Effect of denosumab on semen quality in infertile men selected by serum level of antimüllerian 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.