Transcript Are all Postmenopausal Osteoporosis Patients the Same?

ARE ALL POSTMENOPAUSAL
OSTEOPOROSIS PATIENTS THE SAME?
• ASBMR 2008
• Friday, September 12th, 2008
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.
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
Strontium Ranelate and Fractures
• Reduction in vertebral fracture risk as early as the first
year and over time
• Reduction in hip fracture in high risk patients
• Antifracture efficacy in elderly patients and in patients
with osteopenia
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.)
Determinants of Fracture Risk
Bone Remodelling Cycle
Lining cells
Initiation
Osteoblastic
New Bone
Formation
Quiescence
Osteoclastic
Activation
Osteoblast
activation
Osteoclastic
Bone
Resorption
Bone Remodelling
Anti-Resorptives
Anabolics
OB
OCL
HCl
Proteases
Bone
Resorption
Formation
Relative Risk of New Vertebral Fractures
Adapted from Delmas et al., Lancet 2002, 359:2018–26.
ANTI-RESORPTIVES
Anti-resorptives Inhibit Resorption and
Allow Filling of Cavity
Local and systemic regulators
of bone formation
Anti-Resorptives
OB
OCL
HCl
Proteases
Bone
Resorption
Inhibited
Formation
Continues
Anti-resorptives Also Reduce Bone Formation
Local and systemic regulators
of bone formation
Anti-Resorptives
OB
Ephrin/Eph
OCL
HCl
Proteases
Bone
IGFs, IGFBPs
TGF-β,BMPs,
FGFs
Resorption
Formation
Changes in Biochemical Markers Expressed as Mean
Percentage Change from Baseline {+/-} se at 6, 12, and 24
Months (pp approach)
Adaptedf from Bonnick et al. J Clin Endocrinol Metab 2006;91:2631-37.
Temporal Difference in Reduction of Resorption and
Formation Markers
0
Mean Change(%)
-10
-20
BSAP
-30
-40
NTX
-50
-60
0
3
6
Time(Months)
12
Mean Percentage Changes in BMD from Baseline
Adapted from Bonnick et al. J Clin Endocrinol Metab 2006;91:2631-37.
Bone
formation
Bisphosphonates
SERMs
Calcitonin
Bone
resorption
Mechanism of Osteoporotic Fracture Reduction
by Anti-resorptives
Antiresorptive Therapy
Reduce Bone Turnover
Stabilize or Improve
Microarchitecture
Decrease Fracture Risk
Increase BMD
(Filling plus
hypermineralization)
What Anti-resorptives Will Not Do
•
•
Normalize BMD
Restore trabecular architecture
ANABOLICS
Parathyroid Hormone
1
H2N-
Ser
10
Val
Ser
Glu
Val
20
Arg
Arg
Lys
Lys
Glu
Ile
Gln
Leu
Met
His
Asn
Leu
Gly
Glu
Met
Ser
Asn
Leu
His
Lys
Leu
Gln
Asp
30
Val
His
Asn
Phe
Trp
Leu
40
50
60
70
80
-
COOH
Anabolics Initiate New Bone Formation
PTH
Osteoblast
Osteoblastic
stromal
cell
New Bone
Osteoclast
BONE
Resorption is Also Stimulated by PTH
PTH
Osteoclast Progenitor
Osteoblast
RankL
OPG
Osteoclast
BONE
Osteoblastic
stromal
cell
Mean % change in turnover marker
Early Changes in Biochemical Markers in
Women with Osteoporosis on hPTH(1-34)
80
Osteocalcin
70
nn
N-telopeptide
60
50
Anabolic
Window
40
30
nn
20
nn
10
0
n=17
nn
0
Adapted from Lindsay et al. Lancet 1997.
1
2
3
4
Time (months)
5
6
% change ± SE
Effect of PTH(1-34) on Lumbar Spine BMD in
Postmenopausal Women with Osteoporosis
16
14
12
10
8
6
4
2
0
*
*
*
*
*
*
*
*P<0.001
0
*
*
*
3
6
12
Months
Placebo
PTH(1-34), 20
Adapted from Neer RM et al. N Engl J Med 2001.
18
24
End
PTH(1-34), 40
Bone
formation
Bisphosphonates
SERMs
Calcitonins
PTH
Bone
resorption
Strontium Ranelate
- OOC
Sr
CN
CH 2
CH2
++
- O OC
S
COO-
N
Sr++
C H2
CO O -
Ranelic acid (organic moiety) + 2 stable strontium atoms
5-[bis (carboxymethyl) amino]-2-carboxy-4-cyano-3thiopheneacetic acid, distrontium salt
STRONTIUM RANELATE:
PRE CLINICAL STUDIES
IN VITRO EFFECTS ON BONE TURNOVER
STRONTIUM RANELATE:
PRE CLINICAL STUDIES
IN VIVO EFFECTS ON BONE TURNOVER
STRONTIUM RANELATE:
HUMAN STUDIES
Strontium Ranelate Decreases
Osteoclast Differentiation
Mouse spleen-derived cells (+RANKL & M-CSF)
Adapted from Bonnelye et al. Bone 2008;42:129-38.
Strontium Ranelate Decreases
Osteoclast Lifespan (induces apoptosis)
OC lifespan
% of living cells
100
90
mean + SEM; n=6-12
* P<0.05, **P<0.01, *** P<0.001 vs. Control
*
**
80
***
70
Control
6
9
12
SR (mM Sr2+)
Adapted from Mentaverri et al. Bone 2005;36(S2):S403.
24
Strontium Ranelate Inhibits Bone Resorption in vitro
Pit Area Index(% of control)
Rat osteoclasts
Sr2+
Adapted from Baron et al. Eur J Pharmacol. 2002;450:11-17.
(mM)
Strontium Ranelate Increases Osteoprotegerin While
Decreasing RANKL in Primary Human Osteoblasts
Osteoprotegerin
RANKL
RANKL mRNA
as % of control
OPG mRNA
as % of
control
***
***
**
***
Control 0.01
0.1
1
2
Sr (mM Sr2+)
Adapted from Brennan et al. J Bone Min Res 2006;21(S1):S301.
Control 0.01
**
***
***
0.1
1
SR (mM Sr2+)
Mean +/- sem
** P<0.01, *** P<0.001 vs. Control
2
SR Actions in Bone
Ca
OCL
OB
↓Resorption
Bone
↑Formation
Strontium Ranelate Induces Apoptosis in Rabbit Primary
Osteoclasts and this is Decreased with DN-CaSR Transfection
% of Apoptotic Cells
**
60
**
*
50
*
40
*
30
20
10
0
Control10
15
20
25 Control10
Plasmid control
Adapted from Mentaverri et al. Bone 2005;36(S2):S403.
15
20
25
Dominant Negative CaSR
Mean + SEM, n = 6-10
* P<0.05, ** P<0.01
SR (mM Sr2+)
Strontium Ranelate: Anti-resorptive Effects
Mentaverri Bone 2005
Sr++ = CaR agonist
Sr++ = 
Differentiation
Wattel Osteoporos Int. 2005
Sr++ = 
Apoptosis
Sr++ =
 Activity
Mentaverri Calc Tissue Int. 2004
Bonnelye Bone 2008
Osteoclasts
Osteocytes
Macrophages
-
+
 OPG
 RANKL
Brennan ASBMR 2006
Chattopadhyay Biochem pharmaco 2007
Sr++
Osteoblasts
Bone-lining cells
SR Increases Replication of Pre-osteoblasts
Rat Calvariae Cells
3H-Thymidine
labeled cells (%)
Pre-osteoblasts
6
Osteoblasts
Tissue Culture
*
4
2
0
Controls
10-5
10-3
Strontium ranelate (M)
* P < 0.05 vs Control
Control
Adapted from Canalis E, Hott M, Deloffre P, Marie PJ. Bone. 1996;18(6):517-23.
(10 M-3, 48 h)
Strontium Ranelate Increases Osteoblast Survival
Primary Human Osteoblasts
Cell number as a ratio of control
**
Control 0.01
*
**
0.1
1
2
SR (mM Sr2+)
* P<0.05, ** P<0.01 vs. Control
Adapted from Brennan et al. Calcified Tissue Int. 2007;80(S1):P132T.
Strontium Ranelate Increases Bone Formation
Markers in Primary Human Osteoblasts
Alkaline phosphatase activity
ALP activity as % of vehicle
(corrected per mg total protein)
**
**
Control 0.01 0.1
1
2
SR (mM Sr2+)
** P<0.01 vs. Control
Adapted from Brennan et al. Calcified Tissue Int. 2007;80(S1):P132T.
Strontium Ranelate Increases Collagen Synthesis
by Preosteoblasts and Osteoblasts
Rat Calvariae Cells
Collagen Synthesis (10-3 dpm/well)
30
25
Tissue Culture
*
Pre-osteoblasts
Osteoblasts
Control
20
15
*
10
*
10-3 M, 48 h
5
Bone
0
Controls
10-5
10-4
10-3
Strontium ranelate (M)
* P<0.05 vs Controls
Adapted from Canalis E, Hott M, Deloffre P, Marie PJ. Bone. 1996;18(6):517-23.
Strontium Ranelate Increases Mineralization and
Number of Nodules in Murine Osteoblasts
Number of nodules
Mineralization
***
***
Vehicle
***
SR 1 mM
SR 3 mM
Control 0.1
0.3
1
SR (mM Sr2+)
mean ± SD, n=3, *** P<0.001
Adapted from Bonnelye et al.
J Bone Miner Res 2006;21(S1):S426.
Adapted from Choudhary S et al.
J Bone Miner Res. 2007 Jul;22(7):1002-10.
SR Actions in Bone
Ca
OCL
OB
↓Resorption
Bone
↑Formation
SR-induced Proliferation is Decreased in
DN-CASR Transfected Rat Primary Osteoblasts
Adapted from Chattopadhyay et al. Biochem pharmacol 2007;74:438-47.
Mean + SEM, n=6
*** P<0.001 vs Control
CaSR is Not the Only Receptor Involved in
Strontium Ranelate-induced Osteoblast Replication
Strontium ranelate
CaSR+/+
osteoblasts
CaSR
?
REPLICATION
Strontium ranelate
CaSR-/osteoblasts
CaSR
?
REPLICATION
• CaSR is not essential for strontium ranelate-induced osteoblast replication.
• Strontium ranelate may induce osteoblast replication through another receptor
in addition to CaSR.
Strontium Ranelate Bone Formation Effects
Sr++ = CaR agonist
Sr++ =  COX-2
Chattopadhyay Biochem pharmacol 2007
Choudhary JBMR 2007
 PGE2
 Proliferation /  Differentiation
Osteocyte
 Activity
Osteoclast
Bonnelye Bone 2008
Macrophage
Osteoblast
Bone-lining cell
SR
CaSR
OPG
Pre-osteoblast
RANKL
RANK
Differentiation 
Replication 
Activity 
Osteoblasts
SR
Osteoclasts
Osteoblastic
Differentiation 
Apoptosis 
Matrix
Synthesis 
Bone
Bone
Formation
Adapted from Marie P. Curr Op Rheum 2006.
Strontium ranelate: a dual mode of action rebalancing bone turnover in favour of bone formation.
Resorption
STRONTIUM RANELATE:
PRE CLINICAL STUDIES
IN VITRO EFFECTS ON BONE TURNOVER
STRONTIUM RANELATE:
PRE CLINICAL STUDIES
IN VIVO EFFECTS ON BONE TURNOVER
STRONTIUM RANELATE:
HUMAN STUDIES
Proximal Tibia Histomorphometry
Treatment of Female Rats for 2 years
Control
BV/TV (%)
Tb.Th (µm)
Tb.N
Tb.Sp (µm)
Strontium ranelate 900 mg/kg/d
27 ± 2
74 ± 5
3.5 ± 0.1
216 ± 13
Adapted from Ammann et al. JBMR 2004.19:2012-20.
38 ± 2 ***
84 ± 5 **
4.6 ± 0.1***
135 ± 5 ***
SR Increases Strength of Vertebrae and Long
Bones of Intact Rats (2 years of treatment)
Compression test
Maximal Load (N)
400
3-point bending test
Maximal Load (N)
Strontium ranelate (mg/kg/d)
+ 20 %
*
200
+ 15 %
300
*
150
200
100
100
0
0
900
50
Strontium ranelate
(mg/kg/d)
L4 Vertebra
Adapted from Ammann P. et al. JBMR 2004.19:2012-20.
0
0
225
450
Mid-Shaft Femur
900
Distribution of Strontium (SR), in Monkey ILIAC Cancellous
Bone Visualized by Secondary Electron Imaging (SEI)
After treatment with SR(1250 mg/kg/day)
for 52 weeks (A) and after 10 weeks of treatment withdrawal (B)
A
More Sr deposited
in new bone
than old bone
B
Sr
Adapted from Farlay D et al. J of Bone Miner Res. 2005;20(9):1569-78.
Sr
More Sr released
from new bone
than old bone
Strontium Ranelate Preserves
the Degree of Mineralization of Bone
Monkeys, 1-year treatment
% of the Number of Measurements
Micro radiography - Iliac crest
0 mg/kg/d
200 mg/kg/d
500 mg/kg/d
1250 mg/kg/d
Old
Young
Degree of Mineralization of Bone (g/cm3)
Adapted from Farlay D et al. J of Bone Miner Res. 2005;20(9):1569-78.
Femoral BMD in Strontium Ranelate-treated
Female Rats Correlated with Bone Strength
Adult female rats - 2-year treatment
Ultimate Strength (N)
Correlation BMD-Strength R=0.739
BMD (g/cm2)
Mean ± SEM, n=28-30, * P<0.05 vs. Control
Adapted from Ammann P et al. Bone 2001;28(suppl 5) P537S.
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
STRONTIUM RANELATE:
PRE CLINICAL STUDIES
IN VITRO EFFECTS ON BONE TURNOVER
STRONTIUM RANELATE:
PRE CLINICAL STUDIES
IN VIVO EFFECTS ON BONE TURNOVER
STRONTIUM RANELATE:
HUMAN STUDIES
Strontium Ranelate Simultaneously Increases Bone
Formation Markers and Decreases Bone Resorption Markers
Increased b-ALP and decreased s-CTX
E
SOTI
study
1.2
0.8
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
***
***
*
**
*
bALP (ng/mL)
0.4
0
S-CTX(
pmol/L)
- 300
- 600
*** ***
M0 M3 M6
***
*
**
Months
M12
M24
M36
b-ALP: bone-specific alkaline phosphatase
S-CTX: serum C-telopeptide cross-links
Adapted from Meunier PJ et al., NEJM 2004 ;350;5:459-68.
3D Trabecular and Cortical Microstructure (3 Years of
Treatment in Post Menopausal Osteoporotic Patients)
Bone volume/ Tissue volume
+13%
BV/TV (%) 30
Tb.N p 2.0
(n/mm)
Trabecular Number
+14% P=0.05
25
1.5
20
15
1.0
10
0.5
5
0
Placebo
Placebo 36 Mo
Cortical thickness
Ct.Th
(µm)
0.0
Strontium ranelate
-16% P=0.041
1250
**
1250
Strontium ranelate
Trabecular separation
Tb.Sp p 1500
(µm)
+18%, P=0.008
1500
Placebo
*
1000
1000
750
750
500
500
250
250
0
0
Placebo
Strontium ranelate
SR 36 Mo
Placebo
Strontium ranelate
placebo n=21, strontium ranelate n=20
Adapted from Arlot ME et al. JBMR 2008;23:215-22.
Strontium Ranelate Induces
New Bone Formation in Humans
Protocol :
10 women treated by bisphosphonates for 32 months followed by strontium
ranelate for 12 months
Mean Age 65 years
Paired iliac crest biopsies performed at M0 and M12
Histomorphometric analysis
M0
BP (32
months)
Biopsy
Adapted from Busse et al., 2007 Abstract ASBMR-W477.
M12
Strontium
Ranelate
Biopsy
Strontium Ranelate Improves
Trabecular Bone Micro-architecture
Trabecular Bone Volume
% 12
+30%*
10
11,12
8
8,53
*P 0,05
6
4
2
0
Inclusion
Trabecular Thickness
Tb Th : +10%* (P<0.05)
Adapted from Busse et al., 2007 Abstract ASBMR-W477.
after 12 months of
Strontium ranelate
treatment
Trabecular Interconnection
Tb Pf : -49%* (P<0.05)
Comparative action of strontium ranelate
and other agents on bone metabolism
Bone
formation
Bisphosphonates
SERMs
Calcitonin
Teriparatide
Strontium ranelate
Bone
resorption
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
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
Osteoporosis: Three Millennia
1000 BC
0
400 BC
Hippocrates
of Kos
1940
1948
Albright
Adapted from Cooper et al. (2003).
1000 AD
700 AD
Saxon
tomb, Wells
1950
1960
1963
SPA
2000 AD
1825 AD
Sir Astley
Cooper
1970
1980
1976
HRT
1987
DXA
1850 AD
Osteoporosis
1990 2000
1990–07 WHO
Calcium/D,
Bisphosphonates
SERMs, PTH, Sr,
RANKL Ab
Impact of Osteoporosis-related
Fractures in Europe
Hip
Spine
Wrist
14
3
29
14
13
2
400,000
810,000
330,000
Hospitalisation (%)
100
2-10
5
Relative survival
0.83
0.82
1.00
Lifetime risk (%)
Women
Men
Cases/yr
Costs: All sites combined ~ 25 billion Euros
Adapted from IOF (2005); Harvey & Cooper (2005).
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
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
• 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.
Fracture Risk Reduction with
Bisphosphonates in High Risk Patients
Risk Relative to Placebo
Vertebral
Adapted from MacLean C et al. Ann Intern Med 2008;148(3):197-213.
Hip
Fracture Risk Reduction with
Bisphosphonates in Non-high Risk Patients
Vertebral
Risk Relative to Placebo
Adapted from MacLean C, et al. Ann Intern Med 2008;148(3):197-213.
Hip
European Guidance for Diagnosis and Management
of Osteoporosis in Postmenopausal Women
Antifracture efficacy of the most frequently used treatments for
postmenopausal osteoporosis given with calcium and vitamin D
Adapted from Kanis JA, et al. Osteoporos Int 2008;19:399-428.
Antifracture Efficacy Program of Strontium
Ranelate in Postmenopausal Osteoporosis
Main
statistical
analysis
M0
M12
M24
M36
M48
M60
(months)
strontium ranelate
2g/day
SOTI
(Vertebral fractures)
N=1649
placebo
FIRST (Run-in)
(2 weeks-6 months)
M0
M12
M24
TROPOS
(Peripheral fractures)
N=5091
Calcium and Vitamin D supplements throughout the studies.
M36
M48
M60
(months)
strontium ranelate
2g/day
placebo
Efficacy of Strontium Ranelate in
Reducing Fracture Risk over 5 Years
n=2714
Patients 30
(%)
All nonvertebral
fracture risk
Vertebral
fracture risk
 RR: -15%
 RR: -24%
p=0.032
p<0.001
n=2183
24.9%
20
TROPOS
20.9%
20.8%
strontium
ranelate
16.8%
10
0
Placebo
0-5 years
0-5 years
RR=0.85; 95% CI [0.73; 0.99]
0.76; 95% CI [0.65; 0.88]
Adapted from Reginster JY et al. Arthritis Rheum 2008;58(6):1687-95.
Efficacy of Strontium Ranelate in
Reducing Fracture Risk over 5 Years
Hip fracture risk
Patients (%) 10
10.2%
n=1128
 RR: -43%
p=0.036
TROPOS
7.2%
5
Placebo
strontium ranelate
Patients aged over 74
and 2 T-scores ≤-2.4
0
0 - 5 years
RR: 0.57; 95%CI: [0.33;0.97] adjusted cox model
Adapted from Reginster JY, et al. Arthritis Rheum 2008;58(6):1687-95.
Tolerability Profile of Strontium Ranelate
over 5 Years
Phase III program
Adverse events
Symptoms
SR
placebo
(% patients)
n=3352
n=3317
Nausea
7.1
4.6
Diarrhoea
7.0
5.0
Headache
3.3
2.7
Dermatitis
2.3
2.0
Eczema
1.8
1.4
VTE
4.5
3.0
Post Marketing experience:
16 cases of DRESS among 570 000 patients treated per year .
No Increase in Incidence of VTE for Strontium Ranelate and
Alendronate as Compared to Osteoporotic Population
(GPRD)
Strontium ranelate
Alendronate
(N=2408)
(N=20084)
7.0*
7.2*
versus untreated osteoporotic population
RR**=1.09 [0.60-2.01]
RR**=0.92 [0.63-1.33]
p=0.773
p=0.646
* Annual incidence for 1000 patient year
** relative risk adjusted on age and main risk factors for VTE
Efficacy of Strontium Ranelate in Reducing
Vertebral Fracture Risk According to the
Number of Prevalent Vertebral Fracture(s)
Patients 45
(%)
 RR: -48%
 RR: -45%
 RR: -33%
P<0.001
40.3%
P<0.001
30
SOTI &
TROPOS
29.8%
P<0.001
25.2%
15
14.5%
14.4%
7.5%
0
0
1
>2
n=2605
n=1110
n=1365
RR=0.52; CI [0.40-0.67]
0.55; CI [0.41-0.74]
Placebo
Adapted from Roux C et al. J Bone Miner Res. 2006;21(4):536-42.
No. Prev.
Vert Fracture(s)
0.67; CI [0.55-0.81] Over 3 years
strontium ranelate
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.
Reduction in Vertebral Fracture Risk with Strontium
Ranelate According to the Level of Pretreatment Bone
Turnover Markers
Patients 30
(%)
SOTI &
TROPOS
RR  37%
RR  32%
RR  47%
Over 3 years
25
Placebo
20
strontium
ranelate 2g/d



15
10
5
0
T1
RR= 0.63CI (0.49 ; 081)
*** P<0.001
n=1631
T2
T3
0.68CI (0.54 ; 0.85)
*** P<0.001
n=1630
0.53CI (0.42 ; 0.67)
*** P<0.001
n=1630
s-CTX
Nonvertebral and Vertebral Fracture in the Elderly
Population (> 80 years old)
SOTI
TROPOS
(Spinal Osteoporosis
Therapeutic Intervention)
(Treatment of Peripheral
Osteoporosis)
N = 1649
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
N = 1489 (ITT)
Vertebral fracture assessment
N = 896
Adapted from Seeman et al. J Bone Miner Res 2006;21:1113–20.
Nonvertebral fracture assessment
N = 1489
Baseline Characteristics
of the Elderly Population ( 80 years old)
Strontium ranelate
Placebo
Characteristics
N = 739
N = 750
Age (years)
83.5 (3.0)
83.5 (2.9)
Time since menopause (years)
35.3 (6.1)
35.4 (6.4)
Lumbar BMD T-score
-2.7 (1.7)
-2.8 (1.7)
Femoral neck BMD T-score
-3.3 (0.7)
-3.3 (0.7)
Proportion (%) of patients with at least
one prevalent vertebral fracture
46.4 %
51.4 %
Proportion (%) of patients with at least
one previous nonvertebral fracture
37.1 %
35.1 %
Adapted from Seeman et al. J Bone Miner Res 2006;21:1113–20.
Reduction of Vertebral Fracture Risk with Strontium Ranelate
in Elderly Patients (80 years old) Over 3 Years
 RR: - 32%
N = 895
P = 0.013
NNT = 14
RR= 0.68; 95% CI [0.50; 0.92]
Adapted from Seeman et al. J Bone Miner Res 2006;21:1113–20.
Reduction of Nonvertebral Fracture Risk with
Strontium Ranelate in Elderly Patients
(80 Years Old) over 3 Years
 RR: - 31%
N = 1488
P = 0.011
NNT = 18
RR= 0.69; 95% CI [0.52; 0.92]
Adapted from Seeman et al J Bone Miner Res 2006;21:1113–20.
Extension Study After SOTI and TROPOS
Efficacy assessed by comparison of 0-3
years and 5-8 years cumulative incidence
SOTI
Strontium
ranelate 2g/day
Baseline
0
1
2
3
4
5
6
7
8
TROPOS
Strontium
ranelate 2g/day
Extension study
Strontium ranelate 2g/day
2055 included patients
whatever previous
occurrence of fracture
Data on file
1420 completers (69%)
Baseline Characteristics in Patients Treated for 8
Years with Strontium Ranelate (n=879)
INCL-M060
From
SOTI
n=153
From
TROPOS
n=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
Relative Change in BMD Over 8 Years
Lumbar BMD
Mean relative change (%)
*
*
*
*
*
*
*
*
years
Mean relative change (%)
*
Femoral neck BMD
*
*
*
*
*
*
years
Data on file
* P <0.001
Vertebral Fracture Incidence Over 8 Years
(SOTI+TROPOS)
Cumulative incidence 0-3 years
14.9%
Fractures incidence (%)
Data on file
Cumulative incidence 5-8 years *
13.7%
Fractures incidence (%)
* First new fractures on the period
Non Vertebral Fracture Incidence Over 8 Years
(TROPOS)
Cumulative incidence 0-3 years
11.2%
Fractures incidence (%)
Data on file
Cumulative incidence 5-8 years *
12%
Fractures incidence (%)
* First new fractures on the period
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%
 RR: - 42%
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.
Strontium Ranelate Reduces the Back Pain in
Patients with Spine OA
Patients with an improvement in back
pain after 3 years (%)
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)
45
40
35
41.8%
30
31.3%
25
20
15
P=0.03
10
5
0
Strontium ranelate
Adapted from Bruyère et al. Ann Rheum Dis 2008; 67:335-39.
Placebo
European Guidance for Diagnosis and Management of
Osteoporosis in Postmenopausal Women
Antifracture efficacy of the most frequently used treatments for
postmenopausal osteoporosis given with calcium and vitamin D
Adapted from Kanis JA et al. Osteoporos Int 2008;19:399-428.
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
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
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
% Reduction in VFx Risk
Relationship Between Vertebral Fracture &
Increases in BMD
Prevalent
Vertebral Fx
80
Calcitonin1
Raloxifene2
Raloxifene2
Risedronate3
Risedronate4
Alendronate5
Alendronate6
60
40
20
00
1
2
3
4
5
6
Yes
Yes
No
Yes
Yes
Yes
No
7
% Increase in BMD
*Not head-to-head comparison; †vs. placebo. Error bars represent 95% confidence intervals.
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.
BMD Change and Fracture Risk
%with New Vertebral Fractures
at 36-48 months
2,984 Women, Age 55-81, in FIT with Alendronate
Placebo Vertebral Fractures = 6.9%
“Losers”
“Stable”
“Gainers”
12-Month BMD Change in Treated Patients
Adapted from Hochberg MC et al. Arthritis Rheum 1999:42:1246-54.
Vertebral Fracture Studies 3-Year Data
Study
Increase 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.
Bone Density Response to
Strontium Ranelate Therapy
• Effects of higher atomic number of Sr than Ca
• Effects of increases in bone tissue
Strontium Ranelate Increases Lumbar Spine BMD
Relative change from baseline
SOTI
TROPOS
16
16
*
12
*
*
*
*
8
+14.4%
*
4
4
0
0
-4
-4
0
6
12
18
24
*
*
12
*
8
*
30
36 Months 0
Strontium ranelate 2 g/day
*
+14.7%
*
6
12
Placebo
* P<0.001, hierarchical step-down procedure
Adapted from: Meunier PJ et al. N Engl J Med 2004;350:459-68.
Reginster J.Y et al. data on file.
18
24
30
36
Femur Mid-shaft BMD in Ovx Rats After 52 Weeks
of Strontium Ranelate Preventive Treatment
Max Load Vs. Measured BMD
Adapted from Amman P et al. JBMR 2004;19:2012–20.
Max Load Vs. Adj BMD
Raloxifene Logistic Regression Curves
More Trial Post HOC Analysis
Adapted from Sarkar S et al. JBMR 2002;117:1-10.
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.
Percent of Fracture Risk Reduction Explained by
Change in BMD
•
•
•
•
FIT (ALN)
MORE (RLX)
VERT (RIS)
SOTI TROPOS (SR)
16%
4%
28%
75%
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.
Monitoring Strontium Ranelate Therapy with
Bone Turnover Markers
Adapted from Meunier P et al. N Engl J Med 2004;350:459-68.
Resolution of Effect After Discontinuing Therapy
• Preclinical models
• Clinical trials
Bone Strontium in Monkeys 52 Wks on SR
Then 10 Wks Off
New Bone
Old Bone
Adapted from Farlay et al. JBMR 20:9 2005.
Change in Spine BMD After Cross-over: SOTI
ITT population
-3.4%
Mean+SEM
SWITCH
Change in Femoral Neck BMD After Cross-over: SOTI
Mean+SEM
SWITCH
SOTI: Change in Blood Strontium After Cross-over
Mean SD
µmoL/L
M48
Data on file
M51
M54
M60
Change in Bone Markers After Cross-over: SOTI
b-ALP
S-CTX
N=210
Mean+SEM
PLACEBO
N=210
PLACEBO
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.
DOES MONITORING IMPROVE
ADHERENCE TO OSTEOPOROSIS
THERAPIES?
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