Estrogen Receptors α and β Have Different Gender-Dependent Effects on the Adaptive Responses to Load Bearing in Cancellous and Cortical Bone

To determine the effect of estrogen receptors (ER) alpha and beta on bones' adaptive response to loading, we subjected the right tibiae of mice lacking ER alpha or ER beta activity to either axial loading or to disuse. Adaptive changes in architecture were assessed by comparing differences between the right (treated) and left (control) tibiae in these genotypes as assessed by microcomputed tomography. In female ER alpha(-/-) mice, the net-osteogenic response to loading was lower in cortical bone compared with their wild-type littermates (11.2 vs. 20.9% in ER alpha(+/+)), but it was higher in both cortical and cancellous bone of male ER alpha(-/-) mice (cortical 20.0 vs. 4.6% in ER alpha(+/+); cancellous 30.0 vs. 5.3% in ER alpha(+/+), P < 0.05). In ER beta(-/-) male and female mice, the net-osteogenic response to loading was higher in cortical bone (males 10.9 vs. 3.9% in ER beta(+/+); females 18.5 vs. 15.8% in ER beta(+/+), P < 0.05) but no different from controls in cancellous bone. The bone loss in response to disuse was less in cancellous bone of ER alpha(-/-) mice than in controls (-15.9 vs. -21.3%, respectively, P < 0.05) but no different at any other site or between any other groups. Our conclusion is that functional ER alpha enhances the net-osteogenic response to loading in cortical but not cancellous bone in female mice but reduces it in males. ER beta decreases the response to loading in cortical bone of males and females but has no effect in cancellous bone. Bone loss due to disuse in cortical bone is unaffected by ER status, but in cancellous bone, functional ER alpha contributes to greater disuse-related bone loss. (Endocrinology 153: 2254-2266, 2012)