1. ARE ALL POSTMENOPAUSAL OSTEOPOROSIS PATIENTS THE SAME? ASBMR 2008 Friday, September 12 th, 2008

2. 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.

3. 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

4. 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

5. 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.)

6. Determinants of Fracture Risk

7. Bone Remodelling Cycle Quiescence Lining cells Osteoclastic Activation Osteoblast activation Osteoblastic New Bone Formation Initiation Osteoclastic Bone Resorption

8. Bone Remodelling OB OCL ResorptionFormation Anti-Resorptives Bone Anabolics HCl Proteases

9. Relative Risk of New Vertebral Fractures Adapted from Delmas et al., Lancet 2002, 359:2018–26.

10. ANTI-RESORPTIVES

11. Anti-resorptives Inhibit Resorption and Allow Filling of Cavity OB OCL ResorptionFormation Anti-Resorptives Bone HCl Proteases Local and systemic regulators of bone formation InhibitedContinues

12. Anti-resorptives Also Reduce Bone Formation OB OCL ResorptionFormation Anti-Resorptives Bone HCl Proteases Local and systemic regulators of bone formation Ephrin/Eph IGFs, IGFBPs TGF-β,BMPs, FGFs

13. 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)

14. 0 36 12 -60 -50 -40 -30 -20 -10 0 NTX BSAP Time(Months) Mean Change(%) Temporal Difference in Reduction of Resorption and Formation Markers

15. Mean Percentage Changes in BMD from Baseline Adapted from Bonnick et al. J Clin Endocrinol Metab 2006;91:2631-37.

16. Bisphosphonates SERMs Calcitonin Bone resorption Bone formation

17. Mechanism of Osteoporotic Fracture Reduction by Anti-resorptives (Filling plus hypermineralization) Antiresorptive Therapy Reduce Bone Turnover Decrease Fracture Risk Stabilize or Improve Microarchitecture Increase BMD

18. What Anti-resorptives Will Not Do Normalize BMD Restore trabecular architecture

19. ANABOLICS

20. Parathyroid Hormone 1 10 20 30 SerValSer Glu IleGlnLeuMetHis Asn Leu Gly Lys His Leu Asn Ser Met GluArg Val Glu Trp Leu ArgLys LeuGlnAsp Val His Asn Phe 50 40 60 70 80 - COOH H 2 N-

21. Osteoblast BONE Osteoclast Anabolics Initiate New Bone Formation Osteoblastic stromal cell New Bone PTH

22. Osteoblast Osteoclast Progenitor BONE PTH RankL OPG Osteoclast Osteoblastic stromal cell Resorption is Also Stimulated by PTH

23. n n n n n n n n 0123456 0 10 20 30 40 50 60 70 80 Mean % change in turnover marker 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 Anabolic Window

24. Effect of PTH(1-34) on Lumbar Spine BMD in Postmenopausal Women with Osteoporosis *P<0.001 Months % change ± SE 0 2 4 6 8 10 12 14 16 0612243 * * * * * * End 18 * * Placebo PTH(1-34), 20PTH(1-34), 40 * Adapted from Neer RM et al. N Engl J Med 2001. *

25. Bisphosphonates SERMs Calcitonins PTH Bone resorption Bone formation

26. Strontium Ranelate Sr ++ SN CN Sr ++ CH 2 H 2 C CO - O O OC - O - O H 2 C - 5-[bis (carboxymethyl) amino]-2-carboxy-4-cyano-3- thiopheneacetic acid, distrontium salt Ranelic acid (organic moiety) + 2 stable strontium atoms

27. 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

28. Strontium Ranelate Decreases Osteoclast Differentiation Adapted from Bonnelye et al. Bone 2008;42:129-38. Mouse spleen-derived cells (+RANKL & M-CSF)

29. Strontium Ranelate Decreases Osteoclast Lifespan (induces apoptosis) OC lifespan 70 80 90 100 Control 691224 SR (mM Sr 2+ ) * ** *** % 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.

30. Strontium Ranelate Inhibits Bone Resorption in vitro Adapted from Baron et al. Eur J Pharmacol. 2002;450:11-17. Sr 2+ Pit Area Index(% of control) (mM) Rat osteoclasts

31. Strontium Ranelate Increases Osteoprotegerin While Decreasing RANKL in Primary Human Osteoblasts Mean +/- sem ** P<0.01, *** P<0.001 vs. Control 1Control0.010.1 *** ** Sr (mM Sr 2+ ) OPG mRNA as % of control 2 *** RANKL mRNA as % of control ** *** 1Control0.01 0.1 SR (mM Sr 2+ ) 2 RANKLOsteoprotegerin Adapted from Brennan et al. J Bone Min Res 2006;21(S1):S301.

32. SR Actions in Bone Bone Ca OB OCL ↓Resorption ↑Formation

33. Mean + SEM, n = 6-10 * P<0.05, ** P<0.01 Adapted from Mentaverri et al. Bone 2005;36(S2):S403. * * 0 10 20 30 40 50 60 Control10152025 % of Apoptotic Cells Control10152025 Plasmid control Dominant Negative CaSR * ** SR (mM Sr 2+ ) Strontium Ranelate Induces Apoptosis in Rabbit Primary Osteoclasts and this is Decreased with DN-CaSR Transfection

34. Strontium Ranelate: Anti-resorptive Effects Osteocytes Osteoclasts Macrophages Osteoblasts Bone-lining cells +  OPG  RANKL - Brennan ASBMR 2006 Chattopadhyay Biochem pharmaco 2007 Sr ++ =  Differentiation Wattel Osteoporos Int. 2005 Bonnelye Bone 2008 Sr ++ =  Activity Sr ++ =  Apoptosis Sr ++ = CaR agonist Mentaverri Calc Tissue Int. 2004 Mentaverri Bone 2005 Sr ++

35. 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 3 H-Thymidine labeled cells (%) * 6 4 2 0 Osteoblasts Pre-osteoblasts 10 -5 10 -3 Controls ) Strontium ranelate (M) * P < 0.05 vs Control

36. Strontium Ranelate Increases Osteoblast Survival SR (mM Sr 2+ ) 1Control0.010.12 ** * Cell number as a ratio of control * P<0.05, ** P<0.01 vs. Control Adapted from Brennan et al. Calcified Tissue Int. 2007;80(S1):P132T. Primary Human Osteoblasts

37. Strontium Ranelate Increases Bone Formation Markers in Primary Human Osteoblasts ** P<0.01 vs. Control Alkaline phosphatase activity SR (mM Sr 2+ ) 1Control0.010.12 ** ALP activity as % of vehicle (corrected per mg total protein) ** Adapted from Brennan et al. Calcified Tissue Int. 2007;80(S1):P132T.

38. 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. Control Bone 10 -3 M, 48 h Tissue Culture * * * Controls 10 -4 10 -3 10 -5 25 15 10 0 30 20 5 Osteoblasts Pre-osteoblasts Collagen Synthesis (10 -3 dpm/well) * P<0.05 vs Controls Strontium ranelate (M) Rat Calvariae Cells

39. 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. Mineralization Number of nodules Control 0.11 SR (mM Sr 2+ ) 0.3 *** mean ± SD, n=3, *** P<0.001 Vehicle SR 1 mM SR 3 mM Adapted from Bonnelye et al. J Bone Miner Res 2006;21(S1):S426.

40. SR Actions in Bone Bone Ca OB OCL ↓Resorption↑Formation

41. Mean + SEM, n=6 *** P<0.001 vs Control Adapted from Adapted from Chattopadhyay et al. Biochem pharmacol 2007;74:438-47. SR-induced Proliferation is Decreased in DN-CASR Transfected Rat Primary Osteoblasts

42. Strontium ranelate CaSR -/- osteoblasts REPLICATION ? CaSR CaSR is not essential for strontium ranelate-induced osteoblast replication. Strontium ranelate may induce osteoblast replication through another receptor in addition to CaSR. CaSR is Not the Only Receptor Involved in Strontium Ranelate-induced Osteoblast Replication Strontium ranelate CaSR +/+ osteoblasts REPLICATION ? CaSR

43. Strontium Ranelate Bone Formation Effects Osteocyte Osteoclast Macrophage Osteoblast Bone-lining cell Sr ++ =  COX-2  PGE 2 Choudhary JBMR 2007  Proliferation /  Differentiation Sr ++ = CaR agonist Chattopadhyay Biochem pharmacol 2007 Bonnelye Bone 2008  Activity

44. 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 Bone Formation Bone Resorption SR

45. 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

46. Proximal Tibia Histomorphometry ControlStrontium 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

47. Compression test Maximal Load (N) 0 100 200 300 400 Strontium ranelate (mg/kg/d) 0 900 * + 20 % 3-point bending test Maximal Load (N) SR Increases Strength of Vertebrae and Long Bones of Intact Rats (2 years of treatment) 200 Strontium ranelate (mg/kg/d) 0 50 100 150 0225450 * 900 + 15 % Mid-Shaft Femur L4 Vertebra Adapted from Ammann P. et al. JBMR 2004.19:2012-20.

48. Distribution of Strontium (SR), in Monkey ILIAC Cancellous Bone Visualized by Secondary Electron Imaging (SEI) Sr After treatment with SR(1250 mg/kg/day) for 52 weeks (A) and after 10 weeks of treatment withdrawal (B) More Sr deposited in new bone than old bone More Sr released from new bone than old bone AB Adapted from Farlay D et al. J of Bone Miner Res. 2005;20(9):1569-78.

49. Strontium Ranelate Preserves the Degree of Mineralization of Bone % of the Number of Measurements 0 mg/kg/d 200 mg/kg/d 500 mg/kg/d 1250 mg/kg/d Degree of Mineralization of Bone (g/cm 3 ) 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.

50. 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/cm 2 ) Ultimate Strength (N) R=0.739

51. 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

52. 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

53. 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 Adapted from Meunier PJ et al., NEJM 2004 ;350;5:459-68. b-ALP: bone-specific alkaline phosphatase S-CTX: serum C-telopeptide cross-links

54. 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. Trabecular Number +14% P=0.05 Trabecular separation -16% P=0.041 Cortical thickness +18%, P=0.008 ** * Placebo 36 Mo SR 36 Mo

55. Biopsy 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 M0M12 PAIRED BIOPSIES Adapted from Busse et al., 2007 Abstract ASBMR-W477. BP (32 months) Strontium Ranelate Strontium Ranelate Induces New Bone Formation in Humans

56. Strontium Ranelate Improves Trabecular Bone Micro-architecture Adapted from Busse et al., 2007 Abstract ASBMR-W477. 0 2 4 6 8 10 12 Inclusionafter 12 months of Strontium ranelate treatment 11,12 8,53 %+30% * *P  0,05 Trabecular Thickness Tb Th : +10%* (P<0.05) Trabecular Interconnection Tb Pf : -49%* (P<0.05) Trabecular Bone Volume

57. Comparative action of strontium ranelate and other agents on bone metabolism Bisphosphonates SERMs Calcitonin Strontium ranelate Teriparatide Bone resorption Bone formation

58. 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

59. 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

60. Osteoporosis: Three Millennia 01000 AD2000 AD1000 BC 400 BC Hippocrates of Kos 700 AD Saxon tomb, Wells 1825 AD Sir Astley Cooper 1850 AD Osteoporosis 19502000199019801970 1948 Albright 1963 SPA 1976 HRT 1987 DXA 1990–07 WHO Calcium/D, Bisphosphonates SERMs, PTH, Sr, RANKL Ab 19401960 Adapted from Cooper et al. (2003).

61. Impact of Osteoporosis-related Fractures in Europe HipSpineWrist Lifetime risk (%) Women142913 Men3142 Cases/yr400,000810,000330,000 Hospitalisation (%)1002-105 Relative survival0.830.821.00 Costs: All sites combined ~ 25 billion Euros Adapted from IOF (2005); Harvey & Cooper (2005).

62. 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

63. 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

64. 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.

65. 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

66. 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.

67. 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

68. Calcium and Vitamin D supplements throughout the studies. placebo strontium ranelate 2g/day M0M12M36M24M48M60 (months) M0M12M36M24M48M60 (months) placebo Main statistical analysis SOTI (Vertebral fractures) N=1649 TROPOS (Peripheral fractures) N=5091 FIRST (Run-in) (2 weeks-6 months) strontium ranelate 2g/day Antifracture Efficacy Program of Strontium Ranelate in Postmenopausal Osteoporosis

69. Efficacy of Strontium Ranelate in Reducing Fracture Risk over 5 Years Adapted from Reginster JY et al. Arthritis Rheum 2008;58(6):1687-95. 20.9% 16.8% Vertebral fracture risk p=0.032p<0.001 30 0 10 20  RR: -15% All nonvertebral fracture risk 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

70. 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 in Reducing Fracture Risk over 5 Years TROPOS Adapted from Reginster JY, et al. Arthritis Rheum 2008;58(6):1687-95. Hip fracture risk

71. 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) placebo n=3317 SR n=3352 Dermatitis 2.32.0 Eczema 1.81.4 VTE 4.53.0 Headache 3.32.7 Diarrhoea 7.05.0 Nausea 7.14.6

72. 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)

73. 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] 0 n=2605 1 0.55; CI [0.41-0.74] n=1110 0.67; CI [0.55-0.81] >2>2 n=1365 No. Prev. Vert Fracture(s) 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

74. 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.

75. Reduction in Vertebral Fracture Risk with Strontium Ranelate According to the Level of Pretreatment Bone Turnover Markers T1T2T3 0.63CI (0.49 ; 081) *** P<0.001 n=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  

76. 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 assessment N = 896 Nonvertebral fracture assessment N = 1489 N = 1489 (ITT) Adapted from Seeman et al. J Bone Miner Res 2006;21:1113–20.

77. 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) 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) Placebo Strontium ranelate Characteristics N = 739 N = 750 Adapted from Seeman et al. J Bone Miner Res 2006;21:1113–20.

78. 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

79. 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

80. Efficacy assessed by comparison of 0-3 years and 5-8 years cumulative incidence Extension Study After SOTI and TROPOS Data on file Baseline SOTI Strontium ranelate 2g/day TROPOS Strontium ranelate 2g/day Extension study Strontium ranelate 2g/day 2055 included patients whatever previous occurrence of fracture 045678123 1420 completers (69%)

81. 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/m 2 )26.98 (4.36)25.66 (4.42) Time since menopause (years) 25.4 (7.9)32.1 (6.7) Data on file

82. 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

83. 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 (%) * First new fractures on the period

84. 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 (%) * First new fractures on the period

85.  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.

86. 0 5 10 15 20 25 30 35 40 45 Strontium ranelatePlacebo Patients with an improvement in back pain after 3 years (%) 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%

87. 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

88. 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

89. 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

90. 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

91. Relationship Between Vertebral Fracture & Increases in BMD Adapted from: 1 Chesnut CH et al. Am J Med 2000;109:267-76; 2 Ettinger B et al. JAMA 1999;282:637-45; & data on file, Eli Lilly and Co; 3 Harris ST et al. JAMA 1999;282:1344-52; 4 Reginster J-Y et al. Osteoporosis Int 2000;11:83-91; 5 Black DM et al. Lancet 1996;348:1535-41; 6 Cummings SR et al. JAMA 1998;280:2077-82. *Not head-to-head comparison; † vs. placebo. Error bars represent 95% confidence intervals.

92. BMD Change and Fracture Risk 12-Month BMD Change in Treated Patients 2,984 Women, Age 55-81, in FIT with Alendronate %with New Vertebral Fractures at 36-48 months Adapted from Hochberg MC et al. Arthritis Rheum 1999:42:1246-54. Placebo Vertebral Fractures = 6.9% “Losers” “Stable” “Gainers”

93. Vertebral Fracture Studies 3-Year Data Study Increase in Spine BMD Reduction in Vertebral Fx Baseline Spine T-score Baseline Vertebral Fx TROPOS14.7%39%-2.855% FIT II8.3%44%-2.10% FIT I7.9%47%-2.5100% VERT-MN7.1%49%-2.8100% VERT-NA5.4%41%-2.4100% MORE2.6%40%-2.637% PROOF1.2%36%<-2.0100% Adapted from Faulkner KG et al. J Bone Miner Res 2000;15:183-87; Reginster JCEM 2005.

94. Bone Density Response to Strontium Ranelate Therapy Effects of higher atomic number of Sr than Ca Effects of increases in bone tissue

96. 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 061218243036 + 14.4 % SOTI * * * * * * Relative change from baseline - 4 0 4 8 12 16 061218243036 Mean change (%) * * * * * * + 14.7 % TROPOS * P<0.001, hierarchical step-down procedure Placebo Strontium ranelate 2 g/day Months

97. 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 BMDMax Load Vs. Adj BMD

98. Raloxifene Logistic Regression Curves More Trial Post HOC Analysis Adapted from Sarkar S et al. JBMR 2002;117:1-10.

99. 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.

100. Percent of Fracture Risk Reduction Explained by Change in BMD FIT (ALN)16% MORE (RLX) 4% VERT (RIS)28% SOTI TROPOS (SR)75%

101. 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.

102. Monitoring Strontium Ranelate Therapy with Bone Turnover Markers Adapted from Meunier P et al. N Engl J Med 2004;350:459-68.

103. Resolution of Effect After Discontinuing Therapy Preclinical models Clinical trials

104. 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

105. Change in Spine BMD After Cross-over: SOTI SWITCH ITT population Mean+SEM -3.4%

106. SWITCH Mean+SEM Change in Femoral Neck BMD After Cross-over: SOTI

107. M48M51M54M60 Mean SD µmoL/L SOTI: Change in Blood Strontium After Cross-over Data on file

108. Change in Bone Markers After Cross-over: SOTI PLACEBOPLACEBO Mean+SEM b-ALP S-CTX N=210 PLACEBOPLACEBO

109. 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.

110. DOES MONITORING IMPROVE ADHERENCE TO OSTEOPOROSIS THERAPIES?

111. 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