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.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. DISCUSSION: 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.