la terapia dell`osteoporosi: rischio o beneficio?

ASPETTI ENDOCRINO-­‐METABOLICI NELL’ANZIANO Bari,
7-10 novembre 2013
LA TERAPIA DELL’OSTEOPOROSI: RISCHIO O BENEFICIO? Stefania Bonadonna U.O. di Mala*e Metaboliche Ossee Is3tuto Auxologico Italiano, Milano DEFINIZIONE OSTEOPOROSI Bari,
7-10 novembre 2013
Osteoporosis Is a Common Disease with Increased Fracture Risk Across the EnHre Skeleton Defini3on of osteoporosis: Normal •  Compromised bone strength predispose persons to increased risk of fracture •  Bone strength reflects the integra3on of bone density and bone quality “Osteoporosis is one of the most common and debilita3ng chronic diseases, and a global healthcare problem.” Interna3onal Osteoporosis Founda3on “Osteoporosis has financial, physical, and psychosocial consequences, all of which significantly affect the individual, the family, and the community.” NIH Consensus Statement Boyle WJ, et al. Nature 2003;423: 337-­‐342; NIH Consensus Development Panel. JAMA. 2001;285: 785-­‐795. Osteoporosis RISCHIO FRATTURATIVO Bari,
7-10 novembre 2013
BMD and Age Are Independent Risk Factors for Fracture Ten-­‐year risk of hip fracture by BMD and age in women 10-­‐year risk of hip fracture (%) Age (years) 20 80 70 10 60 50 0 1 0 -­‐1 -­‐2 -­‐3 Femoral neck T-­‐score (SD) Kanis JA, et al. Osteoporos Int 2001;12:989-­‐995. Kanis JA, et al. Osteoporos Int 2001;12:417-­‐427. Kanis JA, et al. Osteoporos Int 2005;16:581-­‐589. INCIDENZA DI FRATTURE OSTEOPOROTICHE
Figure 2 Incidence of osteoporotic fractures.
Richard Eastell
Identification and management of osteoporosis in older adults
Medicine Volume 41, Issue 1 2013 47 - 52
Bari,
7-10 novembre 2013
OsteoporoHc Fracture Incidence in Europe Other 30% Humerus 9% Bari,
7-10 novembre 2013
Mediterranean Osteoporosis Study (MEDOS): Hip 21% Italia 80.800 ricoveri/anno (2002) per fra]ura di femore in sogge^ > 65 aa Spine 16%   1 fra]ura ogni 30 secondi in Europa   500.000 nuovi casi/anno in Europa   Circa 40.000 nuovi casi/anno in Italia Forearm 24% Fractures by sites in women (EU 2000)1 1. Johnell O and Kanis JA. O steoporos Int 2006;17:1726-­‐1733. Handoll H. Clinical Evidence, 2004
Cummings SR, Melton LJI. Epidemiology and Outcome of
Osteoporotic 2002
2. European Commission. Report on osteoporosis in the European Community-­‐ac3on for preven3on, 1998. Proiezione ISTAT: prima fra]ura di femore associata ad osteoporosi 2012 = 45.056 casi 2017 = 48.115 casi + 6.8% COSTI TOTALI FRATTURE FEMORE IN ITALIA CosH Dire^ = Ospedalizzazione 568 milioni di euro/anno = costo giornaliero di ospedalizzazione, spese presidi e diagnosHci, costo del personale, costo sala operatoria, materiali ecc. CosH Indire^ (difficilmente quanHficabili): c o m p a r s a d i p a t o l o g i e a s s o c i a t e permanenH, modificazione stabile dello stato funzionale del paziente, eventuale isHtuzionalizzazione. sanitari e sociali : raddoppiano nell’anno successivo all’intervento (fisioterapia, visite specialisHche, terapie mediche, invalidità ecc.) Costo singola fra]ura : 13.576 Euro Bari,
7-10 novembre 2013
MORTALITA’ e DISABILITA’
Bari,
7-10 novembre 2013
MORTALITA’   5% in acuto   25% ad un anno (sovrapponibile al Ca mammario) DISABILITA’   20% perde l’autonomia nelle ADL   50% perde l’autonomia nel cammino   Nei casi di invalidità permanente circa il 20-­‐25% dei pazienH viene isHtuzionalizzato Rosell PAE. Func3onal Outcome afer Hip Fracture Injury, 2003 DETERMINANTI DEL RISCHIO DI FRATTURA •  Funzione neuromuscolare •  Faiori di rischio ambientali •  Tempo di esposizione ai faiori di rischio ambientali •  Tipo di caduta •  Risposte prote*ve •  Assorbimento dell’energia •  Massa ossea •  Geometria dell’osso •  Qualità della vita Bari,
7-10 novembre 2013
RISCHIO DI CADUTA FORZA DI IMPATTO RESISTENZA OSSEA PREVENZIONE DELLE FRATTURE Bari,
7-10 novembre 2013
TERAPIA NON FARMACOLOGICA -­‐ Valutazione del rischio di caduta e prevenzione -­‐ A*vità fisica -­‐ Proteiori di femore TERAPIA FARMACOLOGICA -­‐  Calcio e vitamina D -­‐  Bisfosfona3 -­‐  Ranelato di Stronzio -­‐  Teripara3de -­‐  Raloxifene -­‐  Denosumab CAUSE DI CADUTA NELL’ANZIANO -­‐ Accidentali/correlate all’ambiente -­‐ Turbe di equilibrio/andatura o debolezza muscolare -­‐ Ver3gine -­‐ Drop aiack -­‐ Stato confusionale -­‐ Ipotensione posturale -­‐ Deficit visivi -­‐ Sincope -­‐ Farmaci Ruolo delle terapie Bari,
7-10 novembre 2013
Table 3
Prescription osteoporosis prevention and treatment options approved by the Food and Drug Administration, and estimates of associated reduction in
fracture risk
Recommended Use for Osteoporosis
Antiresorptive Agents
Bisphosponates
Alendronate (Fosamax)73,74
Ibandronate (Boniva)75,76
Risedronate (Actonel,
Atelvia)77,78
Zolendronic acid (Reclast)64,79
Denosumab (Prolia)80,81
Calcitonin (Miacalcin,
Fortical)82,83
Raloxifene (Evista)84,85
Anabolic Agent
Teriparatide (Forteo)86,87
Effect on Fracture Risk
Prevention
Treatment
in Women
Treatment
in Men
Vertebral
Nonvertebral
Hip
Dosing
O
O
O
O
O
—
O
O
O
—
O
—
O
O
O
O
O
O
O
—
—
O
O
O
O
O
—
O
O
O
O
O
—
O
O
—
70 mg oral weekly
150 mg oral monthly
3 mg IV every 3 mo
35 mg oral weekly (Actonel, Atelvia)
75 mg oral 2 consecutive days each month
(Actonel only)
150 mg oral monthly (Actonel only)
5 mg IV yearly
60 mg SQ every 6 mo
200 IU intranasally daily
O
O
—
O
—
—
60 mg oral daily
—
O
O
O
O
—
20 mg SQ daily
Abbreviations: IV, intravenous; SQ, subcutaneous.
Warriner and Saag, Orthop Clin N Am 44 (2013) 125-135
VITAMINA D E CALCIO Forest plot comparing the risk of hip fracture between vitamin D and calcium and placebo/no-­‐treatment groups. Boonen S et al. JCEM 2007;92:1415-­‐1423 Bari,
7-10 novembre 2013
At baseline, the median 25-hydroxy- the trial. The median 25-hydroxyn
was 49 nmol/L cholecalciferol levels 12 months after
s cholecalciferol
ORIGINALlevel
CONTRIBUTION
HIGH-DOSE
D AND
FALLS
AND FRACTURES
WOMEN
dose in the IN
vitamin
D group ranged
normal lower
limit,
!50
, (IQR, 40-63;VITAMIN
- nmol/L). Less than 3% of the sub- from 55 nmol/L to 74 nmol/L over the
5 intervals
individual
values
r study participants had 25-hydroxycho- 150
nmol/L orwith
higher
(FIGURE 4).
By were considered related to study mediFigure 3. Serum 25-Hydroxycholecalciferol
25 nmol/L
to 25120 cation.
levels lower than 25 nmol/L. 3ranging
. lecalciferol
months, from
the after-dose
median
Levels at Baseline and 12 Months After Dose
nmol/L (FIGURE 3). The medians
25-hydroxycholecalciferol
and hydroxycholecalciferol
and
s The
ON
levels defor Each
Year of the Intervention
IQRs of
the PTH levels
remained
. PTH levels did not differ between the creased
to approximately
90 nmol/L
in COMMENT
150
(Table
1).
Approximately
half
stable
12
months
after
dosing.
- groups
Contrary to our hypothesis, particithe
vitamin
D
group.
Vitamin D
In 2006 and 2007, samples were col- pants receiving annual high-dose oral
n of the substudy
Placebo participants had 25Adverse Events
s hydroxycholecalciferol levels of 50 lected at 1 and 3 months after dose in cholecalciferol experienced 15% more
similar
number
of participants
each falls and 26% more fractures than the
or lower (vitamin D, 45.9% vs A102
(74%)
of the
substudy in
partici- nmol/L
100
at least25-hydroxychole1 adverse event: placebo group. Women not only expepants.reported
The median
- 61.4%, placebo) but less than 5% had group
in the
vitamin
and 17.8%
in rienced excess fractures after more frecalciferol
level
in the D
vitamin
D group
- levels of 25 nmol/L or lower (vitamin 19.7%
the
placebo after
group.dose
The most
1 month
wascommon
slightly quent falls but also experienced more
g D, 4.0% vs 3.5%, placebo).
events
injurywith
including
In50 each year of the study, samples adverse
more than
120were
nmol/L
82% at fractures that were not associated with
e
(172 ofand
1131)
fall. A post hoc analysis found that the
were obtained 12 months after dose fracture—15.2%
100 nmol/L or higher
24%ofat a Kerrie
Sanders, PhD
women taking vitamin D vs 12.1% (136 increasedM.
likelihood of falls in the viAmanda
L. Stuart,
BappSc in the
of 1125) taking placebo (P = .03)— tamin
D group
was exacerbated
0
and cardiovascular
(171
FigureM.
2.
Kaplan-Meier
of Time to Firstevents—1.5%
Fracture and First
Fall 3-month
period
immediately
followBaseline
1
2 Plots3of Cumulative
4
5 Incidence
Kerrie
Sanders,
PhD
Elizabeth
J. Williamson,
MA,
PhD
Context
Improving
vitamin
D
status
may
be
an
important
modifiable
factor
to reYear in Trial
of 1131) vs 1.2% (13 of 1125), respec- ing the annual dose and arisk
similar
temNo. of women
- Amanda
L.
Stuart,
BappSc
duce
falls
and
fractures;
however,
adherence
to
daily
supplementation
is
typically
poor.
Julie A. Simpson, PhD
57
36 Falls54
39
16
Vitamin D 74
tively. Seven womenFractures
(0.6%) in the vi- poral
trend was observed for frac- Elizabeth
49
28
46
34
20
Placebo
100 57
25
J. HR,
Williamson,
MA,
PhD
Objective
To
determine
whether
single tures.
annual
dose
of 500 000
IU
of
cholecalcif1.16 (95% CI, 1.05-1.28)
HR,
1.26
0.99-1.59)
tamin D group
vs(95%
10CI,(0.9%)
in theaplaMarkAn
A. increased
Kotowicz,
MBBS,
FRACP
risk (albeit, not
%
P = .003
P = .06
erol
orally to older
autumn or winter
would
improvenumadher20
ceboadministered
group
were diagnosed
with women
cancer. in significant
A.25-hydroxycholecalciferol
Simpson,
PhD
because
of smaller
Serum
levelsDinstatus
the vita75
- Julie
Context
Improving vitamin
mayence
be anand
important
modifiable
risk
factor
to
re- Doris Young, MD, MBBS, FRACGP
reduce
the
risk
of
falls
and
fracture.
min D group differ from those of the placebo group
Serious
adverse
events
(Internabers)
of
falls
and
fracture
in
the
vitaVitamin
D
A. Kotowicz,
MBBS,
FRACP
15
duce
falls and
fractures;
adherence
to daily
supplementation is typically poor. Geoffrey C. Nicholson, PhD, FRACP
- Mark
at all
12-month
assessments
afterhowever,
dose
(P!.05).
The
Placebo
Design,
Setting, and
A double-blind,
placebo-controlled
2256
tional Conference
on Participants
Harmonization/
min D group
was apparent for trial
eachofyear
medians50are shown as the horizontal bar within the
d Doris
Objective
To determine
whether a singleWHO
annual
dose of
500
000
cholecalcifVitamin
D IU of aged
Young, MD,
MBBS, FRACGP
10Good
women,
70 yearsoforthe
older,
considered The
to beresults
at highwere
risk of
Clinical
Practice
definirectangle and the interquartile range as the ends of community-dwelling
intervention.
HE
RESULTS
OF
RANDOMIZED
administered
orally
to older
women
in
autumn
or
winter
would
improve
adher- Geoffrey
theerol
rectangle.
The
5th
and
95th
percentiles
are
shown
fracture
were recruited
fromPlacebo
June
2003 to June
2005
and
were randomly
assigned
25C. Nicholson, PhD, FRACP
tion including
hospitalization
or death)
similar
after
adjustment
for baseline
cal- to
5
ence
and reduce
risk
of falls
andoutfracture.
(whiskers),
and thethe
closed
circles
represent
controlled
trials
investigating
- as lines
receive
or placebo
each autumn
winter
for 3
to not
5
years.
The study
did notcholecalciferol
differ significantly:
244 among
ciumtointake;
age
was
included
in
liers. The proportion of biochemistry substudy parthe
effects
of
cholecalciferol
Design,
Setting,
and
Participants
A
double-blind,
placebo-controlled
trial
of
2256
e ticipants
HE RESULTS
OF RANDOMIZED
in 2008.
categorized
into 25-hydroxycholecalciferol
sta- concluded
women
taking
vitamin
D
vs 2073women4 the models because its inclusion did not
0
1 n=74 vswomen,
2
3 n=57,
4
0
1
2 be at high
P
tus
is
(vitamin
D
group,
placebo
group,
community-dwelling
aged
70
years
or
older,
considered
to
risk
of
6
(vitamin D) supplementation
controlled trials
investigating Intervention
000
IUEighty-seven
of cholecalciferol
or placebo.
placebo500
(P=.06).
Trial Year
Trial Year
respectively)
25
nmol/L
or less:
4%
vs June
3.5%;2003
26 to to taking
fracture
were
recruited
from
June 2005 and were randomly
assigned to affect the model estimates.
CP No.
the
effects
of 51
cholecalciferol
women
on
falls
andthe
fractures
have
beenthat
incon50 of
nmol/L:
41.9%
vs 57.9%;
to 74 nmol/L: 44.5%
participants
died
during
the study,
40
Data
from
substudy
indicate
Main
Outcome
Measures
Falls
and
fractures
were
ascertained
using
monthly
calreceive
cholecalciferol
or
placebo
each
autumn
to
winter
for
3
to
5
years.
The
study
Vitamin
D
588
382
77
22
1048
963
236
106
1131
1131
1-13
33.3%;
75 nmol/LD)
or higher: 9.5% vs 5.3%. To
-ZED vs
(vitamin
Some
meta-analyses
sistent.
429
87
33 taking
1050D vs985
253
115 the
1125
1125
Placebo
vitamin
47 taking
plaparticipants
had intermediate
25-hy-conconcluded
in 635
2008.supplementation
interview.
Fractures
were radiologically
convert
25-hydroxycholecalciferol
from nmol/L to ng/ endars; details were confirmed by telephone
tting
onmL,
falls
and
fractures
have
been
inconcludeparticipants
that 700 to
800
vitamin
cebo.
None
serious adverse
events selected
divide by 2.496.
droxycholecalciferol
levelsIUatof
baseline,
confirmed.
Inofathe
substudy,
137 using
randomly
underwent
serial
blood D
Intervention
500
000
IU
or colecalciferol
placebo.
This
analysis
censors data
after
first
fallof
or cholecalciferol
fracture.
Time to of
first
fracture and fall was analyzed
Cox pro1-13donne,
2256
>70
aa,
500
000UI
or placebo
merol
Some
meta-analyses
consistent.
daily reduces
fracture
risk byolder
13% to
sampling
for 25-hydroxycholecalciferol
andtypical
parathyroid
hormone
levels.
of community-dwelling
portional hazards
models.
CI indicates confidence
intervals;
HR, hazard
ratio.
Main
Outcome
Measures
Falls
and
fractures
were
ascertained
using
monthly
cal14-18
dion
25
clude
that
800 IU of vitamin D Levels
whereas
others
conclude
26%,
women
the
region
and
typical
of
Figure
4. 700
Serumto25-Hydroxycholecalciferol
Before Dose,
and at
3, cholecalciferol
and 12 Months (vitamin
Results
Women
in 1,
the
D) of
group
had 171
fractures
vsolder
135 that
in
endars;
details
were
confirmed
by
telephone
interview.
Fractures
were
radiologically
,onAfterreduces
Dose
daily
fracture
risk 137
by 13% to selected
women
in Northern
Europe
and
Northper
vitamin
Dfellis2892
ineffective.
A Cochrane
the placebo
group; 837
women Months
in the
vitamin
D group
times (rate,
83.4
confirmed.
In a Pattern
substudy,
blood
14-18
Table
4.whereas
Temporal
of Risk inrandomly
Falls
and Fracture 0participants
to 3 Monthsunderwent
and 4 to 12serial
33 19
,onothers
conclude
that
26%,
The
intervention
effectively
America.
100 person-years) while 769 women in the placebo
groupand
fell 2512
times (rate,
sampling
the Vitamin
D72.7
Indianalysis
175for 25-hydroxycholecalciferol and parathyroid hormone levels.
After
Treatment
Dn vitamin
D is Women
ineffective.
A Cochrane (vitamin
D Results
increased
background
25-hydroxychoper 100 person-years;
rate
ratio
1.15;Patient
95% confidence
interval
[CI],
vidual
Analysis
of Randomin the cholecalciferol
had
171incidence
fractures vs
135
in [RR],
Incidence Rate Ratio D)
forgroup
Vitamin
D Group,
19
%- to
a
and group;
the Vitamin
D Estimate
Indianalysis
1.02-1.30;
P=.03).
The
incidence
for fracture
in the
vitamin
D group
waslev201.26
lecalciferol
levels.
Predictably,
the
PRR
Value
(95%
Confidence
Interval)
the placebo
837 women
in the vitamin
D group
fell
2892
times
(rate, 83.4
per
pubized Trials
(DIPART)
group,
150
- vidual
(95%
CI, 1.00-1.59;
P=.047)
the 72.7
placebo
group
(rates
per 100 person-years,
that
Patient
Analysis
Randomels
increased
substantially
1 month
after4.9
100
person-years)
769
women in the
placebo
group fell 2512
timesvs
(rate,
Time
after
treatment,
mo whileof
lished
after
this
study
commenced,
20
vitamin
D
vs
3.9
placebo).
A
temporal
pattern
was
observed
in
a
post
hoc
analysis
Falls
ane
100 person-years;
incidencepubrate ratio [RR], 1.15; 95% confidence interval [CI], dosing and thereafter declined toward of
ized per
Trials
(DIPART) group,
showed
a nonstatistically
significant
1253
Within
(1.12-1.54)
falls.
The incidence
RR ofDfalling
the.001
vitamin
D group
the placebo
was
1.31inndi1.02-1.30;
P = .03).
The
incidence RR for1.31
fracture
in the vitamin
group in
was
1.26
baseline
butvsremaining
ongroup
average
41%
lished
after this
study
commenced,
creasethan
in levels
hip
fracture
risk associated
After
3 1.00-1.59; P = .047) vs the placebo
1.13 (0.99-1.29)
.084.9
first (rates
3 months
after
dosing and
1.13higher
during
the
following
9 placebo
months
(test for
(95%
CI,
group
per 100
person-years,
omin the
group
showed
a nonstatistically
significant in- in the
19-21
homogeneity;
= .02).
substudy,
medianDbaseline
serum 25Fracture100
vitamin
D vs 3.9 placebo). A temporal pattern
was observedP in
a post In
hocthe
analysis
of atwith
vitamin
supplementation.
fub12the
months.
The pattern
is consistent
crease
in
hip fracture risk associated
Within
1.53
(0.95-2.46)
falls.
The 3incidence RR of falling in 19-21
the vitamin
D group vs the Vitamin
placebo
was.08
1.31
D group
hydroxycholecalciferol
was
49 nmol/L.
Less than
3% of
the substudy
participants
had in
Studies
have
observed
those
living
-ed,
with
serial
measurements
done
in
older
withinvitamin
D supplementation.
Afterfirst
3
1.18
(0.91-1.54)
.21for
the
during
the following 9 months
(test
25-hydroxycholecalciferol
levels lower
than 25
nmol/L. Incare
the vitamin
D group,
2575 3 months after dosing and 1.13
long-term
facilities
aswith
having
-t ina Thehomogeneity;
Studies
haverate
observed
those
living
invitaminhydroxycholecalciferol
P = to
.02).
the
median
serum
incidence
ratio refers
the riskIn
ratio
of thesubstudy,
D groupthe
compared
with thebaseline
placebo
group.
The rate25ratio
levels
increased
at 1 New
monthZealanders
after dosingsupplemented
to approximately
120
34
ated
greater
fracture
risk
reduction
than
within
3
months
after
treatment
is
significantly
different
from
the
rate
ratio
of
the
remaining
9
months
after
treatment
000 IUand
cholecalciferol.
3 long-term
hydroxycholecalciferol
wasas49having
nmol/L. Less
than 3%
of the
substudy participants
hadat 500
care facilities
nmol/L,
were
approximately
90 nmol/L
3 months,
remained higher than the
19-21 for falls (P=.02)
50 but not for fracture (P=.36).
elders.
SimiOnly 1 other study has reported
an in25-hydroxycholecalciferol
levels than
lower than
25 nmol/L.
vitamin
D group,
25- community-dwelling
D greater
placebo
group In
12the
months
after
dosing.
fracture risk reduction
g in hydroxycholecalciferol levels increased at 1 month after dosing
Placebo
to approximately 120 crease
fracture
associated
vita- in
larly,infewer
fractures
werewith
observed
community-dwelling
elders. with
SimiConclusion
Among
older
community-dwelling
women, annual
oral administration
ghts
reserved.
(Reprinted90
Corrections)
Mayand
12,
2010—Vol
303,
No. than
18 1819
8
ing
nmol/L, 25were approximately
nmol/L
at
3 JAMA,
months,
remained
higher
the min
Participants
(4354 was
D treatment.
participants
study
treatment
larly,placebo
fewer fractures
were observed
in of high-dose cholecalciferol resulted in an increased
risk ofwhose
falls and
fractures.
group 12 months
after dosing.
han
4,5,16,22
5086 women)with
75 years
or older
re-Furcoadministered
calcium.
participants whose
study treatment was Trial Registration anzctr.org.au Identifier:men,
miACTR12605000658617;
isrctn.org
0
Conclusion
Among older4,5,16,22
community-dwelling women, annual oral administration ceived
an annual
injection
of
300
000IdenIU
thermore,
many
studies
have
found
0 1 calcium.
3
12 13
15
24
Furcoadministered
with
ISRCTN83409867
d in of high-dose cholecalciferol resulted in antifier:
increased
risk of falls and fractures.
vitamin
D2 asadherence
ergocalciferol
or
placebo.
1,2,6
Months Since Predose, 2006
treatment
to
be
low
and
thermore,
many
studies
have
found
No.
of
women
was TrialVitamin
JAMA.
2010;303(18):1815-1822 isrctn.org Iden- In men, treatment had no effect
www.jama.com
Registration
Identifier:
ACTR12605000658617;
on
frac51anzctr.org.au
53
52
54
54
D 50 54
1,2,6
fracture risk reduction was greater
and
treatment
adherence
to
52 48
44 be low
46 49
48
45
Placebo
Furtifier:
ISRCTN83409867
However
women
treated with
viAuthor Affiliations: Department of Clinical and Biomedi- tures.
Royal Children’s
Hospital
(Dr Williamson);
and Departamong
adherent
than nonadherent
pafracture
risk
reductionItaliano
was -greater
und
b IRCCS
Fond
Ist to
Auxologico
Milano User
10/28/2013
2010;303(18):1815-1822
www.jama.com
calon
Sciences,
Barwon
Melbourne,
ment of D
General
University
Melbourne,
Parktamin
hadPractice,
increased
riskof of
nonverTheJAMA.
points
refer
the median level of 25-hydroxycholecalciferol
at the
timeHealth,
of bloodUniversity
samplingof
and
the error
among
adherent
than nonadherent
pa- sampling
and
Geelong
(Drs
Sanders,
and Nicholson
Ms
ville, Victoria (Dr Young), Australia.
bars represent
the interquartile
range. These 7 blood
time
points
tookKotowicz,
place in 2006,
2007, andand
2008,
tebral
(HR, 1.21),
hip/femur
(HR,
1.80),
Author
Affiliations:
Department
of
Clinical
and
BiomediRoyal
Children’s
Hospital
(Dr
Williamson);
and
DepartStuart);
Centre
for
Molecular,
Environmental,
Genetic
Corresponding
Author:
Kerrie
Sanders,
PhD,
Departto the biochemistry substudy participants.
ater andcalrefer
Sciences, Barwon Health, University of Melbourne, andment
of General
Practice, School
University
of Melbourne,
Park- and
fractures
Analytic
Epidemiology,
of Population
Health,
ment
of
Clinical and
Biomedical Sciences,
Barwon
Forhip/femur/wrist/forearm
editorial
comment
see
p 1861.
pa- Geelong (Drs Sanders, Kotowicz, and Nicholson and Ms University
ville, Victoria
(Dr Young),
Australia.
of Melbourne,
Carlton
(Drs Williamson and
Health, PO Box 281, Geelong, Victoria, Australia 3220
BOLI AD ALTE DOSI DI VITAMINA D Bari,
7-10 novembre 2013
Serum Hydroxycholecalciferol, nmol/L
Annual High-Dose Oral Vitamin D
in Olderprobability Womenof fracture at Annual High-Dose Oral Vitaminand
D Falls and FracturesCumulaHve Randomized Controlled Trialvarious skeletal sites, according to and Falls and Fractures in OlderA Women
-Dose
Oral Vitamin
D Trial
A Randomized
Controlled
d Fractures in Older Women
Cumulative Incidence of Falls, %
Cumulative Incidence of Fractures, %
ontrolled Trial
Median Serum Hydroxycholecalciferol, nmol/L
T
T
For editorial
comment
p 1861.Genetic
Stuart); Centre
for Molecular,see
Environmental,
Corresponding
Author:
Kerrie
Sanders,Institute,
PhD, DepartSimpson);
Children’s
Research
and
(kerrie@barwonhealth.org.au).
1820 JAMA, May 12, 2010—Vol 303, No. 18 (Reprinted
with Murdoch
Corrections)
©2010
American
Medical Association. All rights reserved.
treatment with vitamin D or placebo. Context Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.
Smith H et al. Rheumatology 2007;46:1852-­‐1857 Objective To determine whether a single annual dose of 500 000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.
Design, Setting, and Participants A double-blind, placebo-controlled trial of 2256
community-dwelling women, aged 70 years or older, considered to be at high risk of
soggetti
(4354 assigned
uomini to
– 5086 donne
fracture were recruited from June 2003 to June9440
2005 and
were randomly
receive cholecalciferol or placebo each>70
autumn
winter
forUI
3 to
years. The study or placebo
aa,to300
000
of5ergocalciferolo
concluded in 2008.
Intervention 500 000 IU of cholecalciferol or placebo.
Main Outcome Measures Falls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically
confirmed. In a substudy, 137 randomly selected participants underwent serial blood
sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.
Results Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in
the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per
100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7
per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI],
1.02-1.30; P=.03). The incidence RR for fracture in the vitamin D group was 1.26
(95% CI, 1.00-1.59; P=.047) vs the placebo group (rates per 100 person-years, 4.9
vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of
falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31
in the first 3 months after dosing and 1.13 during the following 9 months (test for
homogeneity; P = .02). In the substudy, the median baseline serum 25hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had
25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120
nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the
placebo group 12 months after dosing.
Conclusion Among older community-dwelling women, annual oral administration
of high-dose cholecalciferol resulted in an increased risk of falls and fractures.
Trial Registration anzctr.org.au Identifier: ACTR12605000658617; isrctn.org Identifier: ISRCTN83409867
JAMA. 2010;303(18):1815-1822
Author Affiliations: Department of Clinical and Biomedical Sciences, Barwon Health, University of Melbourne,
Geelong (Drs Sanders, Kotowicz, and Nicholson and Ms
Stuart); Centre for Molecular, Environmental, Genetic
and Analytic Epidemiology, School of Population Health,
University of Melbourne, Carlton (Drs Williamson and
Simpson); Murdoch Children’s Research Institute, and
and Analytic Epidemiology, School of Population Health,
ment of Clinical and Biomedical Sciences, Barwon
©2010 American Medical Association. All rights reserved.
University of Melbourne, Carlton (Drs Williamson and
Health, PO Box 281, Geelong, Victoria, Australia 3220
1.©2010
American Medical Association. All rights reserved.
(Reprinted with Corrections) JAMA, May 12, 2010—Vol 303, No. 18 1815
Simpson); Murdoch Children’s Research Institute, and
ll rights reserved.
(kerrie@barwonhealth.org.au).
(Reprinted with Corrections) JAMA, May 12, 2010—Vol 303, No. 18
1815
www.jama.com
Royal Children’s Hospital (Dr Williamson); and Department of General Practice, University of Melbourne, Parkville, Victoria (Dr Young), Australia.
Corresponding Author: Kerrie Sanders, PhD, Department of Clinical and Biomedical Sciences, Barwon
Health, PO Box 281, Geelong, Victoria, Australia 3220
(kerrie@barwonhealth.org.au).
(Reprinted with Corrections) JAMA, May 12, 2010—Vol 303, No. 18 1815
!
w
P-value based on two-tailed Fisher exact test.
Adverse events with an incidence of " 2%.
BISFOSFONATI ORALI
OBJECTIVES: To determine
reducing vertebral fracture risk
with osteoporosis.
Bari,
3 years (HR 5 0.61, 95% CI 5 0.51–0.74; Po.001)
and
Safety
7-10 novembre
2013
DESIGN:
analysis
nonvertebral osteoporosis-related fractures after
3 yearsPooled
The adverseofevd
double-blind,
controlled,
(HR 5 0.79, 95% CI 5 0.65–0.97; P 5.025).
were similar3-y
in
conducted from November 19
incidences of
vention Program (HIP), Verteb
1.7%), stomac
TherapyFMultinational
(VE
Effects on Bone Turnover and BMD
America (NA). and duodenal u
low and simila
The changes from baseline in the risedronate 5SETTING:
mg group Office-based
prac
the incidence o
were statistically significantly greater than thoseosteoporosis
in the pla- clinics
in Europe
events were sim
cebo group for urinary deoxypyridinoline/creatinine
tralia. at 1
patients who h
month and each subsequent time point (Po.01)
and for
PARTICIPANTS:
Osteoporot
took concomit
!
w
z
alkaline phosphatase at 3 months and each subsequent
time T-score
eral density
o ! 2.5 s
Steven Boonen, MD, PhD, Michael R. McClung, MD, Richard Eastell, MD,
RAs or PPIs
(F
point (Po.001)
from vertebral
§
k
z (Table 3). In addition, the changes
one
prevalent
fractur
JAGS El-Hajj
NOVEMBER
2004–VOL.
52, NO. 11
RISEDRONATE
REDUCES
FRACTURE
1835
Ghada
Fuleihan,
MD, MPH,
Ian P. Barton, BSc, and
Pierre Delmas,
MD,
PhD RISK IN THE OLDEST OLD
baseline in BMD in the risedronate 5 mg groupINTERVENTION:
were sigPatients r
nificantly greater than those in the placebo grouprisedronate
as early as 5 mg/d (n 5 704) f
6 months
at 212
the lumbar
spine
(Po.001),
femoral
neck
received
1,000 DISCUSSION
mg/d calcium
baseline,
of 1,338
(16%)
patients
were
(Table 140). At
1
(Po.05), and femoral trochanter (Po.01).
low,
up
to
500
IU/d
vitamin
considered to have low vitamin D levels. At 6 months, of the
In this
studyD
MEASUREMENTS:
Cumula
teoporosis, rise
153 patients who had low vitamin D levels at baseline and
bral fractures. of new vertebr
(95% confidence
60–91%; data
Po.001).
The
numOBJECTIVES:
0.75 To determine the efficacy of risedronate in
for interval
whom 56-month
were
available,
vitamin
D
levels
60
RESULTS: After
1 year,
the ri
ber of women who needed to be treated
to prevent one new
reducing vertebral fracture risk in women aged 80 and older
tions
in fractur
had
normalized
in
122This
(80%).
in
the
risedronate
group
was
vertebral fracture after 1 year was
12.
early
onset
of
with osteoporosis.
seen within 1 y8
50
Comparison
of this
groupand
of antivery old patients with
efficacy was consistent
across the clinical
programs,
DESIGN: Pooled analysis of data from three randomized,
benefit experie
0.5
40than
patients
youngerover
80 showed
that the older patients
fracture efficacy
was confirmed
3 years.
Risedronate
double-blind, controlled, 3-year-fracture-endpoint trials
vitamin Center
D supp
From the !Leuven University
fo
was well tolerated,
a safety profile
comparable
with
Division
of Geriatricnificantly
Medicine, Kathol
were with
significantly
shorter,
weighed
significantly
less,
had
conducted from November 1993 to April 1998: Hip Interdecre
30
Belgium; wDepartment of Medical Educ
that of placebo.
vention Program (HIP), Vertebral Efficacy with Risedronate
individuals.32,3
significantly lower BMD, and had a significantly greater
Medical Center and the Oregon Osteop
20
0.25
CONCLUSION:
These
findings
provide
the
first
evidence
TherapyFMultinational
(VERT-MN), and VERT-North
z
groupUniversity
of very o
o
frequency of prevalent vertebral fractures (Table 2). InBone
ad-Metabolism Group,
that, even in the very old, reducing bone resorption rate
America (NA).
United Kingdom; §Calcium
overallMetabolism
populat
dition,
patients
aged
80
and
older
were
at
greater
risk
for
10
American Universityies,
of Beirut
Medical
remains an effective treatment strategy for osteoporosis.
SETTING: Office-based practices, research centers, and
whose
ages
k
Procter
and Gamble Pharmaceuticals,
comorbidities
than
patients
younger
than
80,
including
acBecause
each
therapeutic
agent
used
for
the
treatment
of
0
osteoporosis 0clinics in Europe, North America, and Ausz
knowledge,
thi
INSERM
Any Serious
Any Serious
Any
SeriousResearch 403 Unit, Hôpital
tivehave
GI tract
(relative
(RR)
5 Any
1.1,Serious
95% confiuniquedisease
characteristics,
therisk
observaOverall
HIP Trialsosteoporosis may
VERT Trials
tralia.
antiresorptive
UGI UGI
UG
UGI
UG
UGI
UG
UGI
This work was supported by Procter an
tions made in dence
this study
should not
assumed
to Active
apply
interval
(CI)be5
1.0–1.2;
P 5.003),
cataract (RR
5 andUser
Overall
GIto
Aspirin/NS
HOhio,
calcium and
PARTICIPANTS: Osteoporotic (femoral neck bone min2-RA/PPI
Aventis, Bridgewater,
NewviJ
P=0.509bisphosphonates. J Am Geriatr Soc 52:1832–1839,
Trial-by-Treatment Interaction: other
Tract Disease
AID User
1.7, 95% CI 5 1.6–1.9; Po.001), cardiovascular dysrhytandresearch
older with
eral density T-score o ! 2.5 standard deviations or at least
Dr. Boonen has received
grants
2004.
otheradverse
financial relationship
with Procte
These
find
oneFigure
prevalent
fracture)
women
aged 80during
and older.
Figure95%
2. Incidence
of any upper
hmia (RR 5 1.7,
CI 5 1.3–2.1;
P gastrointestinal
o.001), and(UGI)
glau1. vertebral
Risk of new
vertebral
fracture
1 year of treatthat markets a bisphosphonate.
Dr. Boo
Key words: postmenopausal
osteoporosis;
risedronate;
bone
remodeli
events
and
serious
UGI
adverse
events
associated
with
placebo
INTERVENTION:
Patients
received
placebo
(n
5
688)
or
coma (RR 5 1.8, 95% CI 5 1.4–2.3; Po001) (Table 2).
ment with risedronate 5 mg relative to the risk during treatment
the Fund for Scientific Research, Fland
fractures; aged; aged 80 and(black
older bars) or risedronate 5 mg (white bars) treatment
treatment strat
in all
risedronate
5 mg/d in
(n 5
704) forwith
up toosteoporosis
3 years. All patients
with placebo
patients
(aged !80) in the
Address correspondence to Prof. S. Boo
remains to be d
patients aged 80 and older (overall) and in subgroupsCenter
of patients
received 1,000 mg/d calcium and, if baseline levels were
for Metabolic Bone Diseases an
overall analysis population and in the Vertebral Efficacy with
seenLeuven,
for other
aged
80 and older who had active gastrointestinal (GI)
disease,
low, up to 500 IU/d vitamin D.
Katholieke
Universiteit
Univera
Antifracture
Efficacy
Risedronate Therapy (VERT) and Hip Intervention Program
Herestraat
49, B-3000
Leuven,given
Belgium
relevant
t
who
were
using
aspirin
or
nonsteroidal
antiinflammatory
drugs
MEASUREMENTS: Cumulative incidence of new verteIn patients aged
80 and
older,
after
1 year,
the2-receptor
incidence
of steven.boonen@uz.kuleuven.ac
E-mail:
(HIP)
trials.
Bars
represent
95%
confidence
intervals.
tebral
deformit
(NSAIDs),
or
who
were
using
histamine
antagonists
bral fractures.
ertebral fractures
are the(Hmost
common
new vertebral
fractures
wasserious
2.5%
in the risedronate
5 mg
pump cominhibitors
(PPIs).
the ages of 50 a
2-RAs) or proton
RESULTS: After 1 year, the risk of new vertebral fractures
plication group,
of osteoporosis,
and
their
incidence
increases
compared
with
10.9%
in
the
placebo
group.
This
Withinand
between-treatment
group
differences
in
BMD
in the risedronate group was 81% lower than with placebo
of vertebral
deformsteadily with represents
age.1–5 The prevalence
a reduction
in the risk
of fractures in the JAGS
rise- 52:1832–1839, 2004
were investigated using parametric statistics.
ities, which is 5% to 10% in women aged 50 to 54, inr 2004 by the American Geriatrics Soc
dronate
5
mg
group
of
81%
versus
control
(HR
5
0.19,
!
Adverse
events,
deaths,
gas-to about 45% to 55% in women aged 80 to 89.1,6
From the Leuven
University
Centerwithdrawals,
for Metabolic Bone Diseases
andand upper
creases
% Reporting at Least
One UGI Adverse Event
Hazard Ratio
Safety and Efficacy of Risedronate in Reducing Fracture Risk in
Osteoporotic Women Aged 80 and Older: Implications for the Use
of Antiresorptive Agents in the Old and Oldest Old
V
al.
NIH Public Access
Author Manuscript
ZOLEDRONATO
J Am Geriatr Soc. Author manuscript; available in PMC 2013 May 22.
Published in final edited form as:
J Am Geriatr Soc. 2010 February ; 58(2): 292–299. doi:10.1111/j.1532-5415.2009.02673.x.
Bari,
7-10 novembre 2013
Efficacy and Safety of a Once-Yearly Intravenous Zoledronic
Acid 5 mg for Fracture Prevention in Elderly Postmenopausal
Women with Osteoporosis Aged 75 and Older
NIH
Public Access
Steven Boonen, MD, PhD , Dennis M. Black, PhD , Cathleen S. Colón-Emeric, MD, MHSc
*
†
Author
Manuscript
Richard Eastell,
MD||, Jay S. Magaziner, PhD#, Erik Fink Eriksen, MD, DMSc**, Peter
‡,§,
JMesenbrink,
Am Geriatr Soc
. Author
manuscript;
available
in PMC
2013
May 22.
††, Patrick
‡‡, and
PhD
Haentjens,
MD, PhD
Kenneth
W. Lyles, MD‡,§,§§
Published in final edited form as:
J* Am Geriatr Soc. 2010 February ; 58(2): 292–299. doi:10.1111/j.1532-5415.2009.02673.x.
Leuven University Centre for Metabolic Bone Diseases and Division of GeriatricPage
Medicine,
10
University of Leuven, Leuven, Belgium †Department of Epidemiology and Biostatistics, University
of California at San Francisco, San Francisco, California ‡Department of Medicine, Duke
§Veterans Affairs Medical
Efficacy
and Safety
of a Once-Yearly
Intravenous
Zoledronic
Center, Durham,
North Carolina ||
University, Durham,
North Carolina
Academic Unit of Bone Metabolism, Metabolic Bone Centre, University of Sheffield, Sheffield,
Acid
5 mg for Fracture Prevention in Elderly Postmenopausal
United Kingdom #Department of Epidemiology and Preventive Medicine, University of Maryland,
**Department of Endocrinology, Oslo University Hospital Aker, Oslo, Norway
Baltimore, Maryland
Women
with Osteoporosis
Aged 75 and Older
††Novartis Pharmaceuticals, East Hanover, New Jersey ‡‡Center for Outcomes Research,
Laboratory
for Experimental
Surgery,
Brussel,
Vrije Universiteit
Brussel,
†, Cathleen
‡,§,
Steven
Boonen,
MD,
PhD*, Dennis
M.Universitair
Black, PhDZiekenhuis
S. Colón-Emeric,
MD, MHSc
§§
of Medicine,
Center
for Medical
Excellence,
Brussels,
Belgium
#, Erik Fink
**, PeterCary,
, Jay S. Magaziner,
PhDCarolinas
Eriksen,
MD, DMSc
Richard
Eastell,
MD||Department
North Carolina
Mesenbrink,
PhD††, Patrick Haentjens, MD, PhD‡‡, and Kenneth W. Lyles, MD‡,§,§§
Abstract
*Leuven
University Centre for Metabolic Bone Diseases and Division of Geriatric Medicine,
†Department of Epidemiology and Biostatistics, University
University
of Leuven, Leuven,
Belgium
OBJECTIVES—To
determine
the efficacy
of once-yearly intravenous zoledronic acid (ZOL) 5
‡Department of Medicine, Duke
of California
at
San
Francisco,
San
Francisco,
California
mg in reducing risk of clinical vertebral, nonvertebral,
and
any clinical fractures in elderly
§
Veterans Affairs Medical Center, Durham, North Carolina ||
University,
Durham,
North Carolina
osteoporotic
postmenopausal
women.
Academic Unit of Bone Metabolism, Metabolic Bone Centre, University of Sheffield, Sheffield,
post hoc subgroup
analysis of pooled
data from the
Health Outcome
andofReduced
of Epidemiology
and Preventive
Medicine,
University
Maryland,
UnitedDESIGN—A
Kingdom #Department
**
Incidence
with
Zoledronic
Acid
One
Yearly
(HORIZON)
Pivotal
Fracture
Trial
and
the
Department
of
Endocrinology,
Oslo
University
Hospital
Aker,
Oslo,
Norway
Baltimore,
Maryland
Figure 1.
††Novartis
‡‡Center for Outcomes Research,
HORIZON
Recurrent Fracture
Trial.
Pharmaceuticals,
East
Hanover,
New
Jersey
Event rate of new fractures in patients receiving zoledronic acid (ZOL) 5 mg once yearly
Laboratory
Experimental
Surgery,
Universitair
Ziekenhuis
Vrije Universiteit
*Hazard
ratio (HR) Brussel,
(95% confidence
interval) Brussel,
and those for
receiving
placebo at
1 and 3 years.
§§Department of Medicine, Carolinas Center for Medical Excellence, Cary,
Brussels,
Belgium
of ZOL versus placebo computed from the Cox proportional hazards regression model
North Carolina
according
to study with treatment as a factor within the subgroup. †Event rate
©stratified
2010, Copyright
the Authors
calculated
from Kaplan-Meier
estimates.
Address
correspondence
to Steven Boonen,
Leuven University Centre for Metabolic Bone Diseases & Division of Geriatric Medicine,
Abstract
University Hospital Leuven, Herestraat 49, B-3000 Leuven, Belgium. Steven.Boonen@uz.kuleuven.ac.be.
Submitted to or presented at American Geriatrics Society, April 29 to May 2, 2009, Chicago, IL; International Bone and Mineral
OBJECTIVES—To determine the efficacy of once-yearly intravenous zoledronic acid (ZOL) 5
EVENTI AVVERSI Flue-­‐like syndrome ONJ A3pical fracture Lilly and Company, Indianapolis, Indiana; Center of Bone Research at the
Sahlgrenska Academy, Department of Geriatrics, University of Göteborg,
Göteborg, Sweden; and §Maine Center for Osteoporosis Research and
Education, St. Joseph Hospital, Bangor, Maine.
apies to reduce fracture incidence, many elderly patients do
not receive treatment,10–11 with treatment rates ranging
from 5% to 69%12 and decreasing with increasing age.3
Data previously presented at the 2004 American College of Rheumatology
One explanation for this decrease is the perception thatBari,
it is
7-10 novembre 2013
Annual Meeting, San Antonio, Texas, and 2005 American Geriatrics Society
too
late
to
alter
the
course
of
the
disease
in
its
late
stage.
Annual Meeting, Orlando, Florida.
Given the known antifracture efficacy of available drugs,
Address correspondence to Steven Boonen, MD, PhD, Leuven University
of appropriate
Safety
and Efficacy
in Elderly lack
Women
with and needed therapy in patients with
Center for Metabolic
Bone Diseasesof
andTeriparatide
Division of Geriatric Medicine,
osteoporosis may result in costly and debilitating fractures.
Universitaire Ziekenhuizen, K. U. Leuven, Herestraat 49, B-3000 Leuven,
Established
Osteoporosis: Bone Anabolic Therapy
from a
Belgium. E-mail: steven.boonen@uz.kuleuven.ac.be
Teriparatide stimulates bone turnover,13–16 with a posJAGS
MAY 2006–VOL.
54, NO. 554, NO. 5
TERIPARATIDE
ELDERLY
WOMENWOMEN
OSTEOPOROSIS
JAGS
MAY 2006–VOL.
TERIPARATIDE
IN ELDERLY
WITH OSTEOPOROSIS
MAY 2006–VOL.
54, NO.
TERIPARATIDE
Geriatric
Perspective
DOI: 10.1111/j.1532-5415.2006.00695.x
itive boneJAGS
balance
resulting
in5 INincreases
inWITH
bone
mass
and787 IN E
TERIPARATIDE w
z
w
Steven Boonen, MD, PhD,! Fernando Marin, MD,
PhD,
Dan
MD,
PhD,
Xie,
MS,
2. Summary
Most Relevant
Treatment
Emergent
Events (TEAEs)
an Incidence
of 3%
or Greater
Table
2.Table
Summary
ofMellstrom,
MostofRelevant
Treatment
Emergent
Adverse
Events
(TEAEs)
with anwith
Incidence
ofAdverse
3% or
Greater
in
Table
2.Li
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ofAdverse
Most Relevant
Treatment
Emergent
Events
(TEAE
w
w Any Treatment
§ Randomized
Any Treatment
Group
in All
Patients
Aged
75
and
Older
Group
in
All
Randomized
Patients
Aged
75
and
Older
Any
Treatment
Group
in
All
Randomized Patients Aged 75 and Older
Durisala Desaiah, PhD, John H. Krege, MD, and Clifford J. Rosen, MD
JAGS 54:782–789, 2006
786
BOONEN
ETby
AL.
(See
editorial
comments
Dr. Bruce R. Troen on pp 853–855)
r 2006,
Copyright
the Authors
Journal compilation r 2006, The American Geriatrics Society
Aged oAged
75 o 75
! 75
Aged !Aged
75 o
Aged
75
MAY 2006–VOL. 54, NO. 5
JAGS
Aged !
Teriparatide PlaceboPlacebo
Teriparatide
PlaceboPlacebo Teriparatide
Placebo Teriparatide
Teriparatide
Placebo
(N 5 426) (N 5 415)
(N 5 415) (N 5 118)
(N
(N
126)
(N 5 426)
(N5
5118)
426) (N 5 126)
(N5
50002-8614/06/$15.00
415)
(N 5 118)
In the younger
group,
hypercalcemia
(defined as a se-Interaction
n (%)
P-valu
n (%)
P-values
Adverse
Event
n (%) Interaction
rum
calcium
concentration42.76
mmol/L
or
11
mg/dL)
placebo
group
aged
75
and
older.
There
were
no
treatmentOBJECTIVES: To assess the safety and efficacy of teri-Patients
Patients
343 (83)
.27
with !1with !1
366 (86)366 (86) Patients
343 (83)
107 (91)107
.27
with
!1
366 (91)
(86) 104 (83)104
343(83)
(83)
107 (91)
VFx <75
by-age
for important
treatment-emergent
adparatide in patients
aged 75 and older and compare theseadverse
in 2.9%
of teriparatide-treated
patients and 0.7%
adverse
event occurred
adverse
event
event interactions
verse
events (TEAEs),
including
back
pain,
nausea,
leg 10
findings with those of women younger than 75 using data Asthenia
Asthenia
29 (7)
35 (8)
(8)
(10)
Asthenia
29 In
(7) the13older
35group,
(8)
10 (8).98
29 (7)
35 patients
(8)
10 (8)
(10) 13
.98
of placebo-treated
(Po.05).
Arrhythmia
7 (2) important
8 (2) in womcramps,
and dizziness.7 The
from the Fracture Prevention Trial (FPT).
Arrhythmia
7 (4)
(2)
(2)
Arrhythmia
(2) most
8 (2) TEAEs
5 (4) 5
1 (1) 18(1)
.095 (4).09
VFx ≥75
hypercalcemia
in
of patients
in
teriparatide
Hypertension
31 (7) occurred
(7)1.6%
.62
Hypertension
31 (11)
(7)
30(9)
(7)
13 (11)
(7) patients
30 (7)
13 (11) 13
11 (9) 11
.62
en aged
80 and older31(23
from
the30placebo
group
DESIGN: The FPT was a randomized, multicenter, double- Hypertension
Syncope
8
(2)
14
(3)
1
(1)
3 (2)
Syncope
8
(2)
14
(3)
group
and
0%
in
placebo
group
(P
5.50).
The
treatmentSyncope
8
(2)
14
(3)
1
(1)
3
(2)
.711 (1).71
and 25 patients from the teriparatide group) were also reblind, placebo-controlled study.
Abdominal
pain
35 (8)
(10)
8 (6)
.07
35 (13)
(8)
(10)
15 (13)
Abdominal
pain
35 (8) interaction
40 (10)
15 (13) 15
(6) 40
.07
by-age
was40inpain
not
significant
(P 581.0).
In
the
viewed;
no unexpected
TEAEs wereAbdominal
found
the patients
NonVertThe
F FxFPT
<75multicenter international study.
SETTING:
Constipation
9 (7)
.10
Constipation
14 (10)
(3)
(6)
12 (10)
Constipation
14 (3) 14 (3)
23 (6) 23 (6)
12 (10) 12
9 (7) 23
.10
treated with teriparatide.
These
indicate
that4 the
younger
2.4%
patients
in the
group
25
(6) results
20 (5)
4 (3)
Diarrhea
25
(6)teriparatide
20(10)
(5)
25 (6) group,
20 (5) of
(3)
12 (10) 12
.044 (3).04
PARTICIPANTS: Postmenopausal women aged 42 to 86 DiarrheaDiarrhea
clinical
effects of
teriparatide
were
consistent
in the had
older
Dyspepsia
(4)
(7)
6 (5)
5 (4)
Dyspepsia
19
(4)
(7)
19
(4) 19in
27 (7) 27 group
6 (5) hyperuricemia
5 (4) 27
.346 (5).34
and
0.7%
the placebo
(defined
were NonVert
randomized
to placebo (N 5 544) or teriparatide Dyspepsia
F Fx ≥ 75
andNausea
younger women.30 (7) 30 (7)
Nausea
30 (9)
(7)
41(8)
(10)
11 (9).30
Nausea
41 (10) 41 (10)
11 (9) 11
10 (8) 10
.30
20 mg (N 5 541) by daily self-injection for a median of VomitingVomiting
as a11
serum
uric
acid
concentration40.535
or
9 mg/
(3)affect
15 (4)
4 (3) mmol/L
4 (3)
Vomiting
(4)
(3) 11
15
(4)
4 (3) 11
4 (3) 15
.624 (3).62
CONCLUSION:
Age
does
not
the
safety
and
efficacy
19 months. Patients received daily oral supplements of Ecchymosis
Ecchymosis dL; 24
(4)
6 (5)
8 (6)
Ecchymosis
24
(6)
16
(4)
P 5.06).
older
4%
patients
in teripara(6) 24 (6)In the
16
(4) 16 group,
6 (5) of
8 (6)
.336 (5).33
of teriparatide
in postmenopausal
women
with osteo1,000 mg calcium and0.0
400 to 1,200
IU
vitamin
D.
For
this
Peripheral
edema
13
(3)
15
(4)
10
(8)
4
(3)
Peripheral
edema
13
(3)
15
(4)
10 (8).08
Peripheral
edema
13
(3)
15
(4)
10
(8)
4
(3)
.08
0.5
1.0
1.5
2.0
2.5
3.0
tide group
and 0.9%
in the placebo
group had1046(8)
hyperporosis.
J Am Geriatr
Soc 54:782–789,
2006.
Arthralgia
.28
Arthralgia
37 (10)
(9)
(11)
12 (10)
analysis, subgroups were defined according
to
patient
age
Arthralgia
37 (9) 37 (9)
46 (11) 46 (11)
12 (10) 12
10 (8)
.28
Relative Risk, 95% CI
!
uricemia
(P(22)
5.15).
The
Back
pain teriparatide;
93
72 treatment-by-age
(17) patients;
.32
Back
pain
93 (25)
(22) interaction
72(15)
(17)was
30 (25)
pain
93 (22)osteoporosis;
72 (17)
30 (25) 30
19 (15)!19
.32
words:
geriatric
younger than 75 (N 5 841) and 75 and older (N 5 244). BackKey
! 14 (3)!
Leg cramps
(2)
3 (2)
cramps
4teriparatide
(1)
14
(3)!plaLegefficacy;
cramps
4 (1) 4 (1) (P Leg
14 (3)
2 (2)of2
3 (2) and
.392 (2).39
not
significant
5.80).
The
effect
safety;
elderly
Figure
3.
The
relative
risk
(95%
confidence
interval
(CI))
teriMEASUREMENTS: The effects of teriparatide on bone Headache
Headache
6 (5)
7 (6)
Headache
(9)
(9)
39 (9) 39 (9)
37 (9) 37 (9)
6 (5) 39
7 (6) 37
.846 (5).84
!
cebo24
on hypercalcemia
and
hyperuricemia
was 39similar
mineral
density
(BMD)
of theoflumbar
spine and
femoral
9 (8)
(9)
Dizziness
paratide
versus
placebo
new vertebral
(VFx)
and nonvertebral
Dizziness
(6)
(9)!
9 (8) 24
11 (9) 11
.469 (8).46
Dizziness
(6) 24 (6)
39 (9)! 39 (9)
neck;fragility
the incidence
of new
vertebral
and by
new
nonvertebral Vertigo Vertigo
(3) groups.
5 (4)
6 (5)
Vertigo
(3)
(4)
across
the13age
13 (3)
18 (4) 18 (4)
5 (4) 13
6 (5) 18
.745 (4).74
fractures
(nonvert
F Fx)
age.
! 11
5 (1)
11 (3)
12
3 (2)
.003
Cataract
5 (10)
(1)
(3)!
12 (10)
fragility fractures; bone turnover markers, including bone- CataractCataract
5
(1)
11
(3)
12
(10)
3
(2)
.003
TEAEs
were Deafness
also !reviewed
in women
aged 80 and
old!
!
4
(3)
1
(1)
.006
Deafness
1
(0.2)
8
(2)
4
(3)
1
(0.2)
8
(2)
4
(3)
1
(1)
.006
Deafness
1
(0.2)
8
(2)
specific alkaline phosphatase; and urinary deoxypyridinoer, including
from the
group
6 (5)
0and
(0)
Pruritus
11
(3)
(3)! 25
11 (3) 11 (3) 23 patients
13 (3) 13 (3)
6 (5) placebo
0 (0)! 13
.026 (5).02
line corrected for creatinine clearance, as well as the safety Pruritus Pruritus
steoporosis,
a
skeletal
disorder
characterized
by
comRash
24 (6) the teriparatide
23 (6) group.
5 (4)
8TEAEs
(6)
Rash
24
(6)
23
(6)
Rash
24
(6)
23
(6)
5
(4)
8
(6)
.505 (4).50
patients
from
No
unexpected
new nonvertebral
fragility fractures (RR 5Cyst
0.75,
of teriparatide,
were investigated.
4 (1)
Cyst
5 (0)
(1)
(1)
promised bone strength
predisposing
an increased
Cyst
5 (1) 5 (1)
4 (1) to
0 (0) 0
5 (4) 54(4)
.090 (0).09
were noted
in the
patients
with
teriparatide.
ARR 5There
1.1%,
P no
5.661).
Thetreatment-by-age
treatment-by-age
interaction
(4)
11 (3)treated
7 (6)
1 (1)
RESULTS:
were
significant
in- Fever
Fever
(4)
(3)
(4) 15public
11 (3)problem
7 (6) 15
1 (1) 11
.087 (6).08
health
of older
riskFever
of fracture,1 is a15major
Weightof
loss
3 (1)
8 (2)
6
28(2)
Weight
loss
3 (5)
(1)
(2)
teractions
for significant
the bone turnover
markers,
femoral that
neck the
was not
(P 5.42),
indicating
effect
Weight
loss
3
(1)
8
(2)
6
(5)
2
(2)
.036 (5).03
people.
Most types of osteoporotic
fractures 8increase
in in- 3 (3)
Cancer
18 (4)
(2)
08(0)
Cancer
18 (4)
(2)
Cancer
18
(4)
8
(2)
3
(3)
0
(0)
.533 (3).53
2–4
BMD,
vertebral
fractures,
nonvertebral
fragility
fractures,
teriparatide on nonvertebral fractures was not statistically
and the9 number
of elderly
cidence
with age,
Vaginitis
(2)
10 (2)individuals
4
0 (0)
Vaginitis
9 (3)
(2)
10
(2)
Vaginitis
9
(2)
10
(2)
4
(3)
0
(0)
.104 (3).10
height loss, hyperuricemia, or hypercalcemia. A significant
DISCUSSION
affected with osteoporosis
is expected to increase dramatdifferent in younger and older patients.
AdverseAdverse
Event Event
O
Johnson syndrome was reported during 5 years.
Cost-effectiveness
Contents lists available at ScienceDirect
Bone
RANELATO DI STRONZIO
Fig. 2. Changes from baseline in BMD in the ITT pooled population during 5 years
placebo;
strontium ranelate 2 g/d).
(
Based on the TROPOS population aged 80 years or over, 5-year
treatment with strontium ranelate cost an estimated
j o u r n aSEK
l h o20,888
m e p abut
g e : w w w. e l s e v i e r. c o m / l o c a t e / b o n e
Bari,
saved an estimated SEK 38,527 in fracture-related costs. Increased
7-10 novembre 2013
longevity in the strontium ranelate group cost SEK 4511. Thus, there
obtained and treatment effects persist over time [18–20]. However,
was a net cost saving by avoiding fractures despite the costs of
few studies include subjects over the age of 80 years [8,21–23]. Data
treatment and added years of life. Strontium ranelate increased QALYs
based on pooling of small studies have not found a reduction in
by 0.051 and life-years by 0.017 and so was cost-saving compared to
nonvertebral fracture risk in the very elderly [24,25].
no treatment, i.e., treatment was associated with less costs, more lifeWe report that strontium ranelate reduces the risk of vertebral
years and quality of those life-years. The number needed to treat to
fractures and nonvertebral fractures in elderly women during 5 years.
gain one QALY with strontium ranelate was 19.6 patients while 58.5
Treatment continued to increase BMD at the lumbar spine and
patients had to be treated to gain a life-year. The probabilistic
femoral neck during 5 years. The association between an increase in
sensitivity analysis showed
an 86% chance of a cost-saving
result in
a,
b
f
bonecmineral density andda proportional reduction in fracture
has
Ego Seeman ⁎, Steven Boonen analysis,
, Frederik
Borgström
, Bruno Vellas , Jean-Pierre Aquino e, Juttarisk
Semler
,
favour of strontium ranelate. In sensitivity
strontium
g
hbeen described based on a post
i hoc analysis of the data from the SOTI
Claude-Laurent
Benhamou
,
Jean-Marc
Kaufman
,
Jean-Yves
Reginster
ranelate remained cost-saving over all ages between 80 and 87
and TROPOS studies and is partly due to the substitution of calcium by
a
years and
at Health,
T-score
b−2.1of SD.
Strontium
ranelate
remained coststrontium [26,27].
Austin
University
Melbourne,
Melbourne,
Australia
E. Seeman et al. / Bone 46
Leuven it
University
Center for that
Metabolic
Bone Diseases
and Division
of Geriatric
Leuven, Belgium
saving bwhen
was assumed
patients
immediately
reversed
to Medicine,Strontium
ranelate was cost-saving and increased the number and
c
i3 Innovus,
Stockholm,
the same
fracture
risk asSweden
untreated patients at discontinuation of
quality of life of remaining years of life to a degree comparable
to that
Table 2
d
CHU Purpan, Toulouse, France
Frequency of adverse
treatment.
achieved with treatments for hypertension and hyperlipidemia
[28]. events (N = number of exposed patients, % of patients with at
e
Clinique Médicale de la Porte Verte, Versailles, France
least one emergent AE, E(SE) = estimate (standard error) of the difference between
f
Hydrochlorothiazide and statins were cost-effective
with a cost per
Immanuel Krankenhaus Rheumaklinik, Berlin, Germany
group percentages, 95% CI of the estimate), ⁎statistically significant difference between
g
Hôpital de la Madeleine, Orléans, France
QALY gained close to SEK 40,000. In patients starting
treatment
at an
Discussion
treatment
groups.
h
U.Z. Gent Department of Internal Medicine, Gent, Belgium
age of 80 years, bisphosphonates and strontium ranelate were costi
University of Liège, Liège, Belgium
Strontium
Placebo E (SE)
95% CI
safety set = 1528
saving. The safety profile of strontium ranelate in Nthe
elderly was
The very elderly are at highest risk for fractures because of the high
ranelate
prevalence of osteoporosis, the high frequency of falls, rapid bone loss
similar to that in the SOTI and TROPOS studies and during the 3-year
N = 756
N = 772
et al. /profound
Bone 46 (2010)
1038–1042
studies [12,13], particularly the annual incidence of events more
and
structural
decay. These patients are also most cost%
%
a r
i c provided
l e i n
f nonvertebral
o
b sreduction
t r a c ist
effective
to ttreat
that
fracturearisk
frequently reported in the treatment group did not increase
over time,
Headaches
3.3
1.7
1.6 (0.8) [0.1;3.3]⁎
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
Article history:
± standard
Received 24 September 2009
Revised 4 December 2009
cebo
Accepted 9 December 2009
= 750
Available online 21 December 2009
5 ± 2.9
4 ± 6.4 Edited by: R. Rizzoli
4
Keywords:
Clinical trial
1
Strontium Ranelate
.8 ± 1.7 Antiosteoporotic treatment
.3 ± 0.7 Elderly population
0 ± 659 Osteoporosis
Osteoporotic fracture
seizure
n in the
s DRESS
tevens-
Nauseaaand
vomiting
4.8
2.4 (1.4) [−0.4;5.2]
Introduction: Longevity has resulted in a greater proportion of the population entering
time
of life when7.1
Diarrhea
8.1
6.2
1.9 (1.3) [−0.8:4.5]
increasing bone fragility and falls predispose to fractures, particularly nonvertebral fractures. Women over
Dermatitis and eczema
4.8
5.1
−0.3 (1.1) [−2.5;1.9]
80 years of age constitute 10% of the population but contribute 30% of all fractures and 60% of all
Alopecia
0.5
0.4
0.1 (0.4) [−0.7;1.0]
nonvertebral fractures. Despite this, few studies have examined antifracture efficacy
treatments in this4.5
Deepof
venous
2.5
2.0 (0.9) [0.2;4.0]⁎
high-risk group and none has provided evidence for benefits beyond 3 years.
thromboembolic events
Materials and methods: To determine whether strontium ranelate reduces the
risk of vertebral
and4.1
Disturbance
in
3.8
0.3 (1.0) [−1.7;2.4]
consciousness
nonvertebral fractures during 5 years, we analyzed a subgroup of 1489 female patients
over 80 years of age
Memory intervention)
loss
2.9
1.5 (1.0) [−0.4;3.5]
(mean 83.5 ± 3.0 years) with osteoporosis from the SOTI (spinal osteoporosis therapeutic
and4.4
Seizures and
seizure
0
0.7 (0.3) [0.04;1.54]⁎
TROPOS (treatment of peripheral osteoporosis) studies randomized to strontium ranelate
2 g/d
or placebo.0.7
disorders
All received a supplement of calcium plus vitamin D.
Results: By intention to treat, vertebral fracture risk was reduced by 31% (relative risk, RR = 0.69; 95%
confidence interval, CI 0.52-0.92), nonvertebral fracture risk by 27% (RR = 0.73; 95% CI 0.57-0.95), major
including
VTEs.
A=cohort
nonvertebral fracture risk by 33% (RR = 0.67; 95% CI 0.50-0.89) and hip fracture
risk by 24%
(RR
0.76; study using the General Practice Research
(GPRD)
showed
95% CI 0.50-1.15, not significant). Treatment was cost-saving as it decreased costDatabase
and increased
QALYs
and a greater association of VTE in osteoporotic
life-years.
than nonosteoporotic patients, but did not show any greater
Discussion: Strontium ranelate safely produced a significant reduction in vertebral
andinnonvertebral
association
treated patients with strontium ranelate or alendronate
fracture risk during 5 years in postmenopausal women over 80 years of age and
was costtosaving.
compared
untreated patients [29].
© 2009 Elsevier This
Inc. All
rights
is one
of reserved.
the few studies confirming the long-term antifracture
efficacy of a treatment which included subjects over 80 years of age
Uncertainty regarding the long-term benefits and risks of
treatment
in patients
with osteoporosis of any age, and in the very
Introduction
advances trabeculae with their surfaces are
lost while
increased
elderly,
remains
for several reasons. Studies that report results in the
porosity in cortical bone increases the available
surface
for remodelfourth
year and surfaces
beyond retain only a small fraction of the cohort
Fig. 2. Changes
baseline
BMD in the 10%
ITT pooled
during
Women
over 80from
years
of agein constitute
of thepopulation
population
but5 years
ing and resorption on the endocortical and
intracortical
5-year
Fig. 1. Relative reduction of fracture risk with strontium ranelate over 5 years in the ITT pooled population (□ placebo;
▪
strontium ranelate[30–34].
2 g/d).
DENOSUMAB Bari,
7-10 novembre 2013
DISEGNO DELLO STUDIO FREEDOM
Year
R
A
N
D
O
M
I
Z
A
T
I
O
N
0
1
2
Extension
3
4
5
Denosumab 60 mg
SC Q6M
(N = 3902)
6
7
8
9
10
Denosumab 60 mg
SC Q6M
(N = 2343)
Long-term
Denosumab
Calcium and Vitamin D
Placebo
SC Q6M
(N = 3906)
Year
Denosumab 60 mg
SC Q6M
(N = 2207)
0
1
2
3
4
Cross-over
Denosumab
5
6
7
Red box defines the scope of the current analysis including the first 3 years of the extension (6 years overall) for the long-­‐term denosumab group only. denosumab Bari,
7-10 novembre 2013
Subject Incidence of Fractures in the FREEDOM and Extension Studies Fracture Incidence (%)
A. New Vertebral Fractures
10
9
8
7
6
5
4
3
2
1
0
Overall Long-term Group
FREEDOM
Extension
7.2%
< 75 Years Group
FREEDOM
Extension
≥ 75 Years Group
FREEDOM
Extension
8.6%
6.5%
3.4%
3.5%
2.3%
Placebo
DMAb
N = 3691
N = 3702
Years 1–3
3.1%
2.0%
Long-term
DMAb
N = 2114
Years 4–6
Placebo
DMAb
N = 2545
N = 2547
Years 1–3
Long-term
DMAb
N = 1555
Placebo
DMAb
N = 1146
N = 1155
Years 4–6
Years 1–3
3.6%
Long-term
DMAb
N = 559
Years 4–6
Fracture Incidence (%)
B. Nonvertebral Fractures
10
9
8
7
6
5
4
3
2
1
0
Overall Long-term Group
FREEDOM
Extension
8.0%
< 75 Years Group
FREEDOM
Extension
9.0%
≥ 75 Years Group
FREEDOM
Extension
7.9%
7.6%
6.5%
5.9%
3.8%
Placebo
DMAb
N = 3906
N = 3902
Years 1–3
Long-term
DMAb
N = 2343
Years 4–6
5.4%
3.3%
Placebo
DMAb
N = 2670
N = 2667
Years 1–3
Long-term
DMAb
N = 1681
Years 4–6
Placebo
DMAb
N = 1236
N = 1235
Years 1–3
Long-term
DMAb
N = 662
Years 4–6
Fracture incidence is based on crude incidence rate for panel A and Kaplan-­‐Meier es3mate for panels B and C. N = number of subjects in the respec3ve primary efficacy analysis set. DMAb = denosumab. CONCLUSIONS Bari,
7-10 novembre 2013
•  Denosumab treatment for 6 years (overall long-­‐term group) and regardless of age (< 75 years and ≥ 75 years groups): –  Was associated with low incidences of new vertebral, nonvertebral, and hip fractures –  Con3nued to significantly increase BMD year to year –  Remained well tolerated •  These results underscore the consistent an3-­‐fracture efficacy and safety profile of con3nued denosumab treatment over 6 years. •  Denosumab is a therapeu3c op3on for women at higher risk for fracture, notably those ≥ 75 years, in whom hip fractures increase exponen3ally due to trabecular and cor3cal bone decay. CONCLUSIONI
Bari,
7-10 novembre 2013
ANALISI COMPARATIVA DI EFFICACIA
Terapia anti-ipertensiva
Ictus cerebri
~ 40 %
Terapia ipolipemizzante
Infarto miocardico
~ 30 %
Terapia osteoporosi
Frattura
~ 60 %
! bral, or other weight-bearing osteoporotic fracture,
treatment should be initiated without the need for
BMD measurement, if no other contraindications
exist. Treatment also should be initiated in a patient
without a prior fracture but who has other strong
clinical risk factors for fracture.
Zoledronic aci
sphosphonate av
intravenous optio
completed in pos
acid has also be
prevention of rec
NATIONAL OSTEOPOROSIS FOUNDATION
follow-up of 1.9 y
patients who re
Box 1
90 days of a hip fr
Indications for osteoporosis prescription
strated a 28% red
therapy
use of this agent c
Hip or vertebral fracture
the potential me
unclear. The main
Osteoporosis based on BMD (T-score ! "2.5)
dronic acid infusi
after appropriate evaluation for secondary
consisting of flucauses
occurrence of t
Low bone density by BMD (T-score of "1.0 to
patients who have
"2.5) and risk based on the FRAX algorithm
sphosphonates,
(10-year probability of a major osteoporosispretreatment with
related fracture of #20% or 10-year probability
of a hip fracture of #3%)
All 4 of the bis
United States h
Clinical judgment based on overall fracture risk
randomized cont
CONCLUSIONI Bari,
7-10 novembre 2013