Bone Abstracts

Up to half of women treated with an aromatase inhibitor (AI) for breast cancer develop muscle weakness, bone loss, and joint pain. Moreover, an elevated state of osteoclastic bone resorption has been shown to prime the bone microenvironment in ways that accelerate metastatic growth. We hypothesized that AI-induced bone loss could increase breast cancer progression in bone and exacerbate muscle weakness associated with bone metastases. Four-week female athymic nude mice underwent ovariectomy (OVX) or sham surgery and were treated with vehicle or AI (letrozole; 10 μg/day) ±bisphosphonate (zoledronic acid, ZA; 0.1 μg 3×/week; n=20/group). At week three, bone volume was reduced in OVX-AI mice (−67%, P<0.0001) and increased in OVX-AI-ZA mice (304%, P<0.0001) relative to sham-vehicle. Mice were then inoculated with 100,000 MDA-MB-231 human breast cancer cells into the left cardiac ventricle and followed for cancer progression. Since MDA-MB-231 cells are ER-negative, effects of estrogen deprivation on the tumor can be attributed to changes in the microenvironment. Five weeks after inoculation, osteolytic lesion area by X-ray was increased in OVX-AI mice (14.8 vs 7.1 mm², P<0.05) and reduced in OVX-AI-ZA mice (3.1 vs 7.1 mm² P<0.05) relative to sham-vehicle. Tumor burden in bone was increased in OVX-AI mice relative to sham-vehicle (11.6 vs 6.2 mm², P<0.05) and relative to OVX-AI-ZA mice (6.6 mm², P<0.05). Finally, muscle-specific force of the extensor digitorum longus was reduced in OVX-AI mice relative to sham-vehicle (399 vs 451 kN/m², P<0.05), and unchanged in OVX-AI-ZA (436 kN/m², P=ns). In summary, prevention of AI-induced osteoclastic bone resorption attenuated the development of breast cancer bone metastases and improved muscle function in mice. These findings highlight the bone microenvironment as a powerful modulator of tumor growth locally and muscle function systemically. Further studies are necessary to determine the relative contribution of estrogen deficiency, bone loss, and direct AI toxicities to impaired muscle function in this model.