Hypogonadism represents one of the most important causes of male osteoporosis. Testosterone regulates male bone metabolism both indirectly by aromatization to estrogens and directly through the androgen receptor (AR) on osteoblasts, promoting periosteal bone formation during puberty and reducing bone resorption during adult life. Early onset of testosterone deficiency, as observed in Klinefelter's syndrome (KS), is an important risk factor for precocious osteoporosis. Osteoporosis is present in up to 40% of subjects with KS and has usually been attributed to low testosterone levels. 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 new determinants for osteoporosis in KS might be related to the AR function and insulin-like factor 3 (INSL3) levels. The CAG length and inactivation pattern of the AR in KS have been related to osteoporosis, but definitive proof is lacking. INSL3 has an anabolic role on bone metabolism by acting on osteoblasts and INSL3 levels are low in KS. Therefore, low INSL3 concentrations might represent a possible new pathogenic mechanism for reduced bone mass in KS.