Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates muscle weakness in vivo

// Laura E. Wright 1 , Ahmed A. Harhash 1 , Wende M. Kozlow 2 , David L. Waning 3 , Jenna N. Regan 1 , Yun She 1 , Sutha K. John 1 , Sreemala Murthy 1 , Maryla Niewolna 1 , Andrew R. Marks 4 , Khalid S. Mohammad 1 , Theresa A. Guise 1 1 Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA 2 Department of Internal Medicine, Division of Endocrinology, University of Virginia, Charlottesville, VA, USA 3 Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA 4 Department of Physiology, Columbia University, New York, NY, USA Correspondence to: Laura E. Wright, email: laewrig@iu.edu Keywords: breast cancer, bone, metastasis, aromatase inhibitor, skeletal muscle Received: October 20, 2016      Accepted: November 23, 2016      Published: December 25, 2016 ABSTRACT Aromatase inhibitors (AIs) cause muscle weakness, bone loss, and joint pain in up to half of cancer patients. Preclinical studies have demonstrated that increased osteoclastic bone resorption can impair muscle contractility and prime the bone microenvironment to 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. Female athymic nude mice underwent ovariectomy (OVX) or sham surgery and were treated with vehicle or AI (letrozole; Let). An OVX-Let group was then further treated with bisphosphonate (zoledronic acid; Zol). At week three, trabecular bone volume was measured and mice were inoculated with MDA-MB-231 cells into the cardiac ventricle and followed for progression of bone metastases. Five weeks after tumor cell inoculation, tumor-induced osteolytic lesion area was increased in OVX-Let mice and reduced in OVX-Let-Zol mice compared to sham-vehicle. Tumor burden in bone was increased in OVX-Let mice relative to sham-vehicle and OVX-Let-Zol mice. At the termination of the study, muscle-specific force of the extensor digitorum longus muscle was reduced in OVX-Let mice compared to sham-vehicle mice, however, the addition of Zol improved muscle function. In summary, AI treatment induced bone loss and skeletal muscle weakness, recapitulating effects observed in cancer patients. Prevention of AI-induced osteoclastic bone resorption using a bisphosphonate attenuated the development of breast cancer bone metastases and improved muscle function in mice. These findings highlight the bone microenvironment as a modulator of tumor growth locally and muscle function systemically.