Efficacy of various interventions for the management of white spot lesions associated with fixed orthodontic treatment: a systematic review and network meta-analysis of randomized controlled trials

To synthesize the direct and indirect evidence on comparative effectiveness of various interventions for while spot lesions (WSLs) associated with fixed appliance treatment based on randomized clinical trials (RCTs). Eligibility criteria: RCTs evaluating agents for prevention, reduction, or reversal of WSLs in orthodontic patients with fixed appliances comparing them with placebo, no treatment, or another active agent Information sources: Unrestricted literature search of six databases was conducted up to March 1, 2025 Risk of bias: was conducted using RoB-2 Synthesis of results: Pairwise and network meta-analyses used random-effects (REML) models. Networks (≥10 trials) included only RCTs with labial fixed brackets to ensure transitivity. Inconsistency was assessed via node-splitting; P-scores ranked interventions. Sparse data limited small-study effect assessment and reduced network size in sensitivity analyses. Confidence in NMA(CINeMA) rated confidence. Included studies: Seventy RCTs involving 4,634 participants Synthesis of results: For WSL score, self-assembling peptide, NovaMin, nano-agents, xylitol varnish, and casein phosphopeptide (CPP-ACP) showed the highest efficacy (SMD range: –1.38 to –0.94; P-scores: 0.71–0.86). Probiotics, fluoride combinations, and fluoride varnish also showed significant effects, while laser, chlorhexidine (CHX), and fluoride mouthwash/toothpaste did not. For WSL prevalence, fluoride varnish, fluoride combinations, and CPP-ACP were most effective (OR range: 0.25–0.32). Resin infiltration and fluoride toothpaste also showed benefit. No intervention significantly reduced WSL size. Networks were generally sparse. No major inconsistencies were detected. No small-study effects were found for WSL score (Egger’s p = 0.45). CINeMA ratings ranged from high to low. Limitations of evidence: Clinical heterogeneity, sparse network, moderate risk of bias, and exclusion of studies reporting non-standard outcomes limit the strength and generalizability of the findings. Interpretation: Moderate-quality evidence suggests that CPP-ACP, self-assembling peptide, NovaMin, and nano-agents are effective for reducing WSL severity, while fluoride varnish is most effective for prevention.