Dose-dependent effects of tamoxifen on long bones in growing rats: influence of ovarian status.

Tamoxifen is a nonsteroidal antiestrogen which has been reported by various investigators to have estrogen agonist and antagonist effects on rat bone. These different interpretations may be due to differences in the ovarian status, estrogen levels, and/or tamoxifen levels of the rats. To address this issue, a dose response was determined for the effects of tamoxifen on bone histomorphometry in intact female and ovariectomized (OVX) rats. The results were compared with those obtained after treatment of OVX rats with estrogen alone or a combination of estrogen and tamoxifen. OVX resulted in increases in growth rate (weight gain) and periosteal bone formation rate and decreases in uterine weight and cancellous bone fractional volume (BV/TV). Treatment of OVX rats with estrogen resulted in dose-dependent decreases in growth rate and periosteal bone formation rate as well as dose-dependent increases in uterine weight and BV/TV. Similarly, tamoxifen treatment resulted in dose-dependent decreases in overall growth rate and periosteal bone formation rate in both OVX and intact rats. Tamoxifen treatment prevented the decrease in BV/TV after OVX, although the highest dose of tamoxifen resulted in a small decrease in BV/TV in intact female rats. In contrast to estrogen, tamoxifen treatment prevented the increase in uterine weight in intact female rats as well as the decrease in uterine weight in OVX rats. Tamoxifen treatment did not alter the effects of 17 beta-estradiol on the periosteal bone formation rate in OVX rats, but reduced the increase in BV/TV to values similar to those in intact rats. These results are consistent with tamoxifen behaving as a partial estrogen agonist on rat bone.