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Preliminary evidence suggests remineralizing effects of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP)

L. Virginia Powell DMD, GPR .


Systematic Review Conclusion

Casein phosphopeptide-amorphous calcium phosphate shows promise as an anticariogenic agent.

Critical Summary Assessment

One long-term RCT and several short-term in vivo and in situ randomized control trials demonstrate the remineralizing effect of CPP-ACP, but there is inconclusive evidence to support its clinical use in preventing dental caries.

Evidence Quality Rating

Limited Evidence

Structured Abstract

Clinical Questions:

Is CPP-ACP effective in caries prevention?

Review Methods:

The authors searched multiple databases for articles that referenced CPP-ACP and its equivalent terms. The search was limited to clinical trials and systematic reviews published in English before August 31, 2008. They also reviewed the bibliographies of the selected articles. They excluded case reports, editorials, in vitro studies, and studies of non-human tissues. Two examiners reviewed included studies and conducted a quality assessment. They resolved disagreements through consensus. Primary outcome variables were caries prevention (DMFT/S), enamel remineralization (percent R), and change in lesion depth. The authors illustrated data with Forest plots and combined similar trials for meta-analyses of multiple subgroups.

Main Results:

The authors identified 3459 articles from which they selected 11 trials (nine in situ RCT, two RCT). They evaluated similar in situ studies (five) pooled into three subgroups. They evaluated all other in situ studies and RCT’s descriptively. CPP-ACP compounds were delivered via a variety of vehicles (gum, milk, lozenge, rinse), and in different dosages. All studies reported a significant improvement in percentage remineralization scores, which indicates that CPP-ACP promotes remineralization. Specifically, chewing a pellet of gum containing 18.8 mg CPP-ACP versus chewing gum with no CPP-ACP over a short-term (seven to 21 days) significantly improved percentage remineralization, with lower negative scores favoring the test intervention (weighted mean difference[WMD]of -8.01 [95 percent confidence interval [CI], -16.49 to -10.62; P = 0.00001]. Chewing gum with 10.0 mg of CPP-ACP resulted in a WMD of -7.75 (95 percent CI, -9.84 to -5.66; P = 0.00001). Further, a large clinical trial found that the odds of surface caries progressing in subjects who chewed gum containing 54 mg of CPP-ACP (P = 0.03)were 18 percent less likely to happen than in those who chewed placebo gum.


Short-term clinical in situ trials show that CPP-ACP has a remineralizing effect while a long-term in vivo clinical trial provides evidence of a caries-preventing effect.

Source of Funding:

The authors report no conflict of interest.


Importance and Context:

Recent systematic reviews and commentary have differed in their conclusions as to the clinical effectiveness of CPP-ACP as a caries-preventing agent.(1,2) The authors of this review provide evidence of CPP-ACP as a remineralizing agent in an artificial and “natural” clinical setting. Remineralization as a surrogate for caries prevention is not well established, therefore the authors of this systemic review may be overreaching.

Strengths and Weaknesses of the Systematic Review:

The authors conducted a well-designed search strategy, although they did not include gray literature and non-English studies. They examined the data statistically, and provided graphic representation. They did not discuss the dose-response relationship between CPP-ACP compounds and remineralization, nor did they comment on the relative effectiveness of different delivery vehicles or frequencies.

Strengths and Weaknesses of the Evidence:

The authors included studies that had high quality of randomization, blinding, and follow-up periods. The evidence includes two in vivo RCT’s, with only one having a large sample size. This large trial included only proximal, radiographically-defined caries as an outcome measure; it excluded pit and fissure, clinically-detected decay measurements. This trial, therefore, was a better measure of caries progression rather than of prevention. All other studies were of in situ design (demineralized,human enamel placed in a dental appliance), short-term, usually of two-weeks duration, and conducted by the CPP-ACP patent holders. In addition, these in-situ trials measured remineralization of artifical carious lesions instead of measuring actual prevention of enamel demineralization, eg. caries formation. There was insufficient evidence to conclude that CPP-ACP was superior to other preventive measures for providing anti-carious benefit.

Implications for Dental Practice:

Caries prevention remains a significant challenge despite the widespread use of theraputics such as fluoride, xylitol, and chlorhexidine. Although CPP-ACP products show promising results in slowing caries progression (as of 2009), more clinical trials of high quality are needed to determine additional caries-preventing benefits. REFERENCES: 1. Azarpazhooh, A and Limeback, H. Clinical efficacy of casein derivatives: a systematic review of the literature. J Am Dent Assoc 2008; 139: 915-924. 2. Bader, JD. Casein phophopeptide-amorphous calcium phosphate shows promise for preventing caries. Evid Based Dent 2010; 11(1): 11-12. Date of critical summary initial draft: 04/24/11

Critical Summary Publication Date:


These summaries are not intended to, and do not, express, imply, or summarize standards of care, but rather provide a concise reference for dentists to aid in understanding and applying evidence from the referenced systematic review in making clinically sound decisions as guided by their clinical judgment and by patient needs. American Dental Association © 2019