Osteoporosis in Klinefelter's syndrome

Abstract

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.

TRANSITION IN ENDOCRINOLOGY: Management of Klinefelter syndrome during transition

“…Testosterone supplementation in adulthood " Not surprisingly, testosterone supplementation in young adult men with serum testosterone level in the lower half of the normal range did not result in significant changes in bone mineralization, body composition, or quality of life (43,45,46). No increase in quality of life was observed in testosterone-treated men with KS having normal testosterone values (47).…”

“…DXA scanning at diagnosis and by the end of puberty has been recommended for early detection of bone fragility (46). Indeed, men with KS have an increased risk of mortality related to an osteoporotic hip fracture, pointing to the need for preventive bone health measures in KS (5).…”

“…The low insulin-like factor 3 concentrations found in most adult men with KS have been related to a lower bone mass (81). Vitamin D deficiency is also very common in men with KS, particularly in those with abdominal obesity and a sedentary lifestyle, and can contribute to a lower bone mass (46). Vitamin D and calcium supplements have been used in elderly men to reduce the risk of hip fracture, but there are no data of their efficacy in young men with KS.…”

It's not all about the testes: medical issues in Klinefelter patients

“…KS is an important risk factor for early-onset osteoporosis (10,40). The etiology is multifactorial, with testosterone deficiency the primary cause.…”

“…However, bone mineral density (BMD) is not always correlated with testosterone levels in KS patients, nor does testosterone therapy always increase BMD. Other mechanisms suggested as etiologies for the altered BMD in KS patients include abnormalities of androgen receptor CAG length, low levels of insulin-like factor 3 (produced in the Leydig cells), and X chromosome inactivation (40,41). Further studies are needed to test these proposed mechanisms.…”