Mechanisms and biomarkers for musculoskeletal signs and symptoms in patients treated with aromatase inhibitors: A comprehensive systematic review

BACKGROUND: Aromatase inhibitors anastrozole and letrozole (non-steroidal, reversible), and exemestane (steroidal, irreversible) are approved standard therapies (Food and Drug Administration) for hormone receptor-positive breast cancer. Their use is limited by Aromatase Inhibitor-induced Musculoskeletal Signs and Symptoms (AIMSS). METHODS: Articles on AIMSS mechanisms and biomarkers published between January 1, 1990, and October 31, 2024, in PubMed, EMBASE, and Cochrane Library were identified. Included study designs were randomized and non-randomized trials, observational cohorts, cross-sectional studies, and preclinical animal models. Risk of bias was assessed using the Critical Appraisal Skills Programme tool for observational studies and Risk of Bias 2 for randomized trials. RESULTS: Fifty studies were included (43 human and seven animal). Estrogen deprivation was the central mechanism, affecting immune function, bone remodeling, and nociceptive sensitivity. Genetic variants in Estrogen Receptor 1, CYP19A1, and T-cell Leukemia/Lymphoma 1A were frequently associated with AIMSS. Vitamin D deficiency, polymorphisms in RANKL and Osteoprotegerin contributed to bone-related symptoms. Imaging studies identified tenosynovial thickening, tendon sheath fluid, and subclinical inflammation. Systemic inflammatory markers C-Reactive Protein and Interleukin 6 were elevated in human and animal studies. Transient Receptor Potential Ankyrin 1 and Transient Receptor Potential Vanilloid 4 ion channels were implicated in peripheral sensitization. Insulin-like Growth Factor 1 during AI therapy was independently associated with symptoms. CONCLUSION: AIMSS involves intersecting hormonal, genetic, inflammatory, and neural pathways. Identification of mechanistic biomarkers may support AIMSS risk stratification and targeted interventions. Further research should validate multi-omic models and explore new strategies to reduce AIMSS and improve treatment compliance. REGISTRATION: PROSPERO Registration: CRD42025642540.