Is high-dose estrogen-induced osteogenesis in the mouse mediated by an estrogen receptor?

Although estrogen is known to induce new bone formation in the long bones o f female mice, this response is only thought to occur following administrat ion of high doses, suggesting that it may not be mediated by a conventional estrogen receptor. To address this question further, we first examined the stereospecificity of this response by comparing the potency of 17 beta-est radiol (E-2) in stimulating cancellous bone formation at the proximal tibia l metaphysis of intact female mice with that of the relatively inactive ste reoisomer, 17 alpha-estradiol (alpha E-2). We found that E-2 was significan tly more potent than alpha E-2, as assessed by histomorphometry, To provide further evidence for an estrogen-receptor-mediated process, we examined wh ether E-2-induced osteogenesis in intact female mice could be inhibited by the estrogen receptor antagonist, ICI 182,780 (ICI), Although ICI itself ha d no effect on histomorphometric indices of the proximal tibial metaphysis when given alone, it significantly inhibited the osteogenic response to E-2 . Finally, we examined the dose dependency of E-2-induced osteogenesis at t he proximal tibial metaphysis in intact mice. We found that E-2 stimulated cancellous bone formation in a dose-dependent manner over a wide dose range (i.e., 1-4000 mu g/kg per day), with significant increases observed at dos es of 4 mu g/kg per day and beyond. Our results raise the possibility that estrogen-induced osteogenesis in the mouse represents an estrogen-receptor- mediated response that is not confined solely to supraphysiological estroge n levels; (Bone 27:41-46; 2000) (C) 2000 by Elsevier Science Inc. All right s reserved.