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Skeletal Effects of Cyclosporin A Are Gender Related in Rats

Institute of Physiology (R.G.E., K.S.B., B.B., J.E., M.G.), Physiological Chemistry and Animal Nutrition, Ludwig Maximilians University, 80539 Munich, Germany; and Division of Gastroenterology and Endocrinology (L.C.H.), Philipps University, 35033 Marburg, Germany

Address all correspondence and requests for reprints to: Reinhold G. Erben, M.D., D.V.M., Institute of Animal Physiology, University of Munich, Veterinaerstrasse 13, D-80539 Munich, Germany. E-mail: r.erben{at}lrz.uni-muenchen.de.

The immunosuppressive drug cyclosporin A (CsA) is thought to be involved in the pathogenesis of posttransplantation osteoporosis. To evaluate further the skeletal effects of CsA, we treated aged male and female sham-operated and gonadectomized rats with low doses of CsA for 4 months. Here, we show that CsA is antiresorptive and bone-sparing in aged female rats but increases bone resorption and reduces bone mass in aged male rats. However, even in male rats, CsA treatment, at clinically relevant doses, increased bone resorption only transiently and did not result in pronounced long-term cancellous bone loss. The gender-specific skeletal effects of CsA were not modulated by sex hormones or gonadectomy. CsA did not influence sex steroid metabolism in male or female rats. However, endogenous estradiol in sham-operated female rats (and especially, exogenous administration of 17ß-estradiol in ovariectomized rats) markedly diminished blood levels of CsA, probably by increasing hepatic CsA metabolism. Although the mechanism for the gender-specific skeletal effects of CsA is still obscure, our findings may have important implications for clinical therapy with CsA.

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