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Musculoskeletal Complications and Bone Metastases in Breast Cancer Patients Undergoing Estrogen Deprivation Therapy

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Technical Report,30 Sep 2014,29 Sep 2018

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Indiana University School of Medicine Indianapolis United States

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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 C57BL6 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 BVTVdecreased by 50 percent in OVX-vehicle and OVX-AI mice p0.05, whereas BVTV 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.

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  • Medicine and Medical Research

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