High‐dose estrogen inhibits bone resorption and stimulates bone formation in the ovariectomized mouse

Abstract In This Study, We Have Investigated Estrogen'S Capacity To Regulate Bone Formation And Resorption In The Ovariectomized Mouse, Evaluating The Dose And Site Dependence Of Estrogen Action On Bone Modeling And Remodeling Surfaces. To Quantitate Bone Resorption, The Skeletons Of Fifty 8‐Week‐Old Swiss‐Webster Mice Were Prelabeled With [ 3 H]tetracycline ( 3 H‐T) before initiation of treatment protocols. Ovariectomies (OVX) and sham surgeries were performed 3 days after the final 3 H‐T injection, and the animals were assigned to treatment groups and injected once per week for 4 weeks with one of the following doses of 17β‐estradiol (E 2 ): sham/oil vehicle (SV), OVX/oil vehicle, OVX/50 μg E 2 , OVX/250 μg E 2 , and OVX/500 μg E 2 . To assess bone formation, fluorochrome labels were administered 9 and 2 days before sacrifice. At the conclusion of the 4 week protocol, the femora and thoracic vertebrae were removed to quantitate the levels of bone resorption based on the skeletal retention of 3 H‐T. The tibiae were excised for histomorphometric evaluation of the proximal metaphyses and middiaphyses. Indicative of increased bone resorption, vehicle‐treated OVX animals had significantly reduced levels of 3 H‐T in femora and vertebrae compared to SV mice. This result was consistent with histomorphometric data showing a 49% decrease in cancellous bone area of the proximal tibiae in the OVX/oil‐treated group. Treatment of OVX animals with 50 μg E 2 was sufficient to maintain 3 H‐T levels in vertebrae at SV values, with higher E 2 doses leading to a dose‐dependent increase in the retention of 3 H‐T at this site. In contrast, 3 H‐T levels in the femora of mice treated with 50 and 250 μg E 2 were intermediate between the SV‐ and vehicle‐treated OVX animals. Only at 500 μg E 2 per week were 3 H‐T values in femora maintained at SV values compared to OVX mice treated with vehicle. Histology data indicated that treatment of OVX mice with 250 μg E 2 prevented osteopenia in the proximal metaphyses of the tibiae; the 500 μg dose of E 2 led to a fivefold increase in cancellous bone volume compared to SV mice. In OVX mice treated with 500 μg E 2 , cancellous bone formation rates were increased 83% compared to SV animals and 35% compared to the OVX/oil‐treated group. These increases were a consequence of increased bone‐forming surface. E 2 treatment also stimulated bone formation on the endosteal surface of the diaphysis. In summary, these results indicate that E 2 inhibits bone resorption in femora and vertebrae of OVX mice in a dose‐dependent fashion and has the capacity to stimulate bone formation on both endosteal and cancellous bone surfaces.