Musculoskeletal Complications and Bone Metastases in Breast Cancer Patients Undergoing Estrogen Deprivation Therapy
Technical Report,30 Sep 2014,29 Sep 2015
Indiana University Indianapolis United States
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Adjuvant endocrine therapy using an aromatase inhibitor AI is a standard treatment for postmenopausal women with ER-positive breast cancer. Unfortunately, up to 50 of women treated with an AI develop muscle weakness, bone loss and joint pain that result in treatment discontinuation. I hypothesized that estrogen deprivation and subsequent bone loss could alter the bone microenvironment in ways that accelerate the progression of breast cancer growth in bone and exacerbate muscle weakness systemically. Four-week female athymic nude mice underwent OVX or sham surgery and were treated daily with vehicle or AI 10gday n20group. Three weeks after surgery and onset of treatment, serum levels of 17-estradiol in OVX-AI mice were reduced by 56 p0.01 and trabecular bone volume fraction at the proximal tibia was reduced by 67 relative to vehicle-sham p0.001. After confirming estrogen deficiency and bone loss, the same animals were inoculated with ER-negative MDA-MB-231 human breast cancer cells into the left cardiac ventricle and followed for cancer progression in bone. Five weeks after inoculation, osteolytic lesion area increased by 110 p0.01 and tumor burden in bone was increased by 87 in OVX-AI mice relative to sham-vehicle p0.01. Furthermore, ex vivo maximal contractile force of the extensor digitorum longus EDL muscle was significantly reduced in OVX-AI mice -12, p0.001 relative to sham-vehicle. These studies confirmed that AI treatment induces bone loss and skeletal muscle weakness, recapitulating effects reported in cancer patients. As hypothesized, severe bone loss resulting from AI-induced estrogen depletion may prime the bone microenvironment for the development of breast cancer metastases to bone and potentiate muscle weakness. Ongoing studies will evaluate whether protection of bone with bisphosphonates can prevent AI-induced musculoskeletal complications in my model of breast cancer bone metastases.