Denosumab Linked to Lower Fracture Rate in Postmenopausal Women With Osteoporosis

Laurie Barclay, MD

August 11, 2009

August 11, 2009 — Denosumab injections are associated with lower fracture rate in postmenopausal women with osteoporosis, according to the results of an international, randomized, double-blind, placebo-controlled trial reported online August 11 in the New England Journal of Medicine.

"Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density," write Steven R. Cummings, MD, from University of California–San Francisco, and colleagues from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. "Given its unique actions, denosumab may be useful in the treatment of osteoporosis."

Women aged 60 to 90 years with a bone mineral density T-score of less than −2.5 but not less than −4.0 at the lumbar spine or hip were randomly assigned to receive 60 mg denosumab (n = 3902) or placebo (n = 3906), given every 6 months as subcutaneous injections, for 36 months. The main study endpoint was new radiographic vertebral fracture by 36 months, and secondary outcomes were hip and nonvertebral fractures.

At 36 months, cumulative incidence of new radiographic vertebral fracture was 2.3% in the denosumab group and 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 – 0.41; relative risk reduction, 68%; P < .001). The cumulative incidence of hip fractures was 0.7% in the denosumab group vs 1.2% in the placebo group (hazard ratio [HR], 0.60; 95% CI, 0.37 – 0.97; relative risk reduction, 40%; P =.04). For nonvertebral fractures, the cumulative incidence was 6.5% in the denosumab group compared with 8.0% in the placebo group (HR, 0.80; 95% CI, 0.67 – 0.95; relative risk reduction, 20%; P = .01).

Both groups had similar incidence of serious adverse effects, including infection, cardiovascular disease, cancer, delayed fracture healing, and hypocalcemia. No patients in either group developed jaw osteonecrosis. There were no adverse reactions to denosumab injections. However, eczema occurred more often with denosumab (3.0% vs 1.7%), as did flatulence (2.2% vs 1.4%) and cellulitis (0.3% vs 0.1%).

"Denosumab given subcutaneously twice yearly for 36 months was associated with reduced risk of vertebral, nonvertebral and hip fractures in postmenopausal women with osteoporosis," the study authors write.

In an accompanying editorial, Sundeep Khosla, MD, from the Mayo Clinic in Rochester, Minnesota, notes potential concerns regarding adverse events with long-term use of denosumab, as well as high cost and compliance issues.

"The real need in osteoporosis treatment is for additional anabolic agents," Dr. Khosla writes. "Our success or failure in combating osteoporosis increasingly depends not so much on the drugs available to us but rather on our ability to engage our patients and ensure that they take the medications we prescribe."

Amgen supported this study, employs 6 of its authors, and has various financial relationships with some other study authors. Some of the study authors have disclosed various financial arrangements with other pharmaceutical manufacturers. Dr. Khosla has disclosed no relevant financial relationships.

N Engl J Med. Published online August 11, 2009.

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