Keye Chen, Yan Sun, Longkang Cui, Yuchen Zhu, Bingbing Zhang, Haigang Wang
Twenty-three RCTs met the inclusion criteria. No significant network inconsistency (P > 0.05) or publication bias was detected. For analgesic efficacy, celecoxib ranked highest on VAS pain improvement (MD = -0.48, 95% CI -0.78 to -0.17, SUCRA = 0.93) and WOMAC total scores (SUCRA = 0.912), followed by CS+GH (0.756). Probiotics (0.66) and metformin (0.63) showed potential efficacy, but the final network certainty for most of these auxiliary comparisons was low or very low, mainly due to severe imprecision and the absence of direct head-to-head trials. These SUCRA-based rankings should therefore be interpreted cautiously in clinical settings. On WOMAC subscales, celecoxib was associated with the largest improvements in pain and physical function; krill oil ranked highest on the pain subscale (SUCRA = 0.99), while probiotics and metformin had the most favorable safety profiles (SUCRA = 0.885 and 0.724, respectively).
PURPOSE: Knee osteoarthritis (KOA) creates a substantial global socioeconomic burden. Celecoxib remains a standard pharmacological treatment, but its long-term safety profile raises concerns. Several adjuvant therapies-probiotics, metformin, krill oil, and glucosamine/chondroitin (CS+GH)-have produced encouraging results in individual trials; however, direct head-to-head comparisons are absent. This network meta-analysis (NMA) compares the efficacy and safety of these five interventions to inform individualized treatment decisions in clinical practice.
METHODS: RCTs published from database inception through February 2026 were retrieved from PubMed, Web of Science, Embase, and the Cochrane Library. A random-effects NMA was conducted using Stata 18.0 and R (MetaInsight). Continuous outcomes were synthesized as mean differences (MD) and dichotomous safety endpoints as risk ratios (RR). Interventions were ranked by surface under the cumulative ranking curve (SUCRA), and evidence quality was assessed using the GRADE framework.
RESULTS: Twenty-three RCTs met the inclusion criteria. No significant network inconsistency (P > 0.05) or publication bias was detected. For analgesic efficacy, celecoxib ranked highest on VAS pain improvement (MD = -0.48, 95% CI -0.78 to -0.17, SUCRA = 0.93) and WOMAC total scores (SUCRA = 0.912), followed by CS+GH (0.756). Probiotics (0.66) and metformin (0.63) showed potential efficacy, but the final network certainty for most of these auxiliary comparisons was low or very low, mainly due to severe imprecision and the absence of direct head-to-head trials. These SUCRA-based rankings should therefore be interpreted cautiously in clinical settings. On WOMAC subscales, celecoxib was associated with the largest improvements in pain and physical function; krill oil ranked highest on the pain subscale (SUCRA = 0.99), while probiotics and metformin had the most favorable safety profiles (SUCRA = 0.885 and 0.724, respectively).
SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD420261345598, identifier: CRD420261345598.