1. Novel Treatments for Osteoporosis Prof. Steven R. Cummings, MD San Francisco Coordinating Center Support from Novartis, Lilly, Organon, Pfizer, Amgen, NIH, Zelos

3. Denosumab Anti-RANKL Antibodies

10. Denosumab vs. Alendronate vs. Placebo Alendronate Placebo Denosumab McClung et al, NEJM 2006; 354:821

11. Denosumab vs. Alendronate vs. Placebo Alendronate Placebo Denosumab McClung et al, NEJM 2006; 354:821

12. Stopping and restarting denosumab On Off P. Miller, et al, Bone 2008

13. Stopping and restarting denosumab P. Miller, et al, Bone 2008 On Off

15. The FREEDOM Trial The Effect of Denosumab on Fractures

19. Osteocyte

20. Osteocytes form a network within bone L = Lacune (osteocyte ‘caves’) C = Canaliculi

22. J Feng and LF Bonewald, UMKC (Seeman, E, NEJM, 2006 ) The Osteocyte Network The largest organ in the body

23. d Osteocytes receive signals (e.g. strain) then send signals to osteoclasts and osteoblasts on the surface of bone From Lynda Bonewald Strain

24. Sclerostin A signal from osteocytes to precursors of osteoblasts

26. Absence of sclerostin should increase bone formation

28. Sclerosteosis

33. Lasofoxifene: A Novel SERM

37. 4 years of Raloxifene decreased the risk of vertebral fracture* % with fracture Placebo RLX 60 RLX120 * Among women with vertebral fracture 36% 43%

38. 4 years of raloxifene did not decrease the risk of non-spine fractures % with fractures 0 6 12 18 24 30 36 15 10 5 0 Months Placebo Raloxifene RR = 0.93 (0.81, 1.06)

39. RUTH Trial: Raloxifene does not decrease the risk of CHD Barrett-Connor, N Engl J Med 2006;355:125

40. 5 years of tamoxifen reduced the risk of ER+, not ER- breast cancer Fisher et al. , J Natl Cancer Inst 1998;90:1371-88 # events 76%

41. • 5 years of tamoxifen continues to reduce breast cancer risk and mortality for at least 10 years after stopping treatment • Adverse effects (and costs) last only 5 years Early Breast Cancer Clinical Trialists Group. Lancet 2005;365:1687 Benefits Persist Off Treat

42. RUTH Trial: Raloxifene does not decrease the risk of CHD Barrett-Connor, N Engl J Med 2006;355:125

43. Lasofoxifene improved spine BMD more than raloxifene 3% 1.7% *p<0.05 vs placebo; †p<0.05 vs raloxifene. % Change From Baseline * * † Raloxifene 60 mg/d Lasofoxifene 0.25 mg/d Placebo

47. Percent Change vs. Placebo p ≤ 0.001 for all -12.5 (-25.1, 0.1) -15.8 (-26.7, -4.9) C-reactive Protein -15.8 (-19.5,-12.0) -16.2 (-19.7,-12.7) LDL-cholesterol +3.0 (2.7, 3.4) +2.9 (2.6, 3.2) Fem neck BMD +3.1 (2.8, 3.5) +3.0 (2.6, 3.3) Spine BMD 0.5 0.25 Lasofoxifene, mg/d