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

PREVENTION & TREATMENT HRT tibolone SERMs bisphosphonates strontium calcitonin teriparatide ? strontium ? HRT anti-resorptivebone formation

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:

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 bisphosphon ates oesophageal cancer only with oral bisphosphonates taken for >3 years femoral stress fractures long term bisphosphonates Heckbert et al. Arch Intern Med 2008; 168: Seghizadeh et al. J Am Dent Assoc 2009; 140: Sharma et al. N Engl J Med 2008; 359: Green et al. BMJ 2010; 341: c4444 Schilcher et al. N Engl J Med 2011; 364:

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

OSTEOCLAST REGULATION TRAPcathepsin K RANK-L M-CSF PTH 1,25 (OH) 2 D estrogen calcitonin

OSTEOCLAST REGULATION TRAPcathepsin K RANK-L M-CSF PTH 1,25 (OH) 2 D estrogen calcitonin

DENOSUMAB AND FRACTURES 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 ) clinical hip fracture HR 0.60 (CI ) p<0.001 Cummings et al. N Engl J Med 2009; 361: denosumab placebo p<0.05

OSTEOCLAST REGULATION TRAPcathepsin K RANK-L M-CSF PTH 1,25 (OH) 2 D estrogen calcitonin

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

CATHEPSIN K INHIBITORS odanacatibONO-5334 Bone et al. J Bone Miner Res 2010; 25: Eastell et al. J Bone Miner Res 2011; 26:

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

OSTEOBLAST REGULATION PTH Wnt/LRP BMP estrogen cortisol

OSTEOBLAST REGULATION PTH Wnt/LRP BMP estrogen dkk sclerostin cortisol

OSTEOBLAST REGULATION PTH Wnt/LRP BMP estrogen dkk sclerostin cortisol

SCLEROSTIN ANTIBODY AMG 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

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

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