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Bone Quality 2004

Source:. Bone Quality 2004. Review:. Reviewer Memo:. Slide Modified:. Memo:. Source:. Old Definition of Osteoporosis. Review:. Reviewer Memo:.

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Bone Quality 2004

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  1. Source: Bone Quality 2004 Review: Reviewer Memo: Slide Modified: Memo:

  2. Source: Old Definition of Osteoporosis Review: Reviewer Memo: A systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Conference Report from the Consensus Development Conference. Am J Med 94: 646-650, 1993 Slide Modified: Memo:

  3. Source: Review: Relationship Between BMD and Fracture • Low baseline bone mineral density (BMD) predicts increased risk of subsequent fractures • The magnitude of the increases in BMD with antiresorptive therapies differs greatly, yet the vertebral fracture risk reductions are similar • There is only a weak relationship between changes in BMD with antiresorptive therapy and the reduction in risk of new fractures Reviewer Memo: Slide Modified: Memo:

  4. Source: What May Contribute to an Increase in BMD? Review: • Improvements in mineral and matrix composition • Increased bone tissue per unit of bone volume: • Filling in remodeling space • Widening existing trabeculae • Creating new trabeculae • Increased bone size Reviewer Memo: Slide Modified: Memo:

  5. Age (Years) 160 80+ 140 120 75-79 100 80 Fracture Risk / 1000 Person Year 70-74 60 65-69 60-64 40 55-59 50-54 20 45-49 <45 0 >1.0 0.90-0.99 0.80-0.89 0.70-0.79 0.60-0.69 <0.60 Forearm Bone Mass (g/cm2) Source: Age and Bone Mass as Predictors of Fracture Review: Reviewer Memo: Hui SL et al. J Clin Invest 81:1804-1809; 1988 Slide Modified: Memo:

  6. Source: BMD Change and Fracture Risk Reduction with Antiresorptive Therapy Review: • Fracture Risk decreases by 6-12 months, before maximum BMD response has occurred • Treatment may reduce fracture risk with little or no change in BMD • From regression analyses, only a small proportion of fracture risk reduction is attributable to an increase in BMD Reviewer Memo: Slide Modified: Memo:

  7. Risedronate1 7 – 28% Alendronate2 16% Raloxifene3 4% Source: Vertebral Fracture Risk Reduction Attributable to an Increase in BMDAntiresorptive Therapy Review: Reviewer Memo: • Li et al. Stat Med 20:3175-88; 2001 • Cummings S et al. Am J Med 112:281-289; 2002 • 3. Sarkar Set al. J Bone Miner Res 17: 1-10; 2002 Slide Modified: Memo:

  8. Source: Randomized Studies of Antiresorptives in * Postmenopausal Osteoporotic Women Risk of Vertebral Fractures Review: LS BMD** Relative Risk (95% CI) Raloxifene Preexisting vertebral 2.2 1 60 mg/d fracture (VFx) No preexisting VFx 2.9 1 Reviewer Memo: Alendronate Preexisting VFx 6.2 2 5/10 mg/d No preexisting VFx 6.8 3 Risedronate Preexisting VFx 4.3 4 5 mg/d No preexisting VFx 5.9 5 Calcitonin Preexisting VFx 0.7 6 200 IU/d 0 0.5 1.0 *Not head - to - head comparison, **vs placebo Data on file, Eli Lilly & Co. 1 Harris ST et al. JAMA 282:1344 - 1352, 1999 4 Black DM et al. Lancet 348:1535 - 1541, 1996 2 Reginster JY et al. Osteoporosis Int 11:83 - 91, 2000 5 Cummings SR et al. JAMA 280:2077 - 2082, 1998 3 Chesnut CH et al. Am J Med 109:267 - 276, 2000 6 Slide Modified: Memo:

  9. 20 18 16 14 % Risk of  1 New Vertebral Fracture at 3 Years 12 10 8 6 4 2 0 -3.2 -2.8 -2.8 -2.6 -2.4 -2.2 -2.0 -1.8 -1.6 Relationship Between Baseline Femoral Neck BMD and Vertebral Fracture RiskMORE Trial - 3 Years Source: Review: 22 Raloxifene (pooled) Placebo 95% Confidence Interval Reviewer Memo: Baseline Femoral Neck BMD T-Score (NHANES) Sourced from Sarkar S et al. J Bone Miner Res 17:1-10, 2002 Slide Modified: Memo:

  10. Raloxifene (pooled) 15 Placebo 95% confidence interval 13 11 9 % Risk of  1 New Vertebral Fracture 7 5 3 0 -6 -4 -2 0 2 4 6 8 -10 10 -8 % Change in Femoral Neck BMD Source: Relationship Between Change in Femoral Neck BMD and Vertebral Fracture RiskMORE Trial - 3 Years Review: Reviewer Memo: Sourced from Sarkar S et al. J Bone Miner Res 17:1-10, 2002 Slide Modified: Memo:

  11. 15 13 11 9 A 7 B 5 B A 3 0 10 6 4 2 0 2 4 6 8 10 8 Relationship Between Change in Femoral Neck BMD and Vertebral Fracture Risk Source: MORE Trial – 3 Years Review: Raloxifene (pooled) Placebo Reviewer Memo: Risk of  1 New Vertebral Fractureat 3 Years (%) - - - - - % Change in Femoral Neck BMD at 3 Years Sourced from Sarkar S et al. J Bone Miner Res 17:1-10, 2002 Slide Modified: Memo:

  12. Source: Many Characteristics of Bone Strength Are Not Reflected in DXA Results Review: • Reflected in DXA Measurements: • Bone size • Trabecular volume and cortical thickness • Amount of mineralization in bone and surrounding tissues • Not Reflected in DXA Measurements: • Trabecular connectivity and number • Matrix quality (collagen, mineral) • Microscopic damage (e.g. microcracks) • Bone geometry Reviewer Memo: Slide Modified: Memo:

  13. Source: Current Definition of Osteoporosis Review: Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality. Reviewer Memo: Normal bone Osteoporosis NIH Consensus Development Panel on Osteoporosis JAMA 285:785-95; 2001 Slide Modified: Memo:

  14. Source: Shifting the Osteoporosis ParadigmBone StrengthNIH Consensus Statement 2000 Review: Bone Mineral Density Bone Quality Bone Strength and Reviewer Memo: aBMD (areal) = g/cm2 vBMD (volumetric) = g/cm3 Microarchitecture Geometry Turnover Rate Damage Accumulation Degree of Mineralization Properties of the Collagen/mineral Matrix Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 2001 Slide Modified: Memo:

  15. Source: BONE QUALITY CONCEPT Review: Bone Mass Reviewer Memo: Bone Strength Distribution of Mass Geometry Architecture Turnover Material Properties Mineralization Matrix Quality Microdamage Slide Modified: Memo:

  16. Architecture Macroarchitecture (bone geometry) Microarchitecture (trabecular connectivity and shape) Bone turnover Resorption Formation Material properties Collagen properties (cross-linking) Mineralization (degree and heterogeneity) Microdamage (microcracks) Source: Components of Bone Quality Review: Reviewer Memo: Chesnut III CH. J Bone Miner Res 16:2163-2172, 2001 NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95;2001 Slide Modified: Memo:

  17. Factors Leading to Osteoporotic Fracture: Role of Bone Mass Source: Shape & Architecture Review: Falls Hormones Reviewer Memo: Bone Strength Bone Mass Nutrition Fracture Material Properties Postural Reflexes Exercise & Lifestyle Soft Tissue Padding June 2004 Reproduced with permission from Heaney RP. Bone 33:457-465, 2003 Slide Modified: Memo:

  18. Source: Bone Quality Review: Architecture Turnover Rate Damage Accumulation Degree of Mineralization Properties of the collagen/mineral matrix Reviewer Memo: Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 2001 Slide Modified: Memo:

  19. Source: Distribution of Cortical and Trabecular Bone Review: Thoracic and 75% trabecular Lumbar Spine 25% cortical 1/3 Radius >95% Cortical Reviewer Memo: Femoral Neck 25% trabecular 75% cortical Ultradistal Radius 25% trabecular 75% cortical Hip Intertrochanteric Region 50% trabecular 50% cortical Slide Modified: Memo:

  20. Source: Cortical and Trabecular Bone Review: Cortical Bone • 80% of all the bone in the body • 20% of bone turnover Reviewer Memo: Trabecular Bone • 20% of all bone in the body • 80% of bone turnover Slide Modified: Memo:

  21. Source: Relevance of Architecture Review: Reviewer Memo: Normal Loss of Loss of Quantity Quantity and Quantity and Architecture Architecture Slide Modified: Memo:

  22. Source: Bone ArchitectureTrabecular Perforation Review: The effects of bone turnover on the structural role of trabeculae Reviewer Memo: Risk of Trabecular Perforation increases with: • Increased bone turnover • Increased erosion depth • Predisposition to trabecular thinning Slide Modified: Memo:

  23. Source: Structural Role of TrabeculaeCompressive strength of connected and disconnected trabeculae Review: 1 16 X Reviewer Memo: Bell GH et al. Calcif Tissue Res 1: 75-86, 1967 Slide Modified: Memo:

  24. Normal Osteoporotic Source: Resorption Cavities as Mechanical Stress Risers Review: Reviewer Memo: Sourced fromParfitt AM et al. Am J Med 91, Suppl 5B: 42S-46S Slide Modified: Memo:

  25. Source: Strain Distribution in Relation to Trabecular Perforations Review: • Trabeculae under low strain (blue) can tolerate bone loss better than traceculae under high strain (red) • Resorption of trabeculae causes a larger decrease in stiffness than does thinning of trabeculae Reviewer Memo: Reprinted with Permission from Van der Linden JC et al. J Bone Miner Res 16:457-465; 2001 Slide Modified: Memo:

  26. Source: Trabecular Perforations Review: Reviewer Memo: Seeman E Lancet 359, 1841-1850, 2002. Reprinted with Permission from Mosekilde L. Bone Miner 10: 13-35, 1990 Slide Modified: Memo:

  27. Source: Antiresorptive Agents Help to Preserve Supporting Ties Review: Reviewer Memo: Reprinted with Permission from Mosekilde L. Bone 9: 247-250, 1988 Slide Modified: Memo:

  28. Source: Bone ArchitectureCortical Bone Review: • Key Variables Associated With Cortical Bone Strength • Bone turnover • Cortical thickness • Geometry and Dimensions Reviewer Memo: Slide Modified: Memo:

  29. Source: Effects of Antiresorptive Drugs Review: High turnover state: endosteal resorption and increased porosity Reviewer Memo: Stress Risers Fracture at a Stress Riser Low turnover state: reduced endosteal resorption and porosity Slide Modified: Memo:

  30. BMD Effect of Teriparatide [rh PTH(1-34)] on Radial BMD Source: Review: • Periosteal apposition of new bone that is not yet fully mineralized • Endosteal resorption of normal or highly mineralized bone periosteal Reviewer Memo: endosteal Zanchetta JR et al. J Bone Miner Res18, 539-534, 2003 Slide Modified: Memo:

  31. After Alendronate TPTD Treatment BMD BMD endosteal porosity mineralization porosity periosteal new bone cortical area Source: Possible Mechanism for Reduced BMD Response to TPTD Among Alendronate-Pretreated Patients Review: Pretreatment Reviewer Memo: bone mass remodeling space June 2004 Slide Modified: Memo:

  32. Source: Teriparatide - Effect on Cortical Bone Review: Reviewer Memo: Improves geometry-Increases diameter Increases thickness Slide Modified: Memo:

  33. TPTD (n = 16) ALN (n = 19) Source: RMP.B3DSGHBM.SASPGM(BDS001DD)see reference in notes FACT TrialLumbar Spine BMD Areal (DXA) and Volumetric (QCT) Review: David Donley - statistical review WPDF# DWD200210c WPDF# for global kit: LX200308c (Li Xie 090403) † QCT Subset * Reviewer Memo: † Percent change at 6 months * * McClung MR et al. Osteoporos Int 13(Suppl 3):S18, 2002 June 2004 Within treatment: *P<0.01 Treatment difference: †P<0.01 Slide Modified: on: 9/18/2002 12:45:38 PM SL12 Rev: 272on: 2/3/2003 2:20:55 PM SL12 Rev: 320on: 9/4/2003 8:44:21 AM SL25 Rev: 47 on: 9/25/2003 6:38:58 PM SL1 Rev: 128 Memo: new notes, changed reference to published McClung 18Aug03 - MR

  34. Sham PTH 1 PTH 5 PTH1W Ovx PTH5W Source: Teriparatide Effects on the Femoral Midshaft of Ovariectomized Monkeys Review: Reviewer Memo: Sourced from Sato et al., JBMR 2004 19 623-629 and Data on file, Eli Lilly & Company Slide Modified: Memo:

  35. Source: Patient 1124 B3D-MC-GHAC - UCSF – Jiang 2003 Teriparatide Improves Skeletal Architecture Review: Hong Ren 11-19-02 WPDF# for global kit: LX200308c (Li Xie 090403) Reviewer Memo: Jiang UCSF Follow up Baseline Female, age 65 Duration of therapy: 637 days (approx 21 mos) BMD Change: Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%) Total Hip: +5.2% (group mean = 2.6 ± 4.9%) Patient treated with teriparatide 20 µg Sourced from Jiang et al. J Bone Miner Res18:1932-1941, 2003 Slide Modified: on: 10/22/2002 12:55:03 PM SL10 Rev: 147on: 9/4/2003 8:44:11 AM SL11 Rev: 47 on: 9/25/2003 6:38:58 PM SL1 Rev: 128 Memo: ACR 2002changed title, references, added new notes 16Jul03added to history set, modified notes and title 06Aug03 – MR Added Baseline and Followup with Jiang UCSF under pictures 081603MEP

  36. Source: Jiang et al. JBMR 2003 [in SPOTT] Structural IndicesQuantitative Analysis-significant Changes Review: Hong Ren 102202 WPDF# for global kit: LX200308c (Li Xie 090403) P<0.001 Trabecular bone volume Reviewer Memo: P<0.05 Structure model index P<0.05 Connectivity density P<0.05 Cortical thickness Sourced from Jiang et al. J Bone Miner Res18:1932-1941, 2003 June 2004 Slide Modified: on: 10/22/2002 12:55:04 PM SL11 Rev: 147on: 9/4/2003 8:44:12 AM SL12 Rev: 47 on: 9/25/2003 6:38:58 PM SL1 Rev: 128 Memo: ACR 2002 Slide images created by M.E. Perron Aug 2002 (per E. Eriksen)new notes 12Aug03 - MRedited notes 15Aug03 - MR

  37. Source: see reference in notes Teriparatide Has Positive Effects on Bone Structure Review: WPDF# for global kit: LX200308c (Li Xie 090403) Summary • Teriparatide-induced changes in trabecular and cortical bone morphology: • contribute to increased biomechanical competence • may explain the persistent reduction of vertebral and nonvertebral fractures with teriparatide treatment Reviewer Memo: Sourced from Jiang et al. J Bone Miner Res18:1932-1941, 2003 Slide Modified: on: 10/22/2002 12:55:09 PM SL17 Rev: 147on: 9/4/2003 8:44:12 AM SL13 Rev: 47 on: 9/25/2003 6:38:58 PM SL1 Rev: 128 Memo: ACR 2002changed title, reformatted slide, edited text, changed reference new notes - 16Jul03 - MR

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