A review of the efficacy and safety of denosumab in postmenopausal women with osteoporosis.

Denosumab, a fully human monoclonal antibody to RANK ligand [RANK-L]) was approved for the treatment of postmenopausal osteoporosis in June 2010, and is highly effective in reducing the risk of vertebral, nonvertebral, and hip fracture risk. The registration of denosumab was the culmination of the discovery and clarification of the internal bone microenvironment regulation of bone remodeling: the osteoblast-produced competitors: RANK-L and osteoprotogerin; and the osteoclast receptor: RANK. When RANK-L is upregulated in the estrogen-deficient state and exceeds the amount of osteoprotogerin, there is an increase in osteoclastogenesis and bone resorption, and this is the major mechanism for bone mass loss and osteoporotic fractures in the postmenopausal state. The subsequent development of the human monoclonal antibody to RANK-L (denosumab) was the first product developed to reduce bone resorption by inhibiting RANK-L binding to RANK. Denosumab does not accumulate in bone, and has a unique pharmacokinetics so that its biological effect at the registered dose of 60 mg by subcutaneous injection every 6 months is no longer effective, at least as measured by an increase in the bone resorption marker collagen-cross-link C-telopeptide and a decline in bone mineral density as measured by dual energy X-ray absorptiometry. This unique pharmacokinetic profile thus suggests that in order to maintain the effectiveness of denosumab, continuous administration might be necessary. Extension of the registration trial ('FREEDOM') 5-year data indicates continued safety and efficacy, and will be extended to 10 years so that even longer-term data will be forthcoming. The profound but reversible suppression of bone turnover that is seen with denosumab partly explains the continuous increase in bone mineral density seen through 8 years of the phase II clinical trials. Denosumab offers a highly effective and safe parenteral therapy for osteoporosis and is being studied long term with the extension of the FREEDOM trial, and in other osteoporotic states - in men and glucocorticoid-induced osteoporosis.