ARE ALL POSTMENOPAUSAL OSTEOPOROSIS PATIENTS THE SAME? ASBMR 2008 Friday, September 12 th, 2008.
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Transcript of ARE ALL POSTMENOPAUSAL OSTEOPOROSIS PATIENTS THE SAME? ASBMR 2008 Friday, September 12 th, 2008.
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ARE ALL POSTMENOPAUSAL OSTEOPOROSIS PATIENTS THE SAME?
• ASBMR 2008• Friday, September 12th, 2008
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Learning Objectives
After attending this symposium, participants will be able to: • Explain the heterogeneity of bone fragility in terms of pathogenesis
and structural properties and recognize its impact on fracture risk.
• Distinguish between the mechanisms of action of strontium ranelate, anti-resorptives, and PTH in increasing bone strength.
• Critically assess the antifracture efficacy of strontium ranelate.
• Describe the techniques for monitoring strontium ranelate therapy and their appropriate clinical application.
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MECHANISMS OF STRONTIUM RANELATE AND OTHER ANTIFRACTURE AGENTS IN INCREASING BONE STRENGTH
David Goltzman, MD, FRCPC
Professor of Medicine and Director of the McGill Centre for Bone and Periodontal Research, McGill University, Montréal, Québec, Canada
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Strontium Ranelate and Fractures
• Reduction in vertebral fracture risk as early as the firstyear and over time
• Reduction in hip fracture in high risk patients
• Antifracture efficacy in elderly patients and in patientswith osteopenia
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Contributions to Bone Strength
Quantity of bone
Quality of bone • Structural Properties
– Size and shape of bone– Trabecular connectivity – Trabecular orientation
• Material properties – Content and quality of mineral and matrix (primarily collagen)
• Overall condition (microdamage, etc.)
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Determinants of Fracture Risk
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Bone Remodelling Cycle
Quiescence
Lining cells
OsteoclasticActivation
Osteoblast activation
OsteoblasticNew Bone Formation
Initiation
Osteoclastic BoneResorption
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Bone Remodelling
OBOCL
Resorption Formation
Anti-Resorptives
Bone
Anabolics
HCl
Proteases
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Relative Risk of New Vertebral Fractures
Adapted from Delmas et al., Lancet 2002, 359:2018–26.
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ANTI-RESORPTIVES
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Anti-resorptives Inhibit Resorption and Allow Filling of Cavity
OBOCL
Resorption Formation
Anti-Resorptives
Bone
HCl
Proteases
Local and systemic regulators of bone formation
Inhibited Continues
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Anti-resorptives Also Reduce Bone Formation
OBOCL
Resorption Formation
Anti-Resorptives
Bone
HCl
Proteases
Local and systemic regulators of bone formation
Ephrin/Eph
IGFs, IGFBPs TGF-β,BMPs,
FGFs
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Adaptedf from Bonnick et al. J Clin Endocrinol Metab 2006;91:2631-37.
Changes in Biochemical Markers Expressed as Mean Percentage Change from Baseline {+/-} se at 6, 12, and 24 Months (pp approach)
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0 3 6 12 -60
-50
-40
-30
-20
-10
0
NTX
BSAP
Time(Months)
Me
an
Ch
an
ge
(%)
Temporal Difference in Reduction of Resorption and Formation Markers
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Mean Percentage Changes in BMD from Baseline
Adapted from Bonnick et al. J Clin Endocrinol Metab 2006;91:2631-37.
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Bisphosphonates
SERMs
Calcitonin
Boneresorption
Boneformation
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Mechanism of Osteoporotic Fracture Reduction by Anti-resorptives
(Filling plushypermineralization)
Antiresorptive Therapy
Reduce Bone Turnover
Decrease Fracture Risk
Stabilize or ImproveMicroarchitecture
Increase BMD
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What Anti-resorptives Will Not Do
• Normalize BMD• Restore trabecular architecture
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ANABOLICS
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Parathyroid Hormone
1 10
20
30
Ser Val Ser Glu Ile Gln Leu Met His AsnLeu
GlyLysHisLeuAsnSerMetGluArgValGlu
Trp
LeuArg Lys Lys Leu Gln Asp Val His Asn Phe
50
40
6070
80
-COOH
H2N-
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Osteoblast
BONE
Osteoclast
Anabolics Initiate New Bone Formation
Osteoblastic stromal
cell
New Bone
PTH
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Osteoblast
Osteoclast Progenitor
BONE
PTH
RankLOPG
Osteoclast
Osteoblastic stromal
cell
Resorption is Also Stimulated by PTH
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nn
nn
nn
nn
0 1 2 3 4 5 60
10
20
30
40
50
60
70
80M
ea
n %
ch
ang
e in
turn
ove
r m
ark
er
Time (months)
N-telopeptide
Osteocalcin
Adapted from Lindsay et al. Lancet 1997.
Early Changes in Biochemical Markers in Women with Osteoporosis on hPTH(1-34)
n=17
AnabolicWindow
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Effect of PTH(1-34) on Lumbar Spine BMD in Postmenopausal Women with Osteoporosis
*P<0.001
Months
% c
han
ge
± S
E
0
2
4
6
8
10
12
14
16
0 6 12 243
**
*
* *
*
End
18
*
*
Placebo PTH(1-34), 20 PTH(1-34), 40
*
Adapted from Neer RM et al. N Engl J Med 2001.
*
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Bisphosphonates
SERMs
Calcitonins
PTH
Boneresorption
Boneformation
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Strontium Ranelate
Sr++
S N
CN
Sr++
CH 2
H 2C CO -O
COO
OC- O
OC- O
H 2C -
5-[bis (carboxymethyl) amino]-2-carboxy-4-cyano-3-thiopheneacetic acid, distrontium salt
Ranelic acid (organic moiety) + 2 stable strontium atoms
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STRONTIUM RANELATE:PRE CLINICAL STUDIESIN VITRO EFFECTS ON BONE TURNOVER
STRONTIUM RANELATE:PRE CLINICAL STUDIESIN VIVO EFFECTS ON BONE TURNOVER
STRONTIUM RANELATE:HUMAN STUDIES
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Strontium Ranelate Decreases Osteoclast Differentiation
Adapted from Bonnelye et al. Bone 2008;42:129-38.
Mouse spleen-derived cells (+RANKL & M-CSF)
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Strontium Ranelate Decreases Osteoclast Lifespan (induces apoptosis)
OC lifespan
70
80
90
100
Control 6 9 12 24
SR (mM Sr2+)
* **
***
% of living cells
mean + SEM; n=6-12* P<0.05, **P<0.01, *** P<0.001 vs. Control
Adapted from Mentaverri et al. Bone 2005;36(S2):S403.
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Strontium Ranelate Inhibits Bone Resorption in vitro
Adapted from Baron et al. Eur J Pharmacol. 2002;450:11-17.
Sr2+
Pit
Are
a In
dex
(% o
f co
ntr
ol)
(mM)
Rat osteoclasts
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Strontium Ranelate Increases Osteoprotegerin While Decreasing RANKL in Primary Human Osteoblasts
Mean +/- sem** P<0.01, *** P<0.001 vs. Control
1Control 0.01 0.1
*****
Sr (mM Sr2+)
OPG mRNAas % of control
2
***
RANKL mRNAas % of control
**
******
***
1Control 0.01 0.1
SR (mM Sr2+)
2
RANKLOsteoprotegerin
Adapted from Brennan et al. J Bone Min Res 2006;21(S1):S301.
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SR Actions in Bone
Bone
Ca
OBOCL
↓Resorption ↑Formation
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Mean + SEM, n = 6-10* P<0.05, ** P<0.01Adapted from Mentaverri et al. Bone 2005;36(S2):S403.
*
*
0
10
20
30
40
50
60
Control10 15 20 25
% of Apoptotic Cells
Control10 15 20 25
Plasmid control Dominant Negative CaSR
***
**
SR (mM Sr2+)
Strontium Ranelate Induces Apoptosis in Rabbit Primary Osteoclasts and this is Decreased with DN-CaSR Transfection
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Strontium Ranelate: Anti-resorptive Effects
OsteocytesOsteoclasts
MacrophagesOsteoblasts Bone-lining cells
+ OPG RANKL
-
Brennan ASBMR 2006Chattopadhyay Biochem pharmaco 2007
Sr++ = Differentiation
Wattel Osteoporos Int. 2005
Bonnelye Bone 2008
Sr++ = ActivitySr++ = Apoptosis
Sr++ = CaR agonist
Mentaverri Calc Tissue Int. 2004
Mentaverri Bone 2005
Sr++
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SR Increases Replication of Pre-osteoblasts
Adapted from Canalis E, Hott M, Deloffre P, Marie PJ. Bone. 1996;18(6):517-23.
Tissue Culture
(10 M-3, 48 h)Control
Rat Calvariae Cells
3H
-Thy
mid
ine
labe
led
cells
(%
)
**66
44
22
00
Osteoblasts
Pre-osteoblasts
10-5 10-3Controls
Strontium ranelate (M))* P < 0.05 vs Control
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Strontium Ranelate Increases Osteoblast Survival
SR (mM Sr2+)
1Control 0.01 0.1 2
**
***
Cell number as a ratio of control
* P<0.05, ** P<0.01 vs. ControlAdapted from Brennan et al. Calcified Tissue Int. 2007;80(S1):P132T.
Primary Human Osteoblasts
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Strontium Ranelate Increases Bone Formation Markers in Primary Human Osteoblasts
** P<0.01 vs. Control
Alkaline phosphatase activity
SR (mM Sr2+)
1Control 0.01 0.1 2
**
ALP activity as % of vehicle(corrected per mg total protein)
**
Adapted from Brennan et al. Calcified Tissue Int. 2007;80(S1):P132T.
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Strontium Ranelate Increases Collagen Synthesis by Preosteoblasts and Osteoblasts
Adapted from Adapted from Canalis E, Hott M, Deloffre P, Marie PJ. Bone. 1996;18(6):517-23.
ControlControl
BoneBone
1010-3-3 M, 48 h M, 48 h
Tissue CultureTissue Culture
**
**
**
ControlsControls 1010-4-4 1010-3-31010-5-5
2525
1515
1010
00
3030
2020
55
Osteoblasts Osteoblasts
Pre-osteoblastsPre-osteoblasts
Col
lage
n S
ynth
esis
Col
lage
n S
ynth
esis
(10(1
0-3-3 d
pm/
dpm
/ wwee l
l)ll)
* P<0.05 vs Controls
Strontium ranelate (M)
Rat Calvariae CellsRat Calvariae Cells
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Strontium Ranelate Increases Mineralization and Number of Nodules in Murine Osteoblasts
Adapted from Choudhary S et al. J Bone Miner Res. 2007 Jul;22(7):1002-10.
MineralizationMineralizationNumber of nodulesNumber of nodules
Control 0.1 1
SR (mM Sr2+)
0.3
***
***
***
mean ± SD, n=3, *** P<0.001
Vehicle
SR 1 mMSR 1 mM
SR 3 mMSR 3 mM
Adapted from Bonnelye et al. J Bone Miner Res 2006;21(S1):S426.
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SR Actions in Bone
Bone
Ca
OBOCL
↓Resorption ↑Formation
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Mean + SEM, n=6*** P<0.001 vs ControlAdapted from Adapted from Chattopadhyay et al. Biochem pharmacol 2007;74:438-47.
SR-induced Proliferation is Decreased inDN-CASR Transfected Rat Primary Osteoblasts
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Strontium ranelateStrontium ranelate
CaSR-/-
osteoblasts
REPLICATION
?CaSR
• CaSR is not essential for strontium ranelate-induced osteoblast replication.
• Strontium ranelate may induce osteoblast replication through another receptorin addition to CaSR.
CaSR is Not the Only Receptor Involved in Strontium Ranelate-induced Osteoblast Replication
Strontium ranelateStrontium ranelate
CaSR+/+
osteoblasts
REPLICATION
?CaSR
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Strontium Ranelate Bone Formation Effects
Osteocyte Osteoclast
Macrophage
Osteoblast Bone-lining cell
Sr++ = COX-2
PGE2
Choudhary JBMR 2007
Proliferation / Differentiation
Sr++ = CaR agonist
Chattopadhyay Biochem pharmacol 2007
Bonnelye Bone 2008
Activity
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Replication
Pre-osteoblast
Osteoclasts
Activity
Matrix
Synthesis
Differentiation
Osteoblastic
Differentiation
Adapted from Marie P. Curr Op Rheum 2006.Strontium ranelate: a dual mode of action rebalancing bone turnover in favour of bone formation.
Apoptosis
Osteoblasts
OPG
RANKL
CaSR
RANK
BoneFormation
Bone Resorption
SR
SR
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STRONTIUM RANELATE:PRE CLINICAL STUDIESIN VITRO EFFECTS ON BONE TURNOVER
STRONTIUM RANELATE:PRE CLINICAL STUDIESIN VIVO EFFECTS ON BONE TURNOVER
STRONTIUM RANELATE:HUMAN STUDIES
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Proximal Tibia Histomorphometry
Control Strontium ranelate 900 mg/kg/d
Adapted from Ammann et al. JBMR 2004.19:2012-20.
38 ± 2 ***BV/TV (%) 27 ± 2
84 ± 5 **Tb.Th (µm) 74 ± 5
4.6 ± 0.1***Tb.N 3.5 ± 0.1
135 ± 5 ***Tb.Sp (µm) 216 ± 13
Treatment of Female Rats for 2 years
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Compression testMaximal Load (N)
0
100
200
300
400
Strontium ranelate (mg/kg/d)
0 900
**+ 20 %+ 20 %
3-point bending test Maximal Load (N)
SR Increases Strength of Vertebrae and Long Bones of Intact Rats (2 years of treatment)
200Strontium ranelate (mg/kg/d)
0
50
100
150
0 225 450
*
900
+ 15 %+ 15 %
Mid-Shaft Femur
L4 Vertebra
Adapted from Ammann P. et al. JBMR 2004.19:2012-20.
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Distribution of Strontium (SR), in Monkey ILIAC Cancellous Bone Visualized by Secondary Electron Imaging (SEI)
Sr Sr
After treatment with SR(1250 mg/kg/day) for 52 weeks (A) and after 10 weeks of treatment withdrawal (B)
More Sr depositedin new bonethan old bone
More Sr released from new bone than old bone
A B
Adapted from Farlay D et al. J of Bone Miner Res. 2005;20(9):1569-78.
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Strontium Ranelate Preserves the Degree of Mineralization of Bone
% o
f th
e N
um
ber
of
Mea
sure
men
ts 0 mg/kg/d
200 mg/kg/d
500 mg/kg/d
1250 mg/kg/d
Degree of Mineralization of Bone (g/cm3)
Monkeys, 1-year treatment
Micro radiography - Iliac crest
Young
Old
Adapted from Farlay D et al. J of Bone Miner Res. 2005;20(9):1569-78.
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Femoral BMD in Strontium Ranelate-treated Female Rats Correlated with Bone Strength
Adapted from Ammann P et al. Bone 2001;28(suppl 5) P537S.
Correlation BMD-Strength
Mean ± SEM, n=28-30, * P<0.05 vs. Control
Adult female rats - 2-year treatment
BMD (g/cm2)
Ult
imat
e S
tren
gth
(N
)
R=0.739
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Pre Clinical Studies Conclusions:
Strontium ranelate
•Increases bone formation and decreases bone resorption resutling in an increase in bone
•Improves bone microarchitecture leading to an increase in bone quality
• As a consequence, improves bone strength
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STRONTIUM RANELATE:PRE CLINICAL STUDIESIN VITRO EFFECTS ON BONE TURNOVER
STRONTIUM RANELATE:PRE CLINICAL STUDIESIN VIVO EFFECTS ON BONE TURNOVER
STRONTIUM RANELATE:HUMAN STUDIES
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Strontium Ranelate Simultaneously Increases Bone Formation Markers and Decreases Bone Resorption Markers
Increased b-ALP and decreased s-CTX
E= Estimate of difference between strontium ranelate group and placebo group
- co-variance analysis, baseline adjusted ***P < 0.001** P < 0.01*P < 0.05
E
SOTI study
- 600
- 300
0
0.4
0.8
1.2
M0 M3 M6 M12 M24 M36
*** ****** * **
**
*** **
S-CTX( pmol/L)
-
-
Months*** ***
*** * **
***
**
*** **
bALP (ng/mL)
- pmol/L)
Adapted from Meunier PJ et al., NEJM 2004 ;350;5:459-68.
b-ALP: bone-specific alkaline phosphataseS-CTX: serum C-telopeptide cross-links
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Placebo Strontium ranelate0
5
10
15
20
25
30BV/TV (%)
3D Trabecular and Cortical Microstructure (3 Years of Treatment in Post Menopausal Osteoporotic Patients)
placebo n=21, strontium ranelate n=20
+13%
Bone volume/ Tissue volume
Adapted from Arlot ME et al. JBMR 2008;23:215-22.
Placebo Strontium ranelate0.0
0.5
1.0
1.5
2.0Tb.N p(n/mm)
Trabecular Number
+14% P=0.05
Placebo Strontium ranelate0
250
500
750
1000
1250
1500Tb.Sp p(µm)
Trabecular separation
-16% P=0.041
Placebo Strontium ranelate0
250
500
750
1000
1250
1500Ct.Th(µm)
Cortical thickness
+18%, P=0.008
**** **
Placebo 36 Mo
SR 36 Mo
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Biopsy Biopsy
Protocol :
10 women treated by bisphosphonates for 32 months followed by strontium ranelate for 12 monthsMean Age 65 yearsPaired iliac crest biopsies performed at M0 and M12Histomorphometric analysis
M0 M12
PAIRED BIOPSIES
PAIRED BIOPSIES
Adapted from Busse et al., 2007 Abstract ASBMR-W477.
BP (32 months)
Strontium Ranelate
Strontium Ranelate Induces New Bone Formation in HumansStrontium Ranelate Induces New Bone Formation in Humans
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Strontium Ranelate Improves Trabecular Bone Micro-architecture
Adapted from Busse et al., 2007 Abstract ASBMR-W477.
0
2
4
6
8
10
12
Inclusion after 12 months of Strontium
ranelate treatment
11,12
8,53
%
+30% +30% **
*P 0,05
Trabecular ThicknessTb Th : +10%* (P<0.05)
Trabecular InterconnectionTb Pf : -49%* (P<0.05)
Trabecular Bone Volume
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Comparative action of strontium ranelate and other agents on bone metabolism
Bisphosphonates
SERMs
Calcitonin
Strontium ranelate
Teriparatide
Boneresorption
Boneformation
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Conclusions
• Strontium Ranelate reduces fractures by increasing bone strength
• The mode of action on bone turnover and in increasing bone strength appears to be unique among anti-fracture compounds
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Review of Antifracture Efficacy of Strontium Ranelate: Reducing Fracture Risk Across the Menopause Continuum
• Cyrus Cooper DM, FRCP, FMedSci• Professor of Rheumatology and Director, MRC
Epidemiology Resource Centre, University of Southampton
and
• Norman Collisson Chair of Musculoskeletal Sciences, University of Oxford, United Kingdom
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Osteoporosis: Three Millennia
0 1000 AD 2000 AD1000 BC
400 BCHippocrates
of Kos
700 ADSaxon
tomb, Wells
1825 ADSir AstleyCooper
1850 ADOsteoporosis
1950 2000199019801970
1948Albright
1963SPA
1976HRT
1987DXA
1990–07 WHOCalcium/D,BisphosphonatesSERMs, PTH, Sr,RANKL Ab
1940 1960
Adapted from Cooper et al. (2003).
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Impact of Osteoporosis-related Fractures in Europe
Hip Spine Wrist
Lifetime risk (%)Women 14 29 13Men 3 14 2
Cases/yr 400,000 810,000 330,000
Hospitalisation (%) 100 2-10 5
Relative survival 0.83 0.82 1.00
Costs: All sites combined ~ 25 billion Euros
Adapted from IOF (2005); Harvey & Cooper (2005).
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Osteoporosis Management
• Goal: Prevent or reduce the frequency of vertebral and non-vertebral (especially hip) fractures
• Pharmacological treatment options include bisphosphonates, selective estrogen-receptor modulators, parathyroid hormone, estrogens, and calcitonin– Bisphosphonates remain the standard of care in many
centres throughout the world
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Caveats of Fracture Prevention Trials
• Trials of different agents cannot be compared directly
• Within the bisphosphonate class, superiority for prevention of fractures has not been shown for any agent
• Some agents evaluated in clinical trials with insufficient statistical power to examine protection against nonvertebral and hip fracture
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• Prevention of vertebral fractures – Good evidence for alendronate, etidronate,
risedronate and zoledronic acid
• Prevention of hip fractures
– Good evidence for alendronate, risedronate – Fair evidence for zolendronic acid
Adapted from MacLean C, et al. Ann Intern Med 2008;148(3):197-213.
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Risk Relative to Placebo
Vertebral Hip
Adapted from MacLean C et al. Ann Intern Med 2008;148(3):197-213.
Fracture Risk Reduction with Bisphosphonates in High Risk Patients
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Fracture Risk Reduction with Bisphosphonates in Non-high Risk Patients
Risk Relative to Placebo Vertebral Hip
Adapted from MacLean C, et al. Ann Intern Med 2008;148(3):197-213.
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European Guidance for Diagnosis and Management of Osteoporosis in Postmenopausal Women
Adapted from Kanis JA, et al. Osteoporos Int 2008;19:399-428.
Antifracture efficacy of the most frequently used treatments for postmenopausal osteoporosis given with calcium and vitamin D
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Calcium and Vitamin D supplements throughout the studies.
placebo
strontium ranelate 2g/day
M0 M12 M36M24 M48 M60 (months)
M0 M12 M36M24 M48 M60 (months)
placebo
Mainstatisticalanalysis
SOTISOTI(Vertebral (Vertebral fractures)fractures)N=1649N=1649
TROPOSTROPOS(Peripheral (Peripheral fractures)fractures)N=5091N=5091
FIRST (Run-in)
(2 weeks-6 months)
strontium ranelate 2g/day
Antifracture Efficacy Program of Strontium Ranelate in Postmenopausal Osteoporosis
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Efficacy of Strontium Ranelate inReducing Fracture Risk over 5 Years
Adapted from Reginster JY et al. Arthritis Rheum 2008;58(6):1687-95.
20.9%
16.8%
VertebralVertebralfracture riskfracture risk
p=0.032 p<0.00130
0
10
20
RR: -15%
All nonvertebralAll nonvertebralfracture riskfracture risk
0-5 years 0-5 years
n=2183
RR: -24%
RR=0.85; 95% CI [0.73; 0.99] 0.76; 95% CI [0.65; 0.88]
TROPOS
24.9%
20.8%
n=2714
Patients(%)
strontium ranelate
Placebo
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RR: 0.57; 95%CI: [0.33;0.97] adjusted cox model
n=1128
0 - 5 years
10.2% RR: -43%
0
5
10
strontium ranelate
Placebo
p=0.036
7.2%
Patients (%)
Patients aged over 74 and 2 T-scores ≤-
2.4
Efficacy of Strontium Ranelate inReducing Fracture Risk over 5 Years
TROPOS
Adapted from Reginster JY, et al. Arthritis Rheum 2008;58(6):1687-95.
HipHip fracture fracture riskrisk
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Tolerability Profile of Strontium Ranelate over 5 Years
Post Marketing experience: 16 cases of DRESS among 570 000 patients treated per year.
Phase III program Adverse events
Symptoms(% patients)
placebon=3317
SRn=3352
Dermatitis 2.32.3 2.02.0
Eczema 1.81.8 1.41.4
VTE 4.54.5 3.03.0
Headache 3.33.3 2.72.7
Diarrhoea 7.07.0 5.05.0
Nausea 7.17.1 4.64.6
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RR**=0.92 [0.63-1.33]
p=0.646
RR**=1.09 [0.60-2.01]
p=0.773
* Annual incidence for 1000 patient year** relative risk adjusted on age and main risk factors for VTE
versus untreated osteoporotic population
Alendronate
(N=20084)
7.2*
Strontium ranelate(N=2408)
7.0*
No Increase in Incidence of VTE for Strontium Ranelate and Alendronate as Compared to Osteoporotic Population (GPRD)
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Efficacy of Strontium Ranelate in Reducing Vertebral Fracture Risk According to the Number of Prevalent Vertebral Fracture(s)
Adapted from Roux C et al. J Bone Miner Res. 2006;21(4):536-42.
14.4%
7.5%
25.2%
14.5%
RR=0.52; CI [0.40-0.67]
0n=2605
1
0.55; CI [0.41-0.74]
n=11100.67; CI [0.55-0.81]
>2n=1365
No. Prev. Vert Fracture(s)
P<0.001
P<0.001
40.3%
29.8%
P<0.001
Over 3 years
Patients(%)
SOTI &TROPOS
0
15
30
45 RR: -48% RR: -45% RR: -33%
strontium ranelatePlacebo
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EFFICACY OF STRONTIUM RANELATE IN REDUCING VERTEBRAL FRACTURE RISK IN WOMEN WITH OSTEOPOROSIS (WITH OR WITHOUT A PREVALENT FRACTURE), OSTEOPENIA ALONE OR OSTEOPENIA PLUS A PREVALENT FRACTURE
Seeman E, et al. J Bone Miner Res 2008;23(3):433-438. Meunier PJ, et al. N Eng J Med 2004;350:459-468. Reginster JY, et al. JCE&M 2005;90(5):2816-2822.
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Reduction in Vertebral Fracture Risk with Strontium Ranelate According to the Level of Pretreatment Bone Turnover Markers
T1 T2 T30.63CI (0.49 ; 081)
*** P<0.001n=1631
0.68CI (0.54 ; 0.85)*** P<0.001
n=1630
0.53CI (0.42 ; 0.67)*** P<0.001
n=1630
RR=
RR 37%
RR 32%
RR 47%
s-CTX
Over 3 years
strontium ranelate 2g/d
Placebo
Patients(%)
0
5
10
15
20
25
30
SOTI &TROPOS
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Nonvertebral and Vertebral Fracture in the Elderly Population (> 80 years old)
SOTI (Spinal Osteoporosis
Therapeutic Intervention)N = 1649
TROPOS(Treatment of Peripheral
Osteoporosis)N = 5091
mean age = 70 (50-96) ≥ 80 years old: n=151 (9%)
mean age = 77 (70-100) ≥ 80 years old:n=1405 (27%)
N = 1556 ≥ 80 years old
Vertebral fracture assessmentN = 896
Nonvertebral fracture assessmentN = 1489
N = 1489 (ITT)
Adapted from Seeman et al. J Bone Miner Res 2006;21:1113–20.
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Baseline Characteristics of the Elderly Population ( 80 years old)
35.1 %37.1 %Proportion (%) of patients with at least one previous nonvertebral fracture
51.4 %46.4 %Proportion (%) of patients with at least one prevalent vertebral fracture
-3.3 (0.7)-3.3 (0.7)Femoral neck BMD T-score
-2.8 (1.7)-2.7 (1.7)Lumbar BMD T-score
35.4 (6.4)35.3 (6.1)Time since menopause (years)
83.5 (2.9)83.5 (3.0)Age (years)
PlaceboStrontium ranelateCharacteristics
N = 739 N = 750
Adapted from Seeman et al. J Bone Miner Res 2006;21:1113–20.
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Reduction of Vertebral Fracture Risk with Strontium Ranelate in Elderly Patients (80 years old) Over 3 Years
P = 0.013
RR= 0.68; 95% CI [0.50; 0.92]
N = 895
RR: - 32%
Adapted from Seeman et al. J Bone Miner Res 2006;21:1113–20.
NNT = 14
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P = 0.011
RR= 0.69; 95% CI [0.52; 0.92]
N = 1488 RR: - 31%
Adapted from Seeman et al J Bone Miner Res 2006;21:1113–20.
NNT = 18
Reduction of Nonvertebral Fracture Risk with Strontium Ranelate in Elderly Patients(80 Years Old) over 3 Years
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Efficacy assessed by comparison of 0-3 years and 5-8 years cumulative
incidence
Extension Study After SOTI and TROPOS
Data on file
Baseline
SOTIStrontium ranelate 2g/day
TROPOSStrontium ranelate 2g/day Extension study
Strontium ranelate 2g/day
2055 included patientswhatever previous
occurrence of fracture
0 4 5 6 7 81 2 3
1420 completers (69%)
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Baseline Characteristics in Patients Treated for 8 Years with Strontium Ranelate (n=879)
INCL-M060FromSOTI
n=153
FromTROPOSn=726
Age (years) 72.9 (6.6) 80.5 (4.4)
BMI ( kg/m2) 26.98 (4.36) 25.66 (4.42)
Time since menopause (years)
25.4 (7.9) 32.1 (6.7)
Data on file
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Relative Change in BMD Over 8 Years
Data on file * P <0.001
Mean relative change (%)
years
**
** * * * *Lumbar BMD
Mean relative change (%)
years
** * * *
* *Femoral neck BMD
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Data on file
Cumulative incidence 0-3 years
14.9%
Vertebral Fracture Incidence Over 8 Years (SOTI+TROPOS)
Cumulative incidence 5-8 years *
13.7%
Fractures incidence (%)Fractures incidence (%)
* First new fractures on the period
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Data on file
Cumulative incidence 0-3 years
11.2%
Non Vertebral Fracture Incidence Over 8 Years (TROPOS)
Cumulative incidence 5-8 years *
12%
Fractures incidence (%)Fractures incidence (%)
* First new fractures on the period
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RR: - 42%
Strontium Ranelate Reduces the Spine OA Radiological Progression
Percentage of patients with progression of the overall score after 3 years of follow-up among the whole study population
(n=1105)
17.1%
9.9%
RR=0.58 (95% CI (0.42-0.79); P<0.001
Adapted from Bruyère O et al. Ann Rheum Dis 2008; 67:335-39.
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0
5
10
15
20
25
30
35
40
45
Strontium ranelate PlaceboPa
tie
nts
wit
h a
n i
mp
rov
em
en
t in
ba
ck
p
ain
aft
er
3 y
ea
rs (
%)
P=0.03
Proportion of patients with improvement in back pain (increase of at least one point on the Likert scale) after a follow-up of 3
years.(only in SOTI patients: n=399)
Adapted from Bruyère et al. Ann Rheum Dis 2008; 67:335-39.
Strontium Ranelate Reduces the Back Pain in Patients with Spine OA
41.8%
31.3%
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European Guidance for Diagnosis and Management of Osteoporosis in Postmenopausal Women
Adapted from Kanis JA et al. Osteoporos Int 2008;19:399-428.
Antifracture efficacy of the most frequently used treatments for postmenopausal osteoporosis given with calcium and vitamin D
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Conclusions
• Bisphosphonates have been shown to reduce the risk of both vertebral and non-vertebral fractures and remain an integral part of the pharmacological armamentarium for osteoporosis
• Strontium ranelate has demonstrated antifracture efficacy over the long-term and across a wide range of patients
• Overall, current data support the use of strontium ranelate in the management of postmenopausal osteoporosis
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Clinical Monitoring of Strontium Ranelate Therapy for Osteoporosis
• David Kendler, MD, FRCPC, CCD• Associate Professor of Medicine (Endocrinology),
University of British Columbia, • Vancouver, British Columbia, Canada
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Rationale for Monitoring Osteoporosis Therapy
• Detect non-responders– Use BMD/BTM rather than awaiting fracture endpoints
• Encourage adherence to therapy– Positive results are encouraging to patient and clinician
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Relationship Between Vertebral Fracture & Increases in BMD
0 1 2 3 4 5 6 7
Calcitonin1 YesRaloxifene2 YesRaloxifene2 NoRisedronate3 YesRisedronate4 YesAlendronate5 YesAlendronate6 No
0
20
40
60
80
% Increase in BMD
Prevalent Vertebral Fx
% R
edu
ctio
n i
n V
Fx
Ris
k
Adapted from: 1Chesnut CH et al. Am J Med 2000;109:267-76; 2Ettinger B et al. JAMA 1999;282:637-45; & data on file, Eli Lilly and Co; 3Harris ST et al. JAMA 1999;282:1344-52; 4Reginster J-Y et al. Osteoporosis Int 2000;11:83-91; 5Black DM et al. Lancet 1996;348:1535-41; 6Cummings SR et al. JAMA 1998;280:2077-82.
*Not head-to-head comparison; †vs. placebo. Error bars represent 95% confidence intervals.
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BMD Change and Fracture Risk
12-Month BMD Change in Treated Patients
2,984 Women, Age 55-81, in FIT with Alendronate
%w
ith
New
Ver
teb
ral F
ract
ure
s at
36-
48 m
on
ths
Adapted from Hochberg MC et al. Arthritis Rheum 1999:42:1246-54.
Placebo Vertebral Fractures = 6.9%
“Losers” “Stable” “Gainers”
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Vertebral Fracture Studies 3-Year Data
StudyIncrease in Spine BMD
Reduction in Vertebral Fx
Baseline Spine T-score
Baseline Vertebral Fx
TROPOS 14.7% 39% -2.8 55%
FIT II 8.3% 44% -2.1 0%
FIT I 7.9% 47% -2.5 100%
VERT-MN 7.1% 49% -2.8 100%
VERT-NA 5.4% 41% -2.4 100%
MORE 2.6% 40% -2.6 37%
PROOF 1.2% 36% <-2.0 100%
Adapted from Faulkner KG et al. J Bone Miner Res 2000;15:183-87; Reginster JCEM 2005.
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Bone Density Response to Strontium Ranelate Therapy
• Effects of higher atomic number of Sr than Ca
• Effects of increases in bone tissue
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Strontium Ranelate Increases Lumbar Spine BMD
Adapted from: Meunier PJ et al. N Engl J Med 2004;350:459-68.Reginster J.Y et al. data on file.
Mean change (%)
- 4
12
16
0
4
8
0 6 12 18 24 30 36
+ 14.4 %
SOTI
**
****
****
**
Relative change from baseline
- 4
0
4
8
12
16
0 6 12 18 24 30 36
Mean change (%)
*
*
*
*
**
+ 14.7 %
TROPOS
* P<0.001, hierarchical step-down procedure
Placebo Strontium ranelate 2 g/day
Months
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Femur Mid-shaft BMD in Ovx Rats After 52 Weeks of Strontium Ranelate Preventive Treatment
Adapted from Amman P et al. JBMR 2004;19:2012–20.
Max Load Vs. Measured BMD Max Load Vs. Adj BMD
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Raloxifene Logistic Regression CurvesMore Trial Post HOC Analysis
Adapted from Sarkar S et al. JBMR 2002;117:1-10.
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Relationship of 3yr FN BMD Changes on Therapy to Vertebral Fracture Risk Reduction
Adapted from Bruyere O et al. J Clin Endocrinol Metab 2007;92:3076-81.
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Percent of Fracture Risk Reduction Explained by Change in BMD
• FIT (ALN) 16%• MORE (RLX) 4%• VERT (RIS) 28%• SOTI TROPOS (SR) 75%
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Increases in BMD and Antifracture Efficacy
• Individual patient response to the therapy requires knowledge of “Least Significant Change”– ISCD suggests that if not known, assume 5%-7%
• BMD increases on strontium ranelate indicate:– Medication has been ingested– Strontium has been absorbed– Anti-fracture efficacy in keeping with the results from the pivotal
trials will be achieved.
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Monitoring Strontium Ranelate Therapy with Bone Turnover Markers
Adapted from Meunier P et al. N Engl J Med 2004;350:459-68.
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Resolution of Effect After Discontinuing Therapy
• Preclinical models
• Clinical trials
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Bone Strontium in Monkeys 52 Wks on SR Then 10 Wks Off
Adapted from Farlay et al. JBMR 20:9 2005.
New Bone
Old Bone
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Change in Spine BMD After Cross-over: SOTI
SWITCH
ITT population
Mean+SEM
-3.4%
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SWITCHMean+SEM
Change in Femoral Neck BMD After Cross-over: SOTI
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M48 M51 M54 M60
Mean SD
µmoL/L
SOTI: Change in Blood Strontium After Cross-over
Data on file
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Change in Bone Markers After Cross-over: SOTI
PLACEBOPLACEBOPLACEBOPLACEBOMean+SEM
b-ALP S-CTX
N=210N=210
PLACEBOPLACEBOPLACEBOPLACEBO
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Monitoring Therapy After Strontium Ranelate Discontinuation
• Initial rapid decline in BMD with exchange of easily accessible Sr for Ca– Monkey models show significant mobilization of Sr from bone
within 10 weeks
• Slow mobilization of buried Sr awaiting osteoclastic resorption
• Unknown effects of subsequent therapy, for example bisphosphonates.
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DOES MONITORING IMPROVE ADHERENCE TO OSTEOPOROSIS
THERAPIES?
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Monitoring Osteoporosis Therapy
• Detect non-responders– Use BMD/BTM rather than awaiting fracture endpoints
• Encourage adherence to therapy– Positive results are encouraging to patient and clinician