Circulating osteoprotegerin levels in atrial fibrillation: a systematic review and meta-analysis

Background Atrial fibrillation (AF) is a common arrhythmia associated with stroke, heart failure, and adverse cardiovascular outcomes. Beyond electrical instability, AF is linked to inflammatory, fibrotic, vascular, and metabolic remodeling. Osteoprotegerin (OPG), a soluble decoy receptor within the RANK/RANKL pathway, has emerged as a cardiovascular biomarker and may reflect adverse atrial substrate or systemic cardiovascular risk. However, studies evaluating circulating OPG in AF have been small and heterogeneous. We aimed to synthesize circulating OPG levels in AF and clinically defined comparator populations. Methods We conducted a systematic review and meta-analysis of studies reporting circulating OPG concentrations in adults with AF and eligible comparator populations. PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library were searched from database inception through 5 August 2026. Only English-language reports were eligible. Trial registries were not searched, and study authors were not contacted for unpublished or additional data. Random-effects models estimated pooled mean OPG concentrations within clinically and analytically defined strata using restricted maximum likelihood (REML) estimation with Hartung-Knapp adjustment. Analyses were stratified by clinical category, biological matrix, and reported unit. Heterogeneity was assessed using I2, τ2, and 95% prediction intervals where available. Results Thirty-five publications were included in the final evidence set. In the AF plasma pmol/L stratum, four study arms yielded a pooled mean OPG concentration of 6.47 pmol/L (95% CI, 5.12 to 7.82; 95% prediction interval, 3.50 to 9.44; I2 = 95.4%; τ2 = 0.6882; p < 0.0001). Conventional control strata were also heterogeneous, including plasma pmol/L 3.27 (95% CI, 2.59 to 3.94; I2 = 83.1%) and serum pmol/L 4.47 (95% CI, 3.54 to 5.40; I2 = 98.0%). Garnier 2022 contributed single-study plasma pg/mL estimates for AFDAS and post-stroke sinus rhythm. Other control and clinical-comparator strata also showed substantial heterogeneity. Conclusions Circulating OPG concentrations can be estimated within selected AF and comparator strata, but the available evidence does not support a single universal AF-versus-control effect or a diagnostic threshold. Substantial heterogeneity limits direct clinical interpretation. Larger standardized studies are needed to clarify whether OPG predicts AF onset, recurrence, or adverse outcomes and whether it adds value beyond established clinical risk scores.