Effect of Denosumab on Semen Quality in Infertile Men Selected by Serum Level of Anti-Müllerian Hormone: A Randomized Controlled Trial

OBJECTIVE: To determine whether denosumab could improve sperm concentration in infertile men selected by serum antimüllerian hormone (AMH) ≥ 38 pmol/L. Mouse models, human testicular tissue models, and clinical intervention studies have suggested that the RANKL-inhibitor denosumab, normally used to treat osteoporosis, can improve semen quality in a sub-population of infertile men.

DESIGN: A double-blinded, placebo-controlled, single-center, randomized clinical trial.

SUBJECTS: The study was designed to include 282 infertile men with a planned interim analysis after inclusion of 170 men.

INTERVENTION: The groups were randomized 1:1 to receive either a single subcutaneous injection of denosumab 60 mg or a placebo treatment for 80 days.

MAIN OUTCOME MEASURE: Sperm concentration.

RESULTS: The trial was terminated after the interim analysis (n = 179), with 90 men assigned to denosumab treatment and 89 men to placebo treatment. No difference in sperm concentration was found at day 80 between denosumab and placebo-treated men (difference of -1.0 million/mL [95% CI -2.7, 1.1]). Moreover, no differences in percentages of motile, progressively motile, or morphologically normal spermatozoa were found. An interaction analysis identified a subgroup of men with testis size ≤16 mL and no history of cryptorchidism who had an increase in sperm concentration of 29% (8.5 million/mL at baseline to 11.0 million/mL at day 80) after treatment with denosumab.

CONCLUSIONS: Denosumab did not improve semen quality in infertile men selected on the basis of their serum AMH concentrations. The positive effect of denosumab in a subgroup can only be considered exploratory and needs verification in additional prospective studies.

TRIAL ID: ClinicalTrials.gov: NCT05212337. EudraCT 2021-003451-42.