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. 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 1 and 6 months of use: MD 0.21 (−0.30;0.71); MD 0.60 (−1.70;2.90), but at 3 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 versus fluoride alone at 6 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 products than CPP-ACP are needed in addition to fluoride to achieve robust amelioration of WSLs.

Dental caries is a worldwide public health concern [Peres et al., 2019]. According to Global Burden of Diseases, dental caries is the most common oral health condition, affecting over 2.3 billion people [James et al., 2018]. It is a multifactorial disease, resulting from complex dynamic interactions between pathological factors such as cariogenic bacteria, fermentable carbohydrates, and salivary dysfunction, and protective factors such as antibacterial agents, sufficient saliva, and remineralizing ions [Featherstone and Chaffee, 2018; Philip, 2019].

Despite the technological advancements, the prevalence and incidence of dental caries have remained largely the same over the last 20 years [Kassebaum et al., 2015]. Understanding this dynamic disease process is essential to develop effective strategies to combat dental caries in clinical practice [Gomez, 2015; Cheng et al., 2022], with individual management plans based on accurate diagnosis, including risk level, caries detection, assessment of caries severity and activity [Cheng et al., 2022]. Caries development consists of many alternating cycles of demineralization and remineralization. If net demineralization occurs for a longer period of time, the lesions will advance [Pitts et al., 2017]. The first clinical sign is the appearance of white spot lesions (WSLs) [Featherstone, 2008]. These spots represent non-cavitated enamel incipient carious lesions with an appearance of chalky-white enamel areas, as a result of surface and subsurface demineralization. Fluoride and saliva are usually sufficient to prevent the destruction by remineralization. However, under cariogenic oral conditions, these factors may no longer maintain a good balance, resulting in the progress of lesions to cavitate [Philip, 2019].

The current biological understanding of the caries process has led to the development of early detection, preventive therapy, and tooth structural preservation. New systems have been introduced in the last decades, such as non-fluoride enamel remineralizing agents and fluoride boosters, to increase remineralizing potential of fluoride [Ismail et al., 2013; Gomez, 2015; Philip, 2019]. A range of calcium phosphate technologies has been developed to enhance the ability of fluoride to promote remineralization. The additional presence of calcium phosphate ions can increase diffusion gradients favoring the fluoride ion-mediated remineralization enhancing enamel subsurface remineralization [Shen et al., 2018].

Casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) has been developed to promote that process by increasing the local bioavailability of Ca2+ and PO43– ions [Reynolds, 2008; Abou Neel et al., 2016]. Casein phosphopeptide (CPP) is actually based on casein, a milk protein that binds and chelates calcium, providing the basis for its calcium phosphate donor capacity [Shen et al., 2018; Philip, 2019; Alhamed et al., 2020; Mekky et al., 2021]. CPP may serve as a saliva biomimetic compound with a great capacity of stabilizing calcium and phosphate, preventing the formation of poorly soluble phases and maintaining the bioavailability of ions to facilitate their precipitation on the enamel surface lesions and thus effectively inhibiting demineralization and enhancing remineralization [Cochrane and Reynolds, 2012; Ma et al., 2019; Alagha and Samy, 2021; Sbaraini et al., 2021]. The binding between CPP-ACP is pH-dependent. As expected, at lower pH, the binding is decreased; while higher pH prevents spontaneous precipitation of calcium phosphate [Reynolds, 1987; Ekambaram et al., 2017]. Therefore, this material has been suggested to be particularly effective in the remineralization of early enamel lesions and in the treatment of other types of enamel opacities [Reynolds, 1987; Imani et al., 2019; Varma et al., 2019; Sbaraini et al., 2021].

Previous studies have indicated that CPP-ACP is anticariogenic and capable of reversing the early stages of enamel lesions in vitro and also under clinical conditions [Mendes et al., 2018; Oliveira et al., 2020; Shen et al., 2021]. However, there is still no consensus regarding its remineralizing potential in vivo [Twetman et al., 2003; Bader and Shugars, 2004; Chen et al., 2013; Oliveira et al., 2020]. Previous meta-analyses on the subject suffered from various obstacles and included only a limited number of clinical studies, some of which were not randomized controlled trials, thus leading to contradictory, heterogenous results [Tao et al., 2018; Ma et al., 2019; Wu et al., 2019; Sharda et al., 2021]. Whether CPP-ACP provides additional remineralization benefits over fluoride treatment remains to be determined. Thus, it is still challenging for clinicians and patients to draw reliable conclusions due to the lack of available objective and accurate results.

Therefore, we aimed to investigate whether the combination of CPP-ACP and topical fluoride has superior effects on reversing WSLs over fluoride alone by synthesizing the available data from fluorescence-based methods (laser fluorescence [LF] and quantitative light-induced fluorescence [QLF]) and visual changes in lesion area from randomized controlled trials (RCTs) applying a meta-analysis, to support relevant clinical decision making and to initiate further studies.

Protocol and Registration

The report of this systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Statement [Page et al., 2021]. The PRISMA checklist for our work is available in Supplementary Table 1 (for all online suppl. material, see https://doi.org/10.1159/000533547). The protocol of this review was registered on PROSPERO under CRD42021286245.

Information Sources and Searches

Medline (via PubMed), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were screened until October 17, 2022. No filters or restrictions were applied. Besides electronic databases, an extensive hand search in the reference lists of relevant articles and included records was also performed to find eligible records. The search strategy was built by combining the terms “Casein phosphopeptide-amorphous calcium phosphate” and “white spot lesion.” The complete search strategy is presented in online supplementary Table 2.

Study Selection

EndNote X20.2 (v.7) software (Clarivate Analytics, Philadelphia, PA, USA) was used to manage records. After excluding duplicates, two independent authors (B.C. and A.W.) screened the remaining studies by title, abstract, and finally full text. Cohen’s kappa [McHugh, 2012] coefficient was calculated to assess the agreement between B.C. and A.W at the selection process. Any disagreements between reviewers were resolved by consensus or consulting a third reviewer (G.V.).

Eligibility Criteria

The PICO framework was used to determine whether the combination of CPP-ACP and fluoride is more effective than fluoride alone by evaluating QLF and LF values as estimations of remineralization of early carious lesions. Type of participants: studies involving subjects of any age with early carious lesions. Type of intervention: CPP-ACP agents and fluoride used in combination were included. The fluoride group could include any kind of products that contained fluoride, such as toothpaste, gel, and varnishes. The CPP-ACP could include any kind of products containing CPP-ACP, such as paste, mousse, or varnish, including CP-ACP with built-in fluoride (CPP-ACFP). Control: fluoride therapies alone. Primary outcomes: remineralization potential measured by fluorescence-based method values – QLF and LF. Secondary outcomes: visual evaluation through visual change in lesion area (value obtained as the ratio between the total lesion and total surface area of teeth).

Inclusion and Exclusion Criteria

Our inclusion criteria for the studies were as follows: (1) RCTs only; (2) patients with early carious lesions; (3) intervention group receiving CPP-ACP products and fluoride in combination, and (4) control group receiving fluoride alone. Exclusion criteria were as follows: (1) in vitro studies, observational studies, case reports, case series, reviews, non-randomized trials, and split-mouth studies; (2) trials with no fluoride-only control group; (3) trials with unbalanced intervention and control group that could directly or indirectly influence outcome variables; and (4) associated developmental defects of enamel and molar-incisor hypomineralization, erosion.

Data Extraction

Data were extracted by two investigators (B.C. and A.W.) using the standardized data collection form. Necessary correspondence was conducted with authors of the studies to obtain the full texts when they were not available electronically. We extracted the following data from the eligible articles: title, first author, year of publication, countries, study design, main findings of the study, patient demographics, interventions, outcomes (remineralization efficacy measurements by QLF and LF and indices of caries such as ICDAS, EDI, DMFT/S). A third independent reviewer resolved the disagreements (G.V.).

Risk of Bias Assessment

Following the recommendation of the Cochrane Handbook for Systematic Reviews of Interventions, bias evaluations were performed using the revised Cochrane risk-of-bias tool (RoB 2) for randomized trials. Domains evaluated included random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other biases from each study. They were categorized as a “low” risk of bias when more than half of all the key domains were low. A study was classified as having a “high” risk of bias when there were at least 2 “high” key domains. Apart from these criteria, the overall result was considered to be unclear. Two independent reviewers (B.C. and A.W.) conducted the assessment, and an independent third investigator (G.V.) resolved disagreements.

Certainty of Evidence

The GRADE system was used to summarize and grade the certainty of evidence for each outcome [Guyatt et al., 2008; Schünemann et al., 2013]. Outcomes of interest were tested according to the following criteria: study design, risk of bias, indirectness, inconsistency, imprecision, and publication bias. The baseline grade was downgraded by one level for serious concerns and by two levels for very serious concerns and finally, the certainty of the evidence for each outcome was graded as “high,” “moderate,” “low,” or “very low.” Assessments were performed independently by two authors (B.C. and A.W.).

Statistical Analysis

For the statistical analyses, R-statistics software (ver. 4.1.1., Vienna, Austria) was used. Mean differences (MDs) or standardized MDs (SMDs) for continuous data were calculated for generalizing the effectiveness of treatment in every single report. The choice between these effect measures was based on whether the outcomes of the studies were homogeneous or not. The corresponding 95% confidence intervals (CIs) were estimated using the restricted maximum-likelihood estimator. We used the random-effects models to combine the studies due to the clinical and methodological heterogeneity existing in the studies. After data were collected, statistical heterogeneity was examined using the I2 and χ2 statistics. Forest plots were applied to display the measured effect sizes with their 95% CIs for all studies included.

Study Selection

Our systematic search identified a total of 1,497 related records. After duplicate removal, 973 remained, which were screened by title and abstract. Forty-four items were selected according to inclusion and exclusion criteria, and then went through full-text selection. Twenty-one RCTs were eligible for our qualitative synthesis and fifteen for quantitative synthesis. The PRISMA flow diagram summarizing all stages is shown in Figure 1.

Fig. 1.

PRISMA flow diagram summarizing all inclusion stages.

Fig. 1.

PRISMA flow diagram summarizing all inclusion stages.

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Study Characteristics

Description of Excluded Studies

From the full-text analysis, twenty-three studies were excluded. Nine were not RCTs, six did not measure remineralization outcomes, five did not have a fluoride-only control group, one assessed molar-incisor hypomineralization, one paper was retracted, and one was a split-mouth study. The split-mouth study was excluded because it was not possible to perform separate subgroup meta-analyses for the split-mouth and parallel-arm studies, nor they had a proper control group. Of 21 articles included in the full-text selection, six studies were excluded from the quantitative analysis. There were an insufficient number of studies with the same remineralization outcome and comparable time-points to perform a meta-analysis on the excluded publications.

Description of the Included Studies

The main characteristics of the included studies are presented in Table 1. All studies were published between 2010 and 2021 and were RCTs. The population age ranged from 2 to 35 years. Trials were performed in Jordan [Al-Batayneh et al., 2020], The Netherlands [Beerens et al., 2010, 2018], Denmark [Brochner et al., 2011], Mexico [Esparza-Villalpando et al., 2021], Turkey [Guclu et al., 2016; Yazicioglu et al., 2017], Iran [Memarpour et al., 2015; Heravi et al., 2018], Spain [Llena et al., 2015], Egypt [Mekky et al., 2021], Brazil [Mendes et al., 2018], India [Singh et al., 2016; Radha et al., 2020], and Thailand [Sitthisettapong et al., 2015].

Table 1.

Characteristics of randomized controlled trials (RCTs) included in statistical analysis

Author, yearCountrySample (mean age; range, years)Follow-up, monthsCPP-ACP + fluorideFluoride groupMain outcome
type of combinationfrequencytype of combinationfrequency
Al-Batayneh et al., 2020 Jordan 114 (4.5) Tooth Mousse + FT1 bid + bid Ft1 bid QLF 
Beerens et al., 2010 The Netherlands 54 (15.5) MI Paste Plus + FT qd + bid Control paste + Ft2 bid + qd QLF 
Beerens et al., 2018 The Netherlands 51 (15.32) 12 MI Paste Plus + FT qd + bid Control paste+ Ft2 bid + qd QLF 
Bröchner, 2011 Denmark 50 (15.2) Tooth Mousse + FT3 qd + qd Ft3 bid QLF 
Esparza-Villalpando et al., 2021 Mexico 84 (3–7) MI Paste Plus + Ft4 bid + bid Ft4 bid LF (DIAGNOdent) 
Güclü, 2016a Turkey 21 (8–15) Tooth Mousse + NaF Varnish bid +5 times in 12w NaF Varnish 5 times in 12w LF (DIAGNOdent) 
Güclü, 2016b Turkey 21 (8–15) Tooth Mousse + Ft4 bid + bid Ft4 bid LF (DIAGNOdent) 
Heravi et al., 2018 Iran 24 (16) MI Paste Plus + Ft5 qd + bid Ft5 bid LF (DIAGNOdent) 
Llena et al., 2015a Spain 60 (6–14) MI Paste Plus + Ft6 qd + n.r NaF Varnish + Ft6 Monthly + n.r LF (DIAGNOdent) 
Llena et al., 2015b Spain 60 (6–14) Tooth Mousse + Ft6 qd + n.r Control Paste +Ft6 qd + n.r LF (DIAGNOdent) 
Mekky et al., 2021 Egypt 44 (3–5) MI Varnish + Ft 3 times in 6 months + bid NaF Varnish + Ft 3 times in 6 months + bid LF (DIAGNOdent) 
Memarpour et al., 2015 Iran 140 (21.2*) 12 Tooth Mousse + FT bid + bid Ft qd Mean/median % WSL area 
Mendes et al., 2018a Brazil 36 (5–13) MI Paste + FT w + bid Placebo paste + Ft bid + n.r LF (DIAGNOdent) 
Mendes et al., 2018b Brazil 36 (5–13) MI Paste Plus + FT w + bid Fluoride gel + Ft bid + n.r LF (DIAGNOdent) 
Radha et al., 2020 India 60 (3–6) MI Varnish + FT qd + qd NaF Varnish + Ft n.r. + qd Mean/median % WSL area 
Singh, 2016 India 41 (16–25) Tooth Mousse Plus + FT7 bid + bid Ft7 bid LF (DIAGNOdent); Mean/median % WSL area 
Sitthisettapong, 2015 Thailand 79 (37.51*) 12 Tooth Mousse + FT7 qd + qd Placebo paste + Ft7 qd + qd QLF 
Yazicioglu et al., 2017 Turkey 30 (18–30) MI Paste Plus + FT4 qd + bid Ft4 bid LF (DIAGNOdent) 
Author, yearCountrySample (mean age; range, years)Follow-up, monthsCPP-ACP + fluorideFluoride groupMain outcome
type of combinationfrequencytype of combinationfrequency
Al-Batayneh et al., 2020 Jordan 114 (4.5) Tooth Mousse + FT1 bid + bid Ft1 bid QLF 
Beerens et al., 2010 The Netherlands 54 (15.5) MI Paste Plus + FT qd + bid Control paste + Ft2 bid + qd QLF 
Beerens et al., 2018 The Netherlands 51 (15.32) 12 MI Paste Plus + FT qd + bid Control paste+ Ft2 bid + qd QLF 
Bröchner, 2011 Denmark 50 (15.2) Tooth Mousse + FT3 qd + qd Ft3 bid QLF 
Esparza-Villalpando et al., 2021 Mexico 84 (3–7) MI Paste Plus + Ft4 bid + bid Ft4 bid LF (DIAGNOdent) 
Güclü, 2016a Turkey 21 (8–15) Tooth Mousse + NaF Varnish bid +5 times in 12w NaF Varnish 5 times in 12w LF (DIAGNOdent) 
Güclü, 2016b Turkey 21 (8–15) Tooth Mousse + Ft4 bid + bid Ft4 bid LF (DIAGNOdent) 
Heravi et al., 2018 Iran 24 (16) MI Paste Plus + Ft5 qd + bid Ft5 bid LF (DIAGNOdent) 
Llena et al., 2015a Spain 60 (6–14) MI Paste Plus + Ft6 qd + n.r NaF Varnish + Ft6 Monthly + n.r LF (DIAGNOdent) 
Llena et al., 2015b Spain 60 (6–14) Tooth Mousse + Ft6 qd + n.r Control Paste +Ft6 qd + n.r LF (DIAGNOdent) 
Mekky et al., 2021 Egypt 44 (3–5) MI Varnish + Ft 3 times in 6 months + bid NaF Varnish + Ft 3 times in 6 months + bid LF (DIAGNOdent) 
Memarpour et al., 2015 Iran 140 (21.2*) 12 Tooth Mousse + FT bid + bid Ft qd Mean/median % WSL area 
Mendes et al., 2018a Brazil 36 (5–13) MI Paste + FT w + bid Placebo paste + Ft bid + n.r LF (DIAGNOdent) 
Mendes et al., 2018b Brazil 36 (5–13) MI Paste Plus + FT w + bid Fluoride gel + Ft bid + n.r LF (DIAGNOdent) 
Radha et al., 2020 India 60 (3–6) MI Varnish + FT qd + qd NaF Varnish + Ft n.r. + qd Mean/median % WSL area 
Singh, 2016 India 41 (16–25) Tooth Mousse Plus + FT7 bid + bid Ft7 bid LF (DIAGNOdent); Mean/median % WSL area 
Sitthisettapong, 2015 Thailand 79 (37.51*) 12 Tooth Mousse + FT7 qd + qd Placebo paste + Ft7 qd + qd QLF 
Yazicioglu et al., 2017 Turkey 30 (18–30) MI Paste Plus + FT4 qd + bid Ft4 bid LF (DIAGNOdent) 

Explanations: “qd” means “once daily,” “bid” means “twice daily,” “w” means “weekly,” “LF” means the value of “laser fluorescence,” “QLF” means the value of “quantitative light-induced fluorescence,” “Ft” means “Fluoride toothpaste,” “NaF” means “sodium fluoride.”

MI Paste Plus contains 10% CPP-ACP + sodium fluoride 900 ppm; Tooth Mousse Plus contains 10% CPP-ACP + sodium fluoride 900 ppm. Tooth Mousse contains 10% CPP-ACP. MI Varnish contains 10% CPP-ACP +5% sodium fluoride. These are trademarks of products. NaF varnish contains 5% sodium fluoride. Fluoride gel contains 1.23% acidulated phosphate fluoride.

1Colgate anti-cavity for kids (sodium fluoride 500 ppm).

2Fluoride-free control paste + calcium (Ultradent).

3Colgate (sodium fluoride 1,100 ppm).

4Colgate total (sodium fluoride 1,450 ppm).

5Crest cavity protection (sodium fluoride 1,100 ppm).

6Not specified (sodium fluoride 1,100 ppm).

7Colgate total® (sodium fluoride 1,000 ppm).

*Age in months, not years.

All patients had early stages of carious lesions, i.e., WSLs of orthodontic or non-orthodontic origin and were assessed on the remineralization of those. CPP-ACP was the remineralizing agent used. It was administered in combination with fluoride delivery; these were in the same product as CPP-ACFP (Tooth Mousse Plus – 10% CPP-ACP +0.2% NaF; MI Paste Plus – 10% CPP-ACP +900 ppm fluoride), or CPP-ACP alone products in mousse, paste, or varnish forms, in addition to a separate application of fluoride formulations in toothpaste, gel, or varnish. In all studies, fluoridated toothpaste was used in each group as a part of their daily oral hygiene. Follow-up periods ranged from 1 to 12 months, and their application regimen also varied according to formulations. Mousses and pastes were usually administered by the patients themselves or by their caregivers once or twice a day, while varnishes had a longer period, with weeks to months between applications. Remineralization outcomes were collected from 15 studies including 888 participants for three different assessment criteria: LF, Quantified Light-induced Fluorescence (QLF), and visual assessment (% change in WSL area).

Risk of Bias within Studies

Bias in the studies was assessed according to the Cochrane Risk of Bias 2 Tool [Sterne et al., 2019]. All studies applied random sequence generation but allocation concealment methods were not clearly described for some studies [Brochner et al., 2011; Yazicioglu et al., 2017; Mendes et al., 2018; Radha et al., 2020], leading to an overall low risk for randomization process.

Regarding deviation from intended interventions, most studies exhibited some concerns for the risk of bias [Brochner et al., 2011; Llena et al., 2015; Guclu et al., 2016; Yazicioglu et al., 2017; Heravi et al., 2018; Mendes et al., 2018; Al-Batayneh et al., 2020; Radha et al., 2020; Mekky et al., 2021]. In three cases [Llena et al., 2015; Guclu et al., 2016; Mendes et al., 2018], there was no appropriate analysis used to estimate the effect of assignment to intervention. In others [Brochner et al., 2011; Yazicioglu et al., 2017; Heravi et al., 2018; Al-Batayneh et al., 2020; Radha et al., 2020; Mekky et al., 2021] participants and/or treatment providers were not blinded.

In one study [Al-Batayneh et al., 2020], deviations from intended interventions were reported as high risk of bias after not properly implementing the protocol for the use of CPP-ACP, and this could affect the outcome of the intervention. Furthermore, participants were aware of their assigned interventions.

A low risk of bias was considered for missing outcome data, as loss to follow-up and withdrawal from the study, occurred from reasons not related to the outcome in the included studies. Brochner and coinvestigators [Brochner et al., 2011] had a high risk in outcome measurement, due to the fact that both the clinical scoring and QLF measurements indicated that the WSLs were slightly more severe in the control group at baseline than in intervention.

Study protocols were not found for others [Llena et al., 2015; Memarpour et al., 2015; Guclu et al., 2016; Heravi et al., 2018; Mendes et al., 2018; Radha et al., 2020]. However, no intext evidence of reporting bias was found. The summary of the risk of bias assessment is presented in online supplementary Figures 1 and 2.

Results of Individual Studies and Synthesis of Results

Fifteen studies that provided sufficient data for the analysis were included in our meta-analysis [Beerens et al., 2010, 2018; Brochner et al., 2011; Llena et al., 2015; Memarpour et al., 2015; Sitthisettapong et al., 2015; Guclu et al., 2016; Singh et al., 2016; Yazicioglu et al., 2017; Heravi et al., 2018; Mendes et al., 2018; Al-Batayneh et al., 2020; Radha et al., 2020; Esparza-Villalpando et al., 2021; Mekky et al., 2021].

Primary Outcome (Remineralization Potential)

LF Values

Eight of the fifteen studies assessed the efficacy of CPP-ACP on remineralization using LF values. Of these, four [Llena et al., 2015; Guclu et al., 2016; Yazicioglu et al., 2017; Mendes et al., 2018] showed more than one intervention and control group. Therefore, they were divided into two parts according to the treatments. LF values show the degree of severity of the lesion. The higher the value was, the deeper the lesion. Mean values expressed in forest plots represent the difference in LF values between baseline and a given time-point, demonstrating an increase in mineralization. The more negative the value was, the higher was the remineralization. To understand the remineralization over time, the analysis was performed at 1, 3, and 6 months.

The overall effect size at LF at 1 month (SMD −0.30, 95% CI: −0.64–0.04) did not significantly differ from that of the control group, but still showed a tendency to a superior remineralization of WSLs in the CPP-ACP plus fluoride group (Fig. 2). Heterogeneity was moderate to high (p < 0.01, I2 = 63%), mainly due to different population characteristics, the type of WSL (non-orthodontic/orthodontic), and the differing frequency of application. The obtained SMD (−0.30) does not indicate a clinically significant change. Subgroup analysis for CPP-ACFP and CPP-ACP at 1 month did not provide additional important information (Fig. 2).

Fig. 2.

Forest plot of comparison of CPP-ACP + fluoride versus fluoride alone using LF values difference from baseline and 1, 3, and 6 months of follow-up. CPP-ACP, casein phosphopeptide-amorphous calcium phosphate; LF, laser fluorescence; SD, standard deviation; SMD, standard mean deviation; CI, confidence interval.

Fig. 2.

Forest plot of comparison of CPP-ACP + fluoride versus fluoride alone using LF values difference from baseline and 1, 3, and 6 months of follow-up. CPP-ACP, casein phosphopeptide-amorphous calcium phosphate; LF, laser fluorescence; SD, standard deviation; SMD, standard mean deviation; CI, confidence interval.

Close modal

At 3 months, no significant difference was observed between CPP-ACP combined with fluoride versus fluoride alone (SMD −0.47, 95% CI: −1.02–0.07; I2 = 72%; p < 0.01), even though three studies [Heravi et al., 2018; Mendes et al., 2018; Mekky et al., 2021] showed a tendency to favor the combined treatment group over the one that received fluoride alone (Fig. 2). Subgroup analysis of CPP-ACFP and CPP-ACP at 3 months, however, did not provide further in-depth information (shown in Fig. 2).

At 6 months, only two studies could be included. No statistically significant difference was observed between fluoride given together with CPP-ACP and fluoride alone (SMD −0.49, 95% CI: −1.13–0.15; I2 = 44%; p = 0.18) (Fig. 2), nor did the difference seem to be clinically relevant.

QLF Values

Five studies [Beerens et al., 2010, 2018; Brochner et al., 2011; Sitthisettapong et al., 2015; Al-Batayneh et al., 2020] with a total of 310 patients assessed the efficacy of CPP-ACP by detecting the values of QLF. QLF ∆F (%) values represent the fluorescence loss of an area and correlate it to mineral loss (demineralization). These values are expected to decrease over time, indicating lesion remineralization. Mean values in the forest plots show the difference between baseline and given time-point values.

After 1 month of treatment, the analysis of QLF ∆F did not demonstrate any significant difference between the two groups (MD 0.21, 95% CI: −0.30–0.71; I2 = 0%; p = 0) (Fig. 3). The heterogeneity was low among studies. After 3 months of treatment, the studies demonstrated slightly better remineralization of WSLs in the fluoride-only group over the CPP-ACP plus fluoride group (MD 0.58, 95% CI: 0.25–0.91; I2 = 0%; p = 0) by QLF (Fig. 3). At 6 months (Fig. 3), neither group was better than the other (MD 0.60, 95% CI: −1.70–2.90; I2 = 48%; p = 0.67). In our opinion, none of these forest plots present clinically relevant results in carious lesion improvement and consequent remineralization. The heterogeneity was also low.

Fig. 3.

Forest plot of comparison of CPP-ACP + fluoride versus fluoride alone using QLF ∆F (%) values difference from baseline and 1, 3, and 6 months of follow-up. CPP-ACP, casein phosphopeptide-amorphous calcium phosphate; QLF, quantitative light-induced fluorescence; ∆F (%), fluorescence loss; SD, standard deviation; MD, mean difference; CI, confidence interval.

Fig. 3.

Forest plot of comparison of CPP-ACP + fluoride versus fluoride alone using QLF ∆F (%) values difference from baseline and 1, 3, and 6 months of follow-up. CPP-ACP, casein phosphopeptide-amorphous calcium phosphate; QLF, quantitative light-induced fluorescence; ∆F (%), fluorescence loss; SD, standard deviation; MD, mean difference; CI, confidence interval.

Close modal

QLF area (mm2) detections were analyzed separately. Similar to QLF ∆F(%), the results showed no statistically significant difference at either 1 month (SMD 0.11, 95% CI: −0.2–0.43; I2 = 0%; p = 0.68), 3 months (SMD 0.13, 95% CI: −0.16–0.42; I2 = 0%; p = 0.80), or 6 months (SMD 0.23, 95% CI: −0.04–0.51; I2 = 0%; p = 0.42) (shown in Fig. 4).

Fig. 4.

Forest plot of comparison of CPP-ACP + fluoride versus fluoride alone using QLF area (mm2) values difference from baseline and 1, 3, and 6 months of follow-up. CPP-ACP, casein phosphopeptide-amorphous calcium phosphate; QLF, quantitative light-induced fluorescence; SD, standard deviation; MD, mean difference; CI, confidence interval.

Fig. 4.

Forest plot of comparison of CPP-ACP + fluoride versus fluoride alone using QLF area (mm2) values difference from baseline and 1, 3, and 6 months of follow-up. CPP-ACP, casein phosphopeptide-amorphous calcium phosphate; QLF, quantitative light-induced fluorescence; SD, standard deviation; MD, mean difference; CI, confidence interval.

Close modal

Percent Change in WSL Area (%)

The changes in WSL area values between the baseline and different follow-up time points (one, three, and six months) are shown in Figure 5. No statistically significant difference was found at 1 month (SMD −0.06, 95% CI: −0.54–0.41; I2 = 0%; p = 0.78) and 3 months (SMD −0.24, 95% CI: −0.57–0.10; I2 = 0%; p = 0.89) between the treatment groups. However, at 6 months, a small but statistically significant decrease in the WSL area favoring the CPP-ACP plus fluoride group over fluoride-only treatment alone was observed (SMD −0.38, 95% CI: −0.72 to −0.04; I2 = 0%; p = 0.62). This minor difference does not seem to be relevant as it is not clinically substantial and important.

Fig. 5.

Forest plot of comparison of CPP-ACP + fluoride versus fluoride alone using WSL visual area change (%) values from baseline and 1, 3, and 6 months of follow-up. CPP-ACP, casein phosphopeptide-amorphous calcium phosphate; WSL, white spot lesion; SD, standard deviation; MD, mean difference; CI, confidence interval.

Fig. 5.

Forest plot of comparison of CPP-ACP + fluoride versus fluoride alone using WSL visual area change (%) values from baseline and 1, 3, and 6 months of follow-up. CPP-ACP, casein phosphopeptide-amorphous calcium phosphate; WSL, white spot lesion; SD, standard deviation; MD, mean difference; CI, confidence interval.

Close modal

Publication Bias

Tests for funnel plot asymmetry should only be used if there are at least 10 studies included in the meta-analysis since the power of these tests with fewer studies is not suitable to distinguish chance from real asymmetry, according to the Cochrane Handbook recommendation [Sterne et al., 2011]. A purely visual inspection of funnel plots may also lead to misinterpretation [Simmonds, 2015]. Therefore, due to the relatively low number of studies included in this work, it was not possible to perform a funnel plot analysis.

Certainty of Evidence (GRADE Approach)

Our assessment based on the GRADE approach (online supplementary Table 3) showed that the certainty of evidence for the efficacy of CPP-ACP was rated as very low. This was due to the low number of studies at some investigated time-points, the serious risk of bias from the outcomes due to their unclear status, the serious inconsistency caused by the high heterogeneity of the reported studies, the indirectness of the outcome methods used, imprecision indicated by the wide range of CIs, and the low number of patients within some studies. Publication bias was strongly suspected in outcomes with few studies identified.

Summary of Evidence

Our meta-analysis assessed the efficacy of CPP-ACP combined with fluoride (either in CPP-ACFP form or in separate CPP-ACP plus fluoride products) in ameliorating WSLs compared to topical fluoride-only treatments, synthetizing the results obtained with fluorescence and visual detection methods. Overall, our results showed that CPP-ACP did not have a significant advantage over fluoride alone.

Fluoride (F-) ions in the oral environment can promote Ca2+ and PO43– ion incorporation into the crystal structure forming fluorapatite or fluorhydroxyapatite, which are more resistant to a subsequent acid challenge. This is believed to be its main mechanism of action [tenCate, 1999; Shen et al., 2011, 2018]. Bioavailable Ca2+ and PO43– ions are usually provided by saliva but even in otherwise healthy individuals, other factors such as lifestyle and diet can affect their bioavailability. The availability of calcium and phosphate may be a limiting factor for net remineralization of enamel surface lesions [Reynolds et al., 2008; Cochrane et al., 2010; Shen et al., 2011, 2018].

Therefore, calcium- and phosphate-containing formulations may enhance the ability of fluoride to promote remineralization [Shen et al., 2018, 2021; Philip, 2019]. CPP-ACP nanocomplexes are reported to maintain high levels of calcium and phosphate in an amorphous state close to the enamel surface. In acidic environments, these complexes are released. The potential anticariogenic property of CPP-ACP is thought to be related to ion liberation during remineralization [Reynolds et al., 2008; Cochrane et al., 2010; Shen et al., 2011].

Although CPP-ACP has been demonstrated to have anticariogenic activity in vitro and in situ [Reynolds et al., 1995; Shen et al., 2001; Cochrane et al., 2008; Zhang et al., 2011; Dai et al., 2019], the results of in vivo experiments are still controversial and do not seem to show similar clinical efficacy as it would be expected from in vitro data [Beerens et al., 2010, 2018; Brochner et al., 2011; Sitthisettapong et al., 2015].

To evaluate enamel damage, theoretically multiple evaluation systems are available but their accuracy is still questionable and they are not equally used [Walsh et al., 2022]. The five major diagnostic test systems are fluorescence, visual or visual-tactile classification systems, radiographic imaging, transillumination and optical coherence tomography, and electrical conductance or impedance technologies [Drancourt et al., 2019; Macey et al., 2020; Walsh et al., 2022]. The applicability of these five technologies was recently evaluated in a systematic review based on a great number of studies. By comparing them, broadly similar outcomes were observed in both cases with very wide 95% prediction intervals, indicating uncertainty in diagnostic accuracy for each [Walsh et al., 2022]. To evaluate the effect of CPP-ACP on the improvement of WSLs, our major limitation was to find randomized controlled trials which applied some of these methods for evaluation. In that respect, we found only applicable three evaluation systems [Drancourt et al., 2019; Macey et al., 2020; Walsh et al., 2022].

Therefore, in the present meta-analysis, we assessed LF, QLF, and visual change scores. Fluorescence-based methods are indirect outcomes for remineralization, but despite their limitations, are currently clinically available methods. These methods are accepted over the conventional visual methods for its reproducibility, reliability, and sensitivity in early detection of carious lesions [Bader and Shugars, 2004; Gimenez et al., 2013; Kavvadia et al., 2018]. Diagnostic accuracy analyses suggested that LF methods should be combined with visual methods [Gomez et al., 2013] to obtain accurate results [Kavvadia et al., 2018].

The LF method for WSL detection is based on the fact that the carious tissue emits more fluorescence depending on bacterial by-products (porphyrins). Two devices were used: DIAGNOdent (Kavo, Biberach, Germany) and DIAGNOdent Pen (KaVo Dental GmbH, Germany). DIAGNOdent is regarded to have high sensitivity and low specificity for the detection of primary caries in permanent teeth [Bader and Shugars, 2004; Toraman et al., 2008] and higher accuracy for advanced occlusal lesions. It is sensitive to factors that could influence measurements such as the presence of plaque and calculus, and/or staining in fissures [Gomez et al., 2013]. Therefore, the cleaning procedure before measurement is crucial. Additionally, LF is not the optimal method to measure initial carious lesions as only low levels of bacterial metabolites (porphyrins) are present at early carious stages [Park et al., 2021].

QLF (Inspektor Research Systems, Amsterdam, The Netherlands) allows the quantification of mineral loss from enamel due to changes of fluorescence intensity [Amaechi and Higham, 2002]. In the included publications, two different imaging systems were used. The Inspektor Pro™ (Inspektor Research Systems, Amsterdam, The Netherlands) system has an intra-oral fluorescence camera, illuminating the tooth surface with blue light from a xenon arc lamp and captures green and red fluorescence. While green fluorescence is considered to be an indirect measure of enamel porosity and lesion severity, red fluorescence is used as an indicator of oral hygiene from matured biofilm [Felix Gomez et al., 2016]. The QLF-D Biluminator™ (Inspektor Research Systems BV, Amsterdam, The Netherlands) uses a single lens reflex camera with blue and white LED lights. The images of healthy tooth surfaces have a whitish appearance instead of green, while demineralized areas look darker [Ko et al., 2015; Al-Batayneh et al., 2020]. Through both systems, mineral loss in enamel is estimated by calculating the percentage fluorescence loss between carious enamel and adjacent healthy enamel, expressed as ∆F. This method is suggested as a more specific method than LF for detecting early signs of surface caries [de Jong et al., 2009].

We observed a clinically insignificant effect of CPP-ACP over fluoride remineralization at various time points by both LF and QLF detections. For LF, our results showed a tendency to favor the CPP-ACP and fluoride group after 1 month of treatment, although no statistically significant difference was found. At three and 6 months, there was no difference in fluorescence changes between the CPP-ACP combined with fluoride and the fluoride-only groups. The tendency in favor of CPP-ACP could be explained by the fact that LF actually detects bacterial by-products as described above. QLF studies applying green fluorescence displayed both fluorescence loss (∆F) and lesion area (mm2). The QLF ∆F demonstrated a tendency in favor of the fluoride-only group over the combined application of CCP-ACP with fluoride, actually showing statistically significant differences in ∆F % at 3 months, but not at one and 6 months. However, we have to note that the observed changes were minor and do not seem to represent substantial clinical benefits. Thus, our QLF results do not show a real remineralization benefit of CPP-ACP. In accordance with this, quantitative analysis of QLF values for lesion area (mm2), observed in the same studies with ∆F, revealed no statistically significant differences between CPP-ACP combined with fluoride and fluoride-only at any time-points measured. Nevertheless, as discussed previously, the fluorescence-based tools are indirect methods to monitor the amelioration of non-cavitated carious lesions. Consequently, in spite of the relatively high number of LF/DIAGNOdent assessment studies evaluating remineralizing effects, the results should be interpreted with caution.

Our findings are in contrast, at least in part, to the results of previous meta-analyses. Ma et al. [2019] in vitro study demonstrated that CPP-ACP was effective in repairing the enamel, while in in vivo CPP-ACP plus fluoride was as effective as fluoride alone. However, the in vitro conditions do not replicate the variable effects of acid exposure, dental plaque, salivary fluid, bicarbonate and proteins, and fluoride exposure in vivo.

Tao et al., 2018 found mixed results based on LF values; CPP-ACP plus fluoride was more effective than fluoride alone on the occlusal surfaces but not on the smooth surfaces of teeth. Only three studies were included, pooling together 3–24 week time-points [Tao et al., 2018]. In contrast, we have included more studies at separate follow-up time points, showing the ineffectiveness of CPP-ACP. In QLF data, Tao et al., 2018 also observed no difference in the effect between those groups. Similar to Tao et al., 2018, Wu et al. 2019 also showed a significant difference benefiting CPP-ACP plus fluoride over fluoride alone using LF values by DIAGNOdent. However, in the values of DMFS/dmfs index and enamel decalcification index (EDI), they did not find a significant improvement by CPP-ACP over fluoride alone. Sharda et al. 2021 also tested other agents, besides CPP-ACP, using DIAGNOdent. They showed the superiority of CPP-ACP plus fluoride over fluoride alone, but included only three studies. However, when investigating the caries preventive role of CPP-ACP, they found no significant difference between CPP-ACP and control [Sharda et al., 2021], except when they pooled CPP-ACP and xylitol treatments together. Under those circumstances, they found a significant effect but it was actually not relevant to the assessment of CPP-ACP alone, but rather, to the small but significant effect of xylitol.

Different agents are being clinically used for the remineralization of WSLs such as bioactive glass (BAG) and self-assembling peptides [Salah et al., 2022; Gohar et al., 2023]. Salah et al., 2022 investigated the efficacy of two types of BAG compared to CPP-ACP, combining in-office and home applications for 1 month. Lesions in Bio-BAG group reduced 65% in size at 6 months, while both N-BAG and CPP-ACP decreased WSLs by approximately 32%. Another study [Salah et al., 2022; Gohar et al., 2023] conducted a RCT comparing the effect of fluoride varnish with tricalcium phosphate and self-assembling peptide. This work showed a significant increase in remineralization of post-orthodontic WSLs in both groups in one-to-six month time interval, exhibiting better remineralizing capacity of self-assembling peptides compared to the effect of fluoride varnish. However, further well-controlled clinical trials are necessary to support the effectiveness of these promising materials in this respect.

Strengths of the Study

The strengths of the present meta-analysis are the strict methodology according to the present guidelines and the inclusion of only RCTs. A previous meta-analysis [Ma et al., 2019] included primarily in vitro data, and only two clinical trials were considered. In contrast to other previous meta-analyses [Tao et al., 2018; Sharda et al., 2021], we performed statistical analyses at multiple time-points (one, three, and 6 months) to estimate the effects over time. Additionally, the results of the individual studies were expressed as a difference between baseline (i.e., the starting point) and the given time-point to ensure measurement of lesion improvement despite the size of lesion.

To our best knowledge, this is the most comprehensive systematic review and meta-analysis to examine the efficacy of CPP-ACP versus fluoride alone on remineralization of WSLs. Additionally, we were able to include multiple RCTs in this work, which had not been considered in the previous meta-analyses.

Limitations of the Study

Our study has limitations due to the low number of studies included in some analyses. Standard random-effects meta-analysis methods perform poorly when applied to few studies only [Seide et al., 2019]. In this case, the available data might have insufficient power to estimate the between-study heterogeneity reliably [Bender et al., 2018].

Some studies [Llena et al., 2015; Singh et al., 2016; Yazicioglu et al., 2017; Mekky et al., 2021] reported LF values as means instead of medians, without describing a proper analysis of data normality distribution. This may lead to a misinterpretation of findings as the value of the mean can be easily distorted by the outliers [Jackson and White, 2018].

We included only RCTs, following the recommendation of Cochrane Handbook that RCTs are the best study design to evaluate the effect of interventions properly, in order to avoid potential biases on the effects of intervention [McKenzie et al., 2022]. Thus, excluding observational studies, case series and reports could lead to some potential inclusion bias. In this way, rare outstanding incidences may have been missed [Norris et al., 2010].

Concerning the studies included, our major limitation was the lack of consistent methodology of studies, leading to a high level of heterogeneity due to the protocol, age, and different products. Despite the protocol instructions at the beginning of studies, the papers reported that the patients had difficulties maintaining compliance with the use of CPP-ACP mousse/paste formulation as recommended (usually once or twice every day) [Beerens et al., 2010, 2018]. Some patients stopped using the products after 6 weeks in 12-week studies. There was also no follow-up on the assessment of product use at recall visits. Also to get more accurate results, toothbrushing technique and use of product need to be standardized and supervised in the future.

But the main limitation of the present work is the overemphasis on surrogate outcomes. We must acknowledge that fluorescence-based outcomes, used by the included studies, are indirect measures that cannot show the microstructural features of teeth and the dynamic changes during the early stages of lesions. Therefore, the results should be interpreted with great caution.

There was a high heterogeneity in the applied fluoride concentration, formulation, and dose in the included studies. Fluoride toothpaste ranged from 500 ppm to 1,500 ppm of sodium fluoride. There was 5% NaF Varnish (22,600 ppm) used every 2 weeks, monthly, or every 2 months. One study even used 1.23% acidulated phosphate fluoride gel (12,300 ppm). Additionally, the studies included had a relatively short follow-up period – up to 6 months maximum – and the number of studies that could fit into each time-point the number of included patients was rather low.

Another limitation is that the age of population from the included studies varied from 2 to 35 years old. Therefore, both primary and permanent dentitions were analyzed together since there is no clear evidence on different remineralization behavior between them. In general, clinical data suggest that primary enamel might be more vulnerable to lesion formation and progression than permanent enamel [Lynch, 2013]. Enamel on primary teeth is thinner and there are crystal structural differences that might lead to a higher permeability of primary enamel. Anderson et al. [2001] reported that a higher pH value was found in children than in adult saliva due to the lower calcium concentration. Despite these findings, no clinical difference on the effect of CPP-ACP and fluoride on remineralization between dentitions have been reported. In addition, the compliance to treatment schedule and the quality of self-application may be affected by the age of the patient, as well.

Implications for Clinical Practice

Our results indicate that CPP-ACP in combination with fluoride has very little beneficial effect, if any, over fluoride-induced remineralization. Additionally, our results reinforce the previous observations that daily use of fluoridated toothpaste provides strong remineralization on early stages of carious lesions.

Implications for Research

More high-quality, large-sample size studies with longer follow-up times are needed, applying a more consistent methodology, and assessing true outcomes, such as dentine caries, to further comprehend CPP-ACP action and recommendations. Besides this, the development of substantially more effective products is needed to achieve robust beneficial additional effects over fluoride.

The combination of CPP-ACP and fluoride is not substantially superior compared to the application of fluoride alone on amelioration of WSLs estimated by synthetizing fluorescence and visual methods. Furthermore, the progression of early carious lesions could be arrested and/or reversed by topical fluoride. 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.

An ethics statement is not applicable because this study is based exclusively on published literature.

The authors have no conflicts of interest to declare.

The Centre for Translational Medicine, Semmelweis University, Budapest, Hungary, funded this work. Additional support was received from the Hungarian National Research, Development, and Innovation Fund (NKFIH K-125161).

Bianca Golzio Navarro Cavalcante contributed to the conceptualization and design of the study, data collection, interpretation of data, and drafting of the manuscript. Alexander Schulze Wenning participated in the data collection and revision of the manuscript. Bence Szabó performed the statistical analysis and revision of the manuscript. László Márk Czumbel and Péter Hegyi participated in the conceptualization and design of the study and revision of the manuscript. Judit Borbély and Orsolya Németh participated in the revision of the manuscript. Károly Bartha participated in the interpretation of data and revision of the manuscript. Gábor Gerber and Gábor Varga participated in the conceptual design of the work, the interpretation of data, and revision of the manuscript.

Additional Information

Gábor Gerber and Gábor Varga equally contributed to this work; therefore, they should both be considered as last authors.

All data generated or analyzed during this study are included in this article, its supplementary material files and the article included in the review. Further inquiries can be directed to the corresponding author.

1.
Abou Neel
EA
,
Aljabo
A
,
Strange
A
,
Ibrahim
S
,
Coathup
M
,
Young
AM
et al
.
Demineralization-remineralization dynamics in teeth and bone
.
Int J Nanomedicine
.
2016
;
11
:
4743
63
.
2.
Al-Batayneh
OB
,
Bani Hmood
EI
,
Al-Khateeb
SN
.
Assessment of the effects of a fluoride dentifrice and GC Tooth Mousse on early caries lesions in primary anterior teeth using quantitative light-induced fluorescence: a randomised clinical trial
.
Eur Arch Paediatr Dent
.
2020
;
21
(
1
):
85
93
.
3.
Alagha
E
,
Samy
AM
.
Effect of different remineralizing agents on white spot lesions
.
Open Access Maced J Med Sci
.
2021
9
D
14
8
.
4.
Alhamed
M
,
Almalki
F
,
Alselami
A
,
Alotaibi
T
,
Elkwatehy
W
.
Effect of different remineralizing agents on the initial carious lesions: a comparative study
.
Saudi Dent J
.
2020
;
32
(
8
):
390
5
.
5.
Amaechi
BT
,
Higham
SM
.
Quantitative light-induced fluorescence: a potential tool for general dental assessment
.
J Biomed Opt
.
2002 Jan
7
1
7
13
.
6.
Anderson
P
,
Hector
MP
,
Rampersad
MA
.
Critical pH in resting and stimulated whole saliva in groups of children and adults
.
Int J Paediatr Dent
.
2001
;
11
(
4
):
266
73
.
7.
Bader
JD
,
Shugars
DA
.
A systematic review of the performance of a laser fluorescence device for detecting caries
.
J Am Dent Assoc
.
2004
;
135
(
10
):
1413
26
.
8.
Beerens
MW
,
Ten Cate
JM
,
Buijs
MJ
,
van der Veen
MH
.
Long-term remineralizing effect of MI Paste Plus on regression of early caries after orthodontic fixed appliance treatment: a 12-month follow-up randomized controlled trial
.
Eur J Orthod
.
2018
;
40
(
5
):
457
64
.
9.
Beerens
MW
,
van der Veen
MH
,
van Beek
H
,
ten Cate
JM
.
Effects of casein phosphopeptide amorphous calcium fluoride phosphate paste on white spot lesions and dental plaque after orthodontic treatment: a 3-month follow-up
.
Eur J Oral Sci
.
2010
;
118
(
6
):
610
7
.
10.
Bender
R
,
Friede
T
,
Koch
A
,
Kuss
O
,
Schlattmann
P
,
Schwarzer
G
et al
.
Methods for evidence synthesis in the case of very few studies
.
Res Synth Methods
.
2018
;
9
(
3
):
382
92
.
11.
Bröchner
A
,
Christensen
C
,
Kristensen
B
,
Tranæus
S
,
Karlsson
L
,
Sonnesen
L
et al
.
Treatment of post-orthodontic white spot lesions with casein phosphopeptide-stabilised amorphous calcium phosphate
.
Clin Oral Investig
.
2011
;
15
(
3
):
369
73
.
12.
Chen
H
,
Liu
X
,
Dai
J
,
Jiang
Z
,
Guo
T
,
Ding
Y
.
Effect of remineralizing agents on white spot lesions after orthodontic treatment: a systematic review
.
Am J Orthod Dentofacial Orthop
.
2013
;
143
(
3
):
376
82.e3
.
13.
Cheng
L
,
Zhang
L
,
Yue
L
,
Ling
J
,
Fan
M
,
Yang
D
et al
.
Expert consensus on dental caries management
.
Int J Oral Sci
.
2022
;
14
(
1
):
17
.
14.
Cochrane
NJ
,
Cai
F
,
Huq
NL
,
Burrow
MF
,
Reynolds
EC
.
New approaches to enhanced remineralization of tooth enamel
.
J Dent Res
.
2010
;
89
(
11
):
1187
97
.
15.
Cochrane
NJ
,
Reynolds
EC
.
Calcium phosphopeptides: mechanisms of action and evidence for clinical efficacy
.
Adv Dent Res
.
2012
;
24
(
2
):
41
7
.
16.
Cochrane
NJ
,
Saranathan
S
,
Cai
F
,
Cross
KJ
,
Reynolds
EC
.
Enamel subsurface lesion remineralisation with casein phosphopeptide stabilised solutions of calcium, phosphate and fluoride
.
Caries Res
.
2008
;
42
(
2
):
88
97
.
17.
Dai
Z
,
Liu
M
,
Ma
Y
,
Cao
L
,
Xu
HHK
,
Zhang
K
et al
.
Effects of fluoride and calcium phosphate materials on remineralization of mild and severe white spot lesions
.
BioMed Res Int
.
2019
;
2019
:
1271523
.
18.
de Josselin de Jong
E
,
Higham
SM
,
Smith
PW
,
van Daelen
CJ
,
van der Veen
MH
.
Quantified light-induced fluorescence, review of a diagnostic tool in prevention of oral disease
.
J App Phys
.
2009
;
105
(
10
):
102031
.
19.
Drancourt
N
,
Roger-Leroi
V
,
Martignon
S
,
Jablonski-Momeni
A
,
Pitts
N
,
Doméjean
S
.
Carious lesion activity assessment in clinical practice: a systematic review
.
Clin Oral Investig
.
2019
;
23
(
4
):
1513
24
.
20.
Ekambaram
M
,
Mohd Said
SNB
,
Yiu
CKY
.
A review of enamel remineralisation potential of calcium- and phosphate-based remineralisation systems
.
Oral Health Prev Dent
.
2017
;
15
(
5
):
415
20
.
21.
Esparza-Villalpando
V
,
Fernandez-Hernandez
E
,
Rosales-Berber
M
,
Torre-Delgadillo
G
,
Garrocho-Rangel
A
,
Pozos-Guillén
A
.
Clinical efficacy of two topical agents for the remineralization of enamel white spot lesions in primary teeth
.
Pediatr Dent
.
2021
;
43
(
2
):
95
101
.
22.
Featherstone
JD
.
Dental caries: a dynamic disease process
.
Aust Dent J
.
2008
;
53
(
3
):
286
91
.
23.
Featherstone
JDB
,
Chaffee
BW
.
The evidence for caries management by risk assessment (CAMBRA®)
.
Adv Dent Res
.
2018
;
29
(
1
):
9
14
.
24.
Felix Gomez
G
,
Eckert
GJ
,
Ferreira Zandona
A
.
Orange/red fluorescence of active caries by retrospective quantitative light-induced fluorescence image analysis
.
Caries Res
.
2016
;
50
(
3
):
295
302
.
25.
Gimenez
T
,
Braga
MM
,
Raggio
DP
,
Deery
C
,
Ricketts
DN
,
Mendes
FM
.
Fluorescence-based methods for detecting caries lesions: systematic review, meta-analysis and sources of heterogeneity
.
PLoS One
.
2013
;
8
(
4
):
e60421
.
26.
Gohar
R
,
Ibrahim
SH
,
Safwat
OM
.
Evaluation of the remineralizing effect of biomimetic self-assembling peptides in post-orthodontic white spot lesions compared to fluoride-based delivery systems: randomized controlled trial
.
Clin Oral Investig
.
2023
;
27
(
2
):
613
24
.
27.
Gomez
J
.
Detection and diagnosis of the early caries lesion
.
BMC Oral Health
.
2015
15
Suppl 1
S3
.
28.
Gomez
J
,
Tellez
M
,
Pretty
IA
,
Ellwood
RP
,
Ismail
AI
.
Non-cavitated carious lesions detection methods: a systematic review
.
Community Dent Oral Epidemiol
.
2013
;
41
(
1
):
54
66
.
29.
Güçlü
ZA
,
Alaçam
A
,
Coleman
NJ
.
A 12-week assessment of the treatment of white spot lesions with CPP-ACP paste and/or fluoride varnish
.
BioMed Res Int
.
2016
;
2016
:
8357621
.
30.
Guyatt
GH
,
Oxman
AD
,
Vist
GE
,
Kunz
R
,
Falck-Ytter
Y
,
Alonso-Coello
P
et al
.
GRADE: an emerging consensus on rating quality of evidence and strength of recommendations
.
BMJ
.
2008
;
336
(
7650
):
924
6
.
31.
Heravi
F
,
Ahrari
F
,
Tanbakuchi
B
.
Effectiveness of MI Paste Plus and Remin Pro on remineralization and color improvement of postorthodontic white spot lesions
.
Dent Res J
.
2018 Mar–Apr
15
2
95
103
.
32.
Imani
M
,
Safaei
M
,
Afnaniesfandabad
A
,
Moradpoor
H
,
Sadeghi
M
,
Golshah
A
et al
.
Efficacy of CPP-ACP and CPP-ACPF for prevention and remineralization of white spot lesions in orthodontic patients: a systematic review of randomized controlled clinical trials
.
Acta Inform Med
.
2019
;
27
(
3
):
199
204
.
33.
Ismail
AI
,
Tellez
M
,
Pitts
NB
,
Ekstrand
KR
,
Ricketts
D
,
Longbottom
C
et al
.
Caries management pathways preserve dental tissues and promote oral health
.
Community Dent Oral Epidemiol
.
2013
;
41
(
1
):
e12
40
.
34.
Jackson
D
,
White
IR
.
When should meta-analysis avoid making hidden normality assumptions
.
Biom J
.
2018
;
60
(
6
):
1040
58
.
35.
GBD 2017 Disease and Injur, y Incidence and Prevalence Collaborators
Abate
D
,
Abate
KH
,
Abay
SM
,
Abbafati
C
,
Abbasi
N
.
Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017
.
Lancet
.
2018
;
392
(
10159
):
1789
858
.
36.
Kassebaum
NJ
,
Bernabé
E
,
Dahiya
M
,
Bhandari
B
,
Murray
CJL
,
Marcenes
W
.
Global burden of untreated caries: a systematic review and metaregression
.
J Dent Res
.
2015
;
94
(
5
):
650
8
.
37.
Kavvadia
K
,
Seremidi
K
,
Reppa
C
,
Makou
M
,
Lagouvardos
P
.
Validation of fluorescence devices for evaluation of white spot lesions in orthodontic patients
.
Eur Arch Paediatr Dent
.
2018
;
19
(
2
):
83
9
.
38.
Ko
HY
,
Kang
SM
,
Kim
HE
,
Kwon
HK
,
Kim
BI
.
Validation of quantitative light-induced fluorescence-digital (QLF-D) for the detection of approximal caries in vitro
.
J Dent
.
2015
;
43
(
5
):
568
75
.
39.
Llena
C
,
Leyda
AM
,
Forner
L
.
CPP-ACP and CPP-ACFP versus fluoride varnish in remineralisation of early caries lesions. A prospective study
.
Eur J Paediatr Dent
.
2015
;
16
(
3
):
181
6
.
40.
Lynch
RJ
.
The primary and mixed dentition, post-eruptive enamel maturation and dental caries: a review
.
Int Dent J
.
2013
63
Suppl 2
3
13
.
41.
Ma
X
,
Lin
X
,
Zhong
T
,
Xie
F
.
Evaluation of the efficacy of casein phosphopeptide-amorphous calcium phosphate on remineralization of white spot lesions in vitro and clinical research: a systematic review and meta-analysis
.
BMC Oral Health
.
2019
;
19
(
1
):
295
.
42.
Macey
R
,
Walsh
T
,
Riley
P
,
Glenny
AM
,
Worthington
HV
,
Fee
PA
et al
.
Fluorescence devices for the detection of dental caries
.
Cochrane Database Syst Rev
.
2020
12
CD013811
.
43.
McHugh
ML
.
Interrater reliability: the kappa statistic
.
Biochem Med
.
2012
;
22
(
3
):
276
82
.
44.
McKenzie
J
,
Brennan
S
,
Ryan
R
,
Thomson
H
,
Johnston
R
,
Thomas
J
.
Chapter 3: defining the criteria for including studies and how they will be grouped for the synthesis
. In:
Higgins
JPTTJ
,
Chandler
J
,
Cumpston
M
,
Li
T
,
Page
MJ
,
Welch
VA
(editors). editor.
Cochrane Handbook for Systematic Reviews of Interventions Version 63 (Updated February 2022)
Cochrane
2022
.
45.
Mekky
AI
,
Dowidar
KML
,
Talaat
DM
.
Casein phosphopeptide amorphous calcium phosphate fluoride varnish in remineralization of early carious lesions in primary dentition: randomized clinical trial
.
Pediatr Dent
.
2021
;
43
(
1
):
17
23
.
46.
Memarpour
M
,
Fakhraei
E
,
Dadaein
S
,
Vossoughi
M
.
Efficacy of fluoride varnish and casein phosphopeptide-amorphous calcium phosphate for remineralization of primary teeth: a randomized clinical trial
.
Med Princ Pract
.
2015
;
24
(
3
):
231
7
.
47.
Mendes
AC
,
Restrepo
M
,
Bussaneli
D
,
Zuanon
AC
.
Use of casein amorphous calcium phosphate (CPP-ACP) on white-spot lesions: randomised clinical trial
.
Oral Health Prev Dent
.
2018
;
16
(
1
):
27
31
.
48.
Norris
S
,
Atkins
D
,
Bruening
W
,
Fox
S
,
Johnson
E
,
Kane
R
et al
Selecting Observational Studies for Comparing Medical Interventions. Methods Guide for Effectiveness and Comparative Effectiveness Reviews
.
2010
.
49.
Oliveira
PRA
,
Barboza
CM
,
Barreto
L
,
Tostes
MA
.
Effect of CPP-ACP on remineralization of artificial caries-like lesion: an in situ study
.
Braz Oral Res
.
2020
;
34
:
e061
.
50.
Page
MJ
,
McKenzie
JE
,
Bossuyt
PM
,
Boutron
I
,
Hoffmann
TC
,
Mulrow
CD
et al
.
The PRISMA 2020 statement: an updated guideline for reporting systematic reviews
.
BMJ
.
2021
372
n71
.
51.
Park
KJ
,
Voigt
A
,
Schneider
H
,
Ziebolz
D
,
Haak
R
.
Light-based diagnostic methods for the in vivo assessment of initial caries lesions: laser fluorescence, QLF and OCT
.
Photodiagnosis Photodyn Ther
.
2021
;
34
:
102270
.
52.
Peres
MA
,
Macpherson
LMD
,
Weyant
RJ
,
Daly
B
,
Venturelli
R
,
Mathur
MR
et al
.
Oral diseases: a global public health challenge
.
Lancet
.
2019
;
394
(
10194
):
249
60
.
53.
Philip
N
.
State of the art enamel remineralization systems: the next frontier in caries management
.
Caries Res
.
2019
;
53
(
3
):
284
95
.
54.
Pitts
NB
,
Zero
DT
,
Marsh
PD
,
Ekstrand
K
,
Weintraub
JA
,
Ramos-Gomez
F
et al
.
Dental caries
.
Nat Rev Dis Primers
.
2017
;
3
:
17030
.
55.
Radha
S
,
Kayalvizhi
G
,
Adimoulame
S
,
Prathima
GS
,
Muthusamy
K
,
Ezhumalai
G
et al
.
Comparative evaluation of the remineralizing efficacy of fluoride varnish and its combination varnishes on white spot lesions in children with ECC: a randomized clinical trial
.
Int J Clin Pediatr Dent
.
2020 Jul–Aug
13
4
311
7
.
56.
Reynolds
EC
.
The prevention of sub-surface demineralization of bovine enamel and change in plaque composition by casein in an intra-oral model
.
J Dent Res
.
1987
;
66
(
6
):
1120
7
.
57.
Reynolds
EC
.
Calcium phosphate-based remineralization systems: scientific evidence
.
Aust Dent J
.
2008
;
53
(
3
):
268
73
.
58.
Reynolds
EC
,
Cai
F
,
Cochrane
NJ
,
Shen
P
,
Walker
GD
,
Morgan
MV
et al
.
Fluoride and casein phosphopeptide-amorphous calcium phosphate
.
J Dent Res
.
2008
;
87
(
4
):
344
8
.
59.
Reynolds
EC
,
Cain
CJ
,
Webber
FL
,
Black
CL
,
Riley
PF
,
Johnson
IH
et al
.
Anticariogenicity of calcium phosphate complexes of tryptic casein phosphopeptides in the rat
.
J Dent Res
.
1995
;
74
(
6
):
1272
9
.
60.
Salah
R
,
Afifi
RR
,
Kehela
HA
,
Aly
NM
,
Rashwan
M
,
Hill
RG
.
Efficacy of novel bioactive glass in the treatment of enamel white spot lesions: a randomized controlled trial
.
J Evid Based Dent Pract
.
2022
;
22
(
4
):
101725
.
61.
Sbaraini
A
,
Adams
GG
,
Reynolds
EC
.
Experiences of oral health: before, during and after becoming a regular user of GC Tooth Mousse Plus®
.
BMC Oral Health
.
2021
;
21
(
1
):
14
.
62.
Schünemann
H
,
Brożek
J
,
Guyatt
G
,
Oxman
A
GRADE Handbook for Grading Quality of Evidence and Strength of Recommendations
.
2013
.
63.
Seide
SE
,
Röver
C
,
Friede
T
.
Likelihood-based random-effects meta-analysis with few studies: empirical and simulation studies
.
BMC Med Res Methodol
.
2019
;
19
(
1
):
16
.
64.
Sharda
S
,
Gupta
A
,
Goyal
A
,
Gauba
K
.
Remineralization potential and caries preventive efficacy of CPP-ACP/Xylitol/Ozone/Bioactive glass and topical fluoride combined therapy versus fluoride mono-therapy: a systematic review and meta-analysis
.
Acta Odontol Scand
.
2021
;
79
(
6
):
402
17
.
65.
Shen
P
,
Cai
F
,
Nowicki
A
,
Vincent
J
,
Reynolds
EC
.
Remineralization of enamel subsurface lesions by sugar-free chewing gum containing casein phosphopeptide-amorphous calcium phosphate
.
J Dent Res
.
2001
;
80
(
12
):
2066
70
.
66.
Shen
P
,
Fernando
JR
,
Yuan
Y
,
Walker
GD
,
Reynolds
C
,
Reynolds
EC
.
Bioavailable fluoride in calcium-containing dentifrices
.
Sci Rep
.
2021
;
11
(
1
):
146
.
67.
Shen
P
,
Manton
DJ
,
Cochrane
NJ
,
Walker
GD
,
Yuan
Y
,
Reynolds
C
et al
.
Effect of added calcium phosphate on enamel remineralization by fluoride in a randomized controlled in situ trial
.
J Dent
.
2011
;
39
(
7
):
518
25
.
68.
Shen
P
,
Walker
GD
,
Yuan
Y
,
Reynolds
C
,
Stanton
DP
,
Fernando
JR
et al
.
Importance of bioavailable calcium in fluoride dentifrices for enamel remineralization
.
J Dent
.
2018
;
78
:
59
64
.
69.
Simmonds
M
.
Quantifying the risk of error when interpreting funnel plots
.
Syst Rev
.
2015
;
4
:
24
.
70.
Singh
S
,
Singh
SP
,
Goyal
A
,
Utreja
AK
,
Jena
AK
.
Effects of various remineralizing agents on the outcome of post-orthodontic white spot lesions (WSLs): a clinical trial
.
Prog Orthod
.
2016
;
17
(
1
):
25
.
71.
Sitthisettapong
T
,
Doi
T
,
Nishida
Y
,
Kambara
M
,
Phantumvanit
P
.
Effect of CPP-ACP paste on enamel carious lesion of primary upper anterior teeth assessed by quantitative light-induced fluorescence: a one-year clinical trial
.
Caries Res
.
2015
;
49
(
4
):
434
41
.
72.
Sterne
JAC
,
Savovic
J
,
Page
MJ
,
Elbers
RG
,
Blencowe
NS
,
Boutron
I
et al
.
RoB 2: a revised tool for assessing risk of bias in randomised trials
.
BMJ
.
2019
366
l4898
.
73.
Sterne
JA
,
Sutton
AJ
,
Ioannidis
JP
,
Terrin
N
,
Jones
DR
,
Lau
J
et al
.
Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials
.
BMJ
.
2011 Jul
22
;343:
d4002
.
74.
Tao
S
,
Zhu
Y
,
Yuan
H
,
Tao
S
,
Cheng
Y
,
Li
J
et al
.
Efficacy of fluorides and CPP-ACP vs fluorides monotherapy on early caries lesions: a systematic review and meta-analysis
.
PLoS One
.
2018
;
13
(
4
):
e0196660
.
75.
tenCate
JM
.
Current concepts on the theories of the mechanism of action of fluoride
.
Acta Odontol Scand
.
1999
;
57
(
6
):
325
9
.
76.
Toraman Alkurt
M
,
Peker
I
,
Deniz Arisu
H
,
Bala
O
,
Altunkaynak
B
.
In vivo comparison of laser fluorescence measurements with conventional methods for occlusal caries detection
.
Lasers Med Sci
.
2008
;
23
(
3
):
307
12
.
77.
Twetman
S
,
Axelsson
S
,
Dahlgren
H
,
Holm
AK
,
Källestål
C
,
Lagerlöf
F
et al
.
Caries-preventive effect of fluoride toothpaste: a systematic review
.
Acta Odontol Scand
.
2003
;
61
(
6
):
347
55
.
78.
Varma
V
,
Hegde
KS
,
Bhat
SS
,
Sargod
SS
,
Rao
HA
.
Comparative evaluation of remineralization potential of two varnishes containing CPP-ACP and tricalcium phosphate: an in vitro study
.
Int J Clin Pediatr Dent
.
2019 May–Jun
12
3
233
6
.
79.
Walsh
T
,
Macey
R
,
Ricketts
D
,
Carrasco Labra
A
,
Worthington
H
,
Sutton
AJ
et al
.
Enamel caries detection and diagnosis: an analysis of systematic reviews
.
J Dent Res
.
2022
;
101
(
3
):
261
9
.
80.
Wu
L
,
Geng
K
,
Gao
Q
.
Early caries preventive effects of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) compared with conventional fluorides: a meta-analysis
.
Oral Health Prev Dent
.
2019
;
17
(
6
):
495
503
.
81.
Yazicioglu
O
,
Yaman
BC
,
Güler
A
,
Koray
F
.
Quantitative evaluation of the enamel caries which were treated with casein phosphopeptide-amorphous calcium fluoride phosphate
.
Niger J Clin Pract
.
2017
;
20
(
6
):
686
92
.
82.
Zhang
Q
,
Zou
J
,
Yang
R
,
Zhou
X
.
Remineralization effects of casein phosphopeptide-amorphous calcium phosphate crème on artificial early enamel lesions of primary teeth
.
Int J Paediatr Dent
.
2011
;
21
(
5
):
374
81
.