Regulation of circulating sclerostin levels by sex steroids in women and in men

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.

Fig. 1

Percent change from baseline in serum sclerostin levels in the subjects in study A using either the in-house assay (open bars) or the commercial assay (solid bars). p Values for differences in changes in the control versus E-treated groups are as indicated. ***p < .001 for significance of change from baseline.

Fig. 2

Correlations between percent changes in serum CTX in the two groups of women in study A combined versus percent change in serum sclerostin levels using either the in-house (A) or commercial (B) assay. Panels C and D show the analogous relationships for TRACP5b versus sclerostin using either the in-house assay or commercial assay, respectively.

Fig. 3

Percent change from baseline in serum sclerostin levels in the subjects in study B. The p values for the E and T effects are based on the two-factor ANOVA model described under “Methods.” Briefly, this compares changes in the +E versus –E groups for the E effect and changes in the +T versus the –T groups for the T effect. *p < .05, **p < .01, and ^†p = .051 for significance of change from baseline.