Denosumab in men receiving androgen-deprivation therapy for prostate cancer

Abstract

Background: Androgen-deprivation therapy is well-established for treating prostate cancer but is associated with bone loss and an increased risk of fracture. We investigated the effects of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, on bone mineral density and fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer.

Methods: In this double-blind, multicenter study, we randomly assigned patients to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (734 patients in each group). The primary end point was percent change in bone mineral density at the lumbar spine at 24 months. Key secondary end points included percent change in bone mineral densities at the femoral neck and total hip at 24 months and at all three sites at 36 months, as well as incidence of new vertebral fractures.

Results: At 24 months, bone mineral density of the lumbar spine had increased by 5.6% in the denosumab group as compared with a loss of 1.0% in the placebo group (P<0.001); significant differences between the two groups were seen at as early as 1 month and sustained through 36 months. Denosumab therapy was also associated with significant increases in bone mineral density at the total hip, femoral neck, and distal third of the radius at all time points. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5%, vs. 3.9% with placebo) (relative risk, 0.38; 95% confidence interval, 0.19 to 0.78; P=0.006). Rates of adverse events were similar between the two groups.

Conclusions: Denosumab was associated with increased bone mineral density at all sites and a reduction in the incidence of new vertebral fractures among men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. (ClinicalTrials.gov number, NCT00089674.)

Figure 1. Enrollment, Randomization, and Follow-up of the Study Patients

Figure 2. Mean Percent Changes from Baseline Bone Mineral Density (BMD) Values during the Study Period, According to Skeletal Site and Study Group

Results are presented as least-squares means of the BMDs of the lumbar spine (Panel A), the total hip (Panel B), the femoral neck (Panel C), and the distal third of the radius (Panel D). All values shown were significantly higher in the denosumab group than in the placebo group (P≤0.001). The means were estimated with the use of analysis-of-covariance models adjusting for study group, stratification variables, baseline BMD value, densitometer type, and the interaction between baseline BMD value and densitometer type. The means are based on data for 734 patients in each of the two groups except for the distal third of the radius, for which data were available for 161 patients in the denosumab group and 148 patients in the placebo group. I bars indicate 95% confidence intervals.

Figure 3. Cumulative Incidence of New Vertebral Fracture at 12, 24, and 36 Months, According to Study Group

The relative risk for vertebral fracture among 679 patients in the denosumab group as compared with 673 patients in the placebo group was 0.15 at 12 months, 0.31 at 24 months, and 0.38 at 36 months.