17 beta estradiol stimulation of endosteal bone formation in the ovariectomized mouse: an animal model for the evaluation of bone-targeted estrogens.

To evaluate the potential of an animal model as a means to identify bone-targeted estrogens, we have studied the response of the skeleton of ovariectomized mice to prolonged estrogen treatment. Seventy female Swiss-Webster mice were randomly divided into ten groups, with nine groups undergoing bilateral ovariectomy and one group a sham procedure. Mice were injected subcutaneously once per week for nine weeks with one of the following doses of estrogen (17 beta-E2) in oil vehicle: 19.3, 38.5, 75, 150, 300, 500, 1000, or 3000 micrograms. One group of ovariectomized (OVX) mice and the sham operated animals received vehicle injections only. At the end of the nine-week experimental protocol, there were no significant differences in body weights among any treatment groups. However, when compared to control values, spleen weights in vehicle-treated OVX mice and in mice treated with 1000 micrograms or 3000 micrograms of 17 beta-E2 were significantly elevated (p less than .01). Liver weights in the OVX mice treated with 1000 or 3000 micrograms 17 beta-E2 were also increased significantly (p less than .05). Comparisons of uterine weights and cortical bone areas were strongly correlated with 17 beta-E2 dose (r2 = .86 and .94, respectively), with maximal increases observed at estradiol doses in excess of 500 micrograms per week. Furthermore, based on bone histomorphometry of in vivo fluorochrome labels, increases in cortical bone area could be attributed to accelerated rates of endosteal mineral apposition and bone formation. These results indicate that the comparison of the response of endosteal bone and uterine tissue in the OVX mice to chronic estrogen treatment offers the potential to identify estrogen and/or estrogen-like compounds with bone-specific activity.