Denosumab Increase Bone Mineral Density in Men Receiving Androgen-Deprivation Therapy

Background

Androgen-deprivation therapy (ADT) is the standard of care in the management of men with advanced prostate cancer, and it is achieved through surgical castration or treatment with gonadotropin-releasing hormone agonists. This form of therapy is associated with adverse effects on bone health, resulting in reduced bone mineral density (BMD) and increased fracture risk. The risk for fracture increases with a longer duration of ADT. Although studies have shown that drugs such as bisphosphonates and selective estrogen-receptor modulators can prevent bone loss in men receiving ADT, there is little evidence to suggest that they prevent fractures.¹

Denosumab is a fully human monoclonal antibody that regulates osteoclast formation, function, and survival by targeting nuclear factor kappa-B ligand. Studies have demonstrated that denosumab significantly increases BMD in women with breast cancer receiving aromatase inhibitor therapy. It also improves BMD and bone turnover in postmenopausal women with low bone mass.¹

In this 36-month, phase 3, randomized, double-blind, placebo-controlled trial, Smith and colleagues evaluated the effects of denosumab on BMD and fracture risk in men with nonmetastatic prostate cancer who were receiving ADT.¹

Study Design

The study was conducted at 156 sites in North America and Europe from April 2004 to June 2008 and enrolled men receiving ADT for prostate cancer who were expected to undergo the treatment for at least 12 months of the study duration. Eligible men were 70 years or older, or less than 70 years with a baseline BMD T-score of the lumbar spine, total hip, or femoral neck that was less than −1.0 or a history of osteoporotic fracture.¹

Patients receiving antineoplastic therapy or radiotherapy were excluded, as were those who were currently using oral bisphosphonates, had previously received oral bisphosphonates for 3 or more years, or had received intravenous bisphosphonates within 5 years of the study. Men who had a prostate-specific antigen (PSA) level of more than 5 ng/mL after receiving ADT for more than 1 month, or those with a BMD T-score of the lumbar spine, total hip, or femoral neck of less than −4.0, were also excluded.¹

Patients were stratified according to age (<70 years vs ≥70 years) and duration of previous ADT (≤6 months vs > 6 months). The men were randomized 1:1 to receive subcutaneous injections of denosumab 60 mg or placebo every 6 months. All patients were instructed to take oral calcium and vitamin D supplements.¹

The primary study end point was the percentage change from baseline in BMD at the lumbar spine at 24 months. Secondary end points included the percentage change from baseline in BMD at the femoral neck and total hip at 24 months, and at all 3 sites at 36 months, and the incidence of newly diagnosed vertebral fractures through 36 months. Exploratory end points included the percentage changes in BMD of the whole body and distal third of the radius, and changes in levels of PSA and bone turnover markers (BTMs). Serum levels of the BTMs C-telopeptide, procollagen type 1 N-terminal propeptide, and tartrate-resistant acid phosphatase were also measured at different time points during the study.¹

Results

A total of 1468 patients were randomized; baseline features were similar in both treatment groups (Table 1).¹ Most patients were 70 years or older (83% in each group) and received ADT for at least 6 months (76% in each group).¹

At 24 months, BMD at the lumbar spine increased by 5.6% in patients receiving denosumab, but it decreased by 1.0% in those receiving placebo (P <.001). Compared with patients given placebo, those given denosumab had significantly greater BMD at this location after 1 month of treatment, and levels continued to rise through 36 months (P <.001 at all time points).

At all time points, denosumab performed better than placebo with respect to increasing BMD at the total hip, femoral neck, and distal third of the radius (P <.001 for all comparisons). It also increased BMD of the whole body at 24 months (P <.001 vs placebo).¹

The cumulative incidence of new vertebral fractures at 12, 24, and 36 months was significantly less with denosumab compared with placebo (Table 2).¹ At 36 months, 1.5% of patients who received denosumab had experienced a new vertebral fracture, compared with 3.9% of those who received placebo (relative risk, 0.38; 95% CI, 0.19-0.78; P = .006).¹

Compared with patients who received placebo, those who received denosumab experienced significant reductions in levels of all 3 serum BTMs at 36 months (P <.001 for each comparison). However, PSA levels were unchanged in both groups throughout the study duration.¹

Adverse event (AE) rates were similar in both groups. Although more patients given denosumab developed cataracts compared with those given placebo (4.7% vs 1.2%, respectively), the investigators did not consider this to be related to the study drug.¹

Serious AEs occurred in 34.6% of patients in the denosumab group and 30.6% of those in the placebo group. Mortality was also similar in both groups (6.0% vs 6.3%, respectively). One cardiovascular-related death in the placebo group was considered possibly related to treatment; no deaths in the denosumab group were considered to be linked to the study drug. There were no reports of delayed nonvertebral fracture healing, osteonecrosis of the jaw, or the presence of anti-denosumab antibodies in either group.¹

Conclusions

Results from this randomized trial showed that twice-yearly treatment with denosumab can increase BMD at multiple skeletal locations and reduce the incidence of vertebral fractures in men with prostate cancer who are receiving ADT.¹

Improvements in BMD associated with denosumab were observed at 1 month and continued through 36 months. The increase in BMD at the distal third of the radius was of particular interest, the investigators noted, because this location is composed mostly of cortical bone. Previous studies with bisphosphonates or selective estrogen-receptor modulators have not demonstrated any beneficial effects at this site after treatment.¹

Reference

1. Smith MR, Egerdie B, Herna&#769;ndez Toriz N, et al; Denosumab HALT Prostate

Cancer Study Group. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361(8):745&shy;-755. doi: 10.1056/NEJMoa0809003.