Osteoporotic fractures in men are a major health issue. However, studies involving men with osteoporosis have focused on the surrogate outcomes such as bone mineral density (BMD) and biochemical bone turnover markers (BTM). By contrast, data from randomized, double-blind, clinical trials assessing anti-fracture efficacy in men are lacking. Therefore, the recent multicenter randomized prospective trial assessing the effect of zoledronic on the risk of vertebral fracture in osteoporotic men as a primary end point is of particular interest. Previously, zoledronic acid reduced highly significantly fracture incidence in postmenopausal women and increased BMD in several studies carried out in men with low BMD.
This study was performed in 1199 men aged 50 to 85. Eligible men without fracture had BMD T-score≤-2.5 at total hip, femoral neck or lumbar spine. Eligible men with fracture had BMD T-score≤-1.5 and one to three vertebral fractures. (T-score was calculated as the number of SDs below or above the mean in young men.) Men were randomly assigned to receive zoledronic acid at a dose of 5 mg or placebo administered as a 15 to 30 minute i.v. infusion at baseline and month 12. All men received daily calcium (1000-1500 mg) and vitamin D (800-1200 IU). Men were followed up for 24 months; almost 90% of men completed the study.
Vertebral fracture incidence was 67% lower in the zoledronic acid group compared with the placebo group (RR= 0.33, 95% confidence interval: 0.16-0.70, p=0.002). Loss of height was smaller in the zoledronic acid group vs placebo group (2.2 vs 4.5 mm, p=0.002). Zoledronic acid induced a significant increase in BMD at the lumbar spine, total hip and femoral neck. The difference vs the placebo group was statistically significant for all the skeletal sites. Serum levels of bone formation markers (N-terminal propeptide of type I procollagen [PINP], bone-specific alkaline phosphatase) were significantly lower in men who received zoledronic acid than in men who received placebo. Levels of bone resorption markers (serum C-terminal telopeptide of type I collagen, urinary N-terminal telopeptide of type I collagen) were also significantly lower in men receiving zoledronic acid. The effect of zoledronic acid on the fracture incidence, BMD and BTM levels (except PINP) was similar in men with testosterone levels of >350 ng/dl and in men with testosterone levels of 350 ng/dl or less.
The most frequent adverse effect of zoledronic acid was the influenza-like syndrome (pyrexia, myalgia, arthralgia, headaches, chills, pain in the extremities). It occurred in 15% of men and subsided spontaneously. No case of osteonecrosis of the jaw and no case of subtrochanteric or atypical fracture were observed. No significant differences were observed between the groups with respect to death, cardiac arrhythmias or renal dysfunction, except for myocardial infarction which was slightly more frequent in the zoledronic acid group. However, the analysis of each case showed that these events were not related to the study drug.
A key strength of this study was a population that was large enough to detect the anti-fracture efficacy of zoledronic acid in the osteoporotic men in the framework of a placebo-controlled, randomized, prospective trial. Zoledronic acid increased BMD and decreased bone turnover rate. The effect of zoledronic acid was independent of total testosterone levels. The reduction of fracture risk, the increase in BMD, the decrease in bone turnover rate and the safety profile were similar to those found in postmenopausal women treated with zoledronic acid. These results provide support for the value of antiresorptive therapy in osteoporotic men. They may also contribute to a better definition of treatment recommendations of osteoporosis in men.
Reference: Boonen S et al. Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med 2012, 367:1714-1723.