Table of Contents  
Year : 2021  |  Volume : 13  |  Issue : 2  |  Page : 121-128

Remineralizing Agents in the Prevention of Caries: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Department of Public Health Dentistry, SIBAR Institute of Dental Sciences, Guntur, Andhra Pradesh, India

Date of Submission26-Oct-2021
Date of Acceptance10-Nov-2021
Date of Web Publication14-Jan-2022

Correspondence Address:
Dr. Divya Bhavani Vasamsetti
SIBAR Institute of Dental Sciences, Takkellapadu, Guntur District, Andhra Pradesh, Postal Code-522509
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jofs.jofs_235_21

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Introduction: The systematic review presented here aims to determine and find out the clinical efficacy of various remineralization agents for early enamel caries. Materials and methods: An aggregate of 240 articles has been retrieved from PubMed, Cochrane Library, Trip, and Google scholarly databases from 2010 to 2020, of which 18 randomized controlled trials (RCTs) have been integrated into this systematic review, and six of which were considered for meta-analysis. The risk of bias in each study was evaluated using the Cochrane collaboration’s tool. Results: Ten of the 18 studies suggest that carious lesions are successfully minimized by remineralization. Four studies showed superior efficacy of casein phosphopeptide and amorphous calcium phosphate (CPP-ACP) in the remineralization of white spot lesions. There was no statistically significant difference (standard mean difference = −0.18, 95% confidence interval: −0.48 to 0.12, P = 0.23) between the experimental and control groups. Conclusion: This review has demonstrated an absence of dependable proof supporting the clinical adequacy of remineralizing agents. Therefore, RCTs in well-designed forms are needed to enhance all sorts of evidence in this field.

Keywords: Caries prevention, demineralization, randomized controlled trials, remineralization, remineralizing agents

How to cite this article:
Vasamsetti DB, Pachava S, Talluri D. Remineralizing Agents in the Prevention of Caries: A Systematic Review and Meta-analysis of Randomized Controlled Trials. J Orofac Sci 2021;13:121-8

How to cite this URL:
Vasamsetti DB, Pachava S, Talluri D. Remineralizing Agents in the Prevention of Caries: A Systematic Review and Meta-analysis of Randomized Controlled Trials. J Orofac Sci [serial online] 2021 [cited 2022 Jul 4];13:121-8. Available from:

  Introduction Top

Dental diseases are the most common and expensive chronic diseases for health care worldwide; they have been positioned as the 12 most common and highly prevalent conditions that are supposed to affect more than 560 million kids. Preschool caries prevalence is very high (79%), particularly in Southeast Asian countries, and more than 90% of caries are untreated in most low-income developing countries. The caries formation involves the remineralization cycle and also the process of demineralization, with either reversible or irreversible stages being involved. Demineralization causes a reduction in the pH of the oral cavity, which, if unabated, leads to dental caries and loss of tooth structure. Unfortunately, higher caries incidence and severity exist in children from families with lower household income and restricted access to dental care. In opposite to this context, there are some sorts of expensive treatments that are conventional and restorative and exorbitant for the oppressed kids. It is also challenging for young children to deal with prolonged, complicated restorative care procedures.[1],[2]

The ground-breaking theory “extension for prevention” concept had assumed control longer than a century before dentistry proceeded to a new concept, “minimum intervention.” As the word implies, minimum intervention alludes to the philosophy of care in dentistry, a noninvasive and uneasy approach for tackling young children’s problems regarding dental caries. By the use of noninvasive approaches, the process of remineralization can be accomplished, and, as per investigation, such ways are highly effective in younger children. These techniques and procedures involve the use of minerals such as fluoride, calcium, and phosphates combined with meticulous oral hygiene.[3],[4],[5] Hence, this systematic review finds out the remineralization agents and their efficacies to counter the enamel lesions at the initial stages.

  Methodology Top

Framework and registration

A systematic literature review and meta-analysis were performed in compliance with the PRISMA guidelines [Figure 1]. The PICO framework has been accustomed to executing the quest strategy. The PICO question implemented through this research was “In patients with caries active lesions/white spot lesions (WSLs), which remineralizing agents are more efficacious at regression or disappearance of lesions.” One such methodologic survey strategy was submitted to the International Prospective Register of Systematic Reviews (PROSPERO) and was assigned with an enrollment number CRD42021244894. (
Figure 1 PRISMA 2009 flow diagram of database searches.

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Search strategy and selection criteria

Pertinent articles were retrieved through an exploration of four databases: PubMed, Google Scholar, Cochrane library, and trip databases between January 2010 and May 2020 on studies related to the topic on remineralizing agents in caries prevention using keywords “remineralizing agents,” “caries prevention,” “randomized controlled trials,” and various combinations of keywords were made using the Boolean operator “AND.” A total of 353 articles were found, and after wiping out duplicates, 240 articles were retrieved. Eighteen articles have been retained by applying the criteria of inclusion and exclusion.

Inclusion criteria

  1. Only human clinical trials were included.
  2. Studies published in the English language showing remineralizing agents in caries counteraction.
  3. Studies published within a 10-year time frame (2010–2020).

Exclusion criteria

  1. In vitro studies, abstracts, case reports, pilot studies, narrative reviews, and letters to the editors were excluded.
  2. Adolescents with exceptional health services are at a higher risk of developing a variety of chronic diseases; studies involving these children were excluded.

Quality assessment

A total of 18 articles have been chosen per the defined criteria. All the 18 articles were randomized controlled trials (RCTs) and assessed with a CONSORT checklist. With the aid of the tools of Cochrane collaboration, the bias risk for all kinds of studies was estimated as well. To generate the risk of bias figures, Cochrane Version 5.4 of the Review Manager was used.

Statistical analysis

Meta-analysis was attempted using RevMan Statistical Software version 5.4, The Cochrane Collaboration, 2020, to assess the effectiveness of remineralizing agents. Random effects models were chosen due to heterogeneity across the studies.

  Results Top

Study characteristics

The 18 studies selected were published between 2010 and 2020 and were conducted in seven different countries. An aggregate of 3268 patients was included for these clinical examinations, with an age ranging from 1.5 to 28 years. Examination methods used in this study included clinical examination, quantitative light-induced fluorescence, digital photography, scanning electron microscopy, and DIAGNOdent pen; each study used one or more of them. Further, the length of follow-up in these studies ranged from 2 to 41 months after the intervention. The basic traits of the eighteen included studies are shown in [Table 1].
Table 1 Characteristics of included studies

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Assessment of methodologic quality

The Cochrane risk-of-bias tool was used to assess the quality of the selected RCTs and the risk of bias. RCTs showed a low risk of bias if all areas of bias were classified as low risk; the risk of bias was considered unclear if one or more bias domains had an uncertain result; the risk of bias was high if one or more bias domains were classified as high risk.

In [Figure 2]a,b, the events of methodologic quality assessments are mentioned. There is a lower risk of bias in all the enclosed studies in the generation of random sequences. The concealment of the allocation method was not defined in most of the studies (45%), and 23% of the articles did not address the blinding of outcome measurement. The judgments are delineated in [Figure 2]b regarding the bias items risk, and it is presented in the form of percentages in all the included investigations.
Figure 2 Showing risk of bias (a) summary and (b) graph according to the Cochrane risk of bias tool.

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On pooling six clinical studies, substantial heterogeneity was observed (χ2 = 14.82, degrees of freedom = 5 P = 0.01, I2 = 66%). Hence, for the analysis, the random-effects model was utilized, and no significant difference was shown in the meta-analysis as mentioned in [Figure 3] among the experimental and control groups (standard mean difference = ‒0.18, 95% confidence interval: ‒0.48 to 0.12, P = 0.23). No significant distinction was found between casein phosphopeptide and amorphous calcium phosphate (CPP-ACP) versus fluoride (P = 0.83) [Figure 3]. The meta-analysis did exclude xylitol in light of the fact that the mean and standard deviation were not referenced in the articles comparing xylitol to fluoride.
Figure 3 The forest plot of the meta-analysis for evaluating the effectiveness in the prevention of initial carious lesions.

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  Discussion Top

An evidence-based literature review should be performed to attempt to discover answers to clinical issues. Remineralizing agents constitute the first-line therapy in the anticipation and inversion of carious lesions. On the other hand, on the best remineralizing agents, there is no concession. The pair-wise evidence has been provided by the published systematic reviews. Therefore, it is always an important step to estimate and calculate the remineralization agents and their efficacy in the treatment of lesions of enamel. This review included calcium- and phosphate-based agents, xylitol agents, and fluoride agents.

Vashisht et al.[9] conducted an in vivo study for a period of 12 weeks using CPP-ACP, and the measurements with DIAGNOdent revealed a trivial decline in the demineralization process in the control group. The slender drop in DIAGNOdent readings for the WSLs in the treatment group compared to the control group may have suggested that caries could be reversed by using CPP-ACP, implying that added hydroxylapatite crystals were produced from the minerals present in the paste via physical diffusion of the ions to the broken hydroxyapatite. This is analogous to the findings conducted by Memarpour[15] and Ebrahimi et al.,[19] where the size of WSL was reduced during the study period by CPP-ACP applications.

Xylitol wipes, when used frequently, ended up in a considerable reduction of the caries occurrence in preschoolers compared to wipes without xylitol in a study conducted by Zhan et al.,[8] indicating the use of xylitol wipes could be a valuable adjunct for caries control in infants. This is similar to the Ritter et al.[10] study, in which xylitol appears to influence the root’s caries prevention.

Another study, led by Chi et al.,[14] inferred that cleaning with low strength xylitol/fluoride toothpaste is no longer effective than fluoride-only toothpaste in reducing caries increment or MS levels a high caries risk child population.

The topical application of 25% of silver nitrate solution followed by 5% of the sodium fluoride varnish with functionalized tricalcium phosphate to cure chronic dental caries in the toddlers and preschoolers remained obscure during a study conducted by Chen et al.[21] However, the study concluded that proposed methods of caries arrest are simple, noninvasive, and low-cost and that they can be suggested widely for the treatment of dental caries at earlier stages in kids.

Toothbrushing with fluoridated bioactive glass dentifrices had a beneficial effect on fluoride bioavailability within 2 hours, according to Naumova et al.[23] The bioactive glass with fluoride is thus needed in a new field for research in the prophylaxis of caries. The potential bioactive consequences of tooth remineralization should be further investigated. It is also observed that the prevalence and occurrence of WSLs next to the fixed orthodontic appliances in adults will decrease substantially by the regular use of high fluoride toothpaste; according to the research by Sonesson et al.,[13] it was summarized that the toothpaste containing a higher amount of fluoride could be used as the alternative therapy for dental problems. It can be used in patients that are at increased risk of caries for some time. This is inconsistent with the findings of Bonow et al.,[11] who found that using the gel of fluoride will not provide additional advantages in this case where the kids are exposed to the water and fluoride dentifrice.

In a study conducted by Hedayati-Hajikand et al.,[18] the findings showed that the dental caries was substantially lower (0.2) in the treatment group (receiving probiotic chewing tablets) relative to the placebo arm (0.8), which is statistically significant (P < 0.05) and regarding the evidence of prominent plaque or blood strains while brushing. There was no discernible distinction between the groups. It was therefore considered that caries in early childhood could be reduced by proper toothbrushing. Additionally, children can be suggested to use probiotic chewing tablets as an alternative supplement to fluoride toothpaste. This is most effective in the case of preschoolers.

Six out of 12 articles suggest that carious lesions are minimized successfully by remineralization. Four studies showed superior efficacy of CPP-ACP for remineralization of WSLs. GC tooth mousse (CPP-ACP) is the most commonly available agent in the market. Its nano complexes are readily soluble in saliva, creating a diffusion gradient that allows them to localize in supragingival plaque. Low pH conditions that arise during a cariogenic attack facilitate the release of Ca2+ and PO43–ions, inhibiting demineralization and favoring the remineralization of the incipient lesion by precipitation of the released ions. The ability of CPP-ACP to provide high concentrations of stabilized Ca2+ and PO43–ions could be especially important in highly cariogenic environments (e.g., xerostomia, >6 sugar exposures/day), where fluoride and salivary homeostatic mechanisms alone will not be enough to repair developing lesions.

For all the outcomes, the sample size was not sufficiently larger to make and claim something authoritatively, especially about the remineralizing agents. There was a higher risk of biases, and hence, for many trials, things were not clear, and it is considered that since the patients had not been blinded, the outcomes could be influenced by the biasness. Because of the modest number of homogeneous studies, future studies are needed to make a more precise inference regarding the potency of remineralizing agents.

  Conclusion Top

The review of human RCT findings mentioned that reliable and supportive evidence is lacking regarding the efficacy of remineralization agents clinically. Though remineralizing agents are effective in this review, the results must be perused along with the risk of bias summary provided. In the meta-analysis, CPP-ACP and fluoride demonstrated similar efficiency. It is imperative that all scientific journals have a vigorous policy regarding articles published in the category of a systematic review with reference to methodologies, otherwise they may mislead the evidence with its poor results. To enhance the level of evidence in this field, well-designed and effective RCTs are needed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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[PUBMED]  [Full text]  
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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]


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