Skeletal impact of 17β-estradiol in T cell-deficient mice: age-dependent bone effects and osteosarcoma formation.

Estrogen (E2)-dependent ER+ breast cancer, the most common breast cancer subtype, is also the most likely to metastasize to bone and form osteolytic lesions. However, ER+ breast cancer bone metastasis human xenograft models in nude mice are rarely studied due to complexities associated with distinguishing possible tumoral vs. bone microenvironmental effects of E2. To address this knowledge gap, we systematically examined bone effects of E2 in developing young (4-week-old) vs. skeletally mature (15-week-old) female Foxn1nu nude mice supplemented with commercial 60-day slow-release E2 pellets and doses commonly used for ER+ xenograft models. E2 pellets (0.05-0.72 mg) were implanted subcutaneously and longitudinal changes in hind limb bones (vs. age-matched controls) were determined over 6 weeks by dual-energy X-ray absorptiometry (DXA), microCT, radiographic imaging, and histology, concurrent with assessment of serum levels of E2 and bone turnover markers. All E2 doses tested induced significant and identical increases in bone density (BMD) and volume (BV/TV) in 4-week-old mice with high bone turnover, increasing bone mineral content (BMC) while suppressing increases in bone area (BA). E2 supplementation, which caused dose-dependent changes in circulating E2 that were not sustained, also led to more modest increases in BMD and BV/TV in skeletally mature 15-week-old mice. Notably, E2-supplementation induced osteolytic osteosarcomas in a subset of mice independent of age. These results demonstrate that bone effects of E2 supplementation should be accounted for when assessing ER+ human xenograft bone metastases models.