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Medicographia
Vol 32, No. 4, 2010
105
A
Ser vier
publication
Multiple connections:
new concepts in
bone health
E DITORIAL
335
Bone—more than a standalone organ: a system sharing multiple
connections with other tissues. Plus qu’un organe « en solo » : l’os,
un système partageant des connexions multiples avec d’autres tissus
G. Karsenty, USA
T HEMED
341
ARTICLES
The unexpected links between bone and the immune system
A. Teti and N. Rucci, Italy
349
Impact of psychiatric disease on bone health
B. Cortet and I. Legroux-Gérot, France
357
Serotonin: a new player in the regulation of bone remodeling
V. K. Yadav, P. Ducy, and G. Karsenty, USA
364
Bone health and diabetes
M. L. Brandi, Italy
370
Bone and vascular health and the kidney
J. B. Cannata-Andía, P. Román García, I. Cabezas-Rodriguez,
and M. Rodriguez-García, Spain
377
Physical activity and bone quality
L. Vico, France
384
Contribution of vitamin D to bone health: fall and fracture prevention
H. A. Bischoff-Ferrari, Switzerland
391
Osteoporosis and osteoarthritis: bone is the common battleground
D. Lajeunesse, J.-P. Pelletier, and J. Martel-Pelletier, Canada
Contents continued on next page
Medicographia
Vol 32, No. 4, 2010
105
A
C ONTROVERSIAL
Ser vier
publication
QUESTION
399 What is the goal of antiosteoporotic therapy: improve bone health
or only prevent fractures?
B.-H. Albergaria, Brazil - A. Çetin, Turkey - F. Cons-Molina, Mexico T. J. de Villiers, South Africa - J. Laíns, Portugal - N. Taechakraichana,
Thailand - D. O’Gradaigh, Ireland - P. Sambrook, Australia
P ROTELOS
408 Better bone health for osteoporotic patients: Protelos decreases
fracture risk and improves bone quality
P. Halbout, France
I NTERVIEW
417 Bone health is also for men
M. Audran, France
F OCUS
422 FRAX® and treatment efficacy in osteoporosis
E. V. McCloskey, United Kingdom
U PDATE
429 New techniques for assessing bone health
D. Felsenberg, Germany
A
TOUCH OF
F RANCE
436 New life for old bones: giving a face to Lucy, King Tut, and
an 18th-century shipwrecked scientist
É. Daynès, France
444 The eternal life of bones: tidbits of French history through the trials and
tribulations of relics of the illustrious
C. Portier-Kaltenbach, France
EDITORIAL
‘‘
Recent advances highlighting multiple metabolic connections between bone and the rest
of the organism show that we are
far from having discovered all the
functions exerted by the skeleton.
Since so many hormones regulate
bone mass accrual, could it be that
bone is only a recipient of influences, or rather that it reacts to
them by determining the synthesis
of these hormones? In other words,
is the skeleton an endocrine organ
regulating energy metabolism?
And if this is the case, does the
skeleton have other endocrine
functions as well?”
Bone—more than
a standalone organ:
a system sharing multiple
connections with other tissues
b y G . K a r s e n t y, U S A
or many scientists other than bone biologists, bones are viewed as a mere
assembly of calcified, ie, inert tubes whose study is not of great interest beyond their embryonic development. As usual, in biology, and life in general,
there is more than meets the eyes, and only recently have we come to realize the wealth of biology surrounding bone tissue.
F
Gerard KARSENTY, MD, PhD
Chairman, Department of
Genetics and Development
Columbia University Medical
Center, New York, NY - USA
Address for correspondence:
Dr Gerard Karsenty, Chairman,
Department of Genetics and
Development, Columbia University
Medical Center, 701 W 168th
Street, Room 1602 HHSC,
New York, NY 10032, USA
(e-mail: gk2172@columbia.edu)
Medicographia. 2010;32:335-340.
www.medicographia.com
Bone—more than a standalone organ – Karsenty
Indeed, bone has several peculiarities that suggested from the outset that this superficial view could not be further away from reality. For instance, bone constantly
undergoes destruction followed by de novo bone formation in the context of two
important physiological functions, bone modeling during childhood and bone remodeling during adulthood. To achieve this, bone is the only tissue that contains
a cell type, the osteoclast, whose main—if not only—function is to destroy the host
tissue. This function distinguishes osteoclasts from macrophages, monocytes, or
lymphocytes, which are there to fight foreign bodies. Instead, osteoclasts are there
to destroy what is not a foreign body, but our own mineralized bone extracellular
matrix. Bone is also the tissue in which most of hematopoiesis occurs during adult
life. On the basis of these two features alone, it was therefore likely that bone cells
must be connected, in ways that remained to be defined, to many other organs in
the body. If one comes to think about it, is this not the rule rather the exception
in vertebrate physiology? And if it is the rule, why would skeleton, unlike any other
organ, be a standalone entity not affected by, and not affecting, other organs and
functions?
In the first phase of its history, biology established that bone was influenced by longacting hormones such as parathyroid hormone or sex steroid hormones. This was
a de facto demonstration that there is more to bone biology than bones themselves.
Subsequent phases in the history of bone biology elucidated the molecular bases of
how osteoblasts promote osteoclast differentiation and identified novel hormones
regulating bone mass. Molecular biologists and geneticists are now busily identifying novel bone functions.
This issue of Medicographia, in addition to providing a much needed update on more
traditional issues of bone biology, reviews some of the exciting recent advances that
are changing the way in which we perceive bone, its functions, and its multiple
connections with the rest of the organism. These advances involve two main areas: the first concerns the connections between the control of bone mass and
hematopoiesis and various aspects of immunology; the second, the relationship
between bone and diverse aspects of energy metabolism.
MEDICOGRAPHIA, Vol 32, No. 4, 2010
335
EDITORIAL
Let us look first at the hematopoietic stem cell (HSC) niche.
This is the anatomical location in which HSC cells reside and
self-renew, and which, in addition to hematopoietic cells, also
contains a host of nonhematopoietic cells, such as fibroblasts,
reticular cells, endothelial cells, adipocytes, and osteoblasts.
What we have learned in recent years is that the osteoblasts
are a critical component of the HSC niche in that they are
capable of influencing the size of the HSC pool. We have also
discovered that many of the cytokines whose role was established in lymphopoiesis also affect osteoclast differentiation,
while cytokines or soluble receptors promoting or inhibiting
osteoclast differentiation are also involved in several aspects
of the immune response. This emerging field of osteoimmunology will be expounded by Anna Teti and Nadia Rucci in the
first themed article of this Medicographia monograph.
In relation with this topic, Jorge Cannata-Andía and his colleagues discuss the connection between bone remodeling
and erythropoiesis, which comprises the connections between
kidney and bone. This connection is well known to the clinician since it explains the emergence of a devastating disease,
renal osteodystrophy, which leads to renal failure. However,
the molecular and genetic bases of this relationship are not
all understood.
Several chapters of this monograph touch upon another recent advance in bone biology, the emerging relationship between the control of bone mass and the regulation of energy
metabolism. I postulated this relationship some 10 years ago,
based on the huge energetic needs imposed on the body by
bone modeling and remodeling. Energy metabolism is a broad
entity encompassing food intake, appetite, energy expenditure, and glucose metabolism. As a result, it also includes
many organs such as the gastrointestinal tract where food is
absorbed, the brain, which controls appetite and energy expenditure, the islets of the endocrine pancreas, (which produce not only insulin, but other hormones regulating glucose
metabolism), and, ultimately, all the target tissues of insulin.
The crosstalk between the regulation of bone metabolism and
energy metabolism occurs at multiple levels, several of which
are discussed in this monograph.
A first aspect of this crosstalk has to do with the fortuitous,
but groundbreaking, discovery that serotonin, produced by
the enterochromaffin cells of the gastrointestinal tract, is in
fact a hormone that acts through a specific receptor on osteoblasts to inhibit their proliferation and thereby dampen bone
formation. This discovery is important for several reasons, not
less because it increases our understanding of the molecular regulation of bone remodeling. The fortuitous discovery
that a very-well-known neurotransmitter also is such a powerful hormone illustrates how ignorant we still are about wholeorganism physiology and how an all-out genetic approach to
the entire organism is needed to increase our knowledge.
336
This discovery provided a molecular explanation for two rare
human genetic diseases, osteoporosis-pseudoglioma syndrome and high-bone-mass syndrome, which are caused,
respectively, by loss and gain of function due to mutations
in the surface molecule Lrp5. Lrp5 acts as an inhibitor of
serotonin synthesis by enterochromaffin cells. Patients with
high-bone-mass syndrome have lower circulating serotonin
levels, and provide an in vivo demonstration that inhibiting
serotonin synthesis by enterochromaffin cells of the gut could
be a means to treat osteoporosis, since these patients do not
develop osteoporosis after the menopause. Thus, a direct
outcome of the better understanding of the role of serotonin
in bone remodeling has been the definition of a new class
of bone anabolic drugs.
A second aspect of the crosstalk between the regulation of
bone metabolism and energy metabolism was the identification of the genetic and molecular mechanisms that coordinate bone mass accrual and energy metabolism. Although
not specifically covered in this monograph, this novel area of
bone physiology permeates three of its contributions. As discussed by Vijay Yadav and colleagues, 10 years ago now we
showed that the adipocyte-derived hormone leptin, which,
remarkably, appears during evolution in parallel with the evolution of of bone, inhibits bone mass accrual. This led to the
demonstration that bone mass accrual is regulated centrally,
and is an aspect of bone biology now studied in many laboratories around the world and which is covered in Maria
Luisa Brandi’s article. This aspect is also relevant to the understanding of how the skeletal manifestations of anorexia
nervosa and of obesity develop (see Bernard Cortet’s article).
Looking at bone and its most closely connected “companion”—muscle—Laurence Vico shows that physical exercise—
hence muscle mass—is directly related to bone mass, some
sports being bone-building (eg, jogging and gymnastics),
while others are far less osteogenic (cycling and swimming).
She then discusses the potential osteogenic benefits of wholebody vibrations as a therapeutic means to increase bone
mass.
Heike Bischoff-Ferrari looks at another connection between bone and the organism: the skin, and an old friend,
vitamin D, which is produced there after exposure to the
sun’s ultraviolet B light. The author discusses the benefits of
vitamin D in regard to fracture reduction, related to it dual role
of decreasing falls and increasing bone density.
Finally, in the last themed article, Daniel Lajeunesse and Johanne and Jean-Pierre Pelletier highlight recent advances
concerning two diseases hitherto thought to be mutually exclusive, osteoporosis and osteoarthritis. It now seems increasingly likely that the mechanisms leading to these two major
health burdens overlap, and are ascribable to changes affecting bone and subchondral bone tissue. This of course
EDITORIAL
has major therapeutic implications since osteoarthritis could
benefit from agents inhibiting subchondral bone resorption
and/or promoting bone formation.
These new lines of research are exciting in themselves and
because of the insights they provide into how bone mass is
regulated. They are also a clear indication that we are far from
having discovered all the functions exerted by the skeleton.
Since so many hormones are now known to regulate bone
mass accrual, could it be that bone is only a recipient of influences, or rather that it reacts to them by determining the
synthesis of these hormones? In other words, is the skeleton
an endocrine organ regulating energy metabolism? And if this
is the case, does the skeleton have other endocrine functions
beyond those related to energy metabolism? These questions open up exciting perspectives, and it is increasingly obvious that this is the direction that modern bone biology is
taking. I
Keywords: bone metabolism; physiology; crosstalk; serotonin; energy metabolism; leptin
337
ÉDITORIAL
‘‘
De récentes avancées ont mis
en évidence les connexions métaboliques multiples entre les os
et le reste de l’organisme : nous
sommes loin d’avoir découvert
toutes les fonctions exercées par le
squelette. L’acquisition de la masse
osseuse étant régulée par un grand
nombre d’hormones, le squelette
n’est-il qu’un organe passif ou réagit-il activement aux influences qui
agissent sur lui en déterminant la
synthèse de ces hormones ? En
d’autres termes, le squelette est-il
un organe endocrine régulant le
métabolisme énergétique, voire
d’autres fonctions endocrines ?”
Plus qu’un organe
« en solo » : l’os,
un système partageant
des connexions multiples
avec d’autres tissus
p a r G . K a r s e n t y, É t a t s - U n i s
P
our de nombreux scientifiques, à l’exception des biologistes spécialisés
dans le tissu osseux, les os sont considérés comme un simple ensemble
de tubes calcifiés, inertes, dont l’étude n’est pas d’un grand intérêt misà-part leur développement embryonnaire. Comme c’est souvent le cas en
biologie, et dans les sciences de la vie en général, les apparences peuvent être trompeuses, et ce n’est que récemment que nous avons pris conscience de la richesse
biologique qui émane du tissu osseux.
En effet, les os présentent plusieurs caractéristiques qui ont suggéré dès le début
que cette vision superficielle ne pouvait pas être plus éloignée de la réalité. Par
exemple, les os subissent en permanence une destruction suivie par une formation
osseuse de novo dans le cadre de deux fonctions physiologiques importantes, le
« modelage » (ou phase d’acquisition de la masse osseuse) au cours de l’enfance
et le remodelage osseux au cours de l’âge adulte. Ces phénomènes sont soustendus par un type de cellule spécifique du tissu osseux, les ostéoclastes, dont la
principale fonction – si ce n’est la seule – est de détruire le tissu hôte. Cette fonction
distingue les ostéoclastes des macrophages, des monocytes ou des lymphocytes,
dont le rôle est de combattre les corps étrangers. Au contraire, les ostéoclastes
détruisent, non pas un corps étranger, mais leur propre matrice extracellulaire osseuse minéralisée. Le tissu osseux est le seul dans lequel se déroule la plus grande
partie de l’hématopoïèse au cours de la vie adulte. En ne considérant que ces deux
caractéristiques, il était par conséquent probable que les cellules osseuses soient
connectées, par des liens restant à identifier, à de nombreux autres organes du
corps humain. À la réflexion, cette situation ne constitue-t-elle pas plutôt la règle
que l’exception dans la physiologie des vertébrés ? Et s’il s’agit d’une règle, pourquoi le squelette, contrairement à tout autre organe, constituerait-il une entité indépendante ne subissant ni n’exerçant aucune influence vis-à-vis d’autres d’autres organes et fonctions ?
Dans la première phase de son histoire, la biologie nous a appris que les os étaient
soumis à l’influence d’hormones à longue durée d’action, notamment la parathormone et les hormones stéroïdes sexuelles. Ces découvertes ont constitué de facto
une démonstration que la biologie osseuse s’étendait au-delà des os eux-mêmes.
Les phases ultérieures de l’histoire de la biologie osseuse ont permis d’élucider les
bases moléculaires par lesquelles les ostéoblastes favorisaient la différenciation des
ostéoclastes, et d’identifier de nouvelles hormones régulant la masse osseuse. Les
spécialistes de la biologie moléculaire et de la génétique continuent encore aujourd’hui à découvrir de nouvelles fonctions osseuses.
338
L’os, plus qu’un organe « en solo » – Karsenty
ÉDITORIAL
Ce numéro de Medicographia, outre une mise à jour très attendue sur des aspects plus traditionnels de la biologie osseuse, passe en revue les avancées passionnantes les plus
récentes qui sont en train de changer la manière dont nous
comprenons le tissu osseux, ses fonctions et ses connexions
multiples avec le reste de l’organisme. Ces avancées portent sur deux domaines principaux : le premier concerne les
connexions entre la régulation de la masse osseuse et l’hématopoïèse et différents aspects de l’immunologie ; le second, la relation entre les os et différents aspects du métabolisme énergétique.
Examinons tout d’abord la « niche hématopoïétique ». Il s’agit
de la localisation anatomique dans laquelle les cellules souches
hématopoïétiques (CSH) résident et s’auto-renouvellent, et
qui contient, outre les CSH, un grand nombre de cellules non
hématopoïétiques, notamment des fibroblastes, des cellules
réticulaires, des cellules endothéliales, des adipocytes et les
ostéoblastes. Nous avons appris ces dernières années que
les ostéoblastes constituaient un élément essentiel de la niche
hématopoïétique, dans la mesure où ils sont capables d’influencer la taille de la population des CSH. Nous avons en
outre découvert que de nombreuses cytokines, dont le rôle a
été établi dans la lymphopoïèse, étaient également impliquées
dans la différenciation des ostéoclastes, et que certaines cytokines ou récepteurs solubles favorisant ou inhibant la différenciation des ostéoclastes participaient à divers aspects
de la réponse immunitaire. Ce domaine émergent de l’ostéo-immunologie sera exposé par Anna Teti et Nadia Rucci
dans le premier article de cette monographie thématique de
Medicographia.
Jorge Cannata-Andía et coll. discuteront du lien entre le remodelage osseux et l’érythropoïèse, qui témoigne des connexions
entre les reins et l’os. Ces liens sont bien connus du clinicien,
dans la mesure où ils expliquent le développement d’une maladie extrêmement grave, l’ostéodystrophie rénale, source
d’insuffisance rénale. Cependant, les bases moléculaires et
génétiques de ces liens n’ont pas tous été explicités.
Plusieurs chapitres de cette monographie concernent une
autre avancée récente de la biologie osseuse, la relation nouvellement découverte entre le contrôle de la masse osseuse et
la régulation du métabolisme énergétique. J’avais postulé cette
relation il y a environ 10 ans, sur la base des besoins énergétiques considérables imposés à l’organisme par le modelage
et le remodelage osseux. Le métabolisme énergétique est un
vaste concept qui recouvre l’apport alimentaire, l’appétit, la
dépense d’énergie et le métabolisme glucidique. Il fait intervenir par conséquent de nombreux organes, notamment le tractus gastro-intestinal où sont assimilés les aliments, le cerveau
qui contrôle l’appétit et la dépense énergétique, les îlots pancréatiques endocrines, qui produisent non seulement l’insuline, mais également d’autres hormones régulant le métabolisme glucidique, et enfin tous les tissus cibles de l’insuline.
Les interactions entre la régulation du métabolisme osseux
et le métabolisme énergétique se manifestent à plusieurs niveaux, dont certains sont abordés dans cette monographie.
Un premier aspect de ces interactions concerne la découverte fortuite, mais fondamentale, ayant montré que la sérotonine, produite par les cellules entérochromaffines du tractus
gastro-intestinal, est en fait une hormone qui agit par l’intermédiaire d’un récepteur spécifique situé sur les ostéoblastes
afin d’inhiber leur prolifération, et par conséquent réduire la
formation osseuse. Cette découverte est importante pour
plusieurs raisons, en particulier parce qu’elle enrichit notre
compréhension de la régulation moléculaire du remodelage
osseux. La découverte fortuite que ce neurotransmetteur parfaitement connu était également une hormone particulièrement puissante illustre notre ignorance encore profonde de
la physiologie générale de l’organisme, et la nécessité d’une
approche génétique globale de l’organisme.
Cette découverte fournit une explication moléculaire à deux
maladies génétiques rares chez l’homme, le syndrome d’ostéoporose avec pseudogliome et le syndrome de masse osseuse élevée, qui sont provoquées respectivement par une
perte et un gain de fonction due à des mutations de la molécule de surface Lrp5. La molécule Lrp5 agit comme inhibiteur
de la synthèse de la sérotonine par les cellules entérochromaffines. Les patients souffrant d’un syndrome de masse osseuse élevée présentent des concentrations circulantes de
sérotonine plus faibles, et constituent une démonstration in
vivo du fait que l’inhibition de la synthèse de sérotonine par
les cellules entérochromaffines de l’intestin peut constituer un
mode de traitement de l’ostéoporose, dans la mesure où les
patientes atteintes ne développent pas d’ostéoporose après
la ménopause. Par conséquent, l’un des résultats directs de
la meilleure compréhension du rôle de la sérotonine sur le
remodelage osseux a été la définition d’une nouvelle classe
d’agents anaboliques osseux.
Un second aspect des interactions entre la régulation du métabolisme osseux et du métabolisme énergétique a été l’identification des mécanismes génétiques moléculaires coordonnant l’acquisition de la masse osseuse et le métabolisme
énergétique. Bien que ce sujet ne soit pas spécifiquement
abordé dans cette monographie, ce nouveau domaine de la
physiologie osseuse est évoqué dans trois articles. Comme
l’indiquent Vijay Yadav et coll., il y a maintenant 10 ans, nous
avons montré que la leptine, une hormone dérivée des adipocytes, dont il faut souligner qu’elle apparaît au cours de
l’évolution parallèlement à l’évolution du système osseux,
inhibe l’acquisition de la masse osseuse. Cette observation,
qui démontre que l’acquisition de la masse osseuse est régulée à un échelon central, constitue un aspect de la biologie
osseuse désormais étudié dans de nombreux laboratoires à
travers le monde, et abordé dans cette monographie dans
l’article de Maria Luisa Brandi. Cet aspect est également
339
ÉDITORIAL
abordé par l’article de Bernard Cortet qui fait le point sur notre compréhension des manifestations squelettiques de l’anorexie mentale et de l’obésité.
Laurence Vico, qui examine les os et les organes qui leur sont
le plus étroitement associés, les muscles, montre que l’exercice physique – et par conséquent la masse musculaire –
influe directement sur la masse osseuse, certains sports favorisant la formation osseuse (par exemple, le jogging et la
gymnastique), tandis que d’autres sont nettement moins ostéogènes (cyclisme et natation). L’auteur discute ensuite des
bénéfices ostéogènes potentiels des vibrations du corps entier comme moyen thérapeutique pour entraîner une augmentation de la masse osseuse.
Heike Bischoff-Ferrari évoque sur une autre connexion entre les os et l’organisme : la peau, et une vielle connaissance,
la vitamine D, qui est produite dans cet organe après l’exposition aux rayons ultraviolets B du soleil. L’auteur discute
des bénéfices de la vitamine D au plan de la réduction des
fractures, en relation avec son double rôle dans la diminution
des chutes et l’augmentation de la densité osseuse.
Enfin, dans le dernier article-thème, Daniel Lajeunesse et
Johanne et Jean-Pierre Pelletier soulignent les récentes avancées dans deux maladies considérées jusqu’ici comme mutuellement exclusives, l’ostéoporose et l’arthrose. Il semble
340
désormais de plus en plus probable que les mécanismes
conduisant à ces deux affections majeures partagent les
mêmes mécanismes et soient imputables aux changements
affectant le tissu osseux et le tissu osseux sous-chondral.
Ces phénomènes ont bien entendu des conséquences thérapeutiques déterminantes, dans la mesure où l’arthrose serait de ce fait susceptible de bénéficier de l’action d’agents
inhibant la résorption osseuse sous-chondrale et/ou favorisant la formation osseuse.
Ces nouveaux axes de recherche sont particulièrement intéressants en eux-mêmes, et par les éclairages qu’ils apportent sur les mécanismes de régulation de la masse osseuse.
Ils constituent également un rappel que nous sommes loin
d’avoir découvert toutes les fonctions exercées par le squelette. Dans la mesure où il est désormais établi que l’acquisition de la masse osseuse est régulée par un grand nombre
d’hormones, le squelette apparaît désormais comme étant
loin d’être un organe passif, mais qu’il réagit au contraire aux
diverses influences agissant sur lui en déterminant la synthèse
de ces hormones. Si tel est le cas, le squelette n’est-il pas
un organe endocrine régulant le métabolisme énergétique,
voire d’autres fonctions endocrines au-delà de celles liées au
métabolisme énergétique ? Cette question ouvre des perspectives passionnantes, qui constituent à l’évidence la voie
que la biologie moderne du tissu osseux est en train d’emprunter. I
M U LT I P L E C O N N E C T I O N S : N E W C O N C E P T S
‘‘
Osteoclasts and immune
cells share a common origin: the
hematopoietic stem cell (HSC).
Recognition of this fact has led to
the birth of a new discipline, osteoimmunology, which has clarified the involvement of bone cells
in diseases initially considered as
immunological, and identified the
central role of some cytokines,
produced by immune cells, in the
regulation of bone cells. Recent
advances point to the potential
involvement of osteoclasts and
osteoblasts in the regulation of
HSCs directed to an immunological commitment.”
IN
B O N E H E A LT H
The unexpected links
between bone
and the immune system
b y A . Te t i a n d N . R u c c i , I t a l y
B
Anne TETI, PhD
one is a tissue of central importance, maintaining several relationships
with other organs. Among these, the immune system, with which it
shares molecular pathways, transcription factors, and several cytokines
responsible for bone and immune cell regulation. A paradigm of this crosstalk
comes from the studies of Hiroshi Takayanagi on the mechanisms underlying
the development of rheumatoid arthritis, demonstrating the central role of a
subset of T lymphocytes in the induction of exaggerated osteoclast activity,
thus leading to erosion in the affected joints. RANKL/RANK (receptor activator of nuclear factor–kappaB [ligand]) is an important pathway shared by bone
and the immune system. This pathway is essential for both osteoclastogenesis and lymphocyte differentiation, so that diseases due to inactivating mutations of RANKL or RANK, such as osteopetrosis, result in immunological
defects in addition to altered bone phenotype. This review focuses on the description of the principal molecules/pathways shared with the immune system, which under both physiological and pathological conditions, regulate
bone remodeling by acting on osteoclast formation and activity. We propose
that the evidence available today strongly points to the osteoclast as a cell
with immunological properties, in addition to its role in bone resorption.
Medicographia. 2010;32:341-348 (see French abstract on page 348)
Nadia RUCCI, MD
Department of Experimental
Medicine, University of L’Aquila
L’Aquila, ITALY
Prof Anna Teti, Department of
Experimental Medicine, University
of L’Aquila, Via Vetoio-Coppito 2,
67100 L’Aquila, Italy
(e-mail: annamaria.teti@univaq.it)
he perception of bone as a static organ has changed dramatically over the
past several years. The literature has clearly shown that bone is a tissue of
central importance and that, in addition to its role in locomotion and in the regulation of calcium and phosphate homeostasis, bone actively maintains multiple relationships with other organs.
T
Recent observations have evidenced crucial crosstalk between bone and the immune system, thus leading to the launch of a new interdisciplinary field, osteoimmunology.1 Indeed, several cytokines, molecular pathways, and transcription factors are shared by the immune and skeletal systems. Moreover, immune cells, like
bone cells, arise from hematopoietic stem cells (HSCs) found in the bone marrow,
which is physically as well as functionally associated with bone tissue. Interestingly, cell differentiation from HSCs has been shown to be subject to a fine regulation
by the osteoblasts, which form the HSC niche.2 Kollet et al have consistently found
that, once subjected to specific stressful stimuli, activated osteoclasts degrade
endosteal components, thus promoting the mobilization of hematopoietic progenitors.3
The unexpected links between bone and the immune system – Teti and Rucci
341
IN
Studies on autoimmune diseases, such as rheumatoid arthritis, performed by Hiroshi Takayanagi, have provided a pivotal
contribution in development of the field of osteoimmunology,
with identification of a subset of a T cell population that produces high quantities of interleukin (IL)-17, a pro-osteoclastogenic cytokine that increases osteoclast differentiation by
direct and indirect mechanisms, thus leading to bone destruction.1 Conversely, animal models lacking molecules pivotal for
the regulation of the immune system frequently show an abnormal osteoclast phenotype.1
Based on this evidence, we believe that a more extensive investigation of the mechanisms underlying the bone-immune
interplay could allow the identification of new strategies for
the management of immune system and bone disorders. In
this review, we summarize the recent findings that have contributed to consolidation of the field of osteoimmunology, with
particular focus on the close relationship between the osteoclasts and the immune cells.
SELECTED
ABBREVIATIONS AND ACRONYMS
ARF
activation-resorption-formation (sequence)
ARO
autosomal recessive osteopetrosis
Blimp1
B lymphocyte–induced maturation protein–1
BMP
bone morphogenetic protein
CAMKIV
calcium/calmodulin-dependent protein kinase IV
DC-STAMP dentritic cell–specific transmembrane protein
FcRγ
Fc-receptor common gamma subunit
FGF
fibroblast growth factor
HSCs
hematopoietic stem cells
IL
interleukin
IRF
interferon regulatory factor
ITAM
immunoreceptor tyrosine-based activation motif
LPS
lipopolysaccharide
MAPK
mitogen-activated protein kinase
M-CSF
macrophage-colony stimulating factor
MMP
metalloproteinase
NFATc1 (c2) nuclear factor of activated T cells, cytoplasmic 1
(cytoplasmic 2)
NF-κB
nuclear factor–kappaB
ODF
osteoclast differentiation factor
OPG
osteoprotegerin
OPGL
osteoprotegerin ligand
PGE2
prostaglandin E2
PTH
parathyroid hormone
RANK
receptor activator of nuclear factor-kappaB
RANKL
receptor activator of nuclear factor-kappaB ligand
SOFAT
secreted osteoclastogenic factor of activated T cells
TGFβ
transforming growth factor–beta
TRAF
TNF-receptor associated factor
TRANCE
TNF-related activation induced cytokine
342
B O N E H E A LT H
The bone remodeling process
It is well known that bone tissue is in dynamic flux, continually renewed lifelong by a physiological process termed bone
remodeling.4,5 This process is mandatory for the replacement
of immature bone with mechanocompetent bone, as well as
for repair of fractures and for proper calcium balance. Indeed,
it has been estimated that at least 10% of bone is renewed
per year.
Bone remodeling follows the activation-resorption-formation
(ARF) sequence (Figure 1). The first step, called the activation
phase, starts with stimulation of the lining cells, quiescent osteoblasts, which, in response to appropriate stimuli, increase
their own surface expression of receptor activator of the nuclear factor-kappaB (NF-κB) ligand (RANKL), which in turn
interacts with its receptor RANK (receptor activator of NF-κB),
expressed by preosteoclasts. RANKL/RANK interaction triggers preosteoclast fusion and differentiation to multinucleated
osteoclasts. Once differentiated, osteoclasts polarize, adhere
to the bone surface, and dissolve bone (resorption phase), then
they undergo apoptosis, which is a physiological process, required to prevent excessive bone resorption.
After this resorptive process, there is an intermediate phase
preceding bone formation, called a reversal phase, during
which some macrophage-like uncharacterized mononuclear
cells are observed at the site of remodeling, whose function
consists of removal of debris produced during matrix degradation.
The final step, bone formation, is triggered by several growth
factors stored in the bone matrix and released after its degradation, including bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), and transforming growth
factor–β (TGFβ), which are likely to be responsible for recruitment of osteoblasts in the resorbed area. Once recruited, osteoblasts produce new bone matrix, initially not mineralized
(osteoid), and then they promote its mineralization, thus completing the bone remodeling process.
Under physiological conditions, the coupling of bone formation with previous resorption occurs faithfully. In contrast, an
imbalance between the resorption and formation reflects improper bone remodeling, which in turn affects the bone mass,
eventually leading to a pathological condition.
Osteoblast regulation of osteoclastogenesis
Although the principal function of the osteoblasts is to synthesize bone matrix proteins and to promote the process of
mineralization, a crucial role of osteoblasts in osteoclast biology has been clearly demonstrated by the release of key molecules that regulate osteoclastogenesis and bone resorption.
Osteoclasts are multinucleated cells that arise from the monocyte/macrophage cell line.6 Starting from multipotent HSCs,
transcription factor PU.1, along with the macrophage-colony
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B O N E H E A LT H
Figure 1. The bone
remodeling process.
Resorption phase
Activation phase
preOCLs
OCL
BMPs FGFs TGFβ
Lining cells
Reverse cells
Quiescence
Reverse phase
Osteoid
OBLs
Mineralization
Formation phase
Bone remodeling starts with
activation of the lining cells,
which increase surface expression of RANKL. RANKL
interacts with its receptor
RANK, thus triggering osteoclast differentiation (Activation phase). Osteoclasts
resorb bone (Resorption
phase), thus allowing the
release of factors usually
stored in the bone matrix
(BMPs, TGF웁, FGFs) that
recruit osteoblasts in the
resorbed area. Once recruited, osteoblasts produce
the new bone matrix and
promote its mineralization
(Formation phase), thus
completing the bone remodeling process
Abbreviations: BMPs, bone
morphogenetic proteins;
FGFs, fibroblast growth
factors; Pre-OCLs, preosteoclasts; OCL, osteoclast; OBLs, osteoblasts;
TGF웁, transforming growth
factor–웁.
Figure 2. Schematic representation
of osteoclastogenesis.
The transcription factor PU.1, together with M-CSF
(macrophage-colony stimulating factor), allow the
commitment of hematopoietic stem cells (HSCs) to a
common progenitor for macrophages and osteoclasts
(CFU-M). RANK expression on pre-osteoclast surface
and its interaction with RANKL trigger cellcell fusion and the formation of osteoclasts (OCL).
Mature osteoclasts can resorb bone.
HSC
OCL precursor
(CFU-M)
M-CSF
PU.1
RANKL /RANK
OCL
Active OCL
c-Src a
CIC-7 (CLCN7)b
ATP6i c
CathK d
α v β 3e
CA II f
a. Cellular sarcoma gene
stimulating factor (M-CSF), allows the comb. Antiporter Cl –/H+ type 7
mitment toward a common progenitor for
c. a3 subsunit of V-H+ ATPase
d. Cathepsin K
macrophages and osteoclasts (Figure 2).
e. Integrin α v β 3
In particular, PU.1 positively regulates the
f. Carbonic anhydrase II
M-CSF receptor, c-Fms, while M-CSF stimulates proliferation of osteoclast precursors
and upregulates RANK expression. With the expression of RANKL/RANK signaling
c-Fms and RANK receptors, the precursors become fully com- RANKL is a type II membrane protein belonging to the TNF
mitted to osteoclast lineage.7 The main source of RANKL in superfamily, while its receptor RANK is a type I membrane
bone is the osteoblast, which expresses RANKL on its mem- protein. Osteotropic hormones and factors such as 1,25-dibrane surface, thus inducing osteoclast differentiation by in- hydroxyvitamin D3 [1,25(OH)2D3], parathyroid hormone (PTH),
teracting with the RANK receptor expressed by the osteoclast prostaglandin E2 (PGE2), and IL-11 upregulate the expression of
precursors. Therefore, triggering of the RANKL/RANK path- RANKL in osteoblast/stromal cell plasma membrane. As preway requires a cell-cell contact (Figure 3, page 344). Howev- viously mentioned, RANKL interacts with its receptor RANK,
er, lower quantities of soluble RANKL are also released after located on the preosteoclast surface, which in turn activates
enzymatic cleavage of the surface molecule by metallopro- signaling by recruiting adaptor molecules belonging to the
teinase (MMP)-14. Another key molecule produced by os- TNF-receptor–associated factors (TRAF) family (Figure 3). Inteoblasts that interfere with the RANKL/RANK pathway is deed, the RANK cytoplasmic tail contains three binding sites
osteoprotegerin (OPG), a decoy receptor for RANKL8 with an for TRAF6 9 and this interaction is mandatory for osteoclast
osteoprotective role. Indeed, OPG is a secreted protein shar- differentiation, since TRAF6 knockout mice develop osteopeing the same structure of the extracellular domain of RANK trosis.10 Binding of TRAF6 to RANK induces trimerization of
so that it binds RANKL, preventing its interaction with RANK TRAF6, leading to activation of nuclear factor–kappaB (NFand subsequent inhibition of osteoclastogenesis.
kappaB) and of mitogen-activated protein kinases (MAPKs).11
343
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B O N E H E A LT H
Figure 3. RANKL/RANK pathway activation.
RANKL expressed on the membrane surface of the osteoblast (OBL) interacts with RANK, expressed by preosteoclasts (preOCL). This interaction recruits TRAF6 that
activates NF-κ B and c-Fos, the latter dimerizing with
c-Jun and forming the AP-1 complex. Finally, NFATc1,
AP-1, PU.1, and MITF cooperate to induce transcription
of genes involved in osteoclast differentiation.
OBL
OPG
TRAF6
NF-κB
In cooperation with AP-1, PU.1, NF-κB, and
microphthalmia-associated transcription
factor (MITF), NFATc1 regulates the transcription of several target genes involved in
osteoclast differentiation and function (Figure 3). These include cathepsin K, calcitonin receptor, tartrate-resistant acid phosphatase (TRAcP),17,19 β3 integrin, osteoclastassociated receptor (OSCAR),7 and dendritic cell–specific transmembrane protein
(DC-STAMP), the latter involved in osteoclast fusion.
c-Fos
preOCL
NF-κB
NFATc2
AP-1
NFATc1
AP-1
PU.1 MITF
NF-κB
NFATc1
RANKL
Osteoclastogenesis
M-CSF
c-Fms
RANK
NF-κB includes a family of dimeric transcription factors, which
reside in the cytoplasm under nonstimulated conditions. However, they enter the nucleus upon cell stimulation by various
factors, including RANKL. NF-κB is central to the osteoclastogenic process since the double knockout of the p52 and
p50 subunits leads to blockade of osteoclast formation.12
Another transcription factor crucial for osteoclast differentiation is activator protein 1 (AP-1) complex, which consists of
c-Fos, c-Jun, and ATF proteins. In particular, c-Fos is specifically induced by RANK and is critical for osteoclastogenesis, since c-Fos knockout mice develop osteopetrosis due to
the lack of osteoclasts.13
NF-κB upregulates the expression of another key molecule
for osteoclast differentiation, nuclear factor of activated T cells,
cytoplasmic 1 (NFATc1) transcription factor.14,15 This initial
induction requires the interaction of NF-κB with NFATc2,
which is recruited to the NFATc1 promoter independently of
RANKL stimulation.16 The essential role of NFATc1 in osteoclastogenesis was demonstrated by evidence that NFATc1deficient embryonic stem cells did not differentiate into osteoclasts, while the ectopic expression of NFATc1 induced
osteoclast differentiation also in the absence of RANKL.17
Chromatin immunoprecipitation experiments revealed that
NFATc1 is recruited to the NFATc1 promoter region 24 hours
after RANKL stimulation, and this occupancy persists during
the terminal differentiation of osteoclasts, thus indicating a
mechanism of autoamplification.18
344
RANKL/RANK signaling is shared by
bone and the immune system
When we talk about the role of RANKL/
RANK in the immune system, we need to
point out that RANKL, also known as TNF-related activationinduced cytokine (TRANCE) according to the nomenclature of
the immune system, and its receptor RANK, were first identified as molecules expressed by T cells and dendritic cells,
respectively, and their physical interaction increased the ability of dendritic cells to stimulate naive T cell proliferation as well
as dendritic cell survival.
Therefore, the RANKL/RANK pathway was “born” in an immunologic context. At the same time, bone researchers
identified the so called osteoclast differentiation factor (ODF),
expressed by the osteoblasts, which increased osteoclast
formation,20 and OPG, an osteoblast-derived secreted member of the TNF receptor family, which, in contrast, inhibited
osteoclast development and bone resorption acting as a decoy receptor. The molecule able to interact with OPG, named
OPG-ligand (OPGL),21 was then identified. Finally, bone researchers and immunologists joined in the conclusion that
RANKL/TRANCE, ODF, and OPGL are the same molecule,
and that RANKL-expressing T cells can also activate osteoclasts, thus mimicking the effect of osteoblasts. Based on
this evidence it is not surprising to find bone loss in patients
with disorders characterized by abnormal activation of the
immune system, such as rheumatoid arthritis or other chronic
inflammatory diseases.
Immunological role of the RANKL/RANK pathway
As far as the role of RANKL in the immune system is concerned, it has been demonstrated that, in addition to bone
phenotype, due to the lack of osteoclasts, RANKL-deficient
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B O N E H E A LT H
Figure 4. Ig-like receptors and regulation
of osteoclastogenesis.
Interaction of the Immunoglobulin-like receptor (Ig-like
receptor) expressed on the pre-osteoclast (OCL) surface,
with its ligand, induces phosphorylation of DAP12 or
FcRγ , with subsequent activation of calcium signaling.
Calcium (Ca2+) promotes activation of both
c-Fos and NFATc1 through CAMKIV/CREB and
calcineurin, respectively.
NF-κB
mice show a defect in the development
of secondary lymphoid tissue.22 However,
these mice do not present a severe immunodeficiency, likely due to the fact that
lack of RANKL in T cells is compensated by
CD40.23 RANKL also seems to be important for mammary development24 and has
been found to be involved in inflammatory
bowel diseases by stimulating dendritic
cells.25
Recent evidence identified a role for RANKL
as a chemokine that can attract RANK-expressing tumor cells and osteoclasts,26,27
thus pointing to a role of this factor in tumor-induced bony metastases.
DAP12
Fcr γ
TRAF6
NF-κB
AP-1
SYK
c-Fos
CREB
CAMKIV
PLCγ
Ca2+
Ca2+
Ca2+
Calcineurin
NFATc1
NFATc1
AP-1
PU.1 MITF
NFATc1
NF-κB
Ig-like
receptor ligand
Osteoclastogenesis
RANKL/RANK–linked diseases
The versatility of the RANKL/RANK axis mirrors the complexity of the diseases in which this pathway is lacking. Among
them, osteopetrosis is a rare genetic disorder characterized by
sclerosis of the skeleton due to reduced or complete lack of
osteoclast function and, as a consequence, impairment of
bone resorption.29 This disease is clinically very heterogeneous,
ranging from severe to asymptomatic. Autosomal recessive
osteopetrosis (ARO) is the most severe form of osteopetrosis,
usually diagnosed within the first year of life and in patients with
a resultant life expectancy of 3 to 4 years. Similar clusters of
patients with ARO harbor mutations in the genes encoding
for RANKL and RANK.30,31 In contrast with all the other forms
characterized by a normal or increased number of osteoclasts
that are unable to resorb bone, obviously this is an osteoclast-poor ARO form.
Importantly, beside bone phenotype, there are also immunological defects, such as hypogammaglobulinemia due to impairment in immunoglobulin-secreting B cells. This is in line
with evidence showing the importance of RANKL/RANK in
the immune system, which should be taken into account in
the management of this form of ARO. Indeed, it has been
demonstrated that two ARO patients harboring RANK mutations exhibited impaired fever during pneumonia.28
RANK
M-CSF
Ig-like
receptor
Finally, a recent study (2009) identified an unexpected role
of RANKL/RANK in the central nervous system, showing that
this pathway was involved in thermoregulation and central
fever response in inflammation.28
RANKL
c-Fms
Ig-like receptors and osteoclast regulation
Beside the well-known RANKL/RANK pathway, osteoblasts
can regulate osteoclast differentiation by interacting with immunoglobulin (Ig)-like receptors, such as OSCAR, whose ligand has not yet been clearly identified. These receptors are
associated with immunoreceptor tyrosine-based activation
motif (ITAM)-harboring adaptor molecules DAP12 and Fcreceptor common gamma subunit (FcRγ). The role of the latter molecules in osteoclast regulation has been underlined by
evidence that mice deficient in both DAP12 and FcRγ have
an osteopetrotic phenotype.32 Phosphorylation of the ITAM
sequence in DAP12 or FcRγ, resulting after RANK activation,
allows the recruitment of splenocyte tyrosine kinase (SYK) and
resultant activation of phospholipase C gamma (PLCγ), which
in turn triggers calcium signaling. Calcium signaling promotes
osteoclastogenesis by activating calcium/calmodulin-dependent protein kinase type IV (CAMKIV), which concurs to c-Fos
and calcineurin activation, both cooperating to potentiate
NFATc1 autoamplification (Figure 4).1 Among the molecules
that have a dual role in the regulation of immune cells and
osteoclasts, a recent study33 identified the transcription factor B lymphocyte-induced maturation protein–1 (Blimp1). This
is a transcriptional repressor involved in the differentiation of
B lymphocytes toward plasma cells by direct repression of the
transcription factors Pax5, Bcl, and Myc.34 Nishikawa and
colleagues demonstrated that Blimp1 stimulates osteoclastogenesis by repressing the transcription factors IFN regulatory factor-8 (IRF-8) and v-Maf musculo-aponeurotic fibrosarcoma oncogene family, protein B (MafB), both negatively
affecting osteoclastogenesis.35,36
345
IN
Inflammatory cytokines and osteoclastogenesis
Among the cells of the immune system, T lymphocytes play
a crucial role in the regulation of osteoclastogenesis, which
is indeed the result of a balance between positive and negative factors produced by T cells. As far as the RANKL/
RANK pathway is concerned, it has been demonstrated that
activated T cells express RANKL on their surface, thus activating osteoclastogenesis by cell–cell contact.37 Activated
T cells also produce IL-10, IL-12, and IL-18, which, in contrast, negatively affect osteoclastogenesis.38 As described
below, the CD4+ T helper (TH)-cell subset TH1 and TH2 produce interferon gamma (IFN-γ), which suppresses RANKL
signaling by degrading TRAF6, and IL-4, another cytokine
with an anti-osteoclastogenic role.
Other cells of the immune system, such as the macrophages,
contribute to osteoclast differentiation and function by producing IL-1, IL-6, and TNF-α.20,39 Moreover, a recent study40
showed that lipopolysaccharides (LPS) upregulated the expression of membrane RANKL in human blood neutrophils.
LPS-activated neutrophils were then able to stimulate osteoclastogenesis and bone resorption in co-cultures with osteoclast precursors.
Finally, a recent report from Rifas and Weitzmann41 described
the identification of a new T cell cytokine, called secreted
osteoclastogenic factor of activated T cells (SOFAT), which
induces both osteoblastic IL-6 production and osteoclast
formation in the absence of osteoblasts or RANKL, and was
insensitive to the effects of the RANKL inhibitor OPG.
Immune diseases and osteoclast activation
N Rheumatoid arthritis
One of the milestones that was pivotal in defining the new
field of osteoimmunology came from research by Takayanagi
et al on rheumatoid arthritis.1 This is an autoimmune disease
characterized by inflammation of synovial joints, with CD4+
T-lymphocyte infiltration and synovial cell proliferation, leading to severe bone destruction mediated by osteoclasts.42
The clinical feature of bone loss is not restricted to the affected joints, since systemic osteoporosis can also occur.43 Although the increased inflammatory cytokine levels present in
affected joints may contribute to enhanced osteoclastogenesis, the mechanism of systemic osteoporosis associated with
arthritis remains unclear.
Recent reports have highlighted the crucial role of osteoclasts
in the development of this disease. Indeed, it has been demonstrated that osteoclast-deficient mice were protected from
bone erosion in arthritis models, despite the presence of inflammation.44,45 Moreover, high RANKL expression has been
detected specifically in the synovium of rheumatoid arthritis
patients.46 In rheumatoid arthritis affected joints, different cell
types can be found, including macrophages, fibroblasts, dendritic cells, plasma cells, and CD4+ T helper cells. Takayanagi1
346
B O N E H E A LT H
demonstrated that in the latter cell type there is a subpopulation, defined as osteoclastogenesis TH cells (THO cells),
which, at variance with CD4+ TH 1 cells, does not produce
the anticlastogenic cytokines IFN-γ and IL-4, but secretes high
quantities of IL-17. This cytokine, in turn, triggers RANKL expression by synovial fibroblasts. IL-17 also stimulates local
inflammation, thus inducing macrophages to secrete proinflammatory cytokines such as TNF-α, IL-1, and IL-6. These
cytokines in turn activate osteoclastogenesis, directly as well
as by stimulating RANKL expression by synovial fibroblasts.
Finally, it has been shown that TH O cells themselves express
RANKL, thus activating osteoclastogenesis by direct induction of precursor differentiation.
N Psoriatic arthritis
This is a disease characterized by musculoskeletal inflammation, and several studies have reported the crucial role of
TNF in its pathogenesis. Elevated levels of TNF have been
found in the sera, synovial fluid, and synovial membranes of
psoriatic patients.47 A marked reduction in inflammation and
progressive joint damage was consistently observed in patients treated with anti-TNF drugs, which is not only due to
their ability to reduce inflammation, but also to reduce osteoclast activation, since it is well known that TNF promotes osteoclast formation. On the other hand, recent reports showed
that TNF can affect bone formation by inducing Dickkopf-related protein 1 (DKK-1) to impair bone-forming osteoblast development via inhibition of Wnt signaling.
Is the osteoclast an immune cell?
Based on the aforementioned evidence, it has been hypothesized that osteoclasts are cells that belong to the immune
system.48 This raises the question as to why there is a need
for an immune cell to resorb bone.49 Chambers50 had previously proposed that the bone matrix is recognized by osteoclasts as a peculiar “foreign body.” In fact, as described in the
above (see the bone remodeling process), during the resting
condition the bone matrix is covered by a layer of osteoblasts,
or lining cells (Figure 1), which segregates the bone matrix
from the interstitial fluid, thus probably preventing recognition by the immune system. An external stimulus, such as an
inflammatory response, or exposure to PTH/parathyroid hormone–related protein (PTHrP), could trigger osteoblast retraction, so that the mineralized bone matrix can be exposed and
recognized as a “foreign body” by immune cells, which have
all the requirements to induce osteoclast formation and bone
resorption.
Under physiological conditions, this process, once activated,
must be switched off and, in fact, there are several paracrine
and autocrine mechanisms that negatively regulate osteoclast activity. Consequently, osteoblasts are recalled in the previously resorbed site where they refill the lacunae with newformed bone matrix and again segregate the bone surface
from the interstice so that “foreign bone” is no longer exposed
to the immune system. If the negative regulation of osteoclast
activity fails, this process proceeds longer than necessary,
thus resulting in excess bone resorption, with pathological
consequences.
Conclusions
It is now clear that bone is a tissue of central importance,
therefore, when we study the molecular mechanisms underlying bone remodeling and bone pathological events, we
cannot ignore its multiple interactions with other tissues. The
discipline of osteoimmunology has shown that osteoclasts
and immune cells share a common origin. These two types of
cells arise from the HSCs in the bone marrow, another organ
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B O N E H E A LT H
closely related to bone. Immunology has also clarified the involvement of bone cells in the development of diseases initially classified in an immunological context, and has identified the central role of some cytokines, known to be produced
by immune cells, in the regulation of bone cells. Furthermore,
recent advances suggest the potential involvement of osteoclasts and osteoblasts in the regulation of HSCs directed
to an immunological commitment. We believe that these findings should encourage immunologists and bone researchers
to continue investigating this field, all the more so as better
understanding of the relationships between bone and immune cells could help identify new strategies for the management of patients suffering from bone diseases. I
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34. Martins G and Calame K. Regulation and functions of Blimp-1 in T and B lymphocytes. Annu Rev Immunol. 2008;26:133-169.
35. Zhao B, Takami M, Yamada A, et al. Interferon regulatory factor-8 regulates bone
metabolism by suppressing osteoclastogenesis. Nat Med. 2009;15:1066-1071.
36. Kim K, Kim JH, Lee J, et al. MafB negatively regulates RANKL-mediated osteoclast differentiation. Blood. 2007;109:3253–3259.
37. Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;
397:315-323.
38. Takayanagi H, Ogasawara K, Hida S, et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature. 2000;408:600-605.
39. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation.
Nature. 2003;423:337-342.
40. Chakravarti A, Raquil MA, Tessier P, et al. Surface RANKL of Toll-like receptor 4–stimulated human neutrophils activates osteoclastic bone resorption.
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41. Rifas L. Weitzmann MN. A novel T cell cytokine, secreted osteoclastogenic factor of activated T cells, induces osteoclast formation in a RANKL-independent
manner. Arthritis Rheum. 2009;60:3324-3335.
42. Sato K, Takayanagi H. Osteoclasts, rheumatoid arthritis, and osteoimmunology. Curr Opin Rheumatol. 2006;18:419-426.
43. Schett G, Hayer S, Zwerina J, et al. Mechanisms of disease: the link between
RANKL and arthritic bone disease. Nat Clin Pract Rheumatol. 2005;1:47-54.
44. Pettit AR, Ji H, von Stechow D, et al. TRANCE/RANKL knockout mice are
protected from bone erosion in a serum transfer model of arthritis. Am J Pathol. 2001;159:1689-1699.
45. Redlich K, S. Hayer, R. Ricci, et al. Osteoclasts are essential for TNF-alpha-
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mediated joint destruction. J Clin Invest. 2002;110:1419-1427.
46. Takayanagi H, Iizuka H, Juji T, et al. Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum. 2000;43:
259-269.
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49. Del Fattore A, Teti A, Rucci N. Osteoclast receptors and signaling. Arch Biochem
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Keywords: osteoimmunology; bone tissue; immune system; hematopoietic stem cell; osteoclast; cytokine; rheumatoid
arthritis; bone remodeling
LES
LIENS INATTENDUS ENTRE LE SYSTÈME OSSEUX ET LE SYSTÈME IMMUNITAIRE
Le tissu osseux est un élément essentiel qui entretient un certain nombre de relations avec différents organes.
Parmi ceux-ci, le système immunitaire, avec lequel il partage des voies moléculaires, des facteurs de transcription et
plusieurs cytokines responsables de la régulation des cellules osseuses et immunitaires. L’un des paradigmes de ces
échanges provient des études menées par Hiroshi Takayanagi sur les mécanismes qui sous-tendent le développement de la polyarthrite rhumatoïde, qui ont démontré le rôle central d’un sous-ensemble de lymphocytes T dans l’induction d’une activité exagérée des ostéoclastes, entraînant une érosion des articulations affectées. Les molécules
RANKL et RANK (receptor activator of nuclear factor–kappaB [ligand], récepteur activateur du facteur nucléaire
kappa B [et son ligand]) sont responsables d’une voie moléculaire importante que partagent le système osseux et le
système immunitaire. Cette voie est fondamentale pour l’ostéoclastogenèse et la différenciation des lymphocytes,
de telle sorte que les pathologies provoquées par des mutations inactivant les molécules RANKL ou RANK, par
exemple l’ostéopétrose, entraînent des anomalies immunologiques en plus de l’altération du phénotype osseux. Cette
article porte sur la description des molécules et des voies principales partagées par le tissu osseux et le système immunitaire qui, sous certaines conditions physiologiques et pathologiques, régulent le remodelage osseux en agissant
sur la formation et l’activité des ostéoclastes. Nous suggérons que les données disponibles aujourd’hui désignent
l’ostéoclaste comme une cellule présentant des propriétés immunologiques, en plus de son rôle dans la résorption
osseuse.
348
‘‘
An increase in hip and femur
fracture risk has been reported
in depressed patients receiving
SSRIs. An increase in fracture risk,
albeit of lesser amplitude, was also
found in patients on tricyclic antidepressants. The strength of the
causal relationship was confirmed
by the fact that fracture risk rapidly decreased following antidepressant treatment discontinuation. As for anorexia nervosa, the
reduced bone formation observed
in this disease explains the relative
failure of antiresorptive treatments
and, particularly, estrogens.”
IN
B O N E H E A LT H
Impact of psychiatric disease
on bone health
b y B . C o r t e t a n d I . Le g ro u x- G é rot , Fra n c e
P
L
Bernard CORTET, MD, PhD
Isabelle LEGROUX-GÉROT, MD
Département Universitaire
de Rhumatologie
Université de Lille 2
FRANCE
sychiatric diseases may, via direct and indirect mechanisms, induce
bone fragility. This is particularly the case with depression and anorexia nervosa. Studies show a moderate decrease in bone mineral density
(of the order of 6%) in the spine and hip of depressed patients vs controls.
Similarly, a significant increase in fracture risk is observed, with an up to 2-fold
increase in hip fracture risk. The mechanisms of bone fragility in depressed
subjects are complex, multifactorial, and have yet to be fully elucidated. One
of the major direct mechanisms involves endogenous hyperadrenocorticism—
which is less pronounced than in Cushing’s syndrome, and may be due in
part to a rise in proinflammatory cytokines (notably interleukin 6), which is reported in depressed patients. Also, antidepressant treatment—in particular
serotonin reuptake inhibitors—may have a negative impact on bone. Indirect
factors, whose role is disputed, include weight loss and cigarette and alcohol
abuse, often reported in depressed subjects. Anorexia nervosa (AN) has become a major problem in recent years. AN gives rise to multiple complications
and is frequently associated with bone loss, with osteoporosis occurring in 38%
to 50% of cases. Estrogen deficiency has long been known to play a major role,
but cannot alone explain bone loss. Recent publications have highlighted the
essential role of undernourishment and factors influenced by nutritional status, in particular the growth hormone–insulin-like growth factor I (GH-IGF-I)
axis. The management of anorexia nervosa–related bone loss is debated. While
restoring menstruation and body weight is mandatory, it does not always ensure correction of bone loss. Studies have failed to show any effectiveness of
estrogen treatment.
ertain psychiatric disorders may have a deleterious impact on bone. This occurs via direct and indirect mechanisms, not all of which have been elucidated. Essentially two psychiatric disorders have undergone extensive research to evaluate this relationship: depression and anorexia nervosa (AN). These
two diseases will therefore be addressed in this paper.
C
Professor Bernard Cortet,
Département Universitaire de
Rhumatologie, Université de Lille 2,
59045 Lille, France
(e-mail: bcortet@chru-lille.fr)
IMPACT OF DEPRESSION ON BONE
epression is a frequent disease, affecting about 16% of the North-American
population.1 One of the first publications to link depression and impact on
bone was published by Schweiger et al in 1994.2 These authors determined
D
Impact of psychiatric disease on bone health – Cortet and Legroux-Gérot
349
A
IN
B O N E H E A LT H
B
SPINE
HIP
Whooley et al, 20 1999
Whooley et al, 20 1999
Yazici et al,13 2003
24
Whooley et al, 2004
Whooley et al,24 2004
Wong et al,17 2005
Mussolino et al,14 2004
Jacka et al,15 2005
Wong et al,17 2005
Amsterdam and
Hooper, 22 1998
Jacka et al,15 2005
Kavuncu et al,23 2002
Kavuncu et al,23 2002
Michelson et al,9 1996
Michelson et al,9 1996
Kahl et al,16 2006
Kahl et al,16 2006
Altindag et al,18 2007
Altindag et al,18 2007
Petronijevic et al,19 2008
Petronijevic et al,19 2008
Combined
Combined
–0.30
–0.20
–0.10
0.0
0.10
Mean difference in BMD of spine,
g/cm2
0.20
–0.30
(95% CI)
–0.20
–0.10
0.0
Mean difference in BMD of hip,
0.10
0.20
g/cm2
(95% CI)
Figure 1. Mean differences in bone mineral density (BMD) between depressed and nondepressed groups and corresponding 95%
confidence intervals (CI) for the spine (A) and hip (B) in 12 studies.
Reproduced from reference 22: Wu et al. Osteoporos Int. 2009;20:1309-1320. © 2009, Springer.
bone mineral density (BMD) by quantitative computerized tomography (QCT) in 70 depressed subjects and 88 controls.
The female/male ratio was the same in both groups. The authors found an approximately 15% reduction in BMD in the
depressed subjects, after adjustment for age. Subsequently,
several articles on the same topic were published in which
BMD was measured by dual-energy x-ray absorptiometry
(DXA), the current consensus method; but the findings disagreed: certain authors reported a link between depression
and low BMD,3-14 while others found no such link.15-21 This discrepancy is undoubtedly related to the heterogeneity of the
disease itself. In addition, it is to be noted that most of the subjects enrolled in the studies were, quite logically, on antidepressant treatment, often serotonin reuptake inhibitors (SSRIs),
known to have an impact on bone.
Epidemiology of bone impact in depression
N Densitometric data
A meta-analysis, avoiding the aforementioned pitfalls, was recently published,22 which included 8 cross-sectional and 6
case-control studies. Cohort studies were also evaluated when
densitometric data were available. In all the studies, BMD was
determined by DXA. In the cross-sectional studies, confounding factors such as age, gender, menopausal status, weight,
and body mass index (BMI) were taken into account in the
analysis of the results. The studies are summarized in Figure 1.5,7,11-14,16,17,19-24 Of the 14 studies, BMD data for all sites
(lumbar spine and hip) were only reported in 12 studies, which
350
were thus finally selected for the meta-analysis. The decrease
in BMD was only significant in 6 cases. Mean between-group
BMD difference was only slight: 53 mg/cm2 (95% confidence
interval [CI], 18-87) for the lumbar spine. The difference was
very similar for the hip: 52 mg/cm2 (95% CI, 22-83). In the
depressed subjects, the percentage decrease in BMD was
5.9% for the lumbar spine and 6% for the hip.
When results were expressed as T-scores and Z-scores, the
trend was similar, as expected. The decrease, while real, was
only modest. Thus, mean T-scores in depressed subjects were
SELECTED
AN
anorexia nervosa
BAP
bone alkaline phosphatase
BMD
bone mineral density
CRH
corticotropin-releasing hormone
CTX
C-terminal crosslaps
DXA
dual-energy x-ray absorptiometry
GH
growth hormone
IGF
insulin-like growth factor
IL
interleukin
NTX
N-terminal crosslaps
QCT
quantitative computed tomography
SSRIs
selective serotonin reuptake inhibitors
– 0.73 (95% CI, –1.32/– 0.146) for the lumbar spine and – 0.627
(95% CI, –1.02/– 0.233) for the hip. The Z-scores were again,
as expected, fairly similar. Various sensitivity analyses were conducted, but did not change the results. It should, however, be
noted that when depression was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, the differences were a little more marked. The results for
men, while also significant, were of lesser magnitude.
Author/Year
Greendale et al,25
1999
Forsen et al,26
1999
Sample
size
B O N E H E A LT H
CI, 1.4-4.2), after multiple adjustments. The authors concluded to a relationship between depression severity and the
magnitude of the increase in fracture risk (Table I). Generally speaking, the risk of fracture, particularly peripheral fracture, is conditioned by 3 factors: BMD, the magnitude of the
impact, and the angle of the impact. This likely applies to depressed patients as well. Lastly, it was shown that there is
an increased risk of falls in depression.20,28
Follow-up
duration
Fracture
type
684
7 years
Hip, arm,
spine, wrist
and other
Age, race, gender,
concomitant diseases,
physical exercise, BMI,
smoking, alcohol
No association with
fracture risk
18 612
3 years
Hip
Medication, BMI, smoking,
physical exercise, handicap
Risk gradient as
a function of
depression severity
3.7 years
Vertebral and
nonvertebral
Age, marital status, educational
level, fracture history, fall risk,
diabetes, rheumatologic
disease history, steroids intake,
corticosteroids, estrogen treatment, calcium intake, cognitive
function, hip BMD
Increase in fracture
risk (vertebral
and nonvertebral
fractures)
7 years
Nonvertebral, hip,
pelvis, humerus,
forearm
Age, marital status, smoking,
alcohol
risk in women only
18.5 years
Hip
Age, gender, race, BMI, smoking,
alcohol, physical exercise
risk
Whooley et al,20
1999
7 414
Sogaard et al,15
2005
12 270
Mussolino,27
2005
IN
6 195
Principal
results
Adjustement
Table I. Depression and fracture risk.
Abbreviations: BMD, bone mineral density; BMI, body mass index.
Depression and fracture risk
Bone densitometry is only a surrogate marker and the most
important issue is whether depressed subjects are at greater
fracture risk. As is the case for densitometric assessment,
this requires taking into account numerous factors well known
to influence fracture risk. It should be pointed out that studies aimed at determining fracture risk are few. Moreover,
some of them are open to methodological criticism, particularly those of Kessler et al,1 due to the fact that they are retrospective studies.
Four of the 5 prospective studies on fracture risk available to
date concluded that depression was associated with an increase in fracture risk. In the remaining study, by Greendale et
al,25 which evidenced no such increase, the authors nonetheless showed that those patients with the highest urinary cortisol level were at increased risk of fracture. The main findings from these studies are summarized in Table I.15,20,25-27
Thus, for example, in 467 depressed subjects from a cohort
of 7414, Whooley et al20 reported an increase in relative nonvertebral fracture risk, of 1.3 (95% CI, 1.1-1.6), after multiple
adjustments. Similarly, vertebral fracture risk was 2.1 (95%
Pathophysiology of bone impact in depression
N Hypothalamic-pituitary axis
The various hypotheses are summarized in Figure 2 (page
352). There is substantial evidence to confirm the presence
of hyperadrenocorticism in the context of depression. The
latter results from chronic exposure to stress, which triggers
the release of corticotropin-releasing hormone (CRH) by the
paraventricular nucleus of the hypothalamus. The process
involves frontal cortex, hippocampus, amygdala, and hypothalamus pathways. There is no autonomous hypersecretion
of cortisol in depression, so that cortisol levels are markedly
lower than those observed in Cushing’s syndrome. This hypothesis is corroborated by clinical data,13-23 which show an
increase in plasma cortisol. An increase in urinary cortisol has
also been observed, though some authors failed to evidence
any such increase.29
N Autonomic nervous system
Animal data suggest that there is a relationship between hyperactivity of the efferent autonomic nervous system and risk
of bone demineralization. However, the implications of this finding in depression are still the subject of considerable debate.
351
IN
B O N E H E A LT H
Depression
Markers
Antidepressant
use
Behavior
Cortisol
Smoking
Inflammation
Physical exercise
Catecholamines
Alcohol
Steroids
Confounding factors
Concomitant diseases
Medication
Medical treatment
BMD
Falls
Fractures
Falls
Figure 2. Pathophysiology of the bone impact of depression.
N Leptin
The relationship between leptin metabolism and bone metabolism is complex. Findings relating to circulating leptin levels
in depressed subjects are contradictory. Thus, understanding
of the pathophysiological role of leptin as a factor liable to
explain the bone impact in depression requires further investigation.
N Impairment of the immune system
Impairment of the immune system in depression has been
fairly well established, with an increase in proinflammatory cytokines such as interleukins (IL) 1 and 6 and tumor necrosis
factor.30 Cytokines are stimulants of the hypothalamic-pituitary-adrenal axis, which may account for the hyperadrenocorticism observed in depression. This has been confirmed
by a recent study by Eskandari et al,29 which also reported a
reduction in anti-inflammatory cytokines (IL-10 and IL-13) in
depressed subjects. This reduction was only significant for
IL-13. However, the study population was small, limiting the
scope of the study.
Impact of depression on bone and confounding
factors
Confounding factors include the classic risk factors for osteoporosis, which can be present in depressed subjects just as
in the general population, and a risk factor specific to depression: antidepressant treatment.
N Osteoporosis risk factors in depressed subjects
Certain risk factors for bone fragility are more frequently encountered in depressed subjects, eg, tobacco and alcohol
abuse. Similarly, one of the symptoms of depression, namely,
352
weight loss, is associated with an increase in fracture risk.
These confounding factors are sometimes taken into account in the studies previously cited, but not always, which
makes it difficult to interpret findings.
N Antidepressants and bone metabolism
Antidepressants, in particular SSRIs, undoubtedly are the most
important confounding factor. The presence of serotonin receptors on the osteoblasts and osteocytes lends support to
the involvement of these agents. Some studies are adjusted
to take into account antidepressant intake, but this is not always the case. The adverse effect on bone of SSRIs is supported by in vitro and animals studies. Severe osteoporosis
has been evidenced in serotonin-deficient mice. A clinical
study by Cauley et al31 showed that only SSRIs (and not tricyclic antidepressants) have an adverse impact on bone.
More recently, Diem et al32 were able to show that the effect
of SSRIs persisted even after adjustment for the symptoms
of depression. They also reported accelerated bone loss in
subjects on SSRIs vs nonusers and vs tricyclic antidepressant users.
Obviously, the most important issue is to determine whether
antidepressants are associated with an increase in fracture
risk. Quite logically, and in line with previous studies, a recent large-scale study33 in 6763 subjects on tricyclic antidepressants or SSRIs vs 26 341 controls matched for age, gender, and geographic origin, reported an increase in hip and
femur fracture risk in patients receiving SSRIs: relative risk
(RR), 2.35 (95% CI, 1.94-2.84). An increase in fracture risk,
albeit of lesser amplitude, was also found in patients on tricyclic antidepressants: RR, 1.76 (95% CI, 1.45-2.15). The
strength of the causal relationship was confirmed by the fact
that fracture risk rapidly decreased following antidepressant
treatment discontinuation. In patients receiving SSRIs, there
was a parallel between the latter’s potency in inhibiting serotonin reuptake and the magnitude of the fracture risk increase.
The potential increase in the risk of other fractures due to bone
fragility was not clearly established.
IN
B O N E H E A LT H
Animal models
Yirmiya et al34 developed an experimental model of depression in the mouse, enabling micro-CT scan analysis of the distal metaphysis of the femur and the vertebrae. In both sites,
the authors showed, under physiological and pathological
conditions, a decrease in trabecular bone volume, compared
with controls.
IMPACT OF ANOREXIA NERVOSA ON BONE
norexia nervosa (NA) has become a major public
health concern in industrial countries in recent years.
Its prevalence is 0.5%, vs 2% for bulimia. AN is a syndrome combining an exaggerated fear of excessive weight,
a disorder of body image, significant weight loss, refusal to
maintain a minimum normal weight, and amenorrhea.
A
The course of the disease is accompanied by a variety of
disorders and complications. Bone health is much affected,
with a decrease of more than 1 standard deviation (SD) in spine
and femur neck bone mass in 92% of female patients, which
exceeds 2.5 SD in 38% of cases.35 The mechanisms of bone
loss in AN patients are multiple: hormonal, endocrine, and
nutritional. The disease is more severe when it develops during adolescence, a critical period for acquisition of peak bone
mass. Bone mass increases gradually through childhood
and accelerates during adolescence to reach a peak during
Tanner stages 4 and 5. The greater part of bone mass peak
determination seems to be genetic (60% to 80%); the remaining 20% to 40% of determination is influenced by nutritional
and hormonal factors.36 For a given age, bone loss is more
marked in anorexic women than women with normal BMI and
amenorrhea of hypothalamic origin. Forty percent of anorexic women are osteoporotic vs 16% in the second group.37
BMI in women in whom AN develops before age 18 years is
significantly lower than those in whom it develops later, reflecting the impact of the disease on bone formation.38
Assessment of the bone impact of anorexia nervosa
N Bone mineral density
BMD is determined in the spine and femur neck by means of
bone densitometry measurements using low-dose radiation.
The World Health Organization defines osteoporosis as a BMD
that is at least 2.5 SD lower than the mean for young women
(T-score < –2.5 SD). However, this definition only applies to
postmenopausal women, a fact that must be taken into account when dealing with adolescents who have not always
achieved peak bone mass. Lower BMD is consistently reported in anorexic female patients, and osteoporosis is present in
about 30% of them.35,39-41
N Bone remodeling markers
Bone markers, used to assess bone remodeling, are complementary to BMD determination, but are not diagnostic tools.
The most frequently used bone-formation markers are os-
teocalcin and bone alkaline phosphatase (BAP); bone-resorption markers include deoxypyridinoline (DPD), C-terminal
(crosslaps or CTX), and N-terminal (NTX) extension peptides
and telopeptides (carboxyl terminal telopeptide of collagen I
[ICTP]).39,40 These markers are mainly used in postmenopausal
women and their interpretation is more difficult in young women and adolescents. The literature shows wide divergence
in findings; study populations are frequently small and it is
necessary to distinguish between the studies conducted on
female adolescents and those conducted on adult anorexic
patients. Like postmenopausal women, AN women show an
increase in bone resorption, but studies have also shown that
there is a marked decrease in bone formation.42
This shows that the bone loss in AN patients is also related
to other mechanisms, such as estrogen deficiency, and that
nutritional or nutrition-dependent factors are also involved.
This is confirmed in the literature by the fact that bone loss in
AN patients is more marked than that in women of the same
age suffering from hypogonadism.
Few studies have addressed fracture risk in AN populations.
Lucas et al43 reported a retrospective study in 208 AN patients
over 13 years with 58 fractures. Compared with the expected
number of fractures, the risk in AN patients was 3-fold greater.
Fractures occurred more frequently in inpatients than in outpatients, and bone insufficiency–related cracks were also more
frequent in inpatients. A study in female patients with a mean
AN duration of 5.8 years reported a 7-fold greater fracture
risk than in healthy women of the same age.44 Fractures occurred more frequently at the usual sites (vertebrae, followed
by the radius and the distal extremity of the femur).44
N Hormonal factors
Studies of the time course of BMD in female AN patient populations show that when AN is diagnosed before age 18, BMD
is significantly lower than when diagnosed at a later age, reflecting the impact of the disease on acquisition of peak bone
mass.35,39,40,44,45
Amenorrhea is a diagnostic criterion for AN. Estrogen deficiency is known to play a major role in bone mass loss in the
AN population. The mechanisms underlying estrogen deficiency in AN have yet to be fully elucidated. They are probably multifactorial, and include hypothalamic dysfunction,
353
IN
weight loss, and dysregulation of neurotransmitters such as
GnRH. The literature shows a correlation between BMD and
the duration and age of onset of amenorrhea.35,39,44-46
Estrogen deficiency alone cannot explain bone loss in anorexic female patients. Bone mass gain precedes resumption of
menstrual cycles in recovering anorexic patients, while estrogen therapy does not prevent bone loss in adolescents.42 Other factors are involved in bone loss in AN. Bone remodeling is
differently affected in AN female patients compared with postmenopausal osteoporotic women. Bone resorption and formation are increased, with a balance in favor of resorption,
in postmenopausal women, whereas in AN, although bone
resorption is slightly greater, the predominant disorder is decreased bone formation,37,39 though some authors report that
it is normal.35 In any event, it is never increased. Reduced bone
formation in AN explains the relative failure of antiresorptive
treatments and, particularly, estrogens.42 In all, this suggests
an essential role for undernourishment and factors influenced
by nutritional status in the bone loss of AN.
N Nutritional and endocrine factors
The role of nutritional and endocrine factors is supported by
the literature, which shows a strong correlation between female patient BMD and nutritional indices such as BMI, lean
mass, fat mass, insulin-like growth factor–I (IGF-I), and leptin.37,39 In a previous study, the author and his colleagues
showed a correlation between hip BMD and IGF-I in 113 female patients with AN.46 Hotta et al47 showed that the osteoporotic risk is higher when BMI is less than 15 kg/m2. Other
authors39,47 have also reported a correlation between bone formation markers (osteocalcin and BAP) and nutritional markers
such as BMI, fat mass percentage, IGF-I, and a negative correlation between estradiol and bone resorption markers.
At puberty, the levels of GH-IGF axis hormones increase to
stimulate the proliferation and differentiation of osteoblastic
precursors. IGF-I is a bone tropism hormone that stimulates
bone formation and growth by acting on osteoblasts and stimulating collagen synthesis. Studies have shown an impairment
of the GH-IGF-I axis in AN patients.48,49 Female AN patients
display resistance to GH, with high GH levels, but low IGF-I
levels. Stoving et al48 monitored 24-hour GH secretion in 8
anorexic female patients and showed an increase in the number, duration, and intensity of GH peaks. The authors also
showed an increase in basal secretion (20-fold vs 4 fold for
pulsatile secretion). The increase in the intensity of GH peaks
is ascribed to weight loss, while the number of peaks is related to hypoestrogenism. There was no difference in GH half-life
in anorexic patients compared with healthy controls. Sacchi
et al49 published similar results. Several authors have reported
a decrease in IGF-I levels, but also in binding proteins (IGFBP),
in particular IGFBP3 and 2, in anorexic female patients,50,51
sometimes with an increase in IGFBP1. The decrease in circulating binding-protein levels may in part explain the resis-
354
B O N E H E A LT H
tance to GH, preventing the transfer of IGF-I toward the target
organs. In addition, IGFBP3 is reported to be a good predictive factor for bone loss in anorexic patients, independently
of BMI and IGF-I.
An important role is played by the hormone leptin, an antiorexigenic adipokine secreted by adipose tissue. Leptin’s
physiological effects on bone are debated, particularly as they
differ depending on whether its peripheral or central action is
considered. Measuring BMD and several hormonal factors
in a recent cohort study of 103 young women with AN,52 the
authors found a mean Z-score of –1.17 for the spine, –1.33
2
1.5
1
0.5
0
– 0.5
–1
–1.5
–2
1000
2000
3000
Figure 3. Relationship between circulating leptin level (abscissa:
tertiles 1, 2 and 3) and bone mineral density expressed as lumbar
spine Z-score (as ordinates).
Modified from reference 52: Legroux-Gérot I et al. Osteoporos Int. 2010 Jan 6.
[Epub ahead of print] DOI 10.1007/s00198-009-1120-x. © 2010, International
Osteoporosis Foundation and National Osteoporosis Foundation.
for the hip, and –1.11 for the femur neck, and a modest, but
significant, positive correlation between leptin levels and spinal
BMD (r = 0.30). The correlations were significant, but of lesser amplitude, for the femur neck and whole hip (r = 0.23 and
r = 0.21, respectively). Multiple regression analysis showed
that 27% of spinal BMD variability was explained by differences
in duration of amenorrhea and leptin levels. Figure 3, which
plots BMD values as a function of leptin level divided into 3
tertiles, shows a marked and significant difference between
the patients in the lowest tertile (mean Z-score: –1.25) and
higher tertile (mean Z-score: +0.75).52
Hyperadrenocorticism and calcium and vitamin D deficiency
are reported in AN, in some cases compounded by excessive exercise. Thus, high cortisol levels can be found,38,46 although the circadian rhythm is spared. Similarly, the dexamethasone suppression test frequently evidences an increase
in urinary free cortisol. Hyperadrenocorticism may be related
to impairment of hypothalamic function or CRH hypersecretion. Grinspoon et al35 reported hyperadrenocorticism in only
22% of anorexic patients with severe bone loss. We found
similar results in our study.46 Audi et al53 did not find any signif-
icant difference in urinary free cortisol levels between AN patients and controls. This suggests that while hyperadrenocorticism is a potential cause of bone loss, it is not the only
mechanism involved. The role of vitamin and calcium deficiency in bone loss remains uncertain. In the study by Audi et al53
vitamin D deficiency (25-OH-D3) was observed in 24.6% of
AN patients. Urinary calcium was somewhat higher in the
group of AN patients in the active phase, and lower in those
having regained weight, but still with amenorrhea, and those
who had recovered. Soyka et al40 reported dietary calcium deficiency (<1300 mg/day) in 42% of the AN patients in their
study population, but also in 50% of the controls. Similarly,
vitamin D deficiency was present in 42% of AN patients and
44% of controls.
Course of bone loss after weight recovery
A few studies have addressed the time course of BMD in recovered anorexic patients.40,44,54 Despite the improvement in
bone mass with body weight normalization, certain studies report persistent osteopenia in a high proportion of postanorexic patients. Hartman et al,54 in a study of 19 female patients
with a history of AN, determined bone mass at age 21 years
and found, despite body weight recovery, that femur bone
IN
B O N E H E A LT H
mass was lower than that of the control group. In Zipfel’s
study,44 monitoring of spine BMD showed bone gain after body
weight recovery with a decrease in the percentage of osteopenic and osteoporotic female patients (35% to 13% and 54
to 21%, respectively), but a large proportion of the patients continued to have low BMD values. However, in a recent study,
Wentz et al55 did not confirm those results and found no significant difference in BMD between the patients with a history of AN (11 years previously on average) and the controls.
Overall, specific bone-targeting treatments are of little efficacy in AN. As indicated previously, the primary objective is
to achieve body weight recovery, which has a proven beneficial impact on bone. Various studies, including a recent
one by us, have shown that hormonal treatment is not effective.56 In contrast, achieving a BMI greater than 19 kg/m2 and
resumption of menstrual periods results in bone gains.
In conclusion, bone loss in female patients with AN is rapid
and severe and is associated with a substantial fracture risk,
the mechanism of which has yet to be fully elucidated and
is probably multifactorial. Early screening is necessary and
BMD must be determined as soon as AN is diagnosed. I
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Keywords: psychiatric disorder; depression; anorexia nervosa; hyperadrenocorticism; estrogen; osteoporosis
IMPACT
DES AFFECTIONS PSYCHIATRIQUES SUR LA SANTÉ DE L’ OS
Les affections psychiatriques peuvent, par le biais de mécanismes directs et indirects, engendrer une fragilité osseuse.
Les données les plus conséquentes concernent la dépression et l’anorexie mentale. Au cours de la dépression, les
études font état d’une diminution modérée de la densité minérale osseuse (de l’ordre de 6%) tant au rachis qu’à la
hanche comparativement aux résultats observés chez les témoins. De même, une augmentation significative du risque
fracturaire a été démontrée, notamment au niveau de la hanche avec un doublement du risque fracturaire. Les mécanismes de cette fragilité sont complexes, multifactoriels et incomplètement élucidés. Parmi les mécanismes directs
il faut citer l’hypercorticisme endogène dont l’ampleur est moindre qu’au cours du syndrome de Cushing. Par ailleurs,
des taux élevés de cytokines pro-inflammatoires (interleukine 6 notamment) ont été retrouvés. Ceux-ci pourraient être
en partie responsables de l’hypercorticisme. Le traitement antidépresseur lui-même peut avoir un impact osseux
défavorable. Citons également dans les facteurs indirects dont l’influence est diversement appréciée l’amaigrissement mais aussi le tabagisme et l’intoxication éthylique parfois rencontrés chez les sujets déprimés. L’anorexie mentale est devenue ces dernières années un problème majeur. Ses complications sont multiples et l’atteinte osseuse
est fréquente. Elle est responsable d’une ostéoporose dans 38 à 50 % des cas. Le déficit en œstrogènes a longtemps été incriminé comme facteur principal mais il ne peut l’expliquer à lui seul. Le rôle essentiel de la dénutrition
et des facteurs liés à la nutrition en particulier de l’axe hormone de croissance - somatomédine C (GH-IGF-I) a été
rapporté par divers travaux récents. La prise en charge thérapeutique de l’atteinte osseuse de l’anorexie mentale reste
discutée. Si le retour des règles et la récupération pondérale semblent indispensables, ils ne permettent pas toujours
de corriger cette perte osseuse. Les différentes études n’ont pas montré d’efficacité du traitement par œstrogènes.
356
‘‘
The biology of serotonin, which
was discovered in 1948 as a factor causing vascular contractions,
has expanded exponentially, and
serotonin is now recognized as a
pivotal regulator in many central
and peripheral functions, including mood, gastrointestinal motility,
and, more recently, bone remodeling. As research on the role of
serotonin and its receptors in
bone physiology progresses, we
will likely discover new therapeutic targets for osteoporosis treatments as well as gain a better
understanding of the beauty and
complexity of bone biology.”
IN
B O N E H E A LT H
Serotonin: a new player
in the regulation of
bone remodeling
b y V. K . Yad a v, P. D u c y, a n d
G . K a r s e n t y, U S A
S
L
Vijay K. YADAV, PhD
Gerard KARSENTY, MD, PhD
Department of Genetics and
Development
Patricia DUCY, PhD
Department of Pathology
Columbia University Medical
Center, New York, NY
USA
Vijay K. Yadav, PhD, Department
of Genetics and Development,
Columbia University Medical Center,
701 W 168th Street, HHSC 1614,
New York, NY 10032, USA
(e-mail: vky2101@columbia.edu)
erotonin is a bioamine synthesized in the brain and gut that regulates
diverse functions from mood to gastrointestinal tract motility. This diversity in serotonin function(s) is achieved through one or several of its
14 distinct receptor(s) expressed on the target cells. The emerging concept
that brain- and gut-derived serotonin regulate bone remodeling in opposite
manner has revealed novel mechanism(s) by which bone mass is regulated
and maintained. Advances in our understanding of serotonin synthesis, receptor activation, and participation in distinct regulatory networks demonstrate a
role for serotonin in osteoblast and osteoclast functions. This review focuses
on this new “expanded serotonin biology” and discusses how drugs targeting
serotonin synthesis or signaling can be harnessed for treating low-bone-mass
diseases.
keleton in vertebrates serves multiple mechanical, hematopoietic, and endocrine
functions.1 In order to perform its functions properly, skeleton continuously
renews itself through a homeostatic process known as bone remodeling—a
process carried out by osteoblasts and osteoclasts to maintain a fine balance between bone formation and resorption.1 Bone remodeling occurs constantly and
simultaneously in numerous parts of skeleton and the maintenance of a normal,
healthy skeletal mass depends on continuous exchange of information taking place
among osteoblasts, osteoclasts, osteocytes, constituents of the bone matrix, and
other organs.1 Therefore, understanding what factors are influencing bone mass
in the context of other signals is important. The fact that osteoporosis is a heritable
trait provides an opportunity to use modern molecular genetics to obtain mechanistic insights that were previously unobtainable. If we could find genetic variants
with known or at least tractable functions that are unequivocally associated with
osteoporosis, we might be able to build up a picture of what sorts of biological factors determine why some people are more susceptible to osteoporosis than others.
S
Lrp5: a multifaceted molecule
The low-density lipoprotein receptor (LDLR)-related protein (Lrp)-5 is part of a subset of the LDLR family of cell surface proteins.2,3 Since its cloning in 1998, Lrp5 has
taken biologists to voyages of discoveries from lipoprotein clearance to glucose
homeostasis to bone remodeling. Not surprisingly, it has been shown to bind to multiple ligands and activate a multitude of downstream cascades in distinct cell types
Serotonin: a new player in the regulation of bone remodeling – Yadav and others
357
to regulate different processes (Figure 1). In hepatocytes, Lrp5 binds apolipoprotein E (ApoE) and
plays a role in the hepatic clearance of ApoE-containing chylomicron remnants, a major plasma lipoprotein carrying diet-derived cholesterol.4,5 In pancreatic islets, Lrp5 regulates insulin secretion and
consequently Lrp5-deficient animals are glucose intolerant.6 Consistent with its role in glucose homeostasis, the LRP5 gene is mapped within the region
(IDDM4) linked to type 1 diabetes on chromosome
11q13.7 LRP5 is also the gene responsible for osteoporosis-pseudoglioma (OPPG) syndrome and
high-bone-mass (HBM) syndrome in humans due
to an isolated change in bone formation.8-10
IN
B O N E H E A LT H
ApoE
Unknown?
Wnt
The main question surrounding Lrp5 biology, since
its identification as the cause of OPPG, has been
Insulin secretion
to define how its absence can cause the developmental onset of blindness and postnatal onset of
Lipoprotein clearance
osteoporosis characterizing this disease.8-10 SevBone formation
eral recent studies have now shed11 new light on the
mechanisms associated with these two functions
Eye vascularization
of Lrp5. Indeed, ample studies have conclusively
demonstrated that Lrp5 uses the Norrin and Wnt
signaling pathways during embryogenesis to reg- Figure 1. Lrp5 ligands and targets.
binds to numerous ligands and regulates a wide variety of processes through different
ulate vascularization in the eyes.12-14 That dysregu- Lrp5
mechanisms. Structures not to scale.
lation of Wnt signaling plays a role in the development of blindness in a Lrp5-dependent manner fuelled interest tion mutations regulate bone formation is by regulating seroin this signaling pathway, leading to the identification of crit- tonin production in the gut.19 This dual role of Lrp5—one deical Wnt-dependent mechanisms involved in controlling early velopmental (directly dependent on Wnt signaling in the eye)
differentiation of osteochondroprogenitor cells during embryo- and the other postnatal (relying on the indirect effect of gutgenesis as well as osteoblast and osteoclast functions.11,15-17 derived serotonin on bone cells)—is consistent with the mulSome of these targets have already made it to preclinical trials, tifunctionality of Lrp5, which participates in a wide variety of
viz, sclerostin.18 However, and to our dismay, using an unbi- signaling cascade(s).
ased microarray approach, we serendipitously identified that
the mechanism through which Lrp5 loss- and gain-of-func- We should emphasize that the fact that the deletion of Lrp5
in osteoblasts progenitors or mature osteoblasts did not result in a discernible effect on bone mass in our studies does
SELECTED ABBREVIATIONS AND ACRONYMS
not exclude, however, that Lrp5 could play a role, in a Wntdependent manner, or not, in regulating the response of osteoaBMD areal bone mineral density
cytes to mechanical loading.20-21 Further studies analyzing, in
ApoE
apolipoprotein E
parallel, mice deficient in Lrp5 globally as well as conditionalBDS
brain-derived serotonin
ly in osteocytes will be pivotal to address this specific point.
CREB cAMP response element binding (protein)
GDS
gut-derived serotonin
HBM
high-bone-mass (syndrome)
LDLR
low-density lipoprotein receptor
Lrp
LDLR-related protein
OPPG
osteoporosis–pseudoglioma (syndrome)
PKA
protein kinase A
SSRI
selective serotonin reuptake inhibitor
Tph
tryptophan hydroxylase
vBMD
volumetric bone mineral density
VMH
ventromedial hypothalamus
358
Ever-expanding tenets of serotonin biology
Serotonin (5-hydroxytryptamine) was discovered in 1948 as a
factor causing vascular contractions, hence the name of the
molecule serotonin (L, serum + Gk, tonos, tone).22 Since then
serotonin biology has expanded exponentially and it is now
recognized as a pivotal regulator in many central and peripheral functions.23 Serotonin is generated through an enzymatic pathway in which L-tryptophan is converted into L-5-OHtryptophan by an enzyme called tryptophan hydroxylase (Tph);
this intermediate product is then converted to serotonin by
an aromatic L-aminoacid decarboxylase.24,25 There are two Tph
genes that catalyze the rate-limiting step in serotonin biosynthesis: Tph1 and Tph2. Tph1 is expressed mostly, but not
only, in enterochromaffin cells of the gut and is responsible
for the production of peripheral serotonin.23 Tph2 is expressed
exclusively in raphe neurons of the brainstem and is responsible for the production of serotonin in the brain.25 Remarkably,
serotonin does not cross the blood–brain barrier; therefore it
should be viewed from a functional point of view as two distinct molecules depending on their site of synthesis.24 Brainderived serotonin (BDS) acts as a neurotransmitter, while
gut-derived serotonin (GDS), till now, has only been appreciated as an autocrine/paracrine signal that regulates mammary gland biogenesis, liver regeneration, and gastrointestinal
tract motility.23,26,27
IN
B O N E H E A LT H
primary osteoblasts expressed three serotonin receptors:
Htr1b, 2a, and 2b. Mice with either global deletion of Htr2a
or osteoblast-specific deletion of Htr2b did not display skeletal phenotypes; however, that was not the case for mice with
global or osteoblast-specific deletion of Htr1b gene.19 These
latter animals displayed a high bone mass phenotype, although of lower magnitude than the one displayed by the
mice expressing HBM mutation of Lrp5 (G171V) in the gut,
suggesting that there may be, yet to be identified, mediators
of the HBM mutations. Nevertheless, the fact that the HBM
phenotype of Htr1b-deficient animals was similar in magnitude to one of the mice that had suppressed levels of GDS
demonstrated that it is through Htr1b receptor that GDS regulates bone formation.19 Htr1b is a Gi-protein–coupled recep-
Platelets
Dense granules
HTT
Lrp5
Htr1B
5-HT
?
Trp
Trp-OH
CREB
Tph1
Proliferation
Osteoblasts
Enterochromaffin cells
Figure 2. Gut-bone endocrine axis: potential molecular targets for therapeutic interventions.
Lrp5 regulates synthesis of serotonin by enterochromaffin cells in the gut that is then released into the circulation. In the blood it is taken up mostly in the platelets
and a small amount (≈10% to 12%) is present outside (free) these cells. These free serotonin levels are increased under pathological conditions resulting in decreased
osteoblast proliferation and bone formation through the Htr1b-CREB signaling pathway. Nodes in the pathway that are amenable to therapeutic interventions are
highlighted. Structures not to scale.
Abbreviations: 5-HT, 5-hydroxytryptamine (serotonin); CREB, cAMP response element binding (protein); Htr1b, 5-hydroxytryptamine receptor 1B; HTT, serotonin
transporter; Lrp5, low-density lipoprotein receptor (LDLR)-related protein (Lrp)-5; Tph1, tryptophan hydroxylase–1; Trp, tryptophan.
Regulation of bone formation through
gut-derived serotonin
Our work on the mechanism(s) underlying OPPG and HBM
led us to identify Lrp5 as one of the regulators of GDS (Figure 2).19 Conditional inactivation of Lrp5 and Tph1 in the gut
cells identified that GDS functions as a hormone that directly
inhibits osteoblast proliferation and bone formation.19 We reasoned that if GDS was acting as a hormone one or several of
its 14 receptors must be expressed on osteoblasts. Indeed,
tor and, consistent with its role in neurons, it inhibited cAMP
production and phosphokinase A (PKA)-mediated cAMP response element binding protein (CREB) phosphorylation in
primary osteoblasts. These results identified that a cAMPPKA-CREB pathway regulates osteoblasts proliferation and
bone formation.19 Yet, this signaling pathway in the osteoblasts
is utilized by many other receptors, and future studies would
need to dissociate how this selectivity of Htr1b action on osteoblast proliferation is achieved.
359
IN
Negative association of peripheral serotonin
levels with bone mass in humans
B O N E H E A LT H
In our quest to understand the serotonin regulation of bone
mass in vertebrates, we then inactivated Tph2, the gene that
catalyzes the rate-limiting step in the biosynthesis of BDS.
The absence of serotonin in the brain resulted in a severe
low-bone-mass phenotype affecting the axial (vertebrae) and
appendicular (long bones) skeleton.31 This phenotype was
secondary to a decrease in bone formation parameters (osteoblast numbers and bone formation rate) and to an increase
in bone resorption parameters (osteoclast surface and circulating Dpd levels).31 Hence, BDS is a positive and powerful regulator of bone mass accrual acting on both arms of
bone remodeling.31
Leptin is an adipocyte-derived hormone that regulates many
functions, viz, appetite, energy expenditure, bone mass,
etc.34-39 Studies in the last 16 years have highlighted a more
complete neural and neurochemical circuit diagram for the
leptin regulation of these functions.34-36 These neural circuits
involve many distinct neuronal populations in the brain, including neurons of arcuate, Ventromedial, and lateral hypothalamus, and neurons of the nucleus tractus solitarius (NTS)
etc.34-36,40 Three correlative experiments suggested that leptin might signal in the serotonin neurons, among others, to
regulate some of its downstream functions. First, the leptin
receptor (ObRb) is expressed on serotonin neurons located
in the raphe nuclei of brainstem, where BDS is produced, and
is functional.31,41 Second, serotonin neurons project to the key
hypothalamic nuclei responsible for the regulation of appetite,
energy expenditure, and bone mass.42 Third, patients on selective serotonin reuptake inhibitors (SSRIs) have been reported to have changes in their appetite and bone mass.43,44
To explore that leptin might utilize serotonin as one of its
downstream mediators to regulate these three functions, we
inactivated the leptin receptor in different nuclei of the hypothalamus or in the serotonergic neurons of the brainstem.31
Mice lacking ObRb either in Sf1-expressing neurons of the
ventromedial hypothalamus (VMH) nuclei or in Pomc-expressing neurons of the arcuate (ARC) nuclei had normal sympathetic activity, bone remodeling parameters, and bone mass;
they also had normal appetite and energy expenditure, and
when fed a normal diet, did not develop an obesity phenotype.40,45 In contrast, mice that lack ObRb in Sert-Cre positive serotonin neurons (ObRbSERT -/-) developed a high bone
mass phenotype; they also had an increase in appetite and
displayed low-energy expenditure. As a result, ObRbSERT -/mice, when fed a normal diet, developed an obesity phenotype. These genetic studies demonstrated that leptin signals,
in part, in the serotonin neurons of the brainstem to regulate,
bone mass, appetite, and energy expenditure (Figure 3). The
identification of serotonin as one of its mediators adds to the
list of the multitude of messengers (viz, dopamine, melanocortins, etc) utilized by leptin in the brain to affect peripheral functions.31,34-36
While we were doing these studies we noticed, upon opening the abdominal cavities, that Tph2-deficient animals had
a dramatic decrease in their adipose mass.31 This prompted
us to analyze in great detail their energy metabolism phenotype. The decrease in their fat mass was due, in part, to the
fact that these mice ate less and spent much more energy
compared to their wild-type littermates.31 This observation
was not entirely surprising since serotonin is known to play
important roles in many other physiological processes. However, what caught our attention was the fact that the three
most notable phenotypes of adult Tph2-deficient animals ie,
decrease in bone mass, decrease in appetite, and increase in
energy expenditure are a mirror image of what is observed in
mice that lack leptin.32,33
The demonstration that a leptin-dependent central control of
bone mass, appetite, and energy expenditure occurs, among
other neural relays, through its ability to inhibit serotonin production, raised questions about the location and identity of
serotonin receptors on hypothalamic neurons mediating these
functions. Double fluorescence in situ hybridization and nuclei-specific gene inactivation experiments revealed that serotonin promotes bone mass accrual through Htr2c receptors
expressed on the VMH nuclei, while appetite was promoted
through Htr2b and Htr1a receptors expressed on ARC nuclei of the hypothalamus. Further analysis revealed that Htr2c
receptor expression on VMH nuclei is en route to the sympathetic center of the brain, while Htr1a and Htr2b achieve
their functions on appetite most likely through modulation of
The identification of a gut-derived serotonin-bone endocrine
axis (Figure 2) begged the question of its biomedical importance in humans. Modder et al28 analyzed serum serotonin levels in a population-based sample of 275 women and related
these to bone mineral densities (BMD) at distinct skeletal sites
and bone microstructural parameters. They found that serum
serotonin levels were inversely associated in these women
with body and spine areal bone mineral density (aBMD) as
well as with femur neck total and trabecular volumetric bone
mineral density (vBMD).28 Moreover, multiple LRP5 mutations
associated with decreased BMDs have been analyzed and all
published studies thus far show that these mutations are associated with a 2-to-4 increase in serum serotonin levels.19,29
Conversely, analysis of two HBM patients in the US as well as
a recent study of 9 HBM European patients, who harbor the
T253I gain-of-function mutation of LRP5, showed that their
serotonin concentrations in platelet-poor plasma were significantly lower compared to sex- and age-matched controls.19,30
Collectively, these studies performed in different continents by
different investigators, provide convincing evidence to support a physiological role for circulating serotonin in negatively
regulating bone formation in humans related to one it plays
in mice.
Brain-derived serotonin: an expected player in
the regulation of bone mass
360
melanocortin signaling (Figure 3). These studies emphasized
that with respect to the bone mass and energy metabolism
effects of leptin signaling in the brain, a systems approach
involving anatomically distinct neural elements will provide a
more complete explanation of leptin actions in the brain.
Gain of function in serotonin signaling and
bone mass
Our loss of function studies with GDS and BDS dissociated
the role played by peripheral and central serotonin signaling
in the regulation of bone mass.19,31 As with any other study,
these studies raised many more questions than they answered. For instance, what effect would an increase in sero-
IN
B O N E H E A LT H
serotonin injections on the trabecular bone mass in their study
is consistent with our and earlier mouse genetic studies. We
reported that mice harboring a loss of function mutation for
Lrp5 gene have increased levels of GDS and a low bone mass
at vertebral sites.19 Battaglino et al49 tested the direct effects
of SSRIs on bone mass and they consistently observed an
increase in trabecular bone mass in these animals.49 These
latter results, given the effects of SSRIs in humans, were surprising at the time they were reported, but with the advancement of knowledge related to serotonin signaling in the brain
and periphery we can today explain these results. Likely the
observed effects were due to the fact that, under the conditions tested in their study, SSRIs were having more pro-
Serotonin
NTS
Hypothalamus
Leptin
Figure 3. Neuronal relays
underlying leptin regulation of
bone mass, appetite, and
energy expenditure.
PVH
VMH
Bone mass accrual
ARC
Appetite
?
Energy expenditure
tonin signaling have on the bone mass? SSRIs are a class of
drugs that do exactly that.46 Based on these effects, this class
of drugs is prescribed to cure many psychiatric disorders associated with diminished serotonin signaling and their therapeutic actions are diverse, ranging from efficacy in the treatment of depression to obsessive-compulsive disorder, panic
disorder, bulimia, and other conditions. The plethora of biological substrates, receptors, and pathways for serotonin are candidates to mediate not only the therapeutic actions of SSRIs,
but also their side effects.47 In a cohort of 5008 communitydwelling adults, Richards et al44 revealed that patients that
were taking SSRIs had increased risk of hip fractures. Because SSRIs readily cross the blood–brain barrier, it raised
the question as to the site of action of these drugs to produce
their deleterious actions on bone.
Several approaches have been used in the past to understand
this deleterious effect of SSRIs on bone mass. Gustaffson et
al,48 using naïve rats as a model of serotonin effect on bone
mass, analyzed site-specific alterations in the long bone
when rats were injected daily with serotonin. These authors
reported a decrease in trabecular bone mass and an increase
in cortical thickness in long bones. The negative influence of
Leptin inhibits release of brainstem-derived serotonin, among other neuronal
relays, which favors bone mass accrual
and appetite through its action on
hypothalamic neurons. Serotonergic
neurons are in blue; ARC is in green;
NTS is in orange; and VMH is in
purple. Structures not to scale.
Abbreviations: ARC, arcuate; NTS,
nucleus tractus solitarius; PVH, paraventricular hypothalamus; VMH, ventromedial hypothalamus.
found influences on BDS, a positive regulator of bone mass.
Warden et al,50 taking another approach for a model of chronic use of SSRIs, reported that mice that lack serotonin transporter (Htt-/- mice) have decreased bone mass at both cortical and trabecular sites.
Their study is consistent with Richards et al44 and other clinical reports that show that patients taking SSRIs often have
a decrease in bone mass. Surprisingly, Htt-/- mice have undetectable levels of serotonin in their blood and a twofold reduction in brain serotonin content (VKY, unpublished observations). The low bone mass observed in Htt-/- mice would
suggest that BDS compared to GDS has a dominant role in
the overall regulation of bone mass through serotonin. Indeed,
analyses of mice lacking both the Tph1 and Tph2 genes display a low bone mass phenotype demonstrating that despite accounting for >5% of total serotonin pool in the body,
BDS dominates in the overall regulation of bone mass.31 Since
SSRIs cross the blood–brain barrier, and osteoporosis is only
observed when they are taken in the long term, development of SSRIs with selective central actions would be worth
exploring in the future for curing depression while minimizing
their side effects on bone.
361
IN
Therapeutic implications of serotonin regulation
of bone mass
The richness and complexity of the serotonin modulation of
bone mass discussed in this review provide both a pharmacologic opportunity and a challenge. On the one hand, the involvement of specific serotonin receptors on osteoblasts and
hypothalamic neurons provides an opportunity to pharmacologically target these specific receptors for the treatment of osteoporosis. On the other hand, the fact that each of these serotonin receptors participates in multiple physiologic processes
presents a challenge, since even a drug targeting a single
serotonin receptor is likely to have effects on multiple body
systems. For example, although Htr2c agonists may be used
to increase bone mass through its effect in the brain, their clinical use would be limited by their effects on other organ systems, such as sympathetic tone or melanocortin signaling.31,51
Fortunately, the system is less complex and more amenable
to therapeutic interventions in the periphery. Since the effect
of GDS, a negative regulator of bone formation, is dominant
there, one would be able to suppress its levels mildly in order to avoid side effects of drugs targeting the receptors directly. This way one would be able to maintain basal level of
signaling in other systems dependent on serotonin while at
the same time getting the therapeutic outcome in sensitive
systems such as bone, which responds robustly to >50%
modulation in peripheral serotonin levels.19
As GDS is a potent inhibitor of osteoblast proliferation and
bone formation, we tested the contention that pharmacologically suppressing GDS would be able to prevent, or cure, gonadectomy-induced bone loss. Serendipitously, we came
across an inhibitor that was inhibiting peripheral serotonin
production without having any detectable effect on brain serotonin content.52 This is, and will be, a prerequisite for any drug
that is going to target serotonin synthesis or signaling, as brain
serotonin has opposite influence on bone mass accrual and
B O N E H E A LT H
in fact is beneficial to bone. The drug, LP533401, a Tph1 inhibitor, was effective in preventing and even curing osteoporosis in mice and rats at an oral dose of less than 25 mg/kg/day
through an isolated increase in bone formation.53 The effect
of Tph1 inhibitors on bone mass establishes that inhibition of
GDS biosynthesis can rescue ovariectomy-induced osteoporosis in the mouse through an anabolic mechanism. These
studies further validate the role of GDS as a regulator of bone
formation and provide foundation for the development of other molecules that target the Tph1/Htr1b/osteoblast pathway
for the treatment of low bone mass diseases, either alone or
in combination with other existing therapies (Figure 2).
Future studies would be necessary to investigate four specific issues: First, the absolute threshold levels at which suppression in peripheral serotonin signaling is anabolic to the
bone. Second, to analyze in more detail plasma- vs serumvs platelet-derived serotonin in the regulation of bone mass.
Third, to thoroughly characterize any toxicity or side effects
the drugs that target this pathway might have on any of the
functions of other peripheral organs. Fourth, and most importantly, if these types of drugs can be used to treat low bone
mass conditions associated with specific genetic mutations
in mouse models of human diseases such as osteoporosis
pseudoglioma.
As research on the role of serotonin and its receptors in bone
physiology progresses, the difficulty of these challenges will
become clearer. In the process we will likely discover new
therapeutic targets for osteoporosis treatments as well as
gain a better understanding of the beauty and complexity of
bone biology. I
This work was supported by a NIH grant (DK85328) and a Rodan fellowship from IBMS to VKY. I apologize to numerous researchers whose
work I was unable to discuss due to space constraints.
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Keywords: serotonin; gut; bone; osteoblast; osteoclast
LA
SÉROTONINE
:
UN NOUVEL ACTEUR DANS LA RÉGULATION DU REMODELAGE OSSEUX
La sérotonine est une bioamine synthétisée dans le cerveau et l’intestin, régulant différentes fonctions allant de
l’humeur à la motilité du tractus gastro-intestinal. Cette diversité dans les fonctions de la sérotonine s’exerce par l’intermédiaire d’un ou de plusieurs de ses 14 récepteurs distincts exprimés sur les cellules cibles. La constatation que
la sérotonine cérébrale et la sérotonine intestinale agissent en sens contraires sur le remodelage osseux atteste de
l’existence de mécanismes nouveaux impliqués dans la régulation et le maintien de la masse osseuse. Les avancées
dans la compréhension de la synthèse de la sérotonine, de l’activation de ses récepteurs et de sa participation à des
réseaux de régulation distincts mettent ainsi en évidence le rôle de la sérotonine dans les fonctions des ostéoblastes
et des ostéoclastes. Cet article fait le point sur cette nouvelle « biologie étendue de la sérotonine » et examine comment exploiter les médicaments ciblant la synthèse ou la signalisation de la sérotonine dans le traitement des maladies se traduisant par une diminution de la masse osseuse.
363
‘‘
Type 1 diabetes is clearly associated with bone loss and suppressed bone formation, as more
than 50% of type 1 diabetic patients are thought to have bone
loss vs healthy age-matched subjects and almost 20% of diabetic
patients aged 20 to 56 meet the
criteria for osteoporosis. Adequate
glycemic control and prevention
of diabetic complications are the
mainstay of therapy to lower fracture risk, with the caveat that thiazolidinediones increase fracture
risk in postmenopausal women
with type 2 diabetes.”
IN
B O N E H E A LT H
Bone health and diabetes
b y M . L . B ra n d i , I t a l y
T
Maria Luisa BRANDI, MD, PhD
Metabolic Bone Diseases
Department of Internal Medicine
University of Medicine
Medical School, Florence
ITALY
he association between diabetes and bone health has long been a matter of debate. Both type 1 diabetes and type 2 diabetes have been linked
to increased risk of fractures, with bone mineral density being decreased
in type 1 diabetes and increased in type 2 diabetes. Insulin has an anabolic
effect on bone, and the qualitatively different effects of type 1 and type 2 diabetes on bone mass are consistent with the opposite insulin-secretory states
(hypoinsulinemia vs hyperinsulinemia). The existence of an elevated fracture
risk in type 2 diabetes, despite the underlying hyperinsulinemia, has led to
speculation about differences in bone quality between type 1 diabetes and
type 2 diabetes. This could be explained by the fact that increased blood glucose levels are associated with increased urinary calcium loss, resulting in a
negative calcium balance. There is also speculation about the role of the resistance to parathyroid hormone observed in diabetes, and its effect on calcium and bone turnover. Also, collagen glycosylation may alter bone biomechanical competence. Falls associated with diabetes-related comorbidities
are another possible cause of low-trauma fractures. Adequate glycemic control and prevention of diabetic complications are the mainstay of therapy to
lower fracture risk, with the caveat that thiazolidinediones increase fracture
risk in postmenopausal women with type 2 diabetes. In conclusion, bone health
is an important consideration in diabetes, and caution should be exercised in
prescribing thiazolidinediones to postmenopausal women with low bone mass
and patients with prior fragility fracture. This article reviews the current state
of knowledge on the association between diabetes and bone health.
ore than 180 million people worldwide suffer from type 2 diabetes, a disease that more than doubles the risk of death, mainly from cardiovascular disease.1 Interestingly, the medical literature provides evidence of a
convergence between diabetes, a metabolic disease, and potential mechanisms accounting for osteoporosis. Skeletal involvement in diabetes was first suggested more
than 80 years ago, prompted by radiological findings of retarded bone development
and bone atrophy in children with type 1 diabetes.2 In 2007, a systematic meta-analysis in women with type 2 diabetes reported that, although there was no significant
increase in vertebral or distal forearm fractures, hip fracture risk was elevated 1.7fold.3 Furthermore, it is now recognized that diabetes and hip fractures share common risk factors. Nevertheless, despite a large body of accumulated data on the
skeletal effects of diabetes, many questions remain unresolved, with biochemical
M
Maria Luisa Brandi, MD, PhD,
Metabolic Bone Diseases Unit,
Department of Internal Medicine,
University of Medicine,
Medical School, Viale Pieraccini 6,
50139 Florence, Italy
(e-mail: m.brandi@dmi.unifi.it)
364
Bone health and diabetes – Brandi
IN
B O N E H E A LT H
Ob-Rb
ARC
neurons
GTG-sensitive
neurons
Figure 1. Current
model of the leptindependent regulation
of bone mass.
Abbreviations: Adr웁2, 웁2adrenergic receptor gene;
ARC, arcuate nucleus;
ATF4, activating transcription factor 4; Cart, cocaineand amphetamine-regulated
transcript; GTG, gold thioglucose; Ob-Rb, b isoform
of brain leptin receptor;
PKA, protein kinase A;
RANKL, receptor activator
of nuclear factor-kappaB
ligand; SNS, sympathetic
nervous system.
Modified from reference 7:
Karsenty G. Cell Metab.
2006;4:341-348. © 2006,
Elsevier Ltd.
Cart
?
SNS
RANKL
Adipocyte
Adrβ2
Osteoclast
PKA
ATF4
+
–
Molecular
clock
Osteoblast
–
and imaging studies producing conflicting findings. This is
likely to be due in large part to the complex pathophysiology
of diabetes, the diversity of skeletal sites examined, the multitude of techniques used for measuring bone mass, and variations in the duration, severity, and treatment of diabetes in the
different studies. This paper reviews our current understanding of the pathogenetic bases of bone disease in diabetes.
Pathophysiology
N The biological relevance of bone remodeling
There is a constant turnover of bone through bone remodeling, via a biphasic process occurring throughout the skeleton over a period of approximately 3 months.4 It includes destruction (resorption) of preexisting bone, a function exerted
by a specialized bone-specific cell, the osteoclast, followed by
de novo bone formation, a function exerted by another bonespecific cell, the osteoblast. Normally, resorption and formation of bone occur not only sequentially, but in a balanced
manner in order to maintain bone mass nearly constant during most of adulthood. This qualifies bone remodeling as a
true homeostatic function controlled by cytokines acting locally and hormones acting systemically.
Maintenance of constant bone mass is the aspect of bone
remodeling we are most familiar with, because osteoporosis, the most frequent bone disorder, is a bone-remodeling
disease.5 Osteoporosis results from an increase in bone resorption exceeding bone formation.6 Bone remodeling can
be studied by means of biological markers in serum and
urine, or bone mineral density (BMD). BMD is a strong predictor of fracture risk, but bone mineral quantity is only one
component of bone strength, and various disorders, including diabetes, can be associated with poor bone quality.
Hypothalamus
Leptin
RANKL
+
Cyclin D
c-myc
The relatively recent observation of a convergence between
bone and energy homeostasis suggests that energy metabolism and bone mass are regulated by the same hormones,
such as leptin (Figure 1),7 adiponectin,8 neuropeptide Y,9 and
substance P.10 A remarkable feature of most types of hormonal regulation is that they are controlled by feedback loops,
such that the cells targeted by a hormone send signals influencing the hormone-producing cells. When applied to skeletal biology, the concept of feedback regulation suggests that
bone cells exert an endocrine function.
This was recently demonstrated by the finding that the skeleton exerts an endocrine regulation of glucose homeostasis
through the “secretion” of osteocalcin, one of the very few osteoblast-specific proteins, which improves glucose homeostasis by favoring β-cell proliferation and insulin secretion
(Figure 2, page 366).11 Teleologically, the proliferation function of osteocalcin may have arisen during evolution to maintain the size of the pancreatic islets constant in periods of food
deprivation.
N Bone phenotypes in type 1 and type 2 diabetes
Type 1 diabetes, also called insulin-dependent diabetes mellitus, is characterized by little or no insulin production and hyperglycemia. Improved glucose monitoring, insulin delivery methods, and pharmacologic treatments are increasing patient
lifespan. However, as a result, there is a parallel increase in the
risk of complications due to extended exposure to diabetes.
Attention has been recently focused on diabetic bone pathology, as type 1 diabetes was found to be clearly associated
with bone loss and suppressed bone formation. As reported
by McCabe comparing type 1 diabetic patients and healthy
age-matched subjects, it is estimated that more than 50%
365
B O N E H E A LT H
Pancreatic
beta cell
Figure 2. Regulation
of energy metabolism
by the skeleton.
Insulin
Active, uncarboxylated
osteocalcin produced in
osteoblasts is secreted into
serum and triggers insulin secretion in pancreatic 웁-cells.
Moreover, by increasing
adiponectin synthesis in
adipocytes, insulin sensitivity
is enhanced. Both processes contribute to metabolic
homeostasis. This pathway
is negatively regulated by the
Esp-encoded phosphatase
in osteoblasts, which inactivates osteocalcin by posttranslational γ -carboxylation.
Abbreviation: OST-PTP,
osteotesticular protein tyrosine phosphatase.
Karsenty G. Cell Metab.
2006;4:341-348. © 2006,
Elsevier Ltd.
’
Bone
osteoblast
IN
Insulin
secretion
Carboxylated
osteocalcin
Metabolic
homeostasis
Uncarboxylated
osteocalcin
’
OST-PTP
Insulin
sensitivity
Adiponectin
Adipocytes
of type 1 diabetic patients have bone loss and almost 20% of
patients aged 20 to 56 meet the criteria for osteoporosis.12
Quite logically in this connection, type 1 diabetes has been
shown to be a risk factor for delayed fracture healing.13 Bone
loss can begin as early as at onset of diabetes in children, but
there are reports of children with type 1 diabetes who do not
exhibit bone loss.14,15 Bone loss occurs predominantly in the
appendicular skeleton. A concern is that existing bone loss
in type 1 diabetic patients could compound the fracture risk
associated with conditions such as menopause and aging.
The mechanisms contributing to type 1 diabetic bone loss
are unknown, but several theories have been put forward.
Analysis of type 1 diabetic bone remodeling serum markers
suggests that bone turnover is unaltered or decreased, while
bone formation is decreased, as indicated by reduced serum
levels of osteocalcin and histomorphometric studies.16,17 The
potential contributors to type 1 diabetic bone phenotypes are
listed in Table I.
Type 2 diabetes, also called non–insulin-dependent diabetes
mellitus, develops when cells become resistant to insulin signaling, and accounts for more than 90% of diabetes cases.
Diet, obesity, and reduced physical activity are several of the
factors that are thought to contribute to the development of
type 2 diabetes. Available data concerning an association
between reduced BMD and type 2 diabetes are equivocal.
Type 2 diabetes mellitus in the literature has been reported to
be associated with increased,18 unchanged,19 or decreased20
BMD. However, most large-scale epidemiological studies indicate normal or above-normal BMD.21 Possible contributing
factors to the higher BMD of type 2 diabetes mellitus are listed in Table II.
366
Reduced osteoblast differentiation
Increased marrow adiposity
–
–
–
–
–
Reduced insulin signaling
Hyperglycemia
Adipokine and endocrine changes
Inflammation and cytokines
Hyperlipidemia
Table I. potential contributors of the bone phenotypes in type 1
diabetes mellitus.
– Obesity
– Hyperinsulinemia
– Increased androgen levels associated with obesity (in women)
Table II. Potential contributors of high BMD in type 2 diabetes
mellitus.
N Risk of fracture in type 1 and type 2 diabetes mellitus
The most convincing evidence that osteoporosis is a complication of diabetes mellitus comes from epidemiological studies that have shown an increased risk of fragility fractures.
Diabetes and hip fracture share common risk factors (eg, physical inactivity, advanced age); in contrast, obesity, a risk factor
for diabetes, is associated with a lower risk of fractures, and
any apparent modification in fracture risk by diabetes is likely
to reflect a confounding effect of these and other extraneous
factors.
Investigations into fracture risk in type 1 diabetes have yielded inconsistent results, with increased incidence of hip fracture being reported in some studies, but not in others.22-28 A
recent meta-analysis in patients with type 1 diabetes mellitus
reported that this population is at six- to sevenfold higher risk
of hip fracture than nondiabetic individuals.3 Cross-sectional
and prospective studies have shown type 1 diabetes to confer an increased risk of fragility fracture at other sites, in both
men and women.26,29,30
Even though a recent meta-analysis involving a total of 836 000
participants concluded that hip fracture risk was elevated 1.7fold in women with type 2 diabetes mellitus,3 some studies
have reported either no increase in hip fractures27,31 or risks restricted to patients with a higher duration of disease.22,32,33 The
reports of increased fracture risk are somewhat unexpected
because 2-dimensional areal BMD is normal or elevated in
persons with type 2 diabetes,21,34 and this implies that diabetic individuals are at decreased risk of fracture.
Moreover, the
O
meta-analysis found no significant increase in vertebral or distal forearm fractures in these patients.3 At present, there is no
clear explanation for this apparent contradiction. An increased
risk of falling in diabetic patients35 could account for the elevated hip fracture risk in the face of normal or elevated BMD.
A possible explanation for increased bone fragility in diabetes
mellitus is the accumulation of advanced glycation end products within bone collagen, leading to increased stiffness of
the collagen network.36 Increased blood glucose levels could
also have direct deleterious effects on bone cells,37 with consequences on bone biomechanical competence.38 Moreover,
adipose tissue (usually increased in type 2 diabetes mellitus)
produces cytokines, namely, adipokines, such as leptin, resistin, and adiponectin, which may negatively modulate BMD.39
Figure 3 depicts the potential mechanisms contributing to
fracture susceptibility in diabetes mellitus.
T1DM
Insulin
Amylin
Oral antidiabetic drugs are commonly used to improve glycemic control, but there are concerns that some may increase
the risk of cardiovascular events.40 Moreover, several epidemiological studies have investigated the effects of antihyperglycemic treatment on fracture risk in diabetes. In the largest
of these, in which all individuals diagnosed with fracture in
Denmark in 2000 were matched with controls, it was reported that metformin and sulfonylurea treatments were associated with reduced incidences of fracture, while insulin was
associated with a nonsignificant trend toward reduced risk of
hip, forearm, and spine fractures.26
Conversely, recent evidence suggests that the thiazolidinediones, first introduced for the treatment of type 2 diabetes
mellitus in 1999, may affect the skeleton, with an increase
in fracture risk in women randomized to rosiglitazone versus
those randomized to metformin or glyburide monotherapy.41
In this study, fracture events were not increased in men and
did not increase with time.41 These results were also confirmed
in preliminary data from another study.42
Interestingly, pioglitazone, the other currently available thiazolidinedione, may have similar skeletal effects, with the majority of fractures occurring at nonvertebral sites, including the
lower limb and distal upper limb.43
As these findings support the hypothesis of a class effect of
thiazolidinediones in increasing fracture risk in women with
type 2 diabetes mellitus, letters to health care providers have
been issued by the manufacturers.44,45 However, doubts still
–
Adipocytes
+
’
–
IGF-1
Osteoblast
?
Bone
Bone quality
–
Fractures
+
Osteoclast
+
Adipokines
Glucose
High risk
of falls
RANKL
RANK
Retinopathy
+
™
Cardiovascular
disease
+
Glucose
Neuropathy
T1DM & T2DM
B O N E H E A LT H
Effects of antidiabetic agents on bone
T2DM
Activated
T cells
IN
Type 1 collagen
Figure 3. Potential
mechanisms contributing to low bone
mass and
increased fracture
susceptibility in
diabetes mellitus.
The figure represents a
suggested model of potential deleterious effects of
diabetes on bone based
on in vitro findings, animal
studies, and observational
human data.
Abbreviations: IGF-1, insulin-like growth factor–1;
RANK, receptor activator
of nuclear factor-kappaB;
RANKL, receptor activator
of nuclear factor-kappaB
ligand; T1DM, type 1 diabetes mellitus; T2DM,
type 2 diabetes mellitus.
Modified from reference
34: Hofbauer et al. J Bone
Miner Res. 2007;22:13171328. © 2007, American
Society for Bone and Mineral Research.
367
IN
B O N E H E A LT H
Figure 4. Potential mechanisms for bone fracture with thiazolidinediones (TZDs).
Mesenchymal
progenitor cells
in bone marrow
RunT2
Abbreviations: PPAR-γ , peroxisome proliferator-activated
receptor-gamma; Runx2, runt-related transcription factor-2.
Modified from reference 21: Adami. Curr Med Res Opin.
2009;5:1057-1072. © 2009, Informa UK Ltd.
TZDs
PPAR-γ
Osteoblasts
(bone-forming cells)
exist about the clinical relevance of this phenomenon, and
more studies are needed to address a number of still pending questions,21,46 such as the precise mechanism of action
of these agents (Figure 4).
Physicians should carefully check for the existence of risk factors for osteoporosis and fractures in their patients before putting them on thiazolidinedione treatment, and an adequate
clinical follow-up of treated patients is strongly recommended.
Future prospects
The prevalence of diabetes mellitus is increasing rapidly in the
population, with the implication that adverse outcomes of the
condition are likely to grow in importance as well. Considerable concern has been expressed about fracture risk in these
patients. Although fractures may now be prevented thanks
to the availability of effective treatments, no clear rationale ex-
Adipocytes
(fat cells)
ists for treating patients with type 2 diabetes
with antifracture agents able to increase
BMD, and our knowledge base is not strong
enough for a more effectively tailored prophylaxis to be designed for this group. Additional research is needed to better define
the determinants of bone strength in diabetic individuals, including the abnormal properties of bone
that might respond to treatment of diabetes itself. Conversely,
the differences between type 1-diabetic- and age-associated
bone loss stress the importance of selecting condition-specific individualized treatments for osteoporosis. Because in
type 1 diabetes the bone defect results predominantly from a
decrease in bone formation, anabolic therapies appear likely
to be the most effective treatment.
Future studies should contribute to a more thorough understanding of the mechanisms of diabetic bone loss, enabling
the development of newer and more effective drugs. Optimizing therapies that prevent bone loss or restore bone density
will allow diabetic patients to live longer, with strong healthy
bones. I
This work was supported by FIRMO Fondazione Raffaella Becagli to MLB.
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Keywords: osteoporosis; fracture risk; bone mineral density; diabetes; postmenopause; parathyroid hormone; leptin;
thiazolidinedione
SANTÉ
OSSEUSE ET DIABÈTE
Les liens entre diabète et santé osseuse font débat depuis longtemps. Diabètes de type 1 et de type 2 sont tous
deux associés à une augmentation du risque de fracture, la densité minérale osseuse étant diminuée dans le diabète
de type 1 et augmentée dans le diabète de type 2. L’insuline présente un effet anabolique sur l’os. Ses effets sur la
masse osseuse s’exercent de façon qualitativement différentes dans le diabète de type 1 et de type 2, en rapport
avec les profils sécrétoires insuliniques opposés qu’on y observe (hypo-insulinémie vs hyperinsulinémie). L’existence
d’un risque de fracture élevé dans le diabète de type 2 malgré l’hyperinsulinémie sous-jacente laisse présager de différences de qualité osseuse dans les diabètes de type 1 et 2. Celles-ci s’expliqueraient par une augmentation de la
perte en calcium urinaire liée à l’élévation de la glycémie, conduisant à un équilibre calcique négatif. Le rôle de la résistance à l’hormone parathyroïdienne observée dans le diabète et ses effets sur le calcium et le renouvellement osseux sont également évoqués. En outre, la glycosylation du collagène peut altérer les caractéristiques biomécaniques
osseuses. Les chutes associées aux comorbidités liées au diabète sont une autre cause possible de fractures provoquées par des traumatismes de faible intensité. La diminution du risque de fractures repose essentiellement sur
un contrôle glycémique adapté et la prévention des complications diabétiques, en notant que les thiazolidinediones
augmentent le risque de fracture chez les femmes ménopausées diabétiques de type 2. Pour conclure, la santé osseuse est une question importante dans le diabète. Les thiazolidinediones doivent être prescrites avec prudence aux
femmes ménopausées ayant une faible masse osseuse et aux patientes ayant des antécédents de fracture de fragilité. Cet article passe en revue l’état actuel de nos connaissances sur les liens entre diabète et santé osseuse.
369
‘‘
The increase in SFRP proteins
in areas of severe vascular calcification may be indicative of a wall
artery–defensive mechanism aimed
at attenuating mineralization in the
calcified aortic wall. These proteins
may be able to reach the bone, and
act as they do in the vessels to decrease mineralization, resulting in
reduction of bone mass. This is a
challenging hypothesis that could
help explain the findings reported
in the most severe cases of progressive vascular calcification associated with low bone mass and
a greater percentage of bone fractures.”
IN
B O N E H E A LT H
Bone and vascular health
and the kidney
by J. B. Cannata-Andía,
P. R o m á n G a rc í a , I . C a b e z a s - R o d r i g u e z ,
a n d M . R o d r i g u e z - G a rc í a , S p a i n
I
L
Jorge B. CANNATA-ANDÍA
MD, PhD
Pablo ROMÁN GARCÍA, BSc
Ivan CABEZAS-RODRIGUEZ, MD
Minerva RODRIGUEZ-GARCÍA
MD, PhD
Bone and Mineral Research Unit
Hospital Universitario Central
de Asturias, Instituto Reina Sofía
de Investigación, REDinREN del
ISCIII, Universidad de Oviedo
Oviedo, Asturias, SPAIN
n patients with progressive chronic kidney disease (CKD), the homeostatic mechanisms regulating calcium and phosphate metabolism suffer important changes, resulting in low serum levels of calcitriol and calcium and
phosphorous retention. The regulatory mechanisms fail and several chronic
kidney disease mineral bone disorders (CKD-MBD) occur, including bone disease, vascular calcifications, cardiovascular disorders, bone fragility fractures,
and reduced survival. Vascular calcification, bone loss, and increased fracture
risk are severe disorders associated with aging in chronic CKD, but also generally speaking. Several epidemiological studies have shown the relationship
between impaired bone metabolism, vascular calcification, and increased mortality. Recent data suggest this association may be not just a consequence of
aging. The frequent occurrence of severe cases of vascular calcification together with low bone activity and osteoporosis suggests direct biological links may
exist between bone and the vascular system. New challenging experimental
data suggest that once severe vascular calcifications set in, vessels may develop a mechanism to diminish vascular mineralization in the arterial wall, and
that this defensive mechanism may have a negative impact that favors the reduction of bone mass.
n healthy individuals, the kidneys regulate calcium and phosphorus homeostasis
through active tubular mechanisms. Hormones and factors that contribute to kidney regulation of calcium and phosphorus include 1,25-dihydroxyvitamin D (1,25
[OH]2D or calcitriol), parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF23). In patients with progressive chronic kidney disease (CKD), the normal homeostatic mechanisms are challenged, leading to important compensatory changes in serum
levels of calcium, phosphorus, calcitriol, FGF-23, and PTH. All these changes lead in
part to several manifestations that for almost 60 years have been known as “renal
osteodystrophy.”1 In addition, clinical, epidemiological, and experimental data have
identified a clear association between the aforementioned changes in biochemical
markers and some relevant outcomes such as vascular calcification, myocardial dysfunction, and mortality. As a result, a new term—chronic kidney disease–mineral bone
disorder (CKD-MBD)—has been recently coined to encompass all these disorders.2
I
Prof Jorge B. Cannata-Andía,
Bone and Mineral Research Unit,
Instituto Reina Sofí de Investigación,
Hospital Universitario Central de
Asturias, C/ Julián Clavería s/n,
33006 Oviedo, Asturias, Spain
(e-mail: metoseo@hca.es)
370
Clinical impact and pathogenesis of mineral and bone disorders
The calcium, phosphorus, vitamin D, PTH, and FGF23 axis is closely regulated and
interrelated. Several of the compensatory variations in the aforementioned factors
Bone and vascular health and the kidney – Cannata-Andía and others
IN
B O N E H E A LT H
take place at the same time under the control of complex feedback mechanisms.3-5 The progression of CKD leads to a decrease in active renal mass and then to a reduction in 1-alpha
hydroxylase in the kidney, which in turn results in low levels of
calcitriol, the physiological active form of vitamin D, impairing
calcium absorption in the intestine and favoring the reduction
in serum calcium. As a result, the decreases in serum calcium
stimulate parathyroid hormone (PTH) synthesis and release,
increasing bone turnover, bone resorption, and the stimulation
of 1-alpha hydroxylase. All these mechanisms lead to compensatory increases in serum calcium.
Many of the aforementioned abnormalities and others beyond the scope of this review end up not only inducing several varieties of bone disease, but also vascular calcifications,
cardiovascular disorders, bone fragility fractures, and a higher mortality risk. The recently coined term CKD-MBD encompasses all these mineral and bone metabolism disorders.2-12
As CKD is subdivided according to the degree of renal function into five stages, it is important to stress that marked differences exist between the initial and final periods of CKD.
In addition, the progressive reduction in renal function impairs
phosphorus excretion, leading to increases in serum phosphorus, which stimulates the synthesis of both FGF23 and
PTH. Thee two factors work in the same direction, increasing
urinary phosphorus excretion. However, it is important to
stress that, regarding vitamin D metabolism, the response is
more complex, and FGF23 and PTH work in opposite directions: regarding calcitriol synthesis, FGF23 inhibits 1-alpha hydroxylase, reducing calcitriol synthesis, whereas PTH stimulates it.6-8 As renal function decreases, all these complex and
tightly interrelated mechanisms of parathyroid gland regulation become insufficient and fail to adequately control parathyroid gland function and calcium and phosphorus homeostasis.
The predisposition of CKD patients toward the development
of vascular calcification was mentioned for the first time in
the 19th century; since then, many studies have looked into
this issue. Vascular calcification can be classified into three
types according to the size and structure of the arteries: elastic or large-caliber arteries, muscular or medium-caliber arteries, and small-caliber arteries.13
As a result, low serum levels of calcitriol and calcium, coupled
with a trend toward phosphorus retention, prevail in the more
advanced stages of CKD.3-5 Furthermore, in CKD stage 5D,
severe forms of secondary hyperparathyroidism are frequently found, with diffuse and nodular parathyroid hyperplasia, as
well as clinically relevant monoclonal growth with reduction
in the expression of the vitamin D and calcium-sensing receptors (VDR and CaSR).9-11 These changes are the main culprits for the poor response of the parathyroid glands to the
increments in serum calcium and active vitamin D therapy. Finally, due to the lack of adequate parathyroid gland control,
there is a clear trend toward autonomous parathyroid gland
behavior (tertiary hyperparathyroidism), which frequently requires surgical removal of the glands.
SELECTED
CaSR
CKD
CKD-MBD
EVOS
FGF
GFR
MBD
PTH
SFRP
VDR
calcium sensing receptor
chronic kidney disease
chronic kidney disease–mineral bone disorder
European Vertebral Osteoporosis Study
fibroblast growth factor
glomerular filtration rate
mineral bone disorder
parathyroid hormone
secreted frizzled-related protein
vitamin D receptor
Clinical impact and pathogenesis of vascular
calcification
Elastic or large-caliber arteries show a relatively thin wall in
proportion to their diameter, and the tunica media contains
more elastic fibers than smooth muscle fibers. Muscular or
medium-caliber arteries contain a greater proportion of smooth
muscle fibers than elastic fibers in the tunica media; finally,
small-caliber arteries contain only smooth muscle fibers in the
tunica media. The classic description of arterial calcification
specifies that it may occur in two locations: the intima and
the media layers.14 Nevertheless, this classic concept is not
fully accepted by all authors.15,16
Intimal calcification begins and progresses under the influence of both genetic and lifestyle-related circumstances. It is
associated with a sequence of atherosclerotic events such as
endothelial dysfunction, intimal edema, lipid cell formation,
plaque rupture, and formation of the thrombus.17 They have a
patchy distribution along the length of the artery and cause
local stenoses and occlusions. They are associated with several risk factors such as inflammation, alterations in lipid metabolism, obesity, hypertension, diabetes, smoking, and a family history of heart disease.
Media calcification occurs in the elastic lamina of large-caliber
and medium-to-small-sized arteries; it is either independent of
atherosclerosis or associated with it. X-ray imaging shows them
as railway tracks. They are commonly found in the aorta, but
also appear in arteries that are less likely to develop atherosclerosis, such as the visceral, abdominal, limb, and femoral
arteries.18 Calcification of the media increases linearly with
age and is frequently found in CKD, vitamin D metabolism disturbances, and diabetes, among other situations.19-22
Table I (page 372) summarizes the most prevalent traditional,
uremia-related, and nontraditional risk factors for vascular calcification in CKD patients. Like in the general population, the
371
IN
traditional cardiovascular risk factors, present in a large proportion of patients with CKD, are responsible to a great extent for the progression of vascular calcification. Among these,
nontraditional cardiovascular risk factors, including uremiarelated risk factors, time on dialysis, and hyperphosphatemia,
are the risk factors more strongly associated with increased
vascular calcification and mortality. Elevated C-reactive protein (CRP) and interleukin (IL)-6, as expressions of chronic inflammation, have been also frequently associated with vascular calcification.17
N Traditional risk factors
–
–
–
–
–
–
Hypertension
Dyslipidemia
Diabetes mellitus
Smoking
Older age
Family history of premature coronary heart disease
N Uremia-related and nontraditional risk factors
–
–
–
–
–
–
–
–
–
–
–
Time on dialysis
Hyperphosphatemia
High calcium 쎹 phosphorus product
Hyperparathyroidism and hypoparathyroidism
High dosage of vitamin D metabolites
Low fetuin-A
Anemia
Poor nutrition (low albumin)
Chronic inflammation (CRP, IL-1, IL-6, TNFα)
Hyperhomocysteinemia
Advanced glycated end products
Table I. Risk factors associated with vascular calcification in chronic
kidney disease patients.
Abbreviations: CRP, C reactive protein; IL-1, interleukin 1 ; IL-6, interleukin 6;
TNF움, tumoral necrosis factor–움.
Modified from reference 13: Román-García et al. Med Prin Pract. 2010. In
press. © 2010, S. Karger AG, Basel.
CKD is associated with a high prevalence of vascular calcifications,18,22-25 which leads to a high prevalence of cardiovascular disease and reduced life expectancy.26 A high prevalence of vascular calcifications has been also reported in the
early stages of CKD, where it has been shown that 40% of
patients (CKD stages 2 to 4, mean glomerular filtration rate
[GFR] 33 mL/min) have calcification of the coronary arteries,
compared with 13% of control subjects (similar age, with normal renal function).24 However, vascular calcification is not only
seen in CKD patients; a subgroup of randomly selected European subjects older than 50 years (European Vertebral Osteoporosis Study [EVOS]) showed aortic calcification in 54.2%
of men and 43.1% of women.20
B O N E H E A LT H
nal replacement therapy has been also positively associated with vascular calcification, mainly in medium-caliber arteries; in fact, each year on renal replacement therapy increased
the risk of vascular calcifications by 15%.27 In addition, the
number and severity of vascular calcifications have been positively associated with mortality, both in the general population
and in CKD patients.20,22,26 In CKD, an up to 10 to 30 times
higher mortality than in the general population has been reported.28 Women on hemodialysis showed an increased risk
of severe aortic calcifications compared with women from the
general population, probably due to a combination of atherosclerosis and arteriosclerosis.22
Until recently, vascular calcification was considered the result
of a simple precipitation of circulating calcium and phosphate.
However, the mechanism by which the process of vascular
calcification is produced is complex; it does not consist in a
simple precipitation of calcium and phosphate; on the contrary, it is an active and regulated process in which, step by
step, vascular smooth cells undergo apoptosis and vesicle
formation, changing the phenotype of smooth vascular cells
into osteoblast-like cells. Vascular calcification can be considered as the result of the lack of the physiological equilibrium between the promoters and inhibitors of the calcification process, in which several uremic factors—phosphorus topping
the list—play a key role.
In humans and mammals, serum concentrations of calcium
and phosphate exceed the calcium 쎹 phosphate solubility
product; however, no intravessel precipitation takes place.
This fact stresses the important role played by physiological
inhibitors of calcification, which counterbalance the well-known
effect of calcification promoters. The list of promoters and inhibitors of the calcification process has increased in recent
years.29-32 The main interest has focused on the “modifiable
promoters of calcification” with the aim of developing strategies to minimize them. Some have been associated with the
risk of mortality, such as phosphorus, calcium, vitamin D, PTH,
dyslipidemia, inflammation, nutrition, CRP, homocysteine, fibrinogen, and albumin. Among these, serum phosphorus
needs to be highlighted as one of the more important risk factors, which is strongly associated with increased vascular calcifications and mortality.29-34
In a recent study, the prevalence of aortic calcification was
higher in hemodialysis patients (79%) than in a random-based
and age-matched general population (37.5%).22 Time on re-
Today, the fact that elevated phosphorus is a key factor in
the differentiation of smooth vascular cells into osteoblast-like
cells, triggering signals that will stop the promotion of mineralization, is well accepted.30,32,35 In vitro experiments have
demonstrated that elevated phosphorus levels act directly on
the transcription of bone-related genes, such as Cbfa-1 and
osteocalcin, resulting in the activation of several osteogenic
pathways.35,36 In addition, phosphorus is able to act as a secondary intracellular messenger activating several molecular
pathways involved in bone formation. Other important factors from this list include the following most studied mineral-
372
ization promoters and inhibitors: BMPs (bone morphogenic
proteins), an important family of proteins involved in bone formation and vascular calcifications; Cbfa-1; the Msx-Wnt axis;
vitamin D; calcium; phosphorus; tumor necrosis factor–α
(TNFα); oxidative stress; matrix GLA protein (MGP); osteoprotegerin (OPG); fetuin A; pyrophosphates; and bisphosphonates.13,29-31,36,37
Links between bone metabolism and vascular
calcification
Bone loss, increased fracture risk, and vascular calcification are
severe disorders associated with aging in CKD patients and
the general population.19,20,22,38 Furthermore, several epidemiological studies suggest a relationship between impaired bone
metabolism, vascular calcification, and increased mortality.
The pathogenetic factors linking bone fragility with vascular
calcification are not fully understood, but this relationship has
been known for almost 20 years, when for the first time a significant inverse correlation between osteoporosis and aortic
calcification was reported.39 However, during the following
years, this association was probably underestimated because
osteoporosis and vascular calcification were considered nonmodifiable age-dependent disorders. Nevertheless, recent data
suggest this association may not be just a consequence of
aging.20,22 The role of aging cannot be completely dismissed,
but the clinical coincidence of vascular calcifications with low
bone activity and osteoporosis suggests there might be direct biological links between arteriosclerosis and osteoporosis. In fact, osteoporosis and vascular calcifications are influenced by several common risk factors such as inflammation,
dyslipidemia, oxidative stress, as well as estrogen, vitamin D,
and K deficiencies. Some population-based longitudinal studies have demonstrated an association between osteoporosis and vascular calcification or arterial stiffness.25 A largecohort study published in 2004 showed that the degree of
vascular calcification inversely correlated with bone mineral
A
1.0
In agreement with previous results, a recent study showed
that after 4 years of follow-up, individuals who showed the
most severe vascular calcification or the greatest progression
of vascular calcification were those who showed not only the
lowest bone mass, but also the highest incidence of new osteoporotic fractures.20 In addition, as expected, bone mass
decreased and nontraumatic vertebral fractures increased in
both sexes, as age increased. Also, serum levels of 25(OH)D3
inversely correlated with vascular calcification and bone mass,
and positively correlated with the prevalence of secondary
hyperparathyroidism and nontraumatic vertebral fractures.
The progression of aortic vascular calcifications (new calcifications or increase in the size of preexisting calcifications)
was significantly higher in patients who had a previous aortic calcification regardless of severity (mild, moderate, severe;
P<0.001, age-adjusted). Interestingly, after 4 years of followup, mortality was also significantly and positively associated
with the rate of severe vascular calcifications in men and with
the rate of nontraumatic bone fractures in women.20
Similar results have also been published about patients on hemodialysis, which showed that vascular calcification in some
areas (eg, the large and medium-caliber arteries [utero-sperm],
femoral, iliac; hands [digital, palm arch, radial]), was associated with an increased risk of vertebral fractures.22 In addition,
comparing findings from hemodialysis patients with those of
the EVOS study (age- and sex-matched population), the risk
of aortic calcification was significantly higher in hemodialysis
patients (men: odds ratio [OR], 7.7; women: OR, 9.0). In addition, women on hemodialysis with severe vascular calcifications (any localization), as well as women with vertebral
fractures, showed a high mortality risk after all adjustments
including age (Figure 1). Similarly, women who died during the
Vertebral fractures
1.0
No
No
0.8
Yes
0.6
P=0.036
Survival
Survival
0.8
0.4
0.0
0.0
1
1.5
2
P=0.012
0.4
0.2
0.5
Yes
0.6
0.2
0
B O N E H E A LT H
density. Furthermore, in part of the same cohort followed up
for 2 years, the progression of vascular calcification inversely
correlated with the rate of bone loss.40
B
Severe vascular calcifications
IN
2.5
Years of follow-up
0
0.5
1
1.5
2
Years of follow-up
2.5
Figure 1.
Kaplan-Meyer
analysis in women
(A) with prevalent
severe vascular
calcifications at
any vascular site,
(B) with prevalent
vertebral fractures.
Modified from reference 22: RodriguezGarcia et al. Nephrol
Dial Transplant. 2009;
24(1):239-246.
© 2009, European
Renal Association/
European Dialysis and
Transplant Association.
373
IN
2-year follow-up period had a prevalence of vertebral fractures 3 times higher (58.8% vs 19.3%) than those women
who were alive at the end of the observation period (adjusted for the same variables) (Figure 2).
Age and diabetes were strongly associated with vascular calcifications, but other well-know modifiable risk factors such
as serum PTH, Ca, and P levels, vitamin D, calcium-based
phosphate binders intake, dyslipidemia, hypertension, and
smoking were not associated with the prevalence, severity, or
progression of vascular calcification. If we combine the clinic and epidemiologic data, the association between serum
25(OH)D3 levels, vascular calcification, bone mass, and nontraumatic bone fractures, we may speculate that all of these
could be linked by causes other than aging.20,25,26,41
Vertebral fractures (%)
100
Dead
Alive
B O N E H E A LT H
that the prevalence and progression of vascular calcification
are related to bone mass, bone turnover and mineralization,
bone loss, and osteoporotic fragility fractures.
Likely negative effect of vascular calcification
on bone health: a challenging hypothesis for
further research
An intriguing question is whether the presence of vascular calcification can have a further negative impact on bone metabolism. In a recent study, rats developing severe vascular calcification after a phosphorus load showed no increase in bone
mass at any of the sites studied after 20 weeks.34 In contrast,
rats with no phosphorus load develop no vascular calcification. Furthermore, bone mass increased during the study period as expected. Microarray analysis of the aortas with severe
vascular calcification evidenced overexpression of secreted
frizzled-related proteins (SFRPs). It is well-known that SFRPs
are inhibitors of the canonical Wnt signaling pathway, which
is actively involved in bone formation and vascular calcification.34,45,46
80
P<0.006
60
58.8
(33.82)
40
20
17.6
23
19.3
(4.43)
(13.37)
(7.37)
0
Men
Women
Figure 2. Effect of vertebral fractures on the risk for mortality in
men and women who were on hemodialysis after a 2-year followup period.
Modified from reference 19: Cannata-Andia et al. J Am Soc Nephrol. 2006;17
(12 suppl 3):S267-S273. © 2006, American Society of Nephrology.
The increase in SFRPs in areas of severe vascular calcification may be indicative of a wall artery–defensive mechanism
triggered to block the activation of the Wnt pathway, aimed
at attenuating mineralization in the calcified aortic wall. Since
SFRPs are secreted proteins, they can act not only locally on
the artery wall to reduce the mineralization, but may be able
to reach the bone, where they could act as they do in the vessels to decrease mineralization, resulting in reduction of bone
mass. This is a challenging feedback hypothesis that could
help explain the findings reported in the clinical and epidemiological studies discussed above, in which the most severe
cases of progressive vascular calcification were associated
with low bone mass and a greater percentage of bone fractures.
The relationship between vascular calcification and low bone
turnover has also been assessed by histomorphometry in hemodialysis patients.25 A negative relationship between low
bone turnover and the degree of vascular calcification has
been found.41-43 An inverse relationship between coronary calcification and vascular stiffness with mineralized bone volume has been recently published.42 Nevertheless, despite the
weight of the evidence, the relationship between low bone
turnover and vascular calcification is still a matter of debate.
A recent publication found that vascular calcification was not
influenced by bone turnover when a multivariate analysis was
performed,43 even though a high percentage of patients with
high bone turnover were included in this study. It is known
that high PTH levels are another important pathogenetic factor positively associated with vascular calcification. In fact, it
has been reported that correction of the balance in bone turnover, whether the latter was high or low, protects against the
progression of vascular calcification.44 In any event, overall, the
sum of epidemiological and clinical studies strongly suggests
In summary, in both the general and CKD populations, vascular calcification and its severity seems to correlate inversely related with bone mass, with a resultant increase in bone fractures. In addition, the increase in vascular calcification and
bone fractures is associated with reduced survival. Interestingly, once vascular calcifications appear and progress, arteries
may develop a defensive mechanism aimed at attenuating or
regressing vascular mineralization of the arterial wall, and this
in turn may exert a negative impact on bone health. I
374
Part of the work presented in this review was supported by Fondo de
Investigaciones Sanitarias (FIS 04/1567, 07/0893 and 08/90136), Fundación para el Fomento en Asturias de la Investigación Científica aplicada
Y Técnica (FICYT I30P06P and IB 05-060), Instituto de Salud Carlos III
(Retic-RD06), Red Investigación Renal (16/06), Fondo de Desarrollo Regional (FEDER), Instituto Reina Sofía de Investigación and Fundación
Renal Íñigo Álvarez de Toledo. We also thank Marino Santirso for the
lenguaje review. Pablo Román-García is supported by Fundación para
el Fomento en Asturias de la Investigación Científica aplicada Y Técnica
(FICYT), Spain. Iván Cabezas-Rodriguez is supported by the Rio Hortega
program, Instituto de Salud Carlos III, Spain.
IN
B O N E H E A LT H
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35. Moe SM, Chen NX. Pathophysiology of vascular calcification in chronic kidney
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37. Hruska KA, Mathew S, Saab G. Bone morphogenetic proteins in vascular calcification. Circ Res. 2005;97(2):105-114.
38. Goldsmith D, Ritz E, Covic A. Vascular calcification: a stiff challenge for the
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aorta. Bone Miner. 1992;19(2):185-194.
40. Schulz E, Arfai K, Liu X, Sayre J, Gilsanz V. Aortic calcification and the risk of
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42. Adragao T, Herberth J, Monier-Faugere MC, et al. Low bone volume—a risk
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43. Coen G, Ballanti P, Mantella D, et al. Bone turnover, osteopenia and vascular
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Keywords: bone; vascular calcification; osteoporosis; bone density; bone fracture; low bone mass; bone disease; chronic
kidney disease; mineral bone disorder
375
SANTÉ
IN
B O N E H E A LT H
OSSEUSE ET VASCULAIRE ET REIN
Chez les patients ayant une insuffisance rénale chronique progressive (IRC), les mécanismes homéostatiques régulant le métabolisme phosphocalcique subissent des modifications importantes, conduisant à de faibles concentrations sériques de calcitriol et de calcium et à une rétention de phosphore. L’IRC altère les mécanismes de régulation qui deviennent inefficaces, favorisant ainsi l’apparition de divers troubles minéraux à l’origine de pathologies
osseuses, de calcifications vasculaires, de troubles cardio-vasculaires, de fractures osseuses de fragilité, avec comme
conséquence un effet péjoratif sur la durée de vie. Les calcifications vasculaires, la perte osseuse et l’augmentation
du risque de fracture sont des troubles sévères associés au vieillissement, tant dans le contexte de l’IRC que de façon générale. Plusieurs études épidémiologiques ont montré un lien entre l’altération du métabolisme osseux, les
calcifications vasculaire et l’augmentation de la mortalité. Des données récentes suggèrent que cette association
n’est pas seulement une conséquence du vieillissement. La fréquence de cas sévères de calcifications vasculaires
associés à une faible activité osseuse et à l’ostéoporose laisse supposer l’existence de liens biologiques directs
entre le tissu osseux et le système vasculaire. Selon des données expérimentales récentes, le développement de
calcifications vasculaires graves entraînerait l’apparition de mécanismes de défense vasculaires visant à diminuer la
minéralisation vasculaire de la paroi artérielle, et ces mêmes mécanismes auraient un effet négatif favorisant la réduction de la masse osseuse.
376
‘‘
There is a positive association between areal BMD and physical activity.… An increase in peak
bone mass of 10% during the early stages of puberty would delay
the onset of osteoporosis by 13
years, suggesting that this period
of life is the most important one
for ensuring prevention of osteoporosis later in life…. In the elderly, whole-body vibration training
may be efficient in improving bone
mass and quality, as well as posture, but its use for therapeutic
purposes is far from being standardized.”
IN
B O N E H E A LT H
Physical activity
and bone quality
b y L . V i c o , Fra n c e
P
Laurence VICO, PhD
Université de Lyon
Saint-Etienne and
INSERM U890/IFR143
Saint-Etienne, FRANCE
hysical exercise acts directly on bone through mechanical stress, and
indirectly by changes in cardiovascular, ventilatory, metabolic, and hormonal parameters. Studies in athletes show that activities such as running, performing gymnastics, and weight lifting induce bone gain, whereas
cycling and swimming are poorly osteogenic. Bone gain is mostly observed
in the parts of the body involved in the exercise. Failing to continue exercising during adulthood could be detrimental to bone gain. In the early stages of
puberty, exercising increases bone mass, whereas in postmenopausal women
and in the elderly, exercise does not always provide bone gain. Nevertheless,
it may prevent osteopenia and improve muscle tone, cardiovascular function,
and balance, thus limiting the risk of falling. As is the case for some young
people, too much training can be harmful, as evidenced by cortical thinning
in older cyclists who train more than 6 hours per week. This is evidence of a
nonlinear effect of exercise on the skeleton. High-impact exercises are hardly applicable to fragile subjects. Whole-body vibrations (WBV) may have osteogenic potential. In animal models of bone loss, WBV improves bone mass
and quality. In humans, certain studies show a potential benefit of WBV with
regard to muscle, bone, and posture. The therapeutic use of WBV is not standardized, and the impact and scope of application still needs to be defined in
terms of frequency, amplitude, duration, etc. This will require tailoring WBV to
the characteristics of the users and assessing its effect on the whole body as
well as on individual compartments (cartilage, peripheral circulation, tendons).
s early as 1892, Wolff1 suggested that the distribution of mechanical stress
at the tissue level determines bone architecture. In 1971, Thompson2 and
Frost3 introduced the concept of adaptation of skeletal tissue to stress,
through regulation of bone cell populations. Exposure to stress causes the tissue
to deform, resulting in local alterations designated as microstrains (10 000 microstrain (µε)=1% change in length, or 1 strain (ε)=100%).
A
Laurence Vico, PhD, INSERM U890,
Faculté de Médecine,
42 rue Ambroise Paré
42023 Saint-Etienne CEDEX 2
(e-mail: vico@univ-st-etienne.fr)
Physical activity and bone quality – Vico
Moreover, it appears that the capacity of bone to adapt to mechanical stress occurs
during dynamic stress (cyclic), whereas static stress entails no tissue response.4
These mechanical signals act on the bone cells themselves, which, through a
cascade of reactions starting from the extracellular matrix, transform the mechanical signal into a biological response. This phenomenon is known as mechanotransduction.
377
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B O N E H E A LT H
Mechanoadaptation of the bone—tissue support
N Mechanotransduction: in vitro studies
Bone cells, particularly those of osteoblastic lineage, are the
most studied cells. This lineage comprises mesenchymal precursor cells to osteocytes, which is the final stage of differentiation, and represents 90% of bone cells. Understanding
the mechanotransduction of all these stages is crucial: in precursors, it can guide their commitment to osteoblastogenesis at the expense of adipogenesis5; in osteoblasts, it affects
the physicochemical properties of the newly synthesized matrix6; and finally in osteocytes, it coordinates bone remodeling.7
One of the major cellular components of mechanotransduction is the cytoskeleton. Indeed, it is an intracellular cable network comprising microtubules that are resistant to contractile strains of actin filaments and intermediate filaments that
stabilize microtubules and microfilaments of actin.
This compression-tension network physically links with the extracellular matrix through transmembrane receptors (particularly integrins, mechanical transfer areas). Intracellular tension forces are therefore able, through the connected system,
to balance out the forces of the extracellular matrix (and vice
versa). This regulatory mechanism influences and integrates
the effects of biochemical factors, by using or crossing these
same regulatory pathways.
The model that takes into account all these forces, which,
separately or jointly, affect the fate and/or activity of the bone
cells, is referred to as the tensegrity (= tensional integrity) model (Figure 1).
N At tissue level
The tensegrity model also applies to a musculoskeletal system in which the bones are compressed under the effect of
gravity (weight, load) and under tension caused by the action
of muscles, tendons, and ligaments. Such hierarchical structures can explain the mechanical transmission of information and coordinated response of an organ to a stimulus by
mechanical coupling.
In bone, osteocytes undergo deformation variations resulting
from movements that give rise to compression, tension, and
torsion forces. Without functional osteocytes (targeted deletions) bone cannot adapt to changes in mechanical stress. In
addition, pressure gradients caused by the tissue as it deforms create a flow of extracellular fluid around the osteoSELECTED
BMD
DXA
OPG
RANKL
WBV
osteoprotegerin
receptor activator of nuclear factor kappaB ligand
whole-body vibrations
378
Microtubule
Actin stress
fiber
Focal contact
Extracellular matrix
Figure 1. Cellular mechanotransduction.
The adherent cell stabilizes to its support thanks to equilibrium between forces
of tension and compression. Microtubules are at the center of a network of compressive stress exerted by actin filaments. The focal contacts physically link the
inner cytoskeleton to extracellular matrix. If the matrix changes its physicochemical
properties or if it is subjected to deformation, the forces are re-balancing (in-out
and out-in arrow). The focal contacts are also necessary to activate many intracellular signaling pathways where mechanical effects are coupled with other
biochemical effects (responses to growth factors, for example).
cytes. However, mechanical and shear forces are not the only
phenomena that occur: the deformation creates piezoelectric effects and the fluid causes the formation of electric fields
called “streaming potentials.”8 Each of these three phenomena plays a role in mechanotransduction.
The resistance of bone to stress, to which it is constantly subjected (posture, physical activity), is determined both by its
macroscopic characteristics (shape, size, structure) and a series of microscopic material and structural properties of the
tissue. The stiffness (elastic zone of the bone) and the toughness (plastic zone of the bone) are examples of the biomechanical torque, which is the most studied in mineralized
tissues. As a result of the nature of the materials, it is difficult
to associate a very high stiffness with an extensive range of
mechanical resistances. There are different ways of combining the two, but it might make the material extremely anisotropic, in the sense that it becomes rigid and hard in one direction, but weak and fragile in other directions. The balance
between the function and structure of mineralized biological
materials has led to a compromise between stiffness and
toughness. Bone stiffness is mainly related to its mineral fraction, rendering it resistant to compressive forces. In contrast,
the organic fraction, consisting mainly of collagen, gives bone
its toughness and renders it resistant to tensile forces.
Another aspect of the mechanoadaptation of bone is the formation of microcracks resulting from bone fatigue caused
by cyclic loading of critical areas that concentrate the stress
and which are known to increase with age. The theory of
bone’s adaptation to stress by microcracks is reinforced by
findings from in vivo9 and ex vivo studies, which have analyzed
the initiation and propagation of microcracks in bone samples.10 Microcracks were experimentally generated in vivo by
physiological deformations, and the relatively significant remodeling activities were found to correlate with the experimentally induced damage. These activities that induce elevated remodeling are responsible for maintaining the structural
integrity of bone and repairing fatigue damage produced by
normal mechanical use. The osteocytes are responsible for
this regulatory process by stimulating bone resorption at the
site of a microcrack, either because their apoptosis initiates a
cycle of resorption and the remodeling of a unit, or because the
rupture of osteocyte dendrites affects signaling networks such
as RANKL/OPG (receptor activator of nuclear factor kappaB
ligand / osteoprotegerin). During the remodeling process,
sclerostin, synthesized by osteocytes, has been shown to be
a new player that inhibits bone formation. Its synthesis is stimulated by immobilization, which induces inhibition of the betacatenin Wnt pathway11 and is inhibited by stress.12
>
>
IN
B O N E H E A LT H
The pure effects of mechanical stress on bone, as a result of
physical exercise, are difficult to evaluate because of the numerous concomitant physiological changes (cardiovascular,
ventilatory, metabolic, and hormonal), which are all likely to
modify the bone response. The literature dealing with the effects of exercise on bone reports very heterogeneous results
that can be classified into two types of sporting activities: osteogenic and nonosteogenic.
N Effects of different types of sports
Differences exist with respect to the type of sport performed.
Running, gymnastics, and weight lifting induce bone gain of increasing amplitude.14 In contrast, with low-impact sports with
limited loads, such as swimming, the effects on the bone mass
in the lower limbs, or even the whole body, are negligible (Figure 2).15 Other findings suggest that a physical activity involving a significant impact, physical contact, and/or rotational forces, not only has beneficial effects on the areas under
>
>
Figure 2. Sports inducing an increase in BMD, in decreasing order: weight lifting, gymnastics, running, cycling, and swimming.
It thus appears that accumulation of fatigue is a stimulus of
bone modeling/remodeling, which could explain the osteogenesis triggered by certain types of sports. Moreover, it seems
possible that a mechanically overstretched bone or bone in
an osteoporotic subject may not be able to “repair” the microdamage, thus creating a situation conducive to fracture. This
aspect of bone fatigue is poorly understood, due to a lack of
noninvasive tools for the visualization of microcracks.
Effects of physical exercise on the
human skeleton
Thirty per cent of BMD is independent of genetic factors and
may be controlled by other factors including mechanical stress.
But the bone’s response to physical activity is itself influenced
by a genetic component. In a study in female twins,13 it was
shown that those who had been active over a period of 30
years had increased bone mass at the tibial diaphysis (cortical thickness, bending strength) and epiphysis (trabecular
BMD)—as measured by a tomography device—as compared
with their respective sedentary twin. Moreover, this benefit
was more pronounced in monozygotes than in heterozygotes.
The study demonstrated that physical activity is a major determinant, independent of genotype, capable of acting on
the mechanical properties of bone tissue.
load, but also on the peripheral and axial bones not subjected to load. The magnitude of the difference between a state
under load or not seems to be the decisive parameter. Indeed,
weight lifters who are subjected to very high stresses appear
to increase their bone mass more compared with any other
sport.16 A distinction should be made between sports that generate mechanical stress based on the mode of loading (weight
lifting) and those that generate mechanical stress through
repeated impacts (running).
The musculoskeletal system of humans has evolved to adapt
to endurance running. We can thus imagine that in loadbearing bones, large forces are needed to generate unusual strains. With regard to swimming, the loads developed by
movements against the resistance of water, as well as the
muscle contractions generating them are insufficient for inducing stimuli to the inferior limb bones. However, when it
comes to non–load-bearing bones, such as the humerus, the
deformations caused by muscle contractions are osteogenic.17 Consequently, the effect of pulling the muscles by their
attachments on the bone has an impact on bone that depends on the function of load-bearing bones in the considered area. This has been confirmed in astronauts, another
extreme model in which bone mass is lost in load-bearing
379
IN
bones, but not in non–load-bearing bones18 despite the substantial exercise programs they follow, but with which they
cannot—or rarely—exceed accelerations above 1 g.
N Thresholds effects
Under certain circumstances, carrying out a sport that is
known to be osteogenic may have a deleterious effect on
bone tissue. Intensive running by adults not accustomed to
training can cause stress fractures. In marathon runners, both
male and female, bone deficiency is frequently observed at
the lumbar spine.19 In highly trained female athletes, a problem known as the “female athlete triad” (eating disorders +
amenorrhea/oligomenorrhea + decreased bone mineral density) is more accentuated because of the harmful effects of
overtraining on the hormonal cycle and of inadequate nutrition. This stresses the interdependence of the determinants
of bone mass. These data suggest that exercise of too great
intensity is damaging to the bone tissue. Indeed, a study in
women and men over 50 shows that exercising (with loads)
more than 5 hours per day (running, dancing or brisk walking),
results in a decrease in spinal mineral density.20 This mineral
deficiency can be explained by age, body mass, or estrogen
status. We have also shown that increased bone resorption
occurs in men over 60 practicing more than 6 hours of sport
per week.21 These studies point to a nonlinear effect of exercise on bone mass. Another study showed that in soccer
players training for up to 6 hours per week, femoral mineral density increased in proportion to the duration of training,
but plateaued beyond this limit, without additional benefit to
the bone.22
These studies indicate that not only intensity, but also duration of exercise is an important factor for the bone’s response
to exercise. The tibia is one of site where fractures occur frequently in adolescents and young adults, especially in the diaphyseal region. Very few reports exist with regard to metaphyseal or epiphyseal fractures.23 Similarly, these fractures
are rare in the distal femur24; most studies refer to fractures of
the axis or neck of the femur.
N Prevention of osteoporosis
Studies consistently confirm the role of certain types of physical exercise as a means for preventing osteoporosis. Prevention programs focus primarily on two populations: adolescents, in order to optimize their bone mass at the end of
growth, and female adults and postmenopausal women, in
order to reduce the slope of bone loss. The most important
period for bone gain certainly is the peripubertal period, as
shown in young tennis players in whom the increase in bone
mass—and even more importantly in bone size—in the playing arm, can exceed 10%.25
Even if the effects of exercise on the BMD in postmenopausal
women are modest, epidemiological studies suggest that
physical activity and levels of dietary calcium are capable of
380
B O N E H E A LT H
reducing the risk of fracture.26 Walking alone is not enough
to prevent bone loss. Consequently, exercise—even if it is dynamic and based on feedback of the limbs on the ground—
must also achieve a certain level of frequency and intensity
to be effective on bone tissue.27 More recent studies using
peripheral tomography have shown, in this population, a
positive association between physical activity scored over
several years and cortical bone geometric parameters related to the radius, tibia, or femur.28,29 These data are invaluable
since a minimal diaphyseal expansion induces a substantial
improvement in flexural strength. It is possible that dual-energy x-ray absorptiometry (DXA) is not sufficiently powerful
for the visualization of these changes.30
In elderly subjects
As we saw in the previous section, the knowledge we have
of the effects of exercise on bone tissue is essentially what
high-level athletes have taught us. These effects are much
more difficult to identify in a vast population. In the elderly, it
remains unclear whether exercise programs or the fact of
having been active offers protection from osteoporotic fractures. At a certain age, exercising (gymnastics, walking) does
not always provide significant bone gain. It could, however,
possibly prevent rapid bone loss and thus reduce the risk of
fracture, while also improving muscle tone, cardiovascular
function, balance, and posture, thereby limiting the risk of
fractures from falls. Recent reviews31,32 conclude that there
is a need for better-targeted randomized controlled trials to
evaluate the true effectiveness of exercise. In other words, this
subject is not closed (Figure 3).
Instead of talking about physical activity, particularly when it
comes to the elderly, one could speak of mechanical systems
that are aimed at generating an effective stimulus to the skeleton. Hope is permitted, because it has been shown that use
of vibration programs could be osteogenic. However, given
all that has been said previously, this seems somewhat unlikely. Indeed, we know that very-high-amplitude (>2000 µε)
and low-frequency (<2 Hz) signals, which exist during strongimpact physical activities, are osteogenic4,33 until a threshold
beyond which deleterious effects occur,34 based on Frost’s
mechanostat theory.35
Since a pioneering study from 199036 and the early 2000s,
it has been shown that low-amplitude signals, well below the
amplitudes that can cause fractures, can also, when applied
at high frequencies, induce an osteogenic response. Several
studies using strain gauges attached to the limbs of different
animals report that mechanical stimuli generated during motion (walking, running), or in static position (subject standing,
sitting), induced signals of amplitudes around 500 to 2000 µε
occurring at low frequencies (<2 Hz), but also signals of low
amplitude (<300 µε) occurring at higher frequencies (10 to
50 Hz).37,38 It should be noted that the lower the amplitude of
the signals, the higher their frequency and the more they are
represented during daily activities (thousands of times) in
contrast to high-amplitude signals, which are weakly represented, and this, regardless of the species or the bone site
studied. Moreover, studies have shown that a force applied at
high frequency (10 to 20 Hz) was more osteogenic than the
same force applied at a lower frequency, as the motion frequency (1 Hz).39 This property of high frequencies as well as
the balance of low-amplitude signals during everyday activities, has provided further insights into the understanding of
their roles on bone tissue.
High-intensity resistance training
evidence
conflicting
Prevention of falls
Exercises that challenge balance
combined with strength training
Resistance training alone not
sufficient
Prevention of fractures
Combine weight-bearing, balance,
and strengthening exercises
Whole-body vibration: lack of trials
The origin of these signals is unclear. The observed high frequencies could be harmonics of large-amplitude signals (which
occur at low frequency). The signals could also originate from
muscle activity. A sarcopenia of type II fibers is observed in
the elderly, which causes a decrease in muscle strength, as
well as a decrease in muscle activity, with frequencies ranging
from 30 at 50 Hz. This sarcopenia also causes an alteration
of mechanical signals that regulate bone. Thus, muscle wasting is an etiologic factor in osteoporosis.40
Various studies have therefore investigated the effect of lowamplitude/high-frequency signals on bone. Those of Rubin
et al are the most illustrative.41,42 These researchers showed
that sessions of 20 minutes of low-amplitude (0.3 g, 5 µε),
high-frequency (30 Hz) signals, applied for 1 year to the hindlimbs of adult ewes were able to increase the density and
volume of the trabecular bone in the proximal femur.41
Furthermore, a signal simulating a physical activity (sinusoidal
signal; 3 N; 2 Hz) coupled to low-amplitude (0.3 N) and highfrequency (0 to 50 Hz) signals applied during two consecutive days, 30 s/day, on mouse ulna in vivo has been shown to
raise the rate of bone formation by approximately a factor of
4, as compared to a signal simulation exercise on its own.43
In humans, one can easily understand the relevance of employing this type of noninvasive, nonpharmacological mechanical system in frail or disabled individuals, who are incapable of carrying out regular physical exercise.
B O N E H E A LT H
In 70 postmenopausal women, a prospective, randomized,
double-blind study during a period of 1 year showed that
episodes of less than 20 minutes with subjects standing on
vibrating tables (<0.3 g; 20 to 90 Hz) were able to reduce
bone loss in the lumbar and femoral regions. Compliance was
increasingly high for increasingly frail subjects.44 Another interesting study was carried out in postmenopausal women
undergoing three sessions per week on vibrating tables during 6 months (35 to 40 Hz; 2.28 to 5.09 g), who were asked
to carry out knee bending exercises.
Prevention of bone fragility
High-impact weight-bearing effective
Swimming, slow walking insufficient loading
IN
Figure 3. Exercise
and prevention of
bone fragility.
Exercise plays a pivotal
role in prevention of bone
fragility, and falls in the elderly population. Exercise
regimens chosen for bone
or balance are diverse and
not all exercise regimens
are effective. The optimal
type, intensity, frequency
and duration of exercise to
maximize prevention of
fractures remain incompletely characterized.
Results showed a gain of proximal femur bone and an increase in isometric and dynamic muscle strength.45 Gusi et
al reported improved balance and reduced body fat following a gain in the neck of the femur in postmenopausal women
after 8 months of training (3 times/week, 12.6 Hz, 3 cm displacement amplitude of the pad).46
In contrast, another group of postmenopausal women who
carried out vibration exercises of 30 to 40 Hz 3 times/week in
addition to resistance training during 8 months did not achieve
any additional gain in bone mass or muscle strength, as opposed to those carrying out solely resistance training.47
Studies on a larger scale are now required to not only confirm
the benefits with regard to bone and muscle in different populations, but also to assess micro- and macro-scale changes
in bone architecture at the and the impact on the risk of fracture. Other potential circulatory, postural, and neurovestibular effects should also be studied in parallel. A dosage effect
needs to be established, not only with regard to time of use,
but also with regard to the acceleration transmitted to different segments based on various postures when standing on
the aforementioned vibrating tables.
Conclusion
Optimal response to loading appears to occur during the prepubertal stage, at least in girls (the window might be larger in
boys). According to estimates, an increase in peak bone mass
381
IN
of 10% (depending on the type of sport) would delay the onset of osteoporosis by 13 years,48 suggesting that this period
of life is the most important one for ensuring prevention of
osteoporosis later in life.
Data from short-term prospective studies indicate a positive
association between areal BMD and physical activity, but bone
benefits may be lost if the practice of sports is stopped. In the
elderly, physical activity may also reduce fracture risk through
other mechanisms than those affecting BMD. Decreased bone
mass, muscle strength, tissue perfusion, systemic hormones,
B O N E H E A LT H
and articular cartilage are common in elderly individuals. Wholebody vibration therapy may be efficient in alleviating these deteriorations, but its use for therapeutic purposes is far from
being standardized. Although areal BMD measured by DXA
is a common surrogate for bone strength, it is now possible
to measure other aspects of bone strength such as bone
geometry and volumetric BMD, using three-dimensional imaging techniques. Evaluation of bone macro- and micro-architectural parameters is gaining widespread acceptance
and will improve our understanding of human skeletal adaptation to mechanical loading. I
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Keywords: sports; leisure; bone; whole body vibration therapy; puberty; menopause; cortical bone; mechanotransduction
ACTIVITÉ
PHYSIQUE ET QUALITÉ DE L’ OS
L’exercice physique agit directement sur le système osseux par l’intermédiaire d’un stress mécanique, et indirectement par des changements des paramètres cardio-vasculaires, ventilatoires, métaboliques et hormonaux. Les études
menées chez les athlètes montrent que les activités comme la course, la gymnastique et l’haltérophilie induisent un
gain osseux, tandis que le cyclisme et la natation sont faiblement ostéogènes. Le gain osseux est principalement
observé sur les parties de l’organisme sollicitées par l’exercice. L’arrêt de l’exercice au cours de l’âge adulte peut
avoir un effet négatif sur le gain osseux. Au cours des premiers stades de la puberté, l’exercice physique augmente
la masse osseuse, tandis que chez les femmes ménopausées et chez les personnes âgées, si l’exercice n’apporte pas
toujours un gain osseux, il permet néanmoins de prévenir l’ostéopénie et d’améliorer le tonus musculaire, la fonction cardio-vasculaire et l’équilibre, réduisant ainsi le risque de chute. Comme c’est le cas chez les personnes plus
jeunes, un entraînement excessif peut être dangereux, comme le montre l’amincissement de l’os cortical observé
chez les cyclistes âgés qui s’entraînent plus de 6 heures par semaine. Il a été mis en évidence un effet non linéaire
de l’exercice physique sur le squelette. Des exercices entraînant des impacts importants sont difficilement applicables aux sujets fragilisés. Les plateformes vibrantes peuvent avoir un potentiel ostéogène. Dans des modèles animaux de perte osseuse, les plateformes vibrantes améliorent la masse et la qualité de l’os. Chez l’homme, certaines
études ont montré les bénéfices potentiels des plateformes vibrantes en ce qui concerne le système musculaire, le
système osseux et la posture. L’utilisation thérapeutique des plateformes vibrantes n’est pas standardisée, et l’impact et le cadre de leur application restent à définir en ce qui concerne la fréquence, l’amplitude, la durée, etc. Cela
nécessitera de personnaliser les plateformes vibrantes afin de les adapter aux caractéristiques des utilisateurs et
d’évaluer leurs effets sur le corps entier ainsi que sur les différents compartiments individuels (cartilage, circulation
périphérique, tendons).
383
‘‘
Fall prevention and nonvertebral fracture prevention increase
consistently and significantly with
higher achieved 25-hydroxyvitamin D levels… Optimal fall and
fracture prevention is observed
with 25-hydroxyvitamin D levels of
at least 75 mg and better close to
100 nmol/L. Given the absence of
available data beyond this beneficial range, recent meta-analyses
do not preclude the possibility that
higher doses or higher achieved
25-hydroxyvitamin D concentrations may be even more effective
in reducing falls and nonvertebral
fractures.”
IN
B O N E H E A LT H
Contribution of vitamin D
to bone health:
fall and fracture prevention
b y H . A . B i s c h of f - Fe r ra r i , S w i t z e r l a n d
T
Heike A. BISCHOFF-FERRARI
MD, DrPH
Director, Center on Aging and
Mobility, University of Zurich
Swiss National Foundations
Professor, Department of
Rheumatology and Institute
of Physical Medicine
University Hospital Zurich
Zurich, SWITZERLAND
he overwhelming majority of fractures occur after a fall, and fall rates
increase with age and poor muscle strength or function. Furthermore,
after a first fall, about 30% of persons develop a fear of falling, and as
a result restrict their activities and suffer from decreased quality of life. Thus,
the benefit of vitamin D in terms of fall and fracture prevention has significant
clinical implications, all the more so as there is a growing number of epidemiologic studies linking low vitamin D status with an increase in the risk of colon
and possibly other cancers, as well as in the risk of hypertension, myocardial
infarction, cardiovascular and overall mortality, infections, and diabetes. Several recent meta-analyses have addressed the benefit of vitamin D on fracture reduction, with conflicting findings. This article will first summarize the
findings from double-blind randomized trials of oral vitamin D supplementation with respect to antifracture efficacy. It will then address why meta-analyses using alternative approaches, including open-design trials and trials that
tested intramuscular vitamin D, have reported discordant findings. Finally,
as vitamin D modulates fracture risk in two ways, by decreasing falls and increasing bone density, the efficacy of vitamin D on fall prevention will be reviewed, and the optimal 25-hydroxyvitamin D level to achieve these benefits
will be discussed.
Falls and fractures
ver 90% of fractures occur after a fall and fall rates increase with age and
poor muscle strength or function.1 Mechanistically, the circumstances2 and
the direction3 of a fall determine the type of fracture, whereas bone density and factors that attenuate a fall, such as better strength or better padding, critically determine whether a fracture will take place when the person who falls lands
on a certain bone.4 Moreover, falling may affect bone density through increased
immobility due to self-restriction of activities.5 After their first fall, about 30% of persons develop fear of falling resulting in self-restriction of activities and decreased
quality of life.5
O
Professor Heike A. Bischoff-Ferrari,
MD, DrPH, Director, Center on Aging
and Mobility, University of Zurich,
SNF Professor, Department
of Rheumatology and Institute
of Physical Medicine, University
Hospital Zurich, Gloriastrasse 25,
CH-8091 Zurich, Switzerland
(e-mail: heike.bischoff@usz.ch)
384
In this context, the benefit of vitamin D in terms of fall and fracture prevention has significant clinical importance. In humans, several lines of evidence support a role of
vitamin D in muscle health. First, proximal muscle weakness is a prominent feature
of the clinical syndrome of vitamin D deficiency.6 Vitamin D deficiency myopathy is
characterized by proximal muscle weakness, diffuse muscle pain, and gait impair-
Contribution of vitamin D to bone health – Bischoff-Ferrari
IN
B O N E H E A LT H
ment with a waddling way of walking.7 Second, the vitamin D
receptor gene (VDR) is expressed in human muscle tissue,8
and VDR activation may promote de novo protein synthesis in
muscle.9 Mice lacking the VDR gene show a skeletal muscle
phenotype with smaller and variable muscle fibers and persistence of immature muscle gene expression during adult
life, suggesting a role of vitamin D in muscle development.10,11
These abnormalities persist after correction of systemic calcium metabolism by a rescue diet.11
RR=1.35, 95% CI, 0.98-1.84). Notably, at the higher dose of
700 to 1000 IU vitamin D, this meta-analysis documented a
38% reduction in the risk of falling with treatment duration of
2 to 5 months and a sustained significant effect of 17% fall
reduction with treatment duration of 12 to 36 months, and the
benefit was independent of type of dwelling and age. Thus,
benefits of 700 to 1000 IU vitamin D per day on fall prevention are rapid and sustained and include all subgroups of
the senior population.
Vitamin D supplementation in seniors aged 65
and above
Further support for a dose-response relationship of vitamin D
and fall reduction comes from a multidose double-blind RCT
in 124 nursing home residents receiving 200, 400, 600, or
800 IU vitamin D compared with placebo over a 5-month
period.16 Participants in the 800 IU group had a 72% lower
rate of falls than those taking placebo or a lower dose of vitamin D (rate ratio, 0.28; 95% CI, 0.11-0.75).16
We now look at the available evidence from double-blind randomized controlled trials of oral vitamin D supplementation in
seniors aged 65 and older, and its efficacy in terms of fall and
fracture prevention. Two 2009 meta-analyses of double-blind
randomized controlled trials came to the conclusion that vitamin D reduces the risk of falls by 19%,12 the risk of hip fracture by 18%,13 and the risk of any nonvertebral fracture by
20%.13 However, this benefit was dose-dependent. Fall prevention was only observed in trials with a treatment dose of
at least 700 IU vitamin D per day, and fracture prevention required a received dose (treatment dose*adherence) of more
than 400 IU vitamin D per day. Lower doses failed to reduce
fracture or fall risk, while the benefit of fall prevention and
fracture prevention was present in all subgroups of the senior population at the higher dose of vitamin D. Primary prevention based on received dose (dose*adherence) as opposed
to treatment dose in double-blind randomized controlled trials (RCTs), made it possible to assess antifracture efficacy using a dose that accounted for the low adherence in several
recent large trials.14,15
N 2009 meta-analysis on fall prevention
The 2009 meta-analysis on fall prevention included 8 doubleblind RCTs with predefined fall assessment throughout the
trial period (n=2426) and found significant heterogeneity by
dose (low-dose: <700 IU/day versus higher dose: 700 to
1000 IU/ day; P-value 0.02) and achieved 25-hydroxyvitamin D
level (<60 nmol/L versus ⱖ60 nmol/L; P-value = 0.005).12
Higher-dose supplemental vitamin D reduced fall risk by
19% (pooled relative risk [RR], 0.81; 95% confidence interval [CI], 0.71-0.92; n=1921 from 7 trials) versus a lower dose
did not (pooled RR=1.10, 95% CI, 0.89-1.35 from 2 trials),
also achieved serum 25-hydroxyvitamin D concentrations
less than 60 nmol/L did not reduce the risk of falling (pooled
SELECTED
NHANES III
RCT
VDR
WHI
Third National Health And Nutrition Examination
Survey
randomized controlled trial
vitamin D receptor gene
Women’s Health Initiative [trial]
N 2009 meta-analysis on fracture prevention
This meta-analysis on fracture prevention included 12 doubleblind RCTs for nonvertebral fractures (n=42 279) and 8 RCTs
for hip fractures (n=40 886), and, similar to the meta-analysis on fall prevention, it found significant heterogeneity for received dose of vitamin D and achieved level of 25-hydroxyvitamin D in the treatment group for hip and any nonvertebral
fractures (Figures 1 and 2, page 386).13-15,17-26 No fracture reduction was observed for a received dose of 400 IU or less
per day or achieved 25-hydroxyvitamin D levels of less than
75 nmol/L. Conversely, a higher received dose of 482 to 770 IU
supplemental vitamin D per day reduced nonvertebral fractures by 20% (pooled RR, 0.80; 95% CI, 0.72-0.89; n=33
265 from 9 trials) and hip fractures by 18% (pooled RR,
0.82; 95% CI, 0.69-0.97; n=31 872 from 5 trials). Notably,
subgroup analyses for the prevention of nonvertebral fractures with the higher received dose suggested a benefit in all
subgroups of the older population, and possibly better fracture reduction with vitamin D3 compared with vitamin D2,
while additional calcium did not further improve antifracture
efficacy (Table I, page 386).13
Results from meta-analyses having included
double-blind and open-design trials in their
primary analysis
In August 2007, a review and meta-analysis commissioned
by the US Department of Health and Human Services (HHS)
addressed the effect of vitamin D supplementation on all fractures in postmenopausal women and men ages 50 and older.27 The pooled results for all fractures included 10 doubleblinded and 3 open-design trials (n=58 712) and did not
support a significant reduction of fractures with vitamin D
(pooled odds ratio [OR], 0.90; 95% CI, 0.81-1.02). The report suggested that the benefit of vitamin D may depend on
additional calcium and be primarily seen in institutionalized
individuals, which is consistent with the meta-analysis of Boonen et al.28
385
IN
Antifracture efficacy by received dose
Data points and represented trial
from left to right:
2.0
1.8
RR (95% CI)
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
340 376 380 482 640 640 651 664 700 760 768 770
Received vitamin D in IU per day
2.0
1.8
RR (95% CI)
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
62
Subgroups by received
dose of vitamin D
Pooled analysis from 3 trials with lowdose vitamin D (340-380 IU/day)
62
Triangles indicate trials with
D3, circles trials with D2. Line
= Trend line. All 12 high-quality
trials were included for the
received dose metaregression
(n=42 279 individuals).14,26 For
any nonvertebral fractures,
antifracture efficacy increased
significantly with higher received
dose (meta-regression:
Beta = –0.0007; P=0.003).
Bischoff-Ferrari et al. Arch Intern Med. 2009;169:551-561.
© 2009, American Medical
Association.
64
66
74
Fracture
reduction
+2%
Ø
Sig.
Vitamin D2
Vitamin D3
–10%
–23%
Ø
Sig.
Age 65-74
Age 75+
–33%
–17%
Sig.
Sig.
Institutionalized 65+
Community-dwelling 65+
–15%
–29%
Sig.
Sig.
Vitamin D plus calcium
Vitamin D main effect
–21%
–21%
Sig.
Sig.
Sig. =significant
Table I. Nonvertebral fracture reduction with vitamin D based on
evidence from double-blind RCTs.
Modified from reference 13: Bischoff-Ferrari et al. Arch Intern Med. 2009;169:
551-561. © 2009, American Medical Association.
78
80
84
105
112
Data points and represented trial
from left to right:
62 nmol/L = Lips et al,17 1996
62 nmol/L = RECORD,15 2005
64 nmol/L = Meyer et al,18 2002
66 nmol/L = Pfeifer et al,25 2000
74 nmol/L= Trivedi et al,19 2003
78 nmol/L = Chapuy et al,24 2002,
80 nmol/L = Lyons et al,20 2007
84 nmol/L = Pfeifer et al,23 2009
105 nmol/L = Chapuy et al,22 1992
112 nmol/L = Dawson-Hughes
et al,21 1997
Achieved serum 25(OH)D concentration
in treatment group (nmol/L)
–20%
Pooled analysis from 9 trials with higherdose vitamin D (482-770 IU/day)
Pooled subgroup analysis from trials
higher-dose vitamin D (482-770 IE/Tag):
386
340 IU = Lips et al,17 1996
376 IU = RECORD,15 2005
380 IU = Meyer et al,18 2002
482 IU = WHI (study medication plus
personal intake),14 2006
640 IU (D3) = Trivedi et al,19 2003
640 IU = Lyons et al,20 2007
651 IU = Dawson-Hughes et al,21 1997
664 IU = Chapuy et al,22 1992
700 IU = Pfeifer et al,23 2009
760 IU = Chapuy et al,24 2002
768 IU = Pfeifer et al,25 2000
770 IU = Flicker et al,26 2005
Figure 1. Nonvertebral
fracture prevention by
received daily dose of
25(OH)D.
Antifracture efficacy by achieved serum 25(OH)D
Figure 2. Nonvertebral
fracture prevention by
achieved 25(OH)D levels.
Triangles indicate trials with D3,
circles trials with D2. Line =
Trend line. For achieved 25(OH)D
levels, 2 trials (out of the 12 trials)
did not provide serum 25(OH)D
levels measured in the study
population during the trial
period.14,26 For any nonvertebral
fractures, antifracture efficacy
increased significantly higher
with higher achieved 25-hydroxyvitamin D levels (meta-regression:
Beta = –0.005; P=0.04)
Bischoff-Ferrari et al. Arch Intern
Med. 2009;169:551-561. © 2009,
American Medical Association.
B O N E H E A LT H
A 2010 patient-based meta-analysis of a subgroup of 7 large
trials of vitamin D included 68 500 individuals age 47 and
older.29 The authors defined alternative criteria that permitted
the inclusion of two open-design trials,30,31 one trial with intramuscular vitamin D,32 and 4 of the 12 double-blind RCTs of
oral vitamin D included in the 2009 meta-analysis described
above (one RCT using intermittent vitamin D2 without calcium,20 one RCT with 400 IU vitamin D3 without calcium,18 one
trial with 800 IU vitamin D3 per day with and without calcium
and less than 50% adherence,15 and one trial with 400 IU vitamin D with calcium14 ). The authors did not account for adherence to treatment. Based on these criteria, their findings
showed a reduced overall risk of fracture (hazard ratio [HR],
0.92; 95% CI, 0.86 to 0.99) and a nonsignificant reduction
of hip fractures (HR, 0.84; 95% CI, 0.70 to 1.01) for trials
that used vitamin D plus calcium. Vitamin D alone, irrespective of dose, did not reduce fracture risk. The authors concluded that vitamin D, even in a dose of 400 IU vitamin D
per day, reduces the risk of fracture if combined with calcium.
Notably, this regimen was tested in 36 282 postmenopausal
women in the Women’s Health Initiative (WHI) trial over a treatment period of 7 years and did not reduce the risk of fracture.
In all three reports reviewed under this section, heterogeneity
by dose may have been missed due to the inclusion of opendesign trials plus a dose evaluation that did not incorporate
adherence. Biologically, the exclusion of heterogeneity by dose
seems implausible even if a formal test of heterogeneity is not
statistically significant. A dose-response relationship between
vitamin D and fracture reduction is supported by epidemiologic data showing a significant positive trend between serum
25(OH)D concentrations and hip bone density,33 lower extremity strength,34,35 and trial data for fall prevention.12
Finally, the consistency of the results for both received dose
and achieved 25(OH)D levels in the treatment group across
all 12 masked trials lends support to the presence of a doseresponse relationship between supplemental vitamin D and
fracture reduction (Figures 1 and 2).14,15,17-26
Optimal 25-hydroxyvitamin D levels for bone
and muscle health
The threshold for optimal 25(OH)D and hip BMD was investigated in 13 432 individuals of NHANES III (Third National
Health And Nutrition Examination Survey), including both
younger (20 to 49 years) and older (50+ years) individuals of
various ethnic backgrounds.33 In the regression plots, higher serum 25(OH)D levels were associated with higher BMD
throughout the reference range of 22.5 to 94 nmol/L in all subgroups. In younger whites and younger Mexican-Americans,
higher 25(OH)D was associated with higher BMD, even beyond 100 nmol/L.
The threshold for optimal 25(OH)D and lower-extremity function was evaluated in the same survey (NHANES III) in 4100
ambulatory adults age 60 years and older34 and a Dutch cohort of older individuals.35 Results from the smaller Dutch
cohort suggested a threshold of 50 nmol/L for optimal function,35 while a threshold beyond which function would not
further improve was not identified in the larger NHANES III
B O N E H E A LT H
survey, even beyond the upper end of the reference range
(>100 nmol/L).34 In NHANES III, a similar benefit of higher 25hydroxyvitamin D status was documented by gender, level of
physical activity, and level of calcium intake.
The threshold for optimal 25(OH)D and fracture and fall prevention was assessed in a recent benefit-risk analysis and
is illustrated in Figure 3.39 Based on these data, 75 or better
100 nmol/L (30 or better 40 ng/mL) is suggested as the optimal threshold of 25-hydroxyvitamin D for fall and fracture
prevention.
In addition, greater antifracture efficacy with higher achieved
25(OH)D levels was documented in an earlier meta-analysis
of high-quality primary prevention trials with supplemental
vitamin D.36 Factors that may obscure a benefit of vitamin D
are low adherence to treatment,15 low dose of vitamin D, or
the use of less potent D2.37,38 Furthermore, open-design trials31
may bias results toward nil, because vitamin D is available
over the counter.
Falls (RR)
Fractures (RR)
2
1.6
1.2
RR
Notably, the 2009 meta-analyses on fall12 and fracture13 prevention from double-blind RCTs performed sensitivity analyses that included 4 open-design trials for fracture prevention
and 3 open-design trials for fall prevention. Both analyses
found significant variation in results between open-design and
double-blind trials at any dose of vitamin D, the lower and the
higher dose suggesting that trial quality introduces heterogeneity.
IN
0.8
0.4
0
40
50
60
70
80
100
120
140
Serum 25(OH)D (nmol/L)
Figure 3. Threshold for optimal fall and fracture prevention based
on double-blind randomized controlled trials.
Data points show the relative risk of falls and the relative risk of sustaining any
nonvertebral fracture from double-blind RCTs, by achieved 25-hydroxyvitamin D
levels in the treatment groups. Data were extracted from two 2009 meta-analyses12,13 and summarized in a recent benefit-risk analysis of vitamin D.39 Based
on these data, 75 or better 100 nmol/L (30 or better 40 ng/mL) are suggested
as an optimal threshold of 25-hydroxyvitamin D for fall and fracture prevention.
Modified from reference 39: Bischoff-Ferrari HA et al. Osteoporos Int. 2009.
Dec 3. [Epub ahead of print]. © 2009, © Springer.
Adding calcium to vitamin D
The pooled RR reduction was 21% with or without additional
calcium for the higher dose of vitamin D in the 2009 metaanalysis of double-blind RCTs.13 The observed calcium-independent benefit of vitamin D on nonvertebral fracture prevention at a vitamin D dose greater than 400 IU per day may be
explained by a calcium-sparing effect of vitamin D.40,41 This
is supported by two recent epidemiologic studies suggesting
that both parathyroid hormone suppression41 and hip bone
density 42 may only depend on a higher calcium intake if serum
25-hydroxyvitamin D levels are very low. Other meta-analyses may have missed this finding due to their analyses including all doses of vitamin D.
As calcium absorption is improved with higher serum 25-hydroxyvitamin D levels,41,43 future studies may need to evaluate
whether current calcium intake recommendations with high-
387
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B O N E H E A LT H
er doses of vitamin D beyond 2000 IU per day are safe or require downward adjustment.43 If dietary calcium is a threshold nutrient, as suggested by Heaney,44 then that threshold
for optimal calcium absorption may be at a lower calcium
intake when vitamin D supplementation is adequate.
Due to seasonal fluctuations in 25(OH)D levels,58 some individuals may be in the desirable range during summer months.
However, these levels will not be maintained during the winter
months even in sunny latitudes.59,60 Thus, winter supplementation with vitamin D is needed even after a sunny summer.
Other potential benefits of vitamin D
supplementation
Furthermore, several studies suggest that many older persons will not achieve optimal serum 25(OH)D levels during
summer months, which suggests that vitamin D supplementation should be independent of season in older persons.60-62
Even in younger persons, the use of sunscreen or sun-protective clothing may prevent a significant increase in 25-hydroxyvitamin D levels.62
Many lines of evidence also suggest that low vitamin D status increases the risk of colon45 and possibly other cancers,46
as well as the risk of hypertension,47 myocardial infarction,48
cardiovascular49 and overall mortality,50 infections51 and diabetes.52 The development of mice lacking the receptor for
vitamin D (VDR) has provided insight into the physiological
role of vitamin D. These mice express phenotypes that are
consistent with epidemiologic studies of 25-hydroxyvitamin D
deficiency in humans.10
Are current recommended vitamin D intakes
sufficient for optimal bone and muscle health?
The recommended intake of vitamin D as defined by the Institute of Medicine in 1997 is 200 IU per day for adults up to
50 years of age, 400 IU per day for adults between age 51
and 70, and 600 IU per day for those aged 70 years and
above. These recommendations are insufficient to meet the
requirements for optimal fall and nonvertebral fracture prevention. The current intake recommendation for older persons (600 IU per day) may bring most individuals to 50-60
nmol/L, but not to 75-100 nmol/L.33
Studies suggest that 700 to 1000 IU of vitamin D per day
may bring 50% of younger and older adults up to 75-100
nmol/L.53-55 Thus, to bring most older adults to the desirable
range of 75-100 nmol/L, vitamin D doses higher than 7001000 IU would be needed. According to a recent benefit-risk
analysis on vitamin D, mean levels of 75 to 110 nmol/L were
reached in most RCTs with 1800 IU to 4000 IU vitamin D/d
without risk.39 In a recent trial among acute hip fracture patients, 70% reached the 75 nmol/L threshold with 800 IU vitamin D3 per day, and 93% with 2000 IU vitamin D3 per day,
at 12 months follow-up and with over 90% adherence.56
Heaney and colleagues, in a study of healthy men, consistently estimated that 1000 IU cholecalciferol per day is needed
during the winter months in Nebraska to maintain a late summer starting level of 70 nmol/L, while baseline levels between
20 and 40 nmol/L may require a daily dose of 2200 IU vitamin D to achieve and maintain 80 nmol/L.44,57 These results
indicate that individuals with a lower starting level may need
a higher dose of vitamin D to achieve desirable levels, while
relatively lower doses may be sufficient in individuals who start
at higher baseline levels.
388
The persons most vulnerable to low vitamin D levels include
older individuals,60,63 individuals living in northern latitudes with
prolonged winters,58,64 obese individuals,65 and individuals of
all ages with dark skin pigmentation living in northern latitudes.33,66,67 In healthy outdoor workers, naturally elevated 25hydroxyvitamin D levels are observed: 135 nmol/L68 in farmers
and 163 nmol/L69 in lifeguards. The first sign of toxicity, hypercalcemia, is only observed with serum levels of 25(OH)D
above 220 nmol/L.70,71
In summary
Evidence from double-blind randomized-controlled trials shows
that vitamin D supplementation reduces both falls and nonvertebral fractures, including hip fractures. However, this benefit is dose-dependent. According to two 2009 meta-analyses of double-blind RCTs, no fall reduction was observed at
doses of less than 700 IU per day, while a higher dose of 700
to 1000 IU vitamin D per day reduced falls by 19%.12 Similarly, no fracture reduction was observed for a received dose of
400 IU or less per day, while a higher received dose of 482 to
770 IU vitamin D per day reduced nonvertebral fractures by
20% and hip fractures by 18%. Of note, the antifracture benefit was present in all subgroups of the older population and
was most pronounced among community dwellers (–29%)
and those age 65 to 74 years (–33%).
Fall prevention and nonvertebral fracture prevention increased
consistently and significantly with higher achieved 25-hydroxyvitamin D levels in the 2009 meta-analyses. Fall prevention
started at 25-hydroxyvitamin D levels of 60 nmol/L,12 while
at least 75 nmol/L is required for nonvertebral fracture prevention.13 Optimal fall and fracture prevention was observed
with 25-hydroxyvitamin D levels of close to 100 nmol/L.39 Given the absence of available data beyond this beneficial range,
these recent meta-analyses do not preclude the possibility
that higher doses or higher achieved 25-hydroxyvitamin D
concentrations may be even more effective in reducing falls
and nonvertebral fractures. I
IN
B O N E H E A LT H
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29. DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ. 2010;340:b5463.
30. Porthouse J, Cockayne S, King C, et al. Randomised controlled trial of calcium
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35. Wicherts IS, van Schoor NM, Boeke AJ, et al. Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab.
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38. Houghton LA, Vieth R. The case against ergocalciferol (vitamin D2) as a vitamin
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39. Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E,
Willett WC. Benefit-risk assessment of vitamin D supplementation. Osteoporos
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40. Heaney RP, Barger-Lux MJ, Dowell MS, Chen TC, Holick MF. Calcium absorptive effects of vitamin D and its major metabolites. J Clin Endocrinol Metab.
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41. Steingrimsdottir L, Gunnarsson O, Indridason OS, Franzson L, Sigurdsson G.
Relationship between serum parathyroid hormone levels, vitamin D sufficiency,
and calcium intake. JAMA. 2005;294:2336-2341.
42. Bischoff-Ferrari HA, Kiel DP, Dawson-Hughes B, et al. Dietary calcium and serum
25-hydroxyvitamin D status in relation to BMD among U.S. adults. J Bone Miner Res. 2009;24:935-942.
43. Heaney RP, Dowell MS, Hale CA, Bendich A. Calcium absorption varies within
the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr. 2003;22:
142-146.
44. Heaney RP. The vitamin D requirement in health and disease. J Steroid Biochem Mol Biol. 2005;97:13-19.
45. Feskanich D, Ma J, Fuchs CS, et al. Plasma vitamin d metabolites and risk of
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1502-1508.
46. Giovannucci E, Liu Y, Willett WC. Cancer incidence and mortality and vitamin
D in black and white male health professionals. Cancer Epidemiol Biomarkers
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47. Forman JP, Giovannucci E, Holmes MD, et al. Plasma 25-hydroxyvitamin D
levels and risk of incident hypertension. Hypertension. 2007;49:1063-1069.
48. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med. 2008;168:
1174-1180.
49. Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum
25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and
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50. Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analy-
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51. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311:1770-1773.
52. Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin
resistance and beta cell dysfunction. Am J Clin Nutr. 2004;79:820-825.
53. Tangpricha V, Pearce EN, Chen TC, Holick MF. Vitamin D insufficiency among
free-living healthy young adults. Am J Med. 2002;112:659-662.
54. Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF. Vitamin D and its
major metabolites: serum levels after graded oral dosing in healthy men. Osteoporos Int. 1998;8:222-230.
55. Dawson-Hughes B. Impact of vitamin D and calcium on bone and mineral metabolism in older adults. In Holick MF, ed: Proceedings of the Biologic Effects
of Light, June 16-18, 2001. Boston, MA: Kluwer Academic Publishers; 2002:
175-183.
56. Bischoff-Ferrari HA, Dawson-Hughes B, Platz A, et al. Effect of high-dosage
cholecalciferol and extended physiotherapy on complications after hip fracture: a randomized controlled trial. Arch Intern Med. 2010;170:813-820.
57. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25hydroxycholecalciferol response to extended oral dosing with cholecalciferol.
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59. Grant WB, Holick MF. Benefits and requirements of vitamin D for optimal health:
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60. McKenna MJ. Differences in vitamin D status between countries in young adults
and the elderly. Am J Med. 1992;93:69-77.
61. Theiler R, Stahelin HB, Kranzlin M, et al. Influence of physical mobility and
season on 25-hydroxyvitamin D-parathyroid hormone interaction and bone
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remodelling in the elderly. Eur J Endocrinol. 2000;143:673-679.
62. Holick MF. Environmental factors that influence the cutaneous production of
vitamin D. Am J Clin Nutr. 1995;61(suppl):638S-645S.
63. Theiler R, Stahelin HB, Tyndall A, Binder K, Somorjai G, Bischoff HA. Calcidiol,
calcitriol and parathyroid hormone serum concentrations in institutionalized
and ambulatory elderly in Switzerland. Int J Vitam Nutr Res. 1999;69:96-105.
64. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous
synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton
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1988;67:373-378.
65. Parikh SJ, Edelman M, Uwaifo GI, et al. The relationship between obesity and
serum 1,25-dihydroxy vitamin D concentrations in healthy adults. J Clin Endocrinol Metab. 2004;89:1196-1199.
66. Looker AC, Dawson-Hughes B, Calvo MS, Gunter EW, Sahyoun NR. Serum
25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone. 2002;30:771-777.
67. Nesby-O'Dell S, Scanlon KS, Cogswell ME, et al. Hypovitaminosis D prevalence
and determinants among African American and white women of reproductive
age: third National Health and Nutrition Examination Survey, 1988-1994. Am J
Clin Nutr. 2002;76:187-192.
68. Haddock L, Corcino J, Vazquez MD. 25(OH)D serum levels in the normal Puerto
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70. Gertner JM, Domenech M. 25-Hydroxyvitamin D levels in patients treated with
high-dosage ergo- and cholecalciferol. J Clin Pathol. 1977;30:144-150.
71. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and
safety. Am J Clin Nutr. 1999;69:842-856.
Keywords: vitamin D; fracture; fall; optimal 25-hydroxyvitamin D level; meta-analysis
RÔLE
DE LA VITAMINE
D
DANS LA SANTÉ DE L’ OS
:
PRÉVENTION DES CHUTES ET LES FRACTURES
Les chutes constituent la principale cause des fractures, et leur fréquence augmente avec l’âge et la diminution de
la résistance ou de la fonction musculaire. En outre, après une première chute, environ 30 % des personnes développent une crainte de tomber, et par conséquent restreignent leurs activités et souffrent d’une diminution de leur
qualité de vie. Par conséquent, les bénéfices de la vitamine D sur le plan de la prévention des chutes et des fractures
ont des conséquences cliniques significatives, d’autant plus qu’un nombre croissant d’études épidémiologiques indiquent l’existence de liens entre une carence en vitamine D et l’augmentation du risque de cancers, notamment du
côlon, ainsi qu’avec le risque d’hypertension, d’infarctus du myocarde, de mortalité cardio-vasculaire et globale, d’infections et de diabète. Plusieurs méta-analyses récentes ont porté sur le bénéfice de la vitamine D sur la réduction
des fractures, avec des résultats contradictoires. Cet article commence par passer en revue les résultats d’études
randomisées et en double aveugle portant sur une supplémentation orale en vitamine D et son efficacité dans la
prévention des fractures. Il traitera ensuite des raisons pour lesquelles les méta-analyses utilisant d’autres approches,
notamment des études ouvertes ou des études ayant exploré l’administration intramusculaire de vitamine D, ont montré des résultats discordants. Enfin, puisque la vitamine D module le risque de fractures de deux façons, en diminuant les chutes et en augmentant la densité osseuse, nous discuterons de l’efficacité de la vitamine D sur la prévention des chutes, ainsi que la concentration optimale de 25-hydroxyvitamine D permettant d’obtenir ces bénéfices.
390
‘‘
In osteoarthritis, excessive
subchondral bone formation may
be present, yet it is associated
with abnormal tissue quality. In
osteoporosis, bone tissue formation never seems to attain its peak,
and combined with age-dependent bone loss, leads to poor tissue
quality and quantity. A strong rationale exists for therapeutic approaches that target improving
bone quality by inhibiting bone/
subchondral bone resorption in osteoarthritis and in osteoporosis.”
IN
B O N E H E A LT H
Osteoporosis and
osteoarthritis: bone is
the common battleground
b y D . L a j e u n e s s e , J . - P. Pe l l e t i e r,
a n d J . M a r t e l - Pe l l e t i e r, C a n a d a
O
Daniel LAJEUNESSE, PhD
steoporosis (OP) and osteoarthritis (OA) are two major health burdens
in our modern societies. Both are complex musculoskeletal diseases
and although OA affects different tissues, they both affect bone. Although these diseases affect more women than men and were suggested to
be mutually exclusive, mechanisms leading to them may overlap. Indeed, a
number of factors involved in OP pathophysiology also seem to be involved
in OA subchondral bone; however the mechanisms may be different in both
conditions. The present review explores these two diseases from a perspective of how bone/subchondral bone tissue is modified, and which mechanisms
could be responsible for the alterations.
Pathophysiology of osteoporosis
ccording to the World Health Organization, osteoporosis (OP) is the most
common metabolic bone disorder.1,2 Osteoporosis is characterized by low
bone mass due to an imbalance in favor of bone resorption over bone formation, leading to altered bone remodeling. Indeed, OP is not solely the result of
bone loss since bone loss occurs in both women and men with age, and the failure
to attain an optimal (ie, peak) bone mass during childhood and adolescence is one
of the most important factors leading to OP without any evidence of accrued bone
loss. There are abnormalities in the amount and architecture of bone tissue leading
to altered strength and an increased susceptibility to fractures (Figure 1, page 392).
Osteoporosis presents changes both in bone density and bone quality, with bone
quality including not only microarchitectural deterioration, but also alterations in bone
turnover/remodeling, damage accumulation (microfractures, etc), and mineralization.
The reduction in bone mass can be quantified by measurement of bone mineral
density (BMD) using dual-energy x-ray absorptiometry (DXA), either in the proximal
femur or in the spine.3 Risk factors for postmenopausal OP include, in addition to
female gender, ethnicity with white women being more affected than any other
group, estrogen deficiency, repeated fractures during adult life and/or in first-degree relatives, low body weight or low body mass index (BMI), smoking, and use of
oral corticosteroid therapy for more than 3 months.4,5
A
L
Johanne MARTEL-PELLETIER, PhD
and Jean-Pierre PELLETIER, MD
Osteoarthritis Research Unit
University of Montreal Hospital
Research Center (CRCHUM)
Notre-Dame Hospital, Montreal
Quebec, CANADA
Johanne Martel-Pelletier,
Osteoarthritis Research Unit,
University of Montreal Hospital
Research Center (CRCHUM),
Notre-Dame Hospital,
1560 Sherbrooke Street East,
Montreal, Quebec, Canada, H2L 4M1
(e-mail: jm@martelpelletier.ca)
At the tissue level, OP can be described as a thinning of bony rod-like trabeculae due
to the net loss of calcium and bone structure, eventually leading to overt perforation.
This is due to an imbalance in the sequence of events between bone resorption and
bone formation. Each sequence is composed of a bone resorption period that cre-
Osteoporosis and osteoarthritis: bone is the common battleground – Lajeunesse and others
391
IN
Normal bone
Bone section through hip
ates resorption cavities, followed by osteoblast activation and
formation of the osteoid matrix filling the cavity. Upon completion, the osteoblasts are embedded in the matrix and they become osteocytes.
During physiological bone remodeling, there is a close relationship between cortical and trabecular bone. Chemical/
mechanical factors permitting the cortical and trabecular bone
to adapt to each other control the expansion of the cortical
compartment downregulating the cancellous bone compartment and vice-versa.6-8 These mechanisms appear to fail during post-menopause, with aging, and obviously in OP women, leading to higher mechanical constraints imposed on the
skeleton, loss of bone mineral, and microstructural deteriorations.
Bone remodeling occurs through osteoblast activity for bone
formation via the synthesis of bone matrix, and through osteoclast activity for the degradation of bone matrix. The equi-
B O N E H E A LT H
Bone with
osteoporosis
Figure 1. Representation of normal and osteoporotic bone tissue.
Osteoporotic bone shows thinning of the bone trabeculae and a general decrease in total bone tissue.
From: Aurora Health Care. © 2010,
www.aurorahealthcare.org.
librium between the activities of these
two cells maintains the mineral homeostasis. Osteoblasts, which synthesize
the protein matrix, originate from local
mesenchymal stem cells (MSCs). These
cells form a layer of organic matrix called
osteoid, whose thickness depends on
the time interval between matrix formation and its subsequent calcification. The
plasma membrane of the osteoblast is
rich in alkaline phosphatase, which initiates the bone mineralization process.
Later in the process, osteoblasts are progressively transformed
into osteocytes; they become flat lining cells and are embedded in an organic bone matrix, which becomes mineralized. Osteocytes have long cell processes that form thin
canaliculi, which connect them to each other as well as to active osteoblasts and flat lining cells, and carry circulating bone
extracellular fluid. Osteoclasts are giant multinucleated cells
originating from stem cells of the mononuclear/macrophage
lineage and are responsible for bone resorption. Parathyroid
hormone (PTH), 1,25-dihydroxyvitamin D3 (calcitriol), sex hormones, and cytokines such as tumor necrosis factors (TNFs)
and interleukins (ILs) within the bone marrow control the formation of osteoclasts.
During OP, the osteoclast removes more bone than the osteoblast is able to form, which translates into a reduction in total bone mass. Indeed, less osteoid matrix is produced in OP
bone due to both a reduced organic matrix and less inorganic content.
Pathophysiology of osteoarthritis
SELECTED
BMD
BMI
BML
CTX
DXA
ICAM-1
MSC
NTX
OA
OP
OPG
PTH
RANK(L)
TNF
body mass index
bone marrow lesion
C-telopeptide crosslaps
intercellular adhesion molecule–1
mesenchymal stem cell
N-telopeptide crosslaps
osteoarthritis
osteoporosis
osteoprotegerin
parathyroid hormone
receptor activator of nuclear factor kappaB (ligand)
tumor necrosis factor
392
Osteoarthritis (OA) has been characterized by progressive articular cartilage loss and osteophyte formation. Despite major
progress in the last few decades, we still have much to learn
about the etiology, pathogenesis, and progression of this disease. The slowly progressive and multifactorial nature of OA,
its cyclical course, where a period of active disease is followed
by a period of remission, has limited our comprehension of
this disease. Although OA was long considered to be due only
to an imbalance between loss of cartilage and an attempt to
repair cartilage matrix, it is now known that OA, at least in the
knee, is a heterogeneous disease involving all the articular
tissues including cartilage, subchondral bone, menisci, and
periarticular soft tissues such as the synovial membrane. Synovitis is often present and is considered to be secondary to
the alterations in other joint tissues. Yet, findings indicate that
synovial inflammation could be a component of even the ear-
ly events leading to the clinical stage of the disease. In addition, emerging evidence suggests that changes in subchondral bone and menisci are closely involved in the disease progression.
IN
B O N E H E A LT H
indicates that bone sclerosis is due to an altered microarchitecture of the bone with trabeculae showing more platelike structures than rod-like structures.15,16 Such alterations
in the microarchitecture of bone tissue would also likely alter
bone stiffness.
Subchondral bone is suggested to be the site of the causally
most significant pathophysiological events occurring in car- Morphologically, one of the hallmarks of knee OA is the prestilage (Figure 2A). Although OA is not considered a generalized ence of bone marrow lesions (BMLs) consisting of edema-like
bone metabolic disease,9 data suggest that the subchondral lesions and cysts in subchondral bone as seen with magbone alterations may precede cartilage changes. Indeed, it netic resonance imaging (Figure 2B).17,18 These BMLs were
was long believed that OA subchondral bone underwent only found to be strong indicators of bone turnover indices as
appositional new bone formation and
sclerosis; however, it is now understood
Normal
Osteoarthritis
that there are also phases of resorption
A
in this diseased tissue.10,11 Inasmuch as
Cartilage
early bone resorption features can be
observed in OA, patients with progressive knee OA show increased indices
of bone resorption, whereas, in general,
Subchondral bone
nonprogressing OA patients do not show
altered resorption.12,13
Cyst
Edema
B
®
®
Of importance, subchondral bone plate
and trabecular bone do not show the
same architecture or the same abnormal
cell metabolism during OA. Indeed, as
indices of bone resorption indicate loss
of trabecular tissue, the increase in collagen type I cross-linked N-telopeptide
(NTX) and C-telopeptide (CTX) observed
in subsets of OA patients14 suggests a
progressive loss of trabecular bone, not
subchondral bone, which actually shows
sclerosis. In addition, in those patients
showing sclerosis, recent evidence using
microcomputed tomography (microCT)
Figure 2. Human knee histology and magnetic resonance imaging.
(A) Histological representation of cartilage and subchondral bone in a normal and osteoarthritic human knee.
(B) Representations of bone cysts and edema as seen by magnetic resonance imaging in the human osteoarthritic knee femoral condyle. Red arrows indicate cysts and the red circle the edema.
Figure 2A: Photos by Dr J. Martel-Pelletier. Figure 2B is adapted from reference 17: Raynauld et al. Ann
Rheum Dis. 2008;67:683-688. © 2008, BMJ Publishing Group Ltd.
Parameters
Osteoporosis
Osteoarthritis
Bone mineral density
Bone mineral content
Mineralization
Osteoid matrix
Type I collagen α1/α2 ratio
Fractures
Microfractures
Trabecular bone
Subchondral bone
Bone marrow lesions
Bone remodeling
Bone stiffness
Osteophytes
Reduced
Reduced
Reduced
Unchanged
Unchanged
Yes
Yes
Reduced
Unknown
No (hip?)
Decreased
Decreased
No
Increased
Reduced
Reduced
Increased
Increased
No
Yes
Increased
Altered
Yes
Increased
Increased
Yes
Table I. Comparison of osteoporosis and osteoarthritis bone parameters.
well as progressive structural changes in knee OA patients.
Moreover, BMLs are associated with poorly mineralized sclerotic bone tissue in OA patients.19
Osteoporosis vs osteoarthritis
The prevalence of both OP and OA is higher in women than
men. Risk factors for OA include age, gender (female), genetic predisposition, mechanical stress and/or joint trauma,
and obesity (high BMI). Some of these risk factors are also
associated with OP, yet the opposite weight conditions in
the two diseases and the presence of fractures in OP vs OA
are some of the conditions that distinguish the two diseases
(Table I).4
Although it is well established that in OP the low bone mass
is due to an imbalance in favor of bone resorption over bone
formation (Figure 3, page 394), new hypotheses about OA
pathophysiology have been put forward. Hence, OA was re-
393
B O N E H E A LT H
IN
OSTEOPOROSIS
Bone destruction > formation
Osteoclast
precursor
Osteoclast
Osteoblast
precursor
Mononuclear
cells
Figure 3. Representation of the bone
remodeling cycle in
osteoporosis.
Osteoblast
LC
Resting
bone
Resorption
surface
“Activation”
CL
Reversal
OS
Bone
formation
–3 weeks
–3 months
cently suggested to be related to an inappropriate attempt
at subchondral bone formation leading to cartilage remodeling/degeneration and synovitis.20 Moreover, Aspden21 proposed an alternative theory, in which OA could be a pathological growth, not decay, problem showing excessive and poorly
regulated growth of musculoskeletal tissues, with cells possibly reverting to an abnormal developmental phenotype with
a loss of proper function. Hence, (a) mechanism(s) leading to
normal tissue formation could be altered in such a way that
tissue integrity is never attained. However, although the latter hypothesis is very attractive and deserves consideration,
many questions still remain to be answered.
Another interesting thought is that, as bone resorption is now
considered to be centrally controlled via leptin, an adipocytokine produced by adipocytes that plays a role in bone
homeostasis and is locally modulated by adrenergic β2 receptors in osteoblasts,22,23 this regulation via leptin may be a key
element, whereas leptin levels are different in OP and OA patients.24,25
N Morphological level
Compared with OP, which is a systemic skeletal disorder characterized by a decrease in BMD with alterations in bone microstructure and a reduction in the bone mineral component,
OA does not seem to be a systemic bone disorder, as it shows
increases in BMD, yet reduced bone mineral content and increased osteoid, as well as alterations in subchondral bone
microstructure. In this disease, the progression of joint cartilage degeneration is associated with intensified remodeling
of the subchondral bone and increased subchondral bone
stiffness,26 whereas in OP bone remodeling and bone stiffness
decrease.
A number of studies suggest that OA patients should have
better bone mass. Indeed, data revealed that these patients
have a better preserved bone mass,27-29 and primary OA and
394
BRU
Mineralization
Osteoporotic bone
shows an increase in
the length of the remodeling cycle and reduced capacity to lay
down a new mineralized
bone matrix.
Abbreviations: BRU,
bone remodeling unit;
CL, cement line; LC,
lining cells; OS, osteoid.
From:
www.medscape.com
© 2010, Medscape.
OP rarely coexist.30-32 Indeed, hip and spine BMD were found
higher in women with radiographically defined knee OA. However, low hip BMD levels have also been associated with a
greater risk of progression of OA, and a significant percentage of women with OA undergoing hip replacement met the
criteria for OP.4 Furthermore, there is an association between
osteophytes and the pathophysiology of OA, whereas osteophytes are not observed in OP.
In addition to thicker trabeculae, trabecular microfractures are
also observed in OA bone tissue at a greater frequency, especially in the hip.33,34 This in turn could lead to BML formation, as such lesions may be the result of microfractures.35
Healing of microfractures in OA subchondral bone could generate a stiffer bone, which is no longer an effective shock absorber.36,37 Conversely, subchondral bone stiffness may be
part of a more generalized bone alteration leading to an apparent increase in BMD or volume. However, subchondral
bone thickening reflects osteoid volume increases, but not
necessarily an increase in this tissue’s mineralization.38 In the
knee, BMLs have not been reported in OP, yet in the hip they
can be observed in both OP and OA.39
Stiffness and BMD are not uniform in OA subchondral bone.40,41
The bone closest to the articular cartilage has the greatest effect on cartilage integrity, with variations in stiffness and BMD
probably causing more damage to cartilage than any other
parameters.42,43 Although OA is associated at a later stage
with a thickening of subchondral bone as opposed to a progressive thinning of bone in OP, explants of the femoral head
of OA patients at autopsy showed a low mineralization pattern compared with normal.44-46 Hence, the apparent increase
in BMD in OA may be due to an increase in material density,
not an increase in mineral density. Indeed, bone tissue mineralization in OA has been reported to be lower than normal
(Figure 4) and, very surprisingly, even lower than in OP.47 Although there is an increase in type I collagen production, the
undermineralization could be related to an abnormal increase
in the ratio of type I collagen α1 to α2 chains in OA compared
with normal tissue.48,49 Indeed, data showed a 2- to 3-fold increase in the expression of COL1A1 chains of type I collagen,
with no variations in COL1A2 expression in OA subchondral
bone osteoblasts, leading to an increase in the production of
type I collagen α1 chains. Together with the reduced number
of crosslinks in OA bone tissue,44 this could explain the reduction in bone mineralization. OA osteoblasts also show increased levels of osteocalcin and alkaline phosphatase.50,51
Hence, both the terminal differentiation and the mineralization of OA subchondral bone osteoblasts are altered.
N Cellular level
The hypercellularity observed in OA subchondral bone tissue may be linked with the increased rate of osteoblast proliferation observed in these cells52 or with reduced apoptosis
of OA osteoblasts.52,53 In contrast, OP osteoblasts proliferate
at a slower rate and show more pronounced apoptosis.54,55
Increased cell numbers and more collagen production per cell
would suggest that OA individuals should have better bone
mass as noted above. The molecular mechanisms locally
involved in the bone remodeling process include the coupling between osteoblasts and osteoclasts. Among the factors of importance are the membrane-bound intercellular adhesion molecules-1 (mICAM-1 or CD54) and the molecular
triad receptor activator of nuclear factor κB ligand (RANKL)/
RANK/osteoprotegerin (OPG), which have emerged as essential role players, not only in bone formation, but also in bone
resorption processes. Cellular interactions between osteoblasts and preosteoclasts mediated through adhesion molecules such as mICAM-1 have been recognized as important
modulators of osteoclast recruitment and differentiation.56,57
RANKL, a member of the TNF ligand family and produced by
the osteoblasts, binds to its specific receptor RANK on osteoclast precursors, promoting their differentiation and fusion, and
eventually the formation of mature osteoclasts. RANKL also
binds to RANK on the mature osteoclasts and induces their
activity. OPG, also produced by the osteoblasts, is a decoy
receptor that binds to RANKL, thus inhibiting osteoclastogenesis. From a clinical standpoint, studies reported progressively higher mICAM-1 levels in the synovium of OA, rheumatoid
arthritis (RA), and OP patients, respectively, compared with
healthy individuals, and in bone from hip or knee OA patients
undergoing primary arthroplasty or patients with a hip fracture secondary to OP.58-60
The equilibrium between OPG and RANKL also plays a crucial role in the physiology of bone.61 Under normal conditions
the ratio of OPG to RANKL produced by osteoblasts favors
bone formation by keeping bone resorption under strict control. In OP, the OPG/RANKL ratio decreases, favoring bone
resorption by activating osteoclasts and apoptosis of osteoblasts.62,63 Currently, potential drugs for OP target a reduction
in RANKL or an increase in OPG levels. In contrast to OP, ex
IN
B O N E H E A LT H
vivo studies performed on human OA subchondral bone osteoblasts revealed two distinct subgroups of patients based
on these cells’ low (L) or high (H) endogenous prostaglandin
(PGE2) levels,64 which otherwise demonstrate no different phenotypic features. Interestingly, differences in OPG and RANKL
levels also exist between the two OA subpopulations. In short,
both the L-OA and H-OA subchondral bone osteoblasts
demonstrated an abnormal OPG/RANKL mRNA ratio, yet it
was reduced in the L-OA, suggesting increased subchondral
bone resorption, and increased in H-OA, indicating a shift toward subchondral bone formation.65 This observation was further strengthened by data showing that L-OA osteoblasts
Normal
OA
Figure 4. Representative von Kossa staining in normal and osteoarthritic (OA) subchondral bone osteoblast culture.
(n=3 separate individuals per group) incubated in BGJb media containing 10%
fetal bovine serum (FBS), 50 µg/mL ascorbic acid and 50 µg/mL β-glycerophosphate for 30 days. Of note, less mineralization is seen in OA compared with normal.
After reference 48: Couchourel et al. Arthritis Rheum. 2009;60:1438-1450.
© 2009, American College of Rheumatology.
induced a significantly higher level of mature osteoclasts compared to the H-OA and higher bone resorption activity.65 Such
findings suggest that each human OA subchondral bone subpopulation has reached a different metabolic state; L-OA
being enriched with factors promoting bone resorption and
H-OA having reduced resorptive properties, with the metabolism of the latter cells favoring bone formation. Thus, in
humans, the OA subchondral bone osteoblast subpopulation
could reflect different stages or attempts to repair this damaged tissue: an increase in bone resorption followed by bone
formation.
Another family of signal proteins, the Wnt/LPR5 (a Wnt receptor)/β-catenin canonical signaling pathway, was also identified as a crucial role player in bone formation. Recent studies
suggested the potential direct contribution of mature osteoblasts/osteocytes to the recruitment and fate of MSCs via
the Wnt signaling pathway. Indeed, the control of adipogenesis, osteogenesis, and chondrogenesis in bone marrow appears to be regulated locally, at least in part, by Wnt agonists
and antagonists produced by the mature osteoblast/osteocytes.66,67 Such antagonists include members of the dickkopf
family (DKK1 and DKK2). Osteocytes also contribute to local
control of bone resorption via the production of the Wnt antagonist, sclerostin (SOST).68
395
IN
It is proposed that the alterations in Wnt/LRP5 expression
and/or activity could be implicated in the pathogenesis of OP,
as this system appears to be an important transduction mechanism by which mechanical loading increases bone mass.69
Interestingly, recent evidence also showed that low estrogen
levels diminished the skeletal response by downregulating the
transcriptional activity of β-catenin.70 DKK-1 was suggested
to be directly involved in the pathophysiology of OP,71 but as
DKK-1 may have opposite effects on early and late osteoblast
development,72,73 this could complicate the development of
DKK antagonists for the treatment of OP. In addition, recent
data on humans and mice delineated SOST as a compelling
target for the development of OP therapeutics. With regard to
OA, data on the Wnt signaling system are only emerging, and
contradictory data have been published, even by the same
authors.74,75 This could be due to the fact that this system
does not have a similar involvement in cartilage and subchondral bone. However, this system is involved in the pathophysiological process of this disease, at least in the subchondral
bone, as human OA subchondral bone osteoblasts were
shown to produce abnormal levels of DKK-2 and SOST.76,77
Conclusion
Studies have confirmed that in OA the subchondral bone is
the site of several dynamic morphological changes that appear to be part of the disease process. They have also provided substantial evidence that changes in the metabolism
of the subchondral bone are an integral part of this disease
process, and that these alterations are not merely secondary
B O N E H E A LT H
manifestations, but are part of a more active component of
the disease. Evidence for an imbalance in subchondral bone
remodeling and/or turnover has also been obtained, which
points to the fact that excessive subchondral bone formation
may be present in OA, yet it is associated with abnormal tissue quality. In contrast, bone tissue formation never seems
to attain its peak in OP, and combined with age-dependent
bone loss, leads to poor tissue quality and quantity. However,
these changes are associated with a number of local abnormal biochemical pathways related to altered osteoblast metabolism, which, in contrast to OP, appears to differ during the
OA disease process (ie, OA subchondral bone demonstrated
different phases).
Thus, a strong rationale exists for therapeutic approaches that
target improving bone quality in both diseases by inhibiting
subchondral bone resorption and/or promoting matrix quality
in subchondral bone in OA and reducing bone resorption in
OP. However, therapeutics that would reduce only bone resorption would be more beneficial for the subchondral bone
of the L-OA patients as this tissue is in a resorptive phase, but
in the H-OA patients, antiresorptive agents are expected to
be less effective since the subchondral bone was shown to
be in a formative phase. Nonetheless, more clinical trials exploring the effects of an anti–bone remodeling agent on the
evolution of OA structural changes are required. I
The authors thank Virginia Wallis for assistance with the manuscript preparation.
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2009;17(suppl 1):S38. Abstract.
Keywords: osteoporosis; osteoarthritis; osteoid matrix; mineralization; microfracture; bone marrow lesion; bone stiffness;
bone remodeling; bone turnover; subchondral bone
L’OSTÉOPOROSE
ET L’ARTHROSE
: L’OS,
UN CHAMP DE BATAILLE
L’ostéoporose (OP) et l’arthrose (OA) sont deux maladies dont la prévalence est importante dans nos sociétés modernes. Ces dernières appartiennent au système musculosquelettique et malgré le fait que l’OA affecte plusieurs
tissus de l’articulation, toutes deux présentent des altérations osseuses. Bien que ces maladies affectent plus les
femmes que les hommes et ont été suggérées de s’exclure mutuellement, certains mécanismes responsables de
ces dernières sont similaires. Ainsi, de nombreux facteurs impliqués dans la physiopathologie de l’OP semblent être
présent au niveau de l’os sous-chondral lors de l’OA, cependant les mécanismes sous-jacents apparaissent être différents pour chacune de ces pathologies. La présente revue explore ces deux maladies, discute des facteurs impliqués dans l’os/os sous-chondral et des mécanismes responsables de leur altération.
398
THE QUESTION
CONTROVERSIAL
he current definition of osteoporosis is defined on the
basis of a measured bone
loss of greater than 2.5 SD. And
yet, curiously, the goal of antiosteoporotic treatment up to now has
been to prevent the risk of fractures, but not to treat bone loss per
se. The question posed in this section provides an opportunity to
point out this paradox and highlight the advantages of treatments
with proven benefits on bone architecture, such as strontium ranelate.
QUESTION
T
What is the goal of
antiosteoporotic therapy:
improve bone health or
only prevent fractures?
1.
B.-H. Albergaria, Brazil
2.
A. Çetin, Turkey
3.
F. Cons-Molina, Mexico
4.
T. J. de Villiers, South Africa
5.
J. Laíns, Portugal
6.
N. Taechakraichana, Thailand
7.
D. O’Gradaigh, Ireland
8.
P. Sambrook, Australia
What is the goal of antiosteoporotic therapy: improve bone health or only prevent fractures?
399
CONTROVERSIAL
QUESTION
1. B.-H. Albergaria, Brazil
Ben-Hur ALBERGARIA, MD
Osteoporosis Diagnosis and
Research Center (CEDOES)
Federal University of Espirito Santo
Joao da Silva Abreu 78
Praia do Canto, Vitória
Espirito Santo, 29055 450
BRAZIL
(e-mail: benhur.gaz@terra.com.br)
O
steoporosis is a major public health concern in adults
over age 55, resulting in billions of euros/dollars in
costs. Over the past 20 years, antiresorptive drugs
have been the treatment of choice for osteoporosis. Most of
these drugs are derived from the bisphosphonate molecule.
Large, placebo-controlled trials generally show that these
drugs can indeed increase bone mineral density (BMD) and
reduce the risk of vertebral, hip, and other nonvertebral fractures in women with osteoporosis—at least in the short run.
The main potential problem is that anticatabolic drugs not
only directly—and unnaturally—inhibit osteoclastic bone resorption, they also indirectly inhibit the flip side of the bonebuilding coin, osteoblastic bone formation. What does this
mean for bone health in the long term? This is a crucial question, because there is no such thing as short-term treatment
with these drugs.
Bone remodeling is a physiological process that replaces old
bone with new and preserves the mechanical integrity of the
skeleton. During aging, an increase in the rate of remodeling
is observed, together with incomplete filling of individual bone
remodeling units by osteoblasts, resulting in bone loss and
increased risk of fractures. Most treatments for osteoporosis act predominantly by inhibiting the osteoclasts, hence decreasing bone resorption. While clinical trials, generally performed over 3 years, have shown these drugs to be effective
in reducing fractures, concerns have been expressed about
the potential for long-term suppression of bone remodeling to
produce adverse effects on bone strength and fracture risk.
Recent reports of atypical fractures in patients receiving bisphosphonates, the most commonly used treatment for osteoporosis, have attracted much attention in this respect.
During the past few years, remarkable advances in molecular
biology and genetics have led to deeper understanding of the
bone remodeling cycle and the implications with regard to this
biologic process for the concept of bone quality. Bone quality
is difficult to define and includes aspects such as toughness,
strength, resistance to failure, load-bearing capacity, etc. More
recent definitions include a number of aspects that are part
of a single concept that includes bone intrinsic material properties, bone remodeling, bone microarchitecture, and bone
mass.1
400
This has led to the definition of new therapeutic targets. New
drugs have or are being developed, which reduce the risk of
fracture in patients with osteoporosis and, at the same time,
seek to improve structural and material parameters of bone
quality. This ultimately translates into enhanced bone health
and long-term efficacy and safety.
Strontium ranelate (SR) is a novel antiosteoporotic agent approved for the treatment of postmenopausal osteoporosis
that appears to be going in the right direction. In contrast to
other available treatments for osteoporosis, SR induces antiresorption and bone-forming effects. SR reduces bone resorption by decreasing osteoclast differentiation and activity,
and stimulates bone formation by increasing replication of
preosteoblast cells, leading to increased matrix synthesis. It is
suggested that strontium ranelate exerts its dual mechanism
of action, at least in part, through the calcium-sensing receptor (CaSR), thereby activating osteoblastic cell replication, and
by reducing osteoclastogenesis and bone resorption through
the modulation of the RANKL/OPG ratio (= receptor activator
of nuclear factor-kappaB ligand/ostopreotegerin ratio).1-3
Preclinical studies have shown that this dual effect results in
increased bone mass and improves bone microarchitecture
and strength.4 In clinical trials, strontium ranelate reduces vertebral fractures in women with osteopenia, osteoporosis, and
severe osteoporosis. Reduction in nonvertebral and hip fractures has been documented in elderly subjects with low femoral
density. Histomorphometry and microcomputed tomography
(mCT) of bone biopsies from these osteoporotic patients have
also highlighted the capacity of SR to promote bone quality
and improve bone microarchitecture and strength.5-7
In summary, we are now looking to drugs that are real bone
health builders and not only bone hardeners. I
References
1. Seeman E, Delmas PD. Bone quality—the material and structural basis of bone
strength and fragility. N Engl J Med. 2006;354:2250-2261.
2. Fonseca JE. Rebalancing bone turnover in favour of formation with strontium
ranelate: implications for bone strength. Rheumatology. 2008;47:iv17-iv19.
3. Marie P. Strontium ranelate: a dual mode of action rebalancing bone turnover
in favour of bone formation. Curr Opin Rheumatol. 2006;18:S11-S15.
4. Ammann P, Shen V, Robin B, Mauras Y, Bonjour JP, Rizzoli R. Strontium ranelate
improves bone resistance by increasing bone mass and improving architecture in intact female rats. J Bone Miner Res. 2004;19:2012-2020.
5. 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.
6. 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. Clin Endocrinol Metab. 2005;90:2816-2822.
7. Arlot ME, Jiang Y, Genant HK, et al. Histomorphometric and CT analysis of bone
biopsies from postmenopausal osteoporotic women treated with strontium
ranelate. J Bone Miner Res. 2008;23:215-222.
CONTROVERSIAL
QUESTION
2. A. Çetin, Turkey
Alp ÇETIN, MD
Hacettepe University Medical School
Department of Physical Medicine
and Rehabilitation
Z Kati, 06100 Ankara
TURKEY
(e-mail: acetin@hacettepe.edu.tr)
A
ntiosteoporotic therapy seeks to prevent fragility fractures and improve bone quality. While the effects of
available antifracture treatments on fracture risk have
been relatively well established, the effect of many of them on
bone quality is relatively unknown. Current agents used in the
treatment of osteoporosis are classified either as antiresorptive or bone-forming agents. Thus, their mechanism of action involves only one of the aspects of bone remodeling.
Antiresorptive drugs, particularly bisphosphonates, reduce
bone turnover, resulting in an increase in bone mineralization
and homogeneity of mineralization. It is suggested that most
of the change in bone mineral density induced by antiresorptive agents is a consequence of the increase in mineralization.1 Aging also increases bone mineralization, like antiresorptive therapy, which seems contradictory. Greater mineralization
seems to be beneficial, at least up to a certain extent, since
excessive mineralization may result in poor bone quality. There
is concern that prolonged therapy with bisphosphonates leads
to oversuppression of bone remodeling and overmineralization of bone. This results in impaired ability to repair microfractures and increased bone fragility.2 Increased rates of microfractures have been reported in dogs treated with high doses
of bisphosphonates.3 Although this finding does not appear
to be common among postmenopausal women with osteoporosis treated with bisphosphonates, increased numbers
of cases with atypical subtrochanteric femur fractures have
been reported under bisphosphonate therapy.4 Awaited data
on the material properties of bone and data on the prevention
of fractures after long-term bisphosphonate therapy should
help clarify this issue. Bone-forming agents, such as parathyroid hormone, reduce fracture risk by stimulating the formation of new bone and increasing bone turnover in favor of
bone formation, thus increasing bone mass and improving
bone architectural properties, and by reducing fracture rates.
Parathyroid hormone also influences bone mineralization, leading to decreased mean mineralization of bone and increased
heterogeneity of mineralization.1
Strontium ranelate has been shown to be effective in reducing the risk of vertebral and nonvertebral fractures, including
hip, in postmenopausal women with osteoporosis. In contrast to other available treatments for osteoporosis, strontium
ranelate induces a dual effect on bone resorption and formation: it increases bone formation and reduces bone resorption, thereby rebalancing bone remodeling in favor of bone
formation. In addition to its effect on fracture reduction, strontium ranelate has also been shown to improve bone quality.
Bone biopsies obtained from both the SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment Of
Peripheral OSteoporosis) studies have shown that patients
treated with strontium ranelate have a significant increase in
trabeculae number, a significant decrease in trabecular separation, and a significant increase in cortical thickness when
compared with placebo.5
Although antiresorptive agents such as bisphosphonates also
increase mean bone volume and preserve trabecular microarchitecture, they have no effect on cortical bone. On the other hand, bone-forming agents such as strontium ranelate and
parathyroid hormone improve trabecular microarchitecture
and increase cortical thickness. While strontium ranelate has
a positive effect on bone quality, mean bone mineralization
remains unchanged, regardless of dosage and duration of
treatment.6
In conclusion, the aim of antiosteoporotic therapy should be
not only to prevent fractures, but also to improve bone quality. With its unique dual mode of action, strontium ranelate both
improves bone health and prevents fractures, and should be
considered as a first-choice treatment in the prevention of osteoporotic fractures. I
References
1. Davison KS, Siminoski K, Adachi JD, et al. The effects of antifracture therapies
on the components of bone strength: assessment of fracture risk today and in the
future. Semin Arthritis Rheum. 2006;36:10-21.
2. Drake MT, Clarke BL, Khosla S. Bisphosphonates mechanism of action and role
in clinical practice. Mayo Clin Proc. 2008;83:1032-1045.
3. Chapurlat RD, Arlot M, Burt-Pichat B, et al. Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study. J Bone Miner Res. 2007;22:1502-1509.
4. Solomon DH, Rekedal L, Cadarette SM. Osteoporosis treatment and adverse
events. Curr Opin Rheumatol. 2009;21:363-368.
5. Arlot ME, Jiang Y, Genant HK, et al. Histomorphometric and microCT analysis of
bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate. J Bone Miner Res. 2008;23:215-222.
6. Cortet B. Effects of bone anabolic agents on bone ultrastructure. Osteoporos
Int. 2009;20:1097-1100.
401
CONTROVERSIAL
QUESTION
3. F. Cons-Molina, Mexico
Fidencio CONS-MOLINA, MD
Medical Director
Centro de Investigación
en Artritis y Osteoporosis
Calzada de las Américas # 430
colonia Cuauhtémoc sur
Mexicali BC, México 21200
MEXICO
(e-mail: fidenciocons@prodigy.net.mx)
T
he goal of any treatment for osteoporosis is to improve
bone strength, thereby decreasing fracture risk. In the
past several years, a number of therapies have been
developed that are effective in achieving this goal, but do not
treat bone loss. These therapies, eg, the bisphosphonates,
largely target bone remodeling and increase bone mass by
significantly suppressing bone resorption and also bone formation, resulting in an overall suppression of bone turnover.
Another approach has been to stimulate bone formation and
decrease bone resorption, resulting in an overall stimulation of
bone turnover, by using anabolic agents such as parathyroid
hormone, fluoride, and, recently, strontium ranelate.
These two diametrically opposed ways of treating osteoporosis (the antiresorptive and the anabolic approaches) have been
shown to significantly decrease the risk of fracture by improving the mechanical properties of bone.
Antiresorptive treatment avoids the elimination of bone that
should be reabsorbed chiefly because it is no longer functional (ie, bone that is not deformed as usual by mechanical usage, because of the presence of microcracks), though they
may protect some mechanically useful elements, too. Among
these agents, bisphosphonates have recently been associated with atypical femoral shaft fractures in long-term treated
patients, which could be a consequence of excessive overall bone remodeling suppression.1
In addition, bisphosphonates seem to improve some littleknown aspects of the mechanical quality of bone tissue. In
some cases, the positive effects eventually produced on bone
architecture could be optimized, provided that the drug has
a positive interaction with the bone’s mechanostat, and the
mechanical stimulation of that system is maintained through
adequate control of the patient’s physical activity. The im-
402
pact of the positive effects of some of these treatments on
bone strength does not necessarily correlate with the relatively small improvements (if any) in densitometric bone mass.
The fact that current antiresorptive therapeutic agents produce only modest increases in bone mineral density would
appear to stress the need for anabolic strategies, in order to
produce larger increases in bone mass and strength. One
such strategy is intermittent treatment with anabolic agents
such as parathyroid hormone (PTH) and sodium fluoride.
Anabolic treatments enhance bone mass chiefly by inducing
peritrabecular apposition, with small evidence (if any) of improvement in bone architectural design. Some of these agents
may even deteriorate the mechanical quality of bone material because of crystal contamination (fluoride) or excessive
haversianization (PTH).2
Strontium ranelate, for its part, possesses a novel and unique
dual mode of action, which rebalances bone turnover in favor
of bone formation. It activates the calcium-sensing receptor,
and increases the expression of osteoprotegerin, while decreasing RANKL (receptor activator of nuclear factor-kappaB
ligand) expression by the osteoblast. In addition, micro-CT
analysis of bone biopsies from strontium ranelate–treated patients has evidenced an improvement in intrinsic bone tissue
quality, as shown by an increase in trabecular number, a decrease in trabecular separation, a lower structure model index, and an increase in cortical thickness.3
Our growing knowledge of the cellular and molecular pathways involved in the maintenance of bone homeostasis and
of the disturbances in these pathways caused by osteoporosis has permitted better understanding of the mechanisms
through which antiosteoporotic agents work, and opens up
perspectives for the development of ever-more effective therapeutic options. I
References
1. Schneider JP. Bisphosphonates and low-impact femoral fractures: current evidence on alendronate-fracture risk. Geriatrics. 2009;64(1):18-23.
2. Roldan E, Ferreti JL. How Do Anti-Osteoporotic Agents Prevent Fractures? Abstracts from the Round Table Held at the XVIth Annual Meeting of the Argentine
Association of Osteology and Mineral Metabolism (AAOMM), City of Bahia Blanca, October 29, 1999. Bone. 2000;26(4):393–396.
3. Hamdy NAT. Strontium ranelate improves bone microarchitecture in osteoporosis. Rheumatology. 2009;48(suppl 4):iv9-iv13.
CONTROVERSIAL
QUESTION
4. T. J. de Villiers, South Africa
Tobie J. DE VILLIERS,
MBChB, Mmed (O&G), MRCOG, FCOG(SA)
Consultant Gynaecologist
Panorama MediClinic and Dept O&G
Stellenbosch University
Cape Town
SOUTH AFRICA
(e-mail: tobie@iafrica.com)
T
he primary aim of osteoporosis therapy is the prevention of fragility fractures in patients at increased risk of
fracture. The ability of a drug to significantly reduce fracture risk is judged by comparison versus placebo over a 3-year
period. Such randomized placebo controlled trials have become the golden standard of regulatory approval and prescriber and consumer acceptance. Although this approach
was acceptable in the initial registration of new modalities in
bone therapeutics, it can be questioned presently for various
reasons.
The ethics of conducting placebo-controlled trials are challenged in view of the availability of several approved antifracture agents. This may have a negative impact on the procedure for registration of any new agents. Also, agents registered
under the present rules can be questioned regarding the effects on bone health over periods longer than 3 years.
The longest placebo-controlled antifracture data available are
for alendronate (4 years) and strontium ranelate (5 years). Even
here where the data exceed the compulsory 3 years, interpretation of data beyond 3 years is fraught with statistical pitfalls.1 Thus, smaller numbers in both the placebo and treated
groups compound covariates that influence fracture outcomes
in not being equally distributed in the remaining population.
Also, the removal of subjects from the study after fractures
usually involves more patients from the placebo group, which
may leave patients at lower risk of fracture in the placebo
group. It is unlikely that any antifracture study will extend the
placebo arm beyond 5 years. Typically, studies longer than
5 years drop the placebo group and compare fracture incidence over periods of time to detect a trend of sustained efficacy.2 The numbers involved in these extension studies become small and the ability to detect changes in efficacy is
compromised.
Why is it important to know the effect of drugs on bone health
for periods longer than 3 to 5 years? Clinicians are treating
patients for longer than 5 years in view of lack of evidence as
to the optimal duration of treatment. Patients are being treat-
ed from a younger age because of increased osteoporosis
awareness and wider availability of diagnostic tools such as
dual x-ray absorptiometry (DXA) and integrated risk factor
tools. In the UK, the lower price of generic alendronate has
liberalized intervention thresholds. All these factors, combined
with an ever-increasing life expectancy, increase the likelihood
that patients will be exposed to antifracture drugs for periods
exceeding 5 years.
The possibility of sustained long-term suppression of bone
turnover causing poor bone health has been raised by recent
observations. Alendronate-induced osteonecrosis of the jaw
is an example of a possible negative influence on bone health
by a drug with proven fracture efficacy when given over longer
periods of time at higher dosages. Atypical low-trauma subtrochanteric fractures have likewise been implicated as the
result of long-term effects of bisphosphonates, although this
has not been proven.
It is clear that long-term bone heath in patients on antifracture therapy is of cardinal importance. Available diagnostic
tools for this purpose are limited. Biochemical markers of bone
turnover, DXA, and ultrasound have limited application. Transiliac bone biopsies yield more information, but are limited by
technical and practical considerations.
It is thus with great interest that the study of bone microstructure and changes induced by drugs over time as recorded by
high-resolution peripheral computed tomography (HR-pQCT)
on the radius and tibia is followed.3 This in vivo technique is
noninvasive and produces brilliant images of the trabecular
and cortical structures. The technique is presently being limited by cost, availability, restriction to peripheral sites, and limited validation of the outcomes measured. It is the opinion of
the author that development of HR-pQCT and other techniques will lead to new insights into the effect of drugs on longterm bone health. This will complement knowledge of antifracture efficacy in determining not only the choice of drug,
but also the duration of treatment in osteoporosis based on
bone health. I
References
1. Seeman E, et al. Five years treatment with strontium ranelate reduces vertebral
and nonvertebral fracture and increases the number and quality of remaining lifeyears in women over 80 years. Bone. (2010),DOI1016/J.BONE2009.12.006.
2. Reginster J-Y, Sawicki A, Roces-Varela A. Strontium ranelate: 8 years efficacy on
vertebral and nonvertebral fractures in postmenopausal osteoporotic women.
Osteoporos Int. 2008;19(suppl 1):S131-1S32.
3. Vico L et al. High-resolution pQCT analysis at the distal radius and tibia discriminates patients with recent wrist and femoral neck fractures. J Bone Miner
Res. 2008;23:1741-1750.
403
CONTROVERSIAL
QUESTION
5. J. Laíns, Portugal
Jorge LAÍNS, MD
Centro de Reabilitaçao do Centro
Hospital Rovisco Pais
Rua da Fonte
3060-644 Cantanhede
PORTUGAL
(e-mail: jorgelains@sapo.pt)
I
n 2000, he National Institutes of Health (NIH) Consensus Development Conference Statement defined osteoporosis as:
a skeletal disorder characterized by compromised bone strength
predisposing to an increased risk of fracture. Bone strength
reflects the integration of two main features: bone density and
bone quality. Bone quality refers to architecture, turnover, damage accumulation (eg, microfractures) and mineralization.1
Osteoporosis is a disease, and not part of the natural process
of aging, although age and gender are independent fracture
risk factors. “Bone health” is a dynamic process, involving the
concept of homeostasis, and should be considered over the
entire lifespan.1 The health of any living tissue is dependent
on its metabolism/turnover, which allows the tissue to maintain its properties and functions, ie, its youth. Bone is continuously remodeled by the bone multicellular unit (BMU), dissolving areas of microfractures and/or dysfunctional bone and
filling it with new and “healthy” bone. In osteoporosis there is
a disruption of bone remodeling, leading to microarchitectural damage, namely, disruption of, and reduction in, trabeculae
connections. Bone needs to permanently repair the microfractures that occur in its midst. In this connection, it is believed that the age of the mineral crystal may play a role on
bone strength. Research suggests that older bone is more
brittle and that bone remodeling plays an important role in
bone strength, replacing older with newer bone, which is
more elastic and mechanically resistant.2
404
At first glance, this definition of osteoporosis implies that the
goal of any antiosteoporotic treatment is to decrease fracture
risk by increasing bone resistance. However, bone resistance
is dependent on its health and quality, and bone quality is dependent on its architecture, degree, and age of mineralization, and the accumulation of damage. In turn, all of these depend on turnover and the possibility of maintaining the youth
of all the components of bone tissue.2
All antiosteoporotic drugs act on bone turnover, on the activation frequency of the BMU, either by inhibiting resorption
(estrogens, bisphosphonates, calcitonin, and raloxifene), or
by stimulating formation (parathormone [rhPTH 1-84] and its
fragment [rhPTH 1-34]), or by a simultaneous dual action resulting in stimulation of bone formation and inhibition of bone
resorption (strontium ranelate).3 Most probably, these drugs
act not only on bone mineral density (BMD), but also on bone
quality. Again most probably, it is not a coincidence that osteonecrosis of the jaw and a particular type of fractures in the
shaft of the femur are reported with (prolonged) use of antiresorptives, perhaps in relation with the inhibition of bone
turnover, leading to the so-called “frozen bone.” In contrast,
drugs promoting bone formation are proven to ameliorate microarchitecture.2 Interestingly, to my knowledge, there is no
published article or research mentioning any negative interference with bone health with strontium ranelate.
To conclude, when considering treatment with an antiosteoporotic drug, we should take into account both bone safety
and bone health, and not only the prevention of fractures. I
References
1. NIH Consensus Statement Online. Osteoporosis prevention, diagnosis, and therapy. 2000 March 27-29; [cited 2010, 03, 30]; 17(1):1-36.
2. Ott S. Osteoporosis and Bone Physiology. http://courses.washington.edu/
bonephys/phystrength.html [cited 2010, 04, 01]
3. Geusens PP, Roux CH, Reid DM, et al. Drug insight: choosing a drug treatment strategy for women with osteoporosis—an evidence-based clinical perspective. Nat Clin Pract Rheumatol. 2008;4(5):240-248.
CONTROVERSIAL
QUESTION
6. N. Taechakraichana, Thailand
Nimit TAECHAKRAICHANA, MD
Department of Obstetric and Gynecology
Faculty of Medicine
Chulalongkorn University
Bangkok, 10330
THAILAND
(e-mail: nimit2009@gmail.com)
B
one is a specialized connective tissue endowed with
three functions: mechanical, protective, and metabolic. Bone development and function are dictated by the
activity of the osteoblasts and osteoclasts. These include
growth, modeling, repair, and remodeling. Bone remodeling
is a renewal process geared to removing damage in order to
maintain bone strength. This cellular machinery is effective
during the period of adolescence, but fails with advancing
age as the remodeling balance grows negative. The crucial
window for bone accrual during the third decade of life and
the critical transition of postmenopausal bone loss are key
determinants of skeletal mass in the elderly. However, bone
strength—the maximal load that can be applied before a fracture occurs—is also influenced by factors other than bone
mass. For instance,1 sex differences in bone width with greater
periosteal bone formation in boys and higher endocortical
apposition in girls result in a wider bone in boys, conferring
greater resistance to bending. Bone tissue quality, which is related to the degree of bone mineralization and the characteristics of bone matrix also exerts important role in determining bone strength.
The triad of antiosteoporotic therapy includes: (i) enhancing
peak bone mass during adulthood; (ii) preventing bone loss
after menopause; and (iii) preventing falls in the elderly. Most
antiosteoporotic medications used in advanced age to prevent bone loss can be categorized into three main groups:
antiresorptives, bone-formative agents, and “the others.” Most
of the available antiosteoporotic drugs, particularly the bisphosphonates, have been shown to exert their antifracture
efficacy by retarding osteoclast maturation and inhibiting the
cascade of resorbing activities. Bone-formative agents, which
are fewer in number, play a greater role in osteoblastic bone
formation, in particular intermittent parathyroid hormone (PTH).
Strontium ranelate, a recently developed agent, claims a dual
action on bone resorption and bone formation.2 Vitamin K2
is a key coenzyme critical for the maturation of osteocalcin,3
which seems to play a crucial role in osseous and nonosseous
systems.
Fractures have devastating consequences in terms of physical, economic, and psychosocial outcomes. One of the major goals of antiosteoporotic therapy is to prevent fractures in
order to minimize morbidity and maximize quality of life. However, bone health is an issue that goes far beyond the quantifiable repercussion of fractures, since bone functions are multiple. In addition to antifracture efficacy, long-term safety should
be taken into account when considering antiosteoporotic therapy. The risk-benefit ratios of the short- and long-term safety
and efficacy outcomes of each treatment option should be
thoroughly examined. This would include the cardiovascular
and cancer risks in elderly users of hormone replacement therapy,4 the long-term risk of cerebrovascular accident in raloxifene users at high cardiovascular risk,5 the unresolved issue
of osteonecrosis of the jaw in patients using high-dose intravenous bisphosphonates, and the frozen bone debate around
the long-term use of bisphosphonates.6 I
References
1. Seeman E. Physiology of aging: pathogenesis of osteoporosis. J Appl Physiol.
2003;95:2142-2151.
2. Ammann P. Strontium ranelate: a physiological approach for an improved bone
quality. Bone. 2006;38:S15-S18.
3. Plaza SM, Lamson DW. Vitamin K2 in bone metabolism and osteoporosis. Altern Med Rev. 2005;10:24-35.
4. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits
of estrogen plus progestin in healthy postmenopausal women. JAMA. 2002;
288:321-333.
5. Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;
355:125-137.
6. Silverman SL, Maricic M. Recent developments in bisphosphonate therapy.
Semin Arthritis Rheum. 2007;37:1-12.
405
CONTROVERSIAL
QUESTION
7. D. O’Gradaigh, Ireland
Donncha O'GRADAIGH, MB, PHD, MRCPI
Waterford Regional Hospital
Dunmore Road, Waterford
IRELAND
(e-mail: donncha.ogradaigh@hse.ie)
“The doctor has been taught to be interested
not in health, but in disease.
What the public is taught is that health
is the cure for disease.”
Ashley Montagu
O
steoporosis is the paradigm of impaired bone health,
as it is a condition of reduced bone mass and impaired bone architecture caused by perturbed bone
physiology (bone remodeling), resulting in bone fragility and
fracture. Several classes of antiosteoporotic treatment are
available, and their effects on the determinants of bone strength
differ—hence the potential conflict raised in this question.
A bone that fractures in a low-trauma injury is “fragile.” Can
we recognize, and therefore treat, impaired bone health prior to this first fracture? Our most reliable single tool is the
measurement of areal bone mineral density (BMD) in the hip
and spine. However, the majority of those who fracture have
a normal or only modestly impaired BMD.
Bone architecture is assessed on bone biopsy or high-resolution imaging, which is certainly not applicable clinically. Data
suggest that BMD loss may explain only 20% to 30% of the
microarchitectural deterioration seen in an osteoporotic population with prevalent fractures. Clinical risk factors can predict the risk of fracture independently of BMD measurements,
and the presence of these BMD-independent risk factors correlates with the deterioration in measures of bone microarchitecture. Finally, bone turnover markers also support more
accurate prediction of fracture than BMD alone. The purpose
406
of having thus identified impaired bone health is to prevent
fragility fractures. While it is logical to assume that improving
bone health will do so, this may be a fallacy—an improvement in bone health is a means to an end, not an end in itself.
This does not preclude the argument that a treatment that
best restores bone health should be the preferred choice
when fracture risk reduction is comparable.
Each of the existing treatment options alter one or more determinants of bone strength: (i) tissue properties, such as hardness, maximal strength; (ii) bone architecture such as trabecular number, thickness and connectivity, cortical porosity,
trabecularization, and transformation between plate and rodlike trabecular structures; and (iii) dynamic measures such as
mineral apposition rate, activation frequency, and resorption
surfaces.
Interpretation of these comparative data is complex—for instance, while raloxifene has the most pronounced effects on
tissue quality, as assessed by nanoindentation, teriparatide reduces tissue hardness in trabecular bone, but has the greatest
effect on bone volume. Bisphosphonates increase stiffness,
but not hardness, and do not alter bone volume significantly.
The significance of these findings can only be interpreted in
regard to the clinical utility of these treatment options, ie, in
their ability to protect a patient from fracture.
Strontium ranelate is notable in adjusting bone formation and
bone resorption in a way that most closely resembles preosteoporotic bone health, with desirable effects on trabecular and cortical bone and without adverse effects on tissue
quality such as stiffness. This allows a restoration of bone
quality, mineral properties, and, most crucially normal bone
remodeling.
To paraphrase the architect Leon Battista Alberti, this treatment can “adjust all the parts proportionally so as not to impair the harmony of the whole,” achieving the combined, not
conflicting goals of reduced bone fragility through optimizing
every aspect of bone health. I
CONTROVERSIAL
QUESTION
8. P. Sambrook, Australia
Philip SAMBROOK,
MBBS, MD, FRACP, LLB
Professor, Sydney Medical School
University of Sydney
Level 4, Building 35
Royal North Shore Hospital
St Leonards, Sydney 2065
AUSTRALIA
(e-mail: sambrook@med.usyd.edu.au)
T
he principal functions of the skeleton are mechanical
support, maintenance of calcium homeostasis, and
hematopoiesis in the bone marrow. These functions
can be disturbed in a variety of metabolic bone diseases of
which osteoporosis is the commonest. Metabolic bone disease is a rather loose term that encompasses diseases of
bone in which abnormal bone remodeling results in a reduced
volume of mineralized bone and/or abnormal bone architecture. These processes in turn usually give rise to an increased
risk of fracture. For this reason, the most important complication of osteoporosis is often considered to be fracture, although other manifestations can have significant effects on
patient quality of life.
Osteoporotic fractures result from a combination of decreased
bone strength and increased incidence of falls. Bone mineral
density (BMD), because it is easy to measure and has an excellent precision, was initially the favored end point in most
clinical trials and remains the best noninvasive assessment of
bone strength available in routine clinical practice. Prevention
of fractures subsequently became the more relevant end
point for clinical trials with a view to satisfying regulatory authorities about the efficacy of a particular drug.
However, it is now recognized that bone strength (and hence
fracture risk) depends on many properties including the shape
and size of the bone as well as the strength of the material
inside. Material strength is influenced by architectural abnormalities and microdamage as well as BMD. Assessment
of these other end points (often referred to as “bone quality”
in the past), is now considered a more appropriate reflection
of overall bone health. Architectural abnormalities occur particularly in the trabeculae of vertebral bodies. A loss of trabecular connectivity (density of connections between trabeculae)
especially with horizontal loss, results in increased loads on
remaining trabeculae resulting in a weakened structure. Loss
of trabecular connectivity has been demonstrated in individuals with vertebral crush fractures compared with controls,
even when matched for bone volume. Prior fracture, an independent risk factor for further fracture, may reflect these
existing architectural abnormalities. Measurement of microarchitecture is possible in the research setting,1,2 but is more
problematic in clinical practice. Nevertheless, it is now considered an important end point in all recent major trials of antiosteoporotic therapies.
Biochemical bone markers have also been used as intermediate end points in most recent major studies of antiosteoporotic therapies. Bone resorption markers, in particular, may
add an independent, predictive value to the assessment of
bone loss and fracture risk. There are also potential advantages in monitoring antiosteoporotic treatment in the short
term in addition to bone densitometry, to more quickly identify nonresponders to therapy, or noncompliance.
To summarize, while the clinical goal of antiosteoporotic therapy is to prevent fractures, understanding the mechanism
of action of such benefit to the skeleton is enhanced when
measures of bone health that include not just BMD, but also
bone turnover and microarchitecture are included in trial endpoints. I
References
1. Borah B, Dufresne TE, Ritman EL, et al. Long-term risedronate treatment normalizes mineralization and continues to preserve trabecular architecture: sequential triple biopsy studies with micro-computed tomography. Bone. 2006;39:
345-352.
2. Arlot ME, Jiang Y, Genant HK, et al. Histomorphometric and microCT analysis
of bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate. J Bone Miner Res. 2008;23:215-222.
407
PROTELOS
‘‘
Consistent and robust evidence supports the efficacy of
Protelos in decreasing vertebral,
nonvertebral, and hip fracture risk
in a broad spectrum of patient profiles. Protelos improves both cortical and trabecular bone architecture by building new strong and
healthy bone in postmenopausal
women. It is the only antiosteoporotic agent with proven antifracture efficacy over 5, and even 8
years, with no impairment of safety or tolerability. Protelos ushers in
a new era as first-line treatment in
the management of osteoporosis.”
Better bone health
for osteoporotic patients:
Protelos decreases fracture risk
and improves bone quality
b y P. H a l b o u t , Fra n c e
E
Philippe HALBOUT, PhD
Servier International
Suresnes, FRANCE
strogen depletion in postmenopausal women induces a rapid decrease
in bone quality, bone quantity, and consequently, bone strength, resulting in an increase in fracture risk. Treatments addressing osteoporosis
must be judged not only on their ability to decrease the risk of fractures, but
also to improve the bone status of osteoporotic women and ensure efficacy
and long-term protection, whatever the patient profile, including those patients
most difficult to treat. Protelos (strontium ranelate) is an antiosteoporotic agent
indicated in the prevention of vertebral and hip fracture risk in postmenopausal
women with osteoporosis. The efficacy of Protelos actually goes beyond this
definition inasmuch as its range of efficacy extends from preventing fracture
risk in osteopenic patients to those with the most severe forms of osteoporosis, and from the youngest patients to those most advanced in years. Protelos
is the only among all other antiosteoporotic agents with proven long-term efficacy against vertebral, nonvertebral, and hip fractures over 5 years, as established by a randomized, double-blind controlled trial. This efficacy is acknowledged by the European Society for Clinical and Economic Aspects of
Osteoporosis and Osteoarthritis (ESCEO), which published, in 2008, a European Guidance that ranked Protelos as a first-line treatment with proven efficacy in reducing the risk, not only of vertebral fractures, but also of nonvertebral fractures, among which specifically hip fractures. Protelos’s unrivalled
efficacy results from its ability to build new bone and improve bone health in
osteoporotic women. Three studies have shown that Protelos consistently
improves both cortical and trabecular bone, which are the main determinants
of hip and vertebral fractures, respectively. In osteoporotic women, the improvement in bone architecture with Protelos is already significant after 1 year
of treatment and is maintained over 5 years. Protelos builds strong and healthy
bone and provides full protection against fracture risk in osteoporotic postmenopausal women. Protelos heralds a new therapeutic approach that fills
the bill as first-line treatment in the management of osteoporosis.
Dr Philippe Halbout, Servier
International, 35 rue de Verdun,
92284 Suresnes Cedex, France
(e-mail:
philippe.halbout@ fr.netgrs.com)
408
he changes that take place at bone tissue level in postmenopausal women
lead to a decrease in both quantity and quality of bone. These changes dramatically decrease bone strength while silently increasing the risk of fractures. The main goal of the first-generation drugs that were designed to treat osteoporosis—like the antiresorptives developed 40 years ago—was basically to prevent
the risk of fractures by stopping the degradation of bone. Unfortunately, this strate-
T
Protelos: better bone health for osteoporotic patients – Halbout
PROTELOS
Risk of fractures (FRAX)
Severity of the disease
Comprehensive efficacy: Protelos protects against
vertebral, nonvertebral, and hip fractures
Patient
Osteoporosis treatment
Fractures
Vertebral
Nonvertebral
Bone architecture
Hip
Cortical
bone
Trabecular
bone
Figure 1. Key criteria for the treatment of osteoporosis.
gy was not effective enough to ensure a satisfactory outcome
of the management of osteoporosis. First, these agents failed
to provide complete efficacy in preventing hip and vertebral
fractures; second, they proved unable to build new bone to
counterbalance the bone loss induced by the menopause;
third, their efficacy over the entire range of osteoporosis patient profiles and in the long-term is not established; fourth,
these drugs stop bone remodeling, an effect that may be associated with rare, but severe, side effects on bone.
Today’s treatment of osteoporosis must aim to improve bone
architecture while taking into account the living nature of bone
tissue; this is particularly crucial in view of the long-term nature
of osteoporosis treatment. Protelos is a modern treatment for
postmenopausal osteoporosis with proven efficacy against
vertebral and hip fractures, whatever the risk factors, both in
the short and in the long-term. The antifracture efficacy of Protelos has direct benefits for bone architecture: there is robust
evidence showing that, thanks to its unique dual mode of action, Protelos builds strong and healthy bone in postmeno-
Two types of fractures must be considered in the prevention
of fractures in postmenopausal women with osteoporosis:
N Vertebral fractures: these are the most common type of fracture, which generally occur in the youngest osteoporotic patients; when associated with height loss or back pain they are
designated as “clinical vertebral fractures”;
N Hip fractures: these are definitely the most serious type of
fracture and have a major impact on morbidity and mortality,
especially in elderly subjects.
Two pivotal trials have assessed the efficacy of Protelos: SOTI
(the Spinal Osteoporosis Therapeutic Intervention trial) and
TROPOS (TReatment Of Peripheral Osteoporosis Study). Both
were multinational, randomized, double-blind, and placebocontrolled trials, involving a total of 6740 postmenopausal
women, all of whom received concomitant calcium/vitamin D
supplementation at a dose tailored to the degree of deficiency (calcium 500/1000 mg; vitamin D3 400/800 IU).
RR: -49%
RR: -41%
RR: -33%
P<0.01
P<0.01
P<0.01
40
Patients (%)
Patient profile
pausal osteoporotic women. This chapter focuses on Protelos’
ability to ensure comprehensive antifracture efficacy against
all types of osteoporotic fractures, while at the same time improving bone health in osteoporotic patients (Figure 1).
37.1
35
Protelos
30
Placebo
25
32.8
27.1
20.9
20
15
10
10.2
6.4
5
0
SELECTED
ARR
BMD
BMI
DXA
ESCEO
FRAX®
HR-pQCT
NNT
RRR
SOTI
TROPOS
absolute risk reduction
body mass index
European Society for Clinical and Economic
Aspects of Osteoporosis and Osteoarthritis
Fracture Risk Assessment Tool
high-resolution peripheral quantitative computed
tomography
number needed to treat
relative risk reduction
Spinal Osteoporosis Therapeutic Intervention
TRreatment Of Peripheral Osteoporosis Study
0-1 year
0-3 years
0-4 years
n=1442, RR=0.51
95% CI [0.36; 0.74]
ARR=3.8%
n=1442, RR=0.59
95% CI [0.48; 0.73]
ARR=11.9%
n=1445, RR=0.67
95% CI [0.55; 0.81]
ARR=10%
Figure 2. Effects of Protelos on vertebral fracture risk in women
with postmenopausal osteoporosis.
Abbreviations: ARR, absolute risk reduction; CI, confidence interval; RR, relative risk.
Modified after reference 1: Meunier et al. N Engl J Med. 2004;350:459-468.
© 2004, Massachusetts Medical Society.
N SOTI included 1649 postmenopausal women aged ⱖ50
years with ⱖ1 vertebral fracture(s) and lumbar spine bone mineral density (BMD) ⱕ0.840 g/cm², assessed by means of a
Hologic™ BMD diagnosis system (www.hologic.com). This trial was designed to assess the efficacy of Protelos against vertebral fractures. Protelos decreased new vertebral fracture risk
by 49% after only 1 year (relative risk [RR], 0.51; 95% confi-
409
PROTELOS
dence interval [CI], 0.36-0.74; P<0.001).
Clinical vertebral fractures, defined as
vertebral fracture associated with back
pain and/or height loss ⱖ1 cm, fell by
52%, also as early as by the first year of
treatment (RR, 0.48; 95% CI, 0.29-0.80;
P=0.003). Reductions in vertebral and
clinical vertebral fractures were still significant at 3 years (41%; RR, 0.59; 95%
CI, 0.48-0.73, and 38%; RR, 0.62; 95%
CI, 0.47-0.83, respectively, both P<0.001)
(Figure 2, page 409).1
Prevention of
vertebral fracture
Women with
Women with osteoporosis +
osteoporosis vertebral fracture
Protelos
Alendronate
Risedronate
Ibandronate
Zoledronic acid
HRT
Raloxifene
Teriparatide
and PTH
+
+
+
NA
+
+
+
+
+
+
+
+
+
+
Prevention of
nonvertebral fracture
Women with
Women with osteoporosis +
osteoporosis vertebral fracture
+ (including hip)
NA
NA
NA
NA
+
NA
+ (including hip)
+ (including hip)
+ (including hip)
+*
NA (+)†
+
NA
Patients (%)
N TROPOS assessed the efficacy of ProNA
+
NA
+
telos against nonvertebral and hip fractures in 5091 postmenopausal women
* In subsets of patients only (post hoc analysis).
with femoral neck BMD equivalent to a
† Mixed group of patients with or without prevalent vertebral fractures.
+ = effective drug.
T-score below –2.5 SD (centralized normative data analysis: Dr D. O. Slosman,
Geneva, Switzerland), and age ⱖ74 Table I. Protelos is the only treatment with demonstrated efficacy against vertebral, nonyears or 70 to 74 years with an addition- vertebral, and hip fractures, whatever the severity of osteoporosis.
HRT, hormone replacement therapy; NA, no evidence available; PTH, parathyroid hormone.
al fracture risk factor. At 3 years, Protelos Abbreviations:
Adapted from reference 4: Kanis et al. Osteoporos Int. 2008;19:399-428. © 2008, Springer London.
decreased the risk of nonvertebral fractures by 16% (RR, 0.84; 95% CI, 0.702-0.995; P<0.05) and In summary, SOTI and TROPOS confirmed the efficacy of
the risk of major nonvertebral fractures (hip, wrist, pelvis, Protelos against all types of osteoporotic fractures, including
sacrum, ribs-sternum, clavicle, and humerus) by 19% (RR, vertebral and hip fractures, and thus its comprehensive effi0.81; 95% CI, 0.66-0.98; P<0.05) (Figure 3).2 In the subgroup cacy in postmenopausal women.3
of patients with the highest risk of hip fracture, ie, those aged
ⱖ74 years with femoral neck T score ⱕ–3 SD, Protelos de- Place of Protelos in the treatment of osteoporosis
creased the risk of hip fractures by 36% (RR, 0.64; 95% CI, For clinicians treating patients with osteoporosis, it is difficult
0.412-0.667; P=0.046) over 3 years. TROPOS also confirmed to judge the comparative efficacy of antiosteoporotic treatthe decrease in risk of new vertebral fractures over 1 and 3 ments due to the fact that no comparative studies are availyears by 45% (RR, 0.55; 95% CI, 0.39-0.77; P<0.001) and able. This is because such studies are in practice not feasible,
39% (RR, 0.61; 95% CI, 0.51-0.73; P<0.001), respectively, as they require an exceedingly high number of patients and
versus placebo.
long-term follow-up. In an attempt to obviate this difficulty, the
European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) published in 2008 the
European Guidance for the Treatment and Management of
RR: -16%
RR: -19%
Osteoporosis in Postmenopausal Women, which compared
P<0.05
P<0.05
15
the efficacy of antiosteoporotic treatments on the basis of the
Protelos
12.9
findings of available large trials. In Table 6 of the Guidance,
Placebo
11.2
the board of experts highlights the efficacy of Protelos against
10.4
vertebral and nonvertebral—including hip—fractures in pa10
8.7
tients with osteoporosis and established osteoporosis, in comparison with other treatments (Table I).4
5
0
Full assessment of efficacy requires that the usual analysis of
clinical trials and relative risk reduction (RRR) be complemented by the analysis of absolute risk reduction (ARR) and numNonvertebral
Major nonvertebral
n=4932, RR=0.84
95% CI [0.702; 0.995]
ARR=1.7%
n=4932, RR=0.81
95% CI [0.66; 0.98]
ARR=1.7%
Hip, wrist, pelvis and
sacrum, ribs-sternum,
clavicle, or humerus
410
Figure 3. Decrease in relative risk of nonvertebral and major nonvertebral fractures with Protelos vs placebo in the TROPOS study.
Abbreviations: ARR, absolute risk reduction; BMD, bone mineral density; CI, confidence interval; RR, relative risk; TROPOS, TRreatment Of Peripheral Osteoporosis Study.
Modified after reference 2: Reginster et al. J Clin Endocrinol Metab. 2005;
90:2816-2822. © 2005, The Endocrine Society.
PROTELOS
ber needed to treat (NNT, the reciprocal of ARR).5 Even if it is
not possible to directly compare studies with different populations and different levels of risk, these parameters are fair
indicators of the magnitude of the benefits a physician can expect from a treatment. In a very recent review, J. D. Ringe and
J. G. Doherty showed that Protelos had very low NNTs, with
only 9 patients needing to be treated in order to prevent,
over 3 years, 1 vertebral fracture, vs 21 for ibandronate, and
48 patients needed to be treated to prevent 1 hip fracture, vs
91 for three of the bisphosphonates studied by the authors
(Figure 4).6 These AAR and NNT figures confirm Protelos as a
very effective treatment, and fully justify the
ESCEO Guidance ranking Protelos as firstline treatment.
SOTI and TROPOS populations: 3-year vertebral fracture risk
fell by 37% in women <70 years (RR, 0.63; 95% CI, 0.460.85; P=0.003) and by 42% in those aged 70 to 80 years (RR,
0.58; 95% CI, 0.48-0.68; P<0.001).8
Protelos: efficacy whatever the risk
factor profile and whatever the type
of patient
n
Ale
Elderly osteoporotic women (80 years and more), because of
the frequent combination of risk factors observed in that agegroup, are especially prone to fractures. In these women, osteoporotic fractures have particularly debilitating consequences,
characterized by delayed fracture healing, functional impairment, and loss of autonomy.
A
The diversity of possible risk factor combination profiles makes each osteoporotic patient unique. An ideal treatment should be
able to achieve antifracture efficacy independently of any given risk factor profile. This
has been widely demonstrated to be the
case with Protelos, well before the World
Health Organization (WHO) Fracture Risk
Assessment Tool (FRAX®) to predict fracture
risk came into widespread use.
Absolute risk reduction
for vertebral fracture
0
7.0
8
te
te
na
na
dro
e
Ris
4
dro
te
na
dro
le
Zo
n
Iba
b
ma
ne
xife
osu
lo
Ra
n
De
os
tel
Pro
4.8
5.0
4.9
P=0.003
P<0.0001
P<0.001
6.5
7.6
P<0.001
P<0.001
P<0.001
11.2
12
P<0.001
Corresponding NNT
20
15
B
ate
0
A
14
21
R
d
an
Ib
21
ate
ron
ron
d
ise
16
ate
ate
ron
d
len
Z
9
ab
e
ifen
ron
d
ole
NA
Absolute risk reduction
for hip fracture
Until recently, evaluation of risk of fracture in
postmenopausal women was solely based
on BMD measurement, with osteopenia
being defined by a T-score between –1 SD
and 2.5 SD, and osteoporosis by a T-score
< –2.5 SD. However, epidemiological studies stress the key role played by other risk
factors, the most important one being age,
followed by prevalent fractures, steroid
treatment, smoking, alcohol intake, maternal
fracture history, and low body mass index
(BMI).
te
na
dro
x
alo
R
NA
sum
o
en
D
os
tel
Pro
0.3
P=0.04
1
2
1.1
1.1
1.1
P=0.047
P=0.02
P=0.02
2.1
Corresponding NNT
N Protelos is effective from the youngest
48
91
91
91
NA
334
NA
to the oldest and frailest osteoporotic
patients
In the youngest age-group of postmenopausal women, ie, those aged 50-65 years, Figure 4. Efficacy of antiosteoporotic treatments on vertebral (A) and hip (B) fractures.
ARR, absolute risk reduction; NA not available; NNT, number to treat.
in whom osteoporosis, due to a dramatic Abbreviations:
Modified after reference 6: Ringe and Doherty. Rheumatol Int. 2010;30:863-869. © 2010, Springer.
increase in bone remodeling, is one of the
most common disorders, Roux et al showed that Protelos This results in increased mortality and consumption of nursreduced vertebral fracture risk by 43% (RR, 0.57; 95% CI, ing home and health care financial resources. In such patients,
0.36-0.92; P=0.019) over 3 years and that this effect was sus- Protelos has been shown to have complete and sustained eftained over a further year, as shown by a 35% reduction in ficacy, reducing vertebral fracture risk by 59% (RR, 0.41; 95%
vertebral fracture risk at 4 years (RR, 0.65; 95% CI, 0.42-0.99; CI, 0.22-0.75; P=0.002), clinical fractures by 37% (RR, 0.63;
P=0.049).7 Efficacy was also independent of age in the pooled 95% CI, 0.44-0.91; P=0.012), and nonvertebral fractures by
P=0.046
411
PROTELOS
30
RR: -41%
RR: -31%
P=0.027
P=0.011
RR: -27%
P=0.018
29
Protelos
Placebo
24.9
Patients (%)
25
19.7
20
14.2
15
10
5
0
6.8
4
0-1 year
0-3 years
0-5 years
n=1488, RR=0.59
95%CI=[0.37; 0.95]
ARR=2.8%
n=1488, RR=0.69
95%CI=[0.52; 0.92]
ARR=5.5%
n=1488, RR=0.73
95%CI=[0.57; 0.95]
ARR=4.1%
Figure 5. Decrease in nonvertebral fracture risk in elderly patients
with Protelos.
Abbreviations: ARR, absolute risk reduction; CI, confidence interval; RR, relative risk; SOTI, Spinal Osteoporosis Therapeutic Intervention; TROPOS, TRreatment Of Peripheral Osteoporosis Study.
Modified after reference 10: Seeman et al. Bone. 2010;46:1038-1042. © 2010,
IBMS, International Bone Mineral Society/Elsevier.
41% (RR, 0.59; 95% CI, 0.37-0.95; P=0.027) after 1 year, and
by 32% (RR, 0.68; 95% CI, 0.50-0.92; P=0.013), 22% (RR,
0.78; 95% CI, 0.61-0.99; P=0.040), and 31% (RR, 0.69; 95%
CI, 0.52-0.92; P=0.011) after 3 years.9 Protelos is the only antiosteoporosis agent to have shown long-term efficacy in the
elderly, with decreases of 31% in vertebral fracture risk (RR,
0.69; 95% CI, 0.52-0.92; P=0.010) and 26% in nonvertebral
fracture risk (RR, 0.74; 95% CI, 0.57-0.95; P=0.019) over 5
years (Figure 5).10
N Protelos: proven efficacy whatever the type of patient
In osteoporotic women with a hip/lumbar spine T-score is
ⱕ–2.5 SD, Protelos decreases vertebral fracture risk by 39%
(RR, 0.61; 95% CI, 0.53-0.70; P<0.001).8 Importantly, this decrease is observed whatever the patient’s risk factor profile.
In addition, Protelos is the only treatment able to achieve a
reduction in vertebral fracture risk in osteopenic women (hip/
lumbar spine T-score between –1 and –2.5 SD) by as high
as 72% (RR, 0.28; 95% CI, 0.07-0.99; P=0.045).13 The efficacy of Protelos is also independent of the number of prevalent fractures: in osteoporotic women with 0, 1, or 2 prevalent
fractures, Protelos decreased vertebral fracture risk by 48%
(RR, 0.52; 95% CI, 0.40-0.67; P<0.001), 45% (RR, 0.55; 95%
CI, 0.41-0.74; P<0.001), and 33% (RR, 0.67; 95% CI, 0.550.81; P<0.001), respectively.8 Similarly, in osteopenic women
with and without prevalent fractures, Protelos decreased vertebral fracture risk by 38% (RR, 0.62; 95% CI, 0.44-0.88;
P=0.008) and 59% (RR, 0.41; 95% CI, 0.17-0.99; P=0.039),
respectively.13
With regard to bone markers, Protelos decreased vertebral
fracture risk by 33% (RR, 0.67; 95% CI, 0.47-0.95; P=0.023)
and 49% (RR, 0.51; 95% CI, 0.37-0.70; P<0.001) in postmenopausal osteoporotic women with low- and high-turnover,
respectively.14
Finally, the efficacy of Protelos has been shown to be independent of family history of osteoporosis, bone mass index,
and smoking.8
RR: -45%
RR: -43%
P=0.049
P=0.036
12
Protelos
10.2
The above confirms that Protelos has complete antifracture
efficacy, from the youngest to the most elderly patients. In the
youngest patients, the earlier Protelos is introduced at menopause onset, the greater the anticipated benefit. In the oldest patients, clinical trials show a significant reduction in osteoporotic fractures after only 1 year of treatment, indicating
that it is never too late to prevent fractures in such patients.
412
Placebo
10
Patients (%)
A new approach, taking into account not only age, but a combination of health status factors (decreased strength, tiredness, involuntary weight loss, slowness, and inactivity), has
recently been used to define the “frailty” of the most elderly
patients and analyze the efficacy of antiosteoporotic treatments.11 It was found that frail osteoporotic women were
more vulnerable when exposed to stressors and more likely
not only to fall, but also, as a result, to fracture. Another finding was that Protelos was shown to be the only treatment able
to decrease vertebral fracture risk by 66% (RR, 0.34; 95%
CI, 0.12-0.92; P=0.02) and by 58% (RR, 0.42; 95% CI, 0.230.73; P=0.002) over 1 and 3 years, respectively.12
8
7.2
6.3
6
4
4.0
2
0
0-3 years
0-5 years
n=1128, RR=0.55
95% CI [0.30; 0.99]
ARR=2.3%
n=1128, RR=0.57
95% CI [0.33; 0.97]
ARR=3%
Patients aged 74 years or more
and with femoral neck and lumbar
spine BMD T-score #−2.4 SD
Figure 6. Decrease in hip fracture risk with Protelos. Results at 3
and 5 years.
Abbreviations: ARR, absolute risk reduction; BMD, bone mineral density;
CI, confidence interval; RR, relative risk; TROPOS, TRreatment Of Peripheral
Osteoporosis Study.
Modified after reference 15: Reginster et al. Osteoporos Int. 2008;1(suppl 1):
S26-S27. (Abstract OC49; ECCEO 2008).© 2008, Springer London.
PROTELOS
Protelos: comprehensive efficacy over 5 years,
sustained over 8 years
follow-up of the patients treated with Protelos. Last but not
least, assessment of the long-term safety of Protelos showed
that it was safe and very well tolerated.16
In Western societies, in which life expectancy is growing year
after year, only an antiosteoporotic treatment with long-term
efficacy will be able to guarantee effective protection against Protelos treats osteoporosis by building new strong
the consequences of osteoporotic fractures and preserve the and healthy bone
patients’ quality of life. To date, there is no evidence show- Although mandatory, it is not enough for an antiosteoporotic
ing that conventional antiosteoporotic treatments, even the treatment today to merely prevent osteoporotic fractures: it
bisphosphonates, are able to decrease vertebral or nonver- should also, concomitantly, be able to treat osteoporotic bone
tebral fractures beyond 3 to 4 years of treatment, probably itself. Indeed, since it is the decrease in bone quantity and
because these treatments fail to create a new and healthy quality occurring after menopause that is at the origin of the
bone in osteoporotic patients. In contrast, Protelos has robust fracture risk in osteoporotic patients, improving bone status
evidence derived from studies with the most stringent design is a strong requirement, as only this can ensure strong and
(randomized, double-blind, placebo-controlled trials) that it rapid protection against all osteoporotic fractures, both in
is effective against vertebral, nonvertebral,
and hip fractures over 5 years. This efficacy
was even shown to persist after 8 years of
PROTELOS
treatment, as demonstrated in an open-laBone formation
Bone resorption
bel extension study of TROPOS.
Randomized, double-blind, multicenter, placebo-controlled studies with a preplanned
analysis are the gold standard to assess the
efficacy of a treatment: to date, Protelos is
the only antiosteoporotic treatment for which
long-term efficacy has actually been investigated in such a trial, namely, TROPOS,
which was conducted over 5 years. In this
trial, Protelos was found to have comprehensive efficacy: nonvertebral fracture risk was
reduced by 15% (RR, 0.85; 95% CI, 0.730.99; P=0.032); new major nonvertebral osteoporotic fracture risk was reduced by 18%
(RR, 0.82; 95% CI, 0.69-0.98; P=0.025),
and vertebral fracture risk was reduced by
24% (RR, 0.76; 95%CI, 0.65-0.88; P<0.001)
versus placebo, over 5 years.
Osteoblasts
RANKL
RANK
Preosteoblasts
Osteoclasts
Preosteoclasts
Osteoprotegerin
CaSR
Replication
Differentiation
CaSR
Osteoclasts
Osteoblasts
Activity
Osteoblasts
Lifespan
Figure 7. The unique mode of action of Protelos.
Protelos increases bone formation through an increase in osteoblast replication, differentiation, and
In a subgroup of patients at high risk of hip activity. In parallel, Protelos decreases bone resorption via a decrease in osteoclast differentiation and
activity and the upregulation of the OPG/RANKL ratio in osteoblasts.
fractures (n=1128; ⱖ74 years and lumbar/ Abbreviations: CaSR, calcium-sensing receptor; OPG, osteoprotegerin; RANK(L), receptor activator
femoral neck T-score ⱕ–2.4 SD), Protelos nuclear factor-κ B (ligand).
after references 17 and 18: Marie et al. Calcif Tissue Int. 2001;69(3):121-129. © 2001, Springer;
reduced hip fracture risk by 43% versus pla- Modified
and Brennan et al. Calcif Tissue Int. 2006:78:S129 (Abstract P356). © 2006, Springer.
cebo over 5 years (RR, 0.57; 95% CI,
0.33-0.97; P=0.036) (Figure 6).15 Finally, only 21 patients need- the short and long term. Conventional treatments, including
ed to be treated with Protelos to prevent 1 new osteoporot- antiresorptive treatments, have not been able to prevent fracic fracture.15 The long-term efficacy of Protelos was confirmed ture risk in the long term, nor have they shown effectiveness
in a 3-year open-label extension of TROPOS, including 893 in patients displaying the most severe risk factor profiles,
patients followed for a total of 8 years. Cumulative incidence probably due to the fact that these treatments are unable to
of new vertebral fractures over the 3-year extension period build new bone. It is now well established that the increase
(13.7%, 5-8 years) was fully comparable with that in the first in BMD observed in bisphosphonate-treated patients is due
3 years of TROPOS (11.5%, 1-3 years), thus showing that to the hypermineralization of bone resulting from the marked
Protelos’ efficacy extended for as long as over 8 years. The decrease in bone remodeling induced by these agents. The
same conclusion can be drawn for nonvertebral fractures, for consequence of this negative impact on bone remodeling is
which the cumulative incidence was similar at the beginning illustrated by the rare—but dangerous—occurrence of severe
(12%, 1-3 years) and at the end (9.6%, 5-8 years) of the 8-year side effects on bone leading to atypical fractures—an issue of
413
PROTELOS
growing concern for the European Medicines Agency (EMA)
and US Food and Drug Administration (FDA). The situation
is quite the reverse with Protelos. Protelos provides a new
approach to the management of osteoporosis thanks to its
unique dual mode of action, which enables it to build new and
strong bone (Figure 7, page 413).17,18 It shows comprehensive
and long-term efficacy whatever the type of osteoporotic fracture, whatever the patient’s profile, and whatever the patient’s
risk factors. With Protelos, it is now possible not only to prevent fractures, but also to treat osteoporotic bone, as consistently confirmed in the literature.
Bone biopsies from SOTI and TROPOS patients were the first
to establish the efficacy of Protelos in osteoporotic patients.
Treatment for 3 years resulted in marked bone microarchitecture benefits, as evidenced by an 18% increase in cortical
bone thickness (P=0.008) and a 14% increase in trabecular
number (P=0.05), together with a 16% decrease in trabec-
Placebo 36 months
Protelos 36 months
Cortical thickness
+18%
P=0.008
Trabecular number
+14%
P=0.05
Trabecular separation
–16%
P=0.04
ular separation (P=0.004). These beneficial effects of Protelos
on bone architecture result from increased osteoblast activity, as reflected by an increase in mineral apposition rate
(+9%; P=0.019) and osteoblast surface (+38%; P=0.047), and
a 10% trend toward a decrease in osteoclast surface. These
improvements were associated with a change in bone structure from “rod-like” on placebo to “plate-like” on Protelos, signaling more resistant bone (Figure 8).19
Further demonstration is provided by a comparison of the
effects of Protelos and alendronate in a recent head-to-head
randomized, double-dummy, double-blind study in osteoporotic women.20 In this study, a high-resolution-peripheral
quantitative computed tomography (HR-pQCT, SCANCO
Medical) was used to compare the effect on bone microarchitecture after 1 year of treatment with Protelos versus alendronate. Results showed that cortical thickness was increased
by 5.3% (P<0.001) and trabecular bone volume/tissue volume ratio by 2.0% (P=0.002) with Protelos; the changes in
each parameter were significant as early as by 3 months of
treatment (P=0.012 and P=0.042, respectively) (Figure 9); and
remained so after 2 years.21 No improvement occurred in the
alendronate group, confirming alendronate’s inability to build
new bone.20
Analysis of hip architecture in TROPOS patients is yet another demonstration of the benefits of Protelos on bone. The
relationship between hip geometry and bone strength was
studied in 483 TROPOS patients (Protelos, n=251; placebo,
n=231) after 5 years of treatment, by using the dual-energy
x-ray absorptiometry (DXA)-derived hip structure analysis
(HSA) program devised by Thomas Beck. In this study, Protelos was shown to increase cortical thickness at the femoral
neck, intertrochanteric region, and proximal shaft (+5.2±9.8%
vs –3.6±7.9%, P<0.001 vs placebo). This improvement in
bone microarchitecture was independent of the increase in
BMD and resulted in improved bending strength, with an increase in section modulus of +8.6±14.3% vs –2.3±11.6% vs
placebo (P<0.001; Figure 10).22
Figure 8. Improvement in bone architecture at cortical and trabecular sites in postmenopausal women with osteoporosis with
Protelos.
Modified after reference 19: Arlot et al. J Bone Miner Res. 2008;23:215-222.
© 2008, ASBMR, The American Society for Bone and Mineral Research.
Ct.Th
BV/TV
Protelos
Protelos
6.0
2.5
5.0
P=0.062
4.0
3.0
P=0.012
2.0
1.0
Alendronate
P=0.048
2.0
1.5
P=0.127
1.0
P=0.042
0.5
0.0
Alendronate
–0.5
–1.0
0.0
0
414
Change from baseline (%)
Change from baseline (%)
P=0.045
6
12 Months
0
6
12 Months
Figure 9. Comparison of changes in
cortical thickness
and ratio of bone
volume to tissue
volume for Protelos
and alendronate.
Abbreviations: Ct.Th,
cortical thickness;
BV/TV, bone volume/
tissue volume.
Modified after reference
20: Rizzoli et al. Rhumatol Int. 2010;30:13411348. © 2010, Springer.
PROTELOS
In summary, three independent clinical studies have consistently demonstrated the benefits of Protelos on bone in postmenopausal osteoporotic patients. The improvement in cortical bone—which is the main determinant of hip fracture—is
undoubtedly the basis for Protelos’ efficacy in reducing the
risk of hip fractures, while the efficacy of Protelos in improving trabecular bone—which is the main determinant of vertebral fracture—accounts for its ability to reduce the risk of
vertebral fractures. Importantly, these studies also illustrate the
consistency of the relationship between the improvement in
bone health with Protelos, which has been established by randomized clinical trials after 1, 3, and 5 years of treatment, and
the efficacy of Protelos in decreasing the risk of osteoporotic
fractures, likewise established after 1 to 5 years of treatment.
The fact that Protelos is able to treat the osteoporotic bone
explains its comprehensive efficacy against osteoporotic fractures, whatever the patient profile, whatever the type of fracture, and that this efficacy extends to the long term. Finally,
no abnormalities in bone structure or mineralization have been
reported after 5 years of treatment with Protelos, indicating
that, besides its obvious benefits in terms of bone architecture, Protelos is totally safe for bone, as well as for patients.27
Conclusion
Consistent and robust evidence supports the efficacy of Protelos in improving cortical and trabecular bone, the main determinants of hip and vertebral fractures, respectively. Protelos
treats the bone defects responsible for the increased risk of
fractures in postmenopausal women by building new strong
and healthy bone. This effect accounts for the comprehensive efficacy of Protelos in reducing vertebral, nonvertebral,
and hip fracture risk, no matter what the patient profile. Protelos’ efficacy develops quickly and is sustained in the long-
Narrow neck
Intertrochanteric
Bone mass (g/cm2 )
Finally, four recent studies performed in nonclinical models—
including osteoporotic models—have shown that the effects
of Protelos on bone architecture improved fracture healing
and osseointegration. Thus, Ly et al23 and Haberman et al24
evidenced a consistent improvement in both bone callus architecture and bone strength with Protelos, but not with teriparatide. In parallel, two other studies25,26 showed that treatment with Protelos improved osseointegration by increasing
the resistance of implants in bone.
Shaft
0
1
2
3
4
5
Protelos
(n=251)
Placebo
(n=232)
P
CSA
9.05±10.65
–4.06±8.82
CSMI
8.60±14.06
–4.81±14.63
<0.001
11.07±14.03
–4.72±14.77
<0.001
Endocortical diameter
–1.93±3.19
–0.01±3.59
<0.001
Cortical thickness
10.27±11.57
–4.02±9.33
<0.001
Section modulus
Buckling ratio
–10.32±10.08
5.93±22.00
<0.001
<0.001
Figure 10. Protelos improves hip geometry and bone strength
compared with the placebo group.
Abbreviations: CSA, cross-sectional area; CSMI, cross-sectional moment of inertia.
Modified after reference 22: Briot et al. Ann Rheum Dis. 2009;68(suppl 3)665.
Abstract SAT0375. © 2009, BMJ Publishing Group.
term. Studies consistently show that the efficacy of Protelos
is superior to that of other antiosteoporotic agents, both on
bone architecture and on reduction of fracture risk. By building strong and healthy bone and providing comprehensive
protection against fractures in osteoporotic postmenopausal
women, Protelos ushers in a new era as first-line treatment in
the management of osteoporosis. I
References
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2. Reginster JY, Seeman E, de Vernejoul MC, et al. Strontium ranelate reduces
the risk of nonvertebral fractures in postmenopausal women with osteoporosis:
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3. Protelos Summary of Product Characteristics. London, UK: EMEA; September 2004.
4. 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.
5. MacLaughlin EJ, Raehl CL. ASHP therapeutic position statement on the prevention and treatment of osteoporosis in adults. Am J Health Syst Pharm. 2008;
65:343-335.
6. Ringe JD and Doherty JG. Absolute risk reduction in osteoporosis: assessing
treatment efficacy by number needed to treat. Rheumatol Int. 2010;30:863869.
7. Roux C, Fechtenbaum J, Kolta S, et al. Strontium ranelate reduces the risk of
vertebral fracture in young postmenopausal women with severe osteoporosis.
Ann Rheum Dis. 2008;67:1736-1738.
8. Roux C, Reginster JY, Fechtenbaum J, et al. Vertebral fracture risk reduction with
strontium ranelate in women with postmenopausal osteoporosis is independent of baseline risk factors. J Bone Miner Res. 2006;21:536-542.
9. Seeman E, Vellas B, Benhamou C, et al. Strontium ranelate reduces the risk of
vertebral and nonvertebral fractures in women eighty years of age and older.
J Bone Miner Res. 2006;21:1113-1120.
10. Seeman E, Boonen S, Borgström F, et al. Five Years Treatment with Strontium
Ranelate Reduces Vertebral and Nonvertebral Fractures and increases the Number and Quality of Remaining Life Years in Women Over 80 years of Age. Bone.
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12. Rolland Y, Abellan Van Kan G, Vellas B. Strontium ranelate reduces vertebral
fractures in frail osteoporotic women. J Nutr Health Aging. 2009;13:S425. Abstract.
415
PROTELOS
13. Seeman E, Devogelaer JP, Lorenc R, et al. Strontium ranelate reduces the risk
of vertebral fractures in patients with osteopenia. J Bone Miner Res. 2008;23:
433-438.
14. Collette J, Bruyère O, Kaufman JM, et al. Vertebral anti-fracture efficacy of strontium ranelate according to pre-treatment bone turnover. Osteoporos Int. 2010;
21:233-241.
15. Reginster J, Felsenberg D, Boonen S, et al. Strontium ranelate demonstrates
efficacy agains hip fracture over 3 and 5 years in postmenopausal women at
high risk of hip fracture. Osteoporos Int. 2008;1(suppl1):S26-S27. (Abstract
OC49; ECCEO 2008).
16. Reginster JY, Bruyère O, Sawicki A, Roces-Varela A, Fardellone P, Roberts A,
Devogelaer JP. Long-term treatment of postmenopausal osteoporosis with strontium ranelate: results at 8 years. Bone. 2009;45:1059-1064.
17. Marie PJ, Ammann P, Boivin G, Rey C. Mechanisms of action and therapeutic
potential of strontium in bone. Calcif Tissue Int. 2001;69(3):121-129.
18. Brennan TC, Rybchyn MS, Conigrave AD, Mason RS. Strontium ranelate effect
on proliferation and OPG expression in osteoblasts. Calcif Tissue Int. 2006:78:
S129 (Abstract P356).
19. Arlot ME, Jiang Y, Genant HK, et al. Histomorphometric and muCT analysis
of bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate. J Bone Miner Res. 2008;23:215-222.
20. Rizzoli R, Laroche M, Krieg MA, Frieling I, et al. Strontium ranelate and alen-
dronate have differing effects on distal tibia bone microstructure in women with
osteoporosis. Rhumatol Int. 2010;30:1341-1348.
21. Rizzoli R, Felsenberg D, Laroche M, et al. Beneficial effects of strontium ranelate
compared to alendronate on bone microstructure–a 2-year study. Osteoporos Int. 2010;2(suppl1):S25-S388.
22. Briot K, Benhamou L, Roux C. Effect of strontium ranelate on hip structural
geometry. Ann Rheum Dis. 2009;68(suppl 3):665. Abstract SAT0375.
23. Ly YF, Luo E, Feng G, Zhu SS, Lu JH, Hu J. Systemic treatment with strontium
ranelate promotes tibial fracture healing in ovariectomized rats. Osteoporos
Int. 2010 Dec 3 [Epub ahead of print].
24. Habermann B, Kafchitsas K, Olender G, Augat P, Kurth A. Strontium ranelate
enhances more callus strength than PTH1-34 in an osteoporotic rat model of
fracture healing. Calcified T Int. 2010;86(1):82-89.
25. Ly YF, Feng GE, Gao Y, Luo E, Liu XG, Hu J. Strontium ranelate treatment
enhances hydroxyapatite-coated titanium screws fixation in osteoporotic rats.
J Orthopaedic Res. 2010;28:578-582.
26. Maimoun L, Brennan TC, Badout I, Dubois-Ferrière V, Rizzoli R, Ammann P.
Strontium ranelate improves implant osseointegration. Bone. 2010. In press.
27. Boivin G, Farlay D, Khebbab MT, Jaurand X, Delmas PD, Meunier PJ. In osteoporotic women treated with strontium ranelate, strontium is located in bone
formed during treatment with a maintained degree of mineralization. Osteoporosis Int. 2009 Jul 14. Epub ahead of print.
Keywords: strontium ranelate; osteoporosis; treatment guidelines; Protelos
PROTELOS
UN OS PLUS SAIN POUR LE PATIENT OSTÉOPOROTIQUE :
DIMINUE LE RISQUE FRACTURAIRE TOUT EN AUGMENTANT LA QUALITÉ DE L’ OS
Le déficit en estrogène chez la femme post-ménopausée se traduit par une détérioration rapide de la qualité de
l’os, de sa quantité, et par conséquent de sa solidité, aboutissant ainsi à l’augmentation du risque fracturaire. Les
traitements antiostéoporotiques doivent être évalués non seulement sur leur capacité à diminuer ce risque chez la
femme post-ménopausée, mais aussi à améliorer l’état global de l’os en assurant une efficacité et une protection à
long terme, quel que soit le profil des patientes, y compris celles pour qui le traitement est le plus difficile à mettre
en œuvre. Protelos (ranélate de strontium) est un agent antiostéoporotique indiqué dans la prévention du risque de
fracture vertébrale et de hanche chez la femme post-ménopausée ostéoporotique. À ce titre, l’efficacité de Protelos
va même au-delà de cette définition dans la mesure où il prévient le risque fracturaire tant chez la patiente ostéopénique que dans les formes les plus sévères d’ostéoporose, et ce quel que soit l’âge des patientes, des plus jeunes
aux plus âgées. Protelos est le seul antiostéoporotique pour lequel l’efficacité à long terme sur les fractures vertébrales, non vertébrales et de hanche a pu être démontrée sur une période de 5 ans par une étude contrôlée randomisée en double-aveugle. Cette efficacité est reconnue par l’ESCEO (European Society for Clinical and Economic
Aspects of Osteoporosis) à travers ses Recommandations Européennes pour le Diagnostic et la Prise en Charge
de l’Ostéoporose Post-Ménopausique, publiées en 2008, qui soulignent la place de Protelos comme traitement de
première intention de l’ostéoporose ayant fait la preuve de son efficacité non seulement dans la réduction du risque
de fractures vertébrales, mais également dans la réduction du risque de fractures non-vertébrales, y compris, spécifiquement, au niveau de la hanche. L’efficacité unique de Protelos résulte de sa capacité à construire de l’os nouveau et à améliorer la santé de l’os chez la femme ostéoporotique. Trois études ont montré de façon concordante
que Protelos améliorait tant l’os cortical que l’os trabéculaire, qui sont, respectivement, les principaux déterminants
des fractures de hanche et vertébrales. Chez la femme ostéoporotique, l’amélioration de l’architecture osseuse, sous
Protelos, est déjà significative après 1 an de traitement, et demeure significative à 5 ans. Protelos construit un os robuste et sain tout en assurant une protection entière contre le risque fracturaire chez la femme ostéoporotique postménopausée. Protelos constitue ainsi une approche innovante comme traitement de première intention dans la prise
en charge de l’ostéoporose.
416
INTERVIEW
‘‘
39% of fractures worldwide
occur in men and 1 in 8 men older than 50 years has a risk of sustaining an osteoporotic fracture.
The mortality and morbidity associated with hip fractures are
greater in men than in women, and
men are twice as likely to die in
hospital after a hip fracture. In men
aged 60 to 69, the life expectancy after a hip fracture is 7.9 years,
versus 19.4 in controls. Loss of
physical function and autonomy
results in 50% of men having to
be institutionalized after a hip fracture.”
Bone health is also for men
I n t e r v i e w w i t h M . A u d ra n , Fra n c e
O
Maurice AUDRAN, MD
Head, Department of
Bone and Joint Disorders
INSERM U922
CHU Angers and Faculty
of Medicine, UNAM
Angers, FRANCE
steoporosis is a major health issue in men: 1 in 8 men older than 50
years has a risk of sustaining an osteoporotic fracture. Fractures of
the hip and vertebrae are associated with the greatest morbidity and
mortality. Sexual differences exist in skeletal bone metabolism. Boys have larger bones, thicker cortices, whereas trabecular pattern appears similar at the
end of adolescence. Aging in men is mainly characterized by trabecular thinning and a decrease in trabecular number. A decrease in cortical volumetric
bone mineral density (BMD) due to an increase in midcortical and endocortical porosity has been described. Significant associations between bone loss
and estrogen levels have been found in men. BMD measures are effective to
define the risk of future fractures and should be performed in patients with risk
factors. A careful assessment of secondary osteoporosis as well as of mineralization disorders due to malignant diseases is mandatory in men. The FRAX ®
tool is a significant advance in clinical care and should prove useful in appropriate targeting of osteoporosis therapy. US NOF (National Osteoporosis Foundation) Guidelines recommend treating men older than 50 years with a history
of hip or vertebral fracture, or with a 10-year probability of hip fracture of ⱖ3%,
or a 10-year probability of major fractures ⱖ20% as calculated by FRAX®. Yet,
men rarely receive osteoporosis treatment, despite the availability of a variety of agents (bisphosphonates, teriparatide, and may-be in future strontium
ranelate) with proven efficacy in women, and which are presumed to be as efficient in men with equivalent fracture risk.
Could you describe the epidemiological data of osteoporosis in
men? Is it a common disease?
steoporosis-related fractures constitute a major health concern in men.
Fracture incidence is even higher in men than in women below the age of
50, but they are very often related to high-energy trauma events.
O
Prof Maurice Audran,
Service de Rhumatologie,
CHU d’Angers, 4 rue Larrey,
49033 Angers Cedex 9, France
(e-mail: maaudran@chu-angers.fr)
Bone health is also for men – Audran
After the age of 50, women tend to have a higher incidence of fractures than men;
differences in bone mass and strength, the type and frequency of trauma, the fact
that elderly women appear to have an increased frequency of falls relative to men
may explain this inversion of the curves. Nonetheless, in aging men, fractures may
also occur after minimal trauma; fractures of the hip and vertebrae are associated
with the greatest morbidity and mortality.
417
INTERVIEW
A recent review on the annual worldwide incidence of fractures showed that 39% occur in men and that 1 in 8 men older than 50 years has a risk of sustaining an osteoporotic fracture. In 42% of cases it will be a vertebral fracture, in 30% of
cases a hip fracture, in 20% a wrist fracture, in 25% a fracture
of the humerus. Fragility fractures in aging men may also occur at other sites, including the pelvis, ribs, and collarbone.
With the increasing life expectancy of men, osteoporosis in
men will become a greater burden to society. In 2000, in
France, the medical cost of male osteoporosis was estimated at €197.5 million.
It is also important to take into account that the risk of a subsequent fracture is the same in male patients as in osteoporotic women after a low-energy fracture.
The mortality and morbidity associated with hip fractures are
greater in men than in women. Men are twice as likely to die
in hospital after a hip fracture. Comorbid conditions might contribute to this increased mortality risk. In men aged 60 to 69,
the life expectancy after a hip fracture is 7.9 years, versus 19.4
in controls.1 Loss of physical function and autonomy results
in up to 50% of men having to be institutionalized after a hip
fracture.
What is the pathophysiology of osteoporosis in
men? Are there differences with that in women?
exual differences exist in skeletal development and peak
bone mass acquisition. Boys have larger bones and thicker cortices, whereas trabecular pattern appears similar at
the end of adolescence. Age-related changes in bone mass
have been studied by means of several independent techniques (histomorphometry, x-ray microtomography [microQCT], high resolution QCT [HR-QCT], micro-MRI, synchrotron, finite element analysis). Our group and others have shown
that parameters of trabecular microarchitecture are a major
and independent determinant of vertebral fractures in middle-aged men with osteopenia. Increased cortical porosity has
been observed in patients with severe osteoporosis.2,3 Using
a different approach, significant decreases in trabecular volumetric BMD at the vertebrae have been shown in crosssectional as well as in longitudinal studies. Aging in men is
therefore mainly characterized by trabecular thinning and to a
lesser extent by a decrease in trabecular number. In cortical
S
SELECTED
BMD
DXA
ISCD
SERMs
SHBG
US NOF
International Society for Clinical Densitometry
selective estrogen receptor modulators
sex-hormone binding globulin
United States National Osteoporosis Foundation
418
bone, a decrease in cortical volumetric BMD due to an increase
in the mid-cortical and endocortical porosity is observed. In
contrast, cortical volumetric BMD shows little changes in men
or in women.4 Changes in bone geometry in aging men are defined by an increase in cross-sectional area at different axial
and peripheral sites of the skeleton, mainly due to continued
periosteal apposition.
In men, as in women, sex steroids are important for skeletal
development during growth as well for maintenance of peak
bone mass. Their role in fracture risk in men has been recently extensively studied. Sex steroids, estrogens, and androgens
circulate either free or bound to sex-hormone binding globulin (SHBG). Significant associations between BMD, bone resorption, and bone loss have now been found with estrogen
levels in men. Our group showed that serum SHBG may predict the risk of future fractures. The respective roles of sex
steroids and SHBG have been recently confirmed in the Osteoporotic Fractures in Men (MrOS) studies. In the Swedish
arm of the cohort, elderly men with low serum E2 and high
SHBG levels had an increased risk of fractures. In the US cohort, men with lowest bioavailable estradiol or highest levels
of SHBG had greater risk of all nonvertebral fractures.5 Nonskeletal effects of testosterone, on muscle mass and reduced
risk of falls, might also play a role on fracture risk in elderly men.
Vitamin D deficiency is common among older adults and
may result in secondary hyperparathyroidism and increased
bone resorption. In a US prospective cohort study of community-dwelling men aged 65 or older, the annualized average rate of loss in total hip BMD was twice higher among
men with 25(OH)D levels below 15 ng/mL than among men
with 25(OH)D levels of at least 30 ng/mL, suggesting that
low 25(OH)D levels are detrimental to BMD in older men.
Declining levels of insulin-like growth factor–1 (IGF-1), possibly mediated by alterations of IGF binding proteins with age,
may alter bone microarchitecture, with a thinning of bone trabeculae. The decrease in IGF-1 activity, which is an inhibitor
of SHBG synthesis by the hepatocytes, might also indirectly influence bone metabolism through an increase in SHBG
levels.4
Are risk factors for osteoporosis similar in men
and women?
ow BMD is a major risk factor of osteoporotic fractures in
men. BMD measures are therefore effective to define the
risk of future fractures, regarding low-trauma fractures,
but also high-trauma fractures.
L
Cessation of estrogen secretion is the main causal factor of osteoporosis in women. In men, in the absence of such a cause,
osteoporosis is described as secondary in up to 40% of cases. The causes are heterogeneous and may be combined.
INTERVIEW
N Primary or secondary hypogonadism (hormonal suppressive
therapy for prostate cancer)
N Glucocorticoid treatment
N Alcoholism and cigarette smoking
N Hyperparathyroidism, hyperthyroidism, Cushing’s disease
N Inflammatory bowel disease, gluten enteropathy, malabsorp-
tion syndromes, gastrointestinal disorders
N Primary biliary cirrhosis, hemochromatosis
N Chronic obstructive pulmonary disease
N Hypercalciuria
N Organ transplant
N Rheumatoid arthritis and systemic diseases
N Mastocytosis
N Neuromuscular disorders, anticonvulsants
N Immobilization
N Proton pump inhibitors
Table I. Main causes of secondary osteoporosis in men.
Three major causes have been identified: (i) prolonged glucocorticoid therapy; (ii) hypogonadism (sometimes induced by
gonadotropin-releasing hormone [GnRH] treatment in patients
suffering from prostate cancer); (iii) excessive alcohol intake.
Some others factors have also been consistently documented to be associated in men with a significant increase in fracture risk (Table I). Osteoporosis may be defined as primary or
idiopathic when no cause or risk factor is identified; some cases might be due to genetic factors in the acquisition of peak
bone mass. A careful assessment of secondary osteoporosis as well as of mineralization disorders due to malignant diseases (myeloma, lymphomas) is mandatory in men.
How and when are patients diagnosed? Is it only
after fractures or before? What are the diagnostic
criteria?
revention and treatment of bone loss and fractures are
often underestimated priorities. In many clinical situations it might be useful to perform a careful evaluation because they represent a significant risk factor of osteoporosis
(Table I). Risk factors may interfere with bone fragility in different ways: (i) by decreasing bone mass; (ii) by qualitative alterations of cortical or trabecular bone; (iii) by increasing the
risk of falls. Both the National Osteoporosis Foundation (NOF)
and the International Society for Clinical Densitometry (ISCD)
recommend performing BMD measurement after 70 years
of age (but a cost-effectiveness analysis showed this measure to be effective only over 80 years or in men aged 65 or
more with a prevalent vertebral fracture), after a prior vertebral
or nonvertebral low-trauma fracture, and when secondary
causes (including medications) have been identified. Several
different factors may be associated and should be considered in the future risk of osteoporosis.
P
Bone density (BMD) predicts fracture risk in men as it does
in women, but the prevalence of osteoporosis depends on the
reference population. The World Health Organization (WHO)
definition of osteopenia and osteoporosis (BMD measured by
dual-energy x-ray absorptiometry (DXA) that is 2.5 or more
standard deviations (SD) below that of a young normal adult,
that is, a T-score of –2.5 or below) applies to white postmenopausal women and there is no consensus on the densitometric diagnosis of osteoporosis in men. Nonetheless, using the
WHO criteria to define osteopenia and osteoporosis, two cutoffs have been proposed for men, based either on the young
normal male or female reference groups.
Osteoporosis in men was defined as a BMD value 2.5 SD below the mean of either white men or women aged 20 to 29
years; low BMD or osteopenia was characterized as a BMD
value between 1 and 2.5 SD below the respective young male
and female reference means. Based on data from the Mayo
Clinic, when bone density at any of the total hip, spine, or wrist
sites was used, the prevalence of osteoporosis in men over
age 50 was 19% using male reference ranges, and only 3%
when using the female reference ranges.6 The prevalence
of osteoporosis in men, using sex-specific normal values, is
therefore more substantial and may provide a better estimate
for the proportion of men at risk for an osteoporotic fracture.
The current ISCD recommendation is to use a male database
for T-score derivation in men.
Spinal degenerative changes are common after the age of
65 years and have to be taken into account because they
may falsely elevate the measured spine BMD.
It should also be underlined that, in the Rotterdam study, only
21% of all nonvertebral fractures occurred in men with a
T-score below –2.5.7
How is ostoporososis in men handled by health
autorities? What are the main recommendations
and guidelines? Are doctors aware enough of the
risk of osteoporosis in their elderly male patients?
n 2008, the American College of Physicians, the US NOF,
and the ISCD made recommendations relative to BMD
measurement in men. French guidelines have been also released regarding the indications of the measure by DXA. The
2008 US NOF Guidelines warrant a recommendation for
treatment in men: (i) older than 50 years with a history of hip or
vertebral fracture; or (ii) with a T-score between –1 and –2.45;
or (iii) a T-score between –1 and –2.5 and a 10-year probability of hip fracture of ⱖ3% or a 10-year probability of major
fractures (spine, forearm, hip, humerus fracture) ⱖ20% as calculated by FRAX ®. The French Health Authorities (“Haute Autorité de Santé”) recommended in 2007 to treat male patients
suffering from osteoporosis characterized by a T-score less
than –2.5 with other risk factors or with T-score less than –3.
I
419
INTERVIEW
Is FRAX ® useful in the diagnosis of male patients?
normal BMD measurement is no guarantee that a
fracture will not occur. The use of risk factors may in
this way add useful information on fracture risk independently of BMD.
A
FRAX ® is a computer-based algorithm derived from data obtained in 11 independent cohorts (http://www.shef.ac.uk/
FRAX) that provides models for the assessment of 10-year
probability of fracture risk (hip, clinical spine, humerus, or wrist
fracture) and the 10-year probability of hip fracture alone in
men and women using clinical risk factors. The tool can be
used alone or with femoral neck BMD to enhance fracture
risk prediction. The presence of more than one risk factor increases fracture probability in an incremental manner.
FRAX ® has limitations: (i) it has largely been validated in women and additional evaluation of FRAX ® in men is needed; (ii)
some risk factors are described as dichotomous variables
(yes or no), despite data clearly showing a dose–response
relationship; (iii) silent, radiological vertebral fractures are not
taken into account. It appears nonetheless as a significant
advance in clinical care and should prove useful in appropriate targeting of osteoporosis therapy.
What are the main bases of the management of
osteoporosis in men (pharmacologic, nonpharmacologic treatments)?
n the Framingham osteoporosis study, the proportion of men
meeting the 2008 NOF criterion increased with advancing
age (1.7% of men aged 50 to 65 and 37.9% of men aged
>75 years).8 In total, one sixth of men aged over 50 years
would be recommended for osteoporosis treatment. Nonetheless, the loss of potential years of life in younger age-groups
suggests that preventive strategies for fracture should not
only focus on older patients at the expense of younger highrisk men.
I
Although hypogonadism in men leads to bone loss, deterioration of trabecular architecture, loss of muscle mass, and increased risk of fracture, androgen treatment remains controversial. Testosterone therapy has been shown to increase
BMD in hypogonadal men, but clinical trials concerned a small
number of patients, were of short duration, without any definitive evidence of fracture risk reduction. The issue of the
long-term safety of testosterone treatment in older men, (increased risk of prostate cancer, adverse cardiovascular effects), must be taken into account.
Because of the presumed role of estrogens on bone in men,
the effects of selective estrogen receptor modulators (SERMs)
has been studied. Raloxifene reduced bone turnover in men
with low estradiol concentrations and increased BMD in men
420
treated with GnRH agonists for prostate cancer. Toremifene
reduced the risk of vertebral fractures in patients on androgen deprivation therapy for prostate cancer.
Calcitonin has received limited evaluation in men and no conclusions may be drawn from the small short-term clinical trials.
Most studies with alendronate or risedronate in men have
shown a beneficial effect on BMD at lumbar and femoral sites,
when compared with placebo. Intravenous zoledronic acid
increased BMD in men after hip fracture and in patients with
androgen-deprivation treatment for prostate cancer. Few
clinical trials clearly proved a significant reduction in fracture
risk. Because vertebral and nonvertebral fracture risk reduction has been well documented in women at risk of fractures
receiving bisphosphonate therapy, it has been suggested that
such treatment interventions would have a similar efficacy in
men with equivalent fracture risk, and therefore bisphosphonates are considered to be first-line therapy for men with osteoporosis.4
The effects of daily SC teriparatide appear similar in men and
women. The induced lumbar and femoral increase in BMD was
of the same magnitude as in women, with similar changes in
bone remodeling. Teriparatide appears to reduce the risk of
vertebral fracture, but not of nonvertebral fracture.4
Strontium ranelate induces an increase in bone formation and
a decrease in bone resorption. It has been shown to decrease
vertebral and nonvertebral fracture in women at different ages,
for different levels of risk. This dual-effect bone agent may represent an interesting alternative to bisphosphonates in men.4
A large clinical trial (MALEO) is under way.
Long-term vitamin D daily supplementation (800 IU) is often
required. A daily calcium intake of 1000 to 1200 mg has been
recommended.
Men rarely receive osteoporosis treatment. Following a hip fracture, less than 10% of patients are treated and only one third
of men receiving androgen deprivation therapy for prostate
cancer receive osteoporosis evaluation or treatment.
In 2008, the recommendations of the American College of
Physicians (ACP) were that pharmacologic treatment should
be offered to men with known osteoporosis and those having sustained a fragility fracture, as well as to patients with
BMD T-scores above –2.5, but at risk due to clinical factors.
A cost-effectiveness analysis conducted by NOF found pharmacologic treatment to be cost-effective for both men and
women provided the 10-year estimated fracture risk exceeded approximately 20% for major osteoporotic fracture or
3% for hip fracture, based on a US-adapted FRAX® model.
In future, health and economic considerations, not simply fracture risk, will influence treatment recommendations, based
INTERVIEW
on the resources dedicated to health care. Nonpharmacological measures are useful in the management of male osteoporosis. Increasing physical exercise may be considered,
but the way to optimize its effects on skeleton is not well defined. Prevention of falls is mandatory in elderly patients, with
different measures: correction of functional disability, treatment
of comorbidity known to facilitate gait disorders; reduction of
drug consumption or alcohol abuse; action on architectural
or environmental factors. The interest of hip protectors is still
controversial. I
References
1. Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA. Mortality after
all major types of osteoporotic fracture in men and women: an observational study.
Lancet. 1999;353(9156):878-882.
2. Legrand E, Chappard D, Pascaretti C, et al. Trabecular bone microarchitecture,
bone mineral density, and vertebral fractures in male osteoporosis. J Bone Miner
Res. 2000;15(1):13-19.
3. Ostertag A, Cohen-Solal M, Audran M, et al. Vertebral fractures are associated
with increased cortical porosity in iliac crest bone biopsy of men with idiopathic
osteoporosis. Bone. 2009;44(3):413-417.
4. Khosla S, Amin S, Orwoll E. Osteoporosis in men. Endocr Rev. 2008;29(4):
441-464.
5. LeBlanc ES, Nielson CM, Marshall LM, et al. Osteoporotic fractures in men study
group. The effects of serum testosterone, estradiol, and sex hormone binding
globulin levels on fracture risk in older men. J Clin Endocrinol Metab. 2009;94
(9):3337-3346.
6. Melton III LJ, Atkinson EJ, O'Connor MK, O’Fallon WM, Riggs BL. Bone density
and fracture risk in men. J Bone Miner Res. 1998;13(12):1915-1923.
7. Schuit SCE, van der Klift M, Weel AEAM, et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam study.
Bone. 2004;34(1):195-202.
8. Berry SD, Kiel DP, Donaldson MG, et al. Application of the National Osteoporosis Foundation Guidelines to postmenopausal women and men: the Framingham Osteoporosis Study. Osteoporos Int. 2010;21(1):53-60.
Keywords: osteoporosis; fracture; men; FRAX ®; morbidity; mortality
L’HOMME
A LUI AUSSI BESOIN D ’ OS SOLIDES
Un homme sur 8 après 50 ans est concerné par la survenue de fractures liées à l’ostéoporose, les fractures vertébrales et de hanche étant les plus sévères ; cette incidence de la maladie, bien que moins fréquente que chez la
femme, n’en représente pas moins une préoccupation de santé publique. Le squelette a, dans le genre masculin,
quelques spécificités. Ainsi, à la fin de l’adolescence, les os sont plus volumineux et ont des corticales plus épaisses ;
le système trabéculaire apparaît en revanche similaire à celui de la femme. Plus tard au cours de la vie, on observe
chez l’homme un amincissement des travées, une diminution de leur nombre, une diminution de la densité corticale,
liée à une augmentation de la porosité corticale, et au final à une fragilité parfois excessive. Comme chez la femme,
on a souligné le rôle important des estrogènes et de la sex hormone binding globulin (SHBG) dans le métabolisme
osseux de l’homme et le risque ultérieur de perte osseuse. Comme dans le sexe féminin aussi, en association avec
la recherche de facteurs cliniques de risque, la mesure de la densité minérale osseuse (DMO) revêt un grand intérêt
pour caractériser le risque fracturaire futur et guider le traitement. L’outil FRAX® combinant des facteurs cliniques de
risque et la DMO au col fémoral peut être utilisé dans cette optique. La mise en évidence d’une DMO basse et/ou de
fractures doit néanmoins toujours conduire à éliminer une cause maligne. Des recommandations ont été formulées
pour la prise en charge de l’ostéoporose chez l’homme ; ainsi la National Osteoporosis Foundation propose de traiter les hommes après 50 ans quand ils ont été victimes de fractures vertébrales ou de hanche, ou lorsque la probabilité fracturaire à 10 ans est évaluée à plus de 3 % pour la hanche, à plus de 20 % pour les principales autres fractures telles que définies par le FRAX®. Pourtant, malgré la sévérité pronostique de certaines fractures, en termes de
morbidité, voire de mortalité, et bien que l’on dispose d’agents thérapeutiques dont l’efficacité apparaît similaire
à ce que l’on connaît chez la femme (les bisphosphonates, le tériparatide et peut-être dans l’avenir le ranélate de
strontium…), la prise en charge de l’ostéoporose de l’homme reste encore insuffisante.
421
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‘‘
FRAX® is a potent tool for
calculating the risk of fractures in
individual patients on the basis of
a set of risk factors. This tool is
now also used to assess the efficacy of antiosteoporotic treatments against the risk of fractures
(an European Medicines Agency
[EMEA] requirement for all new antiosteoporotic treatments). This
article reviews the published results for studies of treatment efficacy by baseline FRAX® probabilities for alendronate, clodronate,
and bazedoxifene.”
FRAX® and treatment efficacy
in osteoporosis
b y E . V. M c C l o s ke y, U n i t e d K i n g d o m
F
Eugene V. McCLOSKEY,
MRCP, MD, FRCPI
Academic Unit of
Bone Metabolism
Metabolic Bone Centre
Northern General Hospital
Sheffield, UK
racture risk prediction can be enhanced by the concurrent assessment
of clinical risk factors in addition to measurements of bone mineral density (BMD). FRAX ®, a combination of four algorithms, can calculate the
10-year probability of hip or major osteoporotic fracture, with or without the
input of femoral neck BMD. A number of studies have now examined the efficacy of osteoporosis treatments across a range of fracture probabilities and
are contributing to a body of evidence demonstrating that treatments can generally reduce fracture risk in women identified to be at high risk by FRAX ®.
A community-based study of oral clodronate clearly demonstrated a reduction in nonvertebral fractures, and the treatment was equally or more effective
in women with higher FRAX ® probabilities. The original studies of bazedoxifene and alendronate demonstrated significant reductions in vertebral fractures, but required post hoc subgroup analyses to demonstrate significant reductions in nonvertebral fractures. For bazedoxifene, while the interaction with
treatment was not statistically significant, the efficacy was clearly more obvious in patients with higher baseline FRAX ® probabilities. The interpretation of
the alendronate study (Second Fracture Intervention Trial [FIT2]) is somewhat
more problematic. One conclusion is that the drug is simply not effective in reducing nonvertebral fractures in this study population and that this is equally
true across a wide range of baseline FRAX ® probabilities. The evidence base
will continue to expand as a number of other studies will shortly be examined
to determine the interaction between treatment efficacy and baseline FRAX ®.
number of agents are available for the treatment of osteoporosis, all of which
have been shown to significantly reduce fracture risk in at least one skeletal site.1-11 In the very near future, several new agents that have shown reductions in fracture risk will also be available for clinical use.12-14
A
Professor Eugene V. McCloskey,
Academic Unit of Bone Metabolism,
Metabolic Bone Centre, Sorby Wing,
Northern General Hospital, Herries
Road, Sheffield S5 7AU, UK
(e-mail:
e.v.mccloskey@sheffield.ac.uk)
422
Treatment efficacy, fracture probability, and FRAX®
The efficacy of osteoporosis therapies has usually been characterized in individuals
with low bone mass, such that the bone mineral density (BMD) thresholds published
by the World Health Organization (WHO) in 199415 are widely accepted as both a
diagnostic and an intervention threshold. Indeed, to date most pivotal antifracture
studies have reported on the use of these agents in individuals selected to be at high
risk for fracture usually by the presence of low BMD and/or a prior fragility fracture,
most commonly at the spine. A problem with the predominant use of BMD to direct
FRAX® and treatment efficacy in osteoporosis – McCloskey
FOCUS
interventions is that BMD alone is not optimal for the detection of individuals at high risk of fracture. Indeed, the majority of osteoporotic fractures will occur in individuals without
osteoporosis.16,17
In the past decade, other factors have been identified that
contribute to fracture risk, partially or wholly independent of
BMD, which improve fracture prediction and the selection
of individuals at high risk for treatment.18-22 A series of metaanalyses using individualized data from 12 global population
cohorts23-30 has identified clinical risk factors for use in the assessment of fracture risk with or without the use of BMD. The
adequacy of the risk factors has been validated in a further
12 independent population-based cohorts.31 The risk factors
identified formed the basis for the development of the WHO
algorithms that calculate fracture probability in an individual,
expressed as the 10-year fracture probability (FRAX®).31 Unlike many previous algorithms, the FRAX® tool takes into account the relationship between individual risk factors and both
fracture and death hazards.31 The risk factors in the FRAX® tool
include age, sex, glucocorticoid use, secondary osteoporosis,
parental history of hip fracture, prior fragility fracture, low body
mass index (BMI), current smoking, excess alcohol consumption (3 or more units daily) and femoral neck BMD selected on
the basis of their international validity.32
A critical question in proposing the use of clinical risk factors
for patient risk assessment relates to the reversibility by pharmacological intervention of the risk so identified. The risk factors in FRAX® were also selected on the basis of having at
least indirect evidence that the risk was likely to be modified
by subsequent intervention (modifiable risk). This was validated from clinical trials (BMD, prior fracture, glucocorticoid use,
secondary osteoporosis), or partially validated by excluding
interactions of risk factors on therapeutic efficacy in large randomized intervention studies (eg, smoking, family history,
BMI). It is important to note that risk factors for falling were
not considered for inclusion in the FRAX® tool, since there is
some concern that the risk identified would not be modified
by a pharmaceutical intervention targeted at the skeleton.7
It is notable that in this latter study, the precise criteria for inclusion were not documented, and further work is required
to determine whether risk factors for falls or a history of falls
would identify a risk that was modifiable by pharmacological
intervention.33 A number of studies have now addressed the
interaction between treatment efficacy and fracture probabilities assessed by FRAX®.
Clodronate
Daily oral clodronate 800 mg has been shown to decrease
vertebral fracture risk in women with postmenopausal or secondary osteoporosis.1 More recently, it has been demonstrated to reduce clinical and osteoporotic fracture risk in elderly
women unselected for osteoporosis.34 The latter study was
a double-blind, prospective, randomized, placebo-controlled,
single center study in elderly community-dwelling women aged
75 years or more. Treatment was associated with a significant
reduction in all clinical fractures (hazard ratio [HR], 0.80; 95%
confidence interval [CI], 0.68-0.94)34 and clinical osteoporotic fractures (HR, 0.76, 95% CI, 0.63-0.93, P=0.006).35
The interaction between efficacy and FRAX® probabilities was
conducted in a cohort comprising 76% of the women recruited to the main part of the study, in whom complete data on
clinical risk factors required for the computation of 10-year
fracture probability were available.35 The following clinical
variables were used to compute the 10-year probability of a
major osteoporotic fracture (hip, clinical vertebral, wrist or
humerus) by FRAX®, age, BMI, history, of prior fragility fracture
after the age of 50 years, maternal history of hip fracture (father’s history of hip fracture was not documented), rheumatoid arthritis (yes, if patient self-reported ever being told they
probably had or did have rheumatoid arthritis), oral glucocorticoid use (yes, if ever used) and smoking (yes, if current). Information on alcohol intake was not captured in the study. The
10-year probability was calculated with and without input of
femoral neck BMD.
The mean±SD 10-year probability of a major osteoporotic fracture calculated by clinical risk factors alone was 20%±7%.
When femoral neck BMD was added to the FRAX® calculation, the mean 10-year probability was slightly lower at 18%
±9%.35 This suggests that the mean femoral neck BMD in
the study population was slightly higher than expected for
age and a healthy selection bias had already been noted in
the study.34
The effects of clodronate to reduce fracture incidence at various 10-year probabilities of fracture, calculated with and without femoral neck BMD, are shown in Figures 1 and 2 (page
424). In the absence of BMD, there was a borderline statistically significant interaction (P=0.043) with a better effect of
clodronate at higher probabilities (Figure 1). For example, at a
probability of 15% (25th percentile), the relative risk for fracture was reduced by 8% (NS) whereas at a probability of 24%
(75th percentile) the reduction was 27% (95% CI 8% to 42%).
The interaction between efficacy and probability of fracture
was not statistically significant when BMD was used in the
calculation of probability (P=0.10), but the pattern of efficacy was very similar with more evident fracture reductions at
higher probabilities of fracture (Figure 2).
SELECTED
BMD
BMI
FIT1 and 2
FLEX
NHANES
body mass index
Fracture Intervention Trial (First; Second)
Fracture intervention trial Long-term EXtension
National Health And Nutritional Examination Survey
423
2.0
1.6
1.8
1.4
HR treatment versus placebo
HR treatment versus placebo
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1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
10th 50th
P
1.2
1.0
0.8
0.6
0.4
0.2
10th 50th
90th
0.0
90th
0.0
0
20
40
60
80
10 year probability of osteoporotic fracture
without BMD (%)
0
20
40
60
80
10 year probability of osteoporotic fracture
without BMD (%)
Figure 1. Clodronate and reduction of clinical osteoporotic risk
(clinical risk factors without femoral neck BMD).
Figure 2. Clodronate and reduction of clinical osteoporotic risk
(clinical risk factors + femoral neck BMD).
Relationship between 10-year probabilities of major osteoporotic fracture, calculated with clinical risk factors alone (ie, without femoral neck bone mineral
density [BMD]) and the efficacy of clodronate to reduce clinical osteoporotic
fracture risk (hazard ratio [HR] with 95% confidence intervals). The black horizontal line represents the overall treatment efficacy and the dashed horizontal
line a hazard ratio of 1. The diamonds correspond to the 10th, 50th, and 90th
percentiles of probability in the population studied.
Relationship between 10-year probabilities of major osteoporotic fracture, calculated with clinical risk factors combined with femoral bone mineral density [BMD],
and the efficacy of clodronate to reduce clinical osteoporotic fracture risk (hazard
ratio [HR] with 95% confidence intervals). The black horizontal line represents
the overall treatment efficacy and the dashed horizontal line a hazard ratio of 1.
The diamonds correspond to the 10th, 50th and 90th percentiles of probability
in the population studied.
In summary, this study suggests that those individuals identified at higher risk of fracture by the FRAX® tool are responsive to treatment with clodronate, even when the risk is calculated in the absence of information on BMD.
Medicinal Products for Human Use (CHMP),36 an analysis was
undertaken to test the hypothesis that the combined data for
the two doses of bazedoxifene would demonstrate a reduced
fracture risk in women with the higher fracture probabilities.13
Baseline data were used to calculate 10-year fracture probabilities with the FRAX® tool in placebo- and bazedoxifenetreated patients.13 The risk factors at baseline were further
clarified in the following ways; for a prior fracture, data on selfreported peripheral fractures was combined with the finding
of a grade 2 or greater morphometric vertebral fracture on
baseline spine radiographs. No information was available on
parental history of hip fracture, so that this variable was simulated resulting in a prevalence of 6%—in a sensitivity analysis,
a more conservative position assumed that no patient had a
family history of hip fracture. Three different types of dual-energy x-ray absorptiometry (DXA) equipment were used so that
a machine specific Z-score was calculated by age to remove
the systematic differences between machine manufacturers
and permit the computation of 10-year probabilities with the
FRAX® tool.13
Bazedoxifene
Bazedoxifene acetate is a new agent within the class of drugs
known as selective estrogen receptor modulators (SERMs).
Its fracture efficacy has been examined in a phase 3 study
designed to determine the primary effect of this agent on vertebral fracture risk in postmenopausal women with osteoporosis.14 In brief, the study was a double-blind, randomized,
placebo- and raloxifene-controlled trial including 7492 postmenopausal women with osteoporosis. They were recruited
either on the basis of low BMD (T-score ⱕ−2.5 SD at the lumbar spine or femoral neck) or a prior vertebral fracture, and
were randomized to four treatment groups: two groups received bazedoxifene (20 or 40 mg daily; n=1886 and 1872,
respectively), a third group received raloxifene (60 mg daily),
and a placebo group (n=1885). All patients took calcium (1200
mg daily) and vitamin D (400–800 IU daily). At the two doses
tested, bazedoxifene significantly decreased the risk of vertebral fractures by 37% to 42%. A secondary end point was
the effect of treatment on the risk of nonvertebral fractures,
but overall there was only a nonsignificant 11% reduction in
such fractures. A post hoc analysis in a subgroup of patients
at high risk (femoral neck T-score ⱕ−3 SD and or ⱖ1 moderate or severe, or multiple mild vertebral fractures) reported that
the combined doses of bazedoxifene reduced the incidence
of nonvertebral fractures by 40% (5%-63%). Subsequently,
as requested for new phase 3 studies by the Committee for
424
The mean±SD 10-year probability of a major osteoporotic fracture calculated by clinical risk factors alone was 11%±8% and
was similar when femoral neck BMD was added to the FRAX®
calculation. The probability is somewhat lower than that observed in the population-based cohort recruited to the clodronate study above and reflects the younger age of the present study population (mean age 66 years vs 80 years in the
clodronate study), despite the selection criteria based on BMD
and prior fracture. The latter observation is supportive of the
need to use of age-dependent intervention thresholds as
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1.8
HR bazedoxifene versus placebo
HR bazedoxifene versus placebo
1.8
1.6
41st
6.9%
1.4
1.2
1.0
0.8
0.6
0.4
0.2
10th
50th
90th
P
1.6
80 st
16%
1.4
1.2
1.0
0.8
0.6
0.4
0.2
10th
50th
90th
0.0
0.0
0
10
20
30
40
10-year probability of osteoporotic fracture
calculated with BMD
0
10
20
30
40
10-year probability of osteoporotic fracture
calculated with BMD
Figure 3. Bazedoxifene and reduction of morphometric fracture
risk.
Figure 4. Bazedoxifene and reduction of clinical osteoporotic
fracture risk.
Relationship between 10-year probabilities of major osteoporotic fracture, calculated with clinical risk factors combined with femoral neck bone mineral density
[BMD], and the efficacy of bazedoxifene to reduce morphometric vertebral fracture risk (hazard ratio with 95% confidence intervals). The black horizontal line
represents the overall treatment efficacy and the dashed horizontal line a hazard
ratio [HR] of 1. The diamonds correspond to the 10th, 50th, and 90th percentiles
of probability in the population studied.
Relationship between 10-year probabilities of major osteoporotic fracture,
calculated with clinical risk factors combined with femoral neck bone mineral
density [BMD], and the efficacy of bazedoxifene to reduce clinical osteoporotic
fracture risk (hazard ratio [HR] with 95% confidence intervals). The black horizontal line represents the overall treatment efficacy and the dashed horizontal
line a hazard ratio of 1. The diamonds correspond to the 10th, 50th, and 90th
percentiles of probability in the population studied.
adopted by the UK.37 Overall, bazedoxifene was associated
with a significant 39% decrease in incident morphometric vertebral fractures (P=0.005) and a 16% decrease in the incidence of all clinical fractures (P=0.14). While there was no significant interaction between baseline FRAX® probability and
treatment efficacy (P>0.3), the reduction in fracture risk increased progressively at higher baseline fracture probabilities
(Figures 3 and 4). For morphometric vertebral fractures, treatment with bazedoxifene was associated with a significant decrease in the risk at probability values above 7%, corresponding to the 41st percentile of the study population. In patients
with fracture probabilities above 16%, the 80th percentile,
bazedoxifene was associated with a significant decrease in
all clinical fractures. When BMD was not used in the FRAX®
tools to compute fracture probabilities, similar results were observed, but with wider confidence estimates.
arm (FIT2) sought to determine the efficacy of alendronate
over 4 years on the risk of clinical and vertebral fractures in
over 4000 postmenopausal women with low BMD (defined as
a femoral neck BMD of 0.68 g/cm2 or less on Hologic densitometers), but without prior vertebral fractures.5 As in FIT1,
alendronate was administered at 5 mg daily until the 24 month
visit at which the dose was increased to 10 mg daily. In the primary analysis, alendronate reduced all clinical fractures by
14%, but the reduction was again not of statistical significance
(P=0.07). The reduction in non-spine clinical fractures was
12% (P=0.13). Alendronate did, however, significantly decrease
the risk of radiographic vertebral fractures by 44% (95% CI,
20% to 61%).
Alendronate
The pivotal studies for the clinical use of alendronate in postmenopausal osteoporosis were the two arms of the Fracture
Intervention Trial (FIT). The first (FIT1) examined the efficacy of
alendronate over 36 months in approximately 2000 women
aged 55 to 81 years with low femoral-neck BMD and at least
one vertebral fracture at baseline.4 Under double-blind conditions, the initial dose of alendronate, 5 mg daily by mouth,
was increased to 10 mg daily at the 24-month visit. New vertebral fractures, identified on lateral spine radiographs at 24
and 36 months, were reduced by 47% (95% CI, 32% to 59%)
by alendronate. In contrast, non-spine clinical fractures were
reduced by 20%, an effect that did not quite achieve statistical significance (P=0.06).4 The second placebo-controlled
In a post hoc analysis, an interaction was noted between
baseline BMD and efficacy, so that a further analysis examined efficacy in tertiles of BMD.5 Alendronate apparently reduced clinical fractures (vertebral and non-spine) by 36% in
women with BMDs in the lowest tertile (by chance corresponding to osteoporosis at the femoral neck as defined by
a T-score <−2.5 SDs based on the young adult mean from the
National Health And Nutrition Examination Survey [NHANES]
study). There was no significant reduction in the remaining
women with higher BMD, though all of these had BMD T-score
values less than −1.6.
A pre-planned analysis of the two arms of FIT combined was
subsequently published, though this deviated from the original plan as it concentrated solely on women with BMD Tscores <−2.5 or at least one vertebral fracture.38 This further
post hoc analysis suggested that alendronate treatment was
425
FOCUS
accepted as both a diagnostic and an intervention threshold. BMD alone is not optimal for the detection of individuals
at high risk of fracture and several recent studies indicate
that pharmacological interventions have efficacy in patients
with osteopenia or in whom BMD was not assessed.40-44 It is
clear that the availability of the FRAX® tool for predicting fracture risk will lead to major changes in the management of patients. Indeed, recently developed European guidelines for the
evaluation of drugs in osteoporosis recognize the importance
of global risk assessments and it is likely that further data will
become available from current and future clinical trials of antiosteoporotic agents.
HR
LCL
UCL
2.2
2.0
1.8
1.6
1.4
HR
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0
10
20
30
40
50
60
70
80
90
100
FRAX ® 10-year probability of
major osteoporotic fracture with FN BMD
Figure 5. Alendronate and reduction of clinical osteoporotic fracture risk (clinical risk factors + femoral neck BMD).
Relationship between 10-year probabilities of major osteoporotic fracture, calculated with clinical risk factors combined with femoral neck bone mineral density, and the efficacy of alendronate to reduce clinical osteoporotic fracture risk
(hazard ratio with 95% confidence intervals).
Abbreviations: FN BMD, femoral neck bone mineral density; HR, hazard ratio;
LCL, lower confidence limit; UCL, upper confidence limit.
Modified from reference 39: Cummings et al. J Bone Miner Res. 2009;24(suppl 1):S10. © 2009, American Society for Bone and Mineral Research.
associated with a significant 30% reduction in clinical fractures and a 27% reduction in nonvertebral fractures.38 It should
be borne in mind though that the overall results from the two
individual arms of FIT suggested an overall nonsignificant 12%
to 20% decrease in nonvertebral fractures.
An analysis of the interaction between alendronate efficacy
and baseline FRAX® probabilities in the clinical fracture arm
of the FIT (FIT2) has also recently been presented, but full publication is still awaited.39 The analysis used Cox proportional
hazards models with interaction terms to analyze whether the
effect of alendronate on risk of nonvertebral and major osteoporotic fractures was greater in women with higher baseline
FRAX® probabilities. While FRAX® predicted incident fractures
in the study, there was no significant association between
FRAX® probability, calculated with femoral neck BMD, and
reduction in risk of clinical or nonvertebral fractures by alendronate (Figure 5). Results were similar for “major osteoporotic fractures” and whether or not FRAX® calculations included
FN BMD. The authors concluded that there is no significant
association between FRAX® score and efficacy of alendronate
for nonvertebral or major clinical fractures.
Summary
Relatively little is known about the determinants of antifracture efficacy in patients using osteoporosis medications. The
efficacy of inhibitors of bone resorption has been well characterized in individuals with low bone mass, such that the
BMD thresholds published by the WHO in 1994,15 are widely
426
The studies reviewed here are the first to contribute to the
body of evidence demonstrating that treatments can generally reduce fracture risk in women identified to be at high risk
by FRAX®. Certainly the analysis of clodronate is consistent
with this hypothesis. The original studies of bazedoxifene and
alendronate demonstrated significant reductions in vertebral
fractures, but required post hoc subgroup analyses to demonstrate significant reductions in nonvertebral fractures. There
are obvious difficulties with post hoc analyses that are particularly acute when undertaken on subgroups, especially
subgroups that may be difficult to justify on clinical grounds.
The post hoc nature, the change in the significance of the
primary outcome, and the way of categorizing the high-risk
group, all weaken the validity of these analyses. Against this
background, examination of the interaction of treatment efficacy with baseline FRAX® probabilities, as a continuous variable, while not avoiding post hoc status, aims to avoid subgroup analysis and the associated loss of statistical power.
For bazedoxifene, while the interaction with treatment was
not statistically significant, the efficacy was clearly more obvious in patients with higher baseline FRAX® probabilities. The
interpretation of the alendronate study (FIT2) is somewhat
more problematic. One conclusion is that the drug is simply
not effective at reducing nonvertebral fractures in this study
population and that this is equally true across a wide range
of baseline FRAX® probabilities. The Fracture intervention trial Long-term EXtension (FLEX) trial, a randomized extension
to the FIT, may also be consistent with the lack of efficacy at
nonvertebral sites.45 In this study, women randomized to continue alendronate 10 mg daily for a further 5 years after the
original study showed no difference in nonvertebral fracture
rates compared with those randomized to receive placebo
during the extension. This “lack of offset” has been widely interpreted to suggest that 5 years of therapy with alendronate
shows similar nonvertebral fracture efficacy as 10 years, so
that patients may be able to get “treatment-free” windows.
An alternative interpretation is that it is not possible to show an
offset of effect if one has not demonstrated an onset of effect.
A number of other studies will shortly be examined to determine the interaction between treatment efficacy and baseline
FRAX® probabilities. I
FOCUS
References
1. McCloskey E, Selby P, Davies, et al. Clodronate reduces vertebral fracture risk
in women with postmenopausal or secondary osteoporosis: results of a doubleblind, placebo-controlled 3-year study. J Bone Miner Res. 2004;19(5):728-736.
2. Delmas PD, Recker RR, Chesnut CH, 3rd, et al. Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporos Int. 2004;15(10):
792-798.
3. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy
(VERT) Study Group. JAMA. 1999;282(14):1344-1352.
4. Black DM, Cummings SR, Karpf DB, et al; Fracture Intervention Trial Research
Group. Randomised trial of effect of alendronate on risk of fracture in women
with existing vertebral fractures. Lancet. 1996;348(9041):1535-1541.
5. 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(24):2077-2082.
6. Reginster J, Minne HW, Sorensen OH, et al; Vertebral Efficacy with Risedronate
Therapy (VERT) Study Group. Randomized trial of the effects of risedronate on
vertebral fractures in women with established postmenopausal osteoporosis.
Osteoporos Int. 2000;11(1): 83-91.
7. McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip
fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med.
2001;344(5): 333-340.
8. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34)
on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344(19):1434-1441.
9. Reginster JY, Seeman E, De Vernejoul M, 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.
J Med. 2004;350(5):459-468.
11. Ettinger B, Black DM, Mitlak BH, et al; Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. Reduction of vertebral fracture risk in postmenopausal
women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 1999;282(7):637-645.
12. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention
of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;
361(8):756-765.
13. Kanis, JA, Johansson, H, Oden, A, McCloskey, EV. Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed
with FRAX. Bone. 2009;44(6):1049-1054.
14. Silverman SL, Christiansen C, Genant HK, et al. Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical
trial. J Bone Miner Res. 2008;23(12):1923-1934.
15. World Health Organization. Assessment of fracture risk and its application to
screening for postmenopausal osteoporosis. Report of a WHO Study Group.
World Health Organ Tech Rep Ser. 1994;843:1-129.
16. Siris ES, Miller PD, Barrett-Connor E, et al. Identification and fracture outcomes
of undiagnosed low bone mineral density in postmenopausal women: results
from the National Osteoporosis Risk Assessment. JAMA. 2001;286(22):28152822.
17. Wainwright SA, Marshall LM, Ensrud KE, et al. Hip fracture in women without
osteoporosis. J Clin Endocrinol Metab. 2005;90(5):2787-2793.
18. Black DM, Steinbuch M, Palermo L, et al. An assessment tool for predicting
fracture risk in postmenopausal women. Osteoporos Int. 2001;12(7):519-528.
19. Dargent-Molina P, Douchin MN, Cormier C, Meunier PJ, Breart, G. Use of clinical risk factors in elderly women with low bone mineral density to identify women
at higher risk of hip fracture: the EPIDOS prospective study. Osteoporos Int.
2002;13(7):593-599.
20. Leslie WD, Metge C, Salamon EA, Yuen, CK. Bone mineral density testing in
healthy postmenopausal women. The role of clinical risk factor assessment in
determining fracture risk. J Clin Densitom. 2002;5(2):117-130.
21. Miller PD, Barlas S, Brenneman SK, et al. An approach to identifying osteopenic
women at increased short-term risk of fracture. Arch Intern Med. 2004;164(10):
1113-1120.
22. McGrother CW, Donaldson MM, Clayton D, Abrams KR, Clarke M. Evaluation
of a hip fracture risk score for assessing elderly women: the Melton Osteoporotic Fracture (MOF) study. Osteoporos Int. 2002;13(1):89-96.
23. De Laet C, Kanis JA, Oden A, et al. Body mass index as a predictor of fracture
risk: a meta-analysis. Osteoporos Int. 2005;16(11):1330-1338.
24. Johnell O, Kanis JA, Oden A, et al. Predictive value of BMD for hip and other
fractures. J Bone Miner Res. 2005;20(7):1185-1194.
25. Kanis JA, Johansson H, Johnell O, et al. Alcohol intake as a risk factor for fracture. Osteoporos Int. 2005;16(7):737-742.
26. Kanis JA, Johansson H, Oden A, et al. A meta-analysis of milk intake and fracture risk: low utility for case finding. Osteoporos Int. 2005;16(7):799-804.
27. Kanis JA, Johansson H, Oden A, et al. A family history of fracture and fracture
risk: a meta-analysis. Bone. 2004;35(5):1029-1037.
28. Kanis JA, Johansson H, Oden A, et al. A meta-analysis of prior corticosteroid
use and fracture risk. J Bone Miner Res. 2004;19(6):893-899.
29. Kanis JA, Johnell O, De Laet C, et al. A meta-analysis of previous fracture and
subsequent fracture risk. Bone. 2004;35(2):375-382.
30. Kanis JA, Johnell O, Oden A, et al. Smoking and fracture risk: a meta-analysis.
Osteoporos Int. 2005;16(2):155-162.
31. 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(8):1033-1046.
32. Kanis J. Assessment of Osteoporosis at a Primary Health Care level. 2007.
Sheffield, UK: WHO Collaborating Centre for Metabolic Bone Diseases. 2007.
33. Kayan K, Johansson H, Oden A, et al. Can fall risk be incorporated into fracture risk assessment algorithms: a pilot study of responsiveness to clodronate.
Osteoporos Int. 200920(12):2055-2061.
34. McCloskey EV, Beneton M, Charlesworth D, et al. Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone
Miner Res. 2007;22(1):135-141.
35. McCloskey EV, Johansson H, Oden A, et al. Ten-year fracture probability identifies women who will benefit from clodronate therapy—additional results from
a double-blind, placebo-controlled randomised study. Osteoporos Int. 2009;20
(5):811-817.
36. (CHMP), CfMPfHU, Guideline on the evaluation of medicinal products in the treatment of primary osteoporosis. 2006, CHMP: London, UK. Ref CPMP/EWP/
552/95Rev.2.
37. Compston J, Cooper A, Cooper C, et al. Guidelines for the diagnosis and management of osteoporosis in postmenopausal women and men from the age
of 50 years in the UK. Maturitas. 2009;62(2):105-108.
38. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab. 2000;85(11):4118-4124.
39. Cummings SR, Donaldson ML, Palermo L, et al. Efficacy of alendronate for reducing nonvertebral and clinical fractures by FRAX score. J Bone Miner Res.
2009;24(suppl 1):S10.
40. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in
the community: randomised double blind controlled trial. BMJ. 2003;326(7387):
469.
41. Rossouw JE, Anderson GL, Prentice RL, et al. 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(3):321333.
42. Kanis JA, Johnell O, Black DM, et al. Effect of raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis: a
reanalysis of the Multiple Outcomes of Raloxifene Evaluation trial. Bone. 2003;
33(3):293-300.
43. Marcus R, Wang O, Satterwhite J, Mitlak B. The skeletal response to teriparatide
is largely independent of age, initial bone mineral density, and prevalent vertebral fractures in postmenopausal women with osteoporosis. J Bone Miner Res.
2003;18(1):18-23.
44. Watts NB, Josse RG, Hamdy RC, et al. Risedronate prevents new vertebral fractures in postmenopausal women at high risk. J Clin Endocrinol Metab. 2003;
88(2):542-1549.
45. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term
Extension (FLEX): a randomized trial. JAMA. 2006;296(24):2927-2938.
Keywords: fracture; FRAX ®; osteoporosis; bone mineral density; treatment; alendronate; clodronate; bazedoxifene
427
FOCUS
FRAX® ET
EFFICACITÉ DU TRAITEMENT DE L’ OSTÉOPOROSE
La prévision du risque de fracture peut être améliorée par l’évaluation des facteurs de risque cliniques complétée
par des mesures de la densité minérale osseuse (DMO). FRAX ®, qui associe quatre algorithmes, permet de calculer
la probabilité à 10 ans d’une fracture de la hanche ou de fractures ostéoporotiques majeures, avec ou sans l’utilisation de la DMO du col fémoral. Un certain nombre d’études ont désormais établi l’efficacité des traitements de l’ostéoporose en relation avec différentes probabilités de fracture, et ont permis de constituer un ensemble de données
démontrant que les traitements réduisent généralement le risque de fractures chez les femmes présentant un risque
élevé calculé avec FRAX ®. Une étude sur des patients de ville portant sur l’utilisation du clodronate par voie orale a
clairement mis en évidence une réduction des fractures non vertébrales, et a fait apparaître que le traitement était au
moins aussi efficace chez les femmes présentant un risque élevé calculé avec FRAX ®. Les études originales sur le
bazédoxifène et l’alendronate ont indiqué des réductions significatives des fractures vertébrales, mais ont nécessité
des analyses de sous-groupes post hoc pour déceler des réductions significatives des fractures non vertébrales. Pour
le bazédoxifène, si l’interaction avec le traitement n’a pas été statistiquement significative, l’efficacité a été nettement
plus manifeste chez les patients présentant un risque élevé avec FRAX ®. L’interprétation de l’étude sur l’alendronate
( Second Fracture Intervention Trial, FIT2) est un peu plus problématique. L’une des conclusions est que le médicament est simplement inefficace pour réduire les fractures non vertébrales dans cette population, et que cela est avéré
dans un large éventail de valeurs initiales de probabilités FRAX ®. La base de données continuera à s’enrichir lorsqu’un
certain nombre d’autres études seront prochainement examinées afin de déterminer l’interaction entre l’efficacité
du traitement et la valeur initiale FRAX ®.
428
U P DAT E
‘‘
Peripheral quantitative computing tomography is a new technique for the in vivo approximation
of bone microstructure parameters such as geometry, structural
parameters, and distal radial and
tibial density. It determines the
structural and material properties
of peripheral bone, at the cost of
acceptable whole-body radiation,
within a few minutes, image processing included. The resulting
data extend beyond DXA-BMD
measurement and provide an estimate of bone strength that is
grounded in fundamental mechanics.”
New techniques for
assessing bone health
b y D . Fe l s e n b e r g , G e r m a n y
P
Dieter FELSENBERG,
MD, PhD
Center for Muscle and
Bone Research
Charité Medical School
Free University of Berlin
and Humboldt University
of Berlin
Berlin, GERMANY
eripheral and vertebral fractures are the greatest hazard facing patients with osteoporosis, reducing their physical mobility, quality of life,
and life expectancy. There is increasing evidence, supported by fundamental physics, that more than dual energy x-ray absorptiometry is required
to estimate individual fracture risk and monitor treatment response. The determinants of bone strength are geometry, structural properties (bone distribution), material properties, and direction of force. It is therefore essential to
develop and implement more sophisticated techniques such as in vivo microcomputed tomography. Scanco Medical AG’s peripheral quantitative computing tomography system, XtremeCT, is a relatively new device for the in vivo
approximation of geometry, structural parameters, and distal radial and tibial density. Structural parameters include trabecular thickness, trabecular separation, structural model index, connectivity, anisotropy, and cortical thickness.
Other calculations include bone volume/tissue volume ratios and subregional and cortical bone mineral densities, expressed in mg/cm3. Finite element
analysis based on 3-D reconstructions of 110 slices is used for stress mapping.
The technique’s main limitations are movement artifacts and the fact that calculation of the structural parameters is density-based.
ince bone is a multifunctional tissue, assessment of its health involves multiple parameters. This paper reviews the latest techniques for evaluating two
of these parameters, bone strength and fracture risk, based on the material
and structural properties of bone and the direction of force. Mass does not come
into it, although physicians persist in ignoring the basic mechanics involved, using
terms such as bone quality to simplify a complex system.
S
Prof Dr med Dieter Felsenberg,
Zentrum Muskel & Knochenforschung,
Charité-Universitätsmedizin Berlin,
Campus Benjamin Franklin, Freie
Universität & Humboldt-Universität
Berlin, 12203 Berlin,
Hindenburgdamm 30, Germany
(e-mail: dieter.felsenberg@charite.de)
According to Dalzell et al,1 the material properties of bone cannot currently be studied noninvasively. Of course there is dual energy x-ray absorptiometry (DXA), which
determines bone mineral density (BMD), but the latter is very different from actual
physical density. DXA scanners mainly measure bone mass, which the World Health
Organization (WHO) has deemed important for classifying the clinical impact of
osteoporosis treatments. However, we know from the experience of major pivotal
studies that DXA is of very limited use in monitoring treatment effect, largely because it fails to separate measures for trabecular and cortical bone. Other limitations include the absence of geometric data for calculating cross-sectional moment
of inertia (CSMI) and of structural and material property data.
New techniques for assessing bone health – Felsenberg
429
σ stress (kN/mm2)
U P DAT E
I
Glass
∆A
I + ∆I
F
Y
Bonc
∆σ
Neutral
surface
∆ε
Rubber
ε strain (%)
Figure 2. Mechanics of bending.
Figure 1. The stress/strain curve as a material property.
Strain is the relationship between change of length and original length. With glass
higher stresses are needed to achieve the same strain as with bone or rubber.
Bone strength is dependent on a material property, expressed
by the elastic (Young’s) modulus (E), and the CSMI. The elastic modulus is given by the slope of the stress/strain curve
(stress on the y axis and strain on the x axis) during the linear
elastic phase (Figure 1). It is constant for a given material and
is expressed in N/mm 2 (1 newton/ mm 2 =1 megapascal [MPa],
and 1 kilonewton/mm 2 =1 gigapascal [GPa]) Bone has an E
value of 18 to 21 GPa. For comparison, glass has a very steep
slope, with an E value of 50 to 90 GPa, whereas the E value of silicone rubber is 0.01 to 0.1 GPa. In other words, the
higher the E value the more rigid the material. However, E
values also depend on temperature, humidity, and speed of
deformation.
Fracture risk is a function not only of bone’s material properties, but also of its geometry and the direction of force. The
CSMI reflects the dependence on geometry. These calculations are mostly important in long bones (humerus, radius,
ulna, femur, tibia, fibula, femoral neck, etc) where the direction
of force is not uniaxial, along the long axis, but in all the other
directions for which the bone is not adapted. The CSMI depends mostly on the distance of the bone mass to the neutral surface: I =∫ y 2∆A (Figure 2). Bone strength, expressed as
bending stiffness (EI), is given by the product of E and CSMI.
Peripheral computed tomography (pCT) systems perform
these calculations routinely. Beck et al2 devised an interactive hip structure analysis (HSA) program that derives femoral
neck geometry from raw bone mineral image data in order to
estimate hip strength using single plane engineering stress
analysis. The purpose of the program was to improve the predictive value of hip bone mineral data for osteoporosis fracture risk assessment. The authors reported a series of experiments with an aluminum phantom and cadaver femora
designed to test the accuracy of derived geometric measurements and strength estimates. HSA-computed femoral neck
430
Bending a bar or cylinder compresses the material on the inner side of the
curve and tensions the material on the outer side. The one surface in the model
subject to neither compression nor tension is termed the neutral surface and is
more or less parallel to the axis of the bar or cylinder. A cylinder such as a long
bone increases its bending stiffness (with no change in mass) by distributing its
mass over an increasing diameter as far as possible from the neutral surface.
The integral power of two of all distances to all different cross-sectional areas
(pixel) is called cross-sectional moment of inertia.
cross-sectional areas (CSA) and CSMI on an aluminum phantom agreed closely with actual values (r>0.99). HSA-computed cross-sectional properties of three human cadavers were
compared with measurements derived from sequential CT
cross-sectional images. Discrepancy between the two methods averaged less than 10% along the length of the femoral
neck. The breaking strengths of 20 femora showed better
agreement with HSA-predicted strength (r=0.89) than with
femoral neck BMD (r=0.79).2
It takes more sophisticated devices to calculate the trabecular network in vitro and answer another question of general
interest: how does the most typical fracture in osteoporosis,
vertebral compression fracture (often referred to as “sintering”
in German-language osteoporosis literature, a term taken from
metallurgy), relate to microarchitectural deterioration in other
SELECTED
BMD
CSA
CSMI
DXA
FEA
FPT
HSA
mCT
MORE
SMI
WHO
WISE
cross-sectional areas
cross-sectional moment of inertia
dual energy x-ray absorptiometry
finite element analysis
Fracture Prevention Trial
hip strength analysis
microcomputed tomography
Multiple Outcomes of Raloxifene Evaluation [study]
structural model index
World Health Organization
Women International Space simulation for Exploration [study]
U P DAT E
skeletal regions? Epidemiological studies have shown that
osteoporotic (vertebral and nonvertebral) fracture incidence
relates not only to vertebral fracture prevalence, but also to
prevalent vertebral fracture severity, suggesting that vertebral
fracture severity is a marker for increased bone fragility at all
skeletal sites. Bone architecture, defined as the distribution of
bone mass in a trabecular network, can be directly assessed
by histomorphometry or microcomputed tomography (mCT)
analyses of invasively obtained bone biopsy samples or by
in vivo assessment of the distal forearm or distal tibia.
Since no in vivo measurements are available we have to focus on in vitro data to determine the relationship between
vertebral compression fracture and microarchitectural deterioration elsewhere. Genant et al3 conducted a semiquantitative analysis of baseline vertebral fracture severity on spinal
radiographs from 190 postmenopausal women with osteoporosis. Bone structure indices were obtained by 2-D histomorphometry and 3-D mCT analyses in transiliac bone biopsy samples taken at baseline in a subset of patients from the
Multiple Outcomes of Raloxifene Evaluation trial (MORE)4 and
the teriparatide Fracture Prevention Trial (FPT).5 After adjustment for age, height, and spinal DXA-BMD, there were significant trends for 3-D bone volume, trabecular number, trabecular separation, and connectivity density: mCT bone volume
was significantly lower (P<0.05) in women with mild (-23%),
moderate (–30%), and severe fractures (–51%) than in women
with no fractures. Trabecular number was lower (P<0.05) in
women with mild (–14%), moderate (–18%), and severe (–28%)
vertebral fractures compared to women without vertebral fractures, while trabecular separation was higher (P<0.05) in those
with mild (33%), moderate (42%), and severe (55%) vertebral
fractures. These data show a clear relationship between vertebral fracture severity and microstructural deterioration in
transiliac bone biopsies. The task for the future is to determine how closely these data match the structural deterioration of the distal forearm and tibia as assessed by in vitro mCT.
The device
The only in vivo mCT system currently available for human
measurements is the XtremeCT (Scanco Medical, 8303 Bassersdorf, Switzerland [www.scanco.ch/systems-solutions
/preclinical-systems/xtremect.html]). It scans the distal radius
or tibia in 2.8 minutes, acquiring a 9 mm-high stack of 110
slices at a resolution of 82 µm. Its ability to accommodate
specimen sizes up to 150 mm (height) ×126 mm (diameter)
provides scope for clinical applications (Figures 3 and 4).
Measurement
Each measurement takes about 2.8 minutes, plus another
couple of minutes for calculations that include analysis of the
regional or subregional BMD data: total bone, cortical bone,
trabecular bone, and some trabecular bone subregions (Figure 5, page 432). Measurement is standardized to a defined
distance from the joint endplates of the radiocarpal junction.
Figure 3. XtremeCT peripheral quantitative computed tomography scanner at the Charité Hospital, Benjamin Franklin Campus,
Berlin.
The scanner can be used for both basic research (mouse, rat) and interventional clinical studies.
Figure 4. Microcomputed tomography (mCT) scan of a Russian
cosmonaut at the Charité before leaving for the International
Space Station (ISS).
During measurement the forearm or tibia is fixed in a cast.
The structural parameters measured include trabecular number, trabecular thickness, trabecular separation (Figure 6),
structural model index (Figure 7), connectivity, anisotropy,
and cortical thickness (Figure 5). All structural parameter calculations are based on density measurements.
The mCT methodology has been used in bending tests in rats
to determine the relevance of geometry and cortical thickness. It provides data that accurately describe cortical bone
geometry and parallel cortical bone strength results obtained
by the 3-point bending method. These data meet the criteria
of providing quick, reproducible, and accurate answers regarding cortical bone geometry as a predictor of cortical bone
strength.6
431
U P DAT E
Reference values
and reproducibility
odanacatib, and strontium ranelate,
most of which have just been completed and hence are only available as
posters or abstracts.
The first population-based normative
data for in vivo measurements of bone
microstructure, published in 2006,7
Bed rest studies have measured the
were obtained using a prototype of the
effect of weightlessness on bone dencurrent mCT system. The results may
sity and structure in young healthy
therefore be less robust than subsefemale and male volunteers. In the
quent data. The first reference data obCortical thickness ®
Women International Space simulatained with the current device were
cortical density
tion for Exploration (WISE) study, subreported by Dalzell et al.1 In 2005,
jects remained in bed at 6° head down
Boutroy et al8 published mCT precitilt for 60 days.9 The mCT data showed
sion values of 0.7% to 1.5% for total,
trabecular, and cortical densities and
a clear tendency to a decline in all
2.5% to 4.4% for trabecular architecstructural parameters and an increase
Figure 5. Microcomputed tomography (mCT)
ture. Postmenopausal women had analysis of bone mineral density in the distal
in trabecular separation, but at 60
lower density, trabecular number, and tibia.
days the values did not differ significortical thickness than premenopausal The scan shows specific subregions and includes tracantly from baseline. We found no sigand cortical density. Cortical thickness is as
women (P<0.001) at both radius and becular
nificant differences between the conreadily assessable as cortical circumference.
tibia. Osteoporotic women had lower
trol group (no exercise), the exercise
density, cortical thickness, and increased trabecular separa- group (resistive exercise plus endurance training), and the nution than osteopenic women (P<0.01) at both sites. Further- trition group (specific amino acid-enriched diet). In the Berlin
more, although spine and hip BMD were similar, fractured Bed Rest-2 (BBR2) study, mCT revealed significant tibial corosteopenic women had lower trabecular density and more tex loss in the control group.10 The bone loss observed in
heterogeneous trabecular distribution (P<0.02) at the radius both studies showed high interindividual variation, with no
than nonfractured osteopenic women.
conclusive pattern. A randomized double-blind prospective
study compared strontium ranelate (SrR) and alendronate
(70 mg once weekly) in postmenopausal women with osteoClinical applications
Recent clinical applications of in vivo mCT include space re- porosis (spine and/or total hip T-scores ⱕ–2.5 SD) over 24
search (effect of bed rest) and therapeutic trials with various months.11 Preplanned interim analysis of the mCT data at 12
bisphosphonates (risedronate, ibandronate), denosumab, months documented a 5.3% increase in cortical thickness in
+
157.57
®
®
*
349.18
*
®
®
+
Figure 6. Synchrotron computed tomography image of the
trabecular network in a vertebra.
Trabecular distance (50 µ to 200 µ) and trabecular thickness (150 µ to 600 µ)
in a healthy subject (red arrows). (Photo courtesy of Felsenberg and Giehl.)
432
Figure 7. The structural model index reflects the relationship
between plates (*) and rods (+) in trabecular bone.
The increasing number of rods is typical of bone loss and indicates increasing
plate resorption. (Photo courtesy of Felsenberg, Giehl and Ritter.)
U P DAT E
the SrR group compared to the alendronate group, which did not differ
from baseline (P=0.001). The blood
volume/tissue volume (BV/TV) ratio
increased by 2.1% over baseline
compared with the alendronate
group (P=0.002), which again did
not differ significantly from baseline.
A
B
At 24 months, cortical thickness increased by 6.3% (±9.5%) in the SrR
group and by 0.9% (±6.2%) in the
alendronate group (P=0.004). The
comparative increases in BV/TV ratio [2.5% (±5.1%) vs 0.8% (±3.8%)] Figure 8. Microcomputed tomography (mCT) images of a vertebra: (A) Stress areas; (B) Stress
distribution.
also differed significantly in favor of (A) mCT scan of a vertebral body. Stress regions are color-coded (high: red; low: yellow and green). High stress
SrR (P=0.040), as did those in tra- areas are seen in thin trabeculae and low stress areas in plate-like structures. (B) Stress distribution in the entire
body with endplate deformation. High stress areas are seen in midvertebral structures concentrated on
becular and cortical BMD: 2.5% vertebral
endplate cortical bone. (Both images by courtesy of Scanco Medical, Switzerland.)
(±5.1%) vs 0.9% (±4.0%) (P=0.048)
and 1.4% (±2.8%) vs 0.7% (±2.1%) (P=0.045). The marker of culation” generates important data about stress risers in the
bone formation, bone alkaline phosphatase, showed an 18% trabecular network, sites of treatment effect, and increases/
increase over baseline (P<0.001), while the marker of bone decreases in structural strength (Figure 8).1,12
resorption, serum C-telopeptide crosslinked collagen type I,
decreased –16% vs baseline (P=0.002), thereby confirming The Pros and Cons
the dual mode of action of SrR. The results point to signifi- N Pros
cant structural benefit in the distal tibia in women with post- In vivo mCT determines the structural and material properties
menopausal osteoporosis treated for 2 years with SrR com- of peripheral bone at the cost of acceptable whole-body rapared to alendronate.
diation (<15 µSv) within a few minutes, image processing included. The resulting data extend beyond DXA-BMD measurement and provide an estimate of bone strength that is
Finite element analysis
Scanco provides specific finite element analysis (FEA) soft- grounded in fundamental mechanics. The mCT images can
ware for their image format. (FEA is a mathematical technique be processed by FEA to simulate mechanical testing and dethat originated from the need to solve complex elasticity and rive estimates of stress distribution and failure load. The techstructural problems in civil and aeronautical engineering.) It nique measures cortical bone separately from trabecular bone.
is used to simulate tests and measure mechanical and elasticity properties such as stiffness, estimated failure load, tra- Physical density (mass/volume) reflects the material properbecular/cortical load distribution, and changes in mechanical ties of bone. However, we are not yet able to match structural
properties. For example, the “von Mises stress distribution cal- information to mechanical strength tests.
A
B
C
®
®
®
®
®
®
Figure 9. Microcomputed tomography (mCT) scan of the distal radius in an interventional study (A-C).
(A & B) Follow-up scans showing grade 2 movement artifacts in the second scan with cortical discontinuity in places (red arrows) and multiple contour-blurring horizontal lines (yellow arrows). (C) Severe grade 3 movement artifacts caused the scan to be discarded.
433
U P DAT E
N Cons
The local radiation dose is quite high. In the event of procedural error (wrong positioning, movement artifacts, etc), measurement can be repeated only twice, to a total of three measurements of the same region. Despite the short scan time
(2.8 minutes), the very high resolution, visualizing structures
down to 82 µm in diameter, produces multiple movement artifacts (MA) (Figure 7). We have identified MA in 38% of a total of several thousand mCT scans, 79% of which were in the
forearm and 21% in the tibia. Even after repeating the forearm measurements twice, only 40% were MA-free. An MA
grading system may help to increase the quality of forearm
analyses. We have detected no pattern to the MA seen in
repeated measurements. The problem is less evident with
the tibia but still present. It can be decreased by shortening
the scan time even further.
Another limitation is the peripheral measurement region. To
measure bending stiffness together with cortical thickness
and density, measurements should ideally be taken at the midshaft of radius and tibia. But the design of the device allows
only very distal measurements. Reference values are not yet
robust because of the relatively few normal subjects who
have been scanned. A final limitation is that most of the programs for analyzing structural parameters are density based
(Figure 9, page 433). I
References
1. Dalzell N, Kaptoge S, Morris N, et al. Bone micro-architecture and determinants of strength in the radius and tibia: age-related changes in a population
based study of normal adults measured with high-resolution pQCT. Osteoporos Int. 2009;20(10):1683-1694.
2. Beck TJ, Ruff CB, Warden KE, Scott WW Jr, Rao GU. Predicting femoral neck
strength from bone mineral data. A structural approach. Invest Radiol. 1990;
25(1):6-18.
3. Genant HK, Delmas PD, Chen P, et al. Severity of vertebral fracture reflects
deterioration of bone microarchitecture. Osteoporos Int. 2007;18(1):69-76.
4. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a
3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation
(MORE) Investigators. JAMA. 1999;282(7):637-645.
5. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34)
on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344(19):1434-1441.
6. Bagi CM, Andresen C, Pero R, Lariviere R, Turner CH, Laib A. The use of microCT to evaluate cortical bone geometry and strength in nude rats: correlation
with mechanical testing, pQCT and DXA. Bone. 2006;38(1):136-144.
7. Khosla S, Riggs BL, Atkinson EJ, et al. Effects of sex and age on bone microstructure at the ultradistal radius: a population-based noninvasive in vivo
assessment. J Bone Miner Res. 2006;21(1):124-131.
8. Boutroy S, Bouxsein ML, Munoz F, Delmas PD. In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed
tomography. J Clin Endocrinol Metab. 2005;90(12):6508-6515.
9. Defontaine M, Nasser-Eddin M, Rittweger J, Lazerges M. A 60 days Bed Rest
study: preliminary QUS BUA changes at the calcaneus site. Ultrasonics Symposium, 2005 IEEE, Sept 18-21 2005;4:2014-2017.
10. Felsenberg D. Results of Berlin BedRest Study II. Personal communication.
2010.
11. Reginster JY, Felsenberg D, Boonen S, et al. Effects of long-term strontium
ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis: Results of a five-year, randomized, placebo-controlled trial. Arthritis Rheum. 2008;58(6):1687-1695.
12. Boutroy S, van Rietbergen B, Sornay-Rendu E, Munoz F, Bouxsein ML, Delmas PD. Finite element analysis based on in vivo HR-pQCT images of the distal radius is associated with wrist fractures in postmenopausal women. J Bone
Miner Res. 2008;23:392-399.
Keywords: osteoporosis; fracture; vertebral fracture; fracture risk; bone strength; dual-energy x-ray absorptiometry;
microcomputed tomography; peripheral quantitative computing tomography
NOUVELLES
TECHNIQUES D ’ ÉVALUATION DE LA SANTÉ OSSEUSE
Les fractures périphériques et vertébrales constituent le risque le plus important auquel ont à faire face les patients
atteints d’ostéoporose, dans la mesure où elles réduisent leur mobilité physique, leur qualité de vie et leur espérance
de vie. Un nombre croissant de données, fondées sur les notions fondamentales de la physique, indiquent que l’absorptiométrie biénergétique à rayons X n’est pas suffisante pour estimer le risque individuel de fractures et contrôler
la réponse thérapeutique. Les déterminants de la résistance osseuse sont la géométrie, les propriétés structurales
(distribution osseuse), les propriétés matérielles et la direction des forces. Il est par conséquent essentiel de développer et de mettre en œuvre des techniques plus sophistiquées, par exemple la microdensitométrie. La tomodensitométrie quantitative périphérique de Scanco Medical AG, XtremeCT, est un dispositif relativement nouveau permettant une approximation in vivo de la géométrie, des paramètres structuraux et de la densité du radius et du tibia
distaux. Les paramètres structurels comprennent l’épaisseur trabéculaire, la séparation trabéculaire, l’indice de modèle structural, la connectivité, l’anisotropie et l’épaisseur corticale. D’autres calculs comprennent les rapports entre
le volume osseux et le volume tissulaire et les densités minérales osseuses subrégionales et corticales, exprimées en
mg/cm3. L’analyse par éléments finis (FEA, finite element analysis) basée sur des reconstructions tridimensionnelles
de 110 coupes est utilisée pour une cartographie des contraintes. Les principales limitations techniques sont les
artefacts dus aux mouvements et le fait que le calcul des paramètres structuraux est basé sur la densité.
434
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he first Touch of France article shows how fossil bones
dating back tens of thousands to millions of years ago can
be made to reveal how our hominid
and human ancestors looked like
in real life, leading to a moving
face-to-face encounter. The second article explores how the saints
or famous are, through their bones,
ensured a lasting presence as
relics in churches, ossuaries, museums, or even private homes. To
paraphrase Ian Fleming, bones—
and diamonds—are forever.
T
New life for old bones
Giving a face to Lucy, King Tut, and
b y É . D a y n è s , Fra n c e
Élisabeth Daynès at
work on Paranthropus boisei (2.5 million
years BP) based on a
cast of cranium OH5,
Olduvai, Tanzania.
© 2006 Photographer
P.Plailly/E.Daynès/Eurelios/
Lookatsciences – Reconstitution E.Daynès Paris
The eternal life of bones
Tidbits of French history through the trials
and tribulations of relics of the illustrious
b y C . Po r t i e r- K a l t e n b ac h , Fra n c e
Holy bones in Saint
Victor Abbey in
Marseilles: display of
reliquaries containing
osseous remains of
early Christian saints
and martyrs.
© Abbaye Saint-Victor –
Ville de Marseille. All rights
reserved.
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‘‘
Internationally renowned
Élisabeth Daynès possesses a rare
combination of specialties that
make her and her Parisian “Atelier”
absolutely unique: as an anthropologist cum sculptress, she gives
new life to skulls and skeletons. By
no means the result of artistic whim
or fancy, her work derives from
state-of-the-art morphological and
anatomical techniques allowing
her to painstakingly reconstruct
muscles, fat, skin, and hairs—implanted one by one by hand—
thereby achieving as close a likeness as possible of the “owners”
of the bones entrusted to her skills.
OF
FRANCE
New life for old bones
Giving a face to Lucy, King Tut, and
b y É . D a y n è s , Fra n c e
© P.Plailly/Eurelios/Lookatsciences
T
Élisabeth DAYNÈS
Paleoartist and Founder
Atelier Daynès
Hyperrealistic Reconstructions
Paris, FRANCE
rained as painter and sculptor, Élisabeth Daynès has, since the 1990s,
combined scientific research, technological innovation, and art to bring the
latest anthropological discoveries back to life. She discovered a passion for
prehistory, when in 1988 the Thot Museum in Montignac, France, commissioned
her to create a life-size mammoth and a group of Magdalenians. Her meeting with
Dr Jean-Noël Vignal, a forensic anthropologist, was a turning point in her career
as a prehistoric sculptress. He brought her technological skills, as she deepened
her knowledge of anatomy. “Lucy,” the Australopithecus, often described as her
finest work, is one of the hundreds of her anthropological sculptures scattered
around the world in leading museums. She gained international fame in 2006 with
her bust of Tutankhamen, depicted on the cover of the 25 international issues of
National Geographic, on the occasion of the “Tutankhamen” exhibition devoted to
the young Egyptian pharaoh, which attracted huge crowds in Los Angeles and
Chicago.
I
Élisabeth Daynès,
Atelier Daynès, 129 rue du Faubourg
du Temple, 75010 Paris, France
Web site: www.daynes.com
(e-mail: info@daynes.com)
n her studio situated in the Belleville neighborhood of Paris, Élisabeth
Daynès breathes life into bones thousands, even millions, of years old as
she sculpts reconstructions of Australopithecus, Paranthropus, and Neanderthals. Where art and science meet, this paleoartist practices an unusual
profession: forensic facial reconstruction. In collaboration with anatomists, anthropologists, archeologists, and prehistorians, she uses techniques drawn
from medical imaging and the latest methods in criminology. Early pioneers
of such work were the 19th-century Swiss anatomist Wilhelm His, who reconstructed the face of Johann-Sebastian Bach from a skull exhumed at the
Johanniskirche (St John’s Church) in Leipzig, and the Russian Mikhail Mikhaylovich Gerasimov, the first anatomist to reconstruct a face in a criminal case,
in 1935. There is an increasing demand from museums from all over the world
to show visitors realistic reconstructions of our hominid ancestors and of modern humans from the more recent past. Through months of work and constant
dialogue with researchers in various fields, Élisabeth Daynès painstakingly
recreates through anthropological sculpture the face and figure of a longgone, but not forgotten, forebear. And each ancient face that peers from the
past helps her challenge our preconceptions and way of seeing our ancestors.
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New life for old bones: hyperrealistic reconstructions – Daynès
A TOUCH
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Select group of humankind’s ancestors: all related, but actually hundreds of thousands of years apart.
© 2007 Photographer P.Plailly/E.Daynès/Eurelios/Lookatsciences – Reconstitution Elisabeth Daynès Paris
ensive in the half-light, plump-cheeked and rubicund,
the child is the cynosure of the exhibition room. “How
cute! He’s lovely. And so lifelike.” A single glance at the
reconstruction of the three-year-old Neanderthal is enough
to dispel any lingering thoughts museumgoers may have that
his people, those “also-rans” of human evolution, were brutish
halfwits on the wrong (the losing) side of humanity.
P
Beyond feelings of tenderness towards
this child from the past, besides an empathy that overcomes latent speciesism,
what is expressed here is the promise of
another way of seeing these people who
are no longer with us (except, it would
seem, among our genes: it has recently
been claimed that up to 1% to 4% of the
present-day Eurasian genome comes from
Neanderthal DNA). And it is this new vision of our ancestors that I strive to transmit through my sculptures, where art and
science meet.
Endearing chubby Neanderthal child
(Gibraltar, Devil’s Tower).
© 2008 Photo S.Plailly/Lookatsciences –
Reconstitution Elisabeth Daynès Paris
In my studio in the Belleville neighborhood of Paris, I have for
twenty years been recreating australopithecines like the famous Lucy, as well as Homo habilis, Homo georgicus from
Dmanisi (Georgia) Homo erectus, and more recent examples
of Homo sapiens, like Tutankhamen and Albert Einstein. My
clients are museums in France and elsewhere seeking to offer visitors a glimpse into the world of some of our forefathers.
A consuming passion
Looking back there was nothing hinting
that one day I would, so to speak, bring
back to life our great family of ancestors.
After courses in painting and sculpture,
at the age of 21 I started to create makeup and masks for the theater and cinema.
As fate would have it, in 1988 I received
a commission from the Thot Museum
at Montignac (near the famous Lascaux
caves) to recreate a campsite with a few
Magdalenians (the first people to produce
cave art). And a mammoth, which was a
big challenge: 4.5 meters high at the withers! But in the end it wasn’t this prehistoric
pachyderm that fascinated me, rather it
was the fossil skulls that the museum’s sci-
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LUCY
IN THE
SKY
WITH
DIAMONDS…
One of our most famous and distant cousins lived more
than 3.2 million years ago in what is present-day Ethiopia,
where her osseous remains were discovered on 24 November 1974 by two American anthropologists, Tom Gray
and Donald Johanson, the members of an international team
that also comprised two Frenchmen, Maurice Taieb, a geologist, Yves Coppens, a paleontologist, and several others.
More than 50 bones and bone fragments were uncovered
in a ravine situated in the Afar Depression. The skeleton,
40% complete, was that of an individual of female sex,
measuring 1.07 m. Her weight was estimated at 29 kg,
and she boasted a brain volume of a mere 450 cm3 vs today’s circa 1200 cm3. At the time of her discovery, AL 288-1
—as the diminutive hominid was immediately named for
the scientific record—was the earliest known hominid and
provided the first proof that bipedalism preceded the increase in brain size in the long path of evolution leading to
present-day humans.
As an exhilarated team gathered at the base camp in the
evening to celebrate the discovery with the help of welldeserved refreshments and a tape recorder playing the
Beatles’ song “Lucy in the Sky with Diamonds,” nonstop,
the group unanimously bestowed the nickname “Lucy”
upon AL-288-1, a name that was to stick and very rapidly
entists showed me. My enthusiasm was immediate. I knew
little of prehistory, but there and then started delving into anthropology and anatomy: I scoured scientific publications, attended major congresses, met the world’s most renowned
anthropologists and anatomists. I needed to convince anthropology departments around the world of the rigor and seriousness of my plans, so as to solicit their help and support.
Australopitheticus afarensis,
aka “Lucy.” (3.2
million years BP
[= Before Present,
ie, before 1st
January 1950]).
P.Plailly/E.Daynès/Eurelios/Lookatsciences –
gain universal and affectionate recognition by the public.
Lucy later was given her formal scientific name, Australopitheticus afarensis. The skeleton was reconstructed by
Owen Lovejoy of Kent State University, Ohio. In 1997, Élisabeth Daynès was commissioned by the National Institute
of Anthropology and History (INAH), in Mexico City, to undertake the reconstruction of Lucy. This was to prove to
be one of her most challenging works—which took a full
8 months to finish—particularly as only several small fragments of Lucy’s skull had been found, and she had to extrapolate by using the cranial bones of another Australopitheticus (cranium AL 417) found later at the same site.
The original skeleton of Lucy is preserved at the National Museum of
Ethiopia in Addis Abeba.
It was far from easy, but I persisted and won them over, and
for the last 15 years recognition by the scientific community
has enabled me to work with exceptional fossils, the essential basis of my work, access to which would otherwise have
been impossible. Moreover, without relations of trust that I
have forged with the researchers, without the dialogue and
permanent exchanges I have set in place with them, I would
never be able to take up the scientific and artistic challenge of facial reconstruction. For recreating from skull fragments the facial shapes and
traits of a human being is a long and delicate
operation based notably on methods developed
for use in forensic medicine.
A little history
These methods go back to the work of the
French anatomist Paul Broca (1824-1880) who
was the first to consider the human face scientifically and to show the relations between bone
Dr Jean-Noël Vignal, Forensic Anthropologist,
discussing skull features with Élisabeth Daynès.
© 2008 Photo S.Plailly/Lookatsciences – Reconstitution
Elisabeth Daynès Paris
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From the early 1980s, the Americans J. S. Rhine, H. R. Campbell, and C. E. Moore revisited Gerasimov’s work and established tables of soft tissue thicknesses as a function of sex,
ethnic group, and build. These values are often still used by
some research teams, even if new medical imaging techniques
are now able to visualize the inside of the body and distinguish
soft tissues from bone.
structures and soft parts. He rigorously described the different
proportions of the skulls and faces of several ethnic groups.
His results are still valid and confirmed in the anthropology
laboratory every day, as anthropologists realize that the skulls
of each species have particular features, such as those of the
facial bones, that distinguish them from the skulls of other
species. For the form of the skull shapes the face: we may all
have two eyes, a nose, lips, and a chin, but it is their interrelations and relative proportions that make faces different.
Methods
From this principle stems the technique of facial reconstruction, which uses bone fragments to recreate the face they
once formed. The soft tissues (fat, muscles, skin), between
the skull and the face, define facial contours and topography.
The German anatomist Hermann Welcker measured soft tissue thicknesses in 1883, using nine median points in 30 male
cadavers. Twelve years later, the Swiss anatomist Wilhelm
His examined 28 cadavers using a needle introduced at nine
Whether the commission is for a reconstruction of a Neanderthal boy, a young Australopithecus girl, or a Cro-Magnon
man, the first step is to make a cast of a skull. This presupposes that the original is complete, or almost, or at least that
the researchers have been able to reconstruct the missing
parts (often the jawbone) using similar skulls, for the more
complete the cast, the more accurate the reconstruction. The
proportions and shape of the cast enable me to reconstruct
the most logical likeness closest to the original. In my studio
Reconstruction
stages, Homo
sapiens.
P.Plailly/E.Daynès/
Eurelios/Lookatsciences –
Reconstitution Elisabeth
Daynès Paris
Cromanoid-type
head in the course
of reconstruction.
P.Plailly/E.Daynès/Eurelios/Lookatsciences –
Daynès Paris
median points and six lateral points. The distance between
the surface of the skin and the surface of the bone was calculated by measuring the space separating the point of the
needle from a rubber washer pressed against the skin. Wilhelm
His was an innovator and used his results to recreate the face
of Johann-Sebastian Bach from a skull found during renovation work at the Johanniskirche (St John’s Church) in Leipzig.
Many names are associated with the development of facial
reconstruction—Kollmann and Buchly, Merkel, Czekanowski,
Henri-Martin—but it was unquestionably Mikhail Gerasimov
in the Soviet Union who pioneered forensic sculpture. Anthropologist, archeologist, ethnologist, Gerasimov experimented with forensic facial reconstruction using skulls, and in 1935
used his skills in the first facial reconstruction in a criminal
case, to enable witnesses to recognize the victim. In 1950, the
Soviet Union set up a Laboratory for Plastic Reconstruction
where Gerasimov continued his work, recreating, for example,
the faces of Ivan the Terrible and the German poet Friedrich
Schiller. As he later wrote in his autobiography, The Face Finder, Gerasimov was fascinated by the opportunity to “gaze
upon the faces of the long departed.”
I make two copies of the skull. One serves as a support for
the sculpture and I keep the other constantly in view so as to
stick closely to the bone structures. The same method is then
always applied. Using the skull, a veritable identity map of the
subject must be drawn by observing the principles used in a
criminal investigation. For this I have collaborated since 1996
with Dr Jean-Noël Vignal, forensic anthropologist and paleopathologist, the erstwhile director of the Department of Anthropology of the Institut de Recherche Criminelle de la Gendarmerie Nationale (Police Forensic Research Institute) at
Rosny-sous-Bois. He uses the latest technologies to uncover a skull’s secrets. To someone who knows how to examine
it, a skull speaks volumes. Its shape, for instance, can be used
to determine which hominid family it belongs to, but also to
estimate age at the time of death, sex (especially if other—
postcranial [= all save the skull]—bones are available, notably
the pelvis), diseases, deficiencies, and diet. Armed with this
information, Jean-Noël Vignal can calculate the values of 18
craniometric points (soft tissue thicknesses) and generate the
curve of the forehead, the slope of the chin, and precious indications for the reconstruction of the nose.
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TUTANKHAMEN
The facial reconstruction of Tutankhamen was preceded
by an anthropological study using computed tomography
scans recorded by Egyptian experts. This anthropological
study revealed information crucial to the facial reconstruction. First of all, the cranial index indicated an extremely
dolichocephalic skull (long-headed), but without synostosis of the sagittal suture. This showed that the skull was
not scaphocephalic (pathological), but rather has been deformed artificially, a practice used in some cultures for esthetic reasons. The nasal spine was developed and the
lower edge of the nasal orifice was pointed, and there was
no nasal groove. The nasal index showed a long narrow
nose. This leptorhiny was associated with well-developed
nasal bones, suggestive of the type of nose seen in white
subjects, and was corroborated by the absence of maxillary prognathism. The skull was gracile, with thin zygomatic
arches (cheek bones) and poorly developed glabella and
inion.
All these morphological criteria were taken into account in
the facial reconstruction. Facial reconstruction cannot, of
course, provide a photographic image of the subject, but
rather represents the most consistent approximation to the
various features of the face. The color of the eyes, hair, or
skin cannot be established by examining bone fragments.
Cranial and facial indices for a white subject are not at
all incompatible with a representation
of someone with a dark complexion.
It is important to remember that the
people who live around the Mediterranean basin have craniofacial characteristics of whites, but show a wide
range of skin color. By applying the
techniques of forensic science to the
mummy of Tutankhamen, it was possible to rediscover the long-lost facial
traits of the young pharaoh.
Dr Jean-Noël Vignal
Forensic Anthropologist
Reconstruction of Pharaoh Tutankhamen, King of Egypt (ca 1370-1352 BP).
© 2005 Photographer P.Plailly/E.Daynès/Eurelios/
Lookatsciences – Reconstitution
Elisabeth Daynès Paris
The method is spectacularly reliable for Homo sapiens and
the Neanderthals. Older skulls pose greater problems: no
anatomist has ever examined the cadaver of a Paranthropus
or an Australopithecus, and the farther back in time we go
the greater the role of informed guesswork, whence the importance of working directly on the bony structures.
It’s all in the look
Once these calculations are materialized using short sticks
pushed into the cast to indicate the range of soft tissue thicknesses, I use clay to model the muscle masses for the whole
skull. Far from being an artist’s mannerism, this step is essential to visualize the relative proportions of the face and
check its self-consistency. It is at this point that I see the face
beginning to emerge: the lacrimal punctum gives the position of the eye, the opening of the corner of the mouth, between the first and second premolar, indicates the width of
the smile, eye orbits with downturned or upturned ends will
determine whether the look is sad or happy. The shape of the
440
nasal spine, when there is one, indicates whether the nose
was straight, hooked, or upturned. The width of the nasal fossa provides an estimate of the width of the nose, and so forth.
I then add the thickness of the skin and that of the subcutaneous fat. Here too interpretation plays a part: it is impossible know for certain whether a subject was plump or lean,
had full or hollow cheeks. I stay close to the bone structures
without adding too much fat, but the amount of muscle mass
will depend on the indications gleaned from the skull and the
postcranials.
Still to be defined are the wrinkles, the grain of the skin, and
the last absolutely crucial touch: the eyes. For when completely covered by soft parts, the skull reveals a face that is
lifeless, soulless. To breathe life into the reconstruction, I seek
to invest it with character, personality, an air of goodness, a
spark of intelligence, a moment of fear—an emotion however fleeting must animate the eyes and look. I spend hours
working and refining the effect until I find the right expres-
A TOUCH
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Elisabeth Daynès at
work on Paranthropus
boisei (2.5 million years
BP) based on a cast
of cranium OH5,
Olduvai, Tanzania.
Female Homo
georgicus (1.7 million
years BP) based on
cast of cranium
D2282 discovered at
Dmanisi in Georgia.
sion. When I was reconstructing Paranthropus, an African
hominid (2.6 to 1.3 million years ago), Yoël Rak, Professor of
Anatomy at the Tel-Aviv Faculty of Medicine, author of a thesis
on Paranthropus, told me many times: “Think that he wasn’t
carnivorous, wasn’t aggressive.” That marked me. I gave the
Paranthropus a soft look, to the point that when he was finished people passing through the studio could not stop themselves from caressing his head.
Some projects are an even greater challenge. The Science
Museum in Barcelona asked me to represent a Neanderthal
helping one of his fellows who is dying after a hunting accident. How could I show the wounded Neanderthal’s fear of
dying, his friend’s compassion? In the end I found the answer
in a photo in an old issue of LIFE magazine, showing a dying
American soldier, staring into space, in the arms of a comrade
who is looking at him with pain and powerlessness.
“Ecce Homo”
Now it remains to give a body to this head from the distant
past. Here too collaboration with scientists is essential to
acquire all the data on the postcranial bones (length of long
bones, shape of the pelvis and rib cage, muscle insertions…).
For as we delve ever deeper into the past, we move further
away from the anatomy of our contemporaries, and the data
are scarcer, uncertain, debatable. There are, for instance,
numerous hypotheses on the locomotion of our distant ancestors. To reconstruct the gait and postures of Australopithecines, I spent whole days in the Anvers Zoo observing
bonobos, great apes that are our closest extant relatives (along
with the common chimpanzee). I drew much inspiration from
their powerful musculature. This work is important because
I am not seeking to erect a static statue or to produce an
archetype, but to give my sculpture movement, an attitude
Homo floresiensis,
18 000 years BP,
based on a cast of
cranium LB1, discovered on Flores Island,
Indonesia.
© 2009 Photo S.Plailly/
Lookatsciences – Reconstitution Elisabeth Daynès
Paris
Left: Neanderthal,
50 000 BP,
La Chapelle-aux-Saints,
Corrèze, France.
Right: Homo sapiens,
14 000 BP, Chancelade,
Dordogne, France.
© 2008 Photo
S.Plailly/Lookatsciences –
Daynès Paris
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THE
UNKNOWN MAN OF
As he mounted steps leading to the guillotine, Louis XVI
is said to have asked “Have we any news of Monsieur
Lapérouse?” Such concern moments before death testifies
to the immense importance that the King of France accorded to the expedition led by Lapérouse which he himself had ordered as France’s wish to complete the exploration of the Pacific Ocean started by James Cook. In 1788,
the expeditions two frigates the Boussole and the Astrolabe ran aground and 220 crew and scientists perished.
Forty years later, in 1827, the Irish captain Pierre Dillon found
one of the wrecks on the Vanikoro reef, south of the archipelago of the islands of Santa Cruz, the easternmost part
of the Solomon Islands, in the Pacific, west of New Guinea.
The second wreck was only discovered in the early 1960s,
less than one mile from the first. Since 1981, the Association Salomon has been trying to elucidate the circumstances
in which Lapérouse and his men disappeared. In 2003, a
skeleton was discovered at a depth of 15 meters, under a
thick layer of sediment. These bones were sent for identification to the Institut de Recherche Criminelle de la Gendarmerie Nationale in Rosny-sous-Bois in France, and
Élisabeth Daynès was commissioned by the French Navy
to reconstruct the face of “the unknown man of Vanikoro.”
The skeleton was remarkably preserved and virtually complete, which is extremely rare for a body found in seawater. Anthropological and paleopathological studies indicate
a man of European type, aged 30 to 34, 1.65 to 1.70 m in
height, with smallish muscle insertions suggesting that his
evocative of its environment by using all
known scientific data, always with the
aim of transmitting an emotion through
a poignant vision of the march of humanity.
When the clay model is finished, I make
a mold for the final silicone model, ie,
the sculpture on which I make the finishing touches: tinting the skin, inserting the ocular and dental prostheses,
adding liver spots and so forth, before
using a needle to insert one by one thousands of (human or yak) hairs. Whereas the face’s shape and proportions are
strictly objective (being related to the
underlying bone structures), the colors
of the eyes, skin, and hair are subjective. Yet my choices are not random, but
rather the fruit of a long process of im-
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VANIKORO
musculature was not well developed. The left humerus had
a deformation with an angle of 15°, most likely an old consolidated fracture without functional consequences. The
right femur was shorter than the left, although this would
not have a functional impact on walking. The right fibula
had a fracture, but it was not possible to say whether this
occurred perimortem or postmortem. The dentition was
incomplete (teeth lost postmortem), but was remarkably
healthy for the period. The cuspids showed severe abrasion suggestive of bruxism, type of diet, or regular use of
teeth-cleaning twigs. The time since death, estimated by
means of Nile blue staining, was 201±29 years, which is
fully compatible with the disappearance of the two ships of
Lapérouse’s expedition.
However, the anthropological and paleopathological characteristics of the skeleton did not match those of this illustrious navigator (who was about 47 years of age when
he disappeared). But taking into account the state of the
teeth, the weak musculature, the subject’s age and height
(above the average for the time), it was hypothesized that
the remains likely belonged to a royal navy officer or to a
scientist. This was corroborated by the fact that the skeleton was found in the stern of the vessel, where officers were
generally accommodated. Reconstruction has given a facial likeness to this unknown, the only latter-day witness to
the fate of Lapérouse and his men.
Dr Jean-Noël Vignal
Forensic Anthropologist
mersion in the universe in which the men
and women I recreate lived, taking into
account their culture, way of life, eating
habits, the climate they lived in, and so
on. For example, if the fauna associated with the bones is African, we can deduce that the climate was hot, which
suggests a dark skin and dark eyes.
Sometimes even, for certain hominids
from very long ago, like Homo ergaster,
Homo habilis, and Australopithecus,
published studies suggest that the sclera of the eye could be very dark. For
Neanderthals, on the other hand, certain studies of fossil DNA suggest that
they had reddish hair and pale eyes.
Charles Darwin (1809-1882),
as reconstructed by Élisabeth Daynès.
© 2009 Photo S.Plailly/Lookatsciences – Reconstitution Elisabeth Daynès Paris
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My greatest pleasure then is to see the surprise and emotion of the researchers with whom I have worked as they contemplate the final result. They are face to face with an ancestor recreated using the latest scientific findings, an ancestor
they thought they knew and who had peopled their most
secret dreams. And suddenly, in the studio in Belleville, their
dream takes shape.
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from our past and to rehabilitate them, banishing forever an
all-too-common perception of them as brutish and dull-witted. Through my work, I hope to change such attitudes and
to help people recognize the extraordinary achievements of
our hominid ancestors over millions of years. I
A plea for our ancestors
My main aim is to give the museums or institutions that exhibit my sculptures a teaching tool that will encourage visitors to think about our origins through a face-to-face encounter with a representative of a prehistoric population. I
hope in some small way to enhance understanding of the
physical appearance of these prehistoric men and women
Abduction? Elisabeth Daynès transporting a nearly
completed Homo georgicus (1.7 million years BP).
© 2002 Photographer P.Plailly/E.Daynès/Eurelios/Lookatsciences –
UNE NOUVELLE VIE POUR DE VIEUX OS : LUCY, TOUTANKHAMON,
ET UN SCIENTIFIQUE NAUFRAGÉ DU XVIII E SIÈCLE RETROUVENT LEUR VISAGE
Dans son atelier de Belleville à Paris, Élisabeth Daynès exerce un métier rare : sculpteur en anthropologie. En collaboration avec des anatomistes, des anthropologues, des archéologues, et des préhistoriens elle donne une nouvelle
vie à des ossements vieux de plusieurs milliers, voire plusieurs millions d’années en sculptant des australopithèques,
des paranthropes, des néanderthaliens. Aux confins de l’art et de la science, la paléoartiste utilise des techniques de
reconstruction faciale issues des méthodes mises au point pour la criminologie. Des méthodes devenues aujourd’hui
très fiables avec les progrès de l’imagerie médicale mais qui s’enracinent dans les recherches du suisse Wilhelm His
qui reconstitua à la fin du XIX e siècle le visage de Jean-Sébastien Bach à partir d’un crâne présumé qui avait été
exhumé de l’église Saint Jean de Leipzig (Johanniskirche), et dans celles plus récentes du russe Mikhail Gerasimov,
premier anatomiste à reconstituer un visage dans le cadre d’une affaire criminelle en 1935. Travaillant essentiellement
pour des musées dans le monde entier soucieux de montrer à leurs visiteurs d’anciens représentants de la grande
famille humaine plus vrais que nature, chaque sculpture, dans un dialogue permanent avec les chercheurs, exige des
mois de travail pour redonner un visage et une silhouette à l’un de nos aïeux disparus. Le résultat sert efficacement
l’objectif de l’artiste : changer le regard de ses contemporains sur nos ancêtres.
443
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‘‘
When Voltaire died, his admirers took his heart and brain, a
heel bone and a few teeth. Descartes’ index finger was pocketed by the French ambassador to
Sweden, rings were sculpted from
his pelvic bone, and his skull, after
many twists and turns, is now on
display at the French National Museum of Natural History. Vivant
Denon’s amazing reliquary contains bone fragments belonging
to Abélard and Héloïse, Molière,
La Fontaine, El Cid, and others.
The bones of the famous live on
for eternity in museums, churches,
and even private homes…”
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The eternal life of bones
Tidbits of French history through
the trials and tribulations of relics
of the illustrious
b y C . Po r t i e r- K a l t e n b ac h , Fra n c e
© All rights reserved
A
Clémentine PORTIERKALTENBACH
Journalist, historian
Paris, FRANCE
graduate of Sciences Po, the prestigious French institution that trains French
elites, Clémentine Portier-Kaltenbach is a journalist who specializes in the
history of the city of Paris, as well as in the fascinating sidelights of history
at large. She has authored the questions of the French “Paris version” of the Trivial
Pursuit game. She was a columnist for the French newsweekly Le Nouvel Observateur, and makes regular appearances on French radio and television. She is a member of several historical societies. She is the author of Histoires d'Os et Autres Illustres Abattis (A History of Bones and Other Famous Remains), in which she discloses
the often burlesque destiny of the relics of great French historical figures. In April
2010, Éditions Lattès published her latest book, Grands Z’Héros de l’Histoire de
France (The Great Z/Heroes of French History), a play on words between “heroes”
and “zeroes,” in which she shuns the customary panegyric to glorious events to
cast instead an amused look at some of the “major failures and bloomers” that
have changed—not for the best—the course of French history.
P
Clémentine Portier-Kaltenbach
1, rue Clovis 75005 Paris, France
(e-mail: clementinepk@free.fr)
haraoh Ramses II almost started a diplomatic row between Egypt and
France in 2006—more than 3200 years after his death. Or rather his hair
did. French police found a few tufts (of a rather fetching auburn, even
after all these years) when they raided the home of postal worker Jean-Michel
Diebolt in the Alpine town of Grenoble. It turned out that Diebolt père had
done research on the mummy in the 1970s and bequeathed the pharaonic
keratin to Diebolt fils, who offered it for sale on the Internet, for 2000 euros.
Such relic-mongering for gain, monetary here, but also spiritual or secular, has
a long and colorful history. A couple of Venetian merchants may have started the craze back in 828 when they stole Saint Mark’s bones from a church
in Alexandria and took them back to Venice. From then onwards, human remains were on everyone’s wish list—Buddha’s teeth, Saint Matthew’s legs (all
eleven of them), Voltaire’s heart, Napoleon’s hair—but especially bits of bone:
bones are long-lasting, don’t stain, and can be fashioned into trinkets. But after centuries of bony prominence, the whole business became, well, ossified.
Nowadays, there’s a more personal touch to commemoration. Why bother
with body parts from people you’ve never met, however illustrious, when you
need look no further than your nearest and dearest? Take a deceased loved
one or pet, cremate, extract carbon, heat and compact for months, and voilà
a diamond. Ashes to ashes, dust to diamond.
444
The eternal life of bones – Portier-Kaltenbach
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arthly fame has seldom been rewarded with everlasting
rest. Rather, peddlers of indulgences, collectors, articulators of bones have oft preyed upon the mortal remains
of men and women famed in their lifetimes for righteousness
or might, derring-do, or nimbleness of mind. Displayed for the
curious and gullible, bought and sold, the “choicest morsels”
among relics sacred and profane have always been bones.
E
From holy relics…
N In Christianity
One of the most “encyclopedic” collections of relics of early
Christian saints, in the form of little bits and chips of bone
placed in ornate reliquaries, along with other larger holy remains, can be found in the Abbey of Saint-Victor in Marseilles.
Of the Abbey, one of the first on French soil, only the church
remains after the destructions wrought by the French Revolution in the 18th century. The squat square-shaped twotowered crenellated edifice, which looks more like a toy castle
than a religious building, overlooks the Old Port (Vieux-Port)
of Marseilles and is a must visit. It was named after the eponymous saint martyred in Marseilles in 304 and founded in the
5th century by John Cassian (ca 360-435), who “imported”
oriental monastic spirituality to Europe from the deserts of
Palestine and Egypt. Saint-Victor exemplifies the importance
for the faithful of being able to relate to their illustrious predecessors by enshrining their remains in their churches. Preserving relics of the saints and martyrs is a tradition that goes
back to the dawn of the Church. However, the cult of holy
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relics properly flourished throughout the Middles Ages and
reached its apogee in 13th-century Europe. Every saint was
reputed to have touched God, so the least splinter of his bones
was deemed sacred and, it was believed, had the miraculous capacity to protect its owner against all manner of ills.
And so any good Christian would hope to procure one.
Louis IX (1214-1270), King of France, was one of the greatest collectors in the West and bought up everything linked,
however tenuously, with the Passion of the Christ. The centerpiece of his collection was Christ’s Crown of Thorns, which
he bought in 1238 from a Venetian merchant to whom it had
been pawned for 135 000 livres by Baldwin II of Courtenay,
the last and impecunious emperor of the Latin Empire of Constantinople. Louis IX’s precious acquisition cost three times
more than the Sainte-Chapelle built to house it on the Île de
la Cité in Paris. Today the relic in the treasure of Notre-Dame
cathedral, a 2-minute walk from the Sainte-Chapelle, and is
presented on the first Friday of every month to the veneration
of the faithful at 3 PM (the purported time of the Crucifixion),
as well as on Good Friday. Its official custodians still are the
Knights of the Equestrian Order of the Holy Sepulcher of Jerusalem, whose current Grand Master is John Patrick Foley, an
American Cardinal.
When he died, Louis IX, who was considered a living saint,
was promptly transmuted into relics: his body was boiled in
wine and his bones were held in a silver casket. But not for
long, since from 1308 the bones were shared among vari-
Holy bones in
Saint-Victor
Abbey in Marseilles: display
of reliquaries
containing osseous remains
of early Christian
saints and martyrs, including
the skull of saint
John Cassian
(top middle), and
morsels of saints
Agatha, Benignus, Caesarius, Constant II,
Facondi, Felicity,
Fidelius, Fortunatus, Justin, and
many others.
© Abbaye SaintVictor – Ville de
Marseille. All rights
reserved.
445
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Rock crystal
reliquary containing
Christ’s Crown of Thorns.
This relic, after a long and
troubled history which took it from
Jerusalem to Byzantium, was purchased from Baldwin II, Emperor
of Constantinople by French King
Louis IX in 1238, for 135 000 livres
corresponding roughly today
to 25 million US $.
© Gérard Boullay.
ous churches, a fate that was perhaps to be expected following his canonization as Saint Louis at the close of the 13th
century. On the eve of the French Revolution of 1789, various Parisian churches still possessed one of his ribs, a finger,
a bone from his hand, as well as his skull and a jawbone.
Curiously, his heart is preserved at the cathedral of Monreale,
in Sicily.
In 16th-century Europe there was such a glut of saintly bones
in circulation that in 1543 the Protestant theologian John Calvin
denounced their proliferation and the accompanying unbridled trade in his A Treatise on Relics. Calvin thought it behooved him to point out to guileless believers that supposed
relics were often held in more than one place at the same
time. Leaving aside Christ’s hair, chin whiskers, and milk teeth,
and the Virgin Mary’s breast milk, was it reasonable to suppose that there were also three foreskins of Christ, eleven legs
of Saint Matthew, thirty-two fingers of Saint Peter, ten heads
of Saint Léger, and three bodies of Saint Agnes? Calvin’s treatise doubtless dampened the enthusiasm of collectors, but
failed to stop the veneration of holy relics, to the point that
even today the Vatican unblinkingly admits that it owns two
heads of Saint Peter: one within the Vatican City in Rome, in
Saint Peter’s Basilica, and one without, at the Papal Archbasilica of Saint John Lateran. Pilgrims fond of the Apostle Peter
are therefore spoilt for choice, and can collect their thoughts
alongside either head, with the benediction of the Holy See.
N In other religions
Rest assured, Christianity is not the only religion to prize such
collections. Although Muslims have none of Mohammed’s
bones, hairs from his beard are on display in the Topkapi Museum in Istanbul. As for Buddhists, in Sri Lanka they have one
of Buddha’s teeth, and the ashes from his funeral pyre.
More surprisingly, a country as “modern” as the United States
is a venue of choice for relics, albeit in an “ecumenical” spirit. The relics of Saint Louis travel regularly to Louisiana, for
display in the Saint Louis Cathedral in New Orleans (note that
the name Louisiana has nothing to do with Saint Louis; rather
this vast territory, which originally extended to the Great Lakes,
was named by the French explorer René Robert Cavelier de
La Salle in 1682 in honor of the Sun King Louis XIV). As to
the Buddha, his ashes are held at the United Nations headquarters in New York City, donated by Thailand, Sri Lanka,
and Burma in thanks for the international recognition of the
Day of Vesak, commonly equated with the Buddha’s day of
birth, but in fact encompassing his birth, enlightenment (nirvana), and death.
The Sainte-Chapelle, on the Île de la Cité in Paris,
was built in 1248 by King Louis IX, as a giant reliquary
to preserve the Crown of Thorns.
The sight from within is breathtaking, giving the impression that the church
consists more of glass than stone, with a 360° offering of stained glass windows reaching from top to nearly bottom. © B. Didier. All rights reserved.
446
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John Calvin
(1509-1564),
the French
theologian and
reformer issued
a thundering
Treatise in 1543,
ridiculing the
cult of relics.
Collection of Albert
Rilliet, Geneva,
Switzerland
© Giraudon/Bridgeman Giraudon.
Relics then can play a political role and further friendship between peoples: in 2006, as a gesture of goodwill and to express desire for dialogue and cordial relations with Orthodox
Russians, the Vatican lent Russia the hand that Saint John
the Baptist is reputed to have used to baptize Christ.
…to the bones of the famous
N Man, this admirable creature
The Age of Enlightenment in the 18th century changed the
way holy relics were viewed. The existence of God was called
into question, and if God does not exist then clearly man is
the most fascinating creature in this lowly world, and if there
is no resurrection of the flesh or soul, no eternal life, all that remains of him after death is
his bones. Thereafter, the craze was for bits
of remarkable people.
When the French philosopher Voltaire died,
his admirers took his heart and brain, a heel
bone and a few teeth. The Marquis de Villette
kept the heart in a small mausoleum inscribed
with the words: “His heart is here, but his spirit is everywhere.” A century later, the heart in
question was the subject of a sordid quarrel
over a last will and testament. The heirs of the
Marquis de Villette went to court to assert their
right “to hold in trust” the noble organ. To end
their squabble, the Minister of Public Instruction was reduced to declaring the philosopher’s heart a “national treasure,” to the point
that this desiccated organ was thereafter
deemed part of the nation’s heritage. Every
French person today can therefore consider
him- or herself the proud owner of one 65
millionth of Voltaire’s heart.
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N A free-(bone)-for-all….
The French revolution in 1789 marked a complete turnabout
in the way bones and other relics came to be treated. First
there was the acute sanitary problem posed by the congested cemeteries in Paris in the 17th century. It was decided to
dispose of the overflow of bones by placing them in the ancient empty tunnels of long abandoned stone quarries of which
Paris boasted miles upon miles. This brilliant idea originally
came from Alexandre Lenoir, a revolutionary who fell in love
with bones and about whom more will be said later. But better hygiene was not the only outcome of the Revolution. It was
not long before the rabble bent on revenge for centuries of being the underdogs, broke into the tombs of aristocrats and
above all of the Kings of France, who since the 7th century had
been buried in Saint Denis Cathedral, near Paris. For days on
end, graves were dug up and coffins prized open to recover
the lead, for melting down into bullets, as France was then at
war. Skeletons were desecrated and bones dispersed, but
many vandals also took their pick of gruesome souvenirs. First
come first served: a leg here, an arm there, a few teeth, wisps
of hair, whiskers. The Sun King, Louis XIV (who built the Château de Versailles), lost his last few teeth during these days of
pillaging in the summer of 1793. Meanwhile, in the south of
France, the sans-culottes (meaning “without knee-breeches,”
in reference to the poorer members of society) opened the
tomb of the famous 16th-century apothecary and reputed seer
Nostradamus, and drank out of his skull. The beverage is not
recorded, but vin ordinaire is probably a safe bet.
While no one was overly bothered that royal bones should
be strewn across byways and highways, could not the bones
of illustrious men and women beloved of the people serve
Piles of bones lining the Catacombs in Paris. One of France’s most popular
tourist attractions, the Catacombs are a huge ossuary filling several sections of the
ancient underground limestone quarries crisscrossing the lower depths of Paris.
This particular section contains the remains transferred from the former Parisian cemetery of St Landry.
© Robert Holmes/CORBIS.
447
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Molière (pseudonym Jean-Baptiste Poquelin, 1622-1673) in
the stage costume of Sganarelle. One of France’s greatest
dramatists, his plays are still performed nonstop at the ComédieFrançaise and many other theaters in France and abroad.
A fragment of his jaw is kept at the library of the Comédie-Française. Etching
by Claude Simonin (1635-1721). © RMN/Agence Bulloz.
the cause of the Revolution? As goblets, perhaps, so worthy
citizens could drink to the health of the nation? With this idea
in mind, the bones of the playwright Molière and of the poet
La Fontaine were taken to the Paris Hôtel des Monnaies
(which struck coins and medals). Fortunately, this egregious
plan was stymied by political events which, in those troubled
times, were moving at a frightening pace. The chemist at the
Hôtel des Monnaies did, however, send a piece of Molière’s
jaw to the Comédie-Française, the great Parisian theater,
where it remains to this day, not far, it may be added, from a
statue whose base contains Voltaire’s brain, swapped by its
owners in 1924 for two free seats in the stalls for twenty years.
Descartes fared no better. A few years after his death in Stockholm in 1650, his body was dug up for return to France. The
French ambassador overseeing the exhumation pocketed
part of the philosopher’s index finger, considering it “the instrument of immortal writing.” Meanwhile, one of the Swedish
guards on duty pilfered the skull and flogged it to pay a few
debts. Years later, when entrusted with transferring the philosopher’s remains, the archaeologist Alexandre Lenoir—
who devoted his life to saving historical monuments, tombs,
and other treasures from the destructive fury of the French
448
Statue of Voltaire (7416-1778) by Jean Antoine Houdon
(1741-1828) at the Library of the Comédie-Française in which
the philosopher of the Enlightenment’s brain is enshrined.
© RMN/Agence Bulloz.
Revolution—filched a pelvic bone and sculpted rings for a
few friends. As for the skull, it resurfaced in 1821 when it was
put up for sale at 37 francs, along with the possessions of a
certain Sparrman, the manager of a gambling den in Stockholm. It subsequently came into the hands of the Swedish
chemist Berzelius. Knowing that the “rest” of Descartes was
in France, Berzelius packed the cranium in a pretty hatbox
and sent it to his French colleague Georges Cuvier, one of the
pioneers of a whole new discipline known variously as phrenology, craniology, craniometry, or physiognomony. Cuvier and
the like-minded Franz Joseph Gall, Paul Broca, and George
Combe claimed that personality traits could be divined by examining the shape of a person’s braincase.
As luck would have it, there was at the time a steady supply of
skulls thanks to the zealous use that had recently been made
of “Madame Guillotine” (also dubbed “The National Razor”)
in the Place de la Révolution (now Place de la Concorde) in
Paris. One such came from Charlotte Corday. A noted figure
in the history of France, Charlotte had in July 1793 assassinated Jean-Paul Marat, scourge of the “enemies of the Revolution” and one of the most influential politicians during The
Terror, the 14-month period when revolutionary fervor was
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at its height and perhaps as many as forty thousand victims
had been guillotined. That’s something like one every 8 minutes for a 12-hour working day (no vacation or days off, la Révolution oblige). Charlotte’s skull later found its way into the
possession of a fervent enthusiast of craniology, while the
rest of her was lost to history.
A little over a century later, in 1889, the skull turned up at the
Exposition Universelle organized on the occasion of the centenary of the Storming of the Bastille, the flashpoint of the
revolution. A small label informed the curious that its owner
was Prince Roland Bonaparte, a nephew of Napoleon. At the
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Prince’s request, five experts examined the skull. Two declared that in no way was it that of a criminal; the other three
had rarely seen a more villainous-looking specimen. So much
for experts. Fingering the contours of the heads of the famous
or infamous was all the rage in the 19th century. The heads
of criminals naturally excited much interest. Gall studied the
skulls of Cartouche (17th-century highwayman) and Lacenaire
(19th-century murderer and would-be wordsmith), and of the
Marquis de Sade, not to mention that of Descartes who, wherever he (or rather the rest of him) was, must have thought
things had come to a sorry pass to be lumped together with
these scoundrels. “I think, therefore I am (not like them).”
FABULOUS RELIQUARY OF
“The Emperor’s eye” was how Goethe nicknamed Dominique Vivant Denon (1747-1825), creator of the Louvre
Museum, Director General of Fines Arts for more than fifteen years during the First Empire (1804-1814) and the
Restoration (1814-1830). Instructed by Napoleon to gather for the Louvre the most exceptional collection of works
of art in Europe, Denon went about his task with brio, while
quietly amassing on the side his own personal collection.
Among his treasures was a strange reliquary from the Renaissance: bone fragments from El Cid and his wife Doña
Jimena Díaz, pieces of bone from the 12th-century lovers
Abélard and Héloïse, hair from Agnès Sorel (mistress of
Charles VII of France) and of Inês de Castro (lover of Peter I
of Portugal), part of the mustache of Henri IV of France,
a piece of the shroud of Turenne, Louis XIV’s brilliant Field
Marshall, bone fragments from Molière and La Fontaine,
one of Voltaire’s teeth, Napoleon’s hair, his autograph, a
piece of the bloodied shirt he was wearing on the day of
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VIVANT DENON
his death, a leaf from a willow that weeps over his tomb on
the island of Saint Helena. For Denon it was enough that
there was a certain inspiration, a glimpse of the sublime,
something Homeric in the life of the person thus remembered. Was he not himself an engraver, watercolorist, diplomat, writer, traveler, archeologist? Had he not rubbed shoulders with Louis XV, Madame de Pompadour, Catherine the
Great in Saint Petersburg, Frederick the Great at Potsdam,
and in Naples with the nefarious Count Alessandro di Cagliostro (once held for nine months in the Bastille on suspicion of involvement in the Affair of the Diamond Necklace,
before the charges were dropped for lack of evidence)?
Had he not followed Napoleon into Egypt where he had
many brushes with death?
Denon’s remarkable reliquary is today displayed in the Musée Bertrand at Châteauroux, in Touraine, its contents a
moving homage to famous figures in the history of France.
Vivant Denon’s reliquary,
in Renaissance style
(44 cm), now at the
Musée-Hôtel Bertrand
de Châteauroux.
© Photo by Claude-Olivier
Daré/Musées de
Châteauroux, Indre, France.
With kind permission.
Detail of the reliquary,
showing one its four
sides which contains
bone chips belonging to
Molière and La Fontaine;
a piece of cloth from a
garment belonging to
Marshal Turenne, one of
Voltaire’s teeth, a few
whiskers from Henri IV
and a strand of hair
from General Desaix.
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The Murder of Marat by Charlotte Corday, 13th July 1793.
Oil on canvas by Jean-Jacques Hauer (1751-1829). Musée Lambinet,
Versailles, France. © Giraudon/Bridgeman Giraudon.
Inset: the skull of Charlotte Corday, photograph taken from La
Donna Delinquente, La Prostituta e la Donna Normale [The Female
Offender, the Prostitute, and the Normal Woman] by Cesare Lombroso (1835-1909), a late 19th-century criminology study (unbearably sexist by present-day standards).
The founder of the Italian School of Positivist Criminology and a social Darwinist,
he claimed that criminality was inherited, and that a “born female criminal” could
be identified by physical defects, such as excessive body hair, wrinkles, and an
abnormal cranium.
Napoleon’s brother was in the habit of saying that there was
enough supposed imperial hair around to be woven into a
huge carpet. In passing, it is worth noting that Napoleon had
generously given locks of his hair to his nearest and dearest,
as well as to a few admirers. As it turned out this was most
prescient since scientists were later able to assay arsenic in
the hair and to infer that there had been suspicious amounts
in the imperial body. But that’s another (forensic) story.
Even Napoleon couldn’t escape the craze. When he died on
5 May 1821, after six years of captivity on the island of Saint
Helena, he was autopsied by Dr Antommarchi, who also applied “Gall’s method.” And the startling conclusions of this
scrupulous examination of Napoleon’s cranium? Well, that the
Emperor had the bump corresponding to—yes, you guessed—
conquest. Shrewd indeed. Vive la craniologie! Now, as we
are, so to speak, on Saint Helena along with Napoleon’s mortal remains, let us tarry awhile. It goes without saying that the
greater a person’s notoriety, the greater the likelihood he will
be sliced up post mortem and become part
of a collection (or two). And this is exactly
what happened to Napoleon. The story of
the imperial hair is doubtless the best known.
And what of the other imperial bits and bobs? Well, during the
autopsy, Dr Antommarchi secreted in the pocket of his large
white apron two rib fragments and a tendon, not to mention
a piece of the “imperial penis,” which he gave to the priest
who had administered the last rites to the Emperor, the Abbé
Vignali. Quite what was going through the good doctor’s mind
when offering a piece of imperial genitalia to a man of God is
anyone’s guess. The medically preserved penile relic remained
in the Abbé’s family until 1969, when it was auctioned at
Christie’s for the trifling sum of thirty-eight thousand euros to
an American urologist by the name of John K. Lattimer, who
kept it in a safety-deposit box at the Columbia Presbyterian
Hospital in New York. And what would it fetch today? No need
perhaps for wild speculation since Dr Lattimer died two years
Mozart’s teeth, showing a caries in a
molar tooth (2nd from left), confirming the
authenticity of the skull retrieved from the
communal grave by the anatomist Joseph
Hyrtl in 1842.
René Descartes (1596-1650) “before and after.” All the French hail after Descartes,
fondly dubbing themselves “Cartesian,” ie, arch-rationalists. This is the portrait and
the skull of the author of the Discourse on the Method of Rightly Conducting One’s
Reason and of Seeking Truth in the Sciences and of the celebrated phrase: “Cogito
ergo sum”: I think, therefore I am.
The skull is now kept at the Mozarteum University of
Music and Dramatic Arts in Salzburg, Austria.
© akg-images/Gilles Mermet.
Left: Portrait of René Descartes by Frans Hals (1582-1666). Musée du Louvre, Paris. © Giraudon/
Bridgeman Giraudon. Right: Descartes’ skull, at the Museum National d’Histoire Naturelle, Paris, France.
© MNHN - D. Ponsard.
450
A TOUCH
ago and it may only be a matter of
time before this curio of Napoleonic
masculinity once more finds its way
into an auction house.
Judging by the success of auctions
of Napoleonic body parts (one of his
teeth went for twenty thousand euros in 2005), these relics and bones of
the good and the great are not merely memento mori (literally, “remember
that you must die”), curios of dubious
taste suspended in time (and perhaps
in formaldehyde) for lovers of the macabre. Strange though it may seem, illustrious remains are much in the news.
Not too long ago Mozart’s skull made
the headlines. As for its authenticity,
the owner pointed to a decayed tooth
and reminded one and all that Mozart
was complaining of toothache shortly
before he died. No doubts there then.
OF
FRANCE
If the heart of a boy (the heir to the
French throne, Louis XVII) who died in
the Temple Prison during the French
Revolution had not been kept, together with hairs from the head of MarieAntoinette, it would have been impossible to prove that the child was
indeed the queen’s son. And had not
fervent admirers of Beethoven got hold
of some threads of the composer’s
hair, science would never have been
able to discover that he was probably afflicted by chronic lead poisoning, which may explain his notorious
mood swings.
Then there is the story of Neil Armstrong, commander of the 1969 Apollo 11 mission and the first man to walk
on the moon. A while ago he realized
that his barber was cleaning up at
every trim. Marx Sizemore, the owner
of Marx's Barber Shop in Lebanon,
Ohio, was keeping Armstrong’s hair to
Only last year, the French government
sell to collectors, in one case for three
seriously envisaged organizing (yet anFragment of the heart of Louis XVII, son of
thousand dollars. Incensed, Armstrong
other) transfer of Descartes’ skull, this
Louis XVI and Marie-Antoinette, the 10-yeartook legal action against the barber,
time from the Musée de l’Homme in
old heir to the throne of France who died in
who claimed to have sold the hair to
Paris, where it has been held for thirty
the Temple Prison in Paris on June 8, 1795.
His royal parents were guillotined.
an agent of John Reznikoff, an Ameryears, to the school in Touraine where
Carved crystal reliquary kept at St Denis Basilica,
ican listed by Guinness World Records
the philosopher had studied as a boy.
north of Paris. © SIPA.
as the owner of the world’s largest colHistorians were outraged that the authorities were more concerned with displaying the skull than lection of hair from famous people. Insured for a million dolwith reuniting it with his skeleton, held in the Parisian church lars, the collection includes 115 locks from illustrious figures
of Saint-Germain-des-Prés. What’s more, no comparison of including Charles Dickens, Abraham Lincoln, Marilyn Monroe,
DNAs from the two had been planned. In the end the plan John Kennedy, Albert Einstein, Elvis Presley, and, of course,
Napoleon.
was shelved.
N Fetishistic forefathers?
Of course, to our eyes, all these relics have something repugnant about them and we find it hard to understand what
prompted our forebears to horde bits of skin and bone and
teeth. Yet little by little, as science has advanced, our view of
these organic relics has changed. They now seem precious,
because they may contain the DNA, the unique and virtually
indestructible identity card of the individual from whom they
came. In a way, these relics are proof of the existence of a
form of everlasting life.
Studies on the DNA of organic relics has many a time resolved historical mysteries. If someone hadn’t kept a polyp
from Anna Anderson, who spent her whole life claiming to
be the Grand Duchess Anastasia, one of the daughters of
Nicholas II, the Tsar of Russia murdered with his whole family
at Yekaterinburg on 17 July 1918, it wouldn’t have been possible to prove that she was, in fact, unrelated to the Romanovs.
Perhaps then we are a tad hasty in expressing disgust at
our ancestors’ penchant for “tidbits” of the famous. Readers
would do well to remember that there are companies in America, Russia, Switzerland, and the United Kingdom that create diamonds from the ashes of their clients’ dearly departed.
Ash contains carbon; diamond is nothing but. So, under conditions that “recreate the forces of nature”—months at extreme
The new cult of relics:
Blue LifeGem© diamonds
obtained from cremains
(cremated remains), destined, for example, to be
made into memorial jewelry
for a bereaved pet owner.
Photo courtesy
of LifeGem Europe BV
(www.lifegemeurope.com).
451
A TOUCH
OF
FRANCE
pressure (6 x109 Pascals, ie, 60 million times atmospheric
pressure) and high temperature (1600-2000°C)—carbon from
the cremated remains (shortened to “cremains”) of a loved
one or a pet can be converted to diamond. Ashes to ashes,
dust to diamond… that is the new fad in terms of relics. Which
puts a whole new slant on the Marilyn Monroe song: diamonds really could be “a girl’s best friend.” And not just cremated remains. Hair too. In 2006, one of these companies created three diamonds from ten strands of Beethoven’s hair
(plus a pinch or two of exogenous carbon) from the collection
of—yes, that’s right—John Reznikoff. Is turning loved ones
into brooches, pendants, or perhaps body piercing jewelry really that different from making a ring from Descartes’ bones?
Who now dares smile superciliously at the foibles of those
18th-century eccentrics who sought to preserve their great
men in the form of drinking vessels with which to toast the nation’s health? Far from being laughable, these practices bore
witness to a profound truth: from time immemorial men and
women have shared a craving for immortality. I
LES OSSEMENTS, PARCELLES D’ÉTERNITÉ : MORCEAUX CHOISIS
DE L’ HISTOIRE DE F RANCE À TRAVERS LES RELIQUES D ’ ILLUSTRES PERSONNAGES
En 2006, le pharaon Ramsès II, ou plutôt ses cheveux, ont été à deux doigts de provoquer un incident diplomatique
entre la France et l’Égypte, et ce plus de 3 200 ans après sa mort. En effet, la police française a retrouvé quelques
mèches (châtain aux reflets cuivrés ma foi très seyants, même après tant d’années) lors d’une perquisition au domicile d’un facteur grenoblois dénommé Jean-Michel Diebolt. Il s’est avéré que Diebolt père avait fait des recherches
sur la momie dans les années 70 et légué la kératine pharaonique à Diebolt fils, qui voulut la vendre sur Internet pour
2 000 €. Un tel trafic de reliques, ici pour s’enrichir financièrement, mais ailleurs aussi de façon spirituelle ou profane,
procède d’une longue et pittoresque histoire. L’engouement aurait débuté avec quelques marchands vénitiens qui,
en 828, dérobèrent les os de saint Marc dans une église d’Alexandrie pour les rapporter à Venise. Depuis lors, la
demande pour les restes humains ne s’est jamais tarie, qu’il s’agisse des dents de Bouddha, des jambes de saint
Matthieu (il y en a au moins 11 !), du cœur de Voltaire, des cheveux de Napoléon… mais avant tout des ossements :
ces derniers se conservent indéfiniment, ne tachent pas et peuvent être transformés en colifichets. Mais après des
années de « proéminence »… enfin, prééminence… osseuse, le marché s’est en quelque sorte « consolidé » en acquérant une dimension plus personnelle. Pourquoi s’enticher de restes d’humains qu’on a jamais rencontrés, même
s’ils sont illustres, alors que nos chers et tendres sont sous la main ? Prenez un proche ou un animal de compagnie
passé à trépas, incinérez-le, extrayez-en le carbone, chauffez-le et compactez-le pendant des mois… et voilà un
diamant ! Tu es poussière et tu retourneras en diamant…
452
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