Klinefelter syndrome: The altered bone

Low bone mass is present in up to 50% of subjects with Klinefelter syndrome (KS) and has usually been attributed to low testosterone levels. Indeed, hypogonadism represents one of the most important causes of male osteoporosis and testosterone is known to regulate male bone metabolism both indirectly by aromatization to oestrogens and directly through the androgen receptor (AR). Early onset of testosterone deficiency, as observed in KS, is an important risk factor for precocious osteoporosis. However, reduced bone mass might be present also in KS men with normal testosterone levels and testosterone replacement therapy does not always restore bone density in KS patients. Possible other determinants for osteoporosis in KS might be related to low insulin-like factor 3 (INSL3), 25-hydroxyvitamin D, oestrogen levels, unfavourable fat/muscle ratio, CAG length and inactivation pattern of the AR and high FSH, with different levels of evidence. Although the exact fracture rates in KS are unknown, some epidemiologic studies have shown a correlation between fractures and increased morbidity and mortality in KS. Therefore, it is essential to assess bone density and bone fracture risk in KS patients from a young age, keeping in mind that KS men are at risk of low bone mineral density and fractures regardless of testosterone levels.