Primary biliary cholangitis–associated osteoporosis: contemporary review of pathogenesis and management

Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune disease, often accompanied by osteoporosis (OP), a serious complication that elevates fracture risk and mortality. With rising PBC prevalence, OP incidence in this population is also increasing. Early detection and effective management are essential, yet current OP strategies in PBC largely derive from postmenopausal osteoporosis studies, despite distinct pathophysiological differences. This review comprehensively synthesizes the epidemiology, risk factors, molecular mechanisms, diagnosis, and therapeutic approaches for OP in PBC, highlighting unmet clinical needs and future directions.

Introduction
PBC is characterized by autoimmune-mediated destruction of intrahepatic bile ducts, leading to cholestasis and progressive liver injury. Beyond its hepatic manifestations, PBC frequently coincides with osteoporosis—a condition marked by reduced bone mass, microarchitectural deterioration, and heightened fracture susceptibility. OP in PBC not only compromises quality of life but also increases post-fracture mortality. The pathogenesis is multifactorial, involving immune dysregulation, cholestasis, liver dysfunction, and metabolic alterations. This review consolidates current knowledge on OP in PBC, from epidemiology to emerging therapies, to inform clinical practice and research.

Prevalence and Risk Factors of OP in PBC
Studies report OP prevalence in PBC patients ranging from 20% to 50%, influenced by age, gender, disease duration, and liver fibrosis severity. Meta-analyses indicate that about 38% of PBC patients have OP, with another 39% having osteopenia.

• Demographic and Clinical Factors: Advanced age, prolonged disease duration, low body mass index (BMI), and sarcopenia are significant risk factors. Postmenopausal women with PBC have higher OP rates than age-matched controls without PBC.

• Laboratory and Histological Correlates: Elevated bilirubin and bile acid levels, dyslipidemia, and advanced hepatic fibrosis (assessed by FibroScan or FIB-4) are independently associated with reduced bone mineral density (BMD).

• Genetic Insights: Mendelian randomization studies support a causal link between PBC and increased OP risk.

Pathogenesis of OP in PBC
Bone loss in PBC primarily results from impaired osteoblast-mediated bone formation, though increased osteoclast activity also contributes.

• Immune Dysregulation: Enhanced Th17 cell activity and elevated IL-17 promote RANKL expression, driving osteoclast differentiation. Overexpression of RANKL in the liver and altered osteoprotegerin (OPG) levels further disrupt bone remodeling.

• Cholestasis: Reduced bile acid recycling impairs absorption of fat-soluble vitamins D and K, leading to deficiencies that compromise bone mineralization and osteocalcin activation. Accumulated bile acids and bilirubin directly inhibit osteoblast proliferation and differentiation. Ursodeoxycholic acid may partially counteract these effects.

• Liver Damage: Decreased hepatic synthesis of insulin-like growth factor-1 (IGF-1) reduces osteoblast stimulation. Elevated sclerostin, an inhibitor of the Wnt/β-catenin pathway, further suppresses bone formation.

Diagnosis of OP in PBC
Dual-energy X-ray absorptiometry (DXA) remains the gold standard for OP diagnosis, defined by a T-score ≤ −2.5. Several screening tools aid in risk assessment:

• IOF One-Minute Osteoporosis Risk Test: Quick clinical screening based on age, fracture history, and other risk factors.

• FRAX Tool: Integrates BMD, age, BMI, and clinical factors to estimate 10-year fracture probability.

• OSTA Index: Weight and age-based tool particularly suited for Asian postmenopausal women.

Management of OP in PBC
Treatment strategies are largely adapted from postmenopausal OP, with limited PBC-specific evidence.

• Calcium and Vitamin D: Foundational supplementation is recommended, though data on fracture prevention in PBC are inconclusive.

• Bisphosphonates: Efficacy in PBC-associated OP is inconsistent; some studies show BMD improvement, but meta-analyses lack evidence for fracture risk reduction. Caution is advised in patients with esophageal varices.

• Hormone Replacement Therapy: Not recommended due to risks of cholestasis exacerbation and other adverse effects.

• Denosumab: This RANKL inhibitor has shown promising results in improving BMD in PBC patients, with efficacy comparable to zoledronic acid and a favorable safety profile.

• Romosozumab: A sclerostin-targeting monoclonal antibody approved for severe OP; early reports suggest benefit in PBC patients, even at reduced doses.

Conclusion
OP is a common and serious extrahepatic complication of PBC, driven by a complex interplay of immune, cholestatic, and hepatic factors. Diagnosis relies on DXA and clinical risk tools, while management remains challenging due to insufficient PBC-specific evidence. Calcium and vitamin D form the baseline, with bisphosphonates, denosumab, and romosozumab offering potential therapeutic benefits. Further high-quality, prospective studies are needed to establish evidence-based guidelines for OP prevention and treatment in the PBC population.

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https://www.xiahepublishing.com/2310-8819/JCTH-2025-00505

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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