Regulation of Bone Turnover by Sex Steroids in Men

Abstract

ABSTRACT:Introduction: The mechanism(s) by which sex steroids regulate bone turnover in humans are unclear, and recent studies have suggested that follicle-stimulating hormone (FSH) may play an important role in regulating bone resorption. Materials and Methods: Fifty-nine men (median age, 69 yr) underwent suppression of sex steroids using a gonadotropin-releasing hormone (GnRH) agonist and aromatase blocker and were replaced with testosterone (T; 5 mg/d) and estradiol (E; 37.5 g/d). After assessment of bone resorption markers (serum C-terminal telopeptide of type I collagen [CTX] and TRACP5b), they were randomized to sex steroid deficiency (−T, −E), E alone (−T, +E), T alone (+T, −E), or both (+T, +E) and restudied 3 wk later. Bone marrow aspirates were obtained to isolate osteoblastic, T, and monocytic cells using magnetic-activated cell sorting. Results: Serum CTX and TRACP5b increased significantly (by 71% and 15%, p < 0.01 and < 0.001, respectively) in the −T, −E group, and these increases occurred despite a 60% suppression of serum FSH levels (p < 0.001) caused by the GnRH agonist. There were significant E (but not T) effects on preventing increases in serum CTx and TRACP levels. There was a nonsignificant trend (p ‫ס‬ 0.122) for E to suppress RANKL mRNA levels in bone marrow osteoblastic cells. Changes in mRNA levels for other cytokines (TNF-␣, interleukin (IL)-1␣, IL-1␤, IL-1ra, IFN-␥) in bone marrow cells were not significant. Conclusions: E has greater suppressive effects on bone resorption than T, and increased bone resorption after sex steroid deficiency can occur independently of changes in FSH secretion. E effects on bone resorption may be mediated by regulation of RANKL production by osteoblastic cells, although further studies using more highly purified cells may reduce the variability of the mRNA measurements and allow for clearer definition of the mediators of sex steroid action in vivo.

Reproductive Hormones and Bone

“…Consistent with these findings, clinical studies in men (median age, 69 years) who underwent suppression of sex steroids using a gonadotropin-releasing hormone (GnRH) agonist and aromatase blocker had a 60% reduction in FSH levels. Serum bone resorption markers were increased significantly in the these sex steroid-deficient men, independently of changes in FSH secretion [40]. Together, these data demonstrated that FSH does not appear to modulate in vivo bone mass in males and does not act directly on osteoclastogenesis in vitro.…”

Aging and bone loss: new insights for the clinician

“…A combination of crosssectional and observational studies of aging men showed better correlations between serum estradiol and BMD than testosterone and BMD at various skeletal sites [Slemenda et al 1997;Khosla et al 2001Khosla et al , 2008bMellstrom et al 2008;Szulc et al 2001]. Further studies looking at differential effects between estrogen and testosterone confirmed that estrogen deficiency was more important than testosterone deficiency in causation of bone loss in aging men [Falahati-Nini et al 2000;Leder et al 2003] and that the effects of estrogen on bone were independent of FSH [Sanyal et al 2008]. More recently, a large prospective study of older men again showed a low bio-available estradiol level to be associated with significant increased fracture risk and that testosterone in the presence of high SHBG is associated with significant increased fracture risk when adjusted for estradiol levels [LeBlanc et al 2009].…”

Pathogenesis of Osteoporosis

“…In contrast to these findings, studies by a different group with the identical FSH-receptor null mice used by Sun et al (60) did find deficits in bone mass in these mice (62). Moreover, recent findings demonstrate that at least in men, sex steroid deficiency alone is sufficient to increase bone resorption markers, even in the setting of suppressed FSH levels (63). Thus, the precise role of increases in FSH with aging in women and in men in mediating age-related bone loss remains unclear at this time.…”