Ovarian status influences the skeletal effects of tamoxifen in adult rats

Tamoxifen (TAM), an antiestrogen used in adjuvant therapy for breast cancer, is currently being evaluated for prevention of breast cancer in premenopausal and postmenopausal disease-free women. In light of this clinical application in young women, the skeleton's potential predisposition for osteoporosis following long-term treatment with an antiestrogen is a concern. In postmenopausal women being treated for breast cancer TAM was shown to prevent bone loss. There is little information, however, about the skeletal effects of TAM in premenopausal women. Previous animal studies in ovariectomized (OVX'd) rats have consistently reported TAM to prevent cancellous and cortical bone loss. The effects of TAM on ovary-intact animals, however, are not well established. We have performed a histomorphometric analysis in order to evaluate the influence of ovarian function on the skeletal effects of long-term TAM treatment in the laboratory animal model. Six-month-old rats were implanted subcutaneously with pellets designed for the controlled release of TAM at a dose (5 mg/3 wks) previously shown to be effective at antagonizing short-term bone loss in OVX'd growing rats. TAM acted as an estrogen agonist on cortical bone measurements in tibia of ovary-intact as well as OVX'd rats. In cancellous bone of OVX'd rats, TAM reduced indices of bone formation and resorption and reduced the bone loss from over 90 percent to less than 50 percent. In ovary-intact rats, however, TAM produced a 31 percent loss of cancellous bone, a deficit associated with a 26 percent reduction in the trabecular number. These results clearly demonstrate an interaction between TAM and ovarian status whereby TAM partially prevents estrogen-deficient bone loss in OVX'd animals but antagonizes selective actions of estrogen on the skeleton of ovary-intact animals.