context (risk
of disease versus risk of drug). A first follow-up visit should
BE
STOPPED
take place after 3 months to discuss whether the patients are
taking the drug, whether they are taking it correctly, whether
they are happy to continue, and whether they have experienced any side effects. At this visit the patients should be reeducated as necessary, and the importance of compliance
and persistence should be reemphasized. In patients deemed
“high risk” bone markers may be of assistance.
At year 1, a repeat bone densitometry is useful, as an increase
such as that seen in patients using strontium ranelate, denosumab, and teriparatide is an extremely strong motivator for
continued compliance. Patients taking bisphosphonates, hormone therapy, and SERMs should be informed that maintenance of bone density is the aim of treatment in order to
avoid disappointment and inappropriate discontinuation of
medication when they fail to see “improvement.” In problem
patients, bone markers may once again be of assistance.
Most importantly, time should be spent with the patients,
explaining and reexplaining—as necessary—about the disease, the complications, and the drug therapy. Adherence
is an issue and it is the responsibility of the treating clinician
to improve it. n
References
1. World Health Organization. Tech Report Series. 1994;843:1-129.
2. van Staa TP, Dennison EM, Leufkens HGM, Cooper C. Epidemiology of fractures in England and Wales. Bone. 2001;29(6):517-522.
3. Delmas PD, van de Langerijt L, Watts NB; IMPACT Study Group. Underdiagnosis of vertebral fractures is a worldwide problem: the IMPACT study. J Bone
Miner Res. 2005;20:557-563.
4. Orthopaedic surgeons ARE missing the fracture opportunity. Can we change this?
[Bone and Joint Decade/Int Osteoporosis Foundation survey.] Available at http:
//www.osteofound.org/health_professionals/consensus_guidelines/cd_orf.html
5. Gelbach SH, Bigelow C, Hermisdottir M, et al. Recognition of vertebral fracture
in a clinical setting. Osteoporos Int. 2000;11:577-582.
6. Melton LJ 3rd, Jane AW, Cooper C, Eastell R, O’Fallon WM, Riggs BL. Prevalence and incidence of vertebral deformities. Osteoporos Int. 1993;3:113-119.
7. Klotzbuecher CM, Ross PD, Landsman PB, Abbott TA 3rd, Berger M. Patients
with prior fractures have an increased risk of future fractures: a summary of
literature and statistical synthesis. J Bone Miner Res. 2000;15:721-739.
8. Black DM, Arden NK, Palermo L, Pearson J, Cummings SR. Prevalent vertebral
deformities predict hip fractures and new vertebral deformities but not wrist fractures. Study of Osteoporotic Fractures Research Group. J Bone Miner Res.
1999;14:821-828.
9. Wainwright SA, Marshall CM, Ensrud KE, et al. Hip fracture in women without
osteoporosis. J Clin Endocrin Metab. 2005;90:2787-2793.
10. Reginster JY, Pelousse F, Bruyere O. Safety concerns with long-term management of osteoporosis. Expert Opin Drug Saf. 2013;12:507-522.
11. Kanis JA, McCloskey EV, Johannsson H, Cooper C et al. European guidance for
the diagnosis and management of osteoporosis in postmenopausal women.
Osteopor Int. 2013;24:23-57.
12. Kamatari M, Koto S, Ozawa N, et al. Factors affecting long-term compliance of
osteoporotic patients with bisphosphonate treatment and quality of life assessment in actual practice: alendronate and risedronate. J Bone Miner Metab.
2007;25:302-309.
13. Kendler D, Kung AW, Fuleihan G, et al. Patients with osteoporosis prefer once
weekly to once daily dosing with alendronate. Maturitas. 2004;48:243-251.
14. Ringe JD, Moller G. Differences in persistence, safety and efficacy of generic
and original branded once weekly bisphosphonates in patients with postmenopausal osteoporosis: 1 year results of a retrospective patient chart review analysis. Rheumatol Int. 2009;3:213-221.
15. Cotte FE, Fardellone P, Mercier F, Gaudin AF, Roux C. Adherence to monthly
and weekly oral bisphosphonates in women with osteoporosis. Osteopor Int.
2010;21:145-155.
202
16. Downey TW, Foltz SH, Boccuzzi SJ, Omar MA, Kahler KH. Adherence and persistence associated with the pharmacologic treatment of osteoporosis in a
managed care setting. South Med J. 2006;99:570-575.
17. Weycker D, Macarios D, Edelsberg J, Oster G. Compliance with drug therapy
for postmenopausal osteoporosis. Osteopor Int. 2006;17:1645-1652.
18. Siris ES, Harris ST, Rosen CJ, et al. Adherence to bisphosphonate therapy and
Fracture rates in osteoporotic women: Relationship to vertebral and non-vertebral fractures from 2 US Claims Databases. Mayo Clin Proc. 2006;81:1013-1022.
19. Caro JJ, Ishak KJ, Huybrechts KF, Raggio G, Naujoks C. The impact of compliance with osteoporosis therapy on fracture rates in actual practice. Osteopor
Int. 2004;15:1003-1008.
20. Meijer WM, Penning-van Beest FJ, Olson M, Herings RM. Relationship between duration of compliant bisphosphonate use and the risk of osteoporotic
fractures. Current Med Res and Opinion. 2008;24:3217-3222.
21. Huybrechts KF, Ishak KJ, Caro JJ. Assessment of compliance with osteoporosis treatment and its consequences in a managed care population. Bone. 2006;
38(6):922-928.
22. Penning-van Beest FJ, Erkins JA, Olson M, Herings RM. Loss of treatment benefit due to low compliance with bisphosphonate therapy. Osteopor Int. 2008;
19(4):511-517.
23. Solomon DH, Avorn J, Katz JN, et al. Compliance with osteoporosis medication.
Arch Intern Med. 2005;165:2414-2419.
24. Papaionnou A, Ioannidis G, Adachi JD, et al. Adherence to bisphosphonate
and hormone replacement therapy in a tertiary care setting of patients in the
CANDOO database. Osteoporos Int. 2003;14:808-813.
25. Tosteson AN, Grove MR, Hammond CS, et al. Early discontinuation of treatment
for osteoporosis. Am J Med. 2003;115:209-216.
26. Rossini M, Bianchi G, Di Munno O, et al. Determinants of adherence to osteoporosis medication in clinical practice. Osteoporos Int. 2006;17:914-921.
27. Solomon DH, Avorn J, Katz JN, et al. Compliance with osteoporosis medications. Arch Intern Med. 2005;165:2414-2419.
28. Recker RR, Gallagher R, MacCosbe PE. Effect of dosing frequency on bisphosphonate medication adherence in a large longitudinal cohort of women.
Mayo Clin Proc. 2005;80:856-861.
29. Kendler D, Kung AW, Fuleihan G, et al. Patients with osteoporosis prefer once
weekly to once daily dosing with alendronate. Maturitas. 2004;48:243-251.
30. Weiss M, Vered I, Foldes AJ, et al. Treatment preference and tolerability with
alendronate once weekly over a 3-month period: an Israeli multi-center study.
Aging Clin Exp Res. 2005;17:143-149.
31. Simon JA, Lewiecki EM, Smith ME, et al. Patient preference for once-weekly
OSTEOPOROSIS:
alendronate 70mg versus once-daily alendronate 10mg: a multicenter, randomized, open-label, crossover study. Clin Ther. 2002;24:1871-1886.
32. Reginster J Y, Rabenda V, Neuprez A. Adherence, patient preference and
dosing frequency: understanding the relationship. Bone. 2006;38(4 suppl 1):
S2-S6.
33. Emkey R, Binkley N, Seidman L, Rosen C. BALTO 1: women treated for osteoporosis rate preference and convenience for once-monthly ibandronate versus
once-weekly alendronate. (abstract M435). J Bone Miner Res. 2005;20(suppl 1):S416.
34. Clowes JA, Peel NF, Eastell R. The impact of monitoring on adherence and
persistence with antiresorptive treatment for postmenopausal osteoporosis:
a randomized controlled trial. J Clin Endocrinol Metab. 2004;89:1117-1123.
35. Hough S, Ascott-Evans B, Brown S, et al. NOFSA guideline for the diagnosis
and management of osteoporosis. JEMDSA. 2010;15(suppl 1):S1-S48.
36. Kanis JA; World Health Organization Scientific Group. Assessment of osteoporo-
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BE
STOPPED
sis at the primary health care level. Sheffield, UK: WHO Collaborating Centre,
University of Sheffield. 2008. Available at: http://www.shef.ac.uk/FRAX/.
37. Silverman SL, Minshall ME, Shen W, et al. The relationship of health-related
quality of life to prevalent and incident vertebral fractures in postmenopausal
women with osteoporosis: results from the Multiple Outcomes of Raloxifene
Evaluation Study. Arthritis Rheum. 2001;44:2611-2619.
38. Kanis JA, Johnell O. The burden of osteoporosis. J Endocrinol Invest.1999;22:
583-588.
39. Boonen S, Autier P, Barette M, et al. Functional outcomes and quality of life following hip fracture in elderly women: a prospective controlled study. Osteoporos Int. 2004;15:87-94.
40. Cauley JA, Thompson DE, Ensrud KC, Scott JC, Black D. Risk of mortality following clinical fractures. Osteoporos Int. 2000;11:556-561.
41. Kanis JA, Oden A, Johnell O, et al. The components of excess mortality after
hospitalization for vertebral fracture. Osteoporos Int. 2004;15:108-112.
Keywords: compliance; fracture; medication; non-adherence; non-compliance; osteoporosis; persistence
COMMENT
CONVAINCRE LES PATIENTS OSTÉOPOROTIQUES
DE PRENDRE LEUR TRAITEMENT ?
L’ostéoporose est une pathologie courante aux conséquences graves, les fractures ostéoporotiques s’associant à
une augmentation de la morbidité et de la mortalité. Plusieurs options thérapeutiques sont disponibles pour réduire
le risque de fracture, mais la prise en charge idéale du patient est confrontée à des obstacles tels le manque de sensibilisation à la maladie et à ses conséquences, le sous-diagnostic des patients à risque de fractures et le manque
d’observance et de persistance au traitement. Cet article tente d’identifier ces obstacles à une prise en charge idéale
du patient, en particulier celles à l’origine de mauvaises observance et persistance au traitement chez les patients
à risque de fracture augmenté. Mieux comprendre les raisons de la mauvaise observance permettrait d’intervenir
pour l’améliorer. Une meilleure observance et une persistance au traitement améliore l’évolution clinique. Cet article
analyse diverses stratégies, comme un meilleur diagnostic de l’ostéoporose dans les populations à risque, une meilleure éducation du patient sur la maladie, l’interprétation des scanners par absorptiométrie biphotonique aux rayons
X (DXA), l’information sur le risque de fracture et les bénéfices et risques liés aux traitements spécifiques. La communication avec les patients n’est pas parfaite et nombreux sont ceux qui ne prennent pas leur traitement par méconnaissance de l’ostéoporose et du risque de fracture et parce qu’ils sont mal informés des risques associés au
traitement. C’est finalement la responsabilité du médecin d’améliorer l’observance. Une communication honnête et
ouverte, parfois assistée de programmes spécialisés, est l’outil le plus efficace pour améliorer l’observance et la persistance du patient au traitement.
203
THE QUESTION
CONTROVERSIAL
hen a patient is diagnosed with osteopenia
or osteoporosis, lifestyle
recommendations (physical activity, fall prevention, nutritional intake…) and/or a treatment should
be prescribed. The question is, are
these recommendations or treatments identical whether the patient has already sustained a fracture or not? and do recommendations differ according to the location of the fracture?
QUESTION
W
Is there any difference
between primary and
secondary prevention for
patients with osteoporosis?
1.
J. R. Caeiro Rey, Spain
2.
H. Canhão, Portugal
3.
A. El Garf, Egypt
4.
O. Ershova, Russia
5.
T. S. Fu, Taiwan
6.
D. Grigorie, Romania
7.
J. Li-Yu, Philippines
8.
M. O’Brien, Ireland
9.
V. Povoroznyuk, Ukraine
10 .
S. Rojanasthien, Thailand
11.
E. Rudenka, Belarus
12 .
G. Singh, Malaysia
13 .
B. Stolnicki, Brazil
Is there a difference between primary and secondary osteoporosis prevention?
205
CONTROVERSIAL
QUESTION
1. J. R. Caeiro Rey, Spain
José R. CAEIRO REY, MD, PhD
Coordinator of the Osteoporosis and
Osteoporotic Fracture Study and Research
Group of the Spanish Society of Orthopaedic
Surgery and Traumatology (SECOT-GEIOS)
Associated Professor of Orthopaedic Surgery
and Traumatology and Coordinator of the
Adult Trauma Unit, Orthopaedic Surgery and
Traumatology Department, University Hospital
of Santiago de Compostela, Santiago de
Compostela, University, SPAIN
(e-mail: Jrcaeiro@telefonica.net
jrcaeiro@trabeculae.com)
N
onpharmacological and pharmacological recommendations have different levels of evidence regarding
their efficacy in primary or secondary prevention, and
it is necessary to provide patients with valid preventive advice
according to these data and their risk of osteoporotic fracture.
Several nonpharmacological recommendations can be considered universal 1 for primary and secondary fracture prevention.1,2 Cessation of tobacco, identification and treatment of
patients with excessive alcohol intake (ⱖ3 units per day) are
useful lifestyle recommendations, regardless of risk level.1,2 Although they have a weak impact on fracture outcome, they
are still recommended because general health benefits from
them. Appropriate dietary protein consumption (1g/kg/day),
and adequate calcium (1000-1200 mg per day including supplements) and vitamin D intake (800-1000 IU vitamin D3 per
day including supplements for adults ⱖ50 years) contribute
to bone health and reduce the risk of osteoporotic fractures.1,2
Regular weight-bearing (walking, dancing, etc) and musclestrengthening exercise averts bone loss, reduces the risk of
falls and fractures, and imparts general health benefits.1,2 Fall
prevention strategies (falling risk factors assessment, home
safety improvement, maintenance of vitamin D levels, etc) are
first-line secondary prevention recommendations.1,2 Hip protectors are cost-effective in reducing hip fractures among residents in nursing homes.2
Actually, the major pharmacological interventions for primary
and secondary prevention of osteoporotic fractures are antiresorptive agents (bisphosphonates, denosumab, selective
estrogen receptor modulator [SERMs]), anabolic agents (teriparatide and parathyroid hormone–derived agents), and dualaction drugs (strontium ranelate).1,2
The bisphosphonates alendronate and risedronate are approved for the prevention and treatment of osteoporosis in
postmenopausal women, and for the treatment of osteoporosis in men.1-4 Ibandronate is only approved for the treatment
of osteoporosis in postmenopausal women.1 Zoledronate is
approved for prevention and treatment of osteoporosis in postmenopausal women, and to increase bone mass in men with
206
osteoporosis.1 Denosumab is approved for osteoporosis treatment in postmenopausal women at high risk of fracture and
to increase bone mass in men with osteoporosis at high risk
of fracture.1 Raloxifene is approved for osteoporosis prevention and treatment in postmenopausal women.1 Bazedoxifene
can be used as an alternative to raloxifene.2 Teriparatide is approved for osteoporosis treatment in postmenopausal women
and men who are at high risk of fracture.1,3,4 Strontium ranelate
is recommended for the treatment of severe osteoporosis in
postmenopausal women at high risk of fracture and for the
treatment of severe osteoporosis in men at increased risk of
fracture.3,4
Overall, preventive pharmacotherapy reduces the risk of vertebral fracture by 30% to 70%, depending on the agent used
and on patient compliance.2,5 The effect on nonvertebral fractures is generally lower and varies by fracture site. However,
only some drugs have been shown to reduce the risk of nonvertebral fractures, and just a few drugs specifically decrease
the risk of hip fracture.1,2 For hip fractures, the relative reductions in risk range from 30% to 51%.5
When choosing a particular pharmacological agent one should
keep in mind that agents found to decrease vertebral, nonvertebral, and hip fractures should be used preferentially over
those that only demonstrate vertebral antifracture efficacy. As
a general rule, preventive or therapeutic pharmacological decisions should be based on a balance between the benefits
and risks for each particular patient, as no single agent is appropriate in all circumstances and for all patients.5 ■
References
1. National Osteoporosis Foundation. Newly Revised 2013 Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis
Foundation; 2013. Available at: http://www.nof.org/files/nof/public/content/resource/913/files/580.pdf.
2. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY; Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF). European
guidance for the diagnosis and management of osteoporosis in postmenopausal
women. Osteoporos Int. 2013; 24(1):23-57.
3. National Institute for Health and Clinical Excellence. Alendronate, etidronate,
risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women. NICE technology appraisal guidance 160. Quick reference guide. London, UK: National Institute for Health
and Clinical Excellence; October 2008. Available at: http://www.nice.org.uk/nice
media/live/11746/42486/42486.pdf (Accessed August 10, 2013).
4. National Institute for Health and Clinical Excellence. Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. NICE technology appraisal guidance 161. Quick reference guide. London, UK: National Institute
for Health and Clinical Excellence; October 2008. Available at: http://www.nice.
org.uk/nicemedia/live/11748/42508/42508.pdf (Accessed August 10, 2013).
5. Reginster JY. Antifracture efficacy of currently available therapies for postmenopausal osteoporosis. Drugs. 2011;71(1):65-78.
CONTROVERSIAL
QUESTION
2. H. Canhão, Portugal
Helena CANHÃO, MD, PhD
Rheumatology Research Unit
Instituto de Medicina Molecular
Lisbon, PORTUGAL
(e-mail: helenacanhao@gmail.com)
T
here is a core of measures associated with bone health
that should be followed by all individuals regardless of
whether or not they have a previous history of fragility
fracture.1 Thus, one should answer “No” to the question “is
there any difference between primary and secondary prevention for patients with osteoporosis?”
These measures include an adequate intake/supplementation with calcium and vitamin D; adequate weight-bearing and
muscle-strengthening exercise to increase agility and balance
and decrease the risk of falling; assessment of the risk of falls
and adoption of measures to avoid falls; and a reduction in the
consumption of alcohol and tobacco. All these factors are important in preventing fractures and should be implemented,
together with counseling patients about osteoporosis and fracture prevention, and increasing the awareness and knowledge
of all concerned (health professionals included) on osteoporosis and the risk of fragility fractures.
The issues start when moving from nonpharmacological measures to pharmacological treatments, as there are some difficult and debatable questions. Should the fracture be the trigger to start therapy? or should prevention of the first fracture
be the main goal, starting treatment long before a fracture occurs? Does the site of the fracture matter? Should primary
and secondary prevention be the same for all patients? If not,
why and how would they differ?
Many argue that preventing the first fracture should be THE
goal, while others claim that pharmacological therapy has only
demonstrated robust efficacy in patients with established osteoporosis. There is consensus on the fact that fragility fractures warrant osteoporosis treatment. In fact, secondary pre-
vention for patients with established osteoporosis is recognized
worldwide as a standard recommendation. However, data
show that there is a lack of diagnosis and treatment of osteoporosis in patients after hip and other fragility fractures.
Follin et al reported treatment of osteoporosis in only 25% of
patients that suffered a hip fracture at discharge and during
the first year of follow-up.2
It is well documented that after a fracture the risk of a subsequent fracture increases by 2- to 3-fold.3 So why are so
many patients discharged with no medication after a fragility
fracture? One of the reasons that have been pointed out is that
physicians lack awareness and knowledge of osteoporosis
management. For others, lack of evidence, multiple drugs, and
comorbidities may also hamper treatment. Although there is
some heterogeneity in clinical practice, pharmacological treatment for secondary prevention in established osteoporosis is
recommended and widely used.
Treatment is also recommended for primary prevention in patients with osteoporosis, but the strategy should be individualized according to age, BMD, and other osteoporosis risk factors. The risk of falls and the risk of fracture should be assessed.
The nonpharmacological measures described above should
be implemented to minimize the risk of fracture, and all modifiable risk factors should be addressed. After a thorough
evaluation, pharmacological treatment should be tailored in
accordance with patient risk and using drugs with proven efficacy in osteoporosis treatment.4 ■
References
1. National Osteoporosis Foundation. Newly Revised 2013 Clinician’s Guide to
Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013. Available at: http://www.nof.org/files/nof/public/content/
resource/913/files/580.pdf.
2. Follin SL, Black JN, McDermott MT. Lack of diagnosis and treatment of osteoporosis in women and men after hip fracture. Pharmacotherapy. 2003;23:190-198.
3. Eastell R, Reid DM, Compston J, et al. Secondary prevention of osteoporosis:
when should a non‐vertebral fracture be a trigger for action? QJM. 2001;94:575597.
4. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY; Scientific Advisory Board of the European Society for Clinical and Economic Aspects
of Osteoporosis and Osteoarthritis (ESCEO) and the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF).European guidance for
the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2013;24:23-57.
207
CONTROVERSIAL
QUESTION
3. A. El Garf, Egypt
Ayman EL GARF, MD, PhD
Professor of Rheumatology
Department of Rheumatology
Cairo University Hospitals
Cairo University
Cairo, EGYPT
(e-mail: Ayman.El-Garf@kasralainy.edu.eg)
O
steoporosis has been defined as “a skeletal disease
characterized by compromised bone strength predisposing a person to an increased risk of fracture.”1
“Bone strength primarily reflects the integration of bone density and bone quality.”1 In the absence of a fragility fracture,
bone mineral density (BMD) is used for the diagnosis of osteoporosis according to the World Health organization (WHO).2
Usually, the term “primary prevention” means prevention of an
osteoporosis-related fracture, through maintaining the BMD
above –2.5 SD of the adult normal mean (T-score). On the
other hand, “secondary prevention” means treatment after an
osteoporosis-related fracture, to prevent a second fracture.
Primary prevention of osteoporosis or low BMD aims at maximizing peak bone mass and minimizing the rate of bone loss
through nutrition (adequate calcium and vitamin D intake), highimpact exercise, cessation of smoking and excess alcohol, etc,
with or without pharmacological therapy. Primary prevention
is preferable to secondary prevention. Changes in quality, in
the form of fatigue damage, microarchitectural changes, and
trabecular disconnection associated with osteoporosis are
largely irreversible. Treatment at this stage may stabilize or increase BMD and reduce the risk of a second fracture, but is
unlikely to restore bone quality and bone strength to a considerable extent.
In elderly (>75 years) or institutionalized people, trials have
convincingly shown a lower risk of fracture with supplementation therapy.3 On average, supplementation reduced the risk
of nonvertebral fractures (including hip fractures) by 10% to
20%.4 While the value of nutrition and lifestyle modifications
is obvious in primary prevention, their value in secondary pre-
208
vention is less clear. However, vitamin D supplementation enhances intestinal absorption of calcium, as well as optimal
muscle function and balance. Low concentrations of vitamin D
are associated with impaired calcium absorption, a negative
calcium balance, and a compensatory rise of parathyroid hormone. Vitamin D may also reduce the risk of falling, but only
at a dose of at least 700 IU per day,5 a factor that may be of
critical importance in secondary prevention. Postfracture, the
use of calcium plus vitamin D supplements alone or with antiosteoporotic drugs in females was associated with lower
mortality in older hip fracture patients.6 Furthermore, in patients with osteoporosis with a previous fracture, antiosteoporotic drugs are usually needed, and all the randomized clinical trials with antiosteoporotic drugs have generally been
carried out on a background of calcium and vitamin D supplementation.
In conclusion, lifestyle recommendations are needed for both
the primary and secondary prevention of osteoporosis. Their
role in minimizing bone loss, maintaining BMD, and lowering
fracture risk is obvious in primary prevention. In secondary prevention, high-dose vitamin D (> 700 IU) and calcium supplementation is associated with improved muscle balance, fall
prevention, lower mortality after hip fracture, and enhanced
efficacy of antiosteoporotic therapy. ■
References
1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and
Therapy. Osteoporosis Prevention, Diagnosis and Therapy. JAMA. 2001;285:785.
2. WHO Study Group. Assessment of fracture risk and its application to screening
for postmenopausal osteoporosis (Technical Report Series). Geneva, Switzerland: World Health Organization; 1994.
3. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip
fractures in the elderly women. N Engl J Med. 1992;327:1637-1642.
4. Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P. Need for additional calcium to reduce the risk of hip fracture with vitamin D
supplementation: evidence from a comparative meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2007;92:1415-1423.
5. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with
supplemental and active forms of vitamin D: a meta-analysis of randomized controlled trials. Br Med J. 2009;339:b3692.
6. Nurmi-Lüthje I, Lüthje P, Kaukonen JP, et al. Post-fracture prescribed calcium and
vitamin D supplements alone or, in females, with concomitant anti-osteoporotic
drugs is associated with lower mortality in elderly hip fracture patients: a prospective analysis. Drugs Aging. 2009;26(5),409-421.
CONTROVERSIAL
QUESTION
4. O. Ershova, Russia
Olga ERSHOVA, MD, PhD
Yaroslavl State Medical Academy
Yaroslavl, RUSSIA
(e-mail: yarosteoporosis@list.ru)
I
n order to answer this question, we must first define what
primary and secondary prevention of osteoporosis mean.
If we consider the severity of the osteoporotic process,
osteoporosis prevention should be approached from three
perspectives, by avoiding:
◆ The occurrence of osteoporosis (a decrease in bone mineral density [BMD]);
◆ The development of osteoporotic fractures in the presence
of osteoporosis;
◆ The development of further fractures after a first prevalent
fracture.
In this regard, primary prevention can be considered as prevention of either an early reduction in BMD or the development of low-energy fractures. Therefore, preventive measures
should be aimed at achieving the maximum peak bone mass
in childhood and adolescence, and are based on the adherence of children to a healthy lifestyle—adequate intake of dairy
products, sun exposure, outdoor games, intake of vitamin D
supplements in the winter-spring period, etc.
The next important period for primary prevention is the premenopausal and early postmenopausal years, when the inevitable decline in estrogen levels renders it necessary to
maintain normal serum levels of vitamin D and calcium in order to constrain accelerated bone resorption and the subsequent decrease in BMD with adequate calcium in the diet, sun
exposure and/or intake of calcium and vitamin D supplements,
and adequate physical activity. However, if BMD falls to below –2.5 SD, the administration of antiosteoporotic agents is
required in order to stabilize (or increase) BMD. The prevention of falls, which relies on the fight against sarcopenia, is also
of major significance.
On the one hand, these are primary measures related to preventing the occurrence of fractures, but, on the other hand,
they already represent a treatment, and not a prevention of
the osteoporotic process. In this sense, they are not different
from secondary prevention aimed at reducing the risk of recurrent fractures. For treatment strategies based on the FRAX ®
tool, the identification and treatment of individuals at high risk
of fractures, regardless of (or in combination with) BMD assessment, can also be considered as primary prevention, while
secondary prevention will be the prevention of further fractures.
However, preventive measures are universal and include combating risk factors, sufficient intake of dietary calcium, maintaining normal levels of vitamin D in the blood, slowing the decrease in BMD by administration of antiosteoporotic agents
in combination with calcium and vitamin D supplements, and
the prevention of falls. The choice of drug should be individually tailored and based on the available evidence regarding
efficacy and safety, as well as their indications and contraindications. At the same time, from the prevention viewpoint, improving the strength properties of bone tissue is among the
priority issues and involves increasing bone mass and improving the quality of bone.
These requirements are completely fulfilled by strontium ranelate, which reduces the risk of both vertebral fractures and
peripheral fractures, including proximal femoral fractures, which
has been confirmed by the results of well-designed randomized clinical trials. ■
209
CONTROVERSIAL
QUESTION
5. T. S. Fu, Taiwan
Tsai-Sheng FU, MD
Associate Professor
Department of Orthopaedic Surgery
Chang Gung Memorial Hospital in Keelung
Chang Gung University, School of Medicine
Keelung, TAIWAN
(e-mail: fts111@adm.cgmh.org.tw)
T
he key point of treating osteoporosis is to reduce the
incidence of fractures and their sequelae. Primary prevention is intended to prevent the first fragility fracture.
Since an established osteoporotic fracture strongly indicates
an increased risk of further fractures, secondary prevention
is then needed and intended to prevent new fractures from occurring.1
For primary prevention, multidisciplinary approaches involving patient education, lifestyle modification, fall prevention, appropriate medical treatment based on the guidelines, and adherence to this treatment are important to reduce the rate of
fragility fractures and the growing burden of osteoporotic fractures in society. When a fragility fracture occurs, adequate procedures for stabilization according to the location of the fracture are necessary. Subsequent medical care for secondary
prevention should be started and aim to attain optimal functional recovery, improve the quality of life after the fracture, and
reduce the risk of future fractures.
Among the common types of osteoporotic fractures, hip fractures are the most serious and are easily associated with
major morbidity, loss of independence, and even mortality.2,3
Furthermore, patients may experience a second hip fracture,
especially within the first year after a first hip fracture.4 Therefore, it is essential to provide further pharmacotherapy after
a surgical intervention to lower the risk of subsequent fracture. Vertebral fractures are also associated with a high risk
of subsequent new fracture and morbidity. It is essential to
identify vertebral fractures, even asymptomatic ones, as they
increase the likelihood of new vertebral fractures by at least
4-fold. Compared with hip and vertebral fractures, distal radius fractures have no impact on mortality rates and are associated with a lower risk of recurrent fracture. However, the
risk of osteoporotic fractures is higher than in those who have
no previous wrist fracture; therefore, patients with osteoporotic wrist fractures should be considered as candidates for preventive measures. Unfortunately, although several studies have
strongly indicated the increased risk for further fractures, many
patients still do not undergo adequate investigation and receive any treatment for their underlying osteoporosis. Since
fragility fracture care is often the first opportunity for patients
to be treated for osteoporosis, routine assessments including
210
history taking and physical examination, bone density measurement with dual-energy x-ray absorptiometry scans, and
laboratory tests are necessary so that further treatment is optimal to prevent subsequent fractures.
A coordinated treatment program should be provided for osteoporosis patients with a fragility fracture. The therapeutic
options to reduce the risk of subsequent fracture include calcium and vitamin D supplements and antiosteoporotic pharmacological treatment. Several classes of antiosteoporotic
drugs are currently used, including bisphosphonates, calcitonin, estrogens and/or hormone therapy, raloxifene, denosumab, strontium ranelate, and recombinant parathyroid hormone (teriparatide). There are also guidelines for choosing
pharmacological agents for primary and secondary prevention of osteoporotic fractures.5 Bisphosphonates, administered
both orally or via intravenous infusion, are currently used as
first-line treatment for osteoporosis and are of proven benefit in the prevention of fragility fractures. Teriparatide is recommended as an alternative treatment option for the secondary prevention of fragility fractures in patients who have
contraindications or are intolerant to bisphosphonates. Strontium ranelate is another option with a new mode of action,
which can be used for primary or secondary prevention. When
choosing a pharmacological agent, the therapeutic decision
should be based on a balance between the benefits and risks
of each treatment for each particular patient and the location
of the facture. Therapeutic agents found to decrease vertebral,
hip, and other nonvertebral fractures should be considered
preferentially over those that only have efficacy against vertebral fractures.
A multidisciplinary approach and coordinator-based program
is important to improve postfracture osteoporosis care. Physicians and all health care professionals should cooperate together and follow the practice guidelines to give patients optimal care. Besides, willingness-to-participate and compliance
with osteoporosis treatment are also very important. Educating patients and their families on the consequences and treatments for osteoporosis may help to improve the prevention of
fractures and reduce its burden on society. ■
References
1. British Orthopaedic Association. The care of the patient with fragility fracture.
London, UK: BOA-BGS; 2007.
2. Sweet MG, Sweet JM, Jeremiah MP, Galazka SS. Diagnosis and treatment of
osteoporosis. Am Fam Physic. 2009;79(3):193-200.
3. Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures.
Lancet. 2002;359(9319):1761-1767.
4. Nymark T, Lauritsen JM, Ovesen O, Röck ND, Jeune B. Short time-frame from
first to second hip fracture in the Funen county hip fracture study. Osteoporos Int.
2006;17(9):1353-1357.
5. National Institute for Health and Care Excellence. Alendronate, etidronate, risedronate, raloxifene, strontium, ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. London, UK:
National Institute for Health and Care Excellence; 2008.
CONTROVERSIAL
QUESTION
6. D. Grigorie, Romania
Treatment of severe osteoporosis
Daniel GRIGORIE, MD, PhD
Associate Professor of Endocrinology
National Institute of Endocrinology C. I. Parhon
Carol Davila University of Medicine
Bucharest, ROMANIA
(e-mail: grigorie_d@yahoo.com)
O
steoporosis is a problem of bone fragility and fractures, and reducing the individual risk of fracture is
the cornerstone of osteoporosis management. There
may be some differences between primary and secondary
prevention of fractures, albeit in principle all therapeutic agents
have both indications and lifestyle recommendations are the
same. Nevertheless, several points should be made: (i) After
a fracture is sustained, several issues should be addressed:
the need for fall prevention services, a review of the medications taken for compliance or alternatives, correction of vitamin D insufficiency, and an investigation into possible secondary causes. (ii) There is good evidence that prevention
of the first fracture can be achieved with bisphosphonates,
strontium ranelate, denosumab, and raloxifene, though there
are some differences in their efficacy.
Most clinical trials have looked at vertebral fractures as the
first fractures to prevent, as they are at the start of the fragility fracture cycle. In women without prevalent vertebral fractures treated with alendronate there was no significant decrease in clinical fractures in the overall population, but the
reduction was significant in one-third of patients that had a
baseline hip bone mineral density (BMD) T-score lower than
–2.5 SD.1 Also, there is no evidence that ibandronate reduces
the risk of vertebral fractures in patients with osteoporosis without prior fractures. In contrast, risedronate, zoledronate, and
denosumab have been shown to reduce the incidence of vertebral fractures in patients at low-to-moderate risk (patients
with osteopenia or osteoporosis).2
Strontium ranelate reduces the risk of vertebral fracture in
women with osteopenia and osteoporosis without vertebral
fractures. A 41% reduction in the risk of vertebral fractures was
seen in women with lumbar spine osteopenia and a 52%
reduction was observed in women with osteopenia at both
sites.3 The efficacy of strontium ranelate appears independent of the level of fracture risk assessed by FRAX® (Fracture
Risk Assessment tool),4 as is also the case for raloxifene.5
There is no available evidence for teriparatide in patients without prevalent fractures.
Severe osteoporosis is a special issue as it affects the patients
with the highest risk of fracture, and therefore, it is both ethical and cost-efficient to treat them as a priority. Currently, according to WHO criteria, the diagnosis of osteoporosis is based
on BMD T scores that are ⱕ– 2.5 SD at the spine or hip. Limiting the clinical diagnosis of osteoporosis solely to a T-score–
based criterion creates uncertainty about the use of the term
osteoporosis to diagnose older women and men who have
T-scores > –2.5 SD, but either have already sustained lowtrauma fractures or are recognized as having a high fracture
risk based on absolute fracture risk calculations using FRAX®
or other algorithms. Currently, only few trials have specifically addressed very-high-risk populations, as is the case for
alendronate, risedronate, zoledronate, and denosumab (the
latter two in mixed groups of patients with or without prevalent vertebral fractures), which have shown a significant decrease in the risk of vertebral, nonvertebral, and hip fractures.
Intravenous zoledronic acid has also been shown to decrease
the risk of clinical fracture and mortality when given shortly
after a first hip fracture.6 Teriparatide also reduces the risk of
vertebral and nonvertebral fracture in patients with prevalent
fractures. For ibandronate, an effect on nonvertebral fractures
was only demonstrated in a post-hoc analysis of women with
a baseline BMD T-score below –3 SD.7 With strontium ranelate,
studies conducted up to 5 years have shown fracture efficacy at spinal, nonvertebral, and hip sites in patients with a very
high risk of fracture, whatever the definition used: very low
BMD, irrespective of the number of prevalent fractures, high
FRAX®-based probabilities, frailty, and the oldest old (>80
years).5 ■
References
1. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of
fracture in women with low bone density but without vertebral fractures: results
from the Fracture Intervention Trial. JAMA. 1998;280:2077-2082.
2. Reginster JY, Adami S, Lakatos P, et al. Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the
MOBILE study. Ann Rheum Dis. 2006;65:654-661.
3. Seeman E, Devogelaer JP, Lorenc R, et al. Strontium ranelate reduces the risk
of vertebral fractures in patients with osteopenia. J Bone Miner Res. 2004;23:
433-438.
4. Kanis JA, Johansson H, Oden A, McCloskey EV. A meta-analysis of the effect
of strontium ranelate on the risk of vertebral and non-vertebral fracture in postmenopausal osteoporosis and the interaction with FRAX®. Osteoporos Int. 2011;
22:2347-2355.
5. Kanis JA, McCloskey EV, Johansson H. European guidance for the diagnosis
and management of osteoporosis in postmenopausal women. Osteoporos Int.
2013;24:23-57.
6. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. New Engl J Med. 2007;357:1-11.
7. Harris ST, Blumentals WA, Miller PD. Ibandronate and the risk of non-vertebral
and clinical fractures in women with postmenopausal osteoporosis: results of
a meta-analysis of phase III studies. Curr Med Res Opin. 2008;24:237-245.
211
CONTROVERSIAL
QUESTION
7. J. Li-Yu, Philippine
clinically apparent. Since most patients with osteoporosis are
asymptomatic, case-finding strategies in the presence of clinical risk factors are considered vital in halting the progression of a disease that leads to fragility fractures that will surely
affect the quality of life of patients.
Julie LI-YU, MD, FPRA, MSPH
University of Santo Tomas Hospital
España
Manila, PHILIPPINES
(e-mail: julietanliyu@gmail.com)
O
steoporosis is a worldwide preventable metabolic
bone disease that afflicts millions of postmenopausal
women and should never be regarded as part of the
physiological process of aging. Though diagnosis is confirmed
based on the World Health Organization criteria for bone density using dual-energy x-ray absorptiometry (DXA), it is currently recommended that screening for osteoporosis be performed in all postmenopausal women ⱖ65 years of age and in
women <65 years of age whose 10-year fracture risk is equal
to or exceeds that of a 65-year-old white woman without additional risk factors. However, there is insufficient evidence to
give recommendations to screen men without previous known
fractures or secondary causes of osteoporosis.1
From a public health standpoint, primary prevention is the very
essence of the social responsibility of medical practitioners to
help circumvent diseases like osteoporosis. Primary preventive measures for osteoporosis are considered successful when
fragility fractures are avoided or even proven to have lessened.
This is considered as the most cost-effective way to deliver
health care. In osteoporosis prevention, one needs to focus
on educating the public on the importance of well-balanced
nutrition, sufficient calcium and vitamin D intake, and appropriate age-specific physical activity, which should be started
early in childhood in order to achieve high-quality peak bone
mass. In women past the menopause and elderly men, preventive measures to maintain bone mass that are suited to
their health status should, likewise, be encouraged.2 The use
of pharmacological agents as part of a primary prevention
strategy, especially in high-risk individuals, has been studied
extensively in some countries based on pharmacoeconomic models of therapy. On the other hand, secondary preventive
measures are needed to identify and address modifiable risk
factors or preclinical disease in those whose condition is not
212
Measures to prevent secondary fractures remain a challenge
globally. The majority of patients who suffer from fractures still
fail to receive the appropriate secondary preventive care they
need.3-5 There are effective treatments suited to the various patient clinical profiles, but their availability in a specific country
is subject to the approval of that country’s regulatory agency.
Treatments that are tailored to the needs of patients as well
as the benefit-risk ratio of initiating therapy should always be
considered. Other strategies include national health programs,
such as fracture liaison services,6 which are intended to close
the care gap and were found to be effective in various countries in providing secondary preventive care to patients with
prevalent fractures.
Finally, whatever the plan of action taken by clinicians and
health policy makers in the interest of patients and at-risk individuals, the ultimate goal is to reduce the burden of fragility
fractures, but not to over-treat them, keeping in mind the patients who will most benefit from pharmacological therapies,
irrespective of whether the purpose is primary or secondary
prevention. ■
References
1. US Preventive Services Task Force. Screening for osteoporosis: US Preventive
Services Task Force Recommendation Statement. Ann Intern Med. 2011;154:
356-364.
2. Orimo H, Nakamura T, Hosoi T, Iki M, Uenishi K, Endo N, et al. Japanese 2011
guidelines for prevention and treatment of osteoporosis – an executive summary. Arch Osteopros. 2012;7:3-20.
3. Fraser LA, Ioannidis G, Adachi JD, Pickard L, Kaiser SM, Prior J, et al. Fragility
fractures and the osteoporosis care gap in women: the Canadian Multicentre Osteoporosis Study. Osteoporos Int. 2011;22:789-796.
4. Hagino H, Sawaguchi T, Endo N, Ito Y, Nakano T, Watanabe Y. The risk of a second hip fracture in patients after their first hip fracture. Calcif Tissue Int. 2012;90:
14-21.
5. Leslie WD, Giangregorio LM, Yogendran M, et al. A population based analysis
of the post-fracture care gap 1996-2008: the situation is not improving. Osteoporos Int. 2012;23:1623-1629.
6. Mitchell PJ. Best practices in secondary fracture prevention: Fracture Liaison Services. Curr Osteoporos Rep. 2013;11:52-60.
CONTROVERSIAL
QUESTION
8. M. O’Brien, Ireland
Moira O’BRIEN, FRCPI, FFSEM,
FFSEM (Hon UK), FECSS, FTCD
Professor Emeritus
President, Irish Osteoporosis Society
IRELAND
(e-mail: mobrien@tcd.ie)
P
rimary prevention should be for everybody, as only
15% of cases are diagnosed. Prevention of osteoporosis is now a priority in many countries.1 Primary prevention protects healthy people against the disease, and this
should start in utero and continue throughout the life cycle.
It is therefore important to educate people about preventing
osteoporosis, particularly those who have risk factors. If a person develops a low-trauma fracture or is diagnosed with either
osteopenia or osteoporosis, he/she should be treated. Bones
need normal sex hormones; regular, appropriate, weight-bearing exercise; and adequate intake of calories, vitamin D3 , and
calcium.
Childhood and teenage years are critical periods for developing a strong, healthy skeleton,2 especially pre-puberty. Exercise is most beneficial for additional bone mineral acquisition
before menarche (ie, during the growth spurt) rather than after menarche.3 In Ireland, physical activity levels decline substantially during adolescence.4 The Irish Osteoporosis Society,
(IOS) has developed an educational schools package for 12to 18-year-olds and a children’s book for 7- to12-year-olds.
Low vitamin D3 status is widespread in Ireland; nearly half of
postmenopausal women have low levels during the winter. In
addition, 30% of teenage girls are actually deficient during
the winter months. The Health Service Executive (HSE) has
implemented a recommendation that all babies from 0 to 12
months should be supplemented with vitamin D3 as rickets
is now back in Ireland. Moreover, low vitamin D Levels result
in secondary hyperparathyroidism.
The IOS recommends that from birth and throughout life,
everybody should take the recommended daily amounts of
calcium and vitamin D3 (preferably through food) not only to
help prevent osteoporosis, but to treat osteoporosis and for
overall health.
Secondary prevention should be provided for:
◆ All patients at risk of further fractures.
◆ All patients who have a medical condition that puts them at
high risk of developing osteoporosis and osteoporotic fractures.
◆ All patients who are put on a treatment that will cause a reduction in sex hormone levels, eg, total hysterectomy, chemotherapy and radiation, and aromatase inhibitors for breast or
prostate cancer.
◆ Any medication that will result in bone loss, eg, corticosteroids or prolactin-raising medication.
All patients with a low-trauma fracture or those at risk of fractures should have a dual-energy x-ray absorptiometry (DXA)
scan and a detailed questionnaire to help determine the
cause(s). It is important to carry out hormonal and biochemical investigations and correct any abnormalities. A fracture is
among the strongest risk factor for future fractures. All patients who have had a low-trauma fracture should be put on
antiosteoporotic medication to help prevent further fractures.
The majority of patients with fragility fractures are not evaluated, diagnosed, or treated for osteoporosis. Fracture liaison
services were originally funded by the pharmaceutical industry, despite the fact that they have proved to be the most effective method of preventing future fractures. In Ireland, only
7 hospitals have a fracture liaison service or a dedicated person in charge: either a fracture liaison nurse or a doctor in the
orthopedic outpatients or fracture clinic. Some orthopedic surgeons take an active role in optimizing the care of the fragility fracture patient with the ultimate goal of preventing future
fractures. In Ireland, 14 of the 16 adult trauma units currently
participate in the National Hip Data Audit. Many preventive
measures for osteoporosis have been shown to have strong
or fair evidence for their validity in preventing fractures. It is necessary to provide people with different risks for osteoporosis
with valid preventive measures that correspond to their risk
profile. Finding and addressing the cause(s) of osteoporosis
is essential for secondary prevention. ■
References
1. Kanis JA. Osteoporosis. Oxford, UK: Blackwell Science; 1994:4-36.
2. MacKelvie KJ, Khan KM, McKay HA. Br J Sports Med. 2002;36:250-257.
3. Heinonen A, Sievanen H, Kannus P, Oja P, Pasanen M, Vuori I. High-impact
exercise and bones of growing girls: a 9-month controlled trial. Osteoporosis
Int. 2000;11:1010-1017.
4. Nic Gabhainn S, Kelly C, Molcho M. HBSC Ireland 2006: National Report of the
2006 Health Behaviour in School-aged Children in Ireland. Dublin, Ireland: Department of Health;2007.
213
CONTROVERSIAL
QUESTION
9. V. Povoroznyuk, Ukraine
Vladyslav POVOROZNYUK, MD, PhD
Professor of Medicine, President of the
Ukrainian Association of Osteoporosis
President of the Ukrainian Association of
Menopause, Andropause, and Bone and
Joint Diseases, Director of the Ukrainian
Scientific-Medical Centre for the Problems
of Osteoporosis, Head of the Department
of Clinical Physiology & Pathology of the
Locomotor Apparatus, D. F. Chebotarev
Institute of Gerontology, National Academy
of Medical Science (NAMS), Kiev, UKRAINE
(e-mail: roksolan@zeos.net)
T
he principal goals of primary prevention of osteoporosis at various stages (peak bone mass formation, the
postmenopausal period in women, men aged over 50)
include adequate dietary intake of calcium, vitamin D, and protein; consistent physical activity; reducing the risk of falls; and
the cessation of bad habits. Secondary prevention is used
in patients with osteoporosis and/or in those with a history of
low-energy fractures.
Recommendations on the amount of calcium intake and required doses of vitamin D for osteoporotic patients lack unanimity. The new European guidance for the diagnosis and management of osteoporosis in postmenopausal women states
that postmenopausal women should get at least 1000 mg of
calcium and 800 IU of vitamin D daily,1 while according to the
National Osteoporosis Foundation’s (NOF) 2013 Clinician’s
guide to prevention and treatment of osteoporosis, men aged
between 50 and 70 years need 1000 mg of calcium per day,2
and women aged over 51 years and men aged 71 years and
older must get a daily calcium dose of 1200 mg. As osteoporosis is very often associated with vitamin D deficiency, serum
levels of 25(OH)D should be closely monitored, especially in
case of associated hip fractures. The target of therapy is to
bring the levels of 25(OH)D up to 30 ng/mL (75 nmol/L), with
a subsequent intake of vitamin D to maintain optimum levels,
especially in osteoporotic patients.
Correction of a protein-poor diet in older patients with a recent hip fracture results in clinical improvement during the
period of rehabilitation, with fewer complications and a shorter period of hospitalization. No less than 1 g of protein per 1 kg
of body weight is required.
Regular weight-bearing (walking, jogging, Tai Chi, etc) and muscle-strengthening exercise leads to the general improvement
of health, muscle function, posture, balance, and prevention
of falls in osteoporotic patients. The optimal amount of weightbearing exercise required to maintain a healthy bone state in
osteoporotic patients is unclear; however, physical activity is
214
an integral element of recovery after fragility fractures. Modifiable factors for falls prevention are no less significant and include: improving eyesight, restricting fall-promoting factors,
avoiding medications that reduce alertness, etc.
The essential distinguishing feature of secondary prevention
is its use of pharmacological drugs. An established fragility
fracture is a precondition for starting a medication without any
additional bone mineral density (BMD) assessment. Nowadays, BMD is considered as an important—but not exclusive—criterion for fracture risk assessment; thus, fractures
might be associated with osteopenia or normal BMD parameters, requiring the use of FRAX ® (Fracture Assessment Risk
tool). However, no uniform criteria for the initiation of pharmacological treatment according to the FRAX ® tool have been
developed. NOF advises starting medication in case of clinical/asymptomatic hip or vertebral fractures, osteoporosis established by dual-energy x-ray absorptiometry (DXA) at the
lumbar spine or femoral neck, or osteopenia at the abovementioned sites with a 10-year probability of hip fracture >3%
and a 10-year probability of major fragility fractures >20% according to FRAX ®,2 while the EU guidance contains an agespecific approach to medical interventions.1
According to the EU guidance, in osteoporosis established
by DXA, bisphosphonates, raloxifene, strontium ranelate, and
denosumab were associated with a reduction in the risk of
vertebral fractures, while strontium ranelate and denosumab
were associated with a reduction in the risk of nonvertebral
and hip fractures. In case of established osteoporosis, antiosteoporotic efficacy and prevention of the risk of vertebral
and nonvertebral fractures were proved for bisphosphonates,
teriparatide, strontium ranelate, and denosumab, while prevention of the risk of hip fractures was most prominent with
alendronate, risedronate, and strontium ranelate. Strontium
ranelate has been shown to have the best number-neededto-treat (NNT) parameters for the prevention of vertebral and
hip fractures. ■
Reference
1. Kanis JA, McCloskey EV, Johansson H, et al; Scientific Advisory Board of the
European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2013;24(1):
23-57.
2. National Osteoporosis Foundation. 2013 Clinician’s guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013.
Available at: http://www.nof.org/files/nof/public/content/resource/913/files/
580.pdf.
CONTROVERSIAL
QUESTION
10. S. Rojanasthien, Thailand
Sattaya ROJANASTHIEN, MD
Associate Professor
Department of Orthopedics
Faculty of Medicine
Chiang Mai University
Chiang Mai, THAILAND
(e-mail: srojanas@gmail.com)
T
he prevention of osteoporotic fractures is an important public health intervention. This is particularly true
for hip and clinical vertebral fractures, which are usually associated with a high mortality, morbidity, and financial
burden. In Thailand, the 1-year all-cause mortality rate after a
hip fracture was 18% (males, 31%; females, 16%), which was
8 times higher than that in the general population. The 10-year
mortality rate was 68%. Male gender, age >70 years, and nonoperative treatment showed a high correlation with increased
mortality.1 Between 1996 and 2006, the number and incidence
of osteoporotic hip fractures in Thailand increased, reaching
an average rate of 2% per year.2
Fragility fractures can result in limitations in activities of daily
living, fear of falls, and sometimes chronic pain, all of which can
seriously affect the quality of life (QOL). It was reported that
50% of women who sustain a hip fracture do not return to
their usual daily activities, while 33% will require long-term
care. Restoration of QOL after surgery and fracture healing
can be attained by two objectives: to reestablish mobility and
prevent future falls.
A multinational survey conducted in France, Germany, Italy,
Spain, the UK, and New Zealand reported that only 10% of
patients get a bone mineral density (BMD) measurement after surgical treatment of a fragility fracture. The presence of a
fragility fracture is the strongest indicator of the risk of future
fracture. In the USA, only 2% of patients with a femoral fracture receive in-hospital initiation of osteoporosis treatment.
In Thailand, osteoporosis is diagnosed in only 7% of post-hip
fracture patients, and only 6% of the patients receive antiosteoporotic treatment within 3 months of a fracture.3 Several
explanations have been proposed; a lack of awareness on the
part of surgeons and a fear of delaying fracture healing are
probably the leading causes.
Treatment with intravenous zoledronic acid after a hip fracture is associated with a 28% reduction in all-cause mortality
(hazard ratio, 0.72; 95% confidence interval, 0.5-0.93).4 Strontium ranelate may improve fracture healing in osteoporotic
patients. An observational study of four case reports demonstrated fracture consolidation after 3- to 4-months’ treatment
with strontium ranelate in men and postmenopausal women
who previously had pseudarthrosis.5
Preventing osteoporotic fractures can potentially reduce the
major consequences of osteoporosis. Thus, not only is secondary prevention important, but so is primary prevention.
A 10-mg daily dose of alendronate is effective for secondary
(number needed to treat [NNT]=16) and primary (NNT=50)
prevention of vertebral fractures in postmenopausal women.
It is also effective for secondary prevention of nonvertebral
fractures, including hip or wrist fractures (NNT=100), but it is
not effective for primary prevention of nonvertebral fractures.
Risedronate demonstrated a main benefit in the secondary
prevention of most osteoporotic fractures. At a dose of 5 mg
per day, statistically significant reductions in vertebral, nonvertebral, and hip fractures were observed (but not for wrist
fractures).
Strontium ranelate was shown to have antifracture efficacy
at spinal and nonvertebral sites in a wide range of patients,
from osteopenia sufferers to women over the age of 80 years,
including osteoporotic patients with or without a prior vertebral fracture. A reduction in hip fracture rates has also been
shown in women over the age of 74 years with low bone density at the femoral neck.6 ■
References
1. Vaseenon T, Luevitoonvechkij S, Wongtriratanachai P, Rojanasthien S. Long-term
mortality after osteoporotic hip fracture in Chiang Mai, Thailand. J Clin Densitom.
2010;13:63-67.
2. Wongtriratanachai P, Luevitoonvechkij S, Songpatanasilp T, et al. Increasing Incidence of Hip Fracture in Chiang Mai, Thailand. J Clin Densitom. 2013;16:347352.
3. Rojanasthien S, Chiewchantanakit S, Vaseenon T. Diagnosis and treatment of
osteoporosis following hip fracture in Chiang Mai University Hospital. J Med
Assoc Thai. 2005;88:S65-S71.
4. Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C.
Zoledronic acid and clinical fractures and mortality after hip fracture. New Engl
J Med. 2007;357:1799-809.
5. Alegre DN, Ribeiro C, Sousa C, et al. Rheumatol Int. 2012;32:439-443.
6. Kanis JA, Burlet N, Cooper C, et al. European guidance for the diagnosis and
management of osteoporosis in postmenopausal women. Osteoporos Int. 2008;
19:399-428.
215
CONTROVERSIAL
QUESTION
11. E. V. Rudenka, Belarus
Ema V. RUDENKA, MD, PhD
Scientific Research Laboratory
Belarusian Medical Academy of Postgraduate
Education
Minsk BELARUS
(e-mail: rudenka.ema@gmail.com)
M
y patients often ask me if it is possible to cure osteoporosis. And in each specific case I ponder what
to answer, as every single case is unique. But I always start my conversation with a discussion on the prevention of osteoporosis. In general, in order to improve the health
of the whole population, and of course to strengthen bone
tissue, we should summon six well-known “doctors”: sun,
water, sleep, exercise, diet, and a positive attitude. They are
the ones that know their job. All we need is to motivate ourselves to change our lifestyle in order to improve our health.
It is highly probable that in the absence of genetic predispositions, the risk of onset of osteoporosis will be minimal in the
future in those people who constantly follow the principles of
a healthy way of life. But are there a lot of heroes among us?
At this point, a visit to the doctor is required. And this means
examinations, establishing a diagnosis, and making decisions.
When speaking about osteoporosis more specifically, we are
talking about primary and secondary prevention of the consequences of osteoporosis. It is one thing if there are no fractures,
and entirely another if an osteoporotic fracture has occurred.
At the stage of primary prevention and diagnosed osteoporosis (which is possible only by means of dual-energy x-ray absorptiometry [DXA]), we are faced with a dilemma: is the risk of
osteoporotic fracture high enough to administer medical therapy? In this situation our decision is more likely to depend on
T-score, comorbidity, and the risk factors/patient age ratio.
Thanks to the efforts of the many experts who study osteoporosis, there is already a wealth of evidence regarding the
positive influence of healthy eating and adequate doses of calcium and vitamin D on decreasing the risk of falls and fractures,1 improving muscle strength and movement coordination, as well as providing conditions that enhance the efficacy
of the medical treatment of imbalances in bone metabolism.2
Nevertheless, for the primary prevention of osteoporosis I would
give a leading role in training the patient because knowledge
encourages adherence to the doctor’s recommendations, particularly for long-term drug therapy.3
216
When the osteoporotic process has been complicated by a
fracture, secondary prevention is required. This usually complex set of actions includes the administration of medicines
and is aimed at preventing recurrent fractures or instability of
the metal construct used in the surgical treatment of fractures.
BMD, risk factors, and even age play a lesser role; in this context, antiosteoporotic therapy can be administered if the fracture corresponds to the criteria of osteoporosis—ie, a fracture
that occurred as a result of minimal trauma. In such patients,
when examining x-rays of the zone of fracture, there is evidence of impaired bone mineralization. Fractures do not always happen in the zones subjected to DXA scanning; a literature review—and my own personal experience—has shown
that some patients with fractures have a T-score above –2.0
SD, which is the only dominant risk factor in their history.4
I am very impressed by the expert opinion of the Belgian Bone
Club regarding the organization of a set of measures for the
secondary prevention of osteoporosis.5 These measures are
integrated in multidisciplinary and multifactor nonpharmacological programs for the correction of osteoporosis and its
consequences, and include many aspects that can be influenced to prevent fractures in elderly patients. Prevention of
osteoporosis should therefore involve (i) the correction of osteoporosis risk factors, adequate doses of calcium and vitamin D, healthy nutrition, and—of course—falls prevention by
personal physical mobilization, creating conditions that improve the quality of life, the use of personal protection equipment (prosthetic devices, hip protectors, etc), and controlling
the doses of drugs that influence both bone tissue metabolism and fall frequency; and (ii) modern methods of surgical
treatment of both acute fractures and their consequences.
In conclusion, combining complex nonpharmacological programs aimed at correcting osteoporosis and its consequences
with antiosteoporotic drugs, significant involvement of the patient, and regular support by the doctor in charge can have
fantastic results. ■
References
1. Michael F. Holick, Neil C. Binkley, Heike A. Bischoff-Ferrari et al. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96:1911-1930.
2. Bischoff-Ferrari, HA, Willett WC, Orav EJ, et al. A pooled analysis of vitamin D
dose requirements for fracture prevention. N Engl J Med. 2012;367:40-49.
3. Kanda K, Puech M, Chen JS, et al. Models of care for the secondary prevention
of osteoporotic fractures: a systematic review and meta-analysis. Osteoporosis
Int. 2013;24:393-406.
4. Gourlay ML, Fine JP, Preisser JS, et al. Bone-density testing interval and transition to osteoporosis in older women. N Engl J Med. 2012;366:225-233.
5. Body JJ, Bergmann P, Boonen S, et al. Non-pharmacological management: a
consensus of the Belgian Bone Club. Osteoporosis Int. 2011;22:2769-2788.
CONTROVERSIAL
QUESTION
12. G. Singh, Malaysia
Gobinder SINGH, FRCS
Consultant Orthopaedic Surgeon
Pantai Medical Centre
Pantai Hospital Kuala Lumpur
Kuala Lumpur, MALAYSIA
(e-mail: gsjoints@gmail.com)
P
rimary prevention is understood to mean prevention of
a (first) osteoporosis-related fracture, and secondary
prevention is the prevention of a second fracture, after
detection of a first osteoporotic fracture.1 Common drug treatments for osteoporosis include bisphosphonates, selective
estrogen receptor modulators (SERMs), parathyroid hormone
analogues (teriparatide), anti-RANKL monoclonal antibody
(denosumab), and strontium ranelate.2 In all these treatments,
the patient must be advised to have an adequate intake of
vitamin D (800-1200 IU/day) and calcium (1000-1200 mg/
day),3 or be supplied with supplementation. In addition, hormone replacement therapy, as prescribed by gynecologists,
has a limited but definite role in osteoporosis, but the riskbenefit balance needs individual evaluation.4 All these drugs
can be subdivided into antiresorptive treatments (bisphosphonates, denosumab, SERMs) and anabolic agents (teriparatide, strontium ranelate).
For osteoporosis picked up at screening by dual-energy x-ray
absorptiometry (DXA) scanning or by using the FRAX ® tool,5
the commonest drug treatment prescribed in primary prevention are antiresorptive agents, with alendronate (a bisphosphonate) currently being the most commonly prescribed drug.
Worldwide, secondary osteoporosis prevention uses the same
drugs.6
Many orthopedic surgeons are, however, wary of prolonged
antiresorptive therapy, which can so dramatically reduce bone
resorption that serum CTX levels can approach zero. The concern that these doctors have is that bone remodeling, with a
balance between resorption by osteoclast activity and bone
formation by osteoblasts is important in maintaining bone
health and healing the microfractures that occur naturally dur-
ing the activities of daily living (the “frozen bone” concept).
Orthopedic surgeons have all seen the so-called “atypical fractures”—for example in the subtrochanteric femur—which
occur in patients on prolonged antiresorptive therapy. During surgery, the bone seems very well mineralized, but is extra
hard. These fractures are often treated with internal fixation
with a variety of additional modalities such as bone grafting
or the addition of bone morphogenic proteins, etc. Studies
suggest that these fractures do heal, but the low energy nature of these fractures is worrying.6
Currently, antiresorptive therapy needs, in my opinion, to be
used for short periods of 5 years or less, and not at all unless
frank osteoporosis (as determined by a BMD DXA T-score of
less than –2.5 SD) is present.
My own practice is to use anabolic agents for secondary prevention of osteoporosis, and especially in patients who suffer
fractures while on antiresorptive therapy. The drug of choice
is either parenteral teriparatide or oral strontium ranelate, with
teriparatide usually used in severe osteoporosis for a short period, and strontium ranelate being used for ongoing therapy.
As a result of my own comfort level with the management
of osteoporosis with these drugs, my preference for primary
prevention has also moved to anabolic agents, with strontium
ranelate usually being the drug of choice. In all cases, adequate calcium and vitamin D intake should be ensured. ■
References
1. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2008;19:399-428
2. International Osteoporosis Foundation. Treating osteoporosis. http://www.iofbone
health.org/treating-osteoporosis. Accessed September 16, 2013
3. Body JJ, Bergmann P, Boonen S, et al. Evidenced-based guidelines for the pharmacological treatment of postmenopausal osteoporosis: a consensus document
by the Belgian Bone Club. Osteoporos Int. 2010:21:1657-1680.
4. Vickers MR, MacLennan AH, Lawton B, et al. Main morbidities recorded in the
women’s international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women. BMJ. 2007;335:239.
5. FRAX®. WHO Fracture Risk Assessment Tool. http://www.shef.ac.uk/FRAX/.
Accessed Sept 16, 2013.
6. Body JJ. How to manage postmenopausal osteoporosis? Acta Clin Belg. 2011;
66:443-447.
217
CONTROVERSIAL
QUESTION
13. B. Stolnicki, Brazil
Bernardo STOLNICKI, MD
Federal Hospital
Ipanema
Rio de Janeiro, BRAZIL
(e-mail: stolnick@hotmail.com)
T
he guidelines for treating osteoporosis do not differentiate between osteoporotic patients who have had a
prior fracture and those who have not. They only recommend that patients with prior fractures should be treated. For example, the drugs recommended as first- and second-line are the same.
On the other hand, there are well-defined criteria for changing medication in case of treatment failure. The occurrence of
one or more fractures during treatment is considered as treatment failure. However, there is no indication that these criteria may be used in patients with prior fractures without pretreatment.
The site of the fracture makes a difference. A vertebral fracture increases the chance of another fracture 4-fold; while a
fractured wrist increases it 2-fold. Some fracture liaison services (FLS) consider that the cost-benefit balance of starting
secondary prevention after a fractured wrist is not positive.
Others include this type of patient (which is what I usually do).
Ankle fractures, in this respect, are comparable to wrist fractures. However, there are no questions in relation to fractures
of the hip and proximal humerus. Recommendations for physical activity and rehabilitation are directly linked to the type
of prior fracture and the possible limitations its sequelae can
impose.
Prevention of falls is critical in both primary and secondary
prevention, as is ruling out the causes of secondary osteoporosis. Long-term safety and effective antifracture drugs
must be used and adequate calcium and vitamin D supplementation required. What must differ in our approach to a pa-
218
tient who has already had an osteoporotic low-trauma fracture compared with another who has had no fracture is basically our attitude. The historic low adherence to antiosteoporotic treatment, which in primary prevention is a problem,
becomes a catastrophe in secondary prevention because of
the high risk of new fractures. The use of oral bisphosphonates
is associated with low adherence. In the case of generic alendronate (which is the most used), it is even more obvious and
the fractures that occur as a result of this notorious noncompliance are not taken into account when evaluating this apparently cheaper drug.
One of the strategies recommended by the Committee of
Scientific Advisors of the IOF (International Osteoporosis Foundation), when referring to treatment failure in osteoporosis, is
to replace an oral drug by an injected drug. There is no doubt
that this recommendation is given because injected drugs
are used quarterly, semi-annually, or annually, which improves
treatment adherence.
The new status quo (the new fracture) requires this type of
intervention. However, adherence is still below the desired level. One of the reasons for this lies in the habit of reviewing patients only once per year. There is no other serious illness (and
osteoporosis is a serious illness; osteoporosis with fractures
even more so) for which the follow-up is only done on an annual basis. This is not the case, for example, for diabetes, arterial hypertension, or heart disease.
The routine in our FLS is that there is a visit every four months
in the first year; in the following years, the review is every six
months. At each visit blood samples are collected to assess
total serum calcium and 25OH vitamin D.
Motivating patients is of the utmost importance. The results
of bone densitometry, with their small positive variations, often
discourage patients. However, adequate vitamin D replacement demonstrates encouraging and motivating results. Since
the majority of fractures occur in the first two years following a fracture, maintaining motivation and adherence is crucial at least in this period. ■
‘‘
INTERVIEW
Education and awareness-increasing programs are an essential strategy to increase the rate of
treatment in people who have already sustained an osteoporotic
fracture and who do not realize that
they are at major risk of subsequent
fracture. By taking an active role in
managing or referring patients with
osteoporosis, the orthopedic surgeon can ensure that patients with
fractures are adequately investigated and treated.”
Fracture liaison services and
secondary fracture prevention
“Whoever has a fracture, will fracture again”
Interview with R. Rizzoli
a n d T. C h e va l l e y, S w i t z e r l a n d
S
René RIZZOLI, MD
Thierry CHEVALLEY, MD
Service of Bone Diseases
Geneva University Hospitals
and Faculty of Medicine
Geneva, SWITZERLAND
trategies for osteoporosis prevention may include a population-based
approach through the promotion of modifications in lifestyle habits (including specific exercise regimens, changes in diet, and avoiding risk factors like smoking). Nevertheless, evidence of the efficacy of such a populationbased approach is still missing. Widespread screening at the menopause on
the basis of bone mineral density (BMD) alone is not generally recommended
because of its poor sensitivity and specificity when used for screening. Monitoring by a coordinating nurse and better adherence to treatment have been
shown to decrease the incidence of fractures over 2 years compared with usual medical care. A prevalent low-trauma fracture is the strongest risk factor, independent of BMD values, to identify patients at increased risk of subsequent
fracture. A prevalent vertebral fracture is associated with a 4- to 5-fold increase
in the risk of further vertebral fracture, particularly within the first year, while
a doubling of the risk of a hip fracture is expected after a vertebral fracture or
after a fracture of the proximal humerus or distal forearm. In elderly women, prior wrist fracture is a risk factor for morphometric vertebral fracture independent of BMD, but the association between prior wrist fracture and incident hip
fracture is largely explained by hip BMD. Overall, patients with a history of any
type of prior fragility fracture have a significantly increased risk of any fracture
compared with individuals without a prior fracture. Therefore, patients with a
low-trauma fracture should be considered as a high-risk group to be targeted
for diagnostic and treatment procedures. Despite this evidence, patients with
low-trauma fractures are rarely considered for appropriate measures.
Do you think that there is a lack of awareness
about osteoporosis?
he lack of knowledge about osteoporosis is observed first at the level of the
patients and is influenced by age, level of education, level of physical activity,
calcium intake, and personal experience. A study showed that women admitted to hospital with a hip fracture were unaware that they had osteoporosis or
had never considered treatment for it.1 Moreover, a questionnaire administered within 10 days of a low-trauma fracture to assess patients’ perception of the cause of
their fracture showed that although 79% of patients had already heard of osteoporosis, the majority (73%) believed that their fracture was not related to bone fragility
(Table I, page 220),2 irrespective of the type of facture. This lack of awareness and
T
Prof René Rizzoli, Service of Bone
Diseases, Geneva University
Hospitals and Faculty of Medicine,
1211 Geneva 14, Switzerland
(e-mail: rene.rizzoli @unige.ch
thierry.chevalley@hcuge.ch)
Fracture Liaison Service and secondary fracture prevention – Rizzoli and Chevalley
219
INTERVIEW
Fractures
sites
Hip
Already heard of
osteoporosis (%)
Fracture not related
to bone fragility (%)
87.7
69.9
Humerus
85.7
73.9
Wrist
84.6
66.6
Spine
82.2
73.3
Other
88.8
61.2
effective antiosteoporotic medications and the publication of
clinical guidelines (Table II),12-17 more than 75% of women and
about 90% of men with a high likelihood of osteoporosis are
not investigated and/or treated after a low-trauma fracture.
What are the educational needs of patients and
doctors?
Table I. Patient awareness of osteoporosis according to the site
of fracture (personal data).
n osteoporosis, like in all chronic diseases, persistence and
compliance decrease with time, particularly in the first year.
Lack of adherence has an impact on the individual since lower adherence to osteoporosis treatment is associated with a
significantly greater risk of fracture.
I
knowledge is also observed in orthopedic surgeons, who are
usually the first—and often the only—physician seen by the
fractured patient. Orthopedic surgeons take care of about Information about osteoporosis given by general practitioners,
80% of wrist fractures,3 which may occur well before more especially when supported by a bone mineral density (BMD)
debilitating fractures. The World Orthopaedic Osteoporosis measurement, is associated with a 2- to 3-fold greater likeOrganization (WOOO) strongly advocates a leading role for lihood of a patient receiving specific antiosteoporotic theraorthopedic surgeons in the management of osteoporosis in py.18,19 We conducted a prospective study in the service of
patients with fragility fracture. A survey performed by the In- general internal medicine of a large university teaching hosternational Osteroporosis Foundation (IOF) among 3422 or- pital in Geneva to evaluate the impact of an educational inthopedic surgeons in France, Germany, Italy, Spain, the Unit- tervention on the recognition of vertebral fractures and on the
ed Kingdom, and New Zealand showed that identification and
prescription of antiosteoporosis treatment among general intreatment of the osteoporotic patient were insufficient in many
ternists.20 During a 3.5-month observation period (phase 1),
4
areas. This survey clearly indicated that many orthopedic surall lateral spine or chest radiographs of consecutive inpatients
older than 60 years were reviewed by two independent ingeons still neglect to identify, assess, and treat osteoporosis
patients with fragility fractures. Primary care physicians are vestigators, and vertebral fractures were graded according to
even less likely to recognize and treat osteoporosis than spe- their severity. Radiology reports and general internists’ discharge summaries were compared. During the following 2cialist endocrinologists or rheumatologists, as they have less
month intervention period (phase 2), internists were actively
exposure to specific education about osteoporosis. Regarding vertebral fracture recognition, a prospective study carried educated about vertebral fracture identification by means of
out in the general internal medicine ward of a large univer- lectures, posters, and leaflets. Radiologists did not receive this
sity teaching hospital in Geneva showed that only 22% of pa- educational program and served as controls. In the observatients with vertebral fracture had a diagnosis mentioned in tion phase, the radiologists detected 34%, and the internists
their discharge summary and only 11% benefited from spe- 22%, of prevalent vertebral fractures. During the education
intervention phase, the radiologists detected 22% of prevacific osteoporosis management.5 Efficacious treatments (eg,
hormone replacement therapy, selective
estrogen receptor modifiers, bisphosphoEffect on vertebral
Effect on nonvertebral
nates, denosumab, strontium ranelate, or
fracture risk
fracture risk
teriparatide) reduce the risk of fracture
Established
Established
by 30% to 60%6-9 and are highly costOsteoporosis osteoporosisa
Osteoporosis osteoporosisa
10,11
effective.
Even simple measures like
vitamin D and calcium supplementation
Alendronate
+
+
NA
+ (including hip)
can reduce hip fractures, particularly in
Risedronate
+
+
NA
+ (including hip)
institutionalized and housebound elderly
Ibandronate
NA
+
NA
+b
people. Despite the availability of these
Zoledronic acid
+
+
NA
+c
Table II. Antifracture efficacy of the most
frequently used treatments for postmenopausal osteoporosis when given with calcium
and vitamin D, as derived from randomized
controlled trials.
Abbreviations: HRT, hormone replacement therapy;
NA, no evidence available; PTH, parathyroid hormone.
After reference 17: Kanis et al. Osteoporos Int.
2013;24:23-57. © 2013, International Osteoporosis
Foundation and National Osteoporosis Foundation.
220
HRT
Raloxifene
Teriparatide
and PTH
Strontium ranelate
Denosumab
+
+
+
+
+
NA
+ (including hip)
NA
NA
+
NA
+d
+
+
+
+c
+ (including hipb) + (including hipb)
+ (including hip)
+c
a Women
with a prior vertebral fracture; b In subsets of patients; c Mixed group of patients with or
without prevalent vertebral fracture; d Shown for teriparatide only.
INTERVIEW
SELECTED
BMD
DXA
QALY
quality-adjusted life-year
lent vertebral fractures, whereas among the internists the detection rate almost doubled (43%; P=0.008 compared with
phase 1). The percentage of patients with vertebral fracture
who benefited from medical management of their osteoporosis increased from 11% (phase 1) to 40% (phase 2, P<0.03).
These findings confirm the large underrecognition of vertebral fractures by physicians, irrespective of their severity, and
demonstrate that a simple educational program can improve
their detection on routine radiographs and, consequently, improve osteoporosis management.
Why is a Fracture Liaison Service a good option
for osteoporotic patient management?
rthopedic surgeons are at the forefront for the identification and treatment of patients with fragility fracture, though general practitioners may also play a central role in referral and management. Another option is to use
a nurse-led service to evaluate all patients with a recent fragility fracture. The interventions comprise three components:
(i) prevention of falls; (ii) nutritional deficit correction; and (iii)
pharmaceutical treatment of osteoporosis. An effective osteoporosis service requires a multidisciplinary team of health professionals, headed by a clinician with expertise in osteoporosis to ensure consistent management of osteoporosis.
O
Clinical pathways are already applied to surgical diagnosis and
postsurgical care, particularly in orthopedics, cardiac surgery,
and urology, and for nonsurgical patients (such as those with
inflammatory arthritis, or infectious or thrombotic diseases).
These pathways allow for a reduction in the length of hospital stays and a decrease in health care costs.21-24 As the risk
of fracture increases after the first fracture and the latter often
goes undiagnosed and untreated, education and awarenessincreasing programs are an essential strategy to increase the
rate of treatment in people who have already sustained an
osteoporotic fracture and who do not realize that they are at
major risk of subsequent fracture. By taking an active role in
managing or referring patients with osteoporosis, the orthopedic surgeon can ensure that patients with fractures are
adequately investigated and treated in order to improve the
long-term outcome of these individuals.
A study compared the investigation and treatment of osteoporosis offered to fractured patients at two orthopedic centers
in the UK25; one center had an established fracture liaison
service, while the other center relied upon individual clinicians
to initiate investigation or treatment for osteoporosis in patients
following fracture. In the center with a fracture liaison service,
85% of patients with a proximal humeral fracture and 20%
of those with a hip fracture had been offered a dual-energy
x-ray absorptiometry (DXA) scan. Approximately 50% and
85%, respectively, were receiving treatment for osteoporosis
6 months following their fracture. This compared with DXA examination being offered to only 6% and 9.7% of humeral and
hip fracture patients, respectively, and 20% (hip) and 27%
(proximal humerus) of patients receiving osteoporosis treatment in the other center. Based on this observation, all patients
admitted for fragility fractures in Glasgow are now offered evaluation and treatment of their underlying osteoporosis.
In elderly patients presenting to the orthopedic unit with lowenergy hip or distal radius fractures at Manchester Royal Infirmary, an initial retrospective survey demonstrated that only
16% of elderly female patients with low-energy hip fractures
and none of those (0%) with distal radius fractures were given a treatment or referred for further investigation for possible
osteoporosis.26 Nevertheless, after changes in their practice,
76% (P<0.00001) of patients with hip fractures and 81%
(P<0.00001) of those with distal radius fractures were investigated, given a treatment, or referred to a consultant physician for the management of osteoporosis. A recent randomized study showed that the offer of a free BMD assessment
was associated with a significantly higher rate of investigation
than a personalized letter alone, but this investigation did not
affect the treatment rate, which reflected significant participantand doctor-related barriers to osteoporosis management.
Recently, barriers encountered in setting up these clinical
pathways were reviewed and proven solutions to overcome
them were identified. Thus, treatment of diagnosed vertebral
fractures in primary care is becoming more common. A prospective randomized intervention study has recently shown
that, following distal radius fractures, BMD tests and initiation
of treatments were more frequent in patients for whom the
orthopedic surgeon ordered the tests and forwarded the results to the primary care physician than in those for whom he/
she sent a letter to the primary care physician outlining guidelines for osteoporosis screening. In another randomized clinical trial including 62 patients, management initiated by the
orthopedic surgeon improved the rate of early osteoporosis
treatment after hip fracture compared with osteoporosis management initiated by the primary care physician (58% vs 29%,
P=0.04).27 A recent systematic review and meta-analysis on
models of care for the secondary prevention of osteoporotic
fractures has confirmed that in all models—model A (identification, assessment, and treatment initiation), model B (identification and assessment), and model C (alerting patients plus
primary care physician)—the percentage of patients that had
a BMD test and received treatment was higher in the intervention group.28 Adherence after intervention varied between
34% and 95% at 12 months among type A studies. In one
type B study, there was 86% adherence at 12 months.29
221
INTERVIEW
A recent UK study reported an improvement in adherence to
57% at 1 year through patient support in the form of treatment
monitoring by nurses, and there was a trend for the monitored
group to persist with therapy for 25% longer compared with
no monitoring.30 In this study, monitoring by nurses had a
greater impact on adherence and persistence than the provision of bone marker results to patients. Adherence to various
osteoporosis medications has also been shown to result in a
16% to 36% lower fracture rate over 2 years. A correct understanding of DXA results may lead to higher treatment rates
and better adherence to treatment among patients with low
BMD. One year after initiating treatment for osteoporosis,
45.2% of 40 002 patients were not continuing to fill their prescriptions; although several patient characteristics significantly correlated with compliance, adjusted models explained little of the variation. As the patients, their relatives, and primary
care physicians became more informed and engaged in treatment decisions, compliance with therapy improved. Indeed, in
this study, a telephone survey of 50 randomly selected patients with hip fracture revealed that 82% (41/50) remained on
antiosteoporotic treatment at least 6 months after discharge
from the hospital.
How effective is a fracture liaison service from the
patient’s point of view?
o improve knowledge of the disease and adherence to
osteoporosis treatment, our osteoporosis clinical pathway includes an interactive educational program led by
a multidisciplinary team (nurse, dietitian, physiotherapist, occupational therapist, and physician) approximately 8 to 12
weeks after fracture. Nutrition, physical activity, fall prevention, and available osteoporosis treatments are discussed, as
well as the results of the DXA examination. One of the major
aims is to increase patients’ knowledge and confidence about
what they can do to help themselves (eg, taking medication,
calcium and vitamin D supplements, and lifestyle changes)
and to develop an ongoing partnership between health professionals, the patient, and the patient’s family.
T
An integrated-care delivery model for postfracture care was reported in Ontario, Canada. The initial component of this model focuses on improving emergency department/fracture clinic communication to patients and their family physician. A
multicomponent educational intervention focused on osteoporosis screening and management was associated with a
significant increase in the overall rate of adherence to osteoporosis management guidelines in high-risk older patients.31
Is a Fracture Liaison Service cost-effective?
n a first nonrandomized controlled trial in 102 Canadian patients older than 50 years with a wrist fracture, a multifaceted intervention consisting in faxed physician reminders
about osteoporosis treatment guidelines led to a 30% ab-
I
222
solute increase in osteoporosis treatment within 6 months as
compared with usual care.32 This intervention strategy was
cost-effective, saving Can$13 per patient and gaining 0.012
quality-adjusted life-year (QALYs) per patient.
Another cost-effective analysis in postfracture osteoporosis
management in Canada has shown that hiring a coordinator
costs less than Can$25 000 to avoid one hip fracture and that
it is cost-saving when the coordinator manages as few as 350
patients annually.33
Another cost-benefit analysis of fracture liaison services was
performed based on data collected by the West Glasgow
Fracture Liaison Service. Based on a hypothetical cohort of
1000 fragility fracture patients, it was estimated that 686 of
740 patients requiring treatment would receive treatment by
the fracture liaison service compared with 193 in usual care.
Despite additional costs for assessments and drugs, £21 000
could be saved since 18 fractures (including 11 hip fractures)
would be prevented.29
In an Australian prospective controlled fracture prevention
study, a Markov model was developed that integrated fractures probabilities and resources utilization data obtained directly from their 4-year Minimal Trauma Fracture Liaison Service (MTFL), which significantly reduces the risk of refracture by
80%.34 This model accounted for hip, forearm, and humerus
fractures. Over the 10-year simulation period and as compared
with a parallel control group treated by standard care, the
MTFL improved QALYs by 0.089 years and led to increased
costs of 1486 Australian dollars (AUD) per patient. Overall, the
incremental cost-effectiveness ratio versus standard care was
AUD 17 291 per QALY gained.
In a randomized trial of 220 patients with hip fracture, it was
demonstrated that a hospital-based case manager can increase the rate of appropriate osteoporosis treatment to 51%
compared with 22% for usual care. A Markov decision-analytic model showed that the intervention cost Can$56 per
patient and that for every 100 patients it could prevent approximately 4 hip fractures and 6 fractures in total. This intervention was also associated with a modest increase of 0.04
QALYs and a cost saving of Can$2576 per patient.35
In another randomized trial of 272 patients 50 years of age or
older with wrist fracture, a multifaceted quality improvement
intervention directed at patients and their primary care physicians tripled the rates (22% vs 7%) of osteoporosis treatment
within 6 months of fracture compared with usual care. A costeffectiveness analysis of this intervention has also shown that
for 100 included patients, approximately 1 hip fracture and 3
fractures in total could be avoided. Therefore, compared with
usual care, a modest increase of 0.011 QALYs and a cost
saving of Can$268 per patient were associated with the intervention strategy.36
INTERVIEW
In a 4-year prospective controlled study investigating the effect of a coordinated intervention program, the risk of new
fractures was lower in the intervention group (4% vs 19%,
P<0.01); moreover, the median time to refracture was prolonged to 26 months, while it was 16 months (P<0.01) in the
control group.37 Therefore, the cumulative incidence of first
refracture in the intervention and control groups was 0.5% vs
7.5% at 12 months and 1.5% vs 17% at 24 months. By linking electronic medical records of 620 000 fracture patients
with guidelines for osteoporosis management through a network approach, the Kaiser Southern California Healthy Bones
Program resulted in a significant increase in referrals for bone
densitometry and prescriptions of antiosteoporotic therapies
compared with historical data. In addition, the number of hip
fractures had decreased by an average of 37%, which showed
that this approach is highly cost-effective.29,33
Low-trauma
fracture
Osteoporosis
pathway
STEPS
Fracture
acute care
Information
Risk factors
Dietary intake
Biology
1
2
Primary care
physician
Complementary
investigations
DXA
Bone markers
Rule out
secondary OP
6-Month
evaluation
Treatment proposals
+
Teaching program
3
Orthopedic
surgeon
or
Could you please explain how your fracture
liaison service works?
recent low-trauma fracture is the primary criterion to
identify patients at increased risk of osteoporosis and
of subsequent fracture to whom tailored additional
investigations and preventive strategy of care are proposed
by the orthopedic surgeon and/or primary care physician. In
addition, an interactive educational program on the management of the disease is proposed to the patients and their families.2 After the acute care of the low-trauma fracture by the
orthopedic team, patients are enrolled for medical management into this “osteoporosis pathway,” which includes three
steps (Figure 1).2
A
First, the coordinating nurse collects data on osteoporosis risk
factors—including previous fractures—on the degree of patient awareness of osteoporosis, and on calcium and protein
intake. Second, a bone density measurement and/or additional biochemical determinations to rule out secondary osteoporosis are proposed. The role of the managing nurse is to
coordinate and monitor care in the orthopedic ward, to in-
Constant interaction (information,
chart, e-mail, online advice…)
Figure 1. Course of the osteoporosis clinical pathway.
Green arrows represent the patient’s track from the low-trauma fracture and red
arrows represent the constant interaction between the physician in charge of
the patient and the multidisciplinary team of the osteoporosis clinical pathway.
Abbreviations: DXA, dual-energy x-ray absorptiometry; OP, osteoporosis.
After reference 2: Chevalley et al. Osteoporos Int. 2002;13(6):450-455. © 2012,
International Osteoporosis Foundation and National Osteoporosis Foundation.
crease patient awareness and also to provide education on
osteoporosis to the staff. Referral to a metabolic bone diseases specialist for patients with a complex medical history
and/or other bone disease concerns about 8% of the patients
enrolled in our osteoporosis pathway. Third, treatment proposals, with information on their costs and potential side effects, are forwarded to the orthopedic surgeon or the primary care physician, who decides upon the implementation
of these proposals. These proposals are based on published
clinical guidelines for postmenopausal osteoporosis.17 An educational program is proposed, which is open to family members as well. (Figure 1).2 ■
References
1. Mauck KF, Cuddihy MT, Trousdale RT, et al. The decision to accept treatment
for osteoporosis following hip fracture: exploring the woman’s perspective
using a stage-of-change model. Osteoporos Int. 2002;13(7):560-564.
2. Chevalley T, Hoffmeyer P, Bonjour JP, Rizzoli R. An osteoporosis clinical pathway for the medical management of patients with low-trauma fracture. Osteoporos Int. 2002;13(6):450-455.
3. Cuddihy MT, Gabriel SE, Crowson CS, et al. Osteoporosis intervention following distal forearm fractures: a missed opportunity? Arch Intern Med. 2002;162
(4):421-426.
4. Dreinhofer KE, Anderson M, Feron JM, et al. Multinational survey of osteoporotic fracture management. Osteoporos Int. 2005;16(suppl 2):S44-S53.
5. Casez P, Uebelhart B, Gaspoz JM, Ferrari S, Louis-Simonet M, Rizzoli R. Targeted education improves the very low recognition of vertebral fractures and osteoporosis management by general internists. Osteoporos Int. 2006;17(7):965970.
6. Reginster JY, Adami S, Lakatos P, et al. Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the
MOBILE study. Ann Rheum Dis. 2006;65(5):654-661.
7. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment
of postmenopausal osteoporosis. N Engl J Med. 2007;356(18):1809-1822.
8. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the
risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl
J Med. 2004;350(5):459-468.
9. Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium ranelate reduces the
risk of nonvertebral fractures in postmenopausal women with osteoporosis:
Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab. 2005;90(5):2816-2822.
10. Delmas PD, Rizzoli R, Cooper C, Reginster JY. Treatment of patients with postmenopausal osteoporosis is worthwhile. The position of the International Osteoporosis Foundation. Osteoporos Int. 2005;16(1):1-5.
11. Schousboe JT, Ensrud KE, Nyman JA, Melton LJ, 3rd, Kane RL. Universal bone
densitometry screening combined with alendronate therapy for those diagnosed
with osteoporosis is highly cost-effective for elderly women. J Am Geriatr Soc.
2005;53(10):1697-1704.
12. Seeman E, Eisman JA. 7: Treatment of osteoporosis: why, whom, when and
how to treat. The single most important consideration is the individual's ab-
223
INTERVIEW
solute risk of fracture. Med J Aust. 2004;180(6):298-303.
13. Compston J. Guidelines for the management of osteoporosis: the present and
the future. Osteoporos Int. 2005;16(10):1173-1176.
14. Solomon DH, Morris C, Cheng H, et al. Medication use patterns for osteoporosis: an assessment of guidelines, treatment rates, and quality improvement interventions. Mayo Clin Proc. 2005;80(2):194-202.
15. Kaptoge S, Armbrecht G, Felsenberg D, et al. Whom to treat? The contribution
of vertebral X-rays to risk-based algorithms for fracture prediction. Results from
the European Prospective Osteoporosis Study. Osteoporos Int. 2006;17(9):
1369-1381.
16. McClung MR. Do current management strategies and guidelines adequately
address fracture risk? Bone. 2006;38(2 suppl 2):S13-S17.
17. Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY; Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF). European
guidance for the diagnosis and management of osteoporosis in postmenopausal
women. Osteoporos Int. 2013;24(1):23-57.
18. Fitt NS, Mitchell SL, Cranney A, Gulenchyn K, Huang M, Tugwell P. Influence of
bone densitometry results on the treatment of osteoporosis. CMAJ. 2001;164
(6):777-781.
19. Pickney CS, Arnason JA. Correlation between patient recall of bone densitometry results and subsequent treatment adherence. Osteoporos Int. 2005;16
(9):1156-1160.
20. Casez P, Uebelhart B, Gaspoz JM, Ferrari S, Louis-Simonet M, Rizzoli R. Targeted education improves the very low recognition of vertebral fractures and
osteoporosis management by general internists. Osteoporos Int. 2006;17(7):
965-970.
21. Warner BW, Kulick RM, Stoops MM, Mehta S, Stephan M, Kotagal UR. An evidenced-based clinical pathway for acute appendicitis decreases hospital duration and cost. J Pediatr Surg. 1998;33(9):1371-1375.
22. Dowsey MM, Kilgour ML, Santamaria NM, Choong PF. Clinical pathways in
hip and knee arthroplasty: a prospective randomised controlled study. Med J
Aust. 1999;170(2):59-62.
23. Marrie TJ, Lau CY, Wheeler SL, Wong CJ, Vandervoort MK, Feagan BG. A controlled trial of a critical pathway for treatment of community-acquired pneumonia. CAPITAL Study Investigators. Community-Acquired Pneumonia Intervention Trial Assessing Levofloxacin. JAMA. 2000;283(6):749-755.
24. Bradshaw BG, Liu SS, Thirlby RC. Standardized perioperative care protocols
and reduced length of stay after colon surgery. J Am Coll Cardiol. 1998;186(5):
501-506.
25. Murray AW, McQuillan C, Kennon B, Gallacher SJ. Osteoporosis risk assessment and treatment intervention after hip or shoulder fracture. A comparison of
two centres in the United Kingdom. Injury. 2005;36(9):1080-1084.
26. Charalambous CP, Kumar S, Tryfonides M, Rajkumar P, Hirst P. Management
of osteoporosis in an orthopaedic department: audit improves practice. Int J
Clinl Pract. 2002;56(8):620-621.
27. Miki RA, Oetgen ME, Kirk J, Insogna KL, Lindskog DM. Orthopaedic management improves the rate of early osteoporosis treatment after hip fracture. A randomized clinical trial. J Bone Joint Surg Am. 2008;90(11):2346-2353.
28. Ganda K, Puech M, Chen JS, et al. Models of care for the secondary prevention of osteoporotic fractures: a systematic review and meta-analysis. Osteoporos Int. 2013;24(2):393-406.
29. McLellan AR, Wolowacz SE, Zimovetz EA, et al. Fracture liaison services for the
evaluation and management of patients with osteoporotic fracture: a cost-effectiveness evaluation based on data collected over 8 years of service provision. Osteoporos Int. 2011;22(7):2083-2098.
30. Clowes JA, Peel NF, Eastell R. The impact of monitoring on adherence and
persistence with antiresorptive treatment for postmenopausal osteoporosis: a
randomized controlled trial. J Clin Endocr Metab. 2004;89(3):1117-1123.
31. Simone MJ, Roberts DH, Irish JT, et al. An educational intervention for providers
to promote bone health in high-risk older patients. J Am Geriatr Soc. 2011;59(2):
291-296.
32. Majumdar SR, Johnson JA, Lier DA, et al. Persistence, reproducibility, and costeffectiveness of an intervention to improve the quality of osteoporosis care after
a fracture of the wrist: results of a controlled trial. Osteoporos Int. 2007;18(3):
261-270.
33. Sander B, Elliot-Gibson V, Beaton DE, Bogoch ER, Maetzel A. A coordinator
program in post-fracture osteoporosis management improves outcomes and
saves costs. J Bone Joint Surg Am. 2008;90(6):1197-1205.
34. Cooper MS, Palmer AJ, Seibel MJ. Cost-effectiveness of the Concord Minimal
Trauma Fracture Liaison service, a prospective, controlled fracture prevention
study. Osteoporos Int. 2012;23(1):97-107.
35. Majumdar SR, Lier DA, Beaupre LA, et al. Osteoporosis case manager for patients with hip fractures: results of a cost-effectiveness analysis conducted alongside a randomized trial. Arch Intern Med. 2009;169(1):25-31.
36. Majumdar SR, Lier DA, Rowe BH, et al. Cost-effectiveness of a multifaceted intervention to improve quality of osteoporosis care after wrist fracture. Osteoporos Int. 2011;22(6):1799-1808.
37. Lih A, Nandapalan H, Kim M, et al. Targeted intervention reduces refracture rates
in patients with incident non-vertebral osteoporotic fractures: a 4-year prospective controlled study. Osteoporos Int. 2011;22(3):849-858.
Keywords: fracture liaison service; osteoporosis; patient management; secondary fracture prevention
LES
SERVICES DE PRISE EN CHARGE DES FRACTURES (F RACTURE L IAISON
ET LA PRÉVENTION SECONDAIRE DES FRACTURES
SERVICES)
Promouvoir les modifications des habitudes de vie (activité physique spécifique, régime alimentaire et annuler des
facteurs de risque comme le tabac) fait partie des mesures de prévention de l’ostéoporose comme approche basée
sur la population. Néanmoins, l’efficacité d’une telle approche reste encore à démontrer. Un large dépistage à la ménopause sur la base de la seule densité minérale osseuse (DMO) n’est généralement pas recommandé en raison de
ses faibles spécificité et sensibilité. Le suivi thérapeutique par une infirmière référente et une meilleure adhésion permettent de réduire l’incidence des fractures sur 2 ans, par rapport aux soins médicaux habituels. Le facteur de risque
le plus important, indépendant des valeurs de la DMO, pour identifier les patients à risque augmenté de future fracture, est une fracture à basse énergie prévalente. Une fracture vertébrale prévalente est associée à un risque 4 à 5
fois plus élevé de fracture vertébrale ultérieure et le risque de fracture de la hanche est doublé après une fracture vertébrale ou après une fracture de l’humérus ou du radius. Chez la femme âgée, un antécédent de fracture du poignet
est un facteur de risque de fracture vertébrale indépendant de la DMO, mais l’association entre fracture antérieure
du poignet et fracture incidente de la hanche s’explique en grande partie par la DMO de la hanche. Les patients avec
un antécédent de fracture de fragilité, quel qu’il soit, ont un risque augmenté de toute autre fracture par rapport aux
sujets sans antécédent de fracture. Les patients ayant une fracture traumatique à basse énergie devraient donc être
considérés comme un groupe à haut risque pour bénéficier des méthodes diagnostiques et thérapeutiques, mais
dans la pratique c’est rarement le cas.
224
‘‘
FOCUS
In addition to the well-accepted effects of calcium and vitamin D on the course of osteoporosis, some drugs are putting up
a good performance in the fight
against this silent pathology...
Not only are these drugs used in
the prevention of osteoporotic
fractures, but also in strengthening cortical and cancellous bone
to aid the orthopedic surgeon in
the treatment of fractures: the
bone is rebuilt to restore its form
and function, which have been
compromised by fracture.”
Complicated fractures: how
should one deal with them?
b y D . N . A l e g re , Po r t u g a l
C
Duarte Nuno ALEGRE, MD
Head of Orthopaedics and
Traumatology Unit
Hospital Escola da Universidade Fernando Pessoa
Gondomar
Porto, PORTUGAL
omplicated fractures have always occurred and been a feature in orthopedic trauma centers around the world, but in the very last few
decades, they have occurred with increasing incidence and with a
complexity never seen before. High-energy trauma is in part responsible for
this, but the main cause is osteoporotic fragility fractures in elderly patients.
The reason for the latter is the increased longevity of the world’s population;
a very good event for humanity, but bad news for the body’s support system,
the osteoarticular system, which is generally not prepared for having to bear
us every day for an increasing number of decades. The purpose of this article is not only to alert the reader to this new reality, but also to provide information on how to react to the phenomenon, giving numbers and facts. We’ll
begin with a real clinical case of an osteoporotic fracture patient, moving on
to the incredibly dynamic and alive physiology of bone, followed by a review
of what we can do in practice to help change one of the worst realities of becoming old today: osteoporotic fractures and their frightening progressive
fracture cascade.
rthopedic surgeons are having to treat increasingly more complicated fractures in their hospitals every day. The reason? Osteoporosis, which goes
hand in hand with the increasingly long lives being experienced by people
worldwide. If, some decades ago, osteoporosis was rarely seen, today it is quite common in everyday clinical practice. In past decades, a patient who was over the age
of 65 years would receive the attention and treatment reserved for an “old” person;
nowadays, we see patients over 90 years of age every day in the emergency trauma
unit, often with fractures. Almost 100% of these cases involve osteoporotic fractures.
O
Actually, with the increasing age of the world’s population, osteoporosis is behaving like a global epidemic, a real public health concern, and this will continue if medical care keeps improving and the human lifespan keeps increasing.1
Duarte Nuno Alefre, Hospital Escola,
Avenida Fernando Pessoa, Nº 150,
4420-096 Gondomar,
Portugal
(e-mail: duartealegre@gmail.com)
Osteoporotic fracture: a clinical case
Rather than through just reading a description, a more effective way of understanding the manner in which bone tissue deterioration results in increased fracture probability and incidence is to look at the 3D high-resolution computed tomography images of an old and osteoporotic bone shown in Figure 1 (page 226). It is not difficult
to imagine how the result of all these fragility points is that the bone has an increased
Complicated fractures: how should one deal with them? – Alegre
225
FOCUS
the problem with more surgery (see Figure 2F). However, by
operating on the patient, we are simply fixing the acute problem rather than the basis of the problem. Actually, what we
should do is transform the patient’s bone tissue into a stronger
structure; that would be the gold standard treatment. Of
course, fractures have to be treated when they come along,
but a new fracture around a periarthroplasty in the right hip,
or another in the left hip surrounding or distal to the second
fixation nail, may unfortunately occur in the future.
A
Management of osteoporosis
We must realize that, as orthopedic surgeons, we have to treat
the acute trauma events, but ideally, as well as undertaking
the surgical procedure, we should try to put in place measures to avoid additional future fractures. This is not only because of the well-known increased morbidity and mortality
that comes with osteoporotic fractures in elderly patients, but
also for economic reasons.
B
Nowadays, osteoporosis affects 200 million people around
the world. It is estimated that a fragility fracture occurs every
3 seconds: around 25 000 fractures every day and approximately 9 million fractures per year.2 The economic impact
of this sad reality is estimated to be €39 billion in Europe
alone.3
Figure 1. Impact of osteoporosis on bone microarchitecture
High-resolution 3D computed tomography images of osteoporotic bone showing thinning of bone tissue (A) and loss of trabecular continuity (B).
susceptibility to breaking at several points on the skeleton
(Figure 1B). The final result of all these fragility points is weaker bone that is ready to break in a major way, even with a minor trauma or spontaneously at some key point such as the
hip, wrist, dorsolumbar spine, or shoulder.
It is everyday practice to treat patients with fractures such as
the one shown in Figure 2A (see also Figure 2B). What we
do not see every day is a new fracture in the contralateral hip
following a minor fall at home 3 years after the fracture in the
first hip (Figure 2C), but contralateral hip fractures are appearing more and more frequently in the clinics of orthopedic
surgeons. In the patient shown in Figure 2, after a surgical reduction and fixation (Figure 2D), the unexpected happened:
a third fracture (Figure 2E).
There is no doubt that there is a technical solution to every
surgical fracture that an orthopedic surgeon faces, but the frequency of osteoporotic fractures and the complexity of the
traumatology is becoming increasingly challenging, that’s a
fact. Who’s the guilty culprit? Osteoporosis, no doubt about it.
In the patient shown in Figure 2, all the surgical steps were
undertaken in the correct manner, and even if this patient is
afflicted with more fractures, we will always be able to solve
226
Despite this scenario, osteoporosis continues to be underdiagnosed and undertreated. So maybe we are doing just
half of the job—operating on osteoporotic fractures, but doing nothing to diminish the risk of a new fracture in the future.
Even if there is no way of achieving this surgically, there is
increasingly robust support for the beneficial effects of calcium, vitamin D, and certain antiosteoporotic drugs in reaching
our goal of decreasing the incidence of fractures by strengthening bone tissue structure. Certainly, we would not be able
to avoid all fractures, but we could reduce their complexity
and the recurrence of osteoporotic fractures in other anatomical regions; that’s a fact.4
We need more than just a medical drug intervention after the
first fracture. We are dealing with a silent disease, which—
most of the time—only reveals itself after the first fracture, but
we should try and change the course and destructive acts
of the disease before this. It is well established that there is
an exponential increase in the probability of a fracture occurring after a first osteoporotic fracture; actually, studies show
that there is double the risk of a spine fracture occurring after
a wrist fracture,4 and the appearance of a spine fracture increases the probability of a hip fracture by five times.5 Moreover, the literature shows that after major osteoporotic trauma events, the majority of patients do not receive medical
treatment after the acute problem has been resolved,6 and
the percentage of osteoporotic patients that receive antiosteoporotic medication after suffering a fragility fracture is even
lower.
FOCUS
In addition to the well-accepted effects of calcium and vitamin D on the course of osteoporosis, some drugs are putting up a good performance in the fight against this silent
pathology,7,8 and these should be seen as partners in the difficult struggle against this deceptive and dangerous entity.9,10
Not only are these drugs used in the prevention of osteoporotic fractures, but also in strengthening cortical and cancellous
bone to aid the orthopedic surgeon in the treatment of frac-
tures11,12: the bone is rebuilt to restore its form and function,
which have been compromised by fracture. The purpose of
surgery is to provide stable fixation of the fracture as close to
its original anatomy as possible, while trying to preserve its
biological environment to permit consolidation, an extremely
demanding healing process. Improved knowledge of bone
biology in recent years has led to the development of new
physical therapies and local biological treatment during sur-
A
B
C
D
E
F
Figure 2. Clinical case: sequential hip fractures in an osteoporotic patient.
(A) The first fracture, a femoral neck fracture of the right hip, occurred after a minor fall. (B) This first fracture was corrected with a hemiarthroplasty. (C) Three years later,
a trochanteric femoral fracture occurred on the left side. (D) This second fracture was corrected with intramedullary nail fixation. (E) After another minor fall, a new fracture
occurred on the left side, on the femur that had just been operated on 6 weeks earlier. (F) The femur was reoperated on, and a longer intramedullary nail was inserted.
227
FOCUS
gery to enhance fracture healing, which is being used and
tested around the world with the aim of achieving a more effective and rapid bone healing process.
Bone physiology and osteoporotic
pathophysiology
There is no doubt that systemic drugs are displaying increasingly impressive performances in assisting the recovery
of bone physiology, something that will help us more and
more in our approach to fracture care.13,14 But let us travel
inside bone tissue to try and understand its natural physiological response to aggressive trauma. One can understand
bone structure and physiology very well just by paying attention to the healing process of bone tissue.15,16 It is a fascinating living tissue, with a huge potential for self-regeneration and an extraordinary architecture that permits it to resist all of the forces found in everyday life.17 The metabolic
capacity of bone is so strong and energetic that 10% of the
human body’s bone structure is usually rebuilt each year. So,
theoretically, every 10 years we get a new skeleton.
In osteoporotic bone, this metabolic vigor weakens and all of
the well-known natural steps in bone metabolism become
slower, with the osteoblasts losing their capacity to build and
respond to the osteoclasts’ cleaning process. What happens
is that the action of the osteoclasts becomes harmful, as it is
not met with the fast and effective response of the osteoblasts, so a lack of bone starts to appear everywhere. If not
compensated for, it is only a matter of time before osteopenia gives rise to osteoporosis, which will become more and
more severe.18,19
If even young and healthy bone can break under tensile, compressive, shear forces, then tired osteoporotic bone will fail
much more easily. The reason is not only the decrease in
bone mass, but also changes in metabolism20 and trabecular architecture, the thinning of cortices combined with a loss
of perception, and the reduced capacity for self-protection
among old individuals. With this loss of bone tissue response
comes complex and more comminuted fractures, with recurrent fractures, delayed fracture consolidation, or even an absence of consolidation altogether.21
Future directions
Once again, there will always be an orthopedic answer to possible disorders of bone union—whether surgical or not—disorders that are essentially symptomatic nonunions. In association with the classic removal of necrotic bone and fibrous
scar tissue from the nonunion focus and the filling of bone defects with autologous bone graft, use of local growth factors
during surgery is currently being tested with the aim of stimulating mesenchymal cells, growth and differentiation factors,
and ultimately bone formation.
Noninvasive adjuvant physical therapies like low-intensity
pulsed ultrasound, extracorporeal shockwave therapy, and
electrical stimulation have had some success, but the amount
of evidence is small due to the heterogeneity of results and
lack of a sufficient number of randomized controlled trials.22-26
The next step seems logical; use of medication per os, probably antiosteoporotic drugs, along with the already well-accepted use of calcium and vitamin D supplementation to
help activate the bone’s self-regeneration and healing capacities.27-37
Conclusion
Osteoporosis is a silent worldwide disease that is occurring
with increasing incidence. Despite being silent, when osteoporosis decides to reveal itself through a major fracture, its
destructive effect is usually accompanied by huge morbidity
and mortality, depending on the fracture pattern and anatomical region where it appears. There is always an orthopedic
surgical answer to a fracture, but the more complex the fracture, the more demanding the surgical technique required will
be and the heavier the associated morbidity and mortality. The
best way to solve problems is to avoid them; that is what is
currently missing in the lack of attention given to medical prescription of licensed treatments (calcium, vitamin D, antiosteoporotic drugs) around the time of the fracture event or for
the pre- and postfracture medical care of osteoporotic patients. To understand bone tissue physiology and the way
that certain drugs can help in keeping it healthier, and thus
stronger, in everyday life, it is essential to change our approach
to this prevalent pathology and to be more interventional—
and not only in a surgical manner. ■
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23. Nelson FR, Brighton CT, Ryaby J, et al. Use of physical forces in bone healing.
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24. Rodriguez-Merchan EC, Forriol F. Nonunion: general principles and experimental data. Clin Orthop Relat Res. 2004;419:4-12.
25. Chao EY, Inoue N, Elias JJ, Aro H. Enhancement of fracture healing by mechanical and surgical intervention. Clin Orthop Relat Res.1998;355(suppl):S163-S178.
26. Einhorn TA, Laurencin CT, Lyons K. An AAOS-NIH symposium. Fracture repair:
challenges, opportunities, and directions for future research. J Bone Joint Surg
Am. 2008;90:438-442.
27. Axelrad TW, Kakar S, Einhorn TA. New technologies for the enhancement of
skeletal repair. Injury. 2007;38(suppl 1):S49-S62.
28. Goldhahn J, Little D, Mitchell P, et al. Evidence for anti-osteoporosis therapy in
acute fracture situations–recommendations of a multidisciplinary workshop of
the International Society for Fracture Repair. Bone. 2010;46:267-271.
29. Della Rocca GJ, Crist BD, Murtha YM. Parathyroid hormone: is there a role in
fracture healing? J Orthop Trauma. 2010;24(suppl 1):S31-S35.
30. Aspenberg P, Genant HK, Johansson T, et al. Teriparatide for acceleration of
fracture repair in humans: a prospective, randomized, double-blind study of 102
postmenopausal women with distal radial fractures. J Bone Miner Res. 2010;25:
404-414.
31. Peichl P, Holzer LA, Maier R, Holzer G. Parathyroid hormone 1-84 accelerates
fracture-healing in pubic bones of elderly osteoporotic women. J Bone Joint
Surg Am. 2011;93:1583-1587.
32. Yu CT, Wu JK, Chang CC, Chen CL, Wei JC. Early callus formation in human hip
fracture treated with internal fixation and teriparatide. J Rheumatol. 2008;35:
2082-2083.
33. Rubery PT, Bukata SV. Teriparatide may accelerate healing in delayed unions of
type III odontoid fractures: a report of 3 cases. J Spinal Disord Tech. 2010;23:
151-155.
34. Ozturan KE, Demir B, Yucel I, Cakici H, Yilmaz F, Haberal A. Effect of strontium
ranelate on fracture healing in the osteoporotic rat. J Orthop Res. 2011;29:
138-142.
35. Habermann B, Kafchitsas K, Olender G, Augat P, Kurth A. Strontium ranelate
enhances callus strength more than PTH 1-34 in an osteoporotic rat model
of fracture healing. Calcif Tissue Int. 2010;86:82-89.
36. Alegre DN, Ribeiro C, Sousa C, Correia J, Silva L, de Almeida L. Possible benefits of strontium ranelate in complicated long bone fractures. Rheumatol Int.
2012;32:439-443.
37. Tarantino U, Celi M, Saturnino L, Scialdoni A, Cerocchi I. Strontium ranelate
and bone healing: report of two cases. Clin Cases Miner Bone Metab. 2010;
7:65-68.
Keywords: antiosteoporotic drug; bone biology; bone nonunion; bone repair; complicated fracture; fracture healing;
osteoporotic fracture; medical management
FRACTURES
COMPLIQUÉES
:
COMMENT S ’ Y PRENDRE
?
Les fractures compliquées ont toujours existé et sont le lot quotidien des centres de traumatologie orthopédique dans
le monde, mais ces dernières décennies, leur fréquence et leur complexité augmentent à un rythme encore jamais
vu. Le traumatisme à haute énergie en est en partie responsable, mais la cause principale est la fracture de fragilité
ostéoporotique chez le sujet âgé. Car la longévité augmente partout dans le monde, une bonne nouvelle pour l’humanité mais une bien mauvaise pour « l’armature » du corps, le système ostéoarticulaire, qui n’est pas conçu pour
porter le poids du corps tous les jours pendant une durée de vie de plus en plus longue. Cet article a pour but, non
seulement d’alerter le lecteur sur cette réalité mais aussi d’informer sur la façon de réagir à ce phénomène en donnant des chiffres et des faits. Nous débutons par un cas clinique avéré de fracture ostéoporotique chez un patient
puis nous passons à la physiologie incroyablement vivante et dynamique de l’os pour ensuite passer en revue ce que
nous pouvons faire en pratique pour lutter contre une des pires réalités du vieillissement aujourd’hui : les fractures
ostéoporotiques et leur terrifiante cascade fracturaire.
229
‘‘
U P DAT E
It is expected that marrow fat
could constitute a therapeutic target for osteoporosis in the near
future. Current evidence indicates
that bone mass could be increased
by either decreasing mesenchymal
stem cell differentiation into adipocytes or by blocking the lipotoxic
capacity of marrow adipocytes.
Identification of an effective compound targeting one or both adipocyte-related mechanisms of osteoporosis is currently the subject of
intense research.”
The bone-fat connection:
A Very Bad Trip
b y G . D u q u e , A u s t ra l i a
A
Gustavo DUQUE, MD
PhD, FRACP
Ageing Bone Research
Program, Sydney Medical
School Nepean
The University of Sydney
AUSTRALIA
complex relationship between bone and fat that goes beyond their respective traditional functions of locomotion and energy storage is being
unraveled. In this review, we start first by describing current knowledge
on the systemic endocrine interaction between fat and bone, in which fat-secreted factors are released into the circulation and target bone metabolism in
a positive or negative manner. We then describe an interaction that seems to
play a more important role in the pathogenesis of osteoporosis: the local interaction between fat and bone within the bone marrow milieu. Current evidence
suggests that increased mesenchymal stem cell differentiation into fat could
have a lipotoxic effect on osteoblast function and survival, while simultaneously stimulating osteoclastic activity. This would result in increased bone resorption and decreased bone formation, the typical features of osteoporosis.
Considering that marrow fat activity and volume could be pharmacologically
reduced, we conclude this article by reviewing the new potential therapeutic
approaches to osteoporosis that target the relationship between fat and bone
while favoring bone formation and protecting against osteoporosis.
nterest in the relationship between fat and bone has increased exponentially in recent years. Since both osteoporosis and obesity are becoming epidemic worldwide, initiatives to prevent both entities by identifying their potentially common
mechanisms are subjects of major interest. However, understanding the interaction
between fat and bone is not a simple matter. To understand their relationship better, we have to consider the two ways in which these tissues can interact: systemically (endocrine interaction) and locally (paracrine interaction).1-4 The systemic interaction occurs via the release of adipokines and fatty acids into the circulation.
Some of these factors have a positive effect on bone and are associated with a protective effect of obesity against fracture.5 In contrast, other adipokines have been
associated with either low bone formation or activation of bone resorption, and thus
bone loss.4 High levels of these adipokines are observed in obese subjects and are
associated with a higher risk of fractures.6
I
Professor Gustavo Duque,
Sydney Medical School Nepean,
Level 5, South Block,
Nepean Hospital, Penrith, NSW,
Australia 2750
(e-mail:
gustavo.duque@sydney.edu.au)
230
Although it also occurs through the release of fatty acids and adipokines, the local
(paracrine) interaction of fat and bone takes place in the bone marrow milieu. During the natural process of aging, bone mass declines, while marrow fat increases.7
This progressive fat infiltration is more significant in osteoporotic patients, thus suggesting that marrow fat could have a negative effect on bone structure and metab-
The bone-fat connection – Duque
U P DAT E
olism.7-9 In this review we will compare the characteristics of
the endocrine relationship between fat and bone versus their
local relationship within the bone marrow (summarized in the
Figure). Furthermore, we will review the proposed mechanisms
regulating bone and fat formation in healthy and osteoporotic
patients. Finally, the effect of antiosteoporotic treatment on
this imbalance will also be described.
Obesity, osteoporosis, and fractures:
good vs bad fat
serum leptin and BMD remains unclear, with studies reporting
both positive and negative associations, particularly after body
composition adjustments.12
◆ Adiponectin
Despite adiponectin being secreted by adipocytes, there is
an inverse relationship between BMI and serum adiponectin.
Adiponectin regulates energy homeostasis and inflammatory pathways.21 Despite the positive effect of adiponectin on
osteoblastogenesis in vitro, in vivo evidence suggests that
High body weight is considered as protective for the skeleton.
Indeed, body weight is one of the strongest predictors of bone
mass.10 It has also been shown in several studies that weight
loss is often accompanied by bone loss, especially in the elderly.11 Fracture risk at the hip and spine is also inversely proportional to body weight.12 In fact, it is possible to use body
mass index (BMI) instead of bone mineral density (BMD) in the
FRAX® calculator to estimate the fracture risk.13
Subcutaneous fat
Mesenchymal stem cell
Osteoblast
Adipocyte
Osteoclast
Fatty acids
Adipokines
The protective effect of high BMI seems to be strongly dependent on the effect of mechanical loading exerted by body
weight on bone. However, recent evidence suggests that the
protective effect of weight against fracture is not directly associated with fat mass, but with the proportion of lean mass,
thus indicating that patients with a high BMI and low BMD are
at higher risk of fractures than patients with a normal BMI and
the same low BMD.14 Overall, recent evidence has led to suggest that: i) high lean mass is protective against fracture14;
ii) weight loss is associated with bone loss due to the concomitant loss of lean and fat mass15; and iii) there is a systemic
(endocrine) negative effect of high fat mass on bone, which
predisposes obese sarcopenic patients to falls and fractures.16
+
–
–
◆ Adipokines
◆ Leptin
Leptin regulates appetite and energy use by binding to a receptor in the hypothalamus. Through the sympathetic nervous
system, leptin activates b-2 adrenergic receptors on osteoblasts, thereby decreasing osteoblast activity, while increasing bone resorption via receptor activator of NF-kB ligand
(RANKL).18 On the other hand, peripheral leptin signaling has
been reported to increase cortical bone growth and bone mesenchymal stem cell (MSC) differentiation into osteoblasts rather
than adipocytes.19,20 However, the exact relationship between
Fatty acids
Adipokines
+
Bone marrow
Systemic fat products and bone mass
The adipose tissue secretes factors known as adipokines,
which circulate and affect other organs in an endocrine manner. Although the secretion of these adipokines varies with
changes in food intake and weight, it is well known that, once
in the circulation, some adipokines exert an effect on bone
metabolism either directly or indirectly.17 Here, we will focus on
those adipokines and adipocyte-secreted factors that have
a negative effect on bone metabolism, thus affecting bone
mass and increasing the risk of fracture.
–
Figure 1. Systemic (endocrine) and local (paracrine) effect of fat
on bone metabolism.
Both subcutaneous and marrow fat release fatty acids and adipokines. Subcutaneous fat differs from marrow fat because it secretes osteogenic as well as
adipogenic factors, thus improving bone mass in some cases. In contrast, marrow fat is mostly toxic and affects osteoblast differentiation and survival while
stimulating bone resorption through the activation of osteoclastic activity and
bone resorption.
SELECTED
BMD
BMI
body mass index
CRP
C-reactive protein
FRAX®
MSC
mesenchymal stem cell
PPARg
proliferator-activated receptor-g
PPARg 2 peroxisome proliferator activated receptor gamma 2
PUFA
polyunsaturated fatty acid
RANKL
activator of NF-kB ligand
231
U P DAT E
adiponectin has a deleterious effect on bone, with adiponectin knockout mice exhibiting high bone mass, an effect that
seems to be indirect and probably exerted through the release of leptin into the circulation.22
◆ Adipokines and bone mass – clinical evidence
A recent study by Mohiti-Ardekani et al23 reported the relationship between adipokines and BMD in osteoporotic and
nonosteoporotic nondiabetic individuals. In their population,
leptin did not have a significant correlation with BMD in either
the osteoporosis or nonosteoporosis groups, whereas adiponectin had a significant negative correlation with BMD of the
lumbar spine and femoral neck.
◆ Lipids/oxidative stress and bone
Hyperlipidemia has been shown to increase osteoclastic bone
resorption.24,25 Systemic oxidative stress associated with visceral obesity26 has also been shown to increase bone resorption
and impair bone formation.27 Lipid oxidation products can inhibit the differentiation of preosteoblasts into osteoblasts26 and
activate bone-resorbing osteoclasts by increasing RANKL28;
they also increase peroxisome proliferator–activated receptor-g (PPARg) expression, and diminish Wnt signaling, causing progenitor MSCs to undergo adipogenic—rather than osteogenic—differentiation.29
◆ Chronic low grade inflammation
Obesity is associated with chronic low-grade inflammation.30
The visceral adipose tissue depot releases adipocytokines that
stimulate a greater hepatic release of acute-phase response
proteins such as C-reactive protein (CRP),31 and this is associated with macrophages, which secrete inflammatory cytokines (TNF-a, IL-6, MCP-1, PAI-1).32 IL-6 can stimulate osteoclasts to increase the rate of bone resorption,33 while higher
circulating high-sensitivity CRP levels are associated with higher serum NTx—a marker of bone resorption—and lower bone
mass.34
◆ Systemic and dietary fatty acids
High serum and dietary levels of saturated fatty acids are associated with bone loss.35,36 In contrast, polyunsaturated fatty
acids (PUFAs) have a beneficial effect on BMD.37 The negative
effect on bone induced by high levels of saturated fatty acids
has been associated with induction of adipogenesis within the
bone marrow, whereas the beneficial effect of PUFAs on bone
has been associated with regulation of serum levels of calciotropic hormones.37
In summary, there is evidence suggesting that high levels of
fat and, more importantly, high levels of adipocyte-secreted
factors may have a deleterious effect on bone mass. This negative effect of fat on bone could be significantly higher within the bone marrow milieu, which experiences increasing fat
infiltration with aging and where fat and bone cells share the
same microenvironment.
232
Fat and bone: an odd couple
With aging, hematopoietic tissue is replaced by fatty bone
marrow. This switch from a hematopoietic bone marrow into
a fatty one seems to begin early in life across most species.38
Considering that bone-forming cells (osteoblasts) and adipocytes share the same precursor (MSCs), there is increasing
interest in the process of MSC differentiation in order to understand the mechanisms of their predominant differentiation
into adipocytes in aged and osteoporotic bone.
◆ MSC differentiation: fat or bone? That is the question
MSCs are distributed within the bone marrow in clusters known
as “niches.” These MSC niches are usually adjacent to blood
vessels. The confluence of the MSCs within the bone marrow is pivotal not only for their appropriate response to exogenous growth factors and cytokines, but also to secrete osteogenic/adipogenic factors in an autocrine manner.39 Once
the MSCs are exposed to either osteogenic or adipogenic conditions, these cells activate a complex machinery of transcription factors that will determine their fate as osteoblasts or
adipocytes. For the purpose of this review we will focus on
two major transcription factors, namely peroxisome proliferator activated receptor gamma 2 (PPARg2), for adipogenesis,
and runt-related transcription factor 2 (Runx2), for osteoblastogenesis.8
It has been proposed that the predominant expression of one
of these two factors will determine the final differentiation of
MSCs into fat or bone cells. With aging, levels of expression
of PPARg2 increase within the bone marrow.40 This increase in
PPARg2 is associated with increasing levels of fatty acids,41
as well as inhibition of osteogenesis via the downregulation
of cyclooxygenase-2 and inducible nitric oxide expression.42
In addition, MSCs expressing high levels of PPARg2 differentiate into adipocytes at the expense of osteoblasts, thus decreasing osteogenesis and bone formation.
◆ Marrow adipocytes: the enemy within
In addition to age-related changes in the differentiation of
MSCs, the number and function of mature osteoblasts also
decrease with aging.43,44 With MSCs predominantly differentiating into adipocytes and fewer MSCs available for differentiation into osteoblasts, the total population of osteoblasts is
significantly reduced in aged and osteoporotic bone. However, there are other additional causes of a reduction in osteoblast number that—although not related with adipocyte differentiation—could be a consequence of the increasing levels of
marrow fat (and its secreted factors) within the bone marrow
milieu. These factors could affect osteoblast function and induce osteoblast apoptosis in a process known as lipotoxicity.
Lipotoxicity is an overload of lipids in nonadipose tissues affecting function and inducing cell death.45Ectopic fat releases adipokines, fatty acids, and other metabolites that may
affect the function and survival of other cells in their vicinity.46
U P DAT E
The pancreas is probably the best-studied example of lipotoxicity. In the pancreas, progressive fat infiltration induces activation of apoptotic pathways in b cells, inducing cell death
and affecting the total population of b cells, thereby inducing pancreatic failure.46,47 Considering that fat products are
also increased in the bone marrow of osteoporotic subjects,48
it would be expected that marrow adipocytes have a similar
effect on bone cells than the one observed in pancreatic cells,
which would affect their function and survival.
Lipotoxicity has been demonstrated in bone cells in vitro, using osteoblasts and adipocytes in coculture.49 In these conditions, lipotoxicity was induced by high levels of saturated fatty acids (mostly palmitate) secreted by cultured adipocytes
acting in a paracrine manner. Osteoblasts exposed to adipocyte-secreted fatty acids showed low osteogenic function and
higher levels of programmed cell death or apoptosis. This effect was prevented after treating the adipocytes with cerulenin, which is an inhibitor of fatty acid synthase. By limiting
the capacity of the adipocytes to release fatty acids in vitro,
treatment with cerulenin rescued the osteoblasts from apoptosis and facilitated their function as bone-forming cells.
In fact, apoptosis is a common feature in bone cells. All boneresorbing cells (osteoclasts) ultimately undergo apoptosis mediated by well-defined pathways.50 In contrast, osteoblast
apoptosis increases during aging or corticosteroid treatment
and also in osteoporotic bones.51 The underlying mechanisms
of osteoblast apoptosis remain poorly understood; therefore,
it has been proposed that marrow fat could be responsible
for the high levels of osteoblast apoptosis observed in old and
osteoporotic bone, by secreting saturated fatty acids within
the bone marrow milieu. We have recently tested this hypothesis by treating osteoblasts with palmitate at a dose that is
equivalent to the levels of palmitate found in human bone marrow. Our data showed that palmitate induces not only apoptosis, but also autophagy in osteoblasts, thus increasing cell
death.52
Interestingly, there is also evidence suggesting that adipocytes may have a stimulatory effect on osteoclasts and a negative effect on hematopoietic cells. Bone marrow adipocytes
support osteoclast differentiation through the activation of
PPARg and its ligands, which increases RANKL and promotes
osteoclast differentiation and resorption.53,54
Furthermore, two recent in vivo studies have assessed whether
increased levels of marrow fat are also associated with a “lipotoxic profile.” Using young (4 months old) vs old (24 months
old) C57BL/6 mice,55 we compared levels of adipokine expression in adipocytes obtained from subcutaneous fat and
bone marrow. Our proteomic analysis showed that, when
compared with subcutaneous adipocytes, aging bone marrow adipocytes showed a more proadipogenic, antiosteoblastogenic, and proapoptotic phenotype. In addition, marrow
adipocytes obtained from the old mice showed higher levels
of toxic adipokines than have been associated with the induction of lipoapoptosis in other organs. Another study performed in human subjects of varying bone densities used gas
chromatography to analyze the fatty acid composition of samples of marrow fat and subcutaneous fat from 126 subjects
(98 females, 34 males, mean age 69.7±10.5 years).56 In agreement with our mice data, the authors reported that marrow
fatty acid composition differs from that of subcutaneous fat
and varies between predominantly erythropoietic and fatty
marrow sites. The authors found a significant difference in the
marrow fat concentration of two fatty acids, cis-7-hexadecenoic acid and docosanoic acid, between normal and osteoporotic subjects.56 Taken together, these and other in vivo
studies demonstrate that, with aging, marrow fat becomes
unique and particularly lipotoxic with a high potential to affect osteoblast function and survival at the local bone marrow level.
Fat’s loss is bone’s gain: therapeutic applications
of a bad relationship
Two major therapeutic approaches to osteoporosis that target the relationship between fat and bone have been proposed based on the fact that fat and bone share not only the
same precursor cell, but also the same microenvironment (the
bone marrow milieu).1 The first approach is based on the potential for inhibition of adipogenesis to facilitate osteoblastogenesis and bone formation.8 The second approach is based
on in vitro evidence of the toxic effect that mature adipocytes
can have on bone, including cell dysfunction and cell death.49,52
This approach aims to protect osteoblasts from lipotoxicity by
preventing adipocytes from secreting lipotoxic factors such
as fatty acids and adipokines.
Although several in vitro experiments have shown that current
osteoporosis treatments such as bisphosphonates,57 strontium ranelate,58 and teriparatide59 have an inhibitory effect on
adipocyte differentiation, only two studies have looked at the
effect of osteoporosis treatment on marrow fat in vivo. One
study 60 demonstrated that estrogens decrease marrow fat in
postmenopausal women; a second study looked at biopsies
obtained from osteoporotic women treated with risedronate
for three years and identified a significant reduction in marrow fat and lower levels of PPARg expression in women treated with risedronate as compared with placebo.61 These studies
suggest that, in addition to their antiresorptive effect, estrogens and bisphosphonates may have a positive effect on bone
mass by inhibiting bone marrow adipogenesis. In the case of
bisphosphonates, which are known inhibitors of osteoclastic
activity, a reduction in marrow fat would create a friendly environment for secondary mineralization, a well-known effect of
bisphosphonates that may explain their effect on bone mass.
In fact, there is evidence suggesting that inhibition of PPARg
has a positive effect on bone mass. Heterozygous PPARg-deficient mice exhibit high bone mass with increased osteoblas-
233
U P DAT E
togenesis independently of insulin or leptin levels.62 In a study
in which senescence-accelerated mice (SAMP6) were treated with vitamin D, we showed a significant reduction in fatty
bone marrow and PPARg levels,63 concomitantly with increasing levels of bone formation.64 A recent study has tested the
effect of PPARg inhibitors on bone mass with negative results.65 However, these negative results were probably due to
the fact that the PPARg inhibitor was tested in diabetic mice,
which show significant differences compared with a normal
aging mouse model. To obviate this limitation, we treated
sham and oophorectomized C57BL/6 mice with an inhibitor
of PPARg and found that treated mice showed a significant
gain in bone mass and high levels of osteoblastogenesis.66
In summary, it is expected that marrow fat could constitute
a therapeutic target for osteoporosis in the near future. Current evidence indicates that bone mass could be increased
by either decreasing MSC differentiation into adipocytes or by
blocking the lipotoxic capacity of marrow adipocytes. Identification of an effective compound targeting one or both adipocyte-related mechanisms of osteoporosis is currently the subject of intense research.
Conclusion
In this review, we have summarized the particular features of
the relationship between fat and bone. As well as a systemic
relationship between fat and bone, there seems to be a local
relationship involving a direct interaction between adipocytes
and osteoblasts within the bone marrow milieu. Increasing levels of MSC differentiation into adipocytes in aging bone could
be explained by a combination of age-related mechanisms associated with other factors such as hormones, nutrition, genetics, or a variety of growth factors. Once the process of fat
infiltration starts within the bone marrow, it is associated with
the release of adipokines and fatty acids, which exert a lipotoxic effect against the cells in their vicinity, including osteoblastic and hematopoietic tissue. In contrast, osteoclastic differentiation and activity is stimulated by the presence of marrow fat.
The final consequence of this process is bone loss, due to high
levels of bone resorption and low levels of bone formation.
Although a significant amount of evidence is still required, the
identification of the mechanisms of adipogenesis in bone, the
quantification of marrow fat, and the potential inhibition of marrow adipogenesis will constitute a new approach to the understanding and treatment of osteoporosis in the near future. ■
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39. Ema H, Suda T. Two anatomically distinct niches regulate stem cell activity. Blood.
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41. Lecka-Czernik B, Moerman EJ, Grant DF, Lehmann JM, Manolagas SC, Jilka
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Keywords: adipocyte; apoptosis; fatty acid; lipotoxicity; osteoblast; osteoporosis
LES
RELATIONS OS - GRAISSE
:
DES LIAISONS DANGEREUSES
Au-delà de leurs fonctions traditionnelles respectives de locomotion et de stockage de l’énergie, la relation complexe
entre l’os et la graisse est en train d’être élucidée. Dans cet article, nous commençons par décrire les connaissances
actuelles sur l’interaction endocrine systémique entre la graisse et l’os, des facteurs secrétés par la graisse étant libérés dans la circulation et agissant sur le métabolisme osseux positivement ou négativement. Nous décrivons ensuite une interaction qui semble jouer un rôle plus important dans la pathogenèse de l’ostéoporose : l’interaction
locale entre la graisse et l’os au sein de la moelle osseuse. D’après les données actuelles, la différenciation croissante des cellules souches mésenchymateuses en graisse pourrait avoir un effet lipotoxique sur la fonction et la survie des ostéoblastes tout en stimulant simultanément l’activité ostéoclastique, ce qui entraînerait une augmentation
de la résorption osseuse et une diminution de la formation osseuse, caractéristiques de l’ostéoporose. L’activité et
le volume de la graisse médullaire pouvant être pharmacologiquement diminués, nous concluons cet article par un
tour d’horizon des nouvelles possibilités thérapeutiques pour l’ostéoporose qui ciblent les relations entre la graisse
et l’os tout en favorisant la formation osseuse et en protégeant contre l’ostéoporose.
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hanks to long-standing expert care, Lascaux is like a
patient recovering from what
amounts to genuine diseases
caused by variety of organisms,
the list of which reads like a bacteriology lab report: molds and fungi
(Fusarium solani, Ochroconis lascauxensis and anomala, Chrysosporium, Gliocladium, Gliomastix,
Paecilomyces, Trichoderma, Verticillium), algae (Bracteacoccus minor….), and bacteria (Pseudomonas fluorescens…). A 20 000 yearold-heritage of prehistoric paintings is being preserved for humanity.
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T
Lascaux: preserving
a 20 000-year old legacy
of Paleolithic art
b y M . M a u r i ac , Fra n c e
R
Muriel MAURIAC
General Heritage Curator
Curator of the Lascaux Cave
Muriel Mauriac, Conservateur
Général du Patrimoine, Conservateur
de la Grotte de Lascaux, Direction
Régionale des Affaires Culturelles,
54 rue Magendie CS 41229,
33074 Bordeaux cedex
(e-mail:
muriel.mauriac@culture.gouv.fr)
238
edolent of a “Boys’ Own” or “Famous Five” adventure story, the discovery by four teenagers and their dog of a Paleolithic painted cave in southwestern France, on 12 September in 1940, changed humanity’s perception of our distant, prehistoric, ancestors. The close to 2000 painted figures
easily rank among the most impressive and beautiful in the world. After the
war, the 20 000-year-old Lascaux Cave was opened to the general public. Before long, though, the effects of the ever-swelling number of visitors destabilized the cave’s fragile natural environment, and the cave became what is
tantamount to a “patient” in need of close “medical” attention from hosts of experts to diagnose and treat its many ailments and avoid a treasure being lost
to humanity. Humidity changes, increased carbon dioxide levels, rises in temperature from artificial lighting, changes in climate and in the cave’s environmental conditions, contributed to trigger the likes of “diseases” (green sickness, white sickness, black stains…) caused by infestations by a variety of
organisms, the list of which reads like a bacteriology and pathology lab report.
Thus, molds and fungi (Fusarium solani, Ochroconis lascauxensis and O. anomala, Chrysosporium, Gliocladium, Gliomastix, Paecilomyces, Trichoderma,
Verticillium), algae (Bracteacoccus minor), bacteria (Pseudomonas fluorescens)
required treatment with antifungals and antibiotics (streptomycin, penicillin,
polymyxin,) and various agents (formalin, benzalkonium chloride, quicklime),
and huge apparatuses and systems to ensure adequate climatic conditions.
Lascaux was unwillingly transformed into a place of experimentation, of heuristics, a laboratory for the conservation of parietal art. The cave was closed to
the public in 1963, and listed as a world heritage site by UNESCO in 1979. An
underground replica of the cave opened in 1983, known as Lascaux II, featuring an amazingly faithful full-sized facsimile of the topography (down to the
very texture of the cave’s geological characteristics) and paintings of the Great
Hall of the Bulls and the Axial Gallery, and is visited by approximately 250 000
tourists every year. This was followed in 2009 by the creation of Lascaux III, a
major traveling exhibition of five facsimiles with paintings not reproduced in
Lascaux II. A mammoth project, Lascaux IV, a complete replica of the cave
and its paintings, is due to open in 2016 and is anticipated to attract 400 000
visitors every year.
Top-of-page frieze: based on drawings by Henri Breuil
of paintings in the Combarelles cave at Les-Eyzies-de-Tayac.
© RMN-Grand Palais (Musée de la Préhistoire des Eyzies)/Franck Raux.
Lascaux: preserving a 20 000 year-old legacy of Paleolithic art – Mauriac
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Hall of the Bulls at Lascaux. © akg/Glasshouse Images.
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M
uriel Mauriac has a Degree in Museology from the École du Louvre, an Advanced Degree in the History of Art
from the Sorbonne, and in 1996 a degree from the École Nationale du Patrimoine (now Institut National du Patrimoine – National Institute for Cultural Heritage). After working as Commissioner for Historic Monuments of
Lorraine, France, she took up a position as the Assistant Regional Commissioner in the Regional Office of Cultural Affairs
of the Île-de-France. Muriel Mauriac is now the Commissioner for Historic Monuments at the Aquitaine Regional Office
of Cultural Affairs, where since 2003 she has acquired experience in preventive conservation. Appointed in March 2009,
she also works as Curator of the Lascaux Cave, where she coordinates all research programs.
n 8 September 1940, in the early years of World
War II, but far removed from its turmoil, 17-year old
Marcel Ravidat was taking a stroll with his dog on a
pine- and oak-covered hill above Montignac, in southwestern France, in the picturesque Dordogne region. Suddenly,
his russet-haired setter-terrier started scratching around in
a hole at the base of a long-uprooted tree. Intrigued, Marcel
rolled stones away to uncover the entrance of a seemingly
quite deep cave. Returning four days later to explore further,
Marcel happened across three other teenagers, Jacques Marsal, Simon Coëncas, and Georges Agniel who joined him in
O
his quest. Using makeshift tools, the four boys widened the
hole and stumbled into the cave. Before long, painted likenesses of wild bulls and horses running across the lamplit
cave walls flickered into life, leaving the little group gaping in
amazement and awe. Torn between keeping the discovery
to themselves and revealing their find to the outside world,
the youngsters confided in the local primary school teacher,
Léon Laval. Immediately realizing the significance of their find,
Laval sought the advice of Henri Breuil, the “Pope of prehistory,” who confirmed that the magnificent paintings were a major work of long gone prehistoric humans.
Hall of the Bulls in October 1940. In the center, hand outreached, Count Begouën (in front) and Father Henri Breuil. In the foreground,
sitting, two of the discoverers: Jacques Marsal (seen in profile) and Marcel Ravidat (facing). Work is under way to lower and smoothen out
the floor of the cave to make its access easier for visitors. Laval Collection / Fonds Laval.
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Frieze of the Swimming Stags in the Nave. © Bridgeman Art Library.
Lascaux Cave has since been recognized as among the finest
ever found. The wartime discovery marked a sea change in
the way we view our prehistoric ancestors, and after the war
the 20 000-year-old Lascaux Cave was opened to the general public. Before long though, the effects of the ever-swelling
number of visitors destabilized the cave’s fragile natural environment. Mold, fungal, and bacterial infestation, humidity
changes, increased carbon dioxide levels endangered the paintings, and Lascaux was unwillingly transformed into a place of experimentation, of heuristics, a laboratory for the
conservation of parietal art. Thus it is that from
conundrum to solution and back again the conservation of Lascaux has for the last seventy
years been shedding light on the complex environments of painted caves.
As to the four teenagers who discovered the
cave, their lives forever changed, different fates
awaited them in occupied war-time France. Simon Coëncas returned to Nazi-occupied Paris,
where in 1942 he and his family were arrested
and held at the Drancy internment camp. Because of their youth, the Red Cross was able
to pluck from danger Simon and his sister Éliette, but the rest of the family was deported to
Auschwitz and exterminated. On vacation at
his grandmother’s house at the time of the discovery, George
Agniel returned home to Nogent-sur-Marne, near Paris.
Jacques Marsal and Marcel Ravidat, both locals, looked after
the cave and took part in the early development of the site, before Jacques was requisitioned for forced labor in Germany
and Marcel joined the French Resistance. At the Liberation of
France, they became guides and wardens at Lascaux.
Layout of the Lascaux Cave. © MCC-CNP.
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Lascaux cave
France’s Dordogne region is rich in prehistoric sites, but the
discovery of Lascaux stirred the imagination as none other. Lay
public and experts alike marveled at the quality of the paintings, the freshness of the colors, the richness of the representations —nearly 2000 painted and engraved abstract signs
and figures, including over 900 animals, and but one human
figure. Recognizing its heritage value just months after the discovery, the French government classed Lascaux as a historic
monument, and in 1979 UNESCO listed it as a world heritage
site, along with 14 other prehistoric sites in the Vézère Valley.
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Set apart from other cave art sites around Eyzies-de-Tayac,
Lascaux is unusual for its location at shallow depth, modest
size (volume approximately 3000 m³), and high carbon dioxide content. In its geological setting of limestone, the 235-meter-long cave complex begins with the Hall of the Bulls and
continues into the Axial Gallery. The Passageway leads on the
right to the Apse, which goes down to the lower network of the
Shaft, and straight on to the Nave followed by the Mondmilch
Gallery and lastly the Chamber of Felines. Horses account for
60% of the animals depicted, and stags 14%. Reindeer are
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Upside-Down Horse in the Meander prolonging the Axial Gallery.
© MCC-CNP.
Axial Gallery, with Second and Third Chinese Horses. © MCC-CNP.
Apse, engraved Horse. © MCC-CNP.
pictured but once, yet played a major role in the lives of these
prehistoric people, who lived at a time dubbed the Age of the
Reindeer, providing most of their meat, fat for lamps, hides for
clothing and hut coverings, and bones for needles. Aurochs
(long-horned wild oxen, now extinct, the ancestors of domestic
cattle) account for less than 5% of the animal images, though
one painting of a bull is among the largest (5 meters long)
in prehistoric cave art. Pictured also are bison, ibexes, felines,
one bird, one bear, and the now extinct wooly rhinoceros.
From one sector to the next, the cave varies substantially in
mineralogical characteristics. In the Hall of the Bulls and the
Axial Gallery, the limestone and calcite wall surfaces are too
hard or irregular for engraving work, and instead color pigments were applied by dabbing or spraying. In contrast, the
Passageway, Apse, and Nave have soft limestone walls with
little or no calcite and the images covering them are engraved,
painted, and drawn. The very nature of the walls partly explains the survival of these artworks, though some were already damaged when discovered in 1940. Paleolithic humans
took subtle advantage of the physical characteristics of the
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walls to heighten effects, and employed a multiplicity of techniques, as attested by the wealth of archaeological materials
discovered by the prehistorian André Glory and the palette
of pigments: iron oxide for reds, browns, and ochers, and
manganese oxide for blacks (pyrolusite, manganite, romanechite), particularly in the Hall of the Bulls and the Axial Gallery.
In the weeks following the discovery of the cave, the owner
of the land, Count Charles-Emmanuel de la Rochefoucauld,
had improvements made to facilitate access, by developing
the hole through which Marcel Ravidat and his friends had
entered the cave. But from 1947, the Count financed substantial work done without any real archaeological supervision: creation of the monumental entrance and of the stairway for access, lowering of floors, as in the Passageway where
the headroom was insufficient for comfortable movement. This
work altered the seasonal inflow of rainfall as well as the overall volume of the cave, as several tons of earth were removed
or tipped down the Shaft. These alterations allowed Lascaux
to be opened to the public, in July 1948, but the immense interest generated came at a cost. By making this prehistoric
masterpiece available to ever increasing numbers of visitors—
1800 a day in 1960—the cave’s ecosystem was perturbed
and conservation problems began.
The troubled preservation of Lascaux: 1948-1963
It would be a mistake to imagine that the Lascaux Cave environment had been stable for 20 000 years. Some paintings
had suffered irreversible damage well before their discovery.
Others have largely disappeared from the walls in the Passageway, and engraved lines and vestiges of pigments are all
that remain. This deterioration may perhaps be explained by
air currents linked to the presence of calcite rims recently dated by the French Atomic Energy Commission to around 8000
years before the present day.
A year after Lascaux was opened to the public, mold appeared
on the walls and two airlocks were installed to create a buffer
zone between the cave and the outside world. By 1955, intermittent condensation on the walls, excessive temperatures,
and high carbon dioxide levels were becoming a grave concern and prompted new attempts to restore the climatic balance upset by the influx of visitors, some 30 000 that year.
Chief architect Yves-Marie Froidevaux designed a climatic
regulation system to inject air at 14°C and suck out used air,
thus renewing the atmosphere in the visitor areas and reducing carbon dioxide levels. But the removal of 440 cubic
meters of earth and rock (about 1200 tons), for the installation of ventilation ducts, altered the volumetric configuration
Overall view of the Hall of the Bulls. © MCC-CNP.
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of several parts of the cave and irremediably destroyed some
archaeological layers, despite André Glory’s supervision, now
deemed insufficient. Tasked also with studying the paintings,
Glory took copious notes on the cave layout, drew sketches,
and, despite the meager human and material resources at his
disposal, collected extensive information and many objects:
flint tools and lithic cores, two needles, one of which was for
sewing, charcoal fragments, reindeer bones, pigments, and
the famous lamp now on display at the National Museum of
Prehistory in Eyzies-de-Tayac.
This conservation work proved insufficient and in 1960 the curator at Lascaux, Max Sarradet, noted the presence of green
stains on the walls of the Hall of the Bulls and of the Axial Gallery. Faced with this alarming situation, André Malraux, the
Minister of Cultural Affairs, created a scientific commission “to
study the changes inside the cave, find remedies, and bring
the cave back to stable conditions.” In April 1963, the commission obliged Count de la Rochefoucauld to close Lascaux.
Analyses revealed a diversity of associated microbes, the main
genus being Bracteacoccus of the order of green algae Chlorococcales. To curb this contamination, the commission recommended spraying antibiotics and formaldehyde solutions
on the floors and walls. The worrisome formation of a thin lay-
Entrance to the Lascaux Cave: construction of the vaulted hall of
the first airlock. Standing in the foreground is primary school teacher
Léon Laval, wearing white knee socks. Laval Collection/Fonds Laval.
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er of white calcite on the walls prompted the commission to
set up daily climatic measurements and to remove Froidevaux’s machine, which was deemed unsuitable. In 1965, a
new temperature and moisture control system was put into
service. It replaced the natural “cold spot” of the entrance
rubble by an artificial one, condensed the moisture in the air (if
too humid) on the batteries to avoid condensation on the walls,
and maintained air convection.
From its discovery until its closure twenty-three years later in
1963, Lascaux was adapted for visits and for the physical
conservation of its rock art, to the detriment of its archaeological integrity. The closure of the cave ended access to one of
the world’s most prestigious prehistoric sites and weakened
the local economy, which is closely tied to tourism. The measures put in place and the ensuing relative stability of the
cave enabled the commission to authorize restricted visits—
5 people a day, 5 days a week, for 35 minutes—which naturally fell well short of the demand.
Lascaux II, III, and IV
Having acquired the cave in 1972, the French state authorized the Count de la Rochefoucauld to have a life-size replica
made near the original. Shortage of funds prevented comple-
Longitudinal stratigraphic section of entrance to the Hall of the
Bulls around the time of the discovery in 1940 and after the changes
to make the cave accessible to visitors. © MCC-CNP.
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The Hall of the Bulls at Lascaux.
© Gamma-Rapho via Getty Images.
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Clay shoulders at the foot of the walls of the Axial Gallery, covered with compresses steeped in fungicide in 2002. © D. Bouchardon-LRMH.
tion of this project, which was taken over and successfully concluded by the General Council of the Dordogne, aided by the
French state. The running of the cave replica was entrusted
to the Dordogne tourist board, and then to the semi-public
company Semitour. Inaugurated in 1983, this life-size reproduction of part of the cave—the Hall of the Bulls and the Axial
Gallery—by local artist Monique Peytral and others is known
internationally as Lascaux II.
Located at Montignac, at the foot of the hill, Lascaux IV, which
is slated to open in 2016, will be funded by the French state,
the Aquitaine region, and the Dordogne department, and will
include a complete life-size replica of the Lascaux cave complex and of all of its paintings (as opposed to the partial replica of Lascaux II), as well as a 3-D reconstruction and interactive displays.
The fungal infestation of 2001
But Lascaux II also proved problematic. Its success—250 000
or so visitors every year—led to the construction of an infrastructure which was supposed to be enlarged in 2003. However, the cave is not a closed environment, and, worried by
risks linked to the proposed extension of construction work,
the Scientific Committee wanted greater monitoring of the
cave’s environment. A commission was created to oversee the
coordination of interventions on Lascaux hill. Using the findings of a study showing that Lascaux II’s groundwater basin
extended beyond the land initially acquired, the French state
began buying up plots from which polluted water was likely
to seep into Lascaux.
This was the first step in the plan to turn the Lascaux hill into
a kind of sanctuary, the outcome of which will be an ambitious project for an international cave painting center, Lascaux IV (Lascaux III being an international touring exhibition
called “Scenes from the Stone Age: The Cave Paintings of
Lascaux” in which visitors take a virtual tour of the cave).
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In the 1990s, Jean-Michel Geneste, a curator at Lascaux, noted in his status report Lascaux, état des lieux that equipment
set up as a temporary measure during an earlier fungal outbreak was showing signs of wear and tear. One example was
the climatic regulation machine installed in 1965. Renovation
work on this equipment and on its wooden roofing was entrusted to the chief architect of historic monuments, Philippe
Oudin. A new air recirculation system offering more technical
possibilities was installed, and further improvements and new
equipment brought into service between 2009 and 2011 maintain a wholly satisfactory microclimate within the cave.
Along with this work, an ongoing campaign by the Laboratoire de Recherche des Monuments Historiques to kill lichens
in the Hall of the Bulls was entrusted to a restorer specializing in parietal art, in the Spring of 2001. But there was a sudden proliferation of fungi on the floors and benches in the second airlock, at the entrance to the decorated areas, and in the
newly equipped machine area. Several factors could explain
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THERMIC PROFILES
SPEED PROFILES
1999
1981
Convection
this unexpected fungal growth: confinement of the cave during the renovation work (an extruded rigid polystyrene foam
partition was put up to separate the rock art from the working area), introduction of organic materials, acquired resistance of the microorganisms to biocides used long-term, and
upsetting of the balance of the biotope.
After identification of the culprit fungus, Fusarium solani, the
Laboratoire de Recherche des Monuments Historiques proposed a treatment based on quaternary ammonium, applied
by spraying or using moistened compresses. As this fungicide
is degraded by Pseudomonas fluorescens, a bacterium associated with the fungus, antibiotic is occasionally added to the
treatment. But these microorganisms proved particularly resistant and the initial results were unsatisfactory. In October
2001, it was decided to “sterilize” the floor by spreading quicklime, completed by manual elimination of visible microorganisms from undecorated areas. Weekly monitoring was initiated.
In view of the complexity of the problems encountered, the
Minister of Culture set up a Scientific Committee of curators,
biologists, hydrogeologists, and climatologists, which focused
its efforts on finding the source of the contamination and on
the structural fragility of the cave. After two years of spot treatments with quaternary ammonium, the contamination by Fusarium was stemmed and there was a marked decrease in
fungal growth. The committee drew up a conservation plan
and decided to interrupt the biocidal treatments and to favor
“mechanical” action on the visible microorganisms. Since 2004,
a team of restorers has been monitoring the walls using an
analytical chart and by manually eliminating where possible
visible microorganisms from undecorated walls. The quicklime that had covered the floor since 2001 was removed under archaeological supervision.
A three-dimensional survey of the cave in 2003 has recently
been enriched by the acquisition of data on a submillimeter
scale, yielding a model used for georeferencing of observations in the cave. Using this three-dimensional model, a re-
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Temperature and air flow speed findings
relating to a section in the Passageway and
the Mondmilch Gallery, showing the thermic
profiles in September 1981and December
1999. © I2M – Université Bordeaux.
search program called the Lascaux Simulator has improved understanding of the
climatological phenomena in the cave
and facilitated assessment of perturbations related to air circulation and human
Stratification
presence. Visualization of air flow speeds
and temperatures in the Axial Gallery and
the Hall of the Bulls revealed that the cold
spot located in the upper area in 1981
had shifted to the lower area by 1999.
This temperature inversion led to stratification of the air, with a 100-fold reduction in air flow speeds.
Multidisciplinary modeling identifies sensitive zones by specifying air and moisture transfers within the cave. The resulting data are always correlated with in situ measurements and
human observations. The impact of temperature, humidity,
carbon dioxide concentration, and air speed on deterioration
of the wall paintings can also be studied using measurements
made by probes inside the cave and Lascaux Simulator calculations.
Black stain on the Passageway vault. Photo taken on September 2011 as the phenomenon was being monitored.
© MCC-DRAC Aquitaine.
The black stains of 2006
Faced with difficulties in objective monitoring of the walls, the
Scientific Committee asked a team of restorers aided by geologist and a photographer to review the state of the cave.
Their status report is still a reference. In the Spring of 2006,
new fungi were noted where the substrate, a soft, crumbly
limestone, had long been weakened. Black patches appeared
on the vault of the Passageway, where there are traces of paintings, but also on the vault of the Apse and Nave which is rich
in engravings.
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After a test period, the Scientific Committee approved the principle of a biocide treatment, which was applied to the contaminated surfaces in 2008. Measurements of adenosine triphosphate after treatment indicated reduced metabolic activity in
nine of the eleven test areas. The treatment, which gave rather
satisfying results, was completed by manual elimination of visible microorganisms, outside the decorated zones and under
archaeological supervision. By the summer of that year the
condition of the Hall of the Bulls and of the Axial Gallery had
stabilized well, but contamination persisted in the Passageway, Apse, and Nave, despite regular removal of visible microorganisms.
from the cleaned surfaces). This study confirmed the need to
combine manual cleaning with biocide treatments, but also
showed that such intervention irreversibly damages the wall,
thus discounting its use on archaeological zones, decorated
or not.
Differences of opinion among microbiologists prompted the
Scientific Committee to apply the precautionary principle and
not use biocides, a ruling that is still in force. Regular monitoring of visible microorganisms since 2007 and tracings and
photographs have been used to track microbial growth. Although the appearance of new spots is most unfortunate, the
cumulative surveys are nonetheless encouraging. Since treatments were stopped, visible microorganisms have remained
in certain sectors, notably on the vault of the Passageway, the
Apse, and the Nave, but few new spots have emerged. The
color of many patches has faded from black to gray, and the
few newly affected areas on the vault of the Passageway and
the Nave are usually apparent as pale gray marks or extensions of old blotches in the form of small spots.
Diversified scientific research in the preservation
of Lascaux
Graphic representation of the engravings in Area A of the Passageway in 2008 studied for possible consequences of mechanical cleaning of black stains. © MCC-CNP.
Disagreement about the relevance of the use of biocides led
the Scientific Committee in late 2008 to put in place an impact study before any new intervention. This involved assessment of the efficacy of a biocide treatment combined with
manual cleaning, compared with biocide treatment alone, but
also the collection of data on the feasibility of such interventions in decorated areas where the limestone is fragile.
Four areas on the vault of the Passageway were selected, depending on the nature of the support (fissures, morphology),
their archaeological sensitivity (proximity to engravings, traces
of pigments), and visible microorganisms (appearance, thickness, recent changes). Before any intervention, the Centre National de Préhistoire surveyed the decorated area and the
restorers in charge of cleaning mapped the substrata to assess the impact of possible mechanical action on the vault of
the Passageway and the feasibility of manual intervention. Soft
brushes were used to clean the surface of two zones, while
two other zones were also treated with biocide. Microbiological analyses were done before and after cleaning, before biocide treatment, and, finally, three weeks after a post-treatment
rest period (ATP, epifluorescence, emission spectroscopy, microscopic and molecular analyses, analysis of surface residues
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Following the 2001 fungal infestation, the Scientific Committee
launched multidisciplinary research programs to track down
the source of the microorganisms and to develop effective
monitoring tools. Specialists in microbiology, atmospheric
physics, and the transport properties of rocks conducted a
study to assess the impact of physical parameters of the atmosphere and substrata on growth of microorganisms. They
monitored microbial contamination in three zones at the entrance to the Axial Gallery and correlated changes with physical and microclimatic data recorded at the surface and within the rock substrate. Their findings confirmed the major role
played by the microclimate at the surface of walls in microbial
growth at the air-mineral substrate interface.
Happily, changes in the microclimate were too small to alter
the microbial colonization, which remained largely stable, making it impossible to cross-reference the climatic and microbiological data. At the request of the Scientific Committee,
the focus was shifted to the right sector of the cave, at the
entrance to the Nave. Two new zones were chosen as a function of the nature of the substrate and the level of microbiological contamination. Here too the climatic stability prevented correlation of the parameters studied, and the program was
halted.
In parallel, another program on the microbial ecology of the
Lascaux Cave was designed to shed light on the microorganisms that cause contamination, by studying their metabolic requirements. Rather than eliminating the apparently dominant
species, the aim was to consider all the microbial communities and their equilibria, in an ecosystem approach to the various processes and features of the cave’s biodiversity. In 2011,
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The Panel of the Great Black Cow in the Nave. © MCC-CNP.
this research program confirmed the identification of the fungus Scolecobasidium (Ochroconis) in the black spots, but also
revealed a new species of Scolecobasidium, called Ochroconis lascauxensis. This study moreover posited the possible
role played by the feces of springtails (wingless arthropods)
in the dissemination of Scolecobasidium spores. Given the importance of this fine ecosystem approach, it will be continued
mon underground, the literature on them is sparse. It was therefore decided to appoint a new Scientific Advisory Board, under the presidency of the paleoanthropologist Yves Coppens,
to define an appropriate research program.
A network of specialists undertook a comprehensive study
of the geological, geomorphological, and pedological context
of the Lascaux Cave, to elucidate the role of the soil-organism
system and past and foreseeable changes in the cave ecosystem. The main purpose was to assess the risks related to the
local vegetation and to understand transfers from the surface
of the plateau to the cave.
Conclusion
Wormlike deposits in the Hall of the Bulls. © MCC-DRAC Aquitaine.
through a new program, which is currently being drawn up.
In 2009, wormlike marks were noted in the Hall of the Bulls.
A natural phenomenon observed in other caves in the Dordogne and already seen at Lascaux, these small deposits a
few millimeters in size result from the transport of sedimentary
particles. Regular photographic monitoring showed that the
phenomenon spread slowly. Although such deposits are com-
We are seeking to minimize perturbation of the fragile, living
milieu that is Lascaux, while recognizing that we cannot reverse our heavy-handed interventions since its discovery in
1940. Given the importance of Lascaux in the history of humanity and of art, it was small wonder that the fungal infestations alarmed the scientific community and the public.
Nevertheless, the scientific and financial efforts deployed by
the State are equal to the task. While we cannot restore the
equilibrium procured by the cave’s prolonged isolation, everything has been put in place to stabilize the conditions. The history of Lascaux has highlighted the great vulnerability of this
heritage and is a vital contribution to the conservation of similar heritage sites. As curator of the Lascaux Cave, it is my duty
to watch over this jewel of prehistory and to ensure it is preserved for future generations. ■
Further readings
– Aujoulat N. Lascaux, le geste, l’espace et le temps. Paris, Le Seuil, 2004, 273 p.
(collection “Art rupestre”).
– Bataille G. La Peinture préhistorique. Lascaux, ou la Naissance de l’art. Éditions
Skira, 1955, 152 p. (collection “Les grands siècles de la peinture”).
– Breuil H. Lascaux, in : Quatre cents siècles d’Art pariétal, Montignac, CEDP, 1952.
– Leroi-Gourhan. A. Préhistoire de l’art occidental, Paris, Citadelles et Mazenod,
1965, 485 pp. (collection “L'Art et les grandes civilisations; 1”).
– Symposium “Lascaux et la conservation en milieu souterrain,” Actes du symposium international, Paris, 26 et 27 février 2009, dAf 105, Editions de la Maison des
sciences de l’homme, Paris 2011, 357 pp.
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LASCAUX :
HISTOIRE DE LA CONSERVATION D ' UNE GROTTE ORNÉE EXCEPTIONNELLE
La découverte fortuite de la grotte de Lascaux par quatre adolescents accompagnés de leur chien – telle une aventure du Club des Cinq – va bouleverser le regard de l’Homme moderne sur la préhistoire. C’est dans une Europe en
guerre, le 12 septembre 1940, que près de 2000 peintures préhistoriques – parmi les plus belles au monde – vont se
révéler aux yeux de Marcel Ravidat, Jacques Marsal, Simon Coëncas et Georges Agniel. Cette découverte, immédiatement considérée comme un événement majeur, va offrir au monde une grotte vieille de plus de 20 000 ans, vierge
de toute exploration, suscitant l'enthousiasme de la communauté scientifique internationale mais aussi du grand public. Toutefois son ouverture au public et l'incroyable engouement qu'elle suscite va rapidement déstabiliser ce milieu naturel fragile. Lascaux deviendra comme un patient au chevet duquel se presseront une foule d’experts pour
diagnostiquer et traiter les multiples maux dont souffrent la grotte et ses peintures afin d’éviter que l’humanité ne soit
privée d’un joyau inestimable. Les modifications hygrométriques, l’augmentation des taux de dioxyde de carbone,
l’influence des changements climatiques et de l’environnement de la grotte, contribueront en effet à la survenue de
véritables « maladies » (maladie verte, maladie blanche, taches noires…) causées par toute une série de micro-organismes dont la liste évoque un compte rendu de laboratoire de bactériologie et d’anatomo-pathologie, qu’il s’agisse
de moisissures et champignons (Fusarium solani, Ochroconis lascauxensis et O. anomala, Chrysosporium, Gliocladium, Gliomastix, Paecilomyces, Trichoderma, Verticillium), d’algues (Bracteacoccus minor…), ou de bactéries (Pseudomonas fluorescens…). On tente de les éradiquer à force d’antifongiques et d’antibiotiques (streptomycine, pénicilline, polymyxine…) et autres agents (solutions formolées, chlorure de benzalkonium, chaux vive…), ainsi que par
la mise en place d’un système d’assistance climatique. De crises en solutions, Lascaux va constituer un lieu d’expérimentations multiples qui en fait, malgré elle, un laboratoire pour la conservation des grottes ornées. Lascaux sera
fermée au public en 1963, et inscrite au patrimoine mondial par l’UNESCO en 1979. En 1983 sera inaugurée une réplique souterraine partielle, à taille réelle, de la Salle des Taureaux et du Diverticule Axial, reproduisant de façon particulièrement fidèle la topographie de la grotte, les diverses textures des roches formant les parois, ainsi que les
peintures pariétales. Cette réplique, nommée Lascaux II, accueille actuellement environ 250 000 visiteurs par an. En
2009 fut créé Lascaux III, comportant 5 fac-similés de scènes non reproduites dans Lascaux II à vocation d’exposition itinérante dans le monde. Un projet ambitieux, Lascaux IV, offrira un fac-similé complet de l’ensemble de la grotte
de Lascaux et de ses peintures, à l’horizon 2016, qui devrait accueillir plus de 400 000 visiteurs par an.
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ost paleontologists at the
turn of the 19th century
were convinced that the
skills and capabilities of prehistoric humans were incompatible with
the stunning polychrome frescoes
that covered the walls and ceilings
of newly discovered caves. In short,
cave paintings were fakes. It took
all the acumen of a priest, Henri
Breuil, to dispel these fallacious
opinions. Dedicating his life to research rather than the parish —
though he donned ecclesiastical
garb his entire life — Breuil was to
become hailed as the “Pope of prehistory.”
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M
Abbé Henri Breuil
and the rediscovery of
prehistoric humans
b y A . H u re l , Fra n c e
A
rnaud Hurel is a historian and research engineer in the Department of Prehistory at the French National Museum of Natural History (Mixed Research
Unit [UMR] 7194). He is vice-chairman of the History of Science section at
the Committee of Historic and Scientific Works [CTHS]). His work focuses on the history of the human sciences in the 19th and 20th centuries, and in particular on prehistory in its social, institutional, patrimonial, political and legal dimensions. He is the
author of several books, including L’abbé Breuil. Un préhistorien dans le siècle –
Abbé Breuil: Priest and Prehistorian (Paris, France; CNRS éditions, 2011).
Arnaud HUREL
Research Engineer
National Museum of
Natural History, Paris
Arnaud Hurel, Département
de Préhistoire du Muséum
National d’Histoire Naturelle,
1 rue René Panhard, 75013 Paris
(e-mail: hurel@mnhn.fr)
P
rehistory emerged as a discipline in the second half of the 19th century,
an era in which any developing intellectual enterprise was informed by
the ideology of progress. The material products of prehistoric humans —
the stone and bone artifacts unearthed by excavation, and the pattern of their
evolution over time — were interpreted as confirmation of continuous improvement. At the turn of the century Abbé Henri Breuil (1877-1961) was among
those who overthrew this interpretation. His research revealed the existence
of authentic prehistoric societies and showed that human history could not
simply be subsumed into a history of techniques. In particular, it was his enormous contribution to the recognition of Paleolithic rock paintings that brought
home the realization that the mental world of prehistoric humans was both
rich and complex. Catholic priest cum prehistorian, Breuil built up a body of
work comprising over a thousand references remarkable for their originality,
reliability, and vitality. In his hands, a fashioned stone or a cave painting were
not abstractions but objective expressions of an act of creation and technical
skill that opened a window onto the past. Breuil’s work documented the biological unity of the human species at the same time as its cultural diversity
spanning the divides of continents and millennia. Breuil’s crowning and enduring achievement was arguably the creation of the Institute of Human Paleontology which, with the generous support of Prince Albert I of Monaco, was
inaugurated in Paris in 1910. To this day it has remained a beacon for paleontologists throughout the world, both thanks to its cutting-edge research and as
a repository for the artifacts and publications of the early days of paleontology.
Abbé Henri Breuil and the rediscovery of prehistoric humans – Hurel
Top-of-page frieze: based on drawings by Henri Breuil
of paintings in the Combarelles cave at Les-Eyzies-de-Tayac.
© RMN-Grand Palais (Musée de la Préhistoire des Eyzies)/Franck Raux.
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Gallery of Hominids, designed and sculpted by paleoartist Elisabeth Daynès, with “Mandal Man” (Homo sapiens) in the forefront,
www.daynes.com. © Photo S.Entressangle/E. Daynès/Lookatsciences - Reconstitution Elisabeth Daynès Paris.
rehistoric humans are part of our world. Their stone
tools and their sculptures in ivory or bone, like the images they produced—especially the magnificent Paleolithic bestiaries in the painted caves of France and Spain—
people our imagination and belong to our own world and
mental representations. There is no doubt that it is largely
thanks to Abbé Henri Breuil (1877-1961) that the 21st century
is so familiar with art forms and artifacts that go back tens or
even hundreds of thousands of years. From the seminary of
Saint Sulpice, at Issy-les-Moulineaux just outside Paris, to
the Collège de France, where in 1929 he became the first
professor of prehistory, via the Institute of Human Paleontology, and from Europe to Asia via Africa, Breuil built up a body
of work that was both scientific and accessible. He had a
profound influence on what we know of prehistory and how
we view it.
P
The setting for an encounter
The modern world first encountered its Paleolithic ancestors
in the mid-19th century when artifacts began to afford researchers their initial glimpses of prehistoric humans. The encounter began with the discovery of the mobiliary (or portable)
art of the Upper Paleolithic depicting extinct animals such as
mammoths. From 1865 onwards, the Reliquiae Aquitanicae
254
produced by Édouard Lartet (1801-1871) and Henry Christy
(1818-1865) gave European scholars a window onto a vanished world.1 Alongside the stone tools which the two men
found in proximity to extinct animal remains, readers discovered plates depicting a multitude of enigmatic objects. All were
magnificently engraved or delicately sculpted and could be
dated to Man’s remotest antiquity. In the words of the anthropologist Gabriel de Mortillet (1821-1898), readers felt they
were glimpsing “the childhood of art” as opposed to “the art
of a child.”
In their attempt to reconstitute this previously unknown world,
pioneer prehistorians constructed an image of prehistoric humans and their mentality by mixing biology and physical and
intellectual skills according to the same linearly transformist
approach. They developed classifications based on a naturalist model in which a series of material cultures succeeded
one another in a process of emergence, extinction, and substitution. The classification system was built around the everyday objects of prehistoric humans. The history of Man became
the history of the objects he produced, with ages named according to the technical progress achieved, as uncovered by
archeologists. The works of prehistorians were an account of
these material “civilizations” that extended all the way from
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the barely modified flints of the hypothetical half-human half-ape Anthropopithecus,
through the polished stones of the Neolithic
Age, to the weapons of the first Metal Ages.
The discoveries of the burial sites, cave paintings, and cave engravings that emerged in
the 1870s to 1880s undermined this narrative. They pointed no longer simply to a tangible culture but to entire systems of mental
representations reflecting complex symbolic,
magical, and even spiritual thought processes. Such systems pointed so far back in
time that they contradicted the prevailing
evolutionary narrative. As a result, and for
several decades, the authenticity of burial
sites and cave art was contested, prompting accusations of hoax or scientific error.
Such was the setting in which the young
Henri Breuil embarked on his career as a
Plumbing the depths of the history of Humanity — giving birth to a new science:
prehistorian. From the start, at the turn of the Henri Breuil (1877-1961). © Jacques Boyer/Roger-Viollet.
20th century, his work bore testimony to the
striking complexity of prehistoric societies. For more than 60
town that within a few years proclaimed itself the capital of
years, Breuil put his stamp on prehistory studies from Europe prehistory. He studied several of its classic sites, including the
to Africa, and as far as Asia. His work, which was both innova- Cro-Magnon rock shelter that had become so celebrated aftive and massive (his bibliography runs to over one thousand
ter yielding several human fossils in 1868. This trip also gave
references), reflects his unusual background, that of a man the fledgling archeologist the opportunity to meet his first prewith a dual vocation as scientist and Catholic priest, albeit with
historians, who must have been taken aback by the young
a ministry unattached to any parish. Breuil was a convinced seminarian in the ill-fitting cassock who seemed to have emevolutionist and an exemplary exponent of the non-overlap- barked on an imperious quest to see and know everything
ping magisteria (NOMA) solution that Stephen Jay Gould was about prehistory.
to propose a century later to the supposed conflict between
Science and Faith.2 The unmistakably religious dimension to One such encounter, with Édouard Piette (1827-1906), who
was working on the Brassempouy caves in the Landes, was
his work comes across in his insistence on “Truth” and in his
determination to reconnect with the humanity of our prehis- to change Breuil’s life. Across the age gap, mutual esteem
toric forebears by studying their behavior and the objects developed in the course of long discussions between the two
they produced. Breuil devoted his life to uncovering the unity men. Under the elder man’s watchful eye, Breuil discovered
and aspirations of Man not only across the divides of time an archeological excavation technique that favored the stratiand space, but also across the transformations wrought by graphic or layered approach. Piette admired the young priest’s
evolution. He tracked this common thread in the subtlety of enthusiasm and draughtsman skills, going so far as to comline displayed by Paleolithic artists and at a wider level in the mission drawings from him of artifacts from his vast collection
to illustrate his publications.
manifest richness of the prehistoric humans’ mental world.
The discovery of cave paintings
Breuil entered the Parisian seminary of Saint-Sulpice in 1895.
The following year, the natural sciences and prehistory course
taught by Abbé Jean Guibert (1857-1914) introduced him to
Man’s prehistoric past and the theory of evolution. It was a
“true revelation.” Just one year later, in the summer of 1897,
realizing that it was not enough to read the scientific journals
and that real understanding came only from work in the field,
Breuil visited the prehistoric sites of south-west France. He
was forever on the move afterwards, traveling the world in
search of new sites and artifacts. His initial trips were confined
to the Périgord, more particularly to Eyzies-de-Tayac, a little
Piette remained one of the three key figures in Breuil’s personal Pantheon who shaped his scientific development and fostered his career: Émile Cartailhac (1845-1921), an archeologist from Toulouse who gave the young priest the credibility
he needed if he was to take his place at the prehistorians’ high
table, and a doctor, Louis Capitan (1854-1929), who opened
his eyes to the complexity of the prehistoric eras revealed in
cave paintings and stone artifacts.
Breuil first met the doctor-archeologist in 1898, at a time when
Capitan was a leading figure in the prehistorian community.
Capitan had completed his medical studies at the Faculty of
255
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The young
Henri Breuil as
a seminarian.
© Saint-Germainen-Laye, Musée
d’Archéologie
Nationale,
© Direction des
Musées de
France, 2006.
Saint-Sulpice
Seminary, in Issyles-Moulineaux,
near Paris. Built in
the early years of
the 17th century,
the Seminary (on the
French National Heritage list) continues
to train priests from
France and several
other countries.
© Photo Myrabella
Wikimedia Commons.
All rights reserved.
Medicine in Paris in 1878, but for the previous six years had
regularly attended Mortillet’s prehistory lectures at the School
of Anthropology. His curiosity was such that he also took the
ethnography course taught by another medical doctor, ErnestThéodore Hamy (1842-1908), at the National Museum of Natural History as well as attending lectures by Théodore Vacquer
(1824-1899), who was the first to seriously explore the Roman
and medieval archeology of Paris. Capitan managed to conduct his regular medical career (as a pathologist and bacteriologist) in the Paris public hospital system while at the same
time indulging his passion for archeology and his collections
of artifacts. In 1892, his appointment as a lecturer in pathoStatue of the Eyzies
Prehistoric Man,
by Paul Dardé (1931).
The statue is a landmark
towering over the village
of Les-Eyzies-de-Tayac,
in the Dordogne region
in France, a UNESCO
World Heritage site since
1979. Geologist Louis
Lartet discovered the
earliest known remains of
Homo sapiens sapiens
(Cro-Magnon Man) dating
back between 47 000
and 17 000 BP, in
the rock shelter (Abri
Cro-Magnon) above
the village.
© gettyimages/HUGHES
Hervé/hemis.fr.
256
logical anthropology at the School of Anthropology officialized this combination of careers. In 1894, he was made professor of medical geography, before taking over Mortillet’s
mantle as professor of prehistoric anthropology on the latter’s
death in 1898.
When Breuil first met him, Capitan was campaigning to set
prehistory studies on a new footing by transforming the methods of work and rethinking basic concepts in a multidisciplinary approach that combined the natural sciences, human
sciences, and archeology. This framework conferred a new dimension on excavation by interacting artifacts on the one hand
with their stratigraphic setting and on the other with the early
producers of these material cultures. Capitan taught Breuil the
rudiments of prehistoric archeology viewed from this multifaceted approach, introduced him to his collections of artifacts,
and joined him on field trips. He impressed upon him the
need, if he was to understand the tools created by prehistoric humans, always to take the raw materials they used as
his starting point. Capitan also encouraged Breuil to develop
a technological approach that took every category of object
into account (“experimental pieces, failed pieces, cores, sizeable fragments, flakes and unworked blades, finished tools
that had never been used, tools that had been damaged in
use then repaired, and finally tools definitively discarded as no
longer fit for purpose”).
On one of their joint trips Breuil and Capitan made a crucial
discovery. In the summer of 1901, having just received his
certificate of higher studies in geology along with his license to
celebrate Mass—he had been ordained at the end of 1900—
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Breuil set off on a new field trip. At the beginning of September he met up with Capitan and local primary school teacher
cum prehistorian, Denis Peyrony (1869-1954), at Eyzies-deTayac. After some work at the Laugerie-Haute site, focused
on its Magdalenian strata, the trio began prospecting in the
valley of the Beune, a small tributary of the river Vézère. On
September 2, candles in hand, they entered a cave in the hamlet of Combarelles. Progress was laborious. Several times, Breuil could only squeeze through the
twists and turns of the narrow passage by removing his cassock. As for Capitan, he was
unable to negotiate a particularly tight bend
and remained blocked half-way. The others eventually reached the cave, to be confronted by an unbelievable spectacle on
the walls, still pristine after thousands of
years: around one hundred figures of
horses, reindeer, bears, mammoths, cattle, and ibex. Rooted to the spot, Breuil
spent a dozen or so hours documenting
the paintings.
A few days later, by which time Capitan and
an exhausted Breuil had already left the Périgord, Peyrony informed them that another painted
cave had been discovered near the one at Combarelles.
All hurried to the new site. On September 21 they entered
the Font-de-Gaume cave to be met by the spectacle of almost 200 animal figures, including polychrome paintings of
bison, some of which measured almost 2.5 meters across.
Capitan and Breuil made charcoal sketches of several dozen
images on large sheets of printing paper.
Presentation of their two discoveries to the Academy of Sciences and Academy of Inscriptions and Belles-lettres set the
proverbial cat among the prehistorian pigeons. Other caves
decorated with paintings or engravings had been reported in
the past but had never been recognized as authentic. Since
1895, prehistorians had been sharply divided over La Mouthe,
another cave near Combarelles. But the most emblematic example of the refusal to recognize Paleolithic cave art came in
1901, involving the Altamira cave near Santander in Spain.
In 1879, Marcelino Sanz de Sautuola (1831-1888) discovered
a huge number of paintings, each more beautiful than the other, in the Altamira cave. Captivated by his discovery he published an illustrated brochure the following year describing the
site and its wealth of images. He was convinced that the paintings dated from the same period as the profusion of Paleolithic archeological material in the cave floor. Press reports brought
Altamira international fame. Visitors flocked to the site. Some
were quick to question whether the paintings were as old
as claimed while others denounced promotion of the site as
a discredit to genuine prehistory studies. In order to settle the
question, the French paleontologist Édouard Harlé (1850-
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1922) inspected the site in 1881. His report recognized the
age and authenticity of the cave floor material but doubted
that it was contemporaneous with the wall paintings, some of
which, it hinted, may only have been of recent manufacture.
In a more general judgment, he considered the skills—both
creative and technical—of the cave artists as incompatible
with the prevailing estimate of prehistoric capabilities. Prehistoric humans were considered incapable of executing the vast polychrome frescoes that covered the
cave ceiling.
The Harlé report disqualified the Altamira site
for over twenty years. It ceased to be spoken of in scientific circles except with reference to its archeological material. The
paintings were forgotten, until the proposal by Capitan and Breuil in 1901 to align
Combarelles, Font-de-Gaume, and Altamira in a mutually authenticating chain
of Paleolithic artistic achievement reincorporated the Spanish site into the scientific
canon.
Doctor Joseph Louis Capitan (1854-1929):
physician, anthropologist, and prehistorian.
© Roger-Viollet.
Artist and primitive cease being incompatible
concepts
In the space of a few years a rapid succession of similar discoveries—in France, in addition to Combarelles and Font-deGaume, there was La Mouthe in 1895, Pair-non-Pair in 1896,
Marsoulas in 1897, Mas-d’Azil in 1901, and Bernifal in 1902—
began to convince skeptics of the cave-painting prowess of
prehistoric humans. A revolution in prehistorian mentalities
was under way. Conversions started to be reported. In 1902,
Cartailhac, who had led the movement of nonbelievers in Paleolithic artistic achievement, with particular respect to Altami-
Cranium of a young prehistoric bear (aged approximately 2 years),
dated 35 000 BP, found in the Font-de-Gaume cave (Prat excavations). National Prehistory Museum of Les-Eyzies-de-Tayac.
© RMN-Grand Palais (musée de la Préhistoire des Eyzies)/Franck Raux.
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Altamira, Spain, cave painting of a charging buffalo. Printed color halftone reproduction. Émile Cartailhac & Henri Breuil. In: Cartailhac
E, Breuil H. La caverne d'Altamira à Santillane près Santander (Espagne). Monaco: Impr. de Monaco;1908.
© akg/North Wind Picture Archives.
ra, published a brave autocritique, a “Skeptic’s mea culpa.” He
admitted having been “complicit in an error committed twenty
years ago, an injustice that needs to be clearly recognized and
made good.” He then went further still, pronouncing the befrescoed Spanish cave totally rehabilitated on the strength of
Breuil’s work and joining the young priest on a personal visit
to Altamira.
After a three-week mission, the two men came back from
Spain, their arms full of Breuil’s notes and sketches and their
heads reeling from all their discoveries. Breuil’s portfolio reflects
not only the beauty of the polychrome bestiary they were privileged to study but also the young priest’s skill as an artist-documentalist working by candlelight in a damp cave. In France,
Breuil and Cartailhac informed the scientific community of their
work but had problems raising the requisite funds for publishing a monograph that
would do justice to the beauty of the Altamira paintings and their interplay of colors.
The two men were fortunate in being able
to present their Spanish and French sketches to Monaco’s Albert I (1848-1921). At the
end of 1904, the Prince made them a proposition they had never dared hope for: he
would personally shoulder the cost of pubDrawings by Henri Breuil of mural paintings
and engravings in the Combarelles cave at LesEyzies-de-Tayac, picturing a mammoth, bisons,
and horses. In: Capitan L, Breuil H, Peyrony D.
Les Combarelles aux Eyzies (Dordogne). Paris,
France: Éditions Masson;1924. © RMN-Grand
Palais (musée de la Préhistoire des Eyzies)/Franck Raux.
258
A TOUCH
lishing the Altamira book and even undertake to publish a
series of books promoting “cave wall paintings and engravings from the Reindeer Age.” He then went further by offering to finance all the research Breuil would need to undertake
in order to complete these projects. The Monaco head of state
thus provided crucial support not only for the recognition of
cave art but also for Breuil’s career at a time when French universities had yet to recognize prehistory as a discipline and
when the separation of Church and State tended to marginalize ordained academics. Four years later saw the publication
of a magnificent volume, The Cave of Altamira at Santillana del
Mar, Spain, in a run of 600 copies on large-format paper. Its
main features were its 205 figures and 37 plates, 22 of them
four-color, based on Breuil’s records, but also its multiple photographs overlaid with transparent paper that enabled readers to understand where each painting featured in the whole.
Prince Albert immediately distributed the volume—long since a collectors’ item—to his
network of scientific correspondents.
A short while later, Breuil accepted Prince
Albert’s patronage for all his work. In Spain
he was continuing with his cave explorations and new finds were coming in quick
succession. The Prince understood the situation in which the European practitioners
of prehistory found themselves: many were
unrecognized by any university and had
neither funding nor an institution behind
them that would allow them to undertake
long-term scientific activity. This inspired
Albert I to set up an institution that would
make open-ended research possible. He
used Breuil as a key consultant in the setting up, in Paris in 1910, of the Institute of
Human Paleontology, where Breuil was to
spend the rest of his career as professor of
prehistoric ethnography.
OF
FRANCE
and changes in painting technique. At the same time, he argued that the similarities in content and design between the
various decorated caves were evidence that proper schools
and traditions of artistic practice had developed in the Paleolithic period on both sides of the Pyrenees within veritable
prehistoric societies.
Breuil continued to tweak this basic dating system throughout his career, accommodating each new discovery until publishing his magnum opus in 1952, Four Hundred Centuries of
Cave Art. The book presented several dozen decorated sites
but placed its emphasis squarely on what he dubbed the “six
giants” of Quaternary Period art: Altamira, Font-de-Gaume,
Combarelles, Trois-frères, Niaux, and Lascaux. The Lascaux
cave complex was discovered on September 16 1940: Breuil
visited it just five days later. One look at the magnificent paint-
The Paris Institute of Human Paleontology (Prince Albert I of Monaco Foundation),
inaugurated in 1920 (architect Emmanuel Pontremoli, who also designed the interior
decoration down to the very last fixture), the brainchild of paleontologists Henri Breuil,
Marcellin Boule, and Émile Cartailhac. The Institute is the spiritual “alma mater” of
every paleontologist throughout the world to this very day.
As a leading champion of cave art, Breuil
was able to provide archeological and ge- Photo F. Scheffler © Institut de Paléontologie Humaine, Paris.
ological evidence for dating it to ten or twenty thousand years in the past. He was relatively unconcerned ings convinced him that they were both extraordinary and
with interpretations of the art itself. Although he favored the genuine. He spent three days at the site drawing up an enhypothesis that it served a magical function he was happy thusiastic initial report for the French Institute. A few days later
to leave debate on this topic to his friend Capitan. When it he welcomed the French weekly L’Illustration to the site for
a photographic report by Pierre Ichac (1901-1978), whose arcame to theory, he preferred to follow a novel approach based
on the principle that the cave paintings were not instances of ticle introduced the general public to the latest and perhaps
random art or works created in isolation. He sought to show grandest jewel of Paleolithic art. Lascaux quickly became world
that the art reached back into the very beginnings of human famous, perhaps most of all after the series of color photohistory, that it had been integral to human existence for many graphs published by Life magazine in 1947. Breuil worked on
thousands of years, and that it was subject to organized codes the site up until December 1940, but surprisingly—partly, no
and practices transmitted down the generations. Breuil es- doubt, because he considered that aside from their esthetic
tablished a chronology based on a form of cave wall stratig- perfection the paintings did not fundamentally call his personal theories on the chronology of Paleolithic art into quesraphy derived from his observations of superimposed designs
259
A TOUCH
OF
FRANCE
Reproduction of mural paintings in the Hall
of Bulls in Lascaux cave by Maurice Thaon
(1910-1965). Located at Saint-Germain-en-Laye,
Musée d’Archéologie Nationale and Domaine
National de Saint-Germain-en-Laye.
© RMN-Graind Palais (Musée d’Archéologie Nationale)/
Loïc Hamon.
tion—he was not prepared to undertake an exhaustive study
of the site himself. He preferred to entrust the task to others in
whom he had confidence and he even had preliminary works
carried out to facilitate this for them. The construction work,
followed by an increasing number of visitors, had an irreversible
impact on the caves’ conditions of preservation. Young Maurice Thaon (1918-1999) was tasked with the preliminary documentation of the site. Next came a huge photographic campaign undertaken by Fernand Windels (1893-1954). In 1941,
Breuil left France after the country had been divided by the
German occupation. He reached Spain and Portugal before
settling in South Africa in order to continue his research. His
only subsequent field trip to Lascaux was in 1949 to undertake some brief excavation. In 1952, he entrusted fellow priest
André Glory (1906-1966) with the task of documenting what
he himself had left undone.
Breuil first visited South Africa in 1929. He
stayed there for protracted periods in the
Second World War and then up to 1951.
While associate professor in the department
of prehistoric archeology at the University
of the Witwatersrand (‘Wits’) in Johannesburg and holding a research post in the department of archeology, he discovered a different form of parietal art in the course of
several archeological and geological expeditions in South Africa, Zimbabwe, and Namibia, documenting Middle and Late Stone
Age artifacts and, above all, thousands of
rock paintings. This huge volume of work, much of it still dormant in the Wits archives, surfaced only in a few monographs
and the controversy over the identification and origins of the
Brandberg Mountain painting that he dubbed the White Lady.
Glory did his best over the following decade (1952-1963),
given the great difficulties imposed by the flocks of tourists
and increasingly intensive commercialization, only to die in a
road accident before completing the monograph he had been
preparing on the site.
Prehistoric cultures elsewhere
It soon became apparent that Western Europe was too narrow a theater for the theoretical framework for describing prehistoric civilizations that Breuil was developing based on the
two principles of the biological unity and cultural diversity of
the human species. Already, in the different style and content
of Spanish cave wall art, Breuil could see evidence of migration and interactions within the Mediterranean basin. He felt
it was imperative to go further afield and explore new horizons. Between the two World Wars, he changed the scale of
his field research by turning to Africa and Asia, prompted by
the opportunities afforded him by each new discovery.
260
Jesuit Father and paleontologist Pierre Teilhard de Chardin
(1881-1955) and Father (Abbot) Henri Breuil (1877-1961) at the
Ming Tombs in China, on 7 April 1935. © Fondation Teilhard de Chardin,
Paris, France/Archives Charmet/The Bridgeman Art Library.
A TOUCH
OF
FRANCE
Peking Man Site Museum at Zhoukoudian
(周口店遗址), Beijing, China. © Imaginechina/Corbis.
In Asia, Breuil played a leading role in the
study of Sinanthropus pekinensis. Thanks
to his contacts with the Jesuit Émile Licent
(1876-1952), who set up the Hoang Ho Pai
Ho Museum in Tianjin that was to become
the Chinese Museum of Natural History,
Breuil encouraged his friend, the Jesuit paleontologist Pierre Teilhard de Chardin (18811955), to head a mission exploring the Yellow River basin (1923-1924). Teilhard ended
up spending almost 17 years in the Middle
Kingdom. As honorary adviser on questions
of paleontology to the Geological Survey of
China, he took part in the excavations at
Zhoukoudian, which in 1929 uncovered the
fossilized remains of several Homo erectus
specimens (Sinanthropus pekinensis). It was
immediately apparent that these ranked as perhaps the oldest human remains hitherto identified. Ensuing debate on the
practices and technical skills of Peking Man enabled Breuil to
share in the study of these discoveries. Working from Teilhard’s
reports at his Paris desk, Breuil became convinced that Sinanthropus pekinensis was responsible for the artifacts discovered
in conjunction with the human remains in the Zhoukoudian
caves. To test this view he traveled to the site at the invitation
of the Geological Survey of China and also the Rockefeller
Foundation, which was supporting the Zhoukoudian-based
Cenozoic Research Laboratory. While there, he examined thousands of items discovered at the site (quartz fragments, bones,
antlers) and became convinced beyond doubt that they had
been deliberately carved, fashioned or adapted in the Paleolithic Period by Sinanthropus, who had also learned how to
use fire. He was quick to publish his conclusions in Europe,
ignoring the reservations of the scientific community in China,
headed by Teilhard who was much more circumspect as to the
level of civilization achieved by Sinanthropus.
However, further excavation followed by a second field trip
in 1935 to complete his analysis of the artifacts confirmed
Breuil’s initial hunch: Sinanthropus was indeed Homo faber
and the tools he made were many and varied, even if no relationship could be found with contemporaneous European
counterparts.
Conclusion
Prehistoric African cave paintings, drawings by Henri Breuil.
Paris, Musée du Quai Branly. © RMN-Grand Palais/Michel Bellot.
After the Second World War, a new generation of research
workers began to debate and even question Breuil’s hypotheses. Different issues emerged following a general review of
working methods. The entire research and career framework
that Breuil had been so successful in negotiating was thrown
into question. Prehistoric studies came under new constraints:
the emergence of the concept of heritage, both national and
international, led to the prioritization of archeological site protection, with Governments becoming the main stakeholders
in archeology and research being organized into teams and
projects.
261
A TOUCH
OF
FRANCE
Although Breuil’s work has been to a large extent superseded,
it remains both relevant and topical. The sheer quantity of his
rock painting records remains an unparalleled resource, especially as many of the sites that he originally studied have
since fallen prey to irreversible damage (vandalism, environmental degradation). Similarly, his personal archives have no
equal as a source for documenting the early days of prehistory as a scientific discipline. But over and above this material
legacy, Henri Breuil bequeathed his successors a compendium of original work that is above all striking for its underlying
humanism, the conviction that across epochs and continents
the human species is both singular and diverse. An animal
painted on the wall of a Spanish cave or on an overhang in
South Africa, a biface Acheulean handaxe from the banks of
the river Thames or an artifact from a Middle Stone Age site
in Cape Province each bears witness in its way to the rich intellectual world of prehistoric humans and its tantalizing proximity to our own. ■
References
1. Lartet É, Christy H. Reliquiæ Aquitanicæ. Being contributions to the archæology and palæontology of Périgord and the adjoining provinces of southern
France. vol 2. London, UK/Paris, France: Williams & Norgate/J.B. Baillière; 18651875, pp. 302 & 204.
2. Gould SJ. Nonoverlapping Magisteria. Nat Hist. 1997;106:16-22.
Further reading
– Hurel A. L’Abbé Breuil: Un Préhistorien Dans le Siècle. Paris, France : CNRS Éditions ; 2011.
L’ABBÉ HENRI BREUIL
Father Henri Breuil receiving an Honoris Causa degree at Cambridge, in 1920, with Field Marshal Sir Douglas Haig, a British
senior officer during World War I. Institut de Paléontologie Humaine, Paris.
ET LA REDÉCOUVERTE DE L’ HOMME PRÉHISTORIQUE
Les études préhistoriques émergent dans la seconde moitié du XIXe siècle. À cette époque se construit une image
de la préhistoire conforme à l’idéologie du progrès. Les productions matérielles des Préhistoriques, c’est-à-dire les
industries sur pierre ou os mises au jour à l’occasion de fouilles, et leurs évolutions attesteraient de cette marche.
Au tournant du siècle, l’abbé Henri Breuil (1877-1961) va être l’un de ceux qui vont profondément modifier cette vision. Par ses recherches, il va mettre en lumière l’existence de véritables sociétés préhistoriques et affirmer que l’histoire de l’Homme ne peut se résumer à la seule histoire des techniques. En contribuant en particulier de façon décisive à la reconnaissance de l’art pariétal paléolithique, dont il va être l’un des principaux vulgarisateurs, il souligne
l’idée que l’univers mental des hommes de la préhistoire était riche et complexe. En tant que prêtre de l’Église
catholique et préhistorien, Breuil va construire une œuvre abondante de plus d’un millier de références bibliographiques. Celle-ci se révèle originale, incarnée et vivante. Une pierre taillée tout comme une peinture rupestre ne sont
pas des abstractions mais l’expression objective d’un acte de création et d’une aptitude technique, autant de témoignages qui permettent de renouer le fil avec le passé. Les travaux de Breuil expriment l’unité biologique de l’espèce
humaine et sa diversité culturelle, par-delà les millénaires et les continents.
© Institut de Paléontologie Humaine, Paris.
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