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We provide evidence that elevated serum osteoprotegerin reflects pathophysiological processes of complex regional pain syndrome.Osteoprotegerin (OPG) is important for bone remodeling and may contribute to complex regional pain syndrome (CRPS) pathophysiology. We aimed to assess the value of OPG as a biomarker for CRPS and a possible correlation with radiotracer uptake in 3-phase bone scintigraphy (TPBS). OPG levels were analyzed in 23 CRPS patients (17 women; mean age 50 ± 9.0 years; disease duration: 12 weeks [IQR 8–24]), 10 controls (6 women; mean age 58 ± 9.6 years) and 21 patients after uncomplicated fractures (12 women; mean age: 43 ± 15 years; time after fracture: 15 weeks [IQR: 6–22]). The CRPS and control patients also underwent TPBS. OPG in CRPS patients was significantly increased by comparison with both control groups (P = 0.001; Kruskal-Wallis test; CRPS patients: 74.1 pg/mL [IQR: 47.1–100.7]; controls: 46.7 pg/mL [IQR: 35.5–55.0]; P = 0.004; fracture patients: 45.9 pg/mL [IQR: 37.5–56.7]; P = 0.001). As a diagnostic test for CRPS, OPG had a sensitivity of 0.74, specificity of 0.80, positive predictive value of 68% and negative predictive value of 84%. Receiver operating characteristic curve analysis showed an area under the curve of 0.80 (CI: 0.68–0.91). For the CRPS-affected hand, a significant correlation between OPG and TPBS region of interest analysis in phase III was detected (carpal bones; r = 0.391; P = 0.03). The persistent OPG increase in CRPS indicates enhanced osteoblastic activity shown by increased radiotracer uptake in TPBS phase III. A contribution of bone turnover to CRPS pathophysiology is likely. OPG might be useful as a biomarker for CRPS.