The Journal of EVIDENCE-BASED DENTAL PRACTICE

FEATURE ARTICLE

THERAPIES FOR WHITE SPOT LESIONS—A

SYSTEMATIC REVIEW

ANABELA BAPTISTA PEREIRA PAULA, DMD, MSca, ANA RITA FERNANDES, DMD, MScb,
ANA SOFIA COELHO, DMD, MSca, CARLOS MIGUEL MARTO, DMD, MScc,
MANUEL MARQUES FERREIRA, DMD, PhDd, FRANCISCO CARAMELO, PhDe,
FRANCISCO DO VALE, DMD, PhDf, AND EUNICE CARRILHO, DMD, PhDg
a
Teaching Fellow, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
b
Faculty of Medicine, University of Coimbra, Coimbra, Portugal
c
Teaching Fellow, CNC.IBILI, CIMAGO, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
d
Assistant Professor with “Agregação” of Endodontics, CNC.IBILI, Faculty of Medicine, University of Coimbra, Portugal
e
Assistant Professor of Biophysics, CNC.IBILI, Faculty of Medicine, University of Coimbra, Portugal
f
Assistant Professor of Orthodontics, Faculty of Medicine, University of Coimbra, Portugal
g
Full Professor of Restorative Dentistry, CNC.IBILI, Faculty of Medicine, University of Coimbra, Portugal

ABSTRACT CORRESPONDING AUTHOR:

Anabela Baptista Pereira Paula,
Introduction
Faculty of Medicine, University of
The first sign of dental caries is denoted by white spot lesions (WSLs) which can
Coimbra, Av Bissaya Barreto,
be defined as a demineralization of the enamel surface and subsurface, although
Coimbra, Portugal.
these lesions can be reversed and do not form cavities. The aim of this systematic
E-mail: anabelabppaula@sapo.pt
review was investigate which remineralization agents are effective for the treat-
ment of WSLs.
KEYWORDS
Materials and Methods white spot lesions, fluorides, CPP-
For this systematic review a literature search was conducted on Pubmed, ACP, ICON, prevention, treatment
Cochrane Library and ScienceDirect.

Results
The initial search resulted in 273 references. After elimination of duplicate arti- The second author had an
cles, 236 references remained. After reading titles and abstracts, all non-relevant equivalent contribution to the first
results were excluded, resulting in 45 potentially relevant studies. After reading author in the conduct of the work
the full text, 13 references were included. and preparation of the article.
Source of Funding: This research did
Conclusion
not receive any specific grant from
More studies are required for scientific evidence in order to reach a conclusion of
funding agencies in the public,
the most suitable therapeutic method for the treatment of surface and subsurface
commercial, or not-for-profit sectors.
demineralization of the enamel.
Conflict of Interest: The authors have
INTRODUCTION no actual or potential conflicts of
interest.

D ental caries is one of the most common and preventable diseases of

childhood.1 The process of caries formation is a cycle of remineralization
and demineralization with various stages being either reversible or irreversible.1
Received 3 August 2016; revised 16
October 2016; accepted 17 October
White spot lesions (WSLs) are defined as enamel surface and subsurface 2016
demineralization,2-5 without cavitation.6 These manifestations represent the first J Evid Base Dent Pract 2017: [23-38]
clinical observation of the progression of dental caries, with the possibility of 1532-3382/$36.00
being reversed.2,3,7,8 ª 2016 Elsevier Inc.
All rights reserved.
WSLs develop as a result of prolonged plaque accumulation on the affected doi: http://dx.doi.org/10.1016/
surface,7,9-14 commonly due to inadequate oral hygiene.7,9-13 With the j.jebdp.2016.10.003

March 2017 23

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 The Journal of EVIDENCE-BASED DENTAL PRACTICE
maintenance of these conditions, acids diffuse into the
enamel and begin the demineralization of subsurface
enamel.15 If the demineralization process is not stopped,
the intact enamel surface eventually collapses and
cavitates.15,16
These lesions are characterized by a white, chalky, opaque
appearance and are commonly located in pits, fissures, and
smooth surfaces of teeth.1 However, after the placement of
fixed orthodontic appliances, there is an increasing number
of plaque retention sites due to the presence of brackets,
bands, wires, and other applications, which make oral
hygiene more difficult7,9,11,13,15,17-20 and limit naturally
occurring self-cleansing mechanisms.7 As a consequence,
there is an increased risk of demineralization and,
conclusively, of WSLs forming on smooth surfaces, if there
is no effective plaque removal.20
The clinical characteristics of these lesions include loss of
normal translucency of the enamel because of altered light
properties with a chalky white appearance, particularly when
dehydrated; a fragile surface layer susceptible to damage
from probing, particularly in pits and fissures; increased
porosity, particularly of the subsurface, with increased po-
tential for uptake of stains; reduced density of the subsur-
face, which may be detectable radiographically, with
transillumination or with modern laser detecting devices;
and potential for remineralization, with an increased resis-
tance to further acid challenge particularly with the use of
enhanced remineralization treatments.21
The white appearance of early enamel caries is due to an
optical phenomenon which is caused by mineral loss in the
surface or subsurface enamel.7,19,22 Enamel crystal dissolu-
tion begins with subsurface demineralization, creating pores
between the enamel rods.7 The resultant alteration of the
refractive index in the affected area is then a consequence
of both surface roughness and loss of surface shine and
alterations in internal reflection, all resulting in greater
visual enamel opacity.7,19,22
Figure 1. Example of white spot lesions during
orthodontic treatment.
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The overall prevalence of WSLs amongst orthodontic patients
has been reported as anywhere between 2%7,11,13,18,19,23 and
97%.4,18,24 Its presence can be detected as early as 4 weeks
into orthodontic treatment.19 Usually, orthodontic patients
have a significantly higher incidence of WSLs compared to
nonorthodontic patients4,7 and may also exhibit esthetic
changes few years after treatment.25 Approximately, 50% of
patients develop more than one WSL during orthodontic
treatment,26,27 whereas only 24% of the patients who do not
have this treatment develop them.27 In orthodontic patients,
5.7% of the teeth are affected (Figure 1).26
It is possible to find numerous therapies in the literature, for
instance, education and hygiene education,15,28 fluo-
rides,7,8,10,23,28-33 phosphopeptide compounds,12,15,27,34,35
xylitol,15 infiltrative resins,15,35,36 microabrasion and/or
bleaching,11,16,37 and preparation and restoration.24
In the oral cavity, the presence of fluorides decreases the
development/progression of dental caries by 3 different
mechanisms: inhibition of demineralization of the enamel, in-
crease in remineralization of the enamel,7,8 and inhibition of the
bacterial enzyme producers of acids.29 The professional
application or prescription of fluorides for home use includes:
gels and toothpastes (maximum 5000 ppm), mouthwashes
(223 ppm), and varnishes (23,000 ppm).30 The fluoride ions
are revealed in 3 ways: sodium monofluorophosphate,
sodium fluoride, and amine fluoride.31 It has been described
in the literature that high fluoride concentrations promote
WSL remineralization for hypermineralization.8,10,28,32,33
However, it occurs in the enamel surface and inhibits the ions’
movement through the subsurface, affecting the subsurface
remineralization and therefore, the light reflection.10,23,33
The casein phosphopeptides (CPPs) have the remarkable
ability of stabilizing the calcium and phosphate ions present in
the solution, creating the casein phosphopeptides with
amorphous calcium phosphate (CPP-ACP complex).34 This
complex increases the calcium and phosphate levels,
promoting the remineralization process.12,15,27 Although this
does not occur without the presence of fluorides, the CPP-
Table 1. Drafting scheme of PICO question.
Population Patients with WSLs (white spot lesions)
Intervention Remineralization therapies with different
agents and techniques
Comparison Comparing the different therapies and
agents with each other
Outcome Regression or disappearance of lesions
PICO, problem-intervention-comparison-outcomes.

Figure 2. Diagram of the included studies.
ACFP complex (casein phosphopeptides with amorphous
calcium phosphate and fluoride) exists commercially for
this.15,38
Infiltrative resins had been commercialized as a minimal
invasive restorative treatment which involves the resin
penetration inside the body of the WSL, with minimal enamel
loss.35 This technique uses etch-and-rinse acid to remove the
superficial layer of enamel, exposing the WSL demineraliza-
tion, infiltrating the lesion with a low viscosity resin.35,36 The
therapeutic purposes are the mechanic stabilization of the
hydroxypatite structure instead of WSLs cavitation.15
This systematic review intends to assess which are the most
effective remineralization agents in the treatment of WSLs.
MATERIAL AND METHODS
The population, intervention, comparison, outcome ques-
tion used in this study was “In patients with white spot le-
sions, what are the remineralization therapies more effective
at regression or disappearance of lesions” (Table 1).
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The Journal of EVIDENCE-BASED DENTAL PRACTICE
For this systematic review, a literature search was conducted
in the Pubmed (http://www.ncbi.nlm.nih.gov/pubmed),
Cochrane Library (http://www.cochranelibrary.com/), and
ScienceDirect (http://www.sciencedirect.com/) databases.
In the Pubmed database, the following search equation was
used: ((white spot*)) AND ((“Tooth Demineralization/drug
therapy” [Mesh] OR “Tooth Demineralization/surgery”
[Mesh] OR “Tooth Demineralization/therapy” [Mesh] OR
“Tooth Demineralization” [Mesh] OR “Tooth Reminera-
lization/methods” [Mesh] OR “Fluorides/pharmacology”
[Mesh])). The inclusion criteria were all published between
29-09-2005 and 29-09-2015, in English and Portuguese,
with abstract.
In the ScienceDirect database, the following combinations for
searching were used: (“white spot” and “tooth remineraliza-
tion”), (“white spot” and “tooth demineralization”), and
(“white spot” and “fluorides”) found in the title, abstract, or
keywords. The inclusion criteria were all published between
2005 and 2015; the research date was until 29-09-2015.
March 2017 25
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The Journal of EVIDENCE-BASED DENTAL PRACTICE

Table 2. Summary of included studies.
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Participants Assessment Start End

Therapies agents Authors (control/test(s)) Follow-up method Control/test(s) (control/test(s)) (control/test(s)) Conclusion

Fluorides Sonesson 192/188 20 mo Photographs Colgate 1450 ppm NW 1.0 (1.8)/ NW 1.2 (1.8)/ Significant
et al.39 NaF/Duraphat 0.3 (1.0) 0.4 (1.0) reduction of WSLs
5000 ppm NaF with Duraphat.
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P (%) 18.7/16.5 P (%) 45.3/34.6

Du et al.25 49/47 6 mo DIAGNOdent Saline solution/ DR 16.19 (5.70)/ DR 13.10 (5.19)/ Significant
(monthly pen Duraphat 17.6 (5.36) 10.10 (4.86) reduction of WSLs
checks) with Duraphat.

Ferreira 22/23 1 mo Visual Duraphat + Colgate Difference Reduction of WSLs

et al.40 assessment 1500 ppm of 0-1 mo with Duraphat and
NaF/Duofluorid XII + DUOfluoride XII.
Colgate 1500 ppm NaF No significant
differences in the
efficiency of the 2
products.

NWR 13/14

ARP 29.38/35.64

Zantner 16/17 Debond; QLF Toothpaste with DF 20.31 (41.06)/ DF 26.2 (47.69)/ No improvement in
et al.31 2 wk; 4 wk; 1500 ppm sodium 22.28 (43.86) 26.39 (46.4) the WSLs with
6 wk; 8 wk; fluoride/toothpaste sodium fluoride
10 wk; 12 wk; with 1250 ppm and amine fluoride.
4 mo; 5 mo amine fluoride
and 6 mo.

Jiang et al.41 47/48 18 mo Visual Paste placebo/ P (%) 15/13 P (%) 64/25 Reduction in the
(63.2 mo) assessment 1.23% of APF development of
foam (application WSLs during
2/2 m) orthodontic
treatment.

I 0.43 (1.68)/ I 4.79 (5.58)/

0.31 (1.07) 0.31 (1.07)

(continued )
 Fluorides vs Llena et al.42 40/34/41 8 mo Photographs Colgate 1100 ppm Difference Reduction of WSLs
CPP-ACFP NaF/MI Paste of 0-8 mo with MI Paste Plus
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Plus/PreviDent and PreviDent. No

22,600 ppm NaF significant
differences in
efficiency of MI
Paste Plus and
PreviDent
compared with the
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control group.

ARP 17.2% (18.6)/15.7%

(19.3)/24.6% (24.3)

Fluorides vs Memarpour 32/31/29/30 12 mo Visual No intervention/oral Evaluation Evaluation Oral hygiene with 4
CPP-ACP et al.43 assessment hygiene and after 4 mo after 12 mo applications of
dietary advice/oral DuraShield or
hygiene + DuraShield/ constant
oral hygiene + application of
Tooth Mousse CPP-ACP reduced
the size of WSLs
and caused a
smaller increase in
dmft index values,
contrary to the
other groups.

A +0.62 6 1.04/ A +1.15 6 1.26/

20.02 6 0.41/ 20.10 6 1.12/
20.14 6 0.36/ 20.51 6 0.56/

The Journal of EVIDENCE-BASED DENTAL PRACTICE

20.17 6 0.38 20.63 6 0.62

Evaluation Evaluation
after 4 mo after 12 mo

dmft 0.37 6 1.21/ dmft 2.00 6 2.00/

0.06 6 0.25/ 0.42 6 0.99/
0.14 6 0.52/ 0.30 6 0.90/
0.13 6 0.43 0.17 6 0.53

Robertson 24/26 12 mo Photographs Paste placebo/MI SSI [T1] 116/145 SSI [T2] 145/129 Reduction of WSLs
et al.27 (monthly Paste Plus with MI Paste Plus.
checks)
March 2017

SSI [T3] 150/95

(continued )
27
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The Journal of EVIDENCE-BASED DENTAL PRACTICE

Table 2. (continued)
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Participants Assessment Start End

Therapies agents Authors (control/test(s)) Follow-up method Control/test(s) (control/test(s)) (control/test(s)) Conclusion

SSI [T4] 166/80

DI [T1-T4] +43.1%/244.8%
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Beerens 27/27 Debond; QLF Fluoride DF 9.10 (1.75)/ DF 7.96 (2.76)/ Reduction of WSLs
et al.4 6 wk; 3 mo toothpaste + calcium 8.45 (1.17) 7.52 (1.78) with MI Paste Plus.
+ paste placebo/ Reduction of WSLs
fluoride toothpaste + with MI Paste Plus
MI Paste Plus compared with the
control group.

A 7.29 (7.91)/ A 7.17 (7.76)/

5.07 (5.69) 5.05 (6.98)

CPP-ACP Bröchner 30/30 Debond; QLF; Visual Colgate 1100 ppm PSC 14.9%/15.4% PSC 52.7%/47.7% Reduction of WSLs
et al.44 1 mo assessment NaF/Tooth Mousse (score 1) (score 1) with Tooth Mousse.
No significant
differences in
efficiency of Tooth
Mousse compared
with the control
group.

DF 7.04 (1.65)/ DF 4.51 (2.46)/

6.68 (0.58) 4.45 (1.82)

A 0.19 (0.43)/ A 0.14 (0.31)/

0.12 (0.16) 0.05 (0.09)

Bailey 22/23 Debond; Visual Paste placebo + Difference Significant

et al.23 1 mo; 2 mo; assessment toothpaste 1000 ppm of 0-3 mo reduction of WSLs
3 mo NaF/Tooth Mousse + with Tooth Mousse
toothpaste compared with the
1000 ppm NaF control group.

PSC 8.5%/8.6%
(score 0.1)

(continued )
 Andersson 13/13 Debond; DIAGNOdent Mouthwash with DR 9.4 (9.5)/ DR 6.4 (7.5)/4.4 (5.2) Significant
et al.45 1 mo; 3 mo; pen; Visual 0.05% NaF + toothpaste 7.4 (10.2) improvement of
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6 mo; 12 mo assessment 1100 ppm NaF/ WSLs with Topacal

Topacal + toothpaste compared with the
1100 ppm NaF control group.

Difference of
0-12 mo
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PSC 23%/64%
(score 0.1)

ICON Senestraro 20/46 Before Photographs Control/ICON Difference The resin ICON
et al.24 treatment; of 0-T2 produced a
Debond (T2); significant
2 mo (T3) improvement of
clinical appearance
of WSLs and a
reduction in its size.

ARP 23.3%/61.8%

Difference
of 0-T3

ARP 1.0%/60.9%

VAS (T2) 5.2/67.7

The Journal of EVIDENCE-BASED DENTAL PRACTICE

VAS (T3) 9.2/65.9

A, lesion area; ARP, average reduction percentage; CPP-ACFP, casein phosphopeptides with amorphous calcium phosphate and fluoride; DR, DIAGNOdent readings; DI, difference in ICDAS (International
Caries Detection and Assessment System); dmft, values according to dmft index; NW, number of WSLs; NWR, number of WSLs with size reduced; P, prevalence; PSC, proportion of clinical scores; QLF,
quantitative light-induced fluorescence; SSI, sum of scores of ICDAS (International Caries Detection and Assessment System) for all teeth; VAS, visual analog scale; WSLs, white spot lesions; DF, fluorescence
change.
March 2017
29
 The Journal of EVIDENCE-BASED DENTAL PRACTICE
In the Cochrane Library database, the following combinations
for searching were used: (“white spot” and “tooth reminer-
alization”), (“white spot” and “tooth demineralization”), and
(“white spot” and “fluorides”) found in the title, abstract, or
keywords. The inclusion criteria were all published between
2005 and 2015; the research date was until 29-09-2015.
The inclusion criteria were randomized controlled trials
regarding the application of remineralizing agents for the
treatment of WSLs, randomized controlled trials regarding
the application of agents that promote the non-
demineralization of enamel, studies in which participants
had at least 1 clinically visible lesion, studies in which test
group(s) included remineralizing agents for the treatment of
WSLs, and studies in which the control group consisted of
patients subjected to different agents or not subjected to an
intervention (placebo or no intervention).
The exclusion criterion was any study in which the participants
underwent any nonremineralizing therapy for WSLs treatment,
such as bleaching, enamel microabrasion, or restoration.
According to the predetermined criteria of inclusion and
exclusion, all titles and abstracts were examined by 1 reviewer
(A.R.F.) to find relevant studies; the full texts of the relevant
studies were scrutinized by 2 reviewers (A.R.F. and A.P.)
independently to select eligible studies. Any disagreement
was discussed, and the opinion of third reviewer (E.C.) was
sought if necessary.
For each included study, descriptive and quantitative infor-
mation was extracted, including citation author, number of
participants (control and test groups), treatment duration,
assessment method, baseline and final results, and authors’
conclusions.
The quality of the methodology of each study was assessed
using an assessment based on field data described in the
Cochrane Handbook for systematic review of interventions
5.1.0.37 Using the guidelines in the Cochrane Handbook, 3
reviewers (A.R.F., A.P., and E.C.) independently assessed the
quality of the identified studies.
The reviewers categorized the following 7 quality items as
“low” (low risk of bias), “unclear” (uncertain risk of bias), and
“high” (high risk of bias): sequence generation, allocation
concealment, blinding of participants and personnel,
blinding of outcome assessor, incomplete outcome data,
selective outcome reporting, and other sources of bias. The
level of risk for each study was then classified as low (all
quality items with low risk), medium (1 or 2 quality items with
high risk or unclear risk), and high (more than 3 items with
high risk or unclear risk).
The clinical methodology of all studies was evaluated by the
interventions and results obtained. Due to the disparity of
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methodology, it was not possible to perform a quantitative
analysis (meta-analysis).
RESULTS
The initial search carried out resulted in 273 references: 221
on Pubmed, 31 on ScienceDirect, and 21 on the Cochrane
Library.
After evaluating titles and abstracts, we obtained 45 relevant
studies. After evaluating the full texts, 32 references were
excluded from the study (Figure 2). A list of the excluded
articles and the reasons for exclusion is in Appendix 1.
There were several reasons for exclusion, including in vitro
studies, in vivo studies which did not only use
remineralizing agents and with no control group, clinical
cases, studies with results not specified correctly, with no
target population met or not included in what we intended
to evaluate. After searching the references of the selected
articles and relevant reviews, we identified no additional
eligible studies. Finally, 13 studies were selected (Figure 2).
From each study, several key characteristics were extracted
for the purpose of this systematic review. Among these
characteristics were the number of patients enrolled in the
study, the follow-up time, the type of control group (pla-
cebo, no treatment, or another remineralization therapy)
and the methodology of assessment of damage. The results
of each evaluation of each study and the main conclusions
were also extracted and summarized in Table 2.
Among the 13 included studies, 5 randomized controlled
trials evaluated the effects of fluorides, of which 2 evaluated
the effect of Duraphat, 1 compared the effect of Duraphat
and Duofluoride XII, one compared the effect of sodium
fluoride and amine fluoride, and one evaluated the effect of
1.23% acidulated phosphate fluoride (APF) foam.
In a study that evaluated the efficacy of Duraphat with intraoral
photography, studies observed a significant reduction in
the number of WSLs in the test group [NW(initial)0.3(1.0) and
NW(final)0.4(1.0)] when compared with the control group
[NW(initial)1.0(1.8) and NW(final)1.2(1.8)].39 Another study tested
the efficacy of Duraphat, evaluated using fluorescent laser
(DIAGNOdent), also ascertaining a significant reduction
between the group treated with Duraphat [DR(initial) 17.6(5.36)
to DR(final) 10.10(4.86)] and the control group [DR(initial)
16.19(5.70) to DR(final) 13.10(5.19)].25 In another, Duraphat was
compared with another fluoride varnish using visual assessment,
concluding that a reduction of the WSLs occurred with both
products but without significant differences Duraphat
(NWR(0-1m) 13 and ARP(0-1m) 29.38) and Duofluorid (NWR(0-1m)
14 and ARP(0-1m) 35.64).40 In the studies with fluoride varnish
(Duraphat and Duofluorid), there was a significant reduction
of WSLs but no significant differences between them.
 The Journal of EVIDENCE-BASED DENTAL PRACTICE

Table 3. Risk of bias for every study.

Incomplete
Adequate Blinding of Blinding of outcome Selective
sequence Allocation participants outcome data outcome Free of Level of
Author generation concealment and personnel assessors addressed reporting other bias risk for bias

Sonesson et al.39 Low Low High Low High Low High High

Du et al.25 Low Low High Unclear Low Low High High

Ferreira et al.40 Low Low Unclear Unclear High Low High High

Zantner et al.31 Low Low High Low Low Low High Medium

Jiang et al.41 Low Low Low Low High Low High Medium

Llena et al.42 Low Low High Low High Low High High

Memarpour et al.43 Low Low Low Low High Low High Medium

Robertson et al.27 Low Low Low Low High Low High Medium

Beerens et al.4 Low Unclear Unclear Low Low Low High High

Bröchner et al.44 Low Low High Low Low Low High Medium

Bailey et al.23 Low Low High Low High Low High High

Andersson et al.45 Low High Unclear Unclear Low Low High High

Senestraro et al.24 Low Low Unclear Unclear High Low High High

A study was conducted to compare a toothpaste containing
sodium fluoride and a toothpaste containing amine fluoride
using quantitative light-induced fluorescence (QLF), and
no improvement of WSLs was found in either group–
sodium fluoride [DF(initial) 20.31(41,06) to DF(final) 26.2(47.69)]
and amine fluoride [DF(initial) 22.28(43.86) to DF(final)
26.39(46.4)].31 Jiang et al.41 conducted a study to realize
the efficacy of 1.23% APF foam from visual assessment
and observed a reduction in the development of WSLs
during orthodontic treatment in the test group [P(%)(initial)
13 to P(%)(final) 25] compared to the control group
[P(%)(initial) 15 to P(%)(final) 64]. The fluoride pastes show
different results. In one study, there was no regression of
WSLs, whereas the other showed a reduction in their
development.
Only 2 articles compared the effects of fluorides with phos-
phopeptides compounds: 1 compared PreviDent with MI Paste
Plus and another compared DuraShield with Tooth Mousse.
A study evaluating the effectiveness of MI Paste Plus
and PreviDent with intraoral photographs found a
reduction in WSLs in the test groups—MI Paste Plus [ARP
15.7% (19.3)] and PreviDent [ARP 24.6% (24.3)]—
compared to the control group [ARP 17.2% (18.6)], after
8 months.42 Another study compared the efficacy of
fluoride and CPP-ACP to aid visual examination and
concluded a reduction in size of WSLs and a smaller in-
crease in values of dmft index after 12 months in the
test groups—DuraShield (A(initial) 20.14 6 0.36 to
A(final) 20.51 60.56 and dmft(initial) 0.14 6 0.52 to
dmft(final) 0.30 6 0.90) and Tooth Mousse (A(initial) 20.17 6
0.38 to A(final) 20.63 6 0.62 and dynamical mean-field
theory (dmft)(initial) 0.13 6 0.43 to dmft(final) 0.17 6 0.53)—
compared with other groups—hygienic education and
motivation (A(initial) 20.02 6 0.41 to A(final) 20.10 6 1.12
and dmft(initial) 0.06 6 0.25 to dmft(final) 0.42 6 0.99) and
control group (A(initial) 10.62 6 1.04 to A(final) 11.15 6
1.26 and dmft(initial) 0.37 6 1.21 to dmft(final) 2.00 6
2.00).27,43 Studies that compare the action of fluorides
with phosphopeptides compounds show that there was a
reduction of WSLs with all the agents tested, with no
differences between them.

March 2017 31

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 The Journal of EVIDENCE-BASED DENTAL PRACTICE
Figure 3. Example of a clinical case of fluorosis.
About phosphopeptide compounds, 2 of them evaluate the
effect of MI Paste Plus over WSLs, 2 of them evaluate the
effect of Tooth Mousse, and another evaluates the effect of
Topacal (Enamel Improving Cream, NSI Dental Pty Ltd,
Leighton, Hornsby, Australia).
For CPP-ACFP, 2 studies evaluated the efficacy of MI Paste
Plus. From the photographic intraoral examination, Rob-
ertson et al.27 concluded a reduction of WSLs in the test
group (SSI[T1] 145 to SII[T4] 80) compared to the control
group (SSI[T1] 116 to SSI[T4] 150). Another study using QLF
as the measurement method found a reduction in WSLs
both in the test group [DF(initial) 8,45(1,17) to DF(final)
7.52(1.78) and A(initial) 5.07(5.69) to A(final) 5.05(6.98)], as
Figure 4. Example of a clinical case of incisive-molar syndrome.
32 Volume 17, Number 1
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control group [DF(initial) 9.10(1.75) to DF(final) 7.96(2.76) and
A(initial) 7.29(7.91) to A(final) 7.17(7.76)].4
Regarding CPP-ACP, 2 studies evaluated the efficacy of Tooth
Mousse. The first study used QLF and visual evaluation and
found a reduction in WSLs in the test group [PSC(initial) 15.4% to
PSC(final) 47.7%; DF(initial) 6.68(0.58) to DF(final) 4.45(1.82) and
A(initial) 0.12(0.16) to A(final) 0.05(0.09)] and in the control group
[PSC(initial) 14.9% to PSC(final) 52.7%; DF(initial) 7.04(1.65) to DF(final)
4.51(2.46) and A(initial) 0.19(0.43) to A(final) 0.14(0.31)]44 From the
visual assessment, another study found a significant reduction in
WSLs in the test group (PSC 8.6%) contrary to the control group
(PSC 8.5%), after 3 months.23 In a study evaluating the efficacy of
Topacal using DIAGNOdent pen and visual assessment as
measurement methods, we found a significant improvement
in WSLs in the test group [DR(initial) 7.4(10.2) to DR(final) 4.4(5.2)]
compared to the control group [DR(initial) 9.4(9.5) to DR(final)
6.4(7.5)].45 Studies which used phosphopeptide compounds
as remineralizing agents concluded that there was a reduction
in WSLs with all agents tested.
Referring to ICON, only one article was included. The similarity
between the different studies’ methodologies is inexistent.
Regarding ICON resin, Senestraro et al.24 concluded a
significant improvement in clinical appearance of WSLs
and a reduction in their size after 2 months (ARP 60.9%
and VAS[T3] 65.9) compared to the control group (ARP
1.0% and VAS[T3] 9.2).
Every study that was analyzed presented biases. After a
careful look at every one of them, we proceeded through
the realization of the table presenting the bias risk
(Table 3).
Concerning the diagnosis methods, 2 of the studies used
DIAGNOdent pen but with different agents (Duraphat25 and
 The Journal of EVIDENCE-BASED DENTAL PRACTICE

Figure 5. Example of a clinical case of dental opacity. Figure 6. Clinical case treated with ICON therapy:
initial photograph.

Topacal45). Three studies used QLF, but their agents were

different (sodium and amine fluoride,31 MI Paste Plus4 and parameters should be delimited such as resolution and
Tooth Mousse44). Most studies used visual clinical assessment light conditions; and the number of reviewers should be
or a simple visual assessment by photography. increased to reduce bias and increase the strength of the
evidence. Whenever possible, this evaluation should be
The follow-up between studies ranges from 1 month to done by quantitative methodology, such as DIAG-
18 months, with different evaluation times in some. NOdent25,45 and QLF.4,31 In studies, evaluation of lesions is
also crucial to standardize the diagnosis using the same
Based on these disparities of evaluation methodologies and
scales, such as ICDAS (International Caries Detection and
the different follow-up, the realization of one quantitative
Assessment System).27
analysis was not viable to realize a meta-analysis.
The existence of a control group study design was a crite-
DISCUSSION rion for inclusion in this review, such as another agent to
control, placebo, or no intervention. However, ideally there
WSLs may cause esthetic concerns for patients.20 The most
should always be more than 1 control group: a positive
relevant approaches for assessing these lesions are visual
(another agent or placebo) and a negative (no interven-
inspection,20 tactile examination with probing,20 and
tion).43 This standardization study design could reduce the
photographic examination.46 Other technologies allow
study bias and increase the probability of quantitative
WSL detection such as: QLF,1,5,15 laser fluorescence
comparison studies, increasing the strength of evidence.
(DIAGNOdent),1,5,15 light-emitting diode refraction and reflec-
The number of participants in some studies is limited.
tion,1,15 digital fiber-optic transillumination,1,5,15 electrical
resistance caries monitoring device,5 and optical coherence
tomography.5 The differential diagnosis of WSLs has a special
importance because these are of extrinsic origin, contrary to Figure 7. Clinical case treated with ICON therapy:
other white enamel lesions, which are of intrinsic origin application of infiltrative resin.
(Figures 3-5). The achievement of a good general dental and
medical history to determine the origin of such lesions, as well
as comparative photographic analysis with the previous
clinical situation placing of the orthodontic appliance is
essential to exclude pre-existing WSLs.46

These assessment methods are essential in the diagnosis

of injuries but should also be applied in the monitoring of
injury therapies. Thus, a standardization of these methods
is critical. Clinical visual assessment and via photographs is
the most often used method due to its easy handling and
access. However, due to qualitative and therefore subjec-
tive assessment, this methodology should be standardized
so it can be reproducible. So, some photograph

March 2017 33

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 The Journal of EVIDENCE-BASED DENTAL PRACTICE
Figure 8. Clinical case treated with ICON therapy:
after infiltrative technique.
However, due to the restriction of these injuries to some
patient groups, this issue can be addressed with the
standardization of methodologies.
Some studies’ follow-up was appropriate,31,45 just lacking
standardization. However, the restriction of some studies
relating to the time factor is related to the noninclusion of
various follow-up times to be able to assess the effective-
ness of the agents over time.
The aforementioned limitations have a huge consequence
in the high risk of bias, as obtained from the analysis per-
formed in the Results chapter.
Even with all the limitations of this review due to the different
methods of diagnosis, the different follow-up, the non-
standardization of the control group and the limited number
of patients enrolled in some studies, it is transversal to almost
all studies included in this review that therapy with
Figure 9. Clinical case treated with ICON therapy:
final appearance in treatment appointment.
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Figure 10. Clinical case treated with ICON therapy:
final photograph.
remineralizing agents reduces the WSLs (size or visual
appearance). Regarding compounds with fluorides, Sonesson
et al.39 concluded that daily use of toothpaste containing
high concentrations of fluoride can significantly reduce the
prevalence and incidence of WSLs. Thus, they must be
considered as a fluoride supplement for patients with
temporary increase in dental caries risk. Ferreira et al.40 also
found a reduction and control of cariogenic activity in most
WSLs with 2 fluoride varnishes of high concentration. Other
authors concluded that topical application of fluoride
varnish results in a good method for treating WSLs and
should be considered a routine therapy after orthodontic
treatment due to more pronounced decrease in the
DIAGNOdent pen values in the test group during the first
6 months after removal of the orthodontic appliance.25
The only exception occurs in the study of Zantner et al.
using as remineralizing agents sodium or amina fluoride
pastes. Zantner et al.31 compared sodium fluoride with
amine fluoride and found that these 2 fluoride compounds
have no improvement in WSLs.
However, studies with other remineralizing agents such as
CPP-ACP, CPP-ACFP, and Icon (DMG Chemisch-Pharma-
zeutische Fabrik GmbH, Hamburg) demonstrated regression
of WSLs, either in size or in their clinical visual appearance. In
a controlled clinical trial, the researchers found no significant
differences in the effectiveness of MI Paste Plus or PreviDent
compared with twice-a-day brushing with toothpaste con-
taining 1100 ppm, referring to a period of 8 weeks.42
Memarpour et al.43 concluded that oral hygiene together
with 4 applications of DuraShield or with constant
application of Tooth Mousse during 1 year reduced the size
of WSLs and reflected a smaller increase of the values of
dmft index, in contrast to the control group and the group
with hygienic education and motivation. According to
Bröchner et al.,44 the topical treatment of WSLs with CPP-

ACP after debonding resulted in a significant reduction in the
fluorescence average values and in the lesion area after
4 weeks, when measured by QLF. However, the improvement
was not higher than the natural regression with daily use of
fluoridated toothpastes.44 The same was found in a
controlled clinical trial, in which the CPP-ACP significantly
promoted the regression of WSLs compared with the control
group.23 Andersson et al.45 suggested the existence of
beneficial esthetic effect with CPP-ACP compared with the
daily use of 0.05%NaF, when combined with twice-a-day
brushing with fluoridated toothpaste. A significant reduc-
tion of DIAGNOdent pen readings in both groups after
6 months was observed, with no significant difference be-
tween the 2 treatment regimens.45 Regarding CPP-ACFP (MI
Paste Plus), Beerens et al.4 showed no significant differences
between this blinder and the control group (placebo paste)
on enamel remineralization after 3 months. Finally, a
controlled clinical trial that evaluated the efficacy of ICON
infiltrative resin concluded that this can predictably
and significantly improve the esthetics of most teeth
(Figures 6-10).24
The improvement with regression or disappearance of WSLs
is a conclusion in almost all studies, with a tendency to high
review and outcome level.
CONCLUSIONS
A limited number of studies were included in this systematic
review. None of these has a low risk of bias, with most
having high risk due to weaknesses in many quality items or
due to other biases, such as problems associated with the
evaluation method or inadequate study design.
More studies of scientific evidence should include: a
random sequence generation; allocation concealment;
blinding of participants and personnel as well as outcome
assessors and reporting of appropriate selective outcomes;
strict eligibility criteria; and appropriate analysis to reduce
bias. As a result of poor methodology, disparate measure-
ments and different materials analyzed, it was not possible
to carry out a quantitative analysis.
ACKNOWLEDGMENTS
The authors acknowledge the essential contribution of Dr
Helena Donato (Head of the Documentation Service of
CHUC) in the preparation of the search equation and its
application.
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 The Journal of EVIDENCE-BASED DENTAL PRACTICE

APPENDIX

Appendix 1. Articles excluded in this review.

Article Reason for exclusion

1. Llena C, Leyda AM, Forner L. CPP-ACP and CPP-ACFP versus fluoride varnish in remineralisation of early In vivo study
caries lesions. A prospective study. Eur J Paediatr Dent. 2015 Sep; 16(3):181-6.

2. Oliveira G, Ritter A, Haymann H, Swift E, Donovan T, Brock G, Wright T. Remineralization effect of CPP-ACP In vitro study
and fluoride for white spot lesions in vitro. Journal of Dentistry, Volume 42, Issue 12, December 2014, Pages
1592-1602.

3. Mielczarek A, Gedrange T, Michalik J. An in vitro evaluation of the effect of fluoride products on white spot In vitro study
lesion remineralization. Am J Dent. 2015 Feb; 28(1):51-6.

4. Lausch J, Paris S, Selje T, Dörfer CE, Meyer-Lueckel H. Resin infiltration of fissure caries with various In vitro study
techniques of pretreatment in vitro. Caries Res. 2015; 49(1):50-5. doi: 10.1159/000366082. Epub 2014 Nov 21.

5. Ou XY, Zhao YH, Ci XK, Zeng LW. Masking white spots of enamel in caries lesions with a non-invasive In vitro study
infiltration technique in vitro. Genet Mol Res. 2014 Aug 29; 13(3):6912-9. doi: 10.4238/2014.August.29.14.

6. Tüfekçi E, Pennella DR, Mitchell JC, Best AM, Lindauer SJ. Efficacy of a fluoride-releasing orthodontic primer In vivo study
in reducing demineralization around brackets: an in-vivo study. Am J Orthod Dentofacial Orthop. 2014 Aug;
146(2):207-14. doi: 10.1016/j.ajodo.2014.05.016.

7. Karlinsey RL, Mackey AC, Dodge LE, Schwandt CS. Noncontact remineralization of incipient lesions treated In vitro study
with a 5% sodium fluoride varnish in vitro. J Dent Child (Chic). 2014 Jan-Apr; 81(1):7-13.

8. Aykut-Yetkiner A, Kara N, Ateş M, Ersin N, Ertu

grul F. Does casein phosphopeptid amorphous calcium Results not specified
phosphate provide remineralization on white spot lesions and inhibition of Streptococcus mutans? J Clin correctly
Pediatr Dent. 2014 Summer; 38(4):302-6.

9. Yap J, Walsh LJ, Naser-Ud Din S, Ngo H, Manton DJ. Evaluation of a novel approach in the prevention of In vitro study
white spot lesions around orthodontic brackets. Aust Dent J. 2014 Mar; 59(1):70-80. doi: 10.1111/adj.12142.
Epub 2014 Feb 14.

10. Yetkiner E, Wegehaupt F, Wiegand A, Attin R, Attin T. Colour improvement and stability of white spot In vitro study
lesions following infiltration, micro-abrasion, or fluoride treatments in vitro. Eur J Orthod. 2014 Oct; 36(5):595-
602. doi: 10.1093/ejo/cjt095. Epub 2014 Jan 2.

11. Hattab FN. Remineralisation of carious lesions and fluoride uptake by enamel exposed to various fluoride In vitro study
dentifrices in vitro. Oral Health Prev Dent. 2013; 11(3):281-90. doi: 10.3290/j.ohpd.a30170.

12. Bonow ML, Azevedo MS, Goettems ML, Rodrigues CR. Efficacy of 1.23% APF gel applications on incipient Results not specified
carious lesions: a double-blind randomized clinical trial. Braz Oral Res. 2013 May-Jun; 27(3):279-85. doi: correctly
10.1590/S1806-83242013000300007.

13. Paris S, Schwendicke F, Keltsch J, Dörfer C, Meyer-Lueckel H. Masking of white spot lesions by resin In vitro study
infiltration in vitro. J Dent. 2013 Nov; 41 Suppl 5:e28-34. doi: 10.1016/j.jdent.2013.04.003. Epub 2013 Apr 11.

14. Huang GJ, Roloff-Chiang B, Mills BE, Shalchi S, Spiekerman C, Korpak AM, Starrett JL, Greenlee GM, Not included in what
Drangsholt RJ, Matunas JC. Effectiveness of MI Paste Plus and PreviDent fluoride varnish for treatment of we intend to evaluate
white spot lesions: a randomized controlled trial. Am J Orthod Dentofacial Orthop. 2013 Jan; 143(1):31-41.
doi: 10.1016/j.ajodo.2012.09.007.

15. Hammad SM, El Banna M, El Zayat I, Mohsen MA. Effect of resin infiltration on white spot lesions after Inclusion criteria for
debonding orthodontic brackets. Am J Dent. 2012 Feb; 25(1):3-8. population not met

(continued )

March 2017 37

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 The Journal of EVIDENCE-BASED DENTAL PRACTICE

Appendix 1. Continued

Article Reason for exclusion

16. Akin M, Basciftci FA. Can white spot lesions be treated effectively? Angle Orthod. 2012 Sep; 82(5):770-5. In vivo study
doi: 10.2319/090711.578.1. Epub 2012 Feb 23.

17. Pliska BT, Warner GA, Tantbirojn D, Larson BE. Treatment of white spot lesions with ACP paste and In vivo study
microabrasion. Angle Orthod. 2012 Sep; 82(5):765-9. doi: 10.2319/111611-710.1. Epub 2012 Feb 21.

18. Torres CR, Rosa PC, Ferreira NS, Borges AB. Effect of caries infiltration technique and fluoride therapy on In vitro study
microhardness of enamel carious lesions. Oper Dent. 2012 Jul-Aug; 37(4):363-9. doi: 10.2341/11-070-L. Epub
2012 Feb 15.

19. Baeshen HA, Lingström P, Birkhed D. Effect of fluoridated chewing sticks (Miswaks) on white spot lesions in Not included in
postorthodontic patients. Am J Orthod Dentofacial Orthop. 2011 Sep; 140(3):291-7. doi: 10.1016/ what we intend
j.ajodo.2010.04.034. to evaluate

20. Mensinkai PK, Ccahuana-Vasquez RA, Chedjieu I, Amaechi BT, Mackey AC, Walker TJ, Blanken DD, In vivo study
Karlinsey RL. In situ remineralization of white-spot enamel lesions by 500 and 1100 ppm F dentifrices. Clin Oral
Investig. 2012 Aug; 16(4):1007-14. doi: 10.1007/s00784-011-0591-2. Epub 2011 Jul 13.

21. Nahsan FP, da Silva LM, Baseggio W, Franco EB, Francisconi PA, Mondelli RF, Wang L. Conservative Clinical case
approach for a clinical resolution of enamel white spot lesions. Quintessence Int. 2011 May; 42(5):423-6.

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