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 Table of Contents  
Year : 2022  |  Volume : 14  |  Issue : 1  |  Page : 71-79

Nonfluoride remineralizing agent for caries prevention in children: A systematic review and meta-analysis

1 Department of Pediatric and Preventive Dentistry, Vinayaka Mission's Sankarachariyar Dental College, Vinayaka Mission's Research Foundation (Deemed to be University), Salem, India
2 Department of Oral Medicine and Radiology, AB Shetty Memorial Institute of Dental Sciences, Nitte (Deemed to be University), Mangalore, Karnataka, India
3 Department of Oral and Maxillofacial Surgery, RVS Dental College and Hospital, Coimbatore, Tamil Nadu, India
4 Department of Paediatrics and Preventive Dentistry, Coorg Institute of Dental Sciences, Kodagu, Karnataka, India

Date of Submission17-Apr-2021
Date of Acceptance10-Nov-2021
Date of Web Publication04-Jan-2022

Correspondence Address:
Sowndarya Gunasekaran
Vinayaka Mission's Sankarachariyar Dental College, Vinayaka Mission's Research Foundation (Deemed to be University), NH 47 Sankari Main Road, Ariyanoor, Salem - 636 308, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jorr.jorr_41_20

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Background: The recent outburst of nonfluoride remineralizing agents suggests that it may serve as alternative and as an adjunct for fluoride in preventing, arresting, or even reversing dental caries. Aim: This study aims to assess the caries prevention potential of a variety of nonfluoride agents in children, with an efficient and extended literature database search. Materials and Methods: Electronic (MEDLINE, PubMed, and The Cochrane Library) and manual searches were conducted for relevant studies published till March 2020. Randomized control trials (RCTs) that investigated the effect of nonfluoride remineralizing agents such as casein phosphopeptide-amorphous calcium phosphate (ACP), ACP, arginine, probiotic, xylitol, chlorhexidine, and nanoparticles in remineralization and prevention of dental caries were assessed. Results: Twelve studies met the criteria. There were 2653 patients in the test group and 2596 in the control group. Participants using nonfluoride agents were more likely to experience a reduction in dental caries compared to control ([standardized mean difference {SMD}] −0.55 [−1.06, 0.04], 95% confidence interval [CI], I2 = 98%), but there was substantial heterogeneity (98%) across studies. Moreover, an overall statistically insignificant benefit of Non-fluoride agent was detected (SMD −0.55 [−1.06, 0.04], 95% CI, I2 = 98% P < 0.00001). Conclusion: High-quality RCTs on the preventive effect of nonfluoride agents in children are still important to make a conclusive recommendation.

Keywords: Amorphous calcium phosphate-casein phosphopeptide, bioglass, chlorhexidine, pediatric dentistry, remineralization

How to cite this article:
Gunasekaran S, Sakthivel S, Nainan PI, Shanthala B M. Nonfluoride remineralizing agent for caries prevention in children: A systematic review and meta-analysis. J Oral Res Rev 2022;14:71-9

How to cite this URL:
Gunasekaran S, Sakthivel S, Nainan PI, Shanthala B M. Nonfluoride remineralizing agent for caries prevention in children: A systematic review and meta-analysis. J Oral Res Rev [serial online] 2022 [cited 2023 Jan 27];14:71-9. Available from: https://www.jorr.org/text.asp?2022/14/1/71/334831

  Introduction Top

Dental caries is one of the most common chronic infectious diseases found in children worldwide and if left untreated it progresses expeditiously. It has been escalating in many countries and has become a significant health problem, especially in socially disadvantaged populations.[1] Ideal improvement of oral status in children necessitates a timely and resourceful effort to be implemented by the pedodontist, the child, and parents. Caries is a debilitating condition of the micro and macrostructure of the tooth which in its initial stages is reversible, and essentially it can be prevented with due care.

Higher dental caries prevalence in children can be attributed to increased consumption of sugary substances and acidic beverages in their diet.[2] The progression of carious lesions has been considered as a vicious cycle of de-/re-mineralization, which can be arrested or reversed by preventive factors[3] like fluoride and nonfluoride agents, such as casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), ACP, arginine, probiotic, xylitol, chlorhexidine and nanoparticles, which has demonstrated anti-caries effects in a huge number of in vivo and in vitro studies.[4],[5],[6],[7],[8] Through the numerous studies on topical fluoride agents, especially systematic reviews, the benefits of using fluoride and its cariostatic effects is well documented.[9],[10],[11] Fluoride application should be carefully monitored and administered, as excessive use can lead to adverse effects like fluorosis.[12] Nonfluoride agents can enhance or complement the remineralizing effect of fluorides as evidenced by numerous clinical trials, though studies on its safety and clinical utilization are still in progress. There are three earlier systematic reviews, among which two evaluated the potency of a solitary product for arresting caries in adults and children, and one assessed effect of caries prevention only in primary dentition.[13],[14],[15] The systematic review was aimed to gauge the anti-caries action of a numerous nonfluoride agents in children, with an efficient and extended literature research database (July 2020).

  Materials And Methods Top

Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols [Supplementary Table 1] guidelines were applied to perform this meta-analysis.[16] A nonregistered protocol was prepared to precede the literature search, using the PICOS[17] strategy as follows: population (P): children (0–15 years).

Intervention (I): Nonfluoride remineralizing agents such as CPP-ACP, ACP, arginine, probiotic, xylitol, chlorhexidine, and nanoparticles.

Comparison (C): Fluoride and/or placebos.

Outcome (O): Clinical assessment of white spot lesion size, clinical assessment with International Caries Detection and Assessment System (ICDAS) criteria, defs/Decayed, Missing, Filled Teeth (DMFT) score and salivary MS level.

Study design (S): in vivo randomized control trials (RCTs).

Eligibility criteria

The inclusion criteria were in vivo RCTs that investigated the effect of nonfluoride remineralizing agent such as CPP-ACP, ACP, arginine, probiotic, xylitol, chlorhexidine, and Nanoparticles in remineralization and prevention of dental caries and exclusion criteria were review articles, in vitro studies, animal studies and study conducted in older adults. Research papers not in English were excluded from the study.

Search strategy

The authors performed an extensive bibliographic search using Wiley, Google Scholar, Web of Science (core collection), PubMed, and Scopus databases to identify relevant full-text articles of English language published within March 2020, having zero constraints to the starting year. Grey literature and Hand research of reference areas identifiable to the individual study did not yield subsequent articles. According to the PICOS[17] questionnaire, keywords were utilized for researching all identified databases, divided by the Boolean operator OR, and later combined by the Boolean operator AND. A conventional search performed in PubMed using PICOS strategy is as follows:

(“CPP-ACP” “casein phosphopeptide-amorphous calcium phosphate” “nonfluorine remineralizing agent¨ [All Fields] AND “caries prevention” AND “children” [All Fields]) OR (“Arginine” “nonfluorine remineralizing agent¨ [All Fields] AND “caries prevention” AND “children” [All Fields]) OR (“Probiotics” “nonfluorine remineralizing agent¨ [All Fields] AND “caries prevention” AND “children” [All Fields]) OR (“Xylitol” “nonfluorine remineralizing agent¨ [All Fields] AND “caries prevention” AND “children” [All Fields]) OR (“Chlorhexidine” “nonfluorine remineralizing agent¨ [All Fields] AND “caries prevention” AND “children” [All Fields]) OR (“Nanoparticles” “nonfluorine remineralizing agent¨ [All Fields] AND “caries prevention” AND “children” [All Fields]). An almost identical plan was exercised to execute a precise document search in other databases.

Data management, screening, and selection

The authors (GS and SS) independently screened only titles and abstracts. After eliminating identical and unrelated articles, full-length articles were inspected. To incorporate the article in the final review the approval of all the authors was appraised. Any dispute concerning inclusion and exclusion criteria was collectively rectified with final decision from the third author (BMS). All authors collectively determined the data extraction strategy. The authors categorized the information based on number and age of participants, author/year of publication, follow-up period and assessment methods, and details of interventions and controls. The extracted data were systematically tabulated with Microsoft Excel 2019 version. If missing data was noted, the authors were contacted. Any extra information linked to the outcomes noted in the articles was segregated solely for descriptive review and not for meta-analysis since it did not account for the study objective.

Assessment of risk of bias

The Cochrane Handbook for Systematic Reviews for Interventions 5.1.0[18] was used to assess the risk of bias of every retrieved study included. The assessment tool included blinding of assessment, random sequence generation, selective reporting, incomplete outcome data, allocation concealment, and other plausible origins of bias to estimate the methodological constitution of studies included. Within every study, bias was sub-divided as “low risk of bias,” “high risk of bias” as well as “unclear risk of bias.” Cochrane Review Manager Version 5.4 (Cochrane library) was used to generate risks of bias Figures.

Data analysis

The basis for meta-analysis was from the published standard mean (SM) for the intervention corresponding to 95% confidence interval CI.[19] Statistical data, namely SM difference (SMD) have no innate clinical interpretation, so SM was utilized to assimilate the values for the synthesis and analysis. Heterogeneity of study-specific effects was assessed using Chi-square homogeneity test[20] (v2) and I2 statistics based on Review Manager (RevMan) Version 5.4. Due to the heterogeneity observed, we performed meta-analyses using a random-effects model and Forest plots were created with a 95% CI (Z test).

  Results Top

Data selection

[Figure 1] depicts the preference summary of the articles included in the review. The initial database research culminated in 1609 studies, including 847 studies that were identical. 695 other research data that failed to satisfy the inclusion criteria have been abandoned. The remaining 67 studies were screened and 44 studies were examined using full texts, and another 32 articles were excluded, which did not conform with the inclusion norms - 7 Review articles, 8 studies Focused on microorganism, in 3 studies Intervention was in mother, 9 studies had in vitro human specimen, 5 studies were not RCT. After risk assessment 12 studies were retained for both qualitative and quantitative analysis.
Figure 1: PRISMA flow chart of study selection

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Risk of bias

Outcome of the analysis of methodological quality is shown in [Figure 2]a and [Figure 2]b. The judgments concerning all risk of bias data noted for each included research data have been presented within [Figure 2]a. [Figure 2]b displays our discernment regarding all risk of bias research data, displayed as percentages covering all included research. Allocation concealment of most of the studies were low risk except few studies[21],[22],[23],[24] which did not describe the allocation concealment had marked as unclear risk. Each and every included research data had low risks of bias under random sequencing. However, two studies were deemed to be “unclear risk of bias.”[21],[24] Many studies had only partial result data, due to the lack of follow-up information.[22],[23],[24],[25],[26],[27],[28],[29] Since the amount of high risk of bias happened to be minuscule, the results wouldn't critically weaken in credence. Only one study[30] had high risk of bias in blinding of participants and the two[26],[28] had unclear risks of bias, rest all had low risk of bias. Overall, the included studies had small proportion of high risk of bias.
Figure 2: (a) Risk of bias summary and (b) risk of bias graph

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Characteristics of the included studies [Table 1]
Table 1: Study characteristics of the included studies

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Additional attributes of the features of all the 12 articles that were represented are depicted in [Table 1]. The following studies were chosen from publication years, beginning 2007 and up to 2020. A total of 5249 individuals got included within the clinical research, for whom the age ranges start with 0 and till 15 years. The distribution methods of the contents included under the systematic review were gel, sugarless mint confection, tablets, paste, wipes, varnish, and snacks. One article examined the potency of chlorhexidine for the avoidance of dental caries in deciduous dentition as opposed to other possible interventions.[22] Two studies published on the administration of topical arginine for the avoidance of caries.[31],[32] Another article studied the clinical outcome of 0.3% triclosan varnish for caries deterrence.[23] Four articles differentiated the outcome of daily administration of CPP-ACP for caries in children using placebo or fluoride varnish.[26],[27],[29],[30] Four articles published the anti-caries outcome of xylitol used in the form of snacks, tablets and wipes on dental caries advancement in children.[22],[24],[25],[28] Various quantitative measurements were used to detect the caries prevention and remineralization of nonfluoride agents. Quantitative measurements used were light-induced fluorescence (QLF), Clinical assessment with DMFT and Decayed, Missing, Filled Surface scores, change in mean WSL size using the DIAGNOdent device, Salivary MS level.


Heterogeneity of studies was assessed by visual inspection of forest plot [Figure 3], Chi-square homogeneity test (v2) and Higgins index (I2). A random effects model was used in the presence of heterogeneity (v2) with significance level < 0.10 and I2 >50%.
Figure 3: Forest plot for comparison between non-fluoride agents and control

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The trials selected had inconsistency in reporting the caries prevention. Heterogeneity in trials complicated the attempt to perform quantitative analysis. However, pooling of methodologically homogenous data revealed a probing depth to be comparable between nonfluoride and control. Overall, in 12 pooled studies involving 5249 children, participants using nonfluoride agents were more likely to experience a reduction in dental caries compared to control ([standardized mean difference {SMD}] −0.55 [−1.06, 0.04], 95% CI, I2 = 98%), but there was substantial heterogeneity (98%) across studies. Moreover, an overall statistically insignificant benefit of nonfluoride agent was detected (SMD −0.55 [−1.06, 0.04], 95% CI, I2 = 98% P < 0.00001).

  Discussion Top

In this systematic review, nonfluoride agents such as arginine, chlorhexidine, CPP-ACP, triclosan, xylitol were compared against either placebo or fluoride, in the prevention of dental caries in children of age 0–15 years. In the 12 studies included studies, assessment of caries prevention was different, so a random effect meta-analysis was done. Of the 12 studies, 4 studies were conducted on Xylitol,[21],[23],[25],[28] 4 studies on CPP-ACP,[26],[27],[29],[30] 2 studies on arginine,[31],[32] 1 each on chlorhexidine[22] and triclosan.[23] The existing evidences from studies is not enough to affirm that the utilization of these nonfluoride vehicles is of higher potency as opposed to a fluoride or placebo in avoiding caries in children, since in few studies, no treatment was given to the control group. The commonly repetitive risks of bias noted were detection bias and attrition bias. All subsequent studies need to incorporate a parallel group design that assimilates the utilization of blinding, randomization, as also the allocation privacy techniques. Also an Additional issue is concerning few of the articles within the review which did not showcase data regarding adverse after effects.[21],[22],[24],[25],[28] To illustrate, xylitol is known to elicit side effects such as diarrhea, bloating and flatulence;[14] chlorhexidine often creates discoloration on the tongue and teeth, desquamation and mucosal soreness, hypersensitivity, temporary taste disturbances, and parotid gland swelling.[33],[34] Hence, safety evaluations must be considered as an indispensable segment of a well-structured clinical study.

Triclosan inclusive commodities have been noted for giving exemplary advantages in controlling caries in earlier articles.[35],[36] A RCT studying 0.3% triclosan vanish,[23] which includes triclosan, and has also been incorporated into a varnish, seemed to be potent in decreasing dental caries inception and advancement in children, has been noted in this review. Nevertheless, the sole article in this analysis to satisfy the inclusion and exclusion criteria was this. Hence, well-structured clinical research is still needed to give sufficient proof on the outcomes of triclosan on caries prevention in children.

Fluoride is commonly known to aid remineralization, but the application of only fluoride has been noted to be subpar in intercepting advanced mineral loss.[37] Being a cationic bis-biguanide with a wide range of antibacterial action, chlorhexidine is well identified as a chemical agent effective against Streptococcus mutans, which has a huge part in caries.[13] numerous clinical studies and in vitro study data have showcased that joint therapy using fluoride and chlorhexidine is potent in dental caries cessation.[38],[39],[40],[41],[42] Yet, the collaborative results for fluoride and chlorhexidine is even now hazy.[22] Although this collaborative result comparing chlorhexidine with fluoride was not reinforced by any clinical studies,[43] only in one study,[44] caries occurrence rate was reported to be low after the use of chlorhexidine.

Over time, arginine got added as an ingredient to toothpastes as well as in fluoridating agents. Though previously advertised for use in the care of sensitivity of teeth, arginine is currently known as an agent for dental caries prevention.[45] Products which contain Arginine are identified for giving monumental advantages in controlling caries in children as per earlier research.[46],[47] Under this review two studies[31],[32] scrutinizing arginine as an intervention were compared with fluoride, and it was comparable with fluoride for caries prevention.

CPP-ACP, a nanocomplex derived from milk, can promote enamel remineralization in depth.[48] To complement their high safety level, anticariogenic prospect of CPP-ACP has been showcased in labs and also in human in situ studies.[49],[50],[51] Finally, the benefits of CPP-ACP are upmost tooth material preservation and outstanding utilization by children.[52] Biological remediation effects of CPP-ACP on caries lesion in children was assessed by QLF,[26],[27] Change in mean WSL size using the DIAGNOdent[29] and clinical assessment of size of white spot lesion.[30] Outcomes showed an impressive enhancement in WSLs retrogression while evaluating with QLF by utilizing CPP-ACP[26],[31] and DIAGNOdent.[29] CPP-ACP on caries lesion in children were shown to reduced when clinically assessed.[30] It was also published that CPP-ACP's effectiveness in reconstituting the enamel microstructure via remarkably enlarged hydroxyapatite crystals and increased molar ratios of calcium/phosphorus. The outcome is in concurrence with an earlier article, that specified an extended duration of remineralization effect on carious lesions by CPP-ACP.[53] The benefit of utilizing CPP-ACP instead of fluoride as an agent, is even currently enigmatic. For examining the outcome of remineralization through an increasingly detailed method, continued research on CPP-ACP, specifically in collaboration with recent detection indexes via clinical means is deemed essential. Bearing in mind the benefits of using CPP-ACP instead of conventional fluoride, the ensuing differentiations comparing CPP-ACP and fluoride agents, is inevitable at best.

Xylitol is a naturally occurring five-carbon sugar alcohol[54] and noncariogenic sweetener, the cariostatic effect of xylitol has been investigated in several clinical studies.[6],[55] Its anti-caries outcome is still debatable, the sole cause for this is probably the dose-effect interconnection. For clinical benefits, a notable exposure of minimum 4 g xylitol/day is compulsory.[56],[57] Minimal strength of 0.5–1 g/tablet xylitol dose, that was utilized in an article,[58] was insufficient to protect from caries. Auxiliary causes for insufficient output data are due to sample sizes being constrained. The article which examined the results of xylitol-containing wipes observed that per diem utilization of 4.2 g/day of xylitol is beneficial in preventing dental caries in children,[25] although the sample size was 20 or lesser for every group, therefore, the verdict needs to be viewed with restrain. The chewing gums method of administering xylitol was noted to be beneficial although other methods could be equally effective; though, studies say that high sucrose consumption at 3 years of age magnifies the probability of higher MS count and also magnifies caries occurrence between 3 and 16 years.[59] The benefits of giving nonfluoride agents like topical toothpaste every day, probably influences compliance of patients, mostly in children, especially those with comparatively reduced compliance as opposed to adults.[60]

The assessment methods are essential in the diagnosis of injuries but should also be applied in the monitoring of injury therapies. Therefore, it is essential that these methods are standardized. Clinical visual assessment and through photographs is the most often-used method due to its easy handling and access. However, due to qualitative and therefore subjective assessment, this methodology should be standardized so it can be reproducible. Whenever possible this evaluation should be done by quantitative methodology, such as DIAGNOdent®[61],[62] and QLF.[63],[64] An alternative noninvasive imaging method is optical coherence tomography, which builds cross-sectional images with high-resolution, of our internal organs.[65] In studies, evaluation of lesions is also crucial to standardize the diagnosis using the same scales, such as ICDAS.[65] Only conventional means of identifying and observing caries was utilized within the articles involved in this review. There are possible advantages if future studies utilize a coalition of conventional and electronic diagnosis techniques to study the commencement, development, and also the reversal of caries.[66]

  Conclusion Top

Chlorhexidine gel 0.12% and 0.3% varnish of triclosan were noted to decrease caries progression in children though the verification was limited. An article at reduced risk of bias showed that per diem utilization of Arginine is an advantageous supplement along with fluoride for dental caries control in children. Xylitol can be used for caries prevention in children, but this conclusion should be interpreted with caution as the adverse effects were not explained in the included studies. CPP-ACP may be more effective than placebo in managing caries in primary dentition, but their efficacy relative to fluoride is still unclear Nevertheless, those studies are not of high quality considering the number of biases. High-value RCTs on the protective power of nonfluoride products in children, is to date, highly essential in making a conclusive recommendation.

Why this paper is important to pediatric dentists

  • In view of changes in dietary habits and way of life there is an alarming increase in dentin erosion, dental caries, and other factors which affect the health of dental tissues of children from a very young age, With these alternate remineralization techniques, pediatric dentist will be able to re-establish the oral health of children without being under the risk of fluoride toxicity if ingested at high levels
  • This review suggests researchers to perform more randomized control on other remineralizing agents such as chlorhexidine, triclosan, bioactive glass, and nano-hydroxyapatite
  • The use of both the traditional and electronic diagnosis methods to investigate the initiation, progression, and reversal of dental caries is recommended such that while analyzing the combined results can be standardized to produce a conclusive recommendation.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]


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