Novel Treatments

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  • Novel Treatments

    1. 1. Novel Treatments for Osteoporosis Prof. Steven R. Cummings, MD San Francisco Coordinating Center Support from Novartis, Lilly, Organon, Pfizer, Amgen, NIH, Zelos
    2. 2. Outline <ul><li>Controlling Osteoclasts: Denosumab </li></ul><ul><li>A Potential Cure for Osteoporosis? Osteocytes and Sclerostin </li></ul><ul><li>The Perfect SERM? </li></ul>
    3. 3. Denosumab Anti-RANKL Antibodies
    4. 4. RANK - OPG system <ul><li>Rank is a receptor on osteoclasts; </li></ul><ul><li>Rank-Ligand (Rank-L) binds to Rank. </li></ul><ul><li>This stimulates formation and activity of osteoclasts </li></ul><ul><li>The Rank - RankL interaction is necessary and sufficient for bone resorption by osteoclasts </li></ul>
    5. 5. OPG <ul><li>Rank is a receptor on osteoclasts; Rank-L binds to Rank. </li></ul><ul><li>This stimulates formation and activity of osteoclasts </li></ul><ul><li>The Rank - RankL interaction is necessary and sufficient for bone resorption by osteoclasts. </li></ul><ul><li>OPG (osteoprotegerin) is a soluble receptor for RankL. It binds RankL and inhibits bone resorption. </li></ul>
    6. 6. OPG knockout mouse <ul><li>Deletion of both copies of the OPG gene (-/-) causes severe osteoporosis because RankL acts without any competition from OPG </li></ul>
    7. 7. OPG and Denosumab <ul><li>Denosumab is an antibody to Rank-Ligand </li></ul><ul><li>Denosumab acts like OPG: it binds RankL and inhibits the development and activity of osteoclasts </li></ul>
    8. 8. Denosumab <ul><li>Denosumab is an antibody to Rank-ligand </li></ul><ul><li>Denosumab acts like OPG: it binds RankL and inhibits the development and activity of osteoclasts. </li></ul><ul><li>Given by injection every 6 months </li></ul>
    9. 9. Denosumab Phase II Trial <ul><li>412 postmenopausal women randomly assigned to 7 denosumab groups </li></ul><ul><ul><li>Q3 and Q6 mo intervals </li></ul></ul><ul><ul><li>4 different doses </li></ul></ul><ul><ul><li>Alendronate 70 mg/d </li></ul></ul><ul><ul><li>Placebo </li></ul></ul><ul><li>BMD and markers of bone turnover at 12 months </li></ul>McClung et al, NEJM 2006; 354:821
    10. 10. Denosumab vs. Alendronate vs. Placebo Alendronate Placebo Denosumab McClung et al, NEJM 2006; 354:821
    11. 11. Denosumab vs. Alendronate vs. Placebo Alendronate Placebo Denosumab McClung et al, NEJM 2006; 354:821
    12. 12. Stopping and restarting denosumab On Off P. Miller, et al, Bone 2008
    13. 13. Stopping and restarting denosumab P. Miller, et al, Bone 2008 On Off
    14. 14. Other biological roles of the Rank/RankL/OPG system <ul><li>Vascular calcification </li></ul><ul><ul><li>Loss of OPG causes calcification of the media of arteries; not really atherosclerosis </li></ul></ul><ul><li>Immune system </li></ul><ul><ul><li>T cells express RANKL; RANKL/RANK is essential for lymph node formation in baby mice </li></ul></ul>
    15. 15. The FREEDOM Trial The Effect of Denosumab on Fractures
    16. 16. The FREEDOM Trial <ul><li>Postmenopausal women aged 60 to 90 years </li></ul><ul><li>Spine or hip T-score < -2.5 </li></ul>Subjects: <ul><ul><li>Plus 400-800 IU vitamin D and 1 g of calcium </li></ul></ul><ul><li>Randomized trial </li></ul><ul><li>60 mg denosumab or placebo SC every 6 months for 36 months </li></ul>Study design:
    17. 17. The FREEDOM Trial <ul><li>No overall differences in rates of serious adverse events or of infection, malignancy or cardiovascular disease. </li></ul>Safety <ul><li>Denosumab reduced the risk of vertebral fractures by about 70% </li></ul><ul><li>It also significantly reduced the risk of low trauma nonvertebral and hip fractures </li></ul>Efficacy
    18. 18. Denosumab Summary <ul><li>Works by a unique and fundamental mechanism </li></ul><ul><li>Extremely potent </li></ul><ul><li>Reduces the risk of vertebral, hip and other fractures </li></ul><ul><li>Injection every 6 months may improve compliance </li></ul>
    19. 19. Osteocyte
    20. 20. Osteocytes form a network within bone L = Lacune (osteocyte ‘caves’) C = Canaliculi
    21. 21. Osteocytes, osteoblasts and osteoblasts <ul><li>There are > 100-times more osteocytes in bone than osteoclasts and osteoblasts combined </li></ul><ul><li>Osteocytes live for years. Osteoclasts and osteoblasts live for days to weeks. </li></ul>
    22. 22. J Feng and LF Bonewald, UMKC (Seeman, E, NEJM, 2006 ) The Osteocyte Network The largest organ in the body
    23. 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. 24. Sclerostin A signal from osteocytes to precursors of osteoblasts
    25. 25. Sclerostin <ul><li>Produced by mature osteocytes </li></ul><ul><ul><li>Not found in any other cell </li></ul></ul><ul><li>Produced in response to stimuli, such as decreased loading </li></ul><ul><li>Inhibits the formation of osteoblasts </li></ul>
    26. 26. Absence of sclerostin should increase bone formation
    27. 27. Sclerosteosis: lack of sclerostin <ul><li>Due to mutations in the SOST gene, decreasing the production of biologically active sclerostin </li></ul><ul><li>A disease with very high bone mass </li></ul><ul><ul><li>Narrowing of neural foramina </li></ul></ul><ul><ul><li>Can increase intracranial pressure causing death </li></ul></ul>
    28. 28. Sclerosteosis
    29. 29. Anti-sclerostin monoclonal antibodies (scl mAb) <ul><li>Block the action of sclerostin </li></ul><ul><li>Female rats, ovx (lost 12%) then treated for only 5 weeks </li></ul>
    30. 32. The possibility of ‘curing’ osteoporosis <ul><li>Could treat until BMD reaches a goal </li></ul><ul><li>What would be the goal? </li></ul><ul><ul><li>Normal bone mass for a young adult? </li></ul></ul><ul><ul><li>Normal risk of fractures for a young adult? </li></ul></ul><ul><li>Is there a limit? </li></ul><ul><ul><li>Can you form so much bone safely? </li></ul></ul>
    31. 33. Lasofoxifene: A Novel SERM
    32. 34. SERMs bind to estrogen receptors (ER), changing their conformation Brzozowski AM Nature, 1997 SERM (Raloxifene) Estradiol <ul><li>Depending on the change, the SERM: </li></ul><ul><li>May have anti-estrogen or pro-estrogen effects </li></ul><ul><li>The action is different in different tissues </li></ul>
    33. 35. The search for the perfect SERM <ul><li>From the days when estrogen kept a woman ‘Forever Young’ </li></ul><ul><li>Modulating the estrogen receptor could produce all the benefits without any harms </li></ul>
    34. 36. The Holy Grail: The perfect SERM <ul><li>Decreased risk of </li></ul><ul><li>Breast cancer </li></ul><ul><li>Vertebral fracture </li></ul><ul><li>Nonvertebral fracture </li></ul><ul><li>Cardiovascular disease </li></ul><ul><li>Without . </li></ul><ul><li>Endometrial cancer </li></ul><ul><li>Hot flushes </li></ul><ul><li>Venous thromboembolism </li></ul>
    35. 37. 4 years of Raloxifene decreased the risk of vertebral fracture* % with fracture Placebo RLX 60 RLX120 * Among women with vertebral fracture 36% 43%
    36. 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)
    37. 39. RUTH Trial: Raloxifene does not decrease the risk of CHD Barrett-Connor, N Engl J Med 2006;355:125
    38. 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%
    39. 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
    40. 42. RUTH Trial: Raloxifene does not decrease the risk of CHD Barrett-Connor, N Engl J Med 2006;355:125
    41. 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
    42. 44. The PEARL Trial* <ul><li>Randomized placebo-controlled trial </li></ul><ul><li>Two daily doses (0.25 mg or 0.5 mg) </li></ul><ul><ul><li>All received 400 to 800 IU vitamin D3 and 1 g of calcium daily </li></ul></ul><ul><li>5 years </li></ul>* P ostmenopausal E valuation and R isk-reduction with L asofoxifene
    43. 45. Participants <ul><li>8,556 women 59 to 80 years old </li></ul><ul><li>BMD T-score ≤ -2.5 and ≥ -4.5 at the femoral neck or spine </li></ul>
    44. 46. Doses <ul><li>0.5 mg / day had greater efficacy for most endpoints </li></ul><ul><li>Lasofoxifene 0.5 mg per day is the dose intended for use </li></ul>
    45. 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
    46. 48. Summary of PEARL results <ul><li>0.5 mg / day significantly reduced the risks of vertebral and nonvertebral fractures. </li></ul><ul><li>Lasofoxifene 0.5 mg per day also reduced the risk of breast cancer and cardiovascular disease </li></ul><ul><li>Lasofoxifene increased VTEs, but did not increase the risk of endometrial cancer </li></ul>
    47. 49. Summary <ul><li>Reduces the risk of </li></ul><ul><ul><li>Vertebral and nonvertebral fractures </li></ul></ul><ul><ul><li>ER+ breast cancer </li></ul></ul><ul><ul><li>Major CHD events </li></ul></ul><ul><ul><li>Stroke, not TIA </li></ul></ul><ul><li>Increases the risk of VTE </li></ul><ul><li>With no increased risk of endometrial cancer </li></ul>At the 0.5 mg dose lasofoxifene
    48. 50. Conclusion <ul><li>Advances in bone biology are producing potent new treatments </li></ul><ul><li>Denosumab has reached the maximum effect of antiresorptive therapy </li></ul><ul><li>Blocking sclerostin may allow unlimited bone formation </li></ul><ul><ul><li>Could cure osteoporosis </li></ul></ul><ul><li>Lasofoxifene may have achieved almost all of the benefits desired from hormonal treatments </li></ul>

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