Circulating Molecular Drivers of Bone Remodeling in Pancreatitis

Introduction: Pancreatitis-associated osteopathy is a clinically significant but mechanistically underexplored complication of pancreatic disease. We aimed to characterize stage-specific alterations in bone remodeling biomarkers across the spectrum of disease: recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP). Methods: In a cross-sectional analysis of North American Pancreatitis Study 2 (NAPS2) participants, we measured serum mechanistic (sclerostin, DKK1, RANKL, OPG), hormonal (FGF23, insulin, leptin), and modulatory (osteopontin, oncostatin, osteoactivin) markers in controls (n = 30), RAP (n = 40), and CP (n = 40) using a multiplex assay. Group differences were assessed with ANOVA, Fisher’s exact test, and Kruskal Wallis; multivariable regression identified predictors of biomarker variation. Results: Eight of ten biomarkers differed significantly among groups. Sclerostin, DKK1, RANKL, and OPG were elevated in RAP and CP versus controls, with the highest values in CP. The RANKL/OPG ratio was greatest in CP. FGF23 was increased in RAP, while insulin was reduced in CP. Osteopontin and oncostatin were elevated in pancreatitis groups, with osteopontin increasing progressively from control to RAP to CP. Several bone biomarker patterns varied by sex, tobacco, and alcohol use. Stepwise regression identified several significant predictors. Conclusions: These findings represent the most comprehensive bone metabolism biomarker profiling in pancreatitis to date, revealing stage-specific dysregulation of bone remodeling. Findings suggest a shift toward increased bone resorption and impaired formation with disease progression. Larger longitudinal studies are needed for marker validation, to clarify mechanisms, and guide targeted interventions to reduce bone loss and fracture risk in this high-risk population.