Tibolone exerts its protective effect on trabecular bone loss through the estrogen receptor

Tibolone (Org OD14) has estrogenic, progestogenic, and/or androgenic activi ty depending on the tissue. In postmenopausal women, tibolone prevents bone loss without stimulating the endometrium. Tibolone is effective in prevent ing trabecular bone loss from the peripheral and axial skeleton of young an d old ovariectomized (OVX) rats by reducing bone turnover, that is, bone re sorption, like estrogens. We evaluated the contribution of the various horm onal activities to tibolone's bone-conserving effect. Three-month-old OVX r ats received tibolone (125 mug/rat or 500 mug/rat, twice daily), alone or c ombined with an antiestrogen, antiandrogen, or antiprogestogen, and the eff ects on trabecular bone mass and bone turnover were evaluated. Sham-operate d and control OVX groups were treated with vehicle. The remaining OVX group s received oral doses of tibolone twice daily, alone or with twice daily (a ) antiestrogen ICI 164.384, (b) antiandrogen flutamide, or (c) antiprogesto gen Org 31710. For comparison, the effects of 17 beta -estradiol and testos terone were examined also. After 4 weeks, trabecular bone mineral density ( BMD) in the distal. femur, plasma osteocalcin, and urinary deoxypyridinolin e/creatinine ratio (Dpyr/Cr) were measured. Tibolone or 17 beta -estradiol significantly blocked ovariectomy-induced loss of trabecular BMD and inhibi ted bone resorption and bone turnover as judged by reduced Dpyr/Cr ratio an d osteocalcin, respectively. These effects of both compounds were counterac ted by the antiestrogen. This suggests a major involvement of the estrogen receptor in the action of tibolone on bone metabolism. However, the antiand rogen and the antiprogestogen did not counteract the effects of tibolone, e xcluding a major role of the androgenic and progestogenic activities of tib olone in its action against trabecular bone loss. The results indicate that tibolone acts on bone almost entirely through activation of the estrogen r eceptor.