Mechanisms by which high-dose estrogen therapy produces anabolic skeletal effects in postmenopausal women: Role of locally produced growth factors

Conventional hormone replacement therapy acts primarily by preserving bone, but cannot restore lost bone in women with established osteoporosis. Studi es in rodents have shown that high doses of estrogens have anabolic skeleta l effects, and recent observations in a group of women treated long term wi th high doses of estrogen indicated that similar effects occur in humans. T his study examines the hypothesis that locally produced growth factors, inc luding transforming growth factor-beta (TGF-beta) and platelet-derived grow th factors (PDGFs), are involved in mediating the anabolic effects of high- dose estrogen. Transiliac-crest bone biopsies were taken from ten women, ag ed 52-67 years (mean 58 years), who had been treated with high-dose estroge n for 15 years. Control samples were obtained from four age-matched postmen opausal women not receiving estrogen therapy. TGF-betas and PDGFs were anal yzed for mRNA and protein expression by reverse transcriptase-polymerase ch ain reaction (RT-PCR) and immunohistochemistry. Results showed both TGF-bet a1 and -beta2 mRNA, expressed as a ratio to GAPDH, were increased in the es trogen-treated group with an eightfold increase for TGF-beta1 (0.258 +/- 0. 246 [mean +/- SD] vs. 0.032 +/- 0.053 in the control group, p = 0.02) and a twofold increase for TGF-beta2 (p = n.s.). TGF-beta3 analysis showed only negligible amounts in both groups. Protein expression levels for TGF-beta1, -beta2, -beta RI and -RII were higher in the estrogen-treated group than i n controls, the most marked effects being seen for TGF-beta1. PDGF-A protei n expression was also significantly higher in osteoblasts and osteocytes in women treated with estrogen, whereas PDGF-B showed only modest differences . The percentage of bone surface occupied by osteoclasts, as determined by tartrate-resistant acid phosphatase (TRAP) staining, was significantly redu ced in the estrogen-treated group (p = 0.001). These results demonstrate th at high-dose estrogen therapy is associated with increased TGF-beta, TGF-be taR, and PDGF synthesis and decreased osteoclast activity, consistent with the hypothesis that these growth factors may mediate the actions of estroge n in bone. (Bone 29:216-222; 2001) (C) 2001 by Elsevier Science Inc. All ri ghts reserved.