Decoding the Metabolic Dialogue of the "Liver– Bone Axis": The Necessity of Establishing Animal Models to Investigate the Mechanisms Linking Nonalcoholic Steatohepatitis (NASH) and Osteo porosis

Background: The global rise in metabolic syndrome and obesity has turned the coexistence of nonalcoholic fatty liver disease (NAFLD)—particularly its progressive inflammatory phenotype, nonalcoholic steatohepatitis (NASH)—and osteoporosis into an increasingly common clinical scenario. Multiple clinical studies since 2012 have reported that individuals with NAFLD/NASH, including postmenopausal women and obese children, tend to exhibit lower bone mineral density (BMD) and higher fracture risk, suggesting a pathological metabolic linkage within a “liver–bone axis” [1,2]. Yet, human epidemiology is often constrained by cross-sectional designs and residual confounding (e.g., lifestyle behaviors and medication exposure), limiting causal inference. Purpose: This review synthesizes the current clinical and mechanistic evidence connecting NAFLD/NASH to impaired bone health, highlights the roles of insulin resistance and liver-derived insulin-like growth factor-1 (IGF-1), and critically appraises existing genetic, dietary, and combination animal models for their suitability in modeling NASH-associated bone loss. Methods: We present a narrative synthesis of human observational studies and mechanistic literature, followed by a structured appraisal of commonly used rodent models of NASH. Model suitability is evaluated through a dual lens: (a) metabolic phenotype (obesity and insulin resistance) and (b) liver histopathology (steatosis, inflammation, and fibrosis), with explicit attention to confounders that are especially consequential for bone research (notably weight loss and malnutrition). Results: A convergent body of evidence supports an association between NAFLD/NASH and adverse skeletal outcomes. Mechanistically, hepatic dysfunction may reduce circulating IGF-1—an essential anabolic signal for osteoblast function and type I collagen synthesis [3–5]—while systemic inflammation and insulin resistance may further tilt bone remodeling toward net loss. Importantly, not all NASH animal models are equally informative for the liver–bone axis: models that induce severe steatohepatitis at the cost of profound weight loss can obscure whether bone loss is driven by liver inflammation or by catabolic undernutrition. Conclusions/Implications for Practice: We argue that establishing a translationally faithful NASH animal model that mirrors key human features—obesity, insulin resistance, and fibrotic liver injury—is a critical foundation for dissecting causality, mapping temporal trajectories of bone loss, and testing integrated interventions. For nursing and interdisciplinary care, recognizing skeletal vulnerability in NAFLD/NASH may support proactive risk assessment, patient education, lifestyle counseling, and fall-prevention strategies alongside liver-directed management.