title: Aromatase inhibitor-induced bone loss increases the progression of estrogen receptor-negative breast cancer in bone and exacerbates muscle weakness in vivo.
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.
authors.affiliation: Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Wright
authors.affiliation: Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Harhash
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Wende M
authors.initials: WM
authors.lastname: Kozlow
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Waning
authors.affiliation: Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA.
authors.forename: Jenna N
authors.initials: JN
authors.lastname: Regan
authors.affiliation: Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: She
authors.affiliation: Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA.
authors.forename: Sutha K
authors.initials: SK
authors.lastname: John
authors.affiliation: Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA.
authors.forename: Sreemala
authors.initials: S
authors.lastname: Murthy
authors.affiliation: Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA.
authors.forename: Maryla
authors.initials: M
authors.lastname: Niewolna
authors.affiliation: Department of Physiology, Columbia University, New York, NY, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
authors.affiliation: Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA.
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.affiliation: Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000633:toxicity*; D047072:Aromatase Inhibitors / Q000633:toxicity*; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology; D018450:Disease Progression; D004958:Estradiol / Q000097:blood; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D000077289:Letrozole; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053580:Muscle Strength / Q000187:drug effects*; D018908:Muscle Weakness / Q000139:chemically induced* / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000503:physiopathology; D009570:Nitriles / Q000633:toxicity*; D010014:Osteolysis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D010052:Ovariectomy; D011960:Receptors, Estrogen / Q000172:deficiency*; D013997:Time Factors; D014230:Triazoles / Q000633:toxicity*; D047368:Tumor Burden; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D004958:Estradiol; D000077211:Zoledronic Acid; D000077289:Letrozole
keywords: aromatase inhibitor; bone; breast cancer; metastasis; skeletal muscle