Biomarkers in Chronic Nonbacterial Osteomyelitis: Bridging Autoinflammation and Classical Inflammatory Diseases

Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disorder characterized by sterile bone lesions, heterogeneous clinical presentation, and the absence of validated diagnostic or prognostic biomarkers. Traditionally considered a distinct disease entity, emerging genetic, mechanistic, and translational evidence challenges this view. Emerging genetic, mechanistic, and translational evidence suggests that CNO may represent a convergent clinical phenotype of sterile bone inflammation arising from diverse disturbances in innate immunity. Central to its pathogenesis is the inflammasome-interleukin-1 beta (IL-1β) axis, which integrates upstream signals from genetic variants, cytokine imbalance, and environmental factors, ultimately driving osteoclast activation and bone remodeling. Recent advances highlight the role of biomarkers as translational tools linking molecular mechanisms to clinical phenotypes. Although whole-body MRI remains central to disease assessment, integration of imaging with molecular biomarkers may provide more comprehensive disease stratification. Conventional markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) show limited utility, whereas pathway-relevant biomarkers, including cytokine profiles, P2X purinoceptor 7 (P2X7R) signaling, and the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio provide deeper insight into disease biology. These biomarkers may ultimately enable biologically driven patient stratification and inform future targeted therapeutic approaches, although prospective validation remains necessary. Reframing CNO as a convergent phenotype supports a mechanism-based classification and offers a framework for precision medicine approaches, with implications extending beyond pediatric rheumatology to inflammatory bone diseases more broadly.