Effect of a single-dose denosumab on mineral homeostasis in infertile men: insights from a pilot intervention study and a randomized controlled trial

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BACKGROUND: Denosumab, a drug that inhibits RANKL to reduce bone resorption in osteoporotic postmenopausal women, has been shown to improve semen quality in a subgroup of infertile men. This study aimed to investigate the effects of denosumab on mineral homeostasis in young infertile men. METHODS: Secondary data from two clinical trials designed to test the effect on semen quality were used: (1) a pilot intervention study with 12 men receiving a single-dose of 60 mg denosumab and (2) a single-center, double-blinded, randomized clinical trial, where 100 infertile men were randomized 1:1 to receive denosumab 60 mg once sc. or placebo. A linear mixed model for repeated measures was employed to analyze data from follow-up samples. RESULTS: In the pilot intervention study, denosumab treatment induced a decrease in ionized calcium 5, 20, 40, and 80 days after treatment compared with baseline (all p < 0.05). Serum phosphate decreased on all time points up to and including day 40 (all p < 0.05), while alkaline phosphatase was only lowered at 40 days and onwards (p = 0.014). Serum PTH increased significantly at all time points up to and including day 80 (p = 0.026). One hundred eighty days after treatment, all reported analyses were comparable to baseline levels. The observed temporal changes were confirmed in the RCT with differences in serum calcium (p < 0.001) and phosphate (p < 0.001) on day 14, PTH (p < 0.002), and alkaline phosphatase (p < 0.001) on days 80 and 160. Denosumab treatment had no significant effect on vitamin D status, renal function, or serum albumin concentration after 80 and 160 days. CONCLUSIONS: Small but significant changes in mineral homeostasis and bone mineral content were observed but the changes were transient and normalized after treatment cessation. A single injection of denosumab in infertile men appears to have no major long-term impact on bone or mineral homeostasis. TRIAL REGISTRATION: ClinicalTrials.gov NCT03030196. Registered January 24, 2017.

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