Effect of a High Bone Turnover State Induced by Estrogen Deficiency on the Development and Progression of Breast Cancer Bone Metastases

Aromatase inhibitors (AIs), effective treatment for breast cancer, block estrogen synthesis. Increased bone resorption and decreased bone mineral density (BMD) are predicted consequences. We hypothesized that bisphosphonates (BPs) may prevent bone loss from AI therapy. Four-week-old female nude mice were treated with letrozole (10 mcg/d), zoledronic acid (ZA) (5 mcg/kg twice weekly), letrozole + ZA or control. Mice treated with letrozole alone had lower BMD compared to control (p0.0001; total body, spine, femur and tibia). Mice treated with ZA alone had higher BMD compared to control (p0.0001; total body, spine, femur and tibia). MicroCT analysis of the tibia showed no difference in trabecular bone volume (BV/TV) or trabecular number, thickness or spacing in mice treated with letrozole compared to control. Treatment with ZA (+/- letrozole) resulted in a significant increase in BV/TV and trabecular number and thickness, and the structural model index indicated that the bone structure was unusually solid. ZA prevented AI-induced bone loss, but microCT and dynamic bone histomorphometry suggest reduced bone remodeling. BPs may be useful to prevent AI-induced bone loss, but further studies are needed to assess the effects of these treatments on bone quality. The original document contains color images.