Denosumab, sold under the brand name Prolia among others, is a human monoclonal antibody used for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumor of bone.

The most common side effects are joint and muscle pain in the arms or legs.

Denosumab is an inhibitor of RANKL (receptor activator of nuclear factor kappa-Β ligand), which works by decreasing the development of osteoclasts, which are cells that break down bone. Denosumab is a human monoclonal IgG2 antibody that targets the protein RANKL, which is essential for the formation, function and survival of osteoclasts, the cell type responsible for bone resorption. Denosumab binds to RANKL with high affinity and specificity, preventing the interaction between RANKL and RANK. Increased osteoclast activity stimulated by RANKL is a key mediator of bone destruction in metastatic bone disease. This leads to a reduction in osteoclast numbers and function, and a decrease in bone resorption, cancer-induced bone destruction. It also leads to a decrease in bone resorption in cortical and trabecular bones. It was developed by the biotechnology company Amgen.

Denosumab is used for those with osteoporosis at high risk for fractures, bone loss due to certain medications, and in those with bone metastases.

A 2012 meta-analysis found that denosumab was better than placebo, zoledronic acid, and pamidronate, in reducing the risk of fractures in those with cancer.

In those with postmenopausal osteoporosis denosumab decreases the risk of fractures but increases the risk of infection. A 2013 review concluded that it is a reasonable treatment for postmenopausal osteoporosis. A 2017 review did not find benefit in males.

Bone remodeling is the process by which the body continuously removes old bone tissue and replaces it with new bone.^{[citation needed]} It is driven by various types of cells, most notably osteoblasts (which secrete new bone) and osteoclasts (which break down bone); osteocytes are also present in bone.^{[citation needed]}

Precursors to osteoclasts, called pre-osteoclasts, express surface receptors called RANK (receptor activator of nuclear factor-kappa B). RANK is a member of the tumor necrosis factor receptor (TNFR) superfamily. RANK is activated by RANKL (the RANK-Ligand), which exists as cell surface molecules on osteoblasts. Activation of RANK by RANKL promotes the maturation of pre-osteoclasts into osteoclasts. Denosumab inhibits this maturation of osteoclasts by binding to and inhibiting RANKL. Denosumab mimics the natural action of osteoprotegerin, an endogenous RANKL inhibitor, that presents with decreasing concentrations (and perhaps decreased effectiveness) in people with osteoporosis. This protects bone from degradation, and helps to counter the progression of the disease.