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 of female mice, this response is only thought to occur following administration 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 17β-estradiol (E2) in stimulating cancellous bone formation at the proximal tibial metaphysis of intact female mice with that of the relatively inactive stereoisomer, 17α-estradiol (αE2). We found that E2 was significantly more potent than αE2, as assessed by histomorphometry. To provide further evidence for an estrogen-receptor-mediated process, we examined whether E2-induced osteogenesis in intact female mice could be inhibited by the estrogen receptor antagonist, ICI 182,780 (ICI). Although ICI itself had no effect on histomorphometric indices of the proximal tibial metaphysis when given alone, it significantly inhibited the osteogenic response to E2. Finally, we examined the dose dependency of E2-induced osteogenesis at the proximal tibial metaphysis in intact mice. We found that E2 stimulated cancellous bone formation in a dose-dependent manner over a wide dose range (i.e., 1–4000 μg/kg per day), with significant increases observed at doses of 4 μg/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 estrogen levels.