Combined CPP-ACP and fluoride is not superior to fluoride alone in early carious lesions - a meta-analysis

There is a growing need for effective methods in the management of early-stage carious lesions. Therefore, the aim of this study was to evaluate the effect of combined casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and fluoride on white spot lesions (WSLs) compared to fluoride-only interventions. This meta-analysis was performed according to PRISMA guidelines and registered in PROSPERO (CRD42021286245). The Medline, EMBASE and Cochrane Central databases were searched until October 17, 2022. Eligible studies were randomized controlled trials (RCTs). Outcome variables included Laser Fluorescence (LF), Quantitative Light-Induced Fluorescence (QLF), and lesion area scores. The random-effects model was used for analysis, and results were given as standardized mean difference (SMD) and mean difference (MD) with a 95% Confidence Interval. Risk of Bias was assessed using the RoB 2 tool, and the level of evidence with GRADE. Our systematic search yielded 973 records after duplicate removal, 21 studies were included for qualitative synthesis, and 15 studies were eligible for quantitative analysis. No significant difference was found between CPP-ACP and fluoride versus fluoride alone in LF at 1, 3 and 6 months of use: SMD -0.30 (-0.64; 0.04); SMD -0.47 (-1.02; 0.07); SMD -0.49 (-1.13; 0.15), respectively. For QLF, the analysis did not demonstrate significant differences between these two kinds of treatment at one and six months of use: MD 0.21 (-0.30;0.71); MD 0.60 (-1.70;2.90), but at three months higher QLF values were found in the fluoride-only group compared to the CPP-ACP and fluoride combination was shown regarding the WSLs: MD 0.58 (0.25;0.91). On the contrary, data showed a small but statistically significant decrease in the lesion area in favor of the CPP-ACP plus fluoride vs fluoride alone at six months MD -0.38 (-0.72; -0.04). None of these observed changes indicated substantial clinical relevance. The combination of CPP-ACP and fluoride did not overcome the effect of fluoride given alone. Our data suggest that fluoride itself is effective in improving WSLs. However, the certainty of evidence was very low. These results indicate that further studies and future development of more effective than CPP-ACP are needed in addition to fluoride to achieve robust amelioration of WSLs.