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Advances in osteoporosis treatment

Advances in osteoporosis treatment. John C Stevenson National Heart & Lung Institute Imperial College London Royal Brompton Hospital London, UK. PREVENTION & TREATMENT. anti-resorptive. bone formation. HRT tibolone SERMs bisphosphonates strontium calcitonin. teriparatide

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Advances in osteoporosis treatment

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  1. Advances in osteoporosis treatment John C Stevenson National Heart & Lung Institute Imperial College London Royal Brompton Hospital London, UK

  2. PREVENTION & TREATMENT anti-resorptive bone formation • HRT • tibolone • SERMs • bisphosphonates • strontium • calcitonin • teriparatide • ? strontium • ? HRT

  3. HRT RISKS • breast cancer • inconclusive for E + P • no increase with E alone • stroke • dose / route • no increase if HRT initiated below age 60 years • venous thrombo-embolism • dose / route • transient increase seen with oral HRT • no increase with transdermal HRT Stevenson et al. Atherosclerosis 2009; 207: 336-40

  4. BISPHOSPHONATES: RISKS • gastro-intestinal side-effects • atrial fibrillation • more severe with IV bisphosphonates • osteonecrosis of the jaw • more common with IV bisphosphonates • follows dental extractions only • inflammatory eye disease • only with IV bisphosphonates • oesophageal cancer • only with oral bisphosphonates • taken for >3 years • femoral stress fractures • long term bisphosphonates Heckbert et al. Arch Intern Med 2008; 168: 826-31 Seghizadeh et al. J Am Dent Assoc 2009; 140: 61-66 Sharma et al. N Engl J Med 2008; 359: 1410-11 Green et al. BMJ 2010; 341: c4444 Schilcher et al. N Engl J Med 2011; 364: 1728-37

  5. NEW TREATMENT APPROACHES • target signalling systems to bone cells • target cellular action of bone cells

  6. OSTEOCLAST REGULATION PTH estrogen 1,25 (OH)2D M-CSF calcitonin TRAP cathepsin K RANK-L

  7. OSTEOCLAST REGULATION PTH estrogen 1,25 (OH)2D M-CSF calcitonin TRAP cathepsin K RANK-L

  8. DENOSUMAB AND FRACTURES denosumab • 7.868 osteoporotic women • mean age 72.3 years • randomised to denosumab 60 mg 6-monthly or placebo • studied over median 3 years • radiographic vertebral fracture HR 0.32 (CI 0.26-0.41) • clinical hip fracture HR 0.60 (CI 0.37-0.97) placebo p<0.001 p<0.05 Cummings et al. N Engl J Med 2009; 361: 756-65

  9. OSTEOCLAST REGULATION PTH estrogen 1,25 (OH)2D M-CSF calcitonin TRAP cathepsin K RANK-L

  10. CATHEPSIN K INHIBITORS • odanacatib (Merck) • 50 mg weekly • phase 3 • ONO-5334 (Ono) • 300 mg daily • phase 2 • MIV-711 (Medivir) • pre-clinical

  11. CATHEPSIN K INHIBITORS odanacatib ONO-5334 Bone et al. J Bone Miner Res 2010; 25: 937-47 Eastell et al. J Bone Miner Res 2011; 26: 1303-12

  12. CATHEPSIN K INHIBITORS • similar reduction in bone resorption markers to bisphosphonates • lesser reduction in bone formation markers than with bisphosphonates • rapid offset of action after stopping therapy • skin adverse events seen with balicatib • no serious adverse events seen with odanacatib or ONO-5334 Boonen et al. Curr Osteoporos Rep 2012; 10: 73-79

  13. OSTEOBLAST REGULATION estrogen PTH cortisol BMP Wnt/LRP

  14. OSTEOBLAST REGULATION estrogen PTH cortisol BMP dkk Wnt/LRP sclerostin

  15. OSTEOBLAST REGULATION estrogen PTH cortisol BMP dkk Wnt/LRP sclerostin

  16. SCLEROSTIN ANTIBODY AMG 785 10 mg/kg SC 5 mg/kg IV 10 mg/kg SC 5 mg/kg IV Padhi et al. J Bone Miner Res 2011; 26: 19-26

  17. FUTURE THERAPIES • new bisphosphonates • zoledronate IV infusion annually (safety?) • oestrogen + SERM • CEE + bazedoxifene • cathepsin K inhibitors • odanacatib • antibodies to sclerostin, dickkopf-1 • alternative administration of PTH • e.g. intranasal spray

  18. CONCLUSIONS • various treatment options are available, but all carry risks • HRT remains treatment of choice for prevention in women • new treatments are being developed from our better understanding of bone physiology • targeting cell signalling systems may affect tissues other then bone

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