Endoxifen has recently been identified as the predominant active metabolite of
tamoxifen and is currently being developed as a novel hormonal
therapy for the treatment of endocrine sensitive
breast cancer. Based on past studies in
breast cancer cells and model systems,
endoxifen classically functions as an anti-estrogenic compound. Since
estrogen and
estrogen receptors play critical roles in mediating bone homeostasis, and
endoxifen is currently being implemented as a novel
breast cancer therapy, we sought to comprehensively characterize the in vivo effects of
endoxifen on the mouse skeleton. Two month old ovariectomized C57BL/6 mice were treated with vehicle or 50 mg/kg/day
endoxifen hydrochloride via oral gavage for 45 days. Animals were analyzed by dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, micro-computed tomography and histomorphometry. Serum from control and
endoxifen treated mice was evaluated for
bone resorption and bone formation markers. Gene expression changes were monitored in osteoblasts, osteoclasts and the cortical shells of long bones from
endoxifen treated mice and in a human fetal osteoblast cell line.
Endoxifen treatment led to significantly higher bone mineral density and bone mineral content throughout the skeleton relative to control animals.
Endoxifen treatment also resulted in increased numbers of osteoblasts and osteoclasts per tissue area, which was corroborated by increased serum levels of bone formation and resorption markers. Finally,
endoxifen induced the expression of osteoblast, osteoclast and osteocyte marker genes. These studies are the first to examine the in vivo and in vitro impacts of
endoxifen on bone and our results demonstrate that
endoxifen increases cancellous as well as cortical bone mass in ovariectomized mice, effects that may have implications for postmenopausal
breast cancer patients.