Denosumab

Denosumab is a fully human IgG2 monoclonal antibody that binds and neutralizes RANKL (receptor activator of nuclear factor-κB ligand), the cytokine required for osteoclast differentiation, activation, and survival; by blocking the RANK–RANKL axis it profoundly suppresses bone resorption. It is FDA-approved for osteoporosis in postmenopausal women and men at high fracture risk (Prolia, 60 mg SC every 6 months), prevention of skeletal-related events in bone metastases (Xgeva, higher dose), and giant cell tumour of bone. Unlike bisphosphonates, RANKL inhibition also affects immune cells and tumour microenvironments because RANKL is expressed on osteoblasts, activated T cells, and stromal cells beyond bone; this has prompted research into oncological and immunological applications. Observational data suggest possible cardiovascular and all-cause mortality reductions in denosumab-treated osteoporosis patients beyond fracture prevention, paralleling findings with bisphosphonates, but confounding and frailty-bias complicate interpretation. A critical safety feature is rebound bone loss if therapy is discontinued without transitioning to a bisphosphonate, as osteoclast activity surges; rare osteonecrosis of the jaw and atypical femoral fractures are also reported.