TOPLINE:

Among men with severe oligospermia, a single 60-mg subcutaneous dose of denosumab did not increase sperm concentrations or alter levels of reproductive hormones compared with placebo and was not superior to standard vitamin D and calcium supplementation.

METHODOLOGY:

• Researchers in Denmark conducted a clinical trial to assess the effect of denosumab on semen quality in 39 men with severe oligospermia (mean age, 35.7 years) who had sperm concentrations ≤ 2 million/mL and serum anti-Müllerian hormone concentrations ≥ 28 pmol/L.
• Participants were randomly assigned to receive either 60-mg subcutaneous injection of denosumab (n = 26) or placebo (n = 13) for 80 days; they were also given daily supplements of vitamin D and calcium for 180 days.
• The primary outcome was the difference in sperm concentrations between both groups at day 80 post-injection; secondary endpoints included changes in the total sperm count, semen volume, and serum concentrations of reproductive hormones.

TAKEAWAY:

• At day 80, no significant difference in sperm concentrations was seen between denosumab and placebo groups (1.04 vs 1.15 million/mL; P = .918).
• The positive response rate, defined as a ≥ 5% increase in sperm production from baseline to day 80, did not differ significantly between the two groups (P = .130).
• Both groups showed increases in sperm concentrations and total sperm count from baseline to day 80; by day 80, the total sperm count was similar in both groups (P = .938).
• Furthermore, no significant differences were observed between the two groups in terms of reproductive hormones, including testosterone, luteinising hormone, follicle-stimulating hormone, inhibin B, and anti-Müllerian hormone (P > .05 for all).

IN PRACTICE:

"Male infertility is a heterogeneous disease with multiple etiologies, including genetic factors, hormonal imbalances, structural abnormalities, and environmental influences, making it difficult to develop a one-size-fits-all approach," the authors wrote.

"We have administered denosumab 60 mg (the standard osteoporosis dose) for this different indication, but it remains unclear how much of the antibody penetrates seminal fluid and whether a higher or lower dose would be required to achieve therapeutic levels in that compartment," they added.

SOURCE:

This study was led by Sam Kafai Yahyavi, Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Copenhagen University Hospital – Herlev and Gentofte, Herlev, Denmark. It was published online on August 27, 2025, in The Journal of Clinical Endocrinology & Metabolism.

LIMITATIONS:

This study was limited by its small sample size, particularly in the placebo group. The 80-day endpoint may have been too short to fully capture changes in spermatogenesis. The strict eligibility criteria limited the generalisability to the broader population of infertile men.

DISCLOSURES:

This study was funded by Rigshospitalet, Novo Nordisk Foundation, Candys Foundation, and The Innovation Foundation. One author reported holding two patents on the use of Receptor Activator of Nuclear Factor Kappa-B Ligand inhibitors for male infertility treatment and serving as the CEO and founder of XY Therapeutics.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.