Chronic Liver Disease-Related Osteoporosis: From Mechanisms to Precision Intervention.

Abstract

Background & aims: Patients with chronic liver disease (CLD) frequently develop reduced bone mass and an increased risk of fragility fractures, making osteoporosis a major extrahepatic complication that affects long-term prognosis and quality of life. Although the association between CLD and osteoporosis is well recognized, epidemiological risk factors and the shared versus etiology-specific mechanisms remain incompletely integrated. Current clinical risk assessment relies largely on bone mineral density, which fails to capture microarchitectural deterioration and may underestimate true fracture risk. This review aimed to integrate current epidemiological and mechanistic evidence and examine emerging approaches to precision prevention and management of CLD-related osteoporosis.

Methods: We reviewed relevant literature published between 2000 and 2025 identified through PubMed, Embase, and Web of Science, prioritizing high-quality clinical, translational, and basic research studies. The review focused on four major CLD populations: chronic hepatitis B, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and autoimmune hepatitis.

Results: Evidence supports a multifactorial pathogenesis involving inflammation, endocrine-metabolic dysregulation, and disturbances in the liver-bone and liver-gut-bone axes, which collectively promote osteoclast-osteoblast imbalance and bone loss. Based on these mechanistic insights, we propose a risk-stratified screening and dynamic monitoring framework that emphasizes multidimensional evaluation using bone quality assessment and emerging biomarkers. Individualized prevention and treatment strategies are discussed according to disease etiology and risk profiles, with particular attention to emerging therapeutic directions such as bone-targeted drug delivery and cross-organ metabolic regulation.

Conclusions: Collectively, this review provides a conceptual and translational framework to support precision prevention and management of osteoporosis in patients with chronic liver disease.

Impact and implications: Patients with chronic liver disease (CLD) face a markedly increased risk of osteoporosis and fragility fractures, but this systemic complication remains insufficiently recognized, while conventional assessment based mainly on bone mineral density may underestimate clinically relevant alterations in bone quality and microarchitecture. By synthesizing epidemiological data and both shared and etiology-specific mechanisms across chronic hepatitis B, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and autoimmune hepatitis, this review offers an integrated framework for hepatologists, endocrinologists, and translational researchers. The findings underscore the value of risk-stratified screening, dynamic assessment of bone quality and biomarkers, and individualized preventive and therapeutic strategies to optimize skeletal health in patients with CLD. However, because a substantial proportion of the mechanistic evidence remains preclinical, these translational implications should be interpreted cautiously and require confirmation in well-designed prospective multicenter studies prior to widespread implementation.