Stay Tuned--New Drug on the Horizon for Treating Osteoporosis Denosumab for Prevention of Fractures in Postmenopausal Women With Osteoporosis

Objective: To evaluate denosumab, a human monoclonal antibody against the receptor activator of nuclear factor-κB (RANKL), a cytokine essential for formation, function, and survival of osteoclasts, as a treatment for osteoporosis in postmenopausal women. Design: International, randomized, placebo-controlled trial. Participants: 7868 women between the ages of 60 and 90 years with a bone mineral density T score of less than -2.5 at the lumbar spine or total hip. Methods: 3933 patients treated with denosumab and 3935 controls were given subcutaneous injections of 60 mg denosumab or placebo every 6 months for 36 months after random assignment to treatment groups. All subjects received daily calcium supplements of at least 1000 mg as well as 800 IU vitamin D. Lateral spine radiographs were taken each year and were assessed for vertebral fractures. Subjects were also followed up for non-vertebral fractures. Bone mineral density was measured at baseline and then annually at the hip and lumbar spine. A committee of experts evaluated all subjects for adverse events, assessed the healing of nonvertebral fractures, and looked for denosumab-specific antibodies in serum collections. Side effects were also recorded. Results: The groups were similar at baseline with mean bone mineral density T scores of -2.8 at the lumbar spine, -1.9 at the hip, and -2.2 at the femoral neck. Twenty-four percent of subjects had a vertebral fracture at baseline. Eight-two percent of subjects completed the 36-month study, and 76% received all the planned injections of denosumab. New radiographic vertebral fractures were seen over the 36 months in 7.2% of the placebo patients and only 2.3% of the study patients—a 68% reduction in relative risk. The drug also reduced the risk of non-vertebral fracture by 20% and the risk of hip fracture by 40%. After 36 months, the drug resulted in a relative increase of bone mineral density of 9.2%. At the same time, there were no significant differences in adverse events or the incidence of cancer, cardiovascular events, or infections. No cases of jaw osteonecrosis occurred in either the placebo or denosumab groups. Conclusions: Subcutaneous, twice-annual 60-mg doses of denosumab for 36 months significantly decreased the risk of vertebral, non-vertebral, and hip fractures in postmenopausal, osteoporotic women while increasing bone density. This drug will be an alternative to osteoporosis treatment currently being used by decreasing bone resorption and increasing bone density through inhibition of RANKL. Reviewer's Comments: In this study, there were no adverse effects on fracture healing and no cases of jaw osteonecrosis. There has yet to be a head-to-head trial comparing denosumab and the bisphosphonate drugs. The Food and Drug Administration (FDA) study committee has recommended denosumab for FDA approval. In addition, the next issue of this journal contains several good discussion letters about this article. (ReviewerSterling R. Schow, DMD).