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of Pages 9

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Available online at www.sciencedirect.com

ScienceDirect

journal homepage: www.intl.elsevierhealth.com/journals/jden

Review

Long-term remineralizing effect of casein

phosphopeptide-amorphous calcium phosphate
(CPP-ACP) on early caries lesions in vivo:
A systematic review

Jialing Li a, Xiaoqiu Xie a, Yu Wang b, Wei Yin c, Joseph S. Antoun d,

Mauro Farella d, Li Mei c,d,*
a
Department of Orthodontics, Institute and Hospital of Stomatology, Nanjing University Medical School, Nanjing, China
b
Department of Preventive Dentistry, Institute and Hospital of Stomatology, Nanjing University Medical School, Nanjing, China
c
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
d
Discipline of Orthodontics, Department of Oral Science, Faculty of Dentistry, University of Otago, Dunedin, New Zealand

article info abstract

Article history: Objective: To assess the long-term (>3 months) remineralizing effect of casein phosphopep-
Received 24 October 2013 tide-amorphous calcium phosphate (CPP-ACP) on early caries lesions in vivo.
Received in revised form Data sources: PubMed, Web of Science, Embase, Cochrane-Central, Science Direct, CBM, and CNKI
26 March 2014 were searched up to April 2013. Only articles in English and Chinese were included. Grey literature
Accepted 28 March 2014 wasalsosearched.Randomizedorquasi-randomizedclinicaltrialsinwhichCPP-ACPwasdelivered
Available online xxx by any method were considered. All relevant studies underwent two independent reviews.
Study selection: Of the 738 studies screened, 83 studies were reviewed and eight selected for
Keywords: inclusion in the final sample. The follow-up period of the studies included varied from 3 to 24
CPP-ACP months. The long-term remineralizing effect of CPP-ACP in vivo was demonstrated in
Caries comparison with placebo in randomized controlled trial. However, there is conflicting
Remineralization evidence regarding the clinical efficacy of CPP-ACP when used in conjunction with fluoride
White spot lesions toothpastes. No specific side effect related to CPP-ACP usage was found.
Systematic review Conclusions: CPP-ACP has a long-term remineralizing effect on early caries lesions in
comparison with placebo, although this does not appear to be significantly different from
that of fluorides. The advantage of using CPP-ACP as a supplement to fluoride-containing
products is still unclear. High-quality, well-designed clinical studies in this area are still
required before definitive recommendations can be made.
Clinical significance: CPP-ACP is a promising remineralizing agent with a significant remi-
neralizing effect that has been demonstrated in both in vivo and in vitro studies. The
evidence to support its synergistic effect with fluoride is insufficient based on the current
existing long-term human randomized controlled trials.
# 2014 Elsevier Ltd. All rights reserved.

* Corresponding author at: Discipline of Orthodontics, Department of Oral Science, Faculty of Dentistry, University of Otago, Dunedin 9016,
New Zealand. Tel.: +64 3 479 7480.
E-mail addresses: li.mei@otago.ac.nz, doctormeili@hotmail.com (L. Mei).
http://dx.doi.org/10.1016/j.jdent.2014.03.015
0300-5712/# 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Li J, et al. Long-term remineralizing effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP)
on early caries lesions in vivo: A systematic review. Journal of Dentistry (2014), http://dx.doi.org/10.1016/j.jdent.2014.03.015
JJOD-2271; No. of Pages 9
2 journal of dentistry xxx (2014) xxx–xxx
1. Introduction
Dental caries remains a major health problem in most
countries though its prevalence, incidence, and severity have
declined in much of the developed world since the introduc-
tion of fluoride. In the last decade, the focus in caries research
has shifted to the development of methodologies for the
detection of early caries lesions and the non-invasive
management of caries lesions through remineralization to
preserve tooth structure.1 Fluoride is generally known to
promote remineralization, but its remineralization process
relies on calcium and phosphate ions from saliva. Therefore,
several new remineralizing agents have been introduced to
supplement and enhance the ability of fluoride to restore tooth
minerals.2,3
Casein is the predominant phosphoprotein in bovine milk
and accounts for approximately 80% of its total protein,
primarily as calcium phosphate-stabilized micellar com-
plexes.4 Casein phosphopeptide (CPP), which contains the
amino acid cluster sequence of -Ser(P)-Ser(P)-Ser(P)-Glu-Glu
from casein, is tasteless,5 has low antigenicity,6,7 and can be
purified as CPP-ACP nanocomplexes by selective precipitation,
ion exchange, or ultrafiltration.8 The remineralizing effect of
CPP-ACP has been demonstrated in several in vitro studies.
Reynolds showed that CPP could stabilize free calcium and
phosphate ions, while Rose showed that CPP-ACP bound well
to dental plaque.9,10 CPP-ACP was considered to be a calcium
phosphate reservoir, buffering the activities of free calcium
and phosphate ions, consequently helping maintain a state of
supersaturation that inhibits demineralization and enhances
remineralization.11,12 Additionally, it was indicated that CPP-
ACP interacted with fluoride ions to produce amorphous
calcium fluoride phosphate (ACFP), which was stabilized by
CPP at the tooth surface. This ACFP complex provided all of the
elements that were necessary to promote remineralization
with fluorapatite, which was more resistant to future acid
challenge.13
A large body of studies has demonstrated that CPP-ACP
has an anticariogenic effect by promoting remineralization of
enamel subsurface lesions.14–21 Several authors have
reviewed the literature in this area.22–25 The most recent
systematic review published in 2009, in which a meta-
analysis was conducted on the results of 5 human in situ
experiments, confirmed the short-term (7–21 days) reminer-
alizing effect of CPP-ACP.23 However, the common limitation
of those human in situ experiments was a small sample size
(<15) and a short follow-up period (<3 weeks). In addition,
among the studies that were pooled for a meta-analysis, 4 out
of 5 were conducted by the group of investigators who
patented the CPP-ACP complex.23 Although this latter
concern does not necessarily imply bias, the evidence
regarding the in vivo remineralization effect of CPP-ACP
remains insufficient due to the shortage of randomized
controlled trials at the time when that systematic review was
conducted (August 31, 2008).
Therefore, the aim of this systematic review was to assess
the long-term (>3 months) remineralizing effect of CPP-ACP
on early caries lesions in vivo compared with placebo and/or
fluorides.
Please cite this article in press as: Li J, et al. Long-term remineralizing effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP)
on early caries lesions in vivo: A systematic review. Journal of Dentistry (2014), http://dx.doi.org/10.1016/j.jdent.2014.03.015
2. Materials and methods
2.1. Type of studies
Randomized or quasi-randomized clinical trials with a follow-
up period of more than 3 months were included. In situ RCTs
were not included since these had already been included in an
earlier systematic review.23
2.2. Characteristics of the participants
Age limits were not set for the participants as long as they
were classified as healthy. Studies in which participants had
oral or general diseases were excluded.
2.3. Type of interventions
Studies using topical CPP-ACP in any modality, including
toothpaste, mouth-rinses, tooth mousse, and chewing gum
were included. Moreover, there were no restrictions regarding
the dose, frequency, duration, and method of administration.
2.4. Outcomes of studies
The primary outcome of studies was caries increment or
changes in the proportion of participants developing new
caries. For enamel white spot lesions (WSLs), which are
considered as the first stage of dental caries,26 the primary
outcome of the studies was extent/severity of newly devel-
oped WSLs.
The secondary outcome was the side effects of using CPP-
ACP, including discomfort, dental staining/discoloration, and
oral hygiene deterioration.
2.5. Search strategy
Systematic strategies were used for searching each database
to identify all the studies relevant to this review. The search
strategy developed for Medline (Appendix 1) was revised
appropriately for other databases. The following databases
were searched:
 MEDLINE via PubMed (1970 to 10/04/2013)
 Web of Science (1970 to 10/04/2013)
 EMBASE (1970 to 16/04/2013)
 CENTRAL (The Cochrane Library, 13/04/2013)
 Science Direct (1970 to 10/04/2013)
 CBM (Chinese Biological Medical), CNKI (Chinese National
Knowledge Infrastructure) database (1989 to 10/04/2013)
Our search strategy attempted to identify all relevant
studies written in English and Chinese, irrespective of their
date of publication. The reference lists of all eligible studies
were also hand searched for additional relevant studies.
Unpublished literature was also searched on ClinicalTrial.-
gov, the National Research Register, OpenGrey, and The World
Health Organization’s International Clinical Trial Registry
Platform. We found two ongoing trials that were still recruiting
participants.
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journal of dentistry xxx (2014) xxx–xxx 3

2.6. Data collection and analysis  Assessment methods

Two calibrated reviewers screened the titles and abstracts
(when available) of all identified studies independently and in
duplicate. Once the publication was considered by either
author to meet the inclusion criteria, the full-text article was
obtained and reviewed (Fig. 1). If important information about
a study was not available, the authors were contacted by e-
mail for further clarification. Any disagreement during study
selection and data extraction was solved by discussion and
consensus after consulting a third reviewer. Studies not
meeting our inclusion criteria were excluded and the reasons
for their exclusion were noted in Appendix 2. Data extraction
was completed independently by the two reviewers using a
specifically designed data extraction form. The following data
were collected:
 Authors and year of publication
 Number and age of participants
 Details of interventions and controls
 Follow-up period and check-time points
 Outcomes reported
Each study was assessed using the evaluation method
described in the Cochrane Handbook for Systematic Reviews of
Interventions 5.1.0. (http://handbook.cochrane.org). The domains
evaluated were random sequence generation, allocation conceal-
ment, blinding, incomplete outcome data, selective outcome
reporting, and other biases. 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 (all quality items
were met), unclear (unclear risk of bias for one or more domain), or
high (high risk of bias for one or more domain).
Mean differences (MD) and standard deviations (SD) were
used to summarize data in studies with continuous outcomes,
and Peto odds ratios (OR) and 95% confidence intervals (CI)
were used for studies with dichotomous outcomes. Moreover,
we planned to pool data and carry out a meta-analysis if there
were sufficient similarities among the included studies
regarding the types of participants, interventions, outcomes,
and time point of the outcome measurements.

Records identified (n = 1697)

MEDLINE (n = 211)
Identiication

EMBASE (n = 255) Referencesoffull text

CENTRAL (n = 95) articleschecked
Web of Science (n = 256)
Science Direct (n = 360)
CBM and CNKI (n = 520)

Duplicates removed (n = 959)

Screening

Records screened for relevancy

(n = 738)

Records Excluded (n = 655)

(Animal, in vitro, or irrelevant)
Eligibility

Full-text articles assessed for eligibility

(n = 83)
Study excluded, with reasons (n = 75)
- Not a RCT (n = 8)
- Review article (n = 35)
- In situ experiments (n = 18)
Study included in qualitative synthesis - Study includes non-healthy participants (n = 5)
(n = 8) - Focus on dentin hypersensitivity or tooth
Included

bleaching (n = 3)
- Abstract of another study (n = 1)
Study included in quantitative synthesis - Original article could not be located (n = 1)
(n = 0) - Minimum experimental time not meet (n=4)

Fig. 1 – Overview of the systematic review that illustrates the processes of identification, screening, eligibility assessment,
and retrieval of relevant studies. RCT, randomized controlled trials.

Please cite this article in press as: Li J, et al. Long-term remineralizing effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP)
on early caries lesions in vivo: A systematic review. Journal of Dentistry (2014), http://dx.doi.org/10.1016/j.jdent.2014.03.015
 4

JJOD-2271; No. of Pages 9

Table 1 – Summary of the included studies.
on early caries lesions in vivo: A systematic review. Journal of Dentistry (2014), http://dx.doi.org/10.1016/j.jdent.2014.03.015
Please cite this article in press as: Li J, et al. Long-term remineralizing effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP)

Type of First author Participants Follow-up protocol Type of Comparative/ Assessment Primary Type
demineralization (year) intervention/ Intervention control method outcome of study
control (age)
Early caries Morgan, M.V. 892/857 Baseline, 3% w/w CPP-ACP Control chewing gum + Bitewing radiographic Baseline to 24 m. RCT
lesions (2008) (11.5–13.5 years) 24 months gum, 3 times a Fluoride toothpaste diagnosis of interproximal No progression:
day + Fluoride lesions surface level OR 0.82,
toothpaste 95% (0.74, 0.91)
Progression: subject
level: OR 0.80, 95%
(0.65, 0.97)
Rao, S.K. 47/47/45 Baseline, 12, 2% w/w CPP-ACP 0.76% w/w SMFP/ Clinical assessment with Baseline to 24 month. RCT
(2009) (12–15 years) 24 months tooth paste, placebo toothpaste DS, DMFS, OHI index CPP/SMFP/placebo
2 times a day (Mean DDS  SD):
0.22  0.44/0.24  1.03/

journal of dentistry xxx (2014) xxx–xxx

0.62  1.92
Children without new
caries lesions (number
and percentage): 34
(72.3%)/25 (53.2%)/
14 (31.1%)
Sitthisettapong, 117/112 Baseline, 6, GC mousse Placebo paste + Clinical assessment with Baseline to 12 month CCT
T. (2012) (3.5–4.5 years) 12 months +fluoride fluoride toothpaste ICDAS criteria (No progression/
toothpaste progression):
OR 1.002, 95% CI
(0.86,1.17)

Post-orthodontic Andersson, 13 persons, Baseline, 1, 3, 6, Topical cream Fluoridated dentifrice DIAGOdent, and DIAGOdent value RCT
WSLs A. (2007) 70 sites/13 12 months for 3 months and combined with daily visual evaluation (Mean  SD):
persons, 62 sites daily toothbrush NaF mouth wash Baseline:
(12–16 years) with fluoride dentifrice test 7.4  10.2/
for 3 months control 9.4  9.5
1 m: test 5.5  6.7/
control 7.6  9.2
3 m: test 4.9  5.5/
control 6.8  8.1
6 m: test 4.6  5.1/
control 6.4  7.3
12 m:test 4.4  5.2/
control 6.4  7.5
Bailey, 23 person, 207 Baseline, 4, 8, MI paste + Fluoride toothpaste + Clinical assessment Baseline to 12 w. RCT
D.L. (2009) sites/22 person, 12 weeks Fluoride placebo cream with ICDAS criteria All WSL: OR 1.67,
201 sites toothpaste 95% CI (0.81,3.45)
(12–18 years) WSL with severity
2 or 3: OR 2.33,
95% CI (1.06,5.14)
 JJOD-2271; No. of Pages 9
Table 1 (Continued )
on early caries lesions in vivo: A systematic review. Journal of Dentistry (2014), http://dx.doi.org/10.1016/j.jdent.2014.03.015
Please cite this article in press as: Li J, et al. Long-term remineralizing effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP)

Type of First author Participants Follow-up protocol Type of Comparative/ Assessment Primary Type
demineralization (year) intervention/ Intervention control method outcome of study
control (age)
Beerens, 27 patients, Baseline, 6, MI paste plus + Fluoride-free control paste + QLF Baseline (Mean  SD): RCT
M.W. (2010) 511 surface/27 12 weeks Fluoride toothpaste Calcium + Fluoride toothpaste test: DF: 8.45  1.17, A:
patients, 491 5.07  5.69; Control:
surface DF: 9.10  1.75,
(15.5  1.6 years) A: 7.29  7.91
12 w (Mean  SD):
Test: DF: 7.52  1.78,
A: 5.05  6.98/
control: DF: 7.96  2.76
A: 7.17  7.76

journal of dentistry xxx (2014) xxx–xxx

Demineralization Robertson, 26 patients, Start, 4, 8, Tooth brushing + Tooth brushing + Photographic records Baseline (test/control): RCT
during orthodontic M.A. (2011) 416 tooth/24 12 weeks M1 paste plus Placebo paste with EDI; clinical Sum of EDI: 271/135;
treatment patients, 384 assessment with Sum of ICDAS: 145/116
tooth (>12 years) ICDAS criteria 12 w (test/control):
Sum of EDI: 126/258;
Sum of ICDAS: 80/166
Demineralization He, W.D. 25/25/25 Before, after Tooth brushing + Tooth brushing + Clinical assessment EDI index of GC CCT
before and after (2010) (12–17 years) orthodontic treatment GC moosse Fluoride vanish every with EDI tooth mousse/fluoride/
orthodontic (mean treatment 3 months control group
treatment time: 21.9 months) (Mean  SD):
0.078  0.006/
0.082  0.009/
0.155  0.023
NaF, sodium fluoride; ICDAS, International Caries Detection and Assessment System; WSL, white spot lesion; QLF, quantitative light-induced fluorescence; DF, change in fluorescence; A, lesion area;
SMFP, sodium monofluorophosphate; DS, Decayed surfaces; DMFS, decayed, missing and filled surfaces; OHI, Oral Hygiene Index; EDI, enamel decalcification index; RCT, randomized controlled trial;
CCT, controlled clinical trial.

5
JJOD-2271; No. of Pages 9

6 journal of dentistry xxx (2014) xxx–xxx

chewing CPP-ACP gum significantly enhanced the regression of

3. Results
Of the 738 articles screened for relevancy, 83 articles were
retrieved, reviewed, and critically appraised. Of these, eight
studies (7 in English17,18,27–31 and 1 in Chinese32) met the
inclusion criteria and were used in the present systematic
review (Table 1).
3.1. Study characteristics
Of the 8 articles included in this review, six were randomized
controlled trials (RCTs)17,18,27–30 and two were controlled
clinical trials (CCTs).31,32 A total of 2367 participants were
evaluated, with all of them being classified as healthy by the
authors. All eight studies reported on the age and number of
participants. Most of the participants were adolescents (age:
11.5–18 yrs),17,18,27–30,32 with the exception of one trial which
included preschool children (age: 3.5–4.5 yrs).31
The follow-up studies varied from 3 month18,29,30 to 24
months,17,28 depending on the different outcome measures
used to detect caries lesions. Studies using clinical examina-
tion as a diagnostic method usually had longer observation
periods (>1 year),17,28,31 compared with those using digital
instruments for diagnosis (<6 months).29
CPP-ACP was marketed under the trade names of ‘‘GC
mousse’’, ‘‘MI paste’’, ‘‘MI paste plus’’, and ‘‘Topacal C-5’’ in the
included studies. According to the manufacturer, the concen-
tration of CPP-ACP was 10% w/w in the first three products, and
5% w/w in ‘‘Topacal C-5’’. The ‘‘MI paste plus’’ was a
combination of 900-ppm sodium fluoride and ‘‘MI paste’’.29,30
The modality used to deliver these products included water-
based mousse, topical cream, paste, and chewing gum.
3.2. Primary outcome of studies
Among the eight studies included (Table 1), three evaluated the
effect of CPP-ACP on naturally occurring caries.17,28,31 A
significant reduction in caries increment was observed after
using CPP compared with placebo.28 In a 2-year-follow-up study,
approximal caries compared with placebo gum.17 However, no
clinical advantage was found for using extra CPP-ACP (10%w/w)
after brushing with fluoridated toothpaste.31
Another five trials assessed the effect of CPP-ACP on WSLs
that were associated with orthodontic treatment,18,27,29,30,32
among which three found no clinical advantage for using CPP-
ACP supplements to fluoride toothpaste.18,27,29 In contrast, the
other two trials found that CPP-ACP helped prevent WSLs.30,32
However, both studies failed to clarify whether the toothpaste
used in the controls contained any fluoride.
The primary outcome measures used in the eight studies,
included clinical assessment using the International Caries
Detection and Assessment System (ICDAS) criteria or DS/
DMFS index, clinical or photographical assessment using
Enamel Decalcification Index (EDI), bitewing radiography for
approximal caries increment, and reading of fluorescence-
based devices (QLF/DIAGOdent).
3.3. Secondary outcome of studies
No serious side effects were reported in studies assessing the
clinical safety of CPP-ACP usage.17,18,28,31 In Morgan’s two-year
follow-up study, no significant differences were found in the
incidence of side effects (i.e. nausea, headache, and diarrhoea)
between the intervention and control groups.17 No allergies or
serious side effects were recorded in Rao’s and Bailey’s trials
as well.18,28 Sitthisettapong also confirmed by email corre-
spondence that no extra calculus formation had occurred on
the primary teeth in their experimental group.31 The other
four articles lacked information about the side effects of using
CPP-ACP.27,29,30,32
3.4. Risk of bias
Of the eight studies included (Table 2), only one study was
judged to have a low risk of bias,28 while the other seven were
rated as having a high risk of bias or an unclear risk of bias.
Substantial differences were found in the intervention mea-
sures, time points of outcome assessment, and measurement

Table 2 – Risk of bias of the eight included studies.

First author Adequate Allocation Blinding of Blinding of Incomplete Free of Free Level of
(year) sequence concealment participants outcome outcome data selective of other bias risk
generation and personnel assessment addressed reporting bias
Morgan, M.V. Yes Yes Yes Yes Yes No No High
(2008)
Rao, S.K. Yes Yes Yes Yes Yes Yes Yes Low
(2009)
Sitthisettapong, No Yes Yes Yes Yes Yes No High
T. (2012)
Andersson, Yes No No Yes Yes Yes Unclear High
A. (2007)
Bailey, D.L. Yes Yes Yes Yes Yes Yes Unclear Unclear
(2009)
Beerens, Yes Unclear Yes Yes Yes Yes Yes Unclear
M.W. (2010)
Robertson, Yes Unclear Unclear Yes No Yes No High
M.A. (2011)
He, W.D. (2010) No No No Yes Yes Yes Unclear High

Please cite this article in press as: Li J, et al. Long-term remineralizing effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP)
on early caries lesions in vivo: A systematic review. Journal of Dentistry (2014), http://dx.doi.org/10.1016/j.jdent.2014.03.015
JJOD-2271; No. of Pages 9
journal of dentistry xxx (2014) xxx–xxx
methods. Meta-analysis was impossible both due to high risk of
bias and clinical heterogeneity.
4. Discussion
The present review has highlighted a lack of relevant research
with low risk of bias on the effect of CPP-ACP on caries lesions,
suggesting that CPP-ACP has a long-term (>3 months)
remineralizing effect on early caries lesions in vivo compared
with placebo. But its synergistic effect with fluoride to restore
early caries lesions still remains controversial.
Few eligible studies met the inclusion criteria despite the fact
that both English and Chinese databases were searched. Only
one study was judged to have a low risk of bias,28 while the other
seven were rated as having either a high or an unclear risk of
bias. The main risk of bias associated with these studies
includes incorrect random sequence generation, single-blind-
ing, inadequate sample size, and unreliable statistical analyses
due to failure to consider clustering effects.27,30–32
WSLs resulting from orthodontic treatment were included
in our literature search because they represent the prelimi-
nary stage of subsurface enamel demineralization, and are
generally considered the early stage of the carious process.26,33
In contrast to normal populations, however, the micro-
ecology of orthodontic patients seems to change following
the placement of fixed appliances and this may influence the
effect of CPP-ACP in this population group.34,35 In addition,
orthodontic appliances are known to impede oral hygiene,
which may also reduce the clinical efficacy of CPP-ACP on
WSLs. Since the effect of CPP-ACP may differ in normal and
orthodontic patient groups, future systematic reviews should
analyze these two groups separately.
The concentration of CPP-ACP used in the trials varied from
2% to 10% w/w. It has been reported that CPP-ACP produce a
similar remineralization effect with 2800 ppm F at 2% w/w
concentration,36 and could efficiently promote enamel remi-
neralisation at 3% w/w.37 The highest concentration of CPP-
ACP that is currently available in commercial dental products
is 10% w/w (e.g., 5% w/w in ‘‘Topacal C-5’’ and 10% w/w in ‘‘GC
mousse’’, ‘‘MI paste’’, and ‘‘MI paste plus’’).
The one study that reported positive findings compared the
remineralizing effect of CPP-ACP with a negative control
(placebo) only,28 and not with a positive control, such as
fluoride toothpaste, whose benefits and anti-cariogenic effect
have been well recognized.38–41 Considering that fluoride
toothpastes are widely used nowadays, and participants in
these remineralizing trials have already suffered from enamel
demineralization and can generally be considered as a high-
risk population, we would recommend the use of fluoride
toothpastes as controls in future studies.
Various methods have been used to detect caries lesions in
previous research, with clinical examination and radiography
being the traditional methods for decades. However, even
when these methods are used in conjunction with clinical-
based indices (such as DS/DMFS index,28 ICDAS criteria,18,30,31
and EDI index30,32), their reproducibility are still relatively
poor. Fluorescence-based devices have recently been intro-
duced for the detection of early caries lesions, and these
include laser fluorescence (DIAGNOdent) and Quantitative
Please cite this article in press as: Li J, et al. Long-term remineralizing effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP)
on early caries lesions in vivo: A systematic review. Journal of Dentistry (2014), http://dx.doi.org/10.1016/j.jdent.2014.03.015
7
Light-induced Fluorescence (QLF). DIAGNOdent is a sensitive
tool that can detect lesions at the dentine level, but sometimes
produce false positive results.42,43 QLF can detect a variety of
caries lesion, including secondary caries, smooth surface
caries, and demineralization adjacent to orthodontic brackets.
Similar to DIAGNOdent, results obtained using QLF should be
considered in conjunction with other detection methods.44,45
Since no single method provides adequate reliability for early
caries detection, it may be beneficial to combine at least two of
these detection methods together in future studies.
The follow-up time of studies also varied greatly from 3
months to 2 years. Four studies were excluded from this review
due to their short experimental times.46–49 Although recent
improvement in detecting techniques of early caries has
reduced the time needed to observe changes of demineraliza-
tion/remineralization,45 evidence from studies on fluoride, CPP-
ACP and other caries-preventive agents, suggests that a follow-
up period of more than 3 months is usually needed.29,50–52
Moreover, the observation period needed to determine the
clinical safety of CPP-ACP also requires a relatively long follow-
up.17 In consideration of these factors, a follow-up period of
more than 3 months (preferably, more than 6 months) is
recommended in order to detect any beneficial or adverse
events in future studies on caries-preventive agents.
Some studies failed to present information about the
potential side-effects of CPP-ACP usage.27,29,30,32 In studies that
assessed clinical safety, no significant differences were found
between the CPP-ACP group and the controls with respect to the
incidence of adverse events, including increment of dental
calculus formation, allergies, and other serious side
effects.17,18,28,31 Safety assessment should always be considered
an important and necessary part of a well-designed RCT.53
Half of the studies did not take the clustering effect into
account.27,29–31 The assumption that tooth surfaces are
independent within an individual can result in an underesti-
mation of the standard error for the treatment difference and
an exaggerated p-value for the comparison between the
experimental and control groups.17,54 Two studies accounted
for the clustering effect by reporting the intra-class correlation
coefficient (0.1–0.12).17,18 Ideally, the clustering effect should
be considered either when calculating the sample size at the
design stage of a trial, or when analyzing the data at the final
stage of a trial.55–57
5. Conclusion
Within the limitation of this systematic review, CPP-ACP was
found to have a long-term remineralization effect on early
caries lesions in comparison with placebo, although this effect
was not significantly different from that of fluoride agents.
The clinical benefits of using CPP-ACP supplements over
fluoride are still unclear. Well-designed RCTs are, therefore,
required to improve the level of evidence in this area.
Conflicts of interest
None of the authors have any conflicts of interest in relation to
this study.
JJOD-2271; No. of Pages 9
8 journal of dentistry xxx (2014) xxx–xxx
Acknowledgements
This study was supported by the grants from the National
Natural Science Foundation of China (No. 81301476). The
authors would also like to thank Professor Huang Li for
funding for this review (National Natural Science Foundation
of China, No. 81070807).
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.jdent.2014.03.015.
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