Decoding Chronic Charcot Arthropathy: Molecular Mechanisms, Predictive Biomarkers, and Emerging Therapies.

» Chronic Charcot arthropathy results from the convergence of genetic predisposition (OPG/RANKL/RANK polymorphisms), metabolic disturbances (AGEs, vitamin D deficiency affecting 84.2% of patients), and inflammatory dysregulation (RANKL/OPG axis, IL-17 family cytokines), explaining why only 0.08-1% of diabetic neuropathy patients develop this devastating complication. » The receptor activator of nuclear factor kappa-B ligand (RANKL)/receptor activator of nuclear factor kappa-B (RANK)/osteoprotegerin (OPG) axis dysregulation drives excessive osteoclastogenesis and bone resorption in the acute phase, while impaired Wnt/β-catenin signaling and advanced glycation end products-modified collagen compromise healing quality in the chronic phase, resulting in malunion and permanent deformity. » Magnetic resonance imaging is the best non-invasive imaging modality for differentiating chronic Charcot from osteomyelitis (single bone involvement beneath ulcer, sinus tract, and abscess favor infection; periarticular distribution favors Charcot), though bone biopsy remains the gold standard when diagnostic uncertainty persists. » Current management relies primarily on mechanical interventions (accommodative footwear, bracing, surgical reconstruction for unbraceable deformities), but emerging molecular therapies targeting RANKL (denosumab), pro-inflammatory cytokines (IL-17 inhibitors), and Wnt pathway (romosozumab) show promise for disease modification. » Integrated risk stratification models combining genetic risk scores, serum biomarkers (RANKL/OPG ratio, vitamin D levels), and clinical factors can identify high-risk individuals (AUC 0.89), enabling targeted preventive interventions including vitamin D supplementation, prophylactic off-loading, and potentially pharmacological prevention.