Endocrine Abstracts

The discovery of the RANK/RANKL/OPG axis provides opportunities for targeted interventions in a variety of skeletal disorders characterized by excessive bone resorption. In a proof of concept study, Bekker and colleagues demonstrated prompt, dose-related, reversible reduction in indices of bone turnover following subcutaneous administration of OPG-Fc in healthy adults. Inhibition of RANKL activity with denosumab, a fully human monoclonal IgG2 antibody that specifically inhibits RANKL binding to RANK, is being evaluated. In a placebo-controlled multicenter phase 2 dose-ranging study, biochemical markers of bone turnover were rapidly reduced and bone density in important skeletal sites was increased with various doses of denosumab administered every 3 or 6 months. Treatment was well tolerated without evidence of immunological dysfunction. Effectiveness and safety of denosumab administered every 6 months are being evaluated more extensively in phase 3 osteoporosis treatment and prevention studies. The ease and infrequency of dosing and avoidance of oral administration are attractive attributes, especially in patients with complicated medical regimens or intolerance to other agents.

Denosumab has also been shown to inhibit indices of bone resorption in patients with metastatic breast cancer and multiple myeloma. Inhibition of the RANK/RANKL/OPG axis offers the possibility of clinical benefit in other disorders such as Paget’s disease of bone, drug-induced bone loss, hypercalcemia of malignancy, and bone loss associated with inflammatory diseases like rheumatoid arthritis.

Inhibition of RANKL-dependent osteoclast activity by denosumab or other agents provides a biologically relevant mechanism of action and a convenient dosing regime that may be valuable for the management of patients with or at risk of osteoporosis and other skeletal conditions.