Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis

Denosumab is a fully human monoclonal antibody against the receptor activator of the cytokine, nuclear factor-κB ligand, which is of critical importance for the formation, function, and survival of osteoclasts. This antibody binds nuclear factor-κB ligand and reversibly inhibits osteoclast-mediated bone resorption in osteoclasts and osteoclast precursors. Earlier studies reported that subcutaneous administration of denosumab every 6 months reduced bone turnover and increased bone mineral density. This international, randomized, placebo-controlled trial evaluated the effect of denosumab on the risk of fracture in 7808 postmenopausal women with osteoporosis. Participants had a bone mineral density T score less than -2.5 at the lumbar spine or total hip. Women with T scores less than -4.0 were excluded. Their ages ranged from 60 to 90 years. The study subjects used in the final analysis had been randomized to receive subcutaneous injections of 60 mg of denosumab (n = 3902) or placebo (n = 3906) every 6 months for 36 months. A new vertebral fracture was the primary outcome. The occurrence of nonvertebral fracture and hip fracture were the secondary end points. At 36-months, the cumulative incidence of new radiographic vertebral fracture was reduced by 68% in the denosumab group compared to the placebo group (denosumab: 2.3% vs. placebo: 7.2%); the risk ratio was 0.32, with a 95% confidence interval [CI] of 0.26-0.41; P < 0.001). The risk of hip fracture was reduced by 40% with the drug compared to the placebo group (cumulative incidence of denosumab: 0.7% vs. placebo: 1.2%); the hazard ratio was 0.60, with a 95% CI of 0.37-0.97; P = 0.04. Similarly, denosumab reduced the cumulative incidence of nonvertebral fracture from 8.0% in the placebo group to 6.5% in the denosumab group (hazard ratio, 0.80; 95% CI, 0.67-0.95; P = 0.01)-a 20% relative reduction in risk. During the 36-months of the study, denosumab was not associated with a significant increase in the incidence of infection, cancer, or cardiovascular events. No increase was found in the occurrence of delayed fracture healing or hypocalcemia and other adverse effects associated with potent antiresorptive agents. Osteonecrosis of the jaw was not observed in either group. These findings show that subcutaneous injections of denosumab every 6 months for 36 months is associated with a significant reduction in the risk of vertebral, hip, and nonvertebral fractures among postmenopausal women with osteoporosis.