Effect of Remineralization Agents on White Spot Lesions: A Systematic Review.

Objective: The goal of this systematic review was to evaluate the therapeutic efficacy of Casein Phosphopeptide Amorphous Calcium Phosphate (CPP-ACP) remineralizing potential to that of other remineralizing treatments and placebo in both naturally occurring and postorthodontic white spot lesions (WSL) in vivo. Materials and
Methods: From 2005 to 2020, the literature search used electronic databases PubMed, Embase, Science Direct, and Google Scholar to find studies published solely in English and randomized controlled trials (RCTs) employing CPP-ACP as an intervention. All eligible studies were reviewed by two independent reviewers.
Results: Excluding duplications, 72 articles were identified. Abstracts of 58 articles were reviewed independently, 19 articles were excluded, 36 full text articles were retrieved; finally selecting 14 studies.
Conclusion: The CPP-ACP was found to have efficacious remineralizing potential on naturally occurring and postorthodontic WSL compared to placebo or other preventive measures. Further well-performed RCTs are needed to determine the therapeutic significance of remineralizing medicines, and long-term follow-ups are required. Copyright:

INTRODUCTION

Enamel decalcification or white spot lesions (WSL) are subsurface enamel porosity from carious demineralization, manifested as milky white opacities without cavitation on the smooth tooth surface (prevalence: 2%–96%).[12] WSLs associated with orthodontic appliances are one of the greatest challenges toward orthodontic treatment completion, as they compromise aesthetics and may progress to carious process (prevalence rate: 50%–96%).[3]

Remineralization is the process of using remineralizing chemicals such as topical fluoride, amorphous calcium phosphate (ACP), xylitol, bioactive glass, casein phosphopeptide (CPP) ACP, and self-assembling peptides to stop the advancement of an active first carious lesion.

High fluoride concentrations with bioavailable calcium and phosphate should be carried by phosphopeptide-based preparations such as CPP, CPPs with amorphous calcium fluoride phosphate (CPP-ACFP), and CPP-ACFP.[45]

Previous systematic evaluations looked at the efficiency of several remineralizing treatments in preventing both naturally occurring and postorthodontic WSL. Various randomized controlled trials (RCTs) of postorthodontic WSL regression following the use of remineralizing drugs have also been described.

In both naturally occurring and postorthodontic WSL, this systematic review seeks to investigate the relative remineralizing ability of CPPACP and CPP-ACFP formulations compared to other treatments and/or placebo.

MATERIALS AND METHODS

Structured question

Does CPP-ACP possess remineralizing potential in WSL in naturally occurring and postorthodontic WSL in vivo?

Eligibility criteria and search strategies

The eligibility criteria have been developed based on the PICOS acronym [Table 1]. We assume patients fulfilling inclusion criteria are equally eligible to be randomized to any of interventions compared. A literature search on PubMed (National Library of Medicine, NCBI), Embase, Science Direct and Google Scholar comprising words “WSL,” “fixed orthodontic treatment,” “prevention, management caries lesions,” “RCT,” “remineralization,” “remineralizing agents,” “CPP-ACP,” “GC tooth mousse,” “MI paste,” “calcium sucrose phosphate,” “Tooth mousse” OR “Recaldent” AND “Fluoride varnish” was carried out from 2005 to 2020, followed by manual search of bibliography section, relevant systematic reviews, and narrative reviews.

Table 1

Inclusion and exclusion criteria

Domain	Inclusion	Exclusion
Participants	Patients above 6 years of age with at least one WSL on labial surface of teeth induced by fixed orthodontic treatment or natural process. No restrictions on gender, age, city/country, ethnicity, and/or socio-economic status	Laboratory animals and patients with any illness potentially affecting study outcome, such as enamel hypoplasia, craniofacial deformities, and/or ongoing medication
Interventions	CPP-ACP and CPP-ACFP in any form	Nonremineralised methods for WSL prevention and treatment, like bleaching, micro-abrasion, and resin infiltration. If remineralised and nonremineralised methods were jointly used as an intervention in same study, we will include article but not pool data
Comparisons	Any other kind of remineralized agents such as hydroxyapatite or nanohydroxyapatite, fluoridated toothpaste, fluoride varnish, mouth rinse formulations, antibacterial gels, and/or placebo	-
Outcome	Lesion severity measured by WSL index, enamel decalcification index, DIAGNOdent pen reading, quantitative light-induced fluorescence, and Ekstrand visual examination Lesion progression, stability or regression, and WSL prevalence	-
Study design	Randomized controlled trials	Nonrandomized prospective or retrospective studies, pilot studies, Split-mouth trials, case reports/case series, nonclinical studies (in-vitro, ex-vivo), systematic review
Timing and study setting	The studies from 2005 to 2020 were included. No restrictions in study setting	-
Language	Published studies in English	-

WSL: White spot lesions, CPP: Casein phosphopeptides, CPP-ACP: CPP-amorphous calcium phosphate, CPP-ACFP: CPP-amorphous calcium fluoride phosphateaaaaaaa

Protocol and registration

This systematic review was not registered and was conducted following the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement.

Data collection and analysis

All studies were screened for titles and abstracts independently by two reviewers. Any dissent was resolved consulting a third reviewer. The initial electronic search yielded 152 studies and 27 additional studies by hand-search, screening resulted in 77 full-text articles. The process is presented in a PRISMA[6] flow diagram for study screening [Figure 1].

Figure 1

Preferred Reporting Items for Systematic Reviews and Met analyses flow chart of the included studies (Adapted from Preferred Reporting Items for Systematic Reviews and Met analyses 2009 Flow diagram)

Data extraction

Data were extracted by two independent reviewers using Microsoft Excel 2010 with a specifically developed form [Table 2].

Table 2

Summary of the included studies

Author and year	Study design	Study groups	Intervention	Control group	Outcome/result
Early enamel caries lesion
Rao et al. (2009)[7]	Randomized triple blind study	12-15 years 3 groups 50/50/50	2% CPPACP toothpaste	0.76% w/w SMFP toothpaste and placebo toothpaste	DMFS index and OHI index Baseline at 12, 24 months Significant differences between the CPP and SMFP groups than in placebo group
Güçlü et al. (2016)[8]	Randomized clinical study	8-15 years 4 groups 30 subjects	10% CPP-ACP	5% NaF varnish group, CPP-ACP+fluoride varnish group, no intervention group	Visual appraisal using Ekstrand criteria and LF using DIAGNOdent were made in 1 and 12 weeks. CPP-ACP significantly improved remineralisation of WSL than standard oral hygiene
Ebrahimi et al. (2017)[9]	Parallel group randomized controlled clinical trial	7-12 years Four groups 20 in each group	CPP-ACPF (MI Paste Plus)	2% NaF gel group, fluoridated hydroxyapatite (ReminPro) group and home care group	LF using Vista-Cam iX and DBSWIN imaging software Baseline at (T1) and 1 day after the application of the remineralization agents (T2). MI Paste Plus or ReminPro was as effective as 2% NaF gel in reducing WSL
Llena et al. (2015)[4]	Doubleblindprospective, randomized clinical study	6-14 years Four groups 20 in each group	Group A: CPPACP toothpaste 0.2%w/w	Group B: MI paste plus toothpaste; Group C: 5% NaF varnish; Group D: Nonfluoridated paste	ICDAS II and Ekstrand criteria LF using DIAGNOdent, for baseline at 4, 8 and 12 weeks. Diagnodent values were significantly reduced in group B at 4 weeks, in groups A and C at 8 weeks
Postorthodontic WSL
Bailey et al. (2009)[10]	Randomized clinical trial	12-18 years 2 groups 23/22	10% w/v CPP-ACP cream (tooth mousse)	Placebo cream without CPP-ACP	QLF, digital photographs, ICDAS II Baseline at 4, 8,12 weeks. CPP-ACP significantly enhanced regression of WSL compared with that of placebo cream
Andersson et al. (2007)[11]	Randomized trial	12-14 years 2 groups 13/13	CPPACP tooth paste	Conventional 0.05% NaF toothpaste	Visual examination and LF with DIAGNOdent. Baseline: 1, 3, 6, 12 months. A significant improvement of clinical WSLscores was found in both groups, (P<0.01) in CPPACP regime
Karabekİroğlu et al. (2017)[5]	Parallel design single blinded randomized, controlled trial	14-20 years controls: 18 subjects, 89 teeth. CPP-ACP group: 16 subjects, 89 teeth	10% CPP-ACP	Fluoride tooth paste (colgate 1450 ppm F)	DIAGNOdent, Gorelick index and ICDAS II criteria, DMFT, DMFS, and stimulated salivary flow rate and buffer capacity were calculated at baseline (T1) and 36-month (T2). CPP-ACP found to be more effective than only fluoridated toothpaste for remineralization of WSLs after 36 months
Beerens et al. (2010)[12]	Double blind prospective randomized clinical trial	12-19 years 2 groups 28/27	CPP-ACP+NaF 0.2% w/w	Fluoride free+CaF tooth paste	QLF after debonding and 6 and 12 weeks. No change in lesion noted between groups
Bröchner et al. (2011)[13]	Randomized single blind controlled parallel design	13-18 years 2 groups 22/28	1 g CPP-ACP tooth mousse cream	Standard fluoride tooth paste (colgate, 1100 ppm F)	QLF, digital photograph. Baseline at 0 and 4 weeks. The average lesion was significantly decreased by 58% in CPP-ACP group and by 26% in the controls
Singh et al. (2016)[14]	Block randomization	16-25 years 3 groups 15/15/15	CPP-ACP (GC tooth mousse)	Fluoride tooth paste (colgate, 1000 ppm F) and 5% NaF varnish groups	Boyd criteria and DIAGNOdent. Baseline data at 1, 3 and 6 months. The mean DIAGNOdent scores in CPP-ACP and varnish group were decreased compared to fluoride tooth paste but statistically insignificant
Robertson et al. (2011)[15]	Double blind, randomized clinical trial	12 years and above 2 groups 26/24	MI paste plus	Fluoride varnish	Photographic records, EDI, ICDAS. Baseline at 0, 4, 8, 12 weeks. The mean EDI scores reduced in the MI Paste Plus group and increased for each surface in the placebo
Huang et al. (2013)[16]	Single blinded controlled parallel design	12-20 years 3 groups 45/42/48	MI paste plus	Fluoride varnish 5% and home care group	Digital photographs and visual analog scale. Insignificant differences were found at the end of 8 weeks between the groups
Wang et al. (2012)[17]	A single blinded clinical study	12-14 years 2 groups 20/20	GC tooth mousse recaldent	Toothpaste (colgate, China) 1100 ppm of fluoride	An intraoral images and EDI Baseline at 0 and 6 months. EDI results indicated that the mean EDI decreased significantly (P<0.01) after using tooth mousse
Bangi et al. (2020)[18]	Single blinded block randomized controlled prospective design	12-25 years 4 groups 20 in each group	GC tooth mousse	Colgate strong toothpaste, phosflur mouthwash, SHY-NM	Modified Gorelick scoring criteria and Intraoral photographs at baseline, 3 and 6 months. All four groups showed significant improvement in WSL. GC tooth mousse proved to be most effective over other regimens

WSL: White spot lesions, CPP: Casein phosphopeptides, CPP-ACP: CPP-amorphous calcium phosphate, CPP-ACFP: CPP-amorphous calcium fluoride phosphate, SMFP: Sodium monofluorophosphate, DMFS: Decayed missing filled surfaces, OHI: Oral hygiene index, DMFT: Decayed missing filled teeth, QLF: Quantitative laser fluorescence, ICDAS: The international caries detection and assessment system, EDI: Enamel decalcification index, SHY-NM: Bioactive glass toothpaste with Calcium Sodium Phosphatesilicate, DBSWIN: VistaEasy Dental imaging software

Quality assessment

Two reviewers independently assessed each article using the Cochrane Handbook for Systematic Reviews.[19] Randomization, allocation concealment, participant, employee, and assessor blinding, dropouts, selective reporting, and other forms of bias risk were all examined. Each domain was given a risk of bias rating of low, high, or unclear. Following that, each study's degree of risk was graded as low (all domains met), moderate (1 or 2 domains not met), or high (all domains not met) (3 or more domains not met).[20] Meta-analysis was not possible due to the heterogeneity of the studies.

RESULTS

Study characteristics

In the present review, all 14 studies were RCT and were compared based on number of participants, examination methods, treatment methods, study design, and main findings. Four studies were based on naturally occurring caries and 10 studies were on postorthodontic WSL.

Primary outcome

International Caries Detection and Assessment System II (2 studies), DIAGNOdent (2 studies), decayed missing filled teeth/surfaces and oral hygiene index (OHI) (2 studies), quantitative laser fluorescence (2 studies), digital photograph (2 studies), enamel decalcification index (1 study), Ekstrand criteria (1 study), Gorelick criteria (1 study), and Boyd criteria (1 study) were among the measurement methods used [Table 2].

Three investigations on postorthodontic lesions found no significant decrease with CPP-ACP compared to other treatments, despite the fact that all research on naturally occurring caries lesions showed considerable reduction.

Secondary outcome

In 86 percent of the samples, nonserious side effects such as mild gastrointestinal problems were recorded.[10]

Risk of bias within studies

The risk of bias assessment showed high risk (for at least one bias domain) in 13 trials (93%), low risk level for one study [Table 3].

Table 3

Assessment of risk of bias within studies

Rao et al. (2009)[7]	+	+	+	+	+	+	+	Low
Güçlü et al. (2016)[8]	+	-	-	-	+	+	+	High
Ebrahimi et al. (2017)[9]	+	+	-	-	+	+	+	Moderate
Llena et al. (2015)[4]	+	-	+	-	+	+	+	Moderate
Bailey et al. (2009)[10]	+	+	-	-	+	+	+	Moderate
Andersson et al. (2007)[11]	-	+	-	+	+	?	+	High
Karabekİroğlu et al. (2017)[5]	+	?	?	-	+	+	+	High
Beerens et al. (2010)[12]	+	?	+	-	+	+	?	High
Bröchner et al. (2011)[13]	+	?	?	-	?	+	+	High
Singh et al. (2016)[14]	+	?	-	-	?	+	+	High
Robertson et al. (2011)[15]	+	?	+	-	+	+	+	Moderate
Huang et al. (2013)[16]	+	+	-	+	+	+	-	Moderate
Wang et al. (2012)[17]	-	-	?	-	?		-	High
Bangi et al. (2020)[18]	+	-	?	-	?	+	+	High

Random sequence generation (selection bias). Allocation concealment, (selection bias). Blinding of personnel and participants (performance bias). Blinding of outcome assessor (performance bias). Incomplete outcome data (attrition bias). Selective reporting (reporting bias) Other sources of bias. Risk level

Risk of bias across studies

The domains with high risk of bias were blinding of outcome assessors (78% of trials), followed by blinding of personnel and participants (43% of trials), and allocation concealment (28% of trials). Risk of bias across the studies are shown in Figure 2.

Figure 2

Risk of bias across the studies

DISCUSSION

WSLs associated with orthodontic appliances are one of the greatest challenges toward orthodontic treatment completion, as they compromise aesthetics and may progress to caries. Several in vitro studies reported effectiveness of remineralizing agents on WSL. This review included only RCTs to illustrate the importance of in vivo studies and patient-centered outcomes. Agents containing fluoride and/or CCP-ACP have been proven most effective in WSL prevention and treatment with the additional benefits of supplemental fluoride.[51218] It has highlighted remineralizing effect of CPP-ACP on early caries lesions and postorthodontic WSL compared with placebo and other remineralizing agents.

Four studies on naturally occurring early caries lesions reported significant reduction with CPP-ACP compared to placebo.[78915] Among the 10 studies on WSLs associated with orthodontic treatment, three reported no added benefit of CPP-ACP,[111314] while two studies reported enamel remineralization.[1617] Using combinations of at least two of the methods to assess primary outcome measures may be more reliable.[2]

The follow-up time of studies varied from 1 to 36 months. Only few studies reported concentration of CPP-ACP varying from 0.2% to 10% and 1 g in the study.[4915] Quality assessment presented eight studies with high risk of bias. However, difference in CPP-ACP concentration, outcome assessments, follow-up period, randomization, and blinding methods may affect trial results.

CONCLUSION

According to the findings, CPP-ACP and CPP-ACPF supplements are more effective in reducing naturally occurring and postorthodontic WSL. In order to reduce the occurrence of WSL, innovative techniques and more high-quality research have been highlighted.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.