| Abstract|| |
Background: Although fluoride enables remineralization, presence of calcium and phosphate ions is necessary to promote the process. So, various nonfluoridated remineralizing agents have been emerging to treat the noncavitated carious lesions. Aim: The aim of this systematic review was to assess the clinical effectiveness of nonfluoridated remineralizing agents on initial enamel carious lesions. Methods: Seven electronic databases were searched using the key words. In total, 158 human clinical trials were retrieved in the search from January 1950 to October 2016. Seventy-one repeated articles were excluded. Among the 87 articles obtained, 53 articles were eliminated after reading the title and abstracts. After assessing the full text, 28 articles were excluded. Three more studies were included from the cross references of the articles chosen. Results: All the nine trials included assessed the clinical effectiveness of casein phosphopeptide amorphous calcium phosphate (CPP ACP). They showed a positive effect of CPP ACP on the remineralization of white spot lesions. Conclusion: The use of CPP ACP resulted in significant reduction of the white spot lesion size measured using visual examination methods. This systematic review indicated a lack of reliable evidence supporting the clinical effectiveness of other commercially available nonfluoridated remineralizing agents.
Keywords: Casein phosphopeptide amorphous calcium phosphate, enamel carious lesion, nonfluoridated agents, remineralisation
|How to cite this article:|
Asokan S, Geethapriya P R, Vijayasankari V. Effect of nonfluoridated remineralizing agents on initial enamel carious lesions: A systematic review. Indian J Dent Res 2019;30:282-90
|How to cite this URL:|
Asokan S, Geethapriya P R, Vijayasankari V. Effect of nonfluoridated remineralizing agents on initial enamel carious lesions: A systematic review. Indian J Dent Res [serial online] 2019 [cited 2019 Aug 23];30:282-90. Available from: http://www.ijdr.in/text.asp?2019/30/2/282/259215
| Introduction|| |
Dental caries remains the major public health problem in most countries. It is one of the most common and preventable diseases of childhood. The initial carious lesions or “white spot” lesions implies that there is a subsurface area with most of the mineral loss beneath a relatively intact enamel surface and are capable of being reversible.,
White spot lesions detected in the initial stages can be reversible with good oral hygiene practices and topical fluoride application. Untreated white spot lesions have to be treated by conventional restorative treatment. However, this technique has the disadvantage of being invasive. The goal of modern dentistry is to manage noncavitated carious lesions noninvasively through remineralization in an attempt to prevent disease progression and to improve strength, esthetics, and function of teeth. Early diagnosis of incipient lesions can lead to new era in preventive dentistry in the form of remineralization. If salivary or plaque calcium, phosphate ions, and fluoride ions are present in adequate amounts, they can also promote the remineralization of previously demineralized enamel.
Effective efforts to prevent caries and noninvasive treatment of initial caries lesions in young children are needed. Presently, various remineralizing agents, such as fluoride, calcium phosphate-based systems, calcium sodium phosphosilicate, and nanohydroxyapatite, are available commercially. Fluoride is widely accepted as the most effective tool for caries prevention. Although fluoride enables enamel remineralization, the presence of calcium and phosphate ions in the supragingival plaque is also necessary to promote the process. This can be achieved through use of various nonfluoridated remineralizing agents. Thus, the purpose of this study is to review systematically the effect of nonfluoridated remineralizing agents on initial enamel carious lesions.
| Methods|| |
Cochrane Oral Health Group's Handbook for Systematic Review of Interventions was used to prepare this systematic review.
All the studies published from January 1950 to October 2016 were searched by two authors independently for this review. The following search strings were used in databases like PUBMED, MEDLINE, IndMED, Cochrane, EMBASE, and Google scholar:
(((((initial enamel carious lesion) OR incipient caries) OR white spot lesions) OR early enamel lesions) AND remineralization) AND non-fluoridated remineralising agents
((((((initial enamel carious lesion) OR incipient caries) OR white spot lesions) OR early enamel lesions) AND remineralization) AND non-fluoridated remineralising agents) AND casein phosphopeptide amorphous calcium phosphate
((((((initial enamel carious lesion) OR incipient caries) OR white spot lesions) OR early enamel lesions) AND remineralization) AND non-fluoridated remineralising agents) AND CPP ACP
((((((initial enamel carious lesion) OR incipient caries) OR white spot lesions) OR early enamel lesions) AND remineralization) OR non-fluoridated remineralising agents) AND casein derivatives
((((((initial enamel carious lesion) OR incipient caries) OR white spot lesions) OR early enamel lesions) AND remineralization) OR non-fluoridated remineralising agents) AND amorphous calcium phosphate
((((((initial enamel carious lesion) OR incipient caries) OR white spot lesions) OR early enamel lesions) AND remineralization) OR non-fluoridated remineralising agents) AND Bioactive glass
((((((initial enamel carious lesion) OR incipient caries) OR white spot lesions) OR early enamel lesions) AND remineralization) OR non-fluoridated remineralising agents) AND Sodium calcium phosphosilicate
((((((initial enamel carious lesion) OR incipient caries) OR white spot lesions) OR early enamel lesions) AND remineralization) OR non-fluoridated remineralising agents) AND calcium carbonate carrier
((((((initial enamel carious lesion) OR incipient caries) OR white spot lesions) OR early enamel lesions) AND remineralization) OR non fluoridated remineralising agents) AND Xylitol
((((((initial enamel carious lesion) OR incipient caries) OR white spot lesions) OR early enamel lesions) AND remineralization) OR non-fluoridated remineralising agents) AND Tricalcium phosphate
((((((initial enamel carious lesion) OR incipient caries) OR white spot lesions) OR early enamel lesions) AND remineralization) AND non-fluoridated remineralizing agents) AND Dicalcium phosphate dehydrate
Gray literature search and manual search was also carried out to collect articles for this systematic review.
Criteria for article selection
Only human clinical trials were included in this systematic review. All the trials included i) tested the effectiveness of nonfluoridated remineralizing agents, ii) involved participants in the age group of ≤18 years, iii) consisted of a control group, and iv) was published in English language. In situ studies, in vitro studies, case series, case reports, studies on children undergoing fixed orthodontic therapy or children with special needs, and studies involving participants aged >18 years were excluded. The results of in situ and in vitro studies cannot be extrapolated to clinical effectiveness of the remineralizing agents and hence were excluded from this systematic review. Since children with special healthcare needs are at an increased risk for several chronic conditions, studies involving these children were not included.
Data extraction and quality appraisal
All the titles, abstracts, and full texts were analyzed independently by two authors. Disagreement between the two authors was resolved by the third author. Each study's methodological quality was assessed by using Cochrane Risk of Bias Tool (Modified) for Quality Assessment of Randomized Controlled Trials. The quality of the study was assessed under seven domains as “yes” (low risk of bias), “unclear” (uncertain risk of bias), or “no” (high risk of bias). The seven domains included were i) sequence generation, ii) allocation concealment, iii) blinding of participants and personnel, iv) blinding of outcome assessors, v) incomplete outcome data, vi) selective outcome reporting, and vii) other sources of bias. The level of risk for each study was then charted. “Yes” in all domains placed a study in the “Low Risk of Bias” category. “No” in any of the domains placed a study in the “High Risk of Bias” category. “Unclear” in any of the domains placed the study in the “Unclear Risk of Bias” category.
| Results|| |
The results of the search strategy are shown in flowchart [Figure 1]. The electronic and hand searches retrieved a total of 158 articles after applying limits (human and clinical trials). Seventy-one repeated articles were excluded. The 87 articles obtained were then screened and 53 articles were eliminated after reading the title and abstracts. After assessing the full articles for inclusion criteria, 28 articles were excluded for the following reasons: i) age criteria not matched, ii) age group not mentioned, iii)in vitro studies, iv) in situ studies, and v) assessed dentin remineralization. The search was further extended by searching the cross reference articles in the databases and three more studies were retrieved. After the final scrutiny, nine studies were included in this systematic review and were subjected to data collection. No articles were obtained from the search in unpublished literature. The results of the included articles are summarized in [Table 1].
All the nine studies included evaluated the effect of casein phosphopeptide amorphous calcium phosphate (CPP ACP). Seven studies used commercially available 10% CPP ACP (GC Tooth Mousse, Japan),,,,,,, one study used CPP ACP cream (Topacal C-5 Nulite Systems International, Australia) and one study used custom-made 2% CPP ACP. However, there was no study comparing the effect of 10% and 2% CPP ACP. Commercially available fluoride toothpaste,,,, fluoride mouth rinse, fluoride varnish, and placebo toothpaste,, were used as the control group.
Four studies evaluated the effectiveness of CPP ACP on postorthodontic white spot lesions.,,, Andersson et al. compared the effect of CPP ACP and 0.05% sodium fluoride mouthwash by visual scoring and laser fluorescence (Diagnodent). There was a significant improvement in the clinical white spot lesion scores over a period of 12 months in both groups (P < 0.01). More sites become invisible in CPP ACP group (63% vs. 25%). However, there was no significant difference between the two groups when assessed by laser fluorescence. Bailey et al. compared the effect of 10% CPP ACP paste with placebo paste by visual inspection using International Caries Detection and Assessment System II index criteria (ICDAS II). At the end of treatment period of 12 weeks (OR 2.33, P = 0.04), CPP ACP group showed more regression of white spot lesions (31%) compared with the placebo group. Bröchner et al. compared the effect of 10% CPP ACP and fluoride paste (1,100 ppm F) using quantitative light-induced fluorescence (QLF) and visual index. Both the treatment resulted in significant improvement in change of fluorescence and visual scores (52.3% and 47.3%) compared with base line (84.6% and 85.1%). But, there was no significant difference between groups. Akin and Basciftci assessed the effect of CPP ACP with 0.025% sodium fluoride mouth rinse and microabrasion (18% HCl), using computer-assisted image analysis of photographic records. They found that area of white spot lesions decreased significantly in all groups (P < 0.001). Microabrasion showed the highest success rate of 97% (P < 0.001), whereas CPP ACP showed success rate of 58% (P < 0.05).
Two studies, used the laser fluorescence (Diagnodent) for evaluating the effect of CPP ACP for 3 months. Aykut-Yetkiner et al. compared CPP ACP with fluoride paste (1,450 ppm) and stated there was no statistically significant difference between the groups. There was a decrease in the baseline versus 3-month Diagnodent measurements in the CPP ACP group, but this was not statistically significant. Llena et al. compared CPP ACP and CPP ACFP (990 ppm sodium fluoride) with 5% sodium fluoride varnish. They reported that all groups showed significant difference (P < 0.01) from baseline over a period of 12 weeks. The CPP ACFP group showed highly statistically significant difference (P < 0.001).
Rao et al. used visual indices, DMFS/OHI index to compare the effect of 2% CPP ACP with fluoride (0.76% sodium mono fluoro phosphate, SMFP), and placebo paste for 24 months. The number of new caries lesion increased in all three groups from baseline (P < 0.001), which was significantly smaller in CPP ACP group and SMFP group than placebo group. There was no significant difference between CPP ACP and SMFP group.
Sitthisettapong et al. and Memarpour et al. assessed the effect of CPP ACP on primary dentition for a period of 12 months., Sitthisettapong et al. used visual scoring (ICDAS II criteria) to analyze the effect of CPP ACP on high caries preschool children. They found that mean number of caries outcome measure was increased in both the groups from baseline to 12 months and it was statistically significant (P < 0.001). However, differences between the groups were not statistically significant. Memarpour et al. analyzed the effect of CPP ACP using scored dental probe and dmft index. They reported that CPP ACP (63%) and fluoride varnish (51%) showed decrease in size of the white spot lesions (P < 0.001). The smallest increase in dmft index was evident in CPP ACP group (0.17) followed by fluoride varnish (0.3). However, there was no significant difference between the groups.
The results of the quality analysis are described in [Table 2]. Among the nine studies, only three studies,, were found to have low risk of bias. Information about randomization and blinding of participants and personnel were not reported in four studies.,,, Data on loss of participants and blinding of outcome assessors were not clear in two studies.,
| Discussion|| |
This review assessed the clinical effectiveness of nonfluoridated remineralizing agents on initial enamel carious lesions in children and adolescents up to 18 years of age. All the studies included assessed the effectiveness of CPP ACP with the interventional period varying from 1 to 24 months. Clinically, visible changes in the white spot lesions in remineralization therapy will be detectable only when the interventional periods are >3 months. Among the studies included, only five studies had interventional period >3 months.,,,,
The failure to detect the caries at the early stage and detecting caries at cavitated stage has resulted in poor results and outcomes for remineralization therapies. Visual examination based on the amount of hardness and color of the decayed area is the best tool to diagnose small size caries. But, this kind of examination has low sensitivity. Hence, noninvasive detection methods have been developed to quantitatively measure the caries lesions. The newer methods to detect lesions at an initial stage and subsequently monitor lesion changes over time during which preventive measures could be introduced. Diagnodent and QLF are sensitive techniques that can be used to quantitatively assess the white spot lesions. Diagnodent reading cannot be extrapolated to the clinical setting because of the confounders, such as plaque, stains, and calculus, which tend to give false-positive results. Though QLF is considered as reproducible and valid technique, it can also be influenced by the confounding factors resulting in the images similar to dental demineralization. Since both the gadgets have their own limitations, combined use of both technology-based methods and visual assessment could be the best approach in future studies.
Four studies assessed the remineralization efficacy only through visual examination methods. Two trials used ICDAS II scoring system, an effective assessment tool for caries in both the primary dentition and permanent dentition. Sitthishsettapong et al. did not detect any significant effect on enamel carious lesions. Bailey et al. found that CPP ACP had a significantly greater chance of regressing white spot lesions with severity code of 2 and 3. Rao et al. and Mermapour et al. analyzed the effect using indices (dmft index and scored dental probe, OHI score). Results obtained from the visual assessment methods have been found to be highly specific. But, the limitations of this method include low sensitivity, low reproducibility, and the subjective interpretation of the results.
Among the included studies, four studies assessed only through technology-based methods. Aykut-Yetkiner et al. and Llena et al. assessed the remineralization effect using Diagnodent, which showed statistically significant effect. This Diagnodent result might not necessarily have clinical significance., Akin and Basciftci compared the pre- and postoperative digital photographs through image-processing software to quantify the size (in mm2) of the visible areas of the demineralised lesions. They concluded that both CPP ACP and fluoride controls showed significant effect in reduction in size of the lesion. Photographs are more versatile than visual examination. But, it might tend to overestimate the incidence of opacities and standardization of the procedures may be difficult.
Bröchner et al. measured the outcome using QLF and visual scores from digital photographs. They concluded that both the treatment resulted in significant improvement. The intervention group had a higher attrition rate than the control group. The main reason for exclusion was the relatively high number of the QLF images that had to be omitted due to technical errors like ambient light, dark, or not sharp images and angulation errors.
Andersson et al. assessed the effect of remineralizing agents using both visual and LF-based methods. They concluded that both the clinical scoring and LF assessment suggested that both regimens (CPP ACP and sodium fluoride mouth wash) could promote regression of white spot lesions. However, visual evaluation suggested an esthetically more favorable outcome in the CPP ACP treatment group.
Llena et al. and Bailey et al. reported significant difference in the effectiveness of the groups studied. The former assessed the effect of casein phosphopeptide amorphous calcium fluoride phosphate (CPP ACFP) and showed rapid remineralization with greater decline in carious lesion in a short interventional period. The latter found a significant difference in the effect of CPP ACP over placebo paste on white spot lesions. All the other studies did not get significant results compared with the control group.
Besides CPP ACP, various in vitro and in situ studies have been identified that evaluated the remineralizing efficacy of other nonfluoridated remineralizing agents such as bioactive glass,,,, and nanohydroxyapatite. But, there were no studies assessing their clinical effectiveness, and hence, further in vivo studies have to be carried out to prove their remineralization potential in clinical settings.
| Conclusion|| |
All the studies included in this review assessed the remineralization effect of CPP ACP only. High-quality randomized controlled trials with low risk of bias with combinations of visual and technology-based assessment methods are required.
The following conclusions can be inferred from this systematic review:
- There was a significant reduction in the QLF scores of white spot lesion (WSL) after a minimal use of CPP ACP for a period of 4 weeks. Use of CPP ACP for a period of 4 months and 1 year showed a decrease in the size of WSL and reduction in mean dmft scores. Use of CPP ACP for 2 years showed the least increment in caries compared with fluoridated toothpaste.
- Based on articles with low risk of bias, use of CPP ACP resulted in significant reduction of the WSL lesion size measured using visual examination methods and indices.
- This systematic review indicated a lack of reliable evidence supporting the clinical effectiveness of other commercially available nonfluoridated remineralizing agents like bioactive glass and nanohydroxyapatite crystals.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Dr. Sharath Asokan
Department of Pedodontics and Preventive Dentistry, KSR Institute of Dental Science and Research, Tiruchengode - 637 215, Tamil Nadu
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2]