Incomplete Evidence of Bone Density Normalization Following Long-Term Reproductive Hormone Treatment in Men With Hypogonadotropic Hypogonadism

CONTEXT: The prevalence and severity of low bone mineral density (BMD) in hypogonadotropic hypogonadism (HH), as well as the ability of reproductive hormone treatment to normalize BMD have not been investigated in large multicenter studies. OBJECTIVE: We performed a systemic review and meta-analysis of several small, observational studies to investigate the effect of reproductive hormone treatment on BMD in men with HH compared with control groups where available. METHODS: We searched OVID Medline, Embase, CINAHL, SCOPUS, Web of Science, and Cochrane Library for studies reporting BMD or fractures in men with HH (congenital [CHH] or acquired). Study selection and data extraction were performed using COVIDENCE and a prespecified tool. Results were summarized using descriptive statistics. Meta-analysis compared BMD in men with HH vs healthy controls. Meta-regression assessed relationships between treatment duration and BMD Z-scores against normative population data. RESULTS: Of the 33 eligible studies, 24 included data specific to men with HH (n = 625). Men with HH had low lumbar spine (LS) and femoral neck BMD, improving with hormonal treatment. Meta-analysis of 5 studies found lower LS BMD in men with HH vs healthy controls (SMD -5.98; 95% CI; -11.5 to -0.47). Men with CHH may have persistently low BMD despite prolonged hormonal treatment. Higher BMD in HH was associated with younger age at treatment initiation, partial HH, and higher serum testosterone and estradiol concentrations. Fracture prevalence was high in the few studies systematically studying fractures as an outcome; in other studies, fractures were seldom reported. CONCLUSION: Men with HH have low BMD that improves with reproductive hormone treatment. However, current evidence suggests that incomplete BMD normalization may be common despite long-term reproductive hormone treatment in men with HH, particularly those with CHH.