Clinical Efficacy of Casein Derivatives: A

Systematic Review of the Literature
Amir Azarpazhooh and Hardy Limeback
JADA 2008;139(7):915-924

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DDS. CPP 12 original studies. The objective of this article was to N CON total protein. Azarpazhooh.13. review systematically the clinical trials of casein T T A N I lular complexes.. abstract and full text. in preventing accepted molecular formula for ACP caries in vivo and treating dentin hypersensitivity or dry mouth. and one tiphosphorylated peptides that pre. case reports. DDS asein is the predominant C phosphoprotein in bovine milk and accounts for ABSTRACT J A D A Downloaded from jada. BSc. Nine were clinical trials that focused on caries pre- can remarkably stabilize calcium vention. . The authors included clinical static activity of dairy products studies that examined the efficacy of casein derivatives in dentistry.11 Through these mul. systematic review. according to title. lozenges. Ontario. MSc. 124 Edward St. JADA 2008. They (milk. remineralization. primarily as IO calcium phosphate stabilized micel.13 This complex is results regarding the effect of CPP-ACP on the regression of white-spot a nanocluster of ACP with four mul. review articles and commentaries. lesions. Types of Studies Reviewed.azarpazhooh@dentistry.1 Several laboratory derivatives (specifically casein phosphopeptide– U C A ING EDU 3 and animal experiments2-9 have amorphous calcium phosphate [CPP-ACP] complex) R TICLE investigated the low cariogenic used in dentistry. specifically CPP-ACP. caseinates and excluded in vitro studies. sient phase in biomineralization. PhD.utoronto. Dr. letters to editors (not cheeses). Vol. M5G 1G6. one was a survey of the relief of dry-mouth symptoms. Community Dental cursor to bioapatite and as a tran. University to stable crystalline phases such as of Toronto. editorials.ada. The quantity and quality of clinical trial precipitation. It likely plays a special role as a pre. All rights reserved. eral component in hard tissues.12. Faculty of Dentistry. e-mail “amir. JADA. determined from casein. Canada. One was a clinical trial with conflicting (ACP) complex. [Ca3 (PO4)2 . ACP is converted readily Dr. on September 20. of -Ser (P)-Ser (P)-Ser (P)-Glu-Glu Results. casein derivative. casein be considered a tricalcium phos. preventing dental caries by remineralizing subsurface carious lesions in amorphous calcium phosphate situ in a dose-response fashion. resulting in a yield of tiple phosphoseryl residues. dence that ACP is an integral min. demineralization. Room 521A. ACP also may Key Words. There is no conclusive evi. Hardy Limeback. Health Services Research Unit.139(7):915-924.CLINICAL PRACTICE CRITICAL REVIEW Clinical efficacy of casein derivatives A systematic review of the literature Amir Azarpazhooh. casein. milk or mouthrinse) was effective in insoluble) in a state-forming CPP. Limeback is an associate professor and head. University of Toronto. In Toronto.nH2O]. Preventive Dentistry. The authors searched 98 articles for relevance. Azarpazhooh is a PhD/specialty candidate in endodontics and a researcher. transformation and Clinical”.14 evidence are insufficient to make conclusions regarding the long-term On the basis of the generally effectiveness of casein derivatives.10. phase July 2008 915 Copyright © 2008 American Dental Association. Faculty of Dentistry. case series. 139 http://jada. seven of which showed that CPP-ACP (as found in sugar-free phosphate (which usually is highly pellet or slab chewing gum.ada. Casein phosphopeptides containing primary data). Anticariogenicity. phate. (CPP) contain the cluster sequence but read them to identify any potential studies. potential and the possible cario. 2013 ✷ ✷ almost 80 percent of its ® Background. was an uncontrolled clinical study that showed the lack of effective- vent its growth to the critical size ness and lack of short-term therapeutic effect in treating dentin required for nucleation. phosphopeptide–amorphous calcium phosphate. Address reprint requests to Dr.

All rights reserved. Outside the demonstrated that CPP-stabilized United States. Alsip. . 916 JADA.V. Cadbury Adams tion to the animals’ molar teeth twice daily. Ill. CPP-ACP: Casein phospho- ACP binds readily to the surface of the tooth.J.CLINICAL PRACTICE CRITICAL REVIEW octacalcium phosphate or apatitic concentration of ACP in close proximity to the products. N. RCT: the tooth. therefore. CPP-ACP deposits a high Randomized controlled trial. Australia.13 In contrast. and preventing dental caries is an In an in vitro study. plaque and. Abbotsford.1 percent CPP-ACP provides a Therefore. toothpaste or drinking water. 139 http://jada. tially increasing the level of calcium phosphate in tralia.24 reported that CPP. Aus. Food and Drug Administration (FDA) CPP-ACP. The authors proposed that under The CPP-ACP complex was patented by the acidic conditions. hand scaling or phosphopeptide– produced a 15 percent and a 46 per- root planing). with calcium phosphate. maintaining a state of pany owned by 2. CD-CP: Casein derivatives coupled Reynolds and colleagues12. WSL: White-spot lesion. resulting in high rates of enamel reminer- DERIVATIVES alization.18-23 as an anticariogenic additive to stabilized free calcium and phosphate ions.) for use pri. However. potential of casein cent w/v CPP-ACP. the free calcium and phosphate ions.16 smooth surfaces was reduced significantly in a Downloaded from jada. respectively. NaF: Sodium fluoride.S. marketing rights for CPP-ACP and is the owner Several laboratory and animal experiments of the trademark (Recaldent). respectively. experiments have tion in smooth-surface caries marily as abrasive prophylaxis activity). In a second experi- anticariogenic activity is at least 10 times greater ment. 0. Leuven. Parsippany. They USA. 2013 The FDA has approved products dose-response fashion (0. Reynolds26 17 off-label application. the have demonstrated the anticariogenic potential of U. especially if it is ABBREVIATION KEY. its use has not Rose27 conducted a laboratory experiment in been implemented because of its adverse which he showed that CPP-ACP binds well to organoleptic properties and the large amount dental on September 20.13 calcium carbonate. Rose28 also showed that in streptococcal on a weight basis for CPP than it is for casein. the products are calcium phosphate solutions main- marketed as GC Tooth Mousse and Tooth Mousse tained high concentration gradients of calcium Plus (GC Europe N.0 percent weight per volume Paste and MI Paste Plus containing Several laboratory CPP-ACP. Bonlac Foods Limited (an Australian com. this localized CPP-ACP buffers University of Melbourne.ada. GC and animal 14 percent and a 55 percent reduc- America. In early 1999.15 tooth surface.1 percent and 1. safe” for its intended use as a texturizer in Reynolds and colleagues25 applied CPP-ACP solu- chewing gum (Trident White. and phosphate ions and ion pairs in subsurface carious lesions in the enamel of human third RATIONALE FOR USE OF CASEIN molars. Belgium). providing a large calcium reservoir required for efficacy. ultrasonic scaling. CPP does not that may inhibit demineralization and assist in have these limitations. The potential for a specific subsequent remineralization. substan- torian Dairy Industry Authority. food. FDA: Food and well as to the bacteria in the plaque surrounding Drug Administration. CaCO3: Calcium carbonate. its use for amorphous calcium cent reduction in fissure caries remineralizing dentin and enamel phosphate. consumed at the same time as the cariogenic CaHPO4/CaCO3: Calcium hydrogen phosphate/ challenge. The remineralizing capacity was Although several studies have investigated the greater for solutions with higher levels of CPP- use of casein4. model plaques.) at up to 5 percent weight found that the caries activity of the enamel per weight. In this way.. In a group of specific-pathogen-free accepted Recaldent as “generally recognized as rats inoculated with Streptococcus sobrinus. as peptide–amorphous calcium phosphate.0 per- in-office bleaching July 2008 Copyright © 2008 American Dental Association. Vol. The authors found a sim- demonstrated the pastes and secondarily for the ilar reduction in the caries activity treatment of tooth sensitivity (after anticariogenic of fissures (0. activity). produced a 900 parts per million fluoride.ada.1 percent marketed in the United States (MI and 1. CPP can be used as a food or tooth- paste anticariogenic additive. and the Vic.300 dairy farmers in Victoria supersaturation that inhibits enamel deminerali- and Tasmania) has exclusive manufacturing and zation and enhances remineralization.

Furthermore. The taste 6 years should not use it.). clinicians should consider pH 5. .3) for 30 seconds six times reverse caries: daily for 14 days) when compared with the no. dproducts composed of inorganic calcium phos- treatment control specimens after seven and 14 phate minerals alone33 (Enamel Pro Prophy days of erosive cycling. Alachua. During a cariogenic July 2008 917 Copyright © 2008 American Dental Association. Cochrane Gum) are ingestible. Premier Products. We should note that eralization. Although it is alone. have been published that mens showed that the erosive lesions that devel. Scanning calcium-phosphate precipitates. independent 5 percent casein/calcium phosphate to bovine research is required to study the interaction of enamel specimens for 120 seconds twice daily. Therefore. Paste. children younger than concentrations except 0.125 percent CPP-ACP. no reports. Trident White Central Register of Controlled Trials.25 percent] and through the deposition of fluoride-containing double deionized water as the placebo). Cumulative Index to Nursing & Allied Health Lit- One advantage of this therapy is that the prod. at oped in specimens immersed in Powerade were 900 ppm fluoride.063 percent. therefore.32 However. Evidence Based Medicine of Cochrane ucts (MI Paste. 139 http://jada. to reduce decalcification in ortho. electron microscopic examination of the speci. We conducted a comprehensive sitivity resulting from exposed root surfaces after literature search of databases Ovid MEDLINE. and it Technology. According to the manufac. reduce caries in high-risk patients. to repair enamel in cases report is to systematically review the clinical involving white-spot lesions. to erosive enamel loss (bovine enamel specimens Three main calcium phosphate products have rinsed with artificial saliva interrupted by 1 per. The authors of the casein complex and may precipitate out as concluded that adding CPP-ACP to the sports calcium fluoride. E allergies to milk proteins. designed to increase enamel remineralization ACP [0. rendering both inorganic compo- drinks significantly reduced the beverage’s ero. the purpose of this dontic patients. treating sensitive dentin METHODS in patients with dental erosion and reducing sen.09. CLINICAL PRACTICE CRITICAL REVIEW large number of possible binding sites for calcium therapy poses a risk if the patient ingests a sig- and reduces the free calcium diffusion coefficient nificant amount of fluoride. NovaMin static agent for the control of dental caries. orthodontic decalci. 0. dproducts composed of inorganic calcium phos- turer (GC America). 2013 eliminated with the addition of CPP-ACP at all ingestible and. 0. All rights reserved. potentially can interact with the ACP component erade with 0. this product is not considered Downloaded from jada. to our knowledge.ada.1 percent potential side effects from ingestion of casein CPP-ACP prevented mineral loss and provided a derivative protein in people with immunoglobulin potential source of calcium for subsequent remin. Ramalingam and colleagues29 intolerance. in another in vitro study. Clinical picture. Plymouth Meeting. phate minerals plus silica (NovaMin. topical fluoride Database of Systematic Reviews. Moreover. to reduce To our knowledge. Atlanta] that contains 900 ppm fluoride. for any by about 65 percent at pH 7 and 35 percent at clinical application.). no systematic reviews of the dental erosion in patients with gastric reflux or clinical trials of these products have been con- other disorders. erature. In contrast. Pa. thus restricting the caries process. demonstrate its efficacy in vivo. complex. ducted to date.125 and 0. professional tooth cleaning). can be used as an adjunct preventive therapy to dproducts composed of the CPP-ACP complex.ada. trials of one of these types of products used in fication or fluorosis or before and after tooth dentistry: products composed of the CPP-ACP whitening) and to desensitize teeth (for example. fluoride panel could not distinguish Powerade from Pow. Vol. Lennon nology (as casein in MI Paste Plus) has greatly and colleagues30 applied a tooth cream containing reduced this problem.31 CPP-ACP is a useful cario. the fluoride-enriched CPP-ACP complex with They found no significant difference with respect enamel. calcium and phosphate in the Recaldent tech- However. nents on September 20. been tested or are on the market to inhibit or cent citric acid (pH 2. Powerade with four concentrations of CPP. Tooth Mousse.063. immersed human enamel specimens in an erosive MI Paste Plus is a recently introduced product sports drink (Powerade [Coca-Cola. Development of the carrier for sivity without affecting the product’s taste. However. Data sources. CPP-ACP is digestible by people with lactose In 2005. 0. Fla. reducing hypersensitivity resulting from whitening procedures. Database of JADA.

com”. we limited the We found 12 studies of the efficacy of casein searches to articles in English and to studies that derivatives in clinical dentistry10.recaldent. This system also includes a bidirectional the key words and their combinations used in the classification of its recommendations (that is. Health system developed by the Canadian Task Force on and Psychosocial Instruments. We summa- The Journal of the American Dental Association rized the best available evidence by using Articles scored and included in evidence tables 12 inclusion criteria and measuring the strength and quality of the studies according to the evidence classification Abstracts of Reviews of Effects. as well as Google Scholar. ence. case reports." "Recaldent. “www.11. One of us were randomized clinical trials with crossover (A. sex. graphic location.36. case series. Downloaded from jada.38-42 resolved discrepancies by consensus. prevention (10 studies10. Eight of these studies10. respected authorities. geo- Literature search strategy.ada. them to identify any potential studies.35 The checklist consists of questions vitro studies. EMBASE.) printed the abstraction sheets for anno. included randomized and quasi-randomized con. We retrieved 98 articles. letters to addressing ethics. literature search.11. outcome. with citation.CLINICAL PRACTICE CRITICAL REVIEW TABLE 1 author/date. In reading Relevant articles at title stage 16 the articles. 139 http://jada. we checked the reference lists (agreement between reviewers: 93 percent) to identify any other articles that may have been relevant to the research ques- Relevant articles at abstract stage 11 (agreement between reviewers: 100 percent) tion or provided additional information.ada.gcamerica. intervention or test treatment (number of subjects). All rights reserved. descriptive studies or reports of expert com- com”). study design. This review identified 10 retrieval and copying.11. We critically reviewed the retrieved articles trolled trials of the efficacy of casein derivatives using the checklist for appraising evidence in in any clinical dental application. . 918 JADA. resulted in 12 articles that we selected for Caries prevention. designs that determined the remineralizing tated references (that is. Study selection. This Healthstar and International Pharmaceutical system includes a hierarchy of evidence from the Abstracts for any published and unpublished highest (level I)—a properly randomized con- studies (from their inception until October 2007). After removing duplicates. We selected 53 citations page 920). strength of the recommendation for or against Inclusion and exclusion criteria. which dentin hypersensitivity (one study45). Vol. The outcomes of interest were caries and searched for relevance (determined by title). Relevant articles at full copy stage 11 All of these were found in the original searches. HealthSTAR/Ovid Preventive Health Care34 (Tables 2 and 3).org on September 20. but we read of interest." "CPP-ACP" or “Tooth Mousse” recommendations.36-45 (Table 4.A. We specific clinical preventive actions). phate. relief from dry- which resulted in 16 articles. We excluded in health care. trolled trial—to the lowest (level III)—opinions of We also searched the Web sites of product manu. Both of us reviewed all studies of caries prevention via treatment with articles at each stage independently and we casein derivatives. editorials. based on clinical experi- facturers (“www. control SEARCH HISTORY AND CRITERIA NO. We reviewed the mouth symptoms (one study44) and treating abstracts of these articles for relevance.36-43). data extraction and SUMMARY OF EVIDENCE AND COMPARISON OF OUTCOMES quality assessment. strength of evidence and classification of cium phosphate. Table 1 shows mittees." "casein phosphopeptide-amorphous cal. appropriateness of the results for the population review articles and commentaries. 2013 (agreement between reviewers: 100 percent) Article suggested by reviewers of 1 Best available evidence. methodology and editors (not containing primary data). age." "casein 98 phosphopeptides-amorphous calcium phos- critical appraisal July 2008 Copyright © 2008 American Dental Association. conclusion. effects of CPP-ACP by using in situ caries models. OF ARTICLES treatment (number of subjects). population. involved human subjects. Key Words: "MI Paste. We then read and Duplicate articles removed 58 reviewed the abstraction sheets to deter- Search limited to humans 54 mine relevance and scored them to rate Search limited to English-language articles 53 the evidence for this review.

The other two studies37. Preventive Health Care. I Insufficient evidence (in quantity and/or quality) to make a after subjects consumed sugar-free gum. of the studies except one41 showed that CPP-ACP dramatic results in uncontrolled experiments could be included here had caries-preventive potential and resulted in subsurface remineralization of the enamel with III Opinions of respected authorities.41 While investi. prevention category were in vivo (rather than in gators in the other studies placed enamel slabs at situ) studies. * Adapted with permission of the Canadian Task Force on The only study that did not show a difference Preventive Health Care. direct contact between the slabs and the chewing The investigators measured the coronal caries gums. however. Vol. I Evidence from randomized controlled trials percentage of subsurface remineralization and/or II-1 Evidence from controlled trials without change in mineral profile. preferably from more than one center or research group washout period of four weeks. the clinical preventive action At the end of each treatment period (that is. the length of study varied II-2 Evidence from cohort or case-control analytic from seven to 21 on September 20. does not allow making a recommenda- gators polished sound enamel. all or places with or without the intervention. the factors may influence decision-making investigators took the remineralized enamel half. All rights reserved. These appli.ada. Subjects with salivary gland dysfunc- wing on each side. clinical preventive actions.43 in the caries- domized crossover in situ study. the investi.34 slabs (retained in a humidified environment) and TABLE 3 embedded and sectioned them. the rest had a II-3 Evidence from comparisons between times washout period of five to seven days. tion (resulting from radiotherapy for head and mens were mounted in each wing flush with the neck cancer or Sjögren syndrome) used one of the buccal surface. Overall.* ances contained troughs. these appliances had a buccal resin mouthrinse. subjects in clinical trial comparing a mouthrinse that con- the study by Schirrmeister and colleagues41 wore tained casein derivatives coupled with calcium custom-made removable buccal appliances in the phosphate (CD-CP) with a sodium fluoride (NaF) mandible.41 bovine B Fair evidence to recommend the clinical preventive action enamel sections were used. This procedure produced consis- Downloaded from jada. Only one study39 had a studies. Then they sub- jected the slabs to microradiography and Levels of evidence. C The existing evidence is conflicting and To create the demineralized lesion.41 subjects wore TABLE 2 custom-made removable midpalatal acrylic appli. other milk or mouthrinse containing CPP-ACP). increment with posterior bitewing radiographs JADA. recommendation.* computer-assisted microdensitometric analysis LEVEL TYPE OF EVIDENCE to evaluate the mean subsurface lesion depth. In all but one study. randomization For each test group. The first study37 was a randomized the palate of midpalatal appliances. based on clinical experience. In one study. * Adapted with permission of the Canadian Task Force on slabs and their paired demineralized control half. of recommendation for specific less steel circumferential clasps. This may have resulted in less two mouthrinses three times per day for one year. each of which housed GRADE EVIDENCE two or three demineralized enamel half-slabs by means of wax retention. covered it with an tion for or against use of the clinical preventive action. however. lozenge. . and two bovine enamel speci. Canadian Task Force grades ances that covered the first premolars to the last tooth in the arch and were retained by four July 2008 919 Copyright © 2008 American Dental Association. D Fair evidence to recommend against alizing solutions. descriptive studies or the in situ carious lesion in a dose-response reports of expert committees fashion. 2013 the clinical preventive action tent subsurface lesions of 80 to 110 micrometers E Good evidence to recommend against in depth.34 between the CPP-ACP–containing chewing gums and the control chewing gums was a 2007 ran. 139 http://jada. CLINICAL PRACTICE CRITICAL REVIEW In all but one of these studies. A Good evidence to recommend the clinical preventive action sound human extracted third molars were the source of the enamel.ada. other fac- acid-resistant coating (nail varnish or epoxy tors may influence decision-making resin) and then subjected the enamel to deminer.

visible WSLs*.5 without zinc cit. 2006 40 control milk or week for milk and crossover. small sample ACP/L†† size Reynolds and 30 adults (age. on September 20. with CPP-ACP no added ingredient Schirrmeister 15 subjects In situ: 4 sugar. weight per promote small sample weight ratio) enamel remin. remineraliza. 2003 39 CPP-ACP. each. and 18.Crossover. mouthrinse. CaCO3. POPULATION INTERVENTION CONTROLS OUTCOME STUDY COMMENTS YEAR AUTHORS’ CONCLUSIONS Andersson 26 adolescents 13 subjects. 23-46 free gums: 20 washout 1 remineralization greater blinded. (mean ± SD free gum con.ada. ACP† paste daily 0. or 5 grams CPP. RCT. Mouthrinse: Importance of Double-blinded colleagues. 62 Blind Both treat.8 mg eral level after crossover. domized.§ small colleagues.9 taining 18. 34 ± 6. for fifth mineral change benefit even in situ. . drank 200 mL** washout 1 remineralization alizing ability July 2008 Copyright © 2008 American Dental Association. gum: and stabilizing deionized water.CLINICAL PRACTICE CRITICAL REVIEW TABLE 4 Evidence of clinical efficacy of casein derivatives. 2004 10 age. with gum and observer citrate and dical. test milk with 2 CPP-ACP short washout. mouthrinse with regard to caries preventive up visit. with zinc period (control). All rights reserved.6 with CPP-ACP delivery of crossover. 14.ada. % subsurface More reminer. between the NaF mouthrinse and the CD-CP The other study43 was a single-blinded 920 JADA. 6 scoring. 22-44 years) CPP-ACP. daily assessment ments reversed RCT.5 ± 2. Double-blinded colleagues. 1% and 3% CPP-ACP to short washout. crossover. CPP. free gum remineralization and CPP-ACP RCT. better sample. visual outcome power calcula- years) then fluoride fluoride paste cence scores of for test tion. ran- 2007 42 years) mg¶ citric acid week (P < . CPP-ACP. 2013 citric acid. % subsurface Sugar-free gum Double-blinded colleagues.8 mg lacking CPP. mouthrinse and laser fluores. 152 WSLs. cal. 70 13 controls. weeks for and inorganic ering ACP to crossover. 32. age. no sig- months and 12 months nificant differ- ence with laser fluorescence Cai and 10 subjects In situ: 3 sugar. Control.05% NaF‡ of clinical and WSLs. have resulted with CPP-ACP. (mean ± SD lozenge types remineralization be suitable for RCT. cal. 27. The results showed no difference efficacy. years) (0%. Single-blinded and (60 teeth.05) min.3 ± 7. 139 http://jada. phosphate tooth surface situ phate mixture. subjects wore CPP-ACP blinded. cium appliances mandibular phosphate. washout 1 tion small sample week size Cai and 10 adults In situ: 3 No lozenge % subsurface Lozenges may Double-blinded colleagues. no 2007 43 mean age. 3. colleagues.‡‡ CaHPO4/CaCO3§§ or CPP-ACP Iijima and 10 adults In situ: sugar. Vol. gum % subsurface ACP sugar-free gum: remineralization in situ. % subsurface Significantly Double- colleagues. Chewed test Lesion depth No additional Randomized.6 for 3 months. 2007 41 years) rate. short washout. subjective paste daily for 3 for 6 months WSLs at 1. without buccal appli- cium gluconate. and (mean ± SD# free gums: gums 14 days reduction and remineralizing crossover. sugar. WSLs. (age. in less direct no calcium contact of slabs with gums Walker and 10 adults In situ: subjects Crossover. 2003 36 age. Mouthrinse: 2% Crossover. effective in crossover. years) CPP-ACP ACP. 20 mg acid challenge in situ Downloaded from jada. size eralization (dose-related) obtained at baseline and at the 12-month follow. in cium and phos. not noted for levels. chewing gum ances may calcium lactate. 6% washout 4 plaque calcium CPP in deliv.

with severe days mouth. Descriptive. sensitivity in applied on pain intensity and short-term follow-up loss. ¶ mg: Milligrams. Double-blinded and 20-47 years) with 30 mg washout 5 days in lesion depth preventive RCT.4) xylitol-based sugar-free gum Hay and 124 subjects N = 63. 1 week and analysis. remin- application eralizing potential unknown Hay and 38 adults CD-CP for 14 Patients’ Questionnaire Potential bene. colleagues. self. topical dental cream containing CPP-ACP going debonding of fixed orthodontic appliances (Topacal C-5. # SD: Standard deviation. tion with CPP. 25 mg gum and dical. (age. oral moistening caries- than 25 years) ping water.05% wing radio.V. In situ: no Crossover. and dental prevention chewing gum. 23-40 years) treatment washout 1 remineralization increase in RCT.19. N = 61: self. older strategies (sip. and receiving a professional cleaning. topical CD-CP¶¶ topical 0. % subsurface Dose-related Double-blinded colleagues. Nulite Systems International. about benefit fits of CD-CP self-evaluation 2003 44 xerostomia moistening mouthrinse in questionnaire. Immediately after under. small tion (mean ± mouthrinse 3 NaF graphs at base. tooth-level utes. or CPP-ACP cariogenic drate or 47 mg snack food CPP-ACP Kowalczyk 101 teeth with GC Tooth None Pain intensity at Insufficient Uncontrolled and dentin hyper. § RCT: Randomized controlled trial. ACP and sor- 0. . randomized clinical trial of 26 healthy adoles. urea and no potential of crossover. CLINICAL PRACTICE CRITICAL REVIEW TABLE 4 (CONTINUED) AUTHOR.8. potential artificial saliva) tion in xero.ada. Coronal caries CD-CP RCT (double- Thomson with salivary administered administered increment (bite. no con- Downloaded from jada. phate. Belgium. Mean % change Caries. for caries unclear). control group not good * WSLs: White-spot lesions.or 56. subjects sup- dicalcium phos. short washout ACP mg (0. subjects Hornsby. caries preven. The test cents with 152 visible white-spot lesions on 60 group (n = 13 subjects with 70 sites) applied a incisors and canines. prevention sample for 90% SD age. no (age.. Vol. bitol. and at 15 min. 2006 45 13 patients surfaces for soon after therapeutic no July 2008 921 Copyright © 2008 American Dental on September 20. 139 http://jada. 2001 11 group. may be useful blinding 2002 37 gland dysfunc. gum and week remineraliza. Mousse## baseline. cannot be con- stomia cluded. cium phosphate plied with phate dehy. Leuven. ¶¶ CD-CP: Casein derivatives coupled with calcium phosphate. All rights reserved. ‡ NaF: Sodium fluoride. Australia) daily for three months fol- JADA. crossover. 18. soothing pain outside care. In situ: gum Crossover. §§ CaHPO4 / CaCO3: Calcium hydrogen phosphate/calcium carbonate. 53 ± times daily mouthrinse line and 12 in dry mouth power (type II 14 years) 3 times daily months syndrome error).ada. †† L: Liter. 2013 trol over care outside study Itthagarun 12 adults (age. † CPP-ACP: Casein phosphopeptide—amorphous calcium phosphate. ** mL: Milliliters. different CPP. ## GC Tooth Mousse is manufactured by GC Europe N. 2005 38 calcium phos. ‡‡ CaCO3: Calcium carbonate. Morton. 23-48 3 minutes applying GC effect in control over years) Tooth Mousse. were randomly assigned to two groups. POPULATION INTERVENTION CONTROLS OUTCOME STUDY COMMENTS YEAR AUTHORS’ CONCLUSIONS Shen and 30 adults (age. 10. not 4 weeks after subject. urea-containing short washout. 58% colleagues. testing effectiveness cohort.

preventing caries sample. Although the findings point to signif- authors concluded that the CD-CP mouthrinse. by the same group of investigators cence measurements. as extension to the study by Hay and regarding the long. with 0 being effect of casein derivatives when comparing the no visible color change and 4 being a distinct test groups with control groups. Biberach. Consequently. 2013 group that underwent the CPP-ACP regimen with faction44). These studies were reading (DIAGNOdent. the study38 found no difference in outcomes ever.ada. the results of this recommendation. the study lacked an appropriate control or did not contain calcium with regard to both group and masking of the evaluators. casein derivatives used in dentistry. Hay and Morton term effectiveness of same in situ protocol that resulted administered a self-evaluation casein derivatives in in significant findings in favor of survey to 38 patients in the original this technology. treatment of patients with dentin hypersensi. Second. appraising the evidence. Vol. CPP-ACP molecule consists of any special prop- tified one prospective study45 that evaluated the erties in comparison with dicalcium phosphate efficacy of CPP-ACP (GC Tooth Mousse) in the dehydrate. The survey asked them to Findings. study38 do not support the conclusion that the Treating dentin hypersensitivity. mineral change and depth of demineralized 922 July 2008 Copyright © 2008 American Dental Association.ada. trial evidence to make who patented the CPP-ACP com- Treating dry mouth.36. The situ model. The results of the white color change) and laser fluorescence last study43 were conflicting. six of the follow-up visits—when the investi.42).11. Moreover.37 which included a showed significant improvements (P < . focused on caries prevention. Ger. icant caries preventive potential of CPP-ACP when used as an atomized spray in the mouth. However. We iden. All rights on September 20. provided good moistening and lubrication. well as another study. . while two the use of clinical assessment of the lesions did not find any additional caries-preventive (visual scoring on a scale from 0 to 4.36. The other independent study41 was conducted tivity. studies conducted by groups inde- with their usual mouth-moistening pendent of those that patented the strategies (for example. The con- trol group (n = 13 subjects with 62 sites) rinsed This report aimed to review the clinical trials of daily with a 0. groups—at baseline or at any of the The authors found Investigators. but specifically CPP-ACP) are group across a 12-month follow-up period with efficacious in preventing dental caries.05 percent sodium fluoride mouth. Hong Kong (one study38).40. of the four compare the CD-CP mouthrinse in vivo. How. EVIDENCE-BASED RECOMMENDATIONS brushing with a fluoridated dentifrice. using artificial saliva). Seven of these The results showed a significant improvement studies showed that casein derivatives (both CD- (regression) in white-spot lesions within each CP and CPP-ACP.39.11. chewing gum.CLINICAL PRACTICE CRITICAL REVIEW lowed by a three-month regimen of daily tooth. We identified wash and used fluoridated dentifrice for six 10 studies (eight in situ and two in vivo) that months.42 These six studies. Mousse) in treating dentin hypersensitivity. 139 http://jada. eight in situ studies were conducted insufficient clinical gators considered the laser fluores. we point cant differences between the out the following.38 followed the 37 44 Thomson. We also identi- completely after three months (55 percent in the fied one prospective study conducted in Poland45 test group versus 18 percent in the control group) that found insufficient effectiveness and short- and after 12 months (63 percent in the test group term therapeutic effect of CPP-ACP (GC Tooth versus 25 percent in the control group).01) for the descriptive survey regarding patient satis- Downloaded from jada. First. As an a recommendation plex. when added to urea-containing chewing gum.10. some methodological flaws (Table 2) limited between CPP-ACP and dicalcium phosphate the level of evidence and strength of the dihydrate. as short-term therapeutic effect of CPP-ACP were described earlier. In the study results showed no signifi. Germany (one regard to the number of sites that disappeared study41) and Sweden (one study43). The study concluded that the efficacy and in Germany using a different in situ model. differences between chewing gums that contained However. sipping complex. conducted in Australia (six studies10.39. This study found no significant insufficient in treating dentin hypersensitivity. the clinical visual scoring New Zealand (one study. KaVo. one38 used a similar in water. many).

43 1116-1119. limited or no loss to follow up and carefully stan. Reynolds EC. Caries Res 2004. Dental tivity. This is especially important in clinical caries in the cotton rat. 15. J Dent Res supersaturated calcium phosphate state in 2001.31:439-447. Harper DS. Cai F. Anticariogenic complexes of amorphous calcium phosphate stabilized by casein phosphopeptides: a review. Shaw J. treating dentin hypersensitivity or dry mouth.: U. Guggenheim B. which was conducted in Sweden. Zepplin M. J Dent Res”. Neeser JR. 8. Young DA.: U. The effects of cheese snacks on caries in desalivated rats. Bowen WH.ada. Structures of biological minerals in dental effectiveness of casein derivatives. webcitation.63(1):107-117. Food and Drug Administration. Hefferren JJ.29(11):927-933. Drs.63(6): orthodontic treatment) in the CPP-ACP group 894-896.05 percent NaF mouthrinse daily).33(6):446-454. Protein factors and experimental rat dardized methods of measurement and caries. 2008. ■ of carbohydrate.S. Shaw J. Spec Care We conclude that there is insufficient clinical Dentist 1998. Reynolds EC.38(6):551-556. Rosen S. 2007. Neeser encing tooth loss and dental caries. 3. chewing gum versus dental paste. Center for Devices and Radiological designed and -conducted. Vol. 17. The results For a complete version of Table 4. Schmid R. J Dent Res 1996. Md. Black CL. Jenkins GN. analysis—is needed to enable researchers to eval.75(10):1779-1788. Huq NL. derivatives in various products (for example. J Dent Res 1987. Walker G. cium phosphate complexes of tryptic casein phosphopeptides in the rat.74(6):1272-1279. CLINICAL PRACTICE CRITICAL REVIEW lesions. Modification of compared with the control group (which received food cariogenicity in rats by mineral-rich concentrates from milk.106:1035-1044. Rockville. “www. J Dent Res 1995. 6. GRN 000011. Dental caries in the cotton rat. with and without sucrose. Shen P. However. del Rio A. . Azarpazhooh and Limeback did not report any disclosures. the authors found no significant differ. Caries Res 1987. and car- mouthrinse) in reducing or eliminating dental bohydrate in the diet on the incidence and extent of carious lesions. patience and constructive comments and suggestions to improve the manuscript. random. Molecular modelling of the mul- trial evidence (in quantity. 12. J Nutr 1957. soluble components of cheese on experimental caries in humans. 22. lozenges. Takagi on September 20. Rouvet M. Krobicka 5SfOiUhEu”. Center for Food Safety and Applied Nutrition.webcitation. 2. Food and Drug Administration. The highest level of evidence—that is. Osborn JC. a limitation of the in situ methodolog. 9. part VIII: further studies on the dietary effects trials in which outcomes are measured in vivo. CPP-ACP. Effect of cheese.S. Golliard M. Arch Oral Biol Using a clinical visual scoring system. 4. Mathew M. recruited for this study was at high risk of experi. Schweigert B. Cai F. et al. Aeschlimann JM.ada. see supplemental data in the online version of this article at “http://jada. J Dairy Res 2004. Res 1987. on dental caries and spot lesions (resulting from one year of fixed Downloaded from jada. white-spot lesions or dentin hypersensi. Harper DS. Silva MF. ical approach. We should note that the population 1. Health. Burgess RC. Powdered milk micellar casein prevents oral colonization by Strep- tococcus sobrinus and dental caries in rats: a basis for the caries-protec- results may not be generalizable to a general tive effect of dairy products. were conflicting. 21. bovine enamel and change in plaque composition by casein in an intra- Third. 19. Elvehjem C.66(1):38-41. double-blind. J Dent Res 1987. Effect of casein and whey-protein solutions on caries experience and feeding patterns of the rat. Reynolds EC. Rockville. well. 14. Nutr 1946. 139 http://jada. Reynolds C. however.18(1):8-16. Reynolds EC. Vincent J. J Res Natl Inst Stand Technol 2001. phosphate. the 1984. Reynolds EC. Sandham HJ. the number The authors thank the JADA reviewers for their time. fat. However. in preventing caries in vivo and in 16. Caries Res 1999. oral model.71(1):28-32. 17. The prevention of sub-surface demineralization of ences between the groups over time. ized clinical trials with adequate sample size. 0. The third independent study37 was an in Disclosure. vivo trial that assessed carious lesions in patients with salivary gland dysfunction. McClure FJ. Berrocal R. Webber FL. Potts E. 1999. 510(k) premarket notification database. Agency response letter GRAS notice no. is that long-term caries Incorporation of caseinoglycomacropeptide and caseinophosphopeptide prevention has yet to be fully explored. J Nutr 2004. Cross KJ. Office of Device Evaluation. Reynolds EC. the JR. specifically research. Shen P. protein. Reynolds EC. 18. J Dent Res 1987. Harper WJ. quality or both) to tiphosphorylated casein phosphopeptide alphaS1-casein(59-79) based make a recommendation regarding the long-term on NMR constraints. Accessed June 9. and fat on the incidence and extent of carious JADA. In vivo into the salivary pellicle inhibits adherence of mutans streptococci. uate the efficacy and cost-effectiveness of casein 20. Aimutis WR. 2007. Effects of water- when analyzing the laser fluorescence measure. Zepplin M. Reynolds EC.66(6): The results of the last independent study. Reynolds EC. clinical trials with adequate follow-up are needed 10. All rights reserved. Cariogenicity of a confection supple- mented with sodium caseinate at a palatable level. Accessed Oct. Nowicki A. Md. Beck FM. CONCLUSION 13. J caries. Schupbach P.66(1):42-45. Confectionery composition and rat caries. of teeth lost was significantly higher in the CD- CP group. Bioactive properties of milk proteins with particular focus on anticariogenesis. J Dent ments. Phillips P. Bavetta July 2008 923 Copyright © 2008 American Dental Association. Anticariogenicity of cal- plaque. population. Guggenheim B. Finally. Schweigert B. Office of Premarket Approval. Acid to determine the efficacy of CPP-ACP in caries resistance of enamel subsurface lesions remineralized by a sugar-free chewing gum containing casein phosphopeptide-amorphous calcium prevention.134(4):989S-995S. Clayton R. 7.ada. Cain CJ. Beck EX. Min DB. “www. Iijima Y. thus.80(12):2066-2070. Caries Res 1989. 2013 recovery of Streptococcus mutans in rats.21(6):538-545. Remineraliza- tion of enamel subsurface lesions by sugar-free chewing gum containing potential formation of calculus resulting from the casein phosphopeptide-amorphous calcium phosphate. Black”. Pearson S. 23(5):368-370.66(6):1120-1127. researchers found significant regression of white 5. none of the studies tested for the 11. showed no difference between a NaF mouthrinse and a CD-CP mouthrinse. part VI: the effect of the amount of protein.

Lussi A. 2008. Botulinski B. calcium phosphate complex (DC-CP) [Dentacal] as a mouth moistener 34. Walker GD. Webber FL. Cai F. Binding characteristics of Streptococcus mutans for cal. Kierklo A. Leake JL.: GC America. 32. Evaluation of the product based on Recaldent technology 35. Caries Res com/images/pdfs/mi_clinical_bro. “www. Adv Med Sci 2006. Oral Health Prev Dent 2007.74(6):1272-1279. remineralization of enamel lesions by various forms of calcium in a cium and casein phosphopeptide. et al. 2007. Res 1997. Attin T. enamel carious lesions in situ (published correction in Caries Res 30. N Z Dent J 2003. Remineralization of 23.32:405-412. Shen P.48(4):240-243. Reynolds EC. Accessed June 4. The effect of chewing 26. Dawes C. Alsip. . Yiu C.41(5):377-383. All rights reserved. Caries Res 2005. Ontario: Health Canada.41(2):108-114. Cai F. Remineralization of enamel subsurface lesions by gums containing calcium phosphates on the remineralization of artifi- casein phosphopeptide-stabilized calcium phosphate solutions. 36. part 7: profes. Ill.73(1) fluorescence.39(3):251-254. Shen P. 2008. Hellwig E. Cai F. 38. alization: anticariogenic casein phosphopeptide-amorphous calcium 37. et al. Ramalingam L. Cai F. ACP: the next big thing. “www. J Dent Res 2003. and casein phosphopeptide-amorphous calcium phosphate to a sugar- Downloaded from jada. et al.pdf”. Itthagarun A. amorphous calcium phosphate. 139 http://jada.82(3):206-211. 42. J Dent Res 1995. Hawkins R. Black CL. Cain CJ. 924 JADA. 41. Thomson WM.ada.5(3):229-233. Hay KD.27(1):61-67. Andersson 45. Ottawa. pubs/adanews/adanewsarticle.195(6):313-317. Locker D.asp?articleid=2632”. (suppl 1):40-42.34(5):427-431. Radiol Endod 2002. Prevention. Rose RK. Oral Surg Oral Med Oral Pathol Oral cium phosphate complexes of tryptic casein phosphopeptides in the rat. Caries Res 2006. Morgan MV. Walker G. Effect of a casein/calcium phosphate-containing tooth cream and fluo. King July 2008 Copyright © 2008 American Dental Association. Seger RK.99(2):46-48. Effect of addition of citric acid ride on enamel erosion in vitro.51 dents to evidence-based decisions in dental care.41[3]:243).ada. Messer LB.CLINICAL PRACTICE CRITICAL REVIEW lesions. casein derivatives complexed with calcium phosphate in patients with 25. Jaworska M. Advances in enamel reminer.ada. sionally applied topical fluorides for caries prevention. et al. Manton DJ. Shaw JH. Shen P. Kay EJ. 1994. J Nutr 1950. Adding casein phospho. Shen P. Reynolds EC. Dabrowska E.76(9) on September 20. “www. Accessed June 4. Anticariogenicity of cal. Effect of a dental cream containing amorphous cream 2003. The efficacy of casein phosphoprotein- 2008. Pfeffer M. Br Dent J Twetman S. peptide-amorphous calcium phosphate to sports drinks to eliminate in Effects of various forms of calcium added to chewing gum on initial vitro erosion. casein phosphopeptide-amorphous calcium phosphate. Prospec MI Paste. Vol. Garvin J. 5SfPwrRYq”. Mayhall JT. Aust Dent J 24. in patients with severe xerostomia. Lennon S.41(1):13-24. Increased remineralization of calcium diffusion in streptococcal model dental plaques. Petersson LG. Arch Oral Biol tooth enamel by milk containing added casein phosphopeptide- 2000. 2007. Hay KD. Caries Res 2007. 39.93(3):271-275. J Dent Educ 2008. J Clin Dent 1999. 29. mouthrinse or sugar-free chewing gum. Noble J. 2013 31. Methodology. Pawinska M. 28.40(2):154-157. Cai F. Canadian Task Force on Preventive Health Care.45(7):569-575.gcamerica. Buchalla W. Kowalczyk A. 43. phosphate complexes on white spot lesion regression assessed by laser 33. free chewing gum on enamel remineralization in situ. Reynolds EC. Reynolds EC. Sköld-Larsson K. 2003. Retention in plaque and 27. J Dairy Res 2006. Altenburger MJ.webcitation. Accessed May 22. Introducing dental stu. Effects of dietary composition on tooth decay in the enamel subsurface lesions in situ by sugar-free lozenges containing albino rat. 44. Caries Res 2000. Rose RK. Becker K. Schirrmeister JF. Morton RP. J Nutr 1946. salivary gland dysfunction. in the treatment of dentin hypersensitivity. Azarpazhooh A.10:86-88. 72(1):87-109. A clinical trial of the anticaries efficacy of phosphate. Reynolds EC. Reynolds EC. Pediatr Dent 2005. Hallgren A. J Dent cial caries-like lesions in situ. Lennon AM. Effects of an anticariogenic casein phosphopeptide on 40.