Abstract
Sex steroids are important regulators of bone turnover, but the mechanisms of their effects on bone remain unclear. Sclerostin is an inhibitor of Wnt signaling, and circulating estrogen (E) levels are inversely associated with sclerostin levels in postmenopausal women. To directly test for sex steroid regulation of sclerostin levels, we examined effects of E treatment of postmenopausal women or selective withdrawal of E versus testosterone (T) in elderly men on circulating sclerostin levels. E treatment of postmenopausal women (n = 17) for 4 weeks led to a 27% decrease in serum sclerostin levels [versus +1% in controls (n = 18), p < .001]. Similarly, in 59 elderly men, we eliminated endogenous E and T production and studied them under conditions of physiologic T and E replacement, and then following withdrawal of T or E, we found that E, but not T, prevented increases in sclerostin levels following induction of sex steroid deficiency. In both sexes, changes in sclerostin levels correlated with changes in bone-resorption, but not bone-formation, markers (r = 0.62, p < .001, and r = 0.33, p = .009, for correlations with changes in serum C-terminal telopeptide of type 1 collagen in the women and men, respectively). Our studies thus establish that in humans, circulating sclerostin levels are reduced by E but not by T. Moreover, consistent with recent data indicating important effects of Wnts on osteoclastic cells, our findings suggest that in humans, changes in sclerostin production may contribute to effects of E on bone resorption. © 2011 American Society for Bone and Mineral Research.
Highlights
Both estrogen (E) and testosterone (T) are critical regulators of bone turnover, but the precise mechanisms by which these sex steroids have their effects on bone remain unclear
E deficiency is associated with an increase in bone remodeling,(3) and the associated increase in bone resorption is accompanied by a coupled increase in bone formation at the tissue level.[2] at each basic multicellular unit (BMU) there remains a gap between bone resorption and bone formation, with formation unable to keep up with resorption, resulting in a net loss of bone.[2]. By inference, sex steroid deficiency is associated with a defect in bone formation
Chronic E treatment of postmenopausal women is associated with reduced bone-resorption markers, leading, owing to the ‘‘coupling’’ of bone resorption and bone formation, to a reduction in bone-formation markers.[1,5] Studies in rats have found that histologic bone-formation rates decrease early following ovariectomy, but owing to the coupling with the increase in bone resorption, boneformation rates are elevated 2 to 3 weeks following ovariectomy.[6] at the cellular level, E is important for the maintenance of bone formation in part due to a reduction in osteoblast apoptosis.[7]
Summary
Both estrogen (E) and testosterone (T) are critical regulators of bone turnover, but the precise mechanisms by which these sex steroids have their effects on bone remain unclear. Consistent with this, several studies demonstrate that acute (3 to 4 weeks) E withdrawal[4] or treatment[5] results in a decrease and increase, respectively, in bone-formation markers, reflecting the underlying effects of E in maintaining bone formation at the cellular level. Chronic E treatment of postmenopausal women is associated with reduced bone-resorption markers, leading, owing to the ‘‘coupling’’ of bone resorption and bone formation, to a reduction in bone-formation markers.[1,5] Studies in rats have found that histologic bone-formation rates decrease early (at 5 days) following ovariectomy, but owing to the coupling with the increase in bone resorption, boneformation rates are elevated 2 to 3 weeks following ovariectomy.[6] at the cellular level, E is important for the maintenance of bone formation in part due to a reduction in osteoblast apoptosis.[7]
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