Endoxifen, the primary active metabolite of
tamoxifen, is currently being investigated as a novel endocrine
therapy for the treatment of
breast cancer.
Tamoxifen is a
selective estrogen receptor modulator that elicits potent anti-
breast cancer effects. However, long-term use of
tamoxifen also induces bone loss in premenopausal women and is associated with an increased risk of
endometrial cancer in postmenopausal women. For these reasons, we have used a rat model system to comprehensively characterize the impact of
endoxifen on the skeleton and uterus. Our results demonstrate that
endoxifen elicits beneficial effects on bone in ovary-intact rats and protects against bone loss following
ovariectomy.
Endoxifen is also shown to reduce bone turnover in both ovary-intact and ovariectomized rats at the cellular and biochemical levels. With regard to the uterus,
endoxifen decreased uterine weight but maintained
luminal epithelial cell height in ovariectomized animals. Within
luminal epithelial cells,
endoxifen resulted in differential effects on the expression levels of
estrogen receptors α and β as well as multiple other genes previously implicated in regulating epithelial cell proliferation and
hypertrophy. These studies analyze the impact of extended
endoxifen exposure on both bone and uterus using a Food and Drug Administration-recommended animal model. Although
endoxifen is a more potent
breast cancer agent than
tamoxifen, the results of the present study demonstrate that
endoxifen does not induce bone loss in ovary-intact rats and that it elicits partial agonistic effects on the uterus and skeleton in ovariectomized animals.