Abstract： Objective To study the effects of estrogen on outcomes of exercise therapy for osteoporosis. Methods Forty-eight 5-month-old female SD rats were randomly divided into following groups:sham operated rats (Sham group), sham operated rats on exercise therapy (Sham+run group), ovariectomy rats (Ovx group), Ovx rats on exercise therapy (Ovx+run), and Ovx rats on exercise therapy and 1/4-dose (Ovx+run+e1 group) or full-dose (Ovx+run+e2 group) estrogen. For the last two groups, subcutaneous injection of diethylstilbestrol was started one week after oophorectomy at a dose of 0.025 mg/kg once every 4 days (Ovx+run+e1 group) or once daily (Ovx+run+e2 group) and lasted for 12 weeks. Exercise therapy,designed as in-cage running, was also started one week after operation in the Sham+run, Ovx+run, Ovx+run+e1 and Ovx+run+e2 groups and lasted for 12 weeks. On week 13, bone mineral density (BMD) and bone biomechanical parameters of distal femur and bone histomorphometry of proximal tibia were measured.Results (1)Ovx group had the lowest B MD [ (0.10 ± 0.01 ) g/cm2] compared statistically with the other groups (all P＜0.05). Ovx+run+e2 [ (0.14±0.02) g/cm2] and Sham+run [ (0.13±0.02) g/cm2] groups had BMD that was comparable to each other but significantly higher than the other groups (all P＜0.05). No statistical difference in BMD could be found among Sham [ (0.11 ±0.01) g/cm2], Ovx+run [ (0.12±0.01)g/cm2] and Ovx+run+e1 [(0.12±0.01 ) g/cm2] groups (all P＞0.05). (2)The trabecular thickness, percentage area of trabeculae and trabecular bone mass in Sham group were comparable to those in Ovx+run+e2 and Sham+run groups but were higher than those in Ovx+run+el, Ovx+run and Ovx groups (all P＜0.05). Sham,Ovx+run+e2 and Sham+run groups had trabecular separation that was comparable among each other but less than those in Ovx+run+e1, Ovx+run and Ovx groups (all P＜0.05). The percentage area of trabeculae and the trabecular bone mass increased while trabecular separation decreased in order of groups by Ovx, Ovx+run,and Ovx+run+e1 (all P＜0.05), while the trabecular thickness did not differ among the three groups. (3)The maximum shearing force, maximum shearing stress, maximum shearing strain and shearing elasticity modulus in Ovx group were remarkably lower than those in other groups (all P＜0.05 ). Ovx+run+e2 group had maximum shearing force, maximum shearing stress and maximum shearing strain that were comparaile to Sham + run group but greater than those in other groups (all P＜0.05) , and shearing elasticity modulus comparable to Sham+run and Ovx+run groups but greater than those in Sham, Ovx and Ovx+run+el groups (all P＜0.05). No statistical differences in maximum shearing force, maximum shearing stress and maximum shearing strain were found among Sham, Ovx+run+e1 and Ovx+run groups. The shearing elasticity modulus in Sham group was lower than that in Ovx+run group (P＜0.05) but was not significantly different between Sham and Ovx+run+e1 group and between Ovx+run+e1 and Ovx+run group. Conclusions Estrogen levels may have a strong impact on outcomes of exercise therapy for osteoporosis. Adequate estrogen supplement can be synergistic to the outcomes of exercise therapy for osteoporosis. But inadequate estrogen supplement can not be synergistic.