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Osteoporosis and Fracture in Men with Prostate Cancer

Denosumab increased bone-mineral density and lowered fracture incidence in men receiving androgen-deprivation therapy for nonmetastatic disease.

Rising use of androgen-deprivation therapy (ADT) for men with nonmetastatic prostate cancer has resulted in higher rates of both osteoporosis and nonpathologic fractures in these patients. Bisphosphonates have been widely used to lower incidence of skeletal events (e.g., pathologic fractures in patients with metastatic disease) and to attenuate development of osteoporosis. However, use of this class of drugs carries a small but real risk for development of renal insufficiency and osteonecrosis. A novel compound that might be used in this setting is denosumab, a human monoclonal antibody that binds to the receptor activator of nuclear factor-B ligand (a key mediator of osteoclast function and survival).

To characterize the effects of denosumab on bone-mineral density (BMD) and fracture risk, an international group of investigators conducted an industry-supported, phase III double-blind study involving 1468 prostate cancer patients who received ADT for 12 months. Patients were older than 70 or, if younger, had osteoporosis or histories of osteoporotic fractures. Prior use of bisphosphonates was permitted if 3 years had elapsed since last oral administration or 5 years had elapsed since last intravenous administration. Patients were randomized to receive denosumab (60 mg subcutaneously) or placebo every 6 months; 63% of patients completed the 36-month study.

At 24 months, patients who received denosumab achieved greater improvements in lumbar spine BMD (the primary endpoint) than did those in the placebo group (5.6% vs. –1.0%; P<0.001) and also achieved greater improvements in BMD at the total hip, femoral neck, distal third of the radius, and whole body (P<0.001 for all comparisons). In addition, the denosumab group experienced lower incidence of new vertebral fractures at 36 months (1.5% vs. 3.9%; relative risk, 0.38; P=0.006). Adverse events were relatively rare and were similar for both groups.

Comment: The role of ADT in men with metastatic prostate cancer (particularly those subsets of patients who receive external beam radiotherapy or who have node-positive disease) has been prospectively established. However, the most common use of ADT in the U.S. is for nonmetastatic prostate-specific antigen failure, for which prospective evidence of benefit is lacking. The current findings clearly demonstrate the efficacy and safety of denosumab to improve BMD and lower fracture rates in men who are treated for nonmetastatic disease. However, we must consider whether decreasing the use of ADT for nonmetastatic disease might negate the need for many patients with prostate cancer to receive osteoporosis therapy in the first place.

— Robert Dreicer, MD, MS, FACP

Published in Journal Watch Oncology and Hematology August 11, 2009

Citation(s):

Smith MR et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009 Aug 20; 361:745. (http://dx.doi.org/10.1056/NEJMoa0809003)

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• Medline abstract (Free)

Khosla S. Increasing options for the treatment of osteoporosis. N Engl J Med 2009 Aug 20; 361:818. (http://dx.doi.org/10.1056/NEJMe0905480)

• Original article (Subscription may be required)
• Medline abstract (Free)