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

Tibolone (Org OD14) has estrogenic, progestogenic, and/or androgenic activity depending on the tissue. In postmenopausal women, tibolone prevents bone loss without stimulating the endometrium. Tibolone is effective in preventing trabecular bone loss from the peripheral and axial skeleton of young and old ovariectomized (OVX) rats by reducing bone turnover, that is, bone resorption, like estrogens. We evaluated the contribution of the various hormonal activities to tibolone's bone-conserving effect. Three-month-old OVX rats received tibolone (125 microg/rat or 500 microg/rat, twice daily), alone or combined with an antiestrogen, antiandrogen, or antiprogestogen, and the effects on trabecular bone mass and bone turnover were evaluated. Sham-operated and control OVX groups were treated with vehicle. The remaining OVX groups received oral doses of tibolone twice daily, alone or with twice daily (a) antiestrogen ICI 164.384, (b) antiandrogen flutamide, or (c) antiprogestogen Org 31710. For comparison, the effects of 17beta-estradiol and testosterone were examined also. After 4 weeks, trabecular bone mineral density (BMD) in the distal femur, plasma osteocalcin, and urinary deoxypyridinoline/creatinine ratio (Dpyr/Cr) were measured. Tibolone or 17beta-estradiol significantly blocked ovariectomy-induced loss of trabecular BMD and inhibited bone resorption and bone turnover as judged by reduced Dpyr/Cr ratio and osteocalcin, respectively. These effects of both compounds were counteracted by the antiestrogen. This suggests a major involvement of the estrogen receptor in the action of tibolone on bone metabolism. However, the antiandrogen and the antiprogestogen did not counteract the effects of tibolone, excluding a major role of the androgenic and progestogenic activities of tibolone in its action against trabecular bone loss. The results indicate that tibolone acts on bone almost entirely through activation of the estrogen receptor.