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Bone Quality PART 3 Collagen/Mineral Matrix Conclusions Supplemental Slides

Bone Quality PART 3 Collagen/Mineral Matrix Conclusions Supplemental Slides. Bone Quality. Architecture Turnover Rate Damage Accumulation Degree of Mineralization Properties of the Collagen/Mineral Matrix.

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Bone Quality PART 3 Collagen/Mineral Matrix Conclusions Supplemental Slides

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  1. Bone QualityPART 3Collagen/Mineral MatrixConclusionsSupplemental Slides

  2. Bone Quality Architecture Turnover Rate Damage Accumulation Degree of Mineralization Properties of the Collagen/Mineral Matrix Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 2001

  3. Bone Cells and Matrix • Properties of collagen and mineral matrix • Suppressed turnover and accumulation of microdamage • Altered mechanosensation • State of mineralization

  4. 4505-92TR2 COLL X 60 2.000 50 1.600 40 1.200 Y Axis Title 30 0.8000 0.4000 20 0 10 10 20 30 40 50 60 X Axis Title Properties of the Collagen/Mineral Matrix -Antiresorptive Drugs Fourier Transform Infrared Microscopic Imaging (FTIRI) of Iliac Crest Bone Sections IR-spectrometer Bone section

  5. FTIR Imaging – Mineral Crystallinity Baseline 2 Year Estrogen Therapy Pixel Population Distribution Pixel Population Distribution Mineral Crystallinity Mineral Crystallinity E. Paschalis et al. 2003 (in press).

  6. 2 Year Estrogen Therapy Baseline FTIR Imaging – Mineral:Matrix Ratio Pixel Population Distribution Pixel Population Distribution Mineral Matrix Mineral Matrix E. Paschalis et al. 2003 (in press).

  7. Baseline 2 Year Estrogen Therapy 60 2.000 50 1.600 40 1.200 30 0.8000 collxtr3 0.4000 20 150 0 10 100 10 20 30 40 50 60 Y Axis Title 50 0 0.0 0.5 1.0 1.5 2.0 Axis 4505-92TR2 Pixel Population Distribution collxtr2 Pixel Population Distribution COLL X 150 60 2.000 50 1.600 100 40 1.200 Y Axis Title Y Axis Title 30 0.8000 Pyr/DHLNL 50 0.4000 20 Pyr/DHLNL 0 10 0 0.0 0.5 1.0 1.5 2.0 10 20 30 40 50 60 X Axis Title X Axis Title FTIR Imaging – Collagen Cross-Link Ratio E. Paschalis et al. 2003 (in press).

  8. Conclusion Slides

  9. Bone Quality • Bone quality is an integral component of bone strength • Maintaining or restoring bone architecture is required for optimal bone quality • An imbalance in bone turnover rate affects the degree of mineralization of bone • Optimal collagen/mineral matrix properties contribute to bone quality

  10. Possible Contributing Factors to the Fracture Efficacy of Antiresorptives • Increased bone mineral density • Decreased bone turnover • Improved bone quality • Decrease remodeling sites • Maintain trabecular thickness and connectivity • Decrease number of trabecular perforations • Decrease microfractures • Improve matrix properties

  11. Bone Quality -Raloxifene • Biochemical markers and bone turnover significantly reduced to premenopausal range • Normal bone turnover allows adequate repair of microdamage • No adverse effect on bone architecture (iliac crest histomorphometry)

  12. Bone Quality -Raloxifene • Histomorphometry • No woven bone • No marrow fibrosis • No mineralization defect • No cellular toxicity (light microscopy) • Normal histologic appearance Weinstein RS, et al. J Bone Miner Res. 14:S279; 1999 Prestwood KM, et al. J Clin Endocrinol Metab. 85:2197-2202; 2000 Ott SM, et al. J Bone Miner Res. 17:341-348; 2002

  13. Bone Quality -Raloxifene • No adverse effects on bone histology • Changes in BMD explain only a small proportion of vertebral fracture risk reduction • Reduces bone turnover to the normal premenopausal range allowing • Adequate repair of microdamage • A moderate increase in mineralization and preservation of heterogeneous mineral distribution • Long-term efficacy with sustained fracture reduction in the fourth year of treatment

  14. Bone Quality ConclusionsTeriparatide • Architecture • Increase trabecular thickness and connectivity • Increases cortical thickness and improves cortical geometry • Turnover • Increases formation on quiescent (neutral) surface • Increase in formation is greater than resorption (positive bone balance) • Damage Accumulation • Forms new bone • Increased bone turnover reduces damage accumulation

  15. Relationship Between Excessive Suppression Of Bone Turnover and Damage Accumulation Excessive suppression of bone turnover Insufficient repair of microdamage Prolonged mineralization Damage accumulation Increase in bone fragility Long-term fracture efficacy and safety?

  16. Adequate suppression of bone turnover Physiological repair of microdamage Sufficient mineralization Preservation of architecture Long-term fracture efficacy and safety The Optimal Effect of an Antiresorptive Agent on Bone Quality

  17. Normal Osteoporosis Severe Osteoporosis Courtesy Dr. A. Boyde

  18. Physiological Range Bone Strength Bone Turnover What Is the Optimal Reduction in Bone Turnover for an Antiresorptive Drug? • Insufficient turnover • Accumulation of microdamage • Increased brittleness due to excessive mineralization • Excessive turnover • Increase in stress risers (weak zones) • Increase in perforations • Loss of connectivity Adapted from Weinstein RS, J Bone Miner Res 2000; 15 621-625.

  19. Supplemental Slides

  20. Effect of Size on Areal BMD BMC AREA BMD 1 1 1 1 1 1 2 2 8 4 2 2 3 3 27 9 3 3 “TRUE” VALUE = 1 g/cm3 Adapted from Carter DR, et al. J Bone Miner Res 1992

  21. The Effect of Antiresorptive Therapy on Fracture Healing Study Protocol • Female OVX rats (n=140) • Five study groups • Sham control • OVX placebo control • OVX + estrogen • OVX + raloxifene • OVX + alendronate • Objective: To evaluate the effect of antiresorptives on fracture healing. Cao Y et al. J Bone Miner Res 17:2237-46; 2002

  22. The Effect of Antiresorptive Therapy on Fracture Healing External Callus Formation • 6 Weeks • Callus formation • Fracture visible • 16 Weeks • OVX Fracture line dissapeared • ALN fracture line still visible • Callus width largest in ALN group • Fracture repair was delayed with ALN treatment Reproduced with permission from Cao Y et al. J Bone Miner Res 17:2237-46, 2002

  23. 6 weeks 16 weeks Sham OVX EE2 RLX ALN The Effect of Antiresorptive Therapy on Fracture Healing Cross-sectional Microradiographsat the Fracture Plane Reproduced with permission from Cao Y et al. J Bone Miner Res 17:2237-46; 2002

  24. The Effect of Antiresorptive Therapy on Fracture Healing Photomicrographs of the Callus Sham OVX EE2 RLX ALN Reproduced with permission from Cao Y et al. J Bone Miner Res 17:2237-46, 2002

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