Endocrine Abstracts

Introduction: Klinefelter syndrome has been associated with decreased bone density most likely due to testosterone deficiency. Furthermore, a negative effect of long-lasting follicle-stimulating hormone (FSH) excess (starting from puberty) on trabecular bone has been suggested. Other endocrine mechanisms, such as global Leydig cell dysfunction, higher oestradiol levels, altered 25-OH vitamin D levels, and genetic aspects related to the supernumerary X chromosome might be involved. An increased risk for vertebral fractures has been reported as a complication of Klinefelter syndrome despite testosterone replacement therapy.

Objective: This study aimed to investigate bone health in a cohort of individuals with Klinefelter syndrome (KS) compared to patients with hypogonadotropic hypogonadism (HH) considering the influence of testosterone replacement therapy.

Methods: Ten individuals with known KS (23-78 years) and 15 individuals with HH (33-87 years) were submitted in regard to metabolic markers, bone density (BMD), bone formation markers (alkaline phosphatase and osteocalcin), a bone turnover marker (beta-crosslinks) and 25-OH vitamin D levels. BMD was measured by dual-energy X-ray absorptiometry (DXA) and expressed as T-scores. Nine of the KS individuals and 14 of the HH patients administered testosterone replacement therapy. Serum levels of testosterone, FSH, 25-OH vitamin D and bone markers were measured by commercial immunoassays in a routine clinical laboratory.

Results: All but one individual treated with exogenous testosterone had a bone mineral density within the normal range. Patients with KS had higher FSH concentrations (P=0.0043) but testosterone levels were comparable. The T-score of bone mineral density was found to be lower in lumbar spine than in the femoral neck in KS patients. In contrast, in HH individuals T-score of bone mineral density of lumbar spine was similar to T-scores of the femoral neck, demonstrating a difference in bone mineralization of the lumbar spine in KS vs HH (P=0.04). Bone formation biomarkers (alkaline phosphatase, osteocalcin) and the bone turnover biomarker were comparable between groups.

Conclusions: Despite comparable bone markers, we found significantly lower lumbar spine bone mineralization in patients with Klinefelter syndrome compared to hypogonadotropic hypogonadism under long-term testosterone replacement therapy. The underlying mechanism of this observation remains to be identified but may explain the previously reported increased risk of individuals with Klinefelter syndrome for vertebral fractures.