Bone turnover across the menopause transition The role of gonadal inhibins

Accumulating evidence demonstrates increasing bone turnover and bone loss in women prior to menopause and decreases in serum estradiol levels. Increased follicle-stimulating hormone levels have been correlated with some of these pen-menopausal changes. However, decreases in gonadal inhibins of the transforming growth factor (TGF)-beta superfamily strongly correlate with increases in bone formation and resorption markers across the menopause transition and predict lumbar bone mass in pen-menopausal women, likely as a result of direct inhibin suppression of osteoblastogenesis and osteoclastogenesis. Inhibins bind specifically to cells during osteoblastogenesis and osteoclastogenesis. They can block bone morphogenetic protein (BMP)-stimulated osteoblast and osteoclast development as well as BMP-stimulated SMAD I phosphorylation, likely via inhibin beta-glycan sequestration of BMP Type II receptor (BMPRII). Interestingly, continuous in vivo exposure to inhibin A is anabolic and protective against gonadectomy-induced bone loss in mice, suggesting that inhibins contribute to the endocrine regulation of bone metabolism via a bimodal mechanism of action whereby cycling inhibin exposure suppresses bone turnover and continuous exposure to inhibins is anabolic.