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

• Published in: Journal of bone and mineral research Vol. 26; no. 1; pp. 27 - 34
• Main Authors: Mödder, Ulrike IL, Clowes, Jackie A, Hoey, Kelley, Peterson, James M, McCready, Louise, Oursler, Merry Jo, Riggs, B Lawrence, Khosla, Sundeep
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.01.2011; Wiley; Wiley Subscription Services, Inc
• Subjects: Adult; Aged; Aged, 80 and over; Analysis of Variance; Biological and medical sciences; Biomarkers - metabolism; Bone Morphogenetic Proteins - blood; Bone Remodeling - drug effects; BONE TURNOVER; Collagen Type I - blood; Estradiol - administration & dosage; Estradiol - pharmacology; ESTROGEN; Female; Fundamental and applied biological sciences. Psychology; Genetic Markers; Humans; Male; Middle Aged; Original; Osteoprotegerin - blood; Peptides - blood; SCLEROSTIN; Skeleton and joints; TESTOSTERONE; Testosterone - administration & dosage; Testosterone - pharmacology; Vertebrates: osteoarticular system, musculoskeletal system; Human; Steroid; SCLEROSTIN; Androgen; Estrogen; Sex; Ovarian hormone; Osteoarticular system; Testosterone; Vertebrata; Mammalia; Turnover; Female; Testicular hormone; Bone; Sex steroid hormone; BONE TURNOVER
• DOI: 10.1002/jbmr.128
• ISSN: 0884-0431

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.