Osteoporosis is characterized by compromised bone strength, predisposing to an increased risk of fracture. Because bone is constantly remodeled, and bone mass and structure are determined by the balance between bone resorption and bone formation, it is important to maintain normal bone turnover. Therefore, therapies that reduce bone resorption have been the mainstream of osteoporosis treatment. Receptor activator of nuclear factor-kappa B ligand (RANKL)-RANK signaling was found to play a pivotal role in the regulation of osteoclastic bone resorption, and inhibition of RANKL-RANK system has become an important therapeutic target for the treatment of osteoporosis. Denosumab, a fully human monoclonal anti-RANKL neutralizing antibody, is developed as a drug for the treatment of osteoporosis. This review summarized pharmacokinetic and pharmacodynamic properties of denosumab, clinical studies including phase 2 dose-ranging and its extension study, phase 3 fracture prevention study (FREEDOM) with extension up to 10 years, studies on male osteoporosis (ADAMO study), and on glucocorticoid-induced osteoporosis, along with relevant clinical studies in Japan. In addition, mechanism of denosumab action that can explain its long-term sustained effects, combination and sequential treatment as well as the problems in discontinuation of denosumab, and finally safety of denosumab therapy is discussed.
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