The document discusses several novel treatments for osteoporosis, including denosumab, anti-sclerostin monoclonal antibodies, and lasofoxifene. Denosumab is an antibody to RANK ligand that inhibits bone resorption and reduces fracture risk. Blocking sclerostin may allow unlimited bone formation and a potential cure for osteoporosis. Lasofoxifene reduces fracture risk and also reduces risks of breast cancer and heart disease, with no increased risk of uterine cancer.

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

2. Outline Controlling Osteoclasts: Denosumab A Potential Cure for Osteoporosis? Osteocytes and Sclerostin The Perfect SERM?

3. Denosumab Anti-RANKL Antibodies

4. RANK - OPG system Rank is a receptor on osteoclasts; Rank-Ligand (Rank-L) binds to Rank. This stimulates formation and activity of osteoclasts The Rank - RankL interaction is necessary and sufficient for bone resorption by osteoclasts

5. OPG Rank is a receptor on osteoclasts; Rank-L binds to Rank. This stimulates formation and activity of osteoclasts The Rank - RankL interaction is necessary and sufficient for bone resorption by osteoclasts. OPG (osteoprotegerin) is a soluble receptor for RankL. It binds RankL and inhibits bone resorption.

6. OPG knockout mouse Deletion of both copies of the OPG gene (-/-) causes severe osteoporosis because RankL acts without any competition from OPG

7. OPG and Denosumab Denosumab is an antibody to Rank-Ligand Denosumab acts like OPG: it binds RankL and inhibits the development and activity of osteoclasts

8. Denosumab Denosumab is an antibody to Rank-ligand Denosumab acts like OPG: it binds RankL and inhibits the development and activity of osteoclasts. Given by injection every 6 months

9. Denosumab Phase II Trial 412 postmenopausal women randomly assigned to 7 denosumab groups Q3 and Q6 mo intervals 4 different doses Alendronate 70 mg/d Placebo BMD and markers of bone turnover at 12 months McClung et al, NEJM 2006; 354:821

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

14. Other biological roles of the Rank/RankL/OPG system Vascular calcification Loss of OPG causes calcification of the media of arteries; not really atherosclerosis Immune system T cells express RANKL; RANKL/RANK is essential for lymph node formation in baby mice

15. The FREEDOM Trial The Effect of Denosumab on Fractures

16. The FREEDOM Trial Postmenopausal women aged 60 to 90 years Spine or hip T-score < -2.5 Subjects: Plus 400-800 IU vitamin D and 1 g of calcium Randomized trial 60 mg denosumab or placebo SC every 6 months for 36 months Study design:

17. The FREEDOM Trial No overall differences in rates of serious adverse events or of infection, malignancy or cardiovascular disease. Safety Denosumab reduced the risk of vertebral fractures by about 70% It also significantly reduced the risk of low trauma nonvertebral and hip fractures Efficacy

18. Denosumab Summary Works by a unique and fundamental mechanism Extremely potent Reduces the risk of vertebral, hip and other fractures Injection every 6 months may improve compliance

19. Osteocyte

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

21. Osteocytes, osteoblasts and osteoblasts There are > 100-times more osteocytes in bone than osteoclasts and osteoblasts combined Osteocytes live for years. Osteoclasts and osteoblasts live for days to weeks.

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

25. Sclerostin Produced by mature osteocytes Not found in any other cell Produced in response to stimuli, such as decreased loading Inhibits the formation of osteoblasts

26. Absence of sclerostin should increase bone formation

27. Sclerosteosis: lack of sclerostin Due to mutations in the SOST gene, decreasing the production of biologically active sclerostin A disease with very high bone mass Narrowing of neural foramina Can increase intracranial pressure causing death

28. Sclerosteosis

29. Anti-sclerostin monoclonal antibodies (scl mAb) Block the action of sclerostin Female rats, ovx (lost 12%) then treated for only 5 weeks

32. The possibility of ‘curing’ osteoporosis Could treat until BMD reaches a goal What would be the goal? Normal bone mass for a young adult? Normal risk of fractures for a young adult? Is there a limit? Can you form so much bone safely?

33. Lasofoxifene: A Novel SERM

34. SERMs bind to estrogen receptors (ER), changing their conformation Brzozowski AM Nature, 1997 SERM (Raloxifene) Estradiol Depending on the change, the SERM: May have anti-estrogen or pro-estrogen effects The action is different in different tissues

35. The search for the perfect SERM From the days when estrogen kept a woman ‘Forever Young’ Modulating the estrogen receptor could produce all the benefits without any harms

36. The Holy Grail: The perfect SERM Decreased risk of Breast cancer Vertebral fracture Nonvertebral fracture Cardiovascular disease Without . Endometrial cancer Hot flushes Venous thromboembolism

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

44. The PEARL Trial* Randomized placebo-controlled trial Two daily doses (0.25 mg or 0.5 mg) All received 400 to 800 IU vitamin D3 and 1 g of calcium daily 5 years * P ostmenopausal E valuation and R isk-reduction with L asofoxifene

45. Participants 8,556 women 59 to 80 years old BMD T-score ≤ -2.5 and ≥ -4.5 at the femoral neck or spine

46. Doses 0.5 mg / day had greater efficacy for most endpoints Lasofoxifene 0.5 mg per day is the dose intended for use

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

48. Summary of PEARL results 0.5 mg / day significantly reduced the risks of vertebral and nonvertebral fractures. Lasofoxifene 0.5 mg per day also reduced the risk of breast cancer and cardiovascular disease Lasofoxifene increased VTEs, but did not increase the risk of endometrial cancer

49. Summary Reduces the risk of Vertebral and nonvertebral fractures ER+ breast cancer Major CHD events Stroke, not TIA Increases the risk of VTE With no increased risk of endometrial cancer At the 0.5 mg dose lasofoxifene

50. Conclusion Advances in bone biology are producing potent new treatments Denosumab has reached the maximum effect of antiresorptive therapy Blocking sclerostin may allow unlimited bone formation Could cure osteoporosis Lasofoxifene may have achieved almost all of the benefits desired from hormonal treatments