| Abstract|| |
Objective: The aim of this systematic review was to assess the long term remineralizing potential of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) only in paste form compared with fluoride varnish, and or placebo in both naturally occurring and post-orthodontic white spot lesions in vivo. Data Sources: The literature search covered the electronic databases: PubMed and Google scholar from 2005-2016. Only articles published in English were included. Randomized control trials in which CPP-ACP delivered by paste form were included. All studies which met inclusion criteria underwent two independent reviews. Study Selection: Two ninety five articles were identified from the search after excluding duplications. Abstracts of forty one articles were reviewed independently. Twenty nine articles were excluded after reading abstract. Full text articles were retrieved for fifteen relevant studies. After reviewing articles independently, three articles were excluded after full text reading. Finally twelve studies were selected based on the eligibility criteria. The remineralizing effect of CPP-ACP were compared with placebo and fluoridated toothpaste and fluoride varnish in randomized control trial. Conclusion: A high level evidence of remineralizing potential of CPP-ACP on naturally occurring white spot lesion and WSL post orthodontic treatment was found in comparison with placebo/fluoridated toothpaste and fluoride varnish without any statistically significant difference. Well-designed RCTs are, therefore, required to improve the level of evidence in this area.
Keywords: Casein phosphopeptide-amorphous calcium phosphate, early enamel caries, postorthodontic white spot lesions, remineralization, systematic review, white spot lesion
|How to cite this article:|
Indrapriyadharshini K, Madan Kumar P D, Sharma K, Iyer K. Remineralizing potential of CPP-ACP in white spot lesions – A systematic review. Indian J Dent Res 2018;29:487-96
|How to cite this URL:|
Indrapriyadharshini K, Madan Kumar P D, Sharma K, Iyer K. Remineralizing potential of CPP-ACP in white spot lesions – A systematic review. Indian J Dent Res [serial online] 2018 [cited 2019 Jul 18];29:487-96. Available from: http://www.ijdr.in/text.asp?2018/29/4/487/239390
| Introduction|| |
Dental caries is a multifactorial disease; it is the result of complex interaction between host, agents, environment, and time. Dental caries is an infectious disease caused by acidogenic bacteria, leading to dissolution of enamel, dentin (coronal caries), cementum, and dentin (root caries). It is a common dental problem in the world and affects 60%–90% of children and the majority of adults. Worldwide contribution of dental caries to the burden of oral diseases is about 10 times higher than that of periodontal diseases and other common oral conditions. Owing to its globally high prevalence, dental caries is termed as a “pandemic” disease characterized by a high percentage of untreated carious cavities causing pain, discomfort, and functional limitations. Dental caries results in the dissolution of apatite crystals and the loss of calcium, phosphate, and other ions, which eventually leads to demineralization of the tooth substrate.
Enamel decalcification or the formation of white spot lesions (WSLs) is the first sign of dental caries, usually appearing as chalky white areas on the tooth surface. The subsurface porosity caused by demineralization gives the lesion a milky appearance that can be found on the smooth surfaces of teeth. The prevalence of (WSLs) related to orthodontic treatment ranges from 2% to 96%, and 24% of WSLs may change into cavitated lesions if left untreated. Enamel crystal dissolution begins with subsurface demineralization, creating pores between the enamel rods. The alteration of the enamel refractive index in the affected area of a carious WSL is a consequence of both surface roughness and loss of surface shine plus alteration of internal reflection, all resulting in visual enamel opacity because porous enamel scatters more light than sound enamel.
If suitable treatment is presented to these lesions, enamel caries is capable to arrest, reharden and revert to healthy enamel condition through a remineralization process involving the diffusion of minerals into the defective tooth structure. For this purpose, remineralizing agents such as fluorides, xylitol, bio-active glass, casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), tricalcium phosphate, and self-assembling peptides have been used. CPP-ACP application is one of the many techniques that have been proposed for simultaneously enhancing remineralization and reducing the occurrence of WSLs and dental caries.
The clinical use of calcium and phosphate ions for remineralization has not been successful in the past due to the low solubility of calcium phosphates, particularly in the presence of fluoride ions. Insoluble calcium phosphates are not easily applied and do not localize effectively at the tooth surface. In addition, acid is required to produce ions capable of diffusing into enamel subsurface lesions. In contrast, soluble calcium and phosphate ions can be used only at very low concentrations due to the intrinsic insoluble nature of the calcium phosphates. Hence, soluble calcium and phosphate ions do not substantially incorporate into dental plaque or localize at the tooth surface to produce effective concentration gradients to drive diffusion into the subsurface enamel.
To overcome these difficulties, a new calcium phosphate remineralization technology has been developed based on CPP-ACP, where CPP stabilizes high concentrations of calcium and phosphate ions, together with fluoride ions, at the tooth surface by binding to pellicle and plaque. The calcium phosphate-based remineralization technology has been shown as a promising adjunctive treatment to fluoride therapy in the management of early caries lesions. Casein phosphopeptide forms nanoclusters with amorphous calcium phosphate, thus providing a pool of calcium and phosphate which can maintain the supersaturation of saliva. Since CPP–ACP can stabilize calcium and phosphate in the solution, it can also help in the buffering of plaque pH and so calcium and phosphate level in plaque is increased. Therefore, calcium and phosphate concentration within the subsurface lesions is kept high which results in remineralization.
Systematic reviews in the past have assessed the naturally occurring WSL and postorthodontic WSLs separately. In addition, orthodontic appliances are known to impede oral hygiene, which may also affect the clinical efficacy of CPP-ACP on WSLs. The aim of this systematic review was to assess the long-term remineralizing potential of CPP-ACP only in paste form compared with fluoride varnish and or placebo in both naturally occurring and postorthodontic WSLs.
| Materials and Methods|| |
- Does CPP-ACP possess remineralizing potential in WSLs in vivo?
- PICO analysis
- Population: WSL
- Intervention: CPP-ACP (paste form)
- Comparison: Other oral regimens (fluoridated toothpaste, fluoride varnish, and placebo)
- Outcome: Whether there is significant increase in remineralization.
The eligibility criteria were set as: the review included studies from 2005 to 2016 concerning population of all groups. Only randomized control trials involving human population were considered. The studies assessing WSL due to postorthodontic treatment were also taken into consideration. Case reports, abstracts, editorials, review articles, and non-English articles were excluded from the study. Animal studies and in vitro study were not included in this study. Other formulations of CPP-ACP, such as sugar-free gums, lozenges, fluoridated gels, mouth rinse formulations, antibacterial gels are excluded from the study.
The literature search covered the electronic databases: PubMed and Google Scholar. To search databases, strings of search (MeSH) terms, consisting of relevant text words and Boolean links, were constructed. The string of English search terms: “Incipient caries lesion OR early enamel caries OR CPP-ACP OR Tooth mousse OR recaldent AND Fluoride varnish OR remineralization”. Our search strategy attempted to identify all trials that could be considered for possible inclusion in this review. The reference lists of all eligible studies were also hand searched for additional relevant studies.
Data collection and analysis
Two calibrated reviewers screened the titles and abstracts (when available) of all identified studies independently. Once the publication was considered by either author to meet the inclusion criteria, the full-text article was obtained and reviewed. Any disagreement during study selection and data extraction was solved by discussion and consensus after consulting a third reviewer. Two ninety-five articles were identified from the search after excluding duplications. A total of 251 articles were excluded after reading titles. Abstracts of forty-one articles were reviewed independently. A total of 29 articles were excluded after reading abstract. Full-text articles were retrieved for fifteen relevant studies. After reviewing articles independently, three articles were excluded after full-text reading. Finally, twelve studies were selected based on the eligibility criteria.
Data extraction was completed independently by the two reviewers using a specifically designed data extraction form. Quality assessment criteria to evaluate the studies were decided by two review authors in accordance with CONSORT guidelines. The following data were collected:
- Author and journal
- Study design
- Participants and groups
Each study was assessed using the evaluation method described in the Cochrane Handbook for Systematic Reviews (Higgins and Green. Cochrane reviewers handbook 2009). The quality assessment of the included trials was undertaken independently by two reviewers. The domains evaluated were randomization method, allocation concealment, assessor blinded, dropouts, and risk of bias. Each domain was classified as having a low, high, or unclear risk of bias. Thus, the overall level of risk for each study was subsequently classified as low (if it did not record a “Yes” in three or more of the four main categories), “Moderate Risk” of bias (if two out of four categories did not record a “Yes”), “Low Risk” (if all the four categories recorded were adequate), “Unclear (unclear risk of bias for one or more domain).”
| Results|| |
Twelve studies which met the inclusion criteria were taken for the present systematic review [Table 1].
The age group assessment included in the studies revealed, nine out of twelve studies considered subjects aged between 12 and 20 years. Three studies included an age group of 12–36 months, 2½–3½ years, 6–14 years. Of the twelve studies, five were double-blinded, three-single blinded, and one-triple blinded. Rest of the trials have not mentioned explicitly about the blinding in the methodology.,, The mode of delivery in all the trials included was in tooth paste form. Out the twelve studies, only six studies reported the concentration of CPP-ACP. The concentration used varied from 0.2% w/w, 0.2% w/w, 2% w/w, 10% w/w, 10% w/w, 1 g in studies done by Llena et al., Beerens et al., Rao et al., Bailey et al., Sitthisettapong et al., and Bröchner et al., respectively.,,,,, The remaining six of the studies made no mention regarding the concentration of CPP-ACP.,,,,,
The primary outcome for assessment was considered as the remineralization potential of CPP-ACP on naturally occurring caries and WSLs postorthodontic treatment. In the present systematic review among the twelve studies, four evaluated the effect on naturally occurring caries and eight studies evaluated effect on WSLs postorthodontic treatment. The measurement methods used among the twelve studies included a combination of the following; International Caries Detection and Assessment System (ICDAS) II (5 studies), DIAGNOdent (3studies), decayed-missing-filled surfaces (DMFS) (2 studies), Qualitative laser fluorescence (3 studies), digital photograph (3 studies), and enamel decalcification index (2 studies) [Table 1].
Among the studies evaluating the effect of CPP-ACP on naturally occurring caries lesion, three studies showed a significant reduction in caries increment using CPP-ACP compared with placebo. There were significant differences between groups in the mean DMFT index and decrease in the mean WSL area was also reported. DIAGNOdent values were also found to be significantly reduced. However, one study reported that there was no significant difference in the enamel caries lesion transition using CPP-ACP compared to fluoridated toothpaste.
The remaining eight trials assessed the effect of CPP-ACP on WSLs associated with postorthodontic treatment. The studies reported that there was no significant difference among the intervention and comparison group. However, there was significant improvement in lesion depth over a period, but no significant difference between the groups among four studies. DIAGNOdent values were found to be decreased in one study and enamel decalcification index was decreased in two studies. One study lack adequate information regarding the primary outcome.
One or more nonserious adverse events such as minor gastrointestinal symptoms were recorded in the trial conducted by Bailey et al. Only two studies reported information about side effects of using CPP-ACP., The rest of the studies included in this systematic review did not present information on incidence of any adverse events.
Risk of bias
The risk of bias of the studies included in this review is summarized in [Table 2] and [Table 3]. Out of twelve studies which met eligibility criteria, seven studies have low risk of bias, three studies were judged to have moderate, and two studies were high risk of bias. The main risk of bias associated with these studies included inadequate sample size, unexplained allocation concealment, and lack of mention about attrition rates.
| Discussion|| |
The primary objective of this systematic review was to determine the remineralization effect of CPP-ACP through studying the published clinical trials. The present review has highlighted a lack of relevant research with low risk of bias on the effect of CPP-ACP on carious lesions, suggesting that CPP-ACP has remineralizing effect on early caries lesions in vivo compared with placebo and fluoridated toothpaste and fluoride varnish.
WSLs resulting from orthodontic treatment were also included in our literature search because they represent the preliminary stage of subsurface enamel demineralization and are generally considered the early stage of the carious process. In contrast to normal population, however, the microecology of orthodontic patient seems to change following the placement of fixed appliances and due to inability to maintain proper oral hygiene, this may influence the effect of CPP-ACP in this population group. The WSLs, which determine the earliest phase of the caries process and which are reversible can be treated by conventional approaches, involving the disadvantage of being invasive. Therefore, remineralization agents can be used to promote ion-exchange mechanism instead of invasive techniques. CPP-ACP has been reported to have the potential in promoting remineralization and which maintains calcium and phosphate at a supersaturated level compared to calcium in saliva and helps to preserve them in proximity to the enamel lesion, thereby decreasing demineralization and enhancing remineralization of enamel lesion.
The age group assessment included in the studies revealed, nine out of twelve studies considered subjects aged between 12 and 20 years. CPP-ACP used in the included studies were marketed under the trade names of “ GC Tooth mousse”, “MI Paste”, “ MI Paste plus,” and “Topacal C-5”. The highest concentration of CPP-ACP that is currently available in commercial dental products is 10%w/w (ex: 5%w/w “Topacal C-5” and 10%w/w in “GC Tooth mousse”, “MI Paste” and “MI Paste plus”). The strength or concentration is an important requirement in clinical trials since CPP-ACP has promising effect on dose-related increase in enamel remineralization.
The twelve studies included in this systematic review utilized the following methods to assess the primary outcome measures; clinical assessment using the ICDAS criteria or decayed surface/DMFS index, clinical or photographical assessment using enamel decalcification index, bitewing radiography for proximal caries increment, and reading of fluorescence-based devices (QLF/DIAGNOdent). Since no single method provides adequate reliability for caries detection, it may be beneficial to compile at least two of these detections methods in the future trials.
Four of the twelve studies evaluated the effect of CPP-ACP on naturally occurring early caries lesions, out of which three studies concluded that there was a significant reduction in caries increment after using CPP-ACP compared with placebo. Other eight studies assessed the effect of CPP-ACP on WSLs that were associated with orthodontic treatment, among which four concluded that there was no clinical advantage after using CPP-ACP supplements compared to fluoride varnish. In contrast, four of the studies found that CPP-ACP promotes remineralization of enamel subsurface lesion in postorthodontic WSL population.
The follow-up time of studies also varied from 1 month to 2 years. Evidence from studies on CPP-ACP suggests that a follow-up period of more than 3 months is usually needed to observe the changes of demineralization/remineralization. Moreover, a relatively long follow up is required to determine the efficacy of CPP-ACP. Reporting of adverse effects due to the use of CPP-ACP was lacking in most of the studies. Safety assessment should always be considered as an important and necessary part of a well-designed randomized controlled trial.
Quality assessment of the studies showed that among twelve trials, seven studies showed low risk of bias. However there was a difference in the concentration of CPP-ACP, intervention measurement methods, outcome assessments, and follow-up period, randomization and blinded methods which could affect the trial results.
| Conclusion|| |
Within the limitation of this systematic review, a high level of evidence of remineralizing potential of CPP-ACP on naturally occurring WSL and WSL postorthodontic treatment was found in comparison with placebo/fluoridated toothpaste and fluoride varnish without any statistically significant difference. Reporting of such trials should follow the CONSORT statement and in particular, carry out blinding for reducing the risk of bias which influences the outcome. Well-designed randomized controlled trials are, therefore, required to improve the level of evidence in this area of research.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Balakrishnan M, Simmonds RS, Tagg JR. Dental caries is a preventable infectious disease. Aust Dent J 2000;45:235-45.
Petersen PE. The World Oral Health Report 2003, Continuous Improvement of Oral Health in the 21st
Century – The Approach of the WHO Global Oral Health Programme. World Health Organization; 2003. Available from: http://www.who.int/oral_health/media/en/orh_report03_en.pdf
. [Last accessed on 2017 Jun 30].
Mehta R, Nandlal B, Prashanth S. Comparative evaluation of remineralization potential of casein phosphopeptide-amorphous calcium phosphate and casein phosphopeptide-amorphous calcium phosphate fluoride on artificial enamel white spot lesion: An in vitro
light fluorescence study. Indian J Dent Res 2013;24:681-9.
] [Full text]
Cochrane NJ, Cai F, Huq NL, Burrow MF, Reynolds EC. New approaches to enhanced remineralization of tooth enamel. J Dent Res 2010;89:1187-97.
Mizrahi E. Enamel demineralization following orthodontic treatment. Am J Orthod 1982;82:62-7.
Srivastava K, Tikku T, Khanna R, Sachan K. Risk factors and management of white spot lesions in orthodontics. J Orthod Sci 2013;2:43-9.
Armstrong SG, Chalmers J, Warren J. White spot lesions: Prevention and treatment. Am J Orthod Dentofac Orthop 2010;138:690-6.
Mittal R, Relhan N, Tangri T. Remineralizing agents: A comprehensive review. Int J Clin Prev Dent 2017;13:1-4.
Park SY, Cha JY, Kim KN, Hwang CJ. The effect of casein phosphopeptide amorphous calcium phosphate on the in vitro
shear bond strength of orthodontic brackets. Korean J Orthod 2013;43:23-8.
Reynolds EC. Calcium phosphate-based remineralization systems: Scientific evidence? Aust Dent J 2008;53:268-73.
Gurunathan D, Somasundaram S, Kumar S. Casein phosphopeptide-amorphous calcium phosphate: A remineralizing agent of enamel. Aust Dent J 2012;57:404-8.
Farooq A, Moheet I, Imran Z, Farooq U. A review of novel dental caries preventive material: Casein phosphopeptide – Amorphous calcium phosphate (CPP–ACP) complex. Saudi J Dent Res 2013;4:47-51.
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;24:231-7.
Sitthisettapong T, Phantumvanit P, Huebner C, Derouen T. Effect of CPP-ACP paste on dental caries in primary teeth: A randomized trial. J Dent Res 2012;91:847-52.
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;16:181-6.
Bailey DL, Adams GG, Tsao CE, Hyslop A, Escobar K, Manton DJ, et al.
Regression of post-orthodontic lesions by a remineralizing cream. J Dent Res 2009;88:1148-53.
Andersson A, Sköld-Larsson K, Hallgren A, Petersson LG, Twetman S. Effect of a dental cream containing amorphous cream phosphate complexes on white spot lesion regression assessed by laser fluorescence. Oral Health Prev Dent 2007;5:229-33.
Vashisht R, Indira R, Ramachandran S, Kumar A, Srinivasan MR. Role of casein phosphopeptide amorphous calcium phosphate in remineralization of white spot lesions and inhibition of Streptococcus mutans
? J Conserv Dent 2013;16:342-6.
] [Full text]
Huang GJ, Roloff-Chiang B, Mills BE, Shalchi S, Spiekerman C, Korpak AM, et al.
Effectiveness of MI paste plus and previDent fluoride varnish for treatment of white spot lesions: A randomized controlled trial. Am J Orthod Dentofacial Orthop 2013;143:31-41.
Wang JX, Yan Y, Wang XJ. Clinical evaluation of remineralization potential of casein phosphopeptide amorphous calcium phosphate nanocomplexes for enamel decalcification in orthodontics. Chin Med J (Engl) 2012;125:4018-21.
Robertson MA, Kau CH, English JD, Lee RP, Powers J, Nguyen JT, et al.
MI paste plus to prevent demineralization in orthodontic patients: A prospective randomized controlled trial. Am J Orthod Dentofacial Orthop 2011;140:660-8.
Rao SK, Bhat GS, Aradhya S, Devi A, Bhat M. Study of the efficacy of toothpaste containing casein phosphopeptide in the prevention of dental caries: A randomized controlled trial in 12- to 15-year-old high caries risk children in Bangalore, India. Caries Res 2009;43:430-5.
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;15:369-73.
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;118:610-7.
Lata S, Varghese NO, Varughese JM. Remineralization potential of fluoride and amorphous calcium phosphate-casein phospho peptide on enamel lesions: An in vitro
comparative evaluation. J Conserv Dent 2010;13:42-6.
] [Full text]
Freitas AO, Marquezan M, Nojima Mda C, Alviano DS, Maia LC. The influence of orthodontic fixed appliances on the oral microbiota: A systematic review. Dental Press J Orthod 2014;19:46-55.
Melrose CA, Appleton J, Lovius BB. A scanning electron microscopic study of early enamel caries formed in vivo
beneath orthodontic bands. Br J Orthod 1996;23:43-7.
Chandak S, Bhondey A, Bhardwaj A, Pimpale J, Chandwani M. Comparative evaluation of the efficacy of fluoride varnish and casein phosphopeptide – Amorphous calcium phosphate in reducing Streptococcus mutans
counts in dental plaque of children: An in vivo
study. J Int Soc Prev Community Dent 2016;6:423-9.
Li J, Xie X, Wang Y, Yin W, Antoun JS, Farella M, et al.
Long-term remineralizing effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) on early caries lesions in vivo
: A systematic review. J Dent 2014;42:769-77.
Dr. K Indrapriyadharshini
Department of Public Health Dentistry, Ragas Dental College and Hospital, East Coast Road, Uthandi, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]