Study Summary: Effects of Denosumab in Men With Low Bone Mineral Density

Background

Osteoporosis and osteoporosis-related fracture are important considerations in older patients; however, osteoporosis in men is often underrecognized and undertreated. At the time of this study, it was estimated that 2 million men in the United States had osteoporosis and more than 12 million were at risk. Although men do not experience the rapid phase of bone loss that women experience at menopause, men lose substantial amounts of bone as they age, increasing the risk of fractures. In the United States, an estimated 27% to 30% of all osteoporosis-related fractures among adults older than 50 years occur in men, and worldwide, 39% of osteoporotic fractures occur in men. Given the increasing lifespan of men and the aging of the overall population, the rate of fractures and related healthcare burdens are estimated to increase substantially in the future.¹

At the time of this study, there were several options for the treatment of osteoporosis in men (ie, bisphosphonates such as zoledronic acid), but real-world challenges underscored the need for alternative therapies. Long-term adherence with bisphosphonates, despite the convenience of once-weekly dosing, has proven to be a challenge, and the burden of administering a once-yearly intravenous infusion of zoledronic acid in primary care settings limits its utility. Denosumab, a fully human monoclonal antibody that inhibits the protein receptor activator of nuclear factor kappa-B ligand, is a subcutaneous injection that is administered every 6 months. Given that its dosing is more convenient than bisphosphonates and its administration is less burdensome than zoledronic acid, there is a potential role for denosumab in the treatment of osteoporosis. Prior studies demonstrated that denosumab significantly reduced bone resorption, increased bone mineral density (BMD), and reduced fracture risk in postmenopausal women with osteoporosis. In men receiving androgen deprivation therapy for prostate cancer, denosumab increased BMD and reduced the occurrence of new vertebral fractures.¹

Methods

This phase 3, multicenter, randomized, placebo-controlled study compared the efficacy and safety of denosumab with placebo in men with osteoporosis. The study was composed of 2 treatment phases over 2 years. The first year was a double-blinded treatment phase during which patients were randomized to receive 12 months of denosumab or placebo. Thereafter, all patients received 12 months of open-label denosumab. This summary reports the findings of the first year of the study, the double-blinded, placebo-controlled phase.

This study included men aged 30 to 85 years who had a BMD T-score of −2.0 or less and −3.5 or more at the lumbar spine and the femoral neck or previously had a major osteoporotic fracture and a BMD T-score of −1.0 or less and −3.5 or more at the lumbar spine or femoral neck. Men were excluded if they had any severe vertebral fracture or more than 1 moderate vertebral fracture upon screening, any vertebral or clinical fracture within 6 months before screening, or any disease known to affect bone metabolism. Men were also excluded if they received bisphosphonate treatment for a total of 3 months or more in the past 2 years, for 1 month or more in the past year, or within 3 months of randomization; they were also ineligible if they received bone-active drugs within 3 months of screening. Enrolled patients were randomized to receive subcutaneous injections of denosumab 60 mg every 6 months or placebo. The primary end point was the mean change from baseline to month 12 in lumbar spine BMD. Secondary end points included mean change from baseline to month 12 in BMD of the total hip, femoral neck, hip trochanter, and one-third radius, and change in serum levels of the bone turnover biomarker C-telopeptide (CTX) at day 15.¹

Results

Of the 242 patients enrolled in the study, 228 patients completed the 12-month double-blind treatment phase. The overall patient population was predominantly white (94.2%), with a mean age of 65 years. With regard to the primary end point of change in lumbar spine BMD at 12 months, there was a significant increase in BMD in the denosumab group compared with placebo (5.7% vs 0.9%, respectively), with a between-group difference of 4.8% (95% CI [4.0%-5.6%]; P <.0001). Similar efficacy in increasing BMD was also observed with denosumab at the total hip, femoral neck, hip trochanter, and one-third radius sites compared with placebo (P ≤.0144 for all) (Table).¹

Subgroup analyses were conducted to control for factors that may impact the changes in BMD, such as baseline lumbar spine BMD T-score, baseline testosterone level, age, race, geographic region, and history of osteoporotic fracture. All subgroup analyses were consistent with the primary analysis, demonstrating that denosumab was effective in increasing BMD compared with placebo. Notably, the subgroup analysis by race verified that race did not affect the outcomes of the analysis despite the denosumab group having a larger percentage of white patients than placebo (100% vs 88.4%, respectively). Also notable was the demonstration of similar efficacy with denosumab across the subgroups by testosterone levels, as hypogonadism may contribute to bone loss in men.¹

With regard to the biomarker of bone turnover, CTX, there was a significantly greater decrease in median level compared with placebo at day 15 (−81% vs −7%, respectively; adjusted P <.0001). The occurrence of fractures was also evaluated, with clinical fractures occurring in 3 patients (1 in the denosumab group [rib] and 2 in the placebo group [1 rib and 1 humerus]), and a vertebral fracture occurring in 1 patient in the placebo group. The incidences of adverse events (AEs), serious AEs, and fatal AEs were similar between groups.¹

Discussion

Based on these results, the investigators concluded that denosumab was effective at increasing BMD at the lumbar spine, total hip, femoral neck, trochanter, and one-third radius sites in men with low BMD. The results of subgroup analyses showed that the efficacy of denosumab was independent of baseline BMD T-score, estimated 10-year fracture risk, serum CTX levels, testosterone levels, age, race, geographic region, or previous osteoporotic fractures. The investigators opined that the study’s findings were generalizable to the overall population of men with osteoporosis. They contrasted the results of this study with prior studies evaluating the efficacy of bisphosphonates, where an increase in BMD at the one-third radius, a predominately cortical bone site, was not observed with bisphosphonates. The investigators deduced that the efficacy of denosumab in increasing cortical and trabecular bone may be due to its differing mechanism of action from bisphosphonates. The use of denosumab in the treatment of osteoporosis in men was further supported by the significant reductions in levels of the bone turnover biomarker CTX, which were sustained at month 6 and month 12. Furthermore, the results of the safety analysis demonstrated that denosumab was well tolerated.¹

Reference

Orwoll E, Teglbjærg CS, Langdahl BL, et al. A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab. 2012;97(9):3161-3169. doi: 10.1210/jc.2012-1569.