Conclusion Slides

1. Source: Conclusion Slides Review: Reviewer Memo: Slide Modified: Memo:

2. Source: Bone Quality Review: • Bone quality is an integral component of bone strength • Maintaining or restoring bone architecture is required for optimal bone quality • Bone turnover rate affects the degree of mineralization of bone • Optimal collagen/mineral matrix properties contribute to bone quality Reviewer Memo: Slide Modified: Memo:

3. Source: Bone Quality Review: • Bone quality is an integral component of bone strength • Maintaining or restoring bone architecture is required for optimal bone quality • Bone turnover rate affects the degree of mineralization of bone Reviewer Memo: Slide Modified: Memo:

4. Source: Raloxifene: Summary of Bone Quality Effects Review: • Changes in BMD explain only a small proportion of vertebral fracture risk reduction shown with raloxifene • Raloxifene reduces bone turnover to the premenopausal range allowing • Repair of microdamage • Preservation of heterogeneous mineral distribution • A modest increase in mineralization Reviewer Memo: Slide Modified: Memo:

5. Source: Possible Contributing Factors to the Antifracture Efficacy of Antiresorptives Review: • Increase bone mineral density • Decrease bone turnover • Preserve bone microarchitecture • Decrease number of remodeling sites • Maintain trabecular thickness and connectivity • Decrease number of trabecular perforations Reviewer Memo: Slide Modified: Memo:

6. Source: Bone Quality Raloxifene Review: • Biochemical markers and bone turnover significantly reduced to premenopausal range • Normal bone turnover allows adequate repair of microdamage • No adverse effect on bone histology Reviewer Memo: Slide Modified: Memo:

7. Source: Bone Quality Raloxifene Review: • Histomorphometry • No woven bone • No marrow fibrosis • No mineralization defect • No cellular toxicity (light microscopy) • Normal histologic appearance Reviewer Memo: 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 Slide Modified: Memo:

8. Source: Bone Quality Raloxifene Review: • 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 • A moderate increase in mineralization and preservation of heterogeneous mineral distribution • Long-term efficacy with sustained fracture reduction in the fourth year of treatment • Favorable effects on femoral neck geometry Reviewer Memo: Slide Modified: Memo:

9. Source: Bone Quality ConclusionsTeriparatide Review: • Architecture • Increase trabecular thickness and connectivity • Increase cortical thickness and improves cortical geometry • Favorable effects on femoral neck geometry • Turnover • Increase formation on quiescent (neutral) surface • Increase in formation is greater than resorption (positive bone balance) • Transient increase in cortical porosity without impact on bone strength • Damage Accumulation • Forms new bone • Increased bone turnover reduces damage accumulation Reviewer Memo: Slide Modified: Memo:

10. Source: Bone Quality ConclusionsTeriparatide Review: • Architecture • Increase trabecular thickness and connectivity • Increase cortical thickness and improves cortical geometry • Favorable effects on femoral neck geometry • Turnover • Increase formation on quiescent (neutral) surface • Increase in formation is greater than resorption (positive bone balance) • Transient increase in cortical porosity without impact on bone strength Reviewer Memo: Slide Modified: Memo:

11. Decrease perforations Decrease resorption cavities Maintain Plate-like structure Decrease stress risers Maintain Horizontal struts Preserve strength Source: Turnover Reduction Within normal physiologic range Review: Reviewer Memo: Slide Modified: Memo:

12. Prolonged secondary mineralization Insufficient fatigue damage repair Excessive mineralization + homogeneous bone Microcrack accumulation Microcrack propagation Increased fragility Source: Excessive Turnover Reduction Below normal physiologic range Review: Reviewer Memo: ? Slide Modified: Memo:

13. Normal Osteoporosis Severe Osteoporosis Courtesy Dr. A. Boyde Source: Review: Reviewer Memo: Slide Modified: Memo:

14. 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 Physiological Range Source: What Is the Optimal Reduction in Bone Turnover for an AntiresorptiveDrug? Review: Reviewer Memo: Bone Strength Bone Turnover Sourced from Weinstein RS, J Bone Miner Res 15 621-625, 2000 Slide Modified: Memo:

15. Source: Summary of Bone Quality Effects of Raloxifene and Teriparatide Review: Reviewer Memo: June 2004 Slide Modified: Memo:

16. Source: The Assessment of Bone Quality- Advances in Technology Review: Reviewer Memo: Slide Modified: Memo:

17. 10 ORS 2004 8 6 4 2 0 0 50 100 150 200 250 Source: Cadaver Vertebrae: FEM vs. BCT Experiments QCT BCT Review: Reviewer Memo: 2 r =0.65, SE=1.11 kN Strength (kN) Compressive strength (kN) Crawford et al, Bone 2003 0 50 100 150 200 250 QCT-BMD x A (mg/mm) Model Strength (kN) QCT-BMD xA (mg/mm) min June 2004 min Slide Modified: Memo:

18. Source: Virtual Bone Biopsy Review: • Wrist detection coils • Microscopy-specific MRI scanner software enhancements • 3D image processing and analysis Reviewer Memo: Slide Modified: Memo:

19. Source: Supplemental Slides Review: Reviewer Memo: Slide Modified: Memo:

20. Source: The Effect of Antiresorptive Therapy on Fracture Healing Study Protocol Review: • 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. Reviewer Memo: Cao Y et al. J Bone Miner Res 17:2237-46; 2002 Slide Modified: Memo:

21. Source: The Effect of Antiresorptive Therapy on Fracture Healing External Callus Formation Review: • 6 Weeks • Callus formation • Fracture visible Reviewer Memo: • 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 Slide Modified: Memo:

22. Source: The Effect of Antiresorptive Therapy on Fracture Healing Photomicrographs of the Callus Review: Reviewer Memo: Sham OVX EE2 RLX ALN Reproduced with permission from Cao Y et al. J Bone Miner Res 17:2237-46, 2002 June 2004 Slide Modified: Memo:

23. Source: Urinary Markers of Bone Resorption Review: Marker Abbreviation Hydroxyproline HYP Pyridinoline PYD Deoxypyridinoline DPD N-terminal cross-linking telopeptide of type I collagen NTX C-terminal cross-linking telopeptide of type I collagen CTX Reviewer Memo: Delmas PD. J Bone Miner Res 16:2370; 2001 Slide Modified: Memo:

24. Source: Serum Markers of Bone Turnover Review: Abbreviation Formation Bone alkaline phosphatase ALP (BSAP) Osteocalcin OC Procollagen type I C-propeptide PICP Procollagen type I N-propeptide PINP Resorption N-terminal cross-linking telopeptide of type I collagen NTX C-terminal cross-linking telopeptide of type I collagen CTX Tartrate-resistant acid phosphatase TRAP Reviewer Memo: Delmas PD. J Bone Miner Res 16:2370, 2001 Slide Modified: Memo:

25. Source: Effect of Size on Areal BMD Review: BMC Area BMD 1 1 1 1 1 1 2 2 Reviewer Memo: 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 Slide Modified: Memo:

26. Source: Local Buckling Review: Reviewer Memo: Slide Modified: Memo: