1. Relationship of Drug Associated Change in Bone Mineral Density to Fracture Risk Marc C. Hochberg, MD, MPH FDA Endocrinologic and Metabolic Drugs Advisory Committee 25 September 2002

2. Osteoporosis: Definition (NIH Consensus Conference, 2000)  [A] skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture  Bone strength reflects bone mass and bone quality  Bone mass is estimated by bone mineral density  Bone quality refers to microarchitecture, turnover, damage accumulation (eg, microfractures), and degree of mineralization NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. JAMA. 2001;285:785–795.

3. Bone Mineral Density and Bone Turnover Components of the “new” definition of osteoporosis Are changes in bone mineral density and bone turnover with antiresorptive therapy important in explaining the antifracture efficacy of these agents? –Vertebral fractures –Nonvertebral fractures

4. Pharmacologic Treatment of Osteoporosis Antiresorptive agents –Bisphosphonates Alendronate, Risedronate –Calcitonin –Estrogen (not FDA approved for treatment) –Selective estrogen receptor modulators Anabolic agents –Fluoride (not FDA approved) –Parathyroid hormone (not FDA approved)

5. Antiresorptive Agents  Inhibit bone resorption –Fewer resorption sites; improves bone microarchitecture (fewer cavities) –Shallower resorption sites; improves bone balance (amount of formation greater than resorption) –Slower turnover rate; allows better mineralization of bone  Result: –Increased bone mass –Improved bone strength and bone quality Out of proportion to increase in bone mass

6. Vertebral Fractures

7. Changes in Bone Density and Antifracture Efficacy of Antiresorptive Agents Methods  Identified 13 randomized placebo-controlled trials of antiresorptive agents that reported both vertebral fracture incidence and changes in BMD  Used Poisson regression –Related  BMD and fracture risk reduction –Pooled data to obtain “best fit” –Sensitivity analysis performed Wasnich RD, Miller PD. J Clin Endocrinol Metab. 2000;85:231–236.

8. Greater Increase in Bone Mineral Density (BMD) and Larger Reduction in Fracture Risk Percent Change in Spine BMD (vs Placebo) 0123456789 Relative Risk Reduction (%) -100 -80 -60 -40 -20 0 20 40 60 A = alendronate C = calcitonin E = etidronate H = hormone replacement R = raloxifene T = tiludronate C 54% risk reduction 22% 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Relative Risk of Vertebral Fracture A A A A C E H R R R A C T T T C T E A Wasnich RD, Miller PD. J Clin Endocrinol Metab. 2000;85:231–236.

9. Predicting the Effect of Antiresorptive Treatments on Vertebral Fractures BMD = Bone mineral density. Cummings SR et al. Am J Med 2002;112:281-9. Results (Method 1)  Identified 12 randomized, placebo-controlled trials of antiresorptive agents that lasted  2 years and reported both vertebral fracture incidence (  5 fractures per treatment group) and changes in spine BMD Used weighted regression models to estimate the association of change in spine BMD and reduction in vertebral fracture risk Expected RR = 0.75 - 0.03 X % increase in LSBMD

10. Reduction in Fracture Risk Predicted From  Lumbar Spine Bone Mineral Density (BMD) *Wasnich RD, Miller PD. J Clin Endocrinol Metab. 2000;85:231–236. † Cummings SR et al. Am J Med. 2002;112:281-9.

11. Predicting the Effect of Antiresorptive Treatments on Vertebral Fractures BMD = Bone mineral density. Cummings SR et al. Am J Med 2002;112:281-9. Results (Method 2)  Relative risk reduction in vertebral fractures exceeded that estimated from the regression model using change in lumbar spine BMD. –Observed RR = 0.83 X Expected RR - 0.11  Concluded that observed changes in lumbar spine BMD explain only a small proportion of the actual reduction in risk of vertebral fractures.

12. Extended “New” Analysis Repeated “Wasnich & Miller” analysis excluding trials of non-approved medications and adding risedronate VERT studies; total of 13 trials. Results largely unchanged Change in LSBMD remains significantly associated with reduction in risk of VFx RR = 0.90 (95% CI: 0.83, 0.97) per 1%  in BMD Independent effect of treatment even without any increase in LSBMD RR = 0.81 (95% CI: 0.66, 1.00)

13. Summary: Change in BMD and Reduction in Risk of Vertebral Fractures Greater increase in BMD is associated with greater reduction in fracture risk –Models predict that an 8% increase in BMD at the spine (or 5% increase in BMD at the hip) would decrease risk by ~50%  Significant treatment effect independent of  BMD –Models predict that an antiresorptive agent that does not increase BMD would decrease risk by ~25% –Probably due to  bone turnover (resorption) BMD=Bone mineral density.

14. Different Effects of Antiresorptive Therapies on Vertebral and Nonvertebral Fractures Some agents (eg, calcitonin, raloxifene) decrease vertebral fracture risk, but have not been shown to reduce risk of nonvertebral fractures Smaller changes in BMD and bone turnover were also observed for these agents compared to aminobisphosphonates

15. Nonvertebral Fractures

16. Changes in Bone Density and Turnover: Reductions in Incidence of Nonvertebral Fractures Methods  Pooled all randomized, double-blind, placebo- controlled clinical trials with data on changes in BMD and/or BCM of bone turnover and incidence of nonvertebral fractures –Larger studies given greater weight Related  BMD and  BCM over 1 year to reduction in fracture risk over duration of trial BMD = Bone mineral density. BCM = Biochemical markers. Hochberg MC et al. J Clin Endocrinol Metab. 2002;87:1586-92.

17. Changes in Bone Density and Turnover: Reductions in Incidence of Nonvertebral Fractures Results  18 trials identified –30 active antiresorptive treatment groups  69,369 woman-years of follow-up –92% in the 8 largest studies  2,415 women with new nonvertebral fractures –90% in the 8 largest studies Hochberg MC et al. J Clin Endocrinol Metab. 2002;87:1586-92.

18. BMD = Bone mineral density. Hochberg MC et al. J Clin Endocrinol Metab. 2002;87:1586-92. Relative Risk (RR) of Nonvertebral Fracture

19. BMD = Bone mineral density. Hochberg MC et al. J Clin Endocrinol Metab. 2002;87:1586-92. Relative Risk (RR) of Nonvertebral Fracture

20. Hochberg MC et al. J Clin Endocrinol Metab. 2002;87:1586-92. Relative Risk (RR) of Nonvertebral Fracture

21. Hochberg MC et al. J Clin Endocrinol Metab. 2002;87:1586-92. Relative Risk (RR) of Nonvertebral Fracture

22. Correlation of  BMD or  BCM With Reduction in Nonvertebral Fracture Risk  Increases in BMD and decreases in BCM at 1 year were both significantly associated with reduction in risk of new nonvertebral fractures –Spine BMD0.08 per 1%  (P = 0.02) –Hip BMD0.27 per 1%  (P = 0.006) –Resorption BCM0.07 per 10%  (P < 0.05) –Formation BCM0.14 per 10%  (P = 0.01) BMD = Bone mineral density. BCM = Biochemical markers. Hochberg MC et al. J Clin Endocrinol Metab. 2002;87:1586-92.

23. Sensitivity Analyses Results generally robust to removal of both individual trials as well as all trials of individual agents

24. Extended “New” Analysis Repeated analysis excluding trials of non-approved medications; total of 15 trials. Results largely unchanged Change in BMD at 1 year remains significantly associated with reduction in risk of non-VFx RR = 0.92 (95% CI: 0.86, 0.99) per 1%  in LSBMD RR = 0.78 (95% CI: 0.64, 0.95) per 1%  in HBMD No significant independent effect of treatment without any increase in LSBMD

25. Summary: Nonvertebral Fractures Greater increase in BMD or decline in BCM at 1 year is associated with greater reduction in fracture risk –Models predict that a 6%  in BMD at spine or 3%  BMD at the hip, or 70%  in BCM of resorption or 50%  in BCM of bone formation would decrease risk of nonvertebral fractures by ~40% to 45%  No significant treatment effect independent of  BMD or  BCM BMD = Bone mineral density. BCM = Biochemical markers. Hochberg MC et al. J Clin Endocrinol Metab. 2002;87:1586-92.

26. Conclusions  BMD and  BCM are important indicators of antifracture efficacy of antiresorptive drugs –Both for vertebral and nonvertebral fracture  BMD (and large  BCM) appear to be necessary to  risk of nonvertebral fractures –Is there a threshold effect for vertebral fractures? Consistent with hypothesis of Riggs & Melton (2002) Further analyses of existing data needed Results cannot be extrapolated to anabolic agents such as fluoride or PTH BMD = Bone mineral density, BCM = Biochemical markers, PTH = Parathyroid hormone. Hochberg MC et al. J Clin Endocrinol Metab. 2002;87:1586-92.

27. Extended “New” Analysis Repeated both analyses including data from pivotal phase III trial of teripartide (Neer et al, 2001) Results largely unchanged for both VFx and non-VFx Change in BMD remains significantly associated with reduction in risk of VFx Change in BMD at 1 year remains significantly associated with reduction in risk of non-VFx Significant independent effect of treatment without any increase in BMD for VFx but not for non-VFx

28. Revised Extended Conclusions  BMD is an important indicator of antifracture efficacy for both antiresorptive and anabolic drugs (eg., PTH) –Both for vertebral and nonvertebral fracture Larger  s in BMD appear to be necessary to  risk of nonvertebral fractures Reductions in BCM of bone turnover are independent predictors of reductions in risk of vertebral but not for nonvertebral fractures BMD = Bone mineral density, BCM = Biochemical markers, PTH = Parathyroid hormone. Hochberg MC et al. J Clin Endocrinol Metab. 2002;87:1586-92.

29. Back-ups

30. Osteoporosis: Definition (Consensus Conference, 1993) [A] systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bony tissue, with a consequent increase in bone fragility and susceptibility to fractures.

31. Osteoporosis: Definition (World Health Organization, 1994) Bone mineral density that is more than 2.5 standard deviations below the young average value (T-score > -2.5)

32. 1. Curry JD. Engineering in Medicine. 1986;15:153–154. 2. Cummings SR et al. Lancet. 1993;341:72–75. 3. Ettinger B et al. JAMA. 1999;282:637–645. 4. Hochberg MC et al. J Clin Endocrinol Metab. 2002;87:1586-92. Low Bone Mineral Density: Risk Factor for Fracture  60% to 80% of bone strength is related to bone mineral density 1  Low bone mineral density predicts increased fracture risk 2,3  Increases in bone mineral density are associated with a reduction in fracture risk 4

33. Fracture Rates and Relative Risk by BMD Category* 0 0.5 1 1.5 2 2.5 3 3.5 Rate per 100 Person-Years BMD Category Normal Osteopenia Osteoporosis *Data From National Osteoporosis Risk Assessment (NORA) Siris ES et al: JAMA. 2001;286:2815–2822. Adjusted relative risk: Normal1.0 Osteopenia1.7 (1.6, 1.9) Osteoporosis2.7 (2.4, 3.1)

34. High Bone Turnover: Risk Factor for Fracture  Higher levels of bone turnover are associated with increased rates of bone loss in untreated postmenopausal women  Higher levels of bone turnover are associated with increased risk of hip fracture in postmenopausal women

35. Bone Mineral Density and Bone Turnover: Risk Factors for Hip Fracture 5 4 3 2 1 0 Low Hip BMD 2.7 Risk of Hip Fracture (Odds Ratio) High CTX High free D-Pyr Low Hip BMD + High CTX High Free D-Pyr 2.2 1.9 4.8 4.1 BMD = Bone mineral density. CTX = C–Telopeptide. D-Pyr = Deoxypyridinoline Garnero P et al. J Bone Miner Res. 1996;11:1531–1538.

36. Bone Mineral Density, Quality and Turnover: Independent Risk Factors for Fracture 3 2 1 0 BMDHeel BUA 2.9 Risk of Hip Fracture (Odds Ratio) Urinary CTX 2.5 2.6 BMD = Bone mineral density. BUA = Broadband Ultrasonographic Attenuation. CTX = C–Telopeptide. Garnero P et al. Osteoporos Int. 1998;8:563–569.

37. Antiresorptive Agents Should Prevent Fractures Through Effects on Bone Strength Reduce biochemical markers of bone turnover to premenopausal levels Increase both cortical and trabecular bone mass (bone mineral density) and improve bone quality Decrease fracture risk

38. Reduction in Biochemical Markers Predicts Increase in Bone Mineral Density (BMD)  Changes in markers occur before changes in BMD  Percent changes in bone turnover markers are much greater than the percent change in BMD  Significant, albeit modest, correlations exist between changes in bone turnover markers and changes in BMD within individual studies  Significant strong correlations exist between changes in bone turnover markers and changes in BMD across studies

39. Hochberg MC et al. J Clin Endocrinol Metab. 2002;87:1586-92. Change in Resorption Markers and BMD

40. Hochberg MC et al. J Clin Endocrinol Metab. 2002;87:In press. Change in Formation Markers and BMD

41. Assessing the Effects of Antiresorptive Therapies in Reducing Osteoporotic Fracture “At present …BMD measurement is the best surrogate clinical marker of therapeutic efficacy.” BMD = Bone mineral density. Chesnut CH, Rosen CJ, et al. J Bone Miner Res. 2001;16:2163–72.

42. Relationship of Change in Bone Turnover to Reduction in Risk of Vertebral Fractures Secondary analysis of data from a subset of 2,622 participants in MORE trial who had measurement of bone markers 2-part analysis –Association of tertiles of change in bone markers with risk of vertebral fracture –Multivariate analysis of change in bone markers as continuous variables adjusting for confounders MORE = Multiple Outcomes of Raloxifene Evaluation. Bjarnason NH et al. Osteoporos Int. 2001;12:922–930.

43. Changes in Biochemical Markers Predict Vertebral Fracture Risk Reduction During Raloxifene Therapy 1 0 0.97 0.35* 0.89 Osteocalcin (µg/L) 1 0 0.38* 0.74 1.05 Relative Risk of Spine Fracture Bone Alkaline Phosphatase (µg/L) *P<0.05. Bjarnason et al. Osteoporos Int. 2001;12:922–930. >–8.7 –8.7  –3.1 >–3.1 >–5.7 –5.7  –1.9 >–1.9

44. Relationship of Change in Bone Turnover to Reduction in Risk of Vertebral Fractures  In patients treated with raloxifene, reduction in bone formation at 6 months was significantly related to reduction in vertebral fracture risk after adjustment for age, baseline BMD, BMI, smoking status, and prevalent vertebral fracture –OR 0.76 (0.61, 0.96) for 8.9 µg/L  in serum OC –OR 0.63 (0.50, 0.80) for 5.5 µg/L  in serum BAP BMD = Bone mineral density. BMI = Body mass index. Bjarnason NH et al. Osteoporos Int. 2001;12:922–930.

45. Relationship of Change in Bone Turnover to Reduction in Risk of Vertebral Fractures Secondary analysis of data from a subset of 2,442 participants in VERT study who had measurement of bone markers. In patients treated with risedronate, reduction in bone resorption at 3 months was significantly related to reduction in vertebral fracture risk –30%  in urinary NTX/Cr ~ 17%  in VFx risk VERT = Vertebral Efficacy and Risedronate Therapy. NTX/Cr = N-telopeptide/creatinine. Eastell R et al. J Bone Miner Res. 2001;Abstract 1107.

46. Reduction in Bone Turnover Predicts Fracture in Alendronate Treated Women: The FIT Study DC Bauer et al, for the FIT Research Group Presented at IOF WCO, 14 May 2002

47. Research Question  Among alendronate and placebo treated women, are baseline values and changes in biochemical markers of bone turnover associated with: –Vertebral fracture? –If so, are effects of bone turnover independent of BMD?

48. Methods: Design and Subjects  Prospective cohort study  Fracture Intervention Trial (FIT) – 6459 postmenopausal women – FNBMD < 0.68 gm/cm 2  Randomized to ALN (5 mg/d) or placebo -ALN increased after 2 years to 10 mg/d  Calcium/vit D supplements if needed (>80%)

49. Methods: Measurements  Bone turnover at baseline and 1 year (non-fasting archived serum) – BAP (Hybritech) – sCTX (Crosslaps) – P1NP (Orion)  BMD at baseline and 1 year (Hologic QDR-2000)  Fracture outcomes (3.6 yr follow-up) – Central review of paired lateral spine radiographs

50. Results: Placebo Group  Markers fell 8-31% over 1 year  Neither baseline marker level nor change over 1 year were associated with vertebral fracture

51. Results: Alendronate Group  Baseline marker not associated with fracture  Greater reductions in one or more markers were associated with fewer vertebral fractures

52. Odds (CI) Odds Ratio (CI) Change in BAP (mg/dl) 2929 2828 2222 2020 1919 RR per SD: 0.74 (0.63, 0.87) RR per SD: 0.74 (0.63, 0.87) Alendronate Group: Change in BAP and Risk of Spine Fracture

53. Odds Ratio (CI) Change in BMD (%) RR per SD: 0.92 (0.76, 1.11) RR per SD: 0.92 (0.76, 1.11) Alendronate Group: Change in Spine BMD and Risk of Spine Fracture

54. Additional Analyses  Change in marker results similar after: –Adjustment for baseline BMD or vertebral fx –Limiting analysis to women with osteoporosis low BMD and/or existing VFx  Further adjustment for change in spine BMD did not alter results

55. Conclusions  In the Fracture Intervention Trial: –Baseline markers not associated with fracture –Change in one or more marker was associated with subsequent vertebral fracture in alendronate treated women. –Effect independent of BMD  Reduction in bone turnover clearly plays an important role in the efficacy of alendronate treatment

56. Antiresorptive Therapy Reduce Bone Turnover Improve Bone Microarchitecture Increase BMD Decrease Fracture Risk Antiresorptive Agents: Mechanisms of Fracture Risk Reduction ?