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ARE ALL POSTMENOPAUSAL OSTEOPOROSIS PATIENTS THE SAME?

ARE ALL POSTMENOPAUSAL OSTEOPOROSIS PATIENTS THE SAME?. ASBMR 2008 Friday, September 12 th , 2008. After attending this symposium, participants will be able to:

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ARE ALL POSTMENOPAUSAL OSTEOPOROSIS PATIENTS THE SAME?

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

  2. 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. Learning Objectives

  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 firstyear and over time • Reduction in hip fracture in high risk patients • Antifracture efficacy in elderly patients and in patientswith 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 Lining cells Initiation Osteoblastic New Bone Formation Quiescence Osteoclastic Activation Osteoclastic Bone Resorption Osteoblast activation

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

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

  10. ANTI-RESORPTIVES

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

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

  13. 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.

  14. Temporal Difference in Reduction of Resorption and Formation Markers 0 -10 -20 BSAP Mean Change(%) -30 -40 NTX -50 -60 0 3 6 12 Time(Months)

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

  16. Boneformation Boneresorption Bisphosphonates SERMs Calcitonin

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

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

  19. ANABOLICS

  20. 1 10 H2N- Ser Val Ser Ile Gln Leu Met His Glu Asn 20 Leu Gly Lys His Leu Ser Arg Glu Asn Glu Met Val Trp Leu Val Asn Leu Gln Asp His Phe Lys Arg Lys 30 40 50 60 70 80 COOH - ParathyroidHormone

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

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

  23. Early Changes in Biochemical Markers in Women with Osteoporosis onhPTH(1-34) 80 Osteocalcin 70 n n N-telopeptide 60 50 Anabolic Window 40 Mean % change in turnover marker 30 n n 20 n n 10 n=17 0 n n 0 1 2 3 4 5 6 Time (months) Adapted fromLindsay et al. Lancet 1997.

  24. Effect of PTH(1-34) on Lumbar Spine BMD in Postmenopausal Women with Osteoporosis 16 * * 14 * 12 * * 10 * * % change ±SE 8 *P<0.001 6 * * 4 * 2 0 0 3 6 12 18 24 Months End Placebo PTH(1-34), 20 PTH(1-34), 40 Adapted from Neer RM et al. N Engl J Med 2001.

  25. Boneformation Boneresorption Bisphosphonates SERMs Calcitonins PTH

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

  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 RanelateDecreasesOsteoclastDifferentiation Mouse spleen-derivedcells(+RANKL & M-CSF) Adapted from Bonnelye et al. Bone 2008;42:129-38.

  29. Strontium RanelateDecreasesOsteoclastLifespan (inducesapoptosis) 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 24 SR (mM Sr2+) Adapted from Mentaverri et al. Bone 2005;36(S2):S403.

  30. Strontium Ranelate Inhibits Bone Resorption in vitro Rat osteoclasts Pit Area Index(% of control) Sr2+ (mM) Adapted from Baron et al. Eur J Pharmacol. 2002;450:11-17.

  31. Strontium RanelateIncreasesOsteoprotegerinWhileDecreasing RANKL in PrimaryHumanOsteoblasts Osteoprotegerin RANKL RANKL mRNAas % of control OPG mRNAas % of control *** *** ** ** *** *** *** Control 0.01 0.1 1 2 0.1 Control 0.01 1 2 Sr(mM Sr2+) SR (mM Sr2+) Mean +/- sem**P<0.01, ***P<0.001 vs. Control AdaptedfromBrennan et al. J Bone Min Res2006;21(S1):S301.

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

  33. Strontium RanelateInducesApoptosis in RabbitPrimaryOsteoclasts and thisisDecreasedwith DN-CaSRTransfection ** * 60 50 * 40 * 30 20 10 0 Control Control 10 10 15 15 20 20 25 25 % of Apoptotic Cells ** SR (mM Sr2+) Plasmid control Dominant Negative CaSR Mean+ SEM, n = 6-10 * P<0.05, ** P<0.01 Adapted from Mentaverri et al. Bone 2005;36(S2):S403.

  34. 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 Sr++ Osteoclasts Osteocytes Osteoblasts Bone-lining cells Macrophages - +  OPG  RANKL Brennan ASBMR 2006 Chattopadhyay Biochem pharmaco 2007

  35. SR IncreasesReplication of Pre-osteoblasts Rat Calvariae Cells Tissue Culture Pre-osteoblasts * Osteoblasts 6 4 3H-Thymidine labeledcells (%) 2 0 Controls 10-5 10-3 Strontium ranelate (M) Control (10 M-3, 48 h) * P<0.05 vs Control Adapted from Canalis E, Hott M, Deloffre P, Marie PJ. Bone. 1996;18(6):517-23.

  36. Strontium RanelateIncreasesOsteoblastSurvival 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 AdaptedfromBrennan et al. Calcified Tissue Int. 2007;80(S1):P132T.

  37. Strontium Ranelate Increases Bone Formation Markers in Primary Human Osteoblasts SR (mM Sr2+) Alkaline phosphatase activity ALP activity as % of vehicle(corrected per mg total protein) ** ** Control 0.01 0.1 1 2 **P<0.01 vs. Control AdaptedfromBrennan et al. Calcified Tissue Int. 2007;80(S1):P132T.

  38. Strontium Ranelate Increases Collagen Synthesis by Preosteoblasts and Osteoblasts Rat Calvariae Cells Tissue Culture Pre-osteoblasts Control 30 * Osteoblasts 25 20 15 Collagen Synthesis(10-3 dpm/well) * * 10-3 M, 48 h 10 5 Bone 0 Controls 10-5 10-4 10-3 Strontium ranelate (M) * P<0.05 vsControls Adapted from Canalis E, Hott M, Deloffre P, Marie PJ. Bone. 1996;18(6):517-23.

  39. Strontium RanelateIncreasesMineralization 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.

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

  41. SR-inducedProliferationisDecreased inDN-CASR Transfected Rat PrimaryOsteoblasts Mean+ SEM, n=6 *** P<0.001 vs Control Adapted from Chattopadhyay et al.Biochempharmacol2007;74:438-47.

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

  43. Strontium Ranelate Bone Formation Effects Sr++ = CaR agonist Sr++ =  COX-2 Chattopadhyay Biochem pharmacol 2007 Choudhary JBMR 2007  PGE2  Proliferation /  Differentiation  Activity Osteoclast Osteocyte Bonnelye Bone 2008 Macrophage Bone-lining cell Osteoblast

  44. SR CaSR OPG Pre-osteoblast RANKL RANK Differentiation  Replication  SR Activity  Osteoblasts Osteoclasts Osteoblastic Differentiation  Apoptosis  Matrix Synthesis  Bone Resorption 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.

  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 Treatment of Female Rats for 2 years Control Strontium ranelate 900 mg/kg/d BV/TV (%) 27 ± 2 38 ± 2 *** Tb.Th (µm) 74 ± 5 84 ± 5 ** Tb.N 3.5 ± 0.1 4.6 ± 0.1*** Tb.Sp (µm) 216 ± 13 135 ± 5 *** Adapted from Ammann et al. JBMR 2004.19:2012-20.

  47. 400 Strontium ranelate (mg/kg/d) 300 200 * + 15 % + 15 % 150 200 100 100 50 0 0 0 225 450 900 Mid-Shaft Femur SR Increases Strength of Vertebrae and Long Bones of Intact Rats (2 years of treatment) 3-point bending test Maximal Load (N) Compression test Maximal Load (N) + 20 % * 0 900 Strontium ranelate (mg/kg/d) 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) After treatment with SR(1250 mg/kg/day) for 52 weeks (A) and after 10 weeks of treatment withdrawal (B) A B Sr Sr More Sr deposited in new bone than old bone More Sr released from new bone than old bone 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 Monkeys, 1-year treatment Micro radiography - Iliac crest 0 mg/kg/d 200 mg/kg/d 500 mg/kg/d 1250 mg/kg/d % of the Number of Measurements 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.

  50. Femoral BMD in Strontium Ranelate-treated Female Rats Correlated with Bone Strength Adult female rats - 2-year treatment R=0.739 Correlation BMD-Strength Ultimate Strength (N) 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.

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