Associations Between Peripheral Blood Inflammatory and Immune Markers and Osteoporotic and Fragility Fractures: A Systematic Review and Meta-Analysis.

Abstract

Chronic low-grade inflammation and osteoimmune dysregulation may contribute to skeletal fragility, but evidence across circulating markers and fracture outcomes remains heterogeneous. We evaluated associations between peripheral blood inflammatory or immune markers and osteoporotic or fragility fractures. This PRISMA 2020-compliant systematic review and meta-analysis was registered in PROSPERO (CRD420261441126). Five databases were searched from inception to 25 June 2026. Eligible observational studies evaluated serum, plasma, or whole-blood inflammatory or immune markers in relation to observed osteoporotic, fragility, low-energy, or site-specific fractures. Reported ratio estimates were synthesized within marker-outcome-contrast units using random-effects models, with effect-type sensitivity analyses. Evidence certainty was assessed using GRADE. Forty-eight studies were included. C-reactive protein/high-sensitivity C-reactive protein-related (CRP/hsCRP-related) exposures were associated with hip fracture (pooled ratio estimate 1.39, 95% CI 1.17-1.67) and vertebral fracture (2.16, 95% CI 1.47-3.18). Interleukin-6 was associated with hip fracture (1.40, 95% CI 1.15-1.71), as were tumor necrosis factor-alpha or soluble TNF receptors (1.81, 95% CI 1.34-2.44). Certainty was low. Findings for blood-count-derived indices were less stable, and temporally unclear studies could support only associations with fracture status. Observational evidence supports marker- and site-specific associations, but heterogeneity in design, temporality, populations, bone mineral density adjustment, and covariates precludes causal or established predictive interpretation. These markers should not replace established fracture-risk assessment.Trial registration PROSPERO, CRD420261441126.