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Science 298 (5594): 843-846

Copyright © 2002 by the American Association for the Advancement of Science

Reversal of Bone Loss in Mice by Nongenotropic Signaling of Sex Steroids

S. Kousteni,1 J.-R. Chen,1 T. Bellido,1 L. Han,1 A. A. Ali,1 C. A. O'Brien,1 L. Plotkin,1 Q. Fu,1 A. T. Mancino,125 Y. Wen,125 A. M. Vertino,15 C. C. Powers,1 S. A. Stewart,14 R. Ebert,3 A. M. Parfitt,1 R. S. Weinstein,15 R. L. Jilka,15 S. C. Manolagas15*

We show that sex steroids protect the adult murine skeleton through a mechanism that is distinct from that used to preserve the mass and function of reproductive organs. The classical genotropic actions of sex steroid receptors are dispensable for their bone protective effects, but essential for their effects on reproductive tissues. A synthetic ligand (4-estren-3alpha ,17beta -diol) that reproduces the nongenotropic effects of sex steroids, without affecting classical transcription, increases bone mass and strength in ovariectomized females above the level of the estrogen-replete state and is at least as effective as dihydrotestosterone in orchidectomized males, without affecting reproductive organs. Such ligands merit investigation as potential therapeutic alternatives to hormone replacement for osteoporosis of bone mass in both women and men.

1 Division of Endocrinology and Metabolism, Department of Internal Medicine, and Center for Osteoporosis and Metabolic Bone Diseases;
2 Department of Surgery;
3 Department of Pathology;
4 Biometry Division; University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
5 Central Arkansas Veterans Health Care System, Little Rock, AR 72205, USA.
*   To whom correspondence should be addressed. E-mail: manolagasstavros{at}

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Journal Watch (General) 2002, 7
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