Abstract: OBJECTIVE To unveil the mechanism of Zhuanggu Zhitong Capsule (ZGZTC) protecting against postmenopausal osteoporosis induced by ovariectomy with XCT790 blocking estrogen receptor-related receptor. METHODS seventy 8-month old Sprague Dawley female rats were randomly allocated into sham-operation group, model group, XCT790 group, ZGZTC group, XCT790 high dose + ZGZTC group, XCT790 middle dose + ZGZTC group, XCT790 low dose + ZGZTC group, 10 rats in each group. The rats in sham-operation group were retained ovary with only removing some fat near ovary, those rats in other groups were performed bilateral ovariectomy. One week later, the rats in sham-operation group, model group and ZGZTC group were injected subcutaneously with olive oil every 3 days, other rats were injected subcutaneously with XCT790 dissolved in olive oil every 3 days. Rats in sham-operation group, model group, XCT790 group were administered with distilled water, those rats in other groups were administered ZGZTC with the same dosage for 12 weeks. Then all rats were anaesthetized intraperitoneally with injection of chloral hydrate and abdominal aortic exsanguinated. Right femurs were collected for bone mineral density and biomechanics detection, left femurs for ELISA of ERR_α, left tibias for RT-PCR of ERR_α, right tibias for immunohistochemical detection of ERR_α. RESULTS XCT790 significantly decreased bone mineral density and bone biomechanics (P<0.05) in ovariectomized rats, and decreased the expression of ERR_α in bone tissue. ZGZTC could increase the bone mineral density and bone biomechanics (P<0.05) and the role could be decreased with a dose-dependent pattern by XCT790. ZGZTC significantly enhanced the expression of ERR_α (P<0.05) in ovariectomized rats, and the promoting effect was significantly decreased by XCT790. CONCLUSION ZGZTC plays the role of protecting against postmenopausal osteoporosis through regulating estrogen receptor-related receptor signaling pathway.