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Published at www.nejm.org August 11, 2009 (10.1056/NEJMoa0809493)

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ABSTRACT

Background Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-B ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis.

Methods We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures.

Results As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001) — a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04) — a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) — a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab.

Conclusions Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791 [ClinicalTrials.gov] .)

Source Information

From the San Francisco Coordinating Center, California Pacific Medical Center Research Institute and University of California, San Francisco, San Francisco (S.R.C.); Amgen, Thousand Oaks, CA (J.S.M., H.B.Z., M.A., A.W., C.L., S.S.); Oregon Osteoporosis Center, Portland (M.R.M.); Columbia University Medical Center, New York (E.S.S.); University of Sheffield, Sheffield, United Kingdom (R.E.); University of Auckland, Auckland, New Zealand (I.R.R.); Université de Lyon and INSERM Research Unit 831, Lyon, France (P.D.); the Center for Clinical and Basic Research, Pardubice, Czech Republic (S.K.); University of Verona, Verona, Italy (S.A.); Instituto de Investigaciones Metabolicas and University of Salvador, Buenos Aires, Argentina (J.Z.); and the Center for Clinical and Basic Research, Ballerup, Denmark (C.C.).

This article (10.1056/NEJMoa0809493) was published on August 11, 2009, at NEJM.org.

Address reprint requests to Dr. Cummings at 185 Berry St. Lobby 4, Suite 5700, San Francisco, CA 94107, or at hglicklandes{at}sfcc-cpmc.net.

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