Musculoskeletal Complications and Bone Metastases in Breast Cancer Patients Undergoing Estrogen Deprivation Therapy
Abstract
Between 25-50 percent of women treated with endocrine therapies develop musculoskeletal toxicities that result in treatment discontinuation. In previous reporting periods, I demonstrated that aromatase inhibitor (AI) treatment caused bone loss and skeletal muscle weakness in mice and that prevention of AI-induced osteoclastic bone resorption using a bisphosphonate attenuated ER-negative breast cancer bone metastases and improved muscle function. These preclinical findings highlight the bone microenvironment as a modulator of tumor growth locally and muscle function systemically. Because muscle weakness is also commonly reported in women treated with selective estrogen receptor modulators (SERMs), during this reporting period I compared musculoskeletal effects of AI with a bone-sparing SERM endoxifen in a non-tumor model. Endoxifen (Endx), an active metabolite of tamoxifen, is currently in phase I trials for ER+ advanced breast cancer and little is known of its effects on the musculoskeletal system. Mature female C57BL/6 mice underwent sham surgery or ovariectomy (OVX) and were treated daily with vehicle, the AI letrozole (Let), or Endx. After eight weeks, changes in cancellous and cortical bone indices were assessed by muCT and muscle contractility of the extensor digitalis longus (EDL) was measured ex vivo. Bone volume fraction (BV/TV)decreased by 50 percent in OVX-vehicle and OVX-AI mice (p<0.05), whereas BV/TV increased threefold in Endx mice relative to sham-vehicle. Periosteal expansion of cortical bone was inhibited by Endx evidenced by a decrease in medullary area, total cortical cross-sectional area, and polar moment of inertia relative to sham- and OVX-vehicle. Despite changes in cortical bone deposition, the biomechanical properties of bone in Endx-treated mice were significantly improved relative to OVX-vehicle and OVX-AI mice.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2018
- Accession Number
- AD1095156
Entities
People
- Laura E. Wright
Organizations
- Indiana University School of Medicine