New targets for intervention in the treatment of postmenopausal osteoporosis.

Postmenopausal osteoporosis is a disease of high bone remodeling, with an imbalance of bone resorption over bone formation, resulting in decreased bone mineral density and disruption of bone microarchitecture. With our improved understanding of the molecular and cellular regulators and mediators of bone remodeling, new targets for therapeutic intervention have been identified. Receptor activator of nuclear factor κB ligand (RANKL) is the principal regulator of osteoclast differentiation, activity, and survival; denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and is approved for the treatment of women with postmenopausal osteoporosis at high risk of fractures. Cathepsin K is a protease produced by activated osteoclasts that degrades the protein matrix of bone. An inhibitor of cathepsin K, odanacatib, is in phase III clinical trials for the treatment of postmenopausal osteoporosis; it decreases bone resorption while seeming to suppress bone formation less than other antiresorptive agents. Sclerostin is a cytokine produced by osteocytes that inhibits osteoblastic bone formation; investigational monoclonal antibodies to sclerostin, such as AMG 785, have osteoanabolic properties with the potential to improve clinical outcomes in patients with osteoporosis. These and other novel interventions that target newly recognized regulators of bone remodeling are promising agents for the treatment of osteoporosis.