European Journal of Orthodontics, 2019, 1–5

doi:10.1093/ejo/cjz045
Randomized Controlled Trial

Randomized Controlled Trial

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Fluoride varnish for the prevention of white spot
lesions during orthodontic treatment with fixed
appliances: a randomized controlled trial
Mikael Sonesson1, Anna Brechter2, Salem Abdulraheem1, , Rolf Lindman3
and Svante Twetman4
1
Department of Orthodontics, Faculty of Odontology, Malmö University, 2Bernhold Ortodonti, Private Practice, Hels-
ingborg, Sweden, 3Ortodonti Syd, Private Practice, Hässleholm, Sweden and 4Department of Odontology, Section
for Cariology & Endodontics and Pediatric Dentistry & Clinical Genetics, Faculty of Health and Medical Sciences,
University of Copenhagen, Denmark

Correspondence to: Mikael Sonesson, Department of Orthodontics, Faculty of Odontology, Malmö University, Carl Gustafs
väg 34, SE-205 06 Malmö, Sweden. E-mail: [email protected]

Summary
Background:  Self-applied and professional fluorides are key elements to limit caries-related side-
effects during orthodontic treatment with fixed appliances.
Objective:  To evaluate the effectiveness of a new fluoride varnish formula containing 1.5%
ammonium fluoride in preventing white spot lesions (WSLs) in adolescents undergoing multi-
bracket orthodontic treatment. 
Subjects and methods:  The study employed a randomized controlled triple-blinded design with
two parallel arms. One hundred eighty-two healthy adolescents (12–18  years) referred to three
orthodontic specialist clinics were eligible and consecutively enrolled. Informed consent was
obtained from 166 patients and they were randomly allocated to a test or a placebo group (with
aid of a computer program, generating sequence numbers in blocks of 15). In the test group,
fluoride varnish was applied in a thin layer around the bracket base every sixth week during the
orthodontic treatment, while patients in the placebo group received a varnish without fluoride. The
intervention started at onset of the fixed appliances and continued until debonding. The endpoint
was prevalence and severity of WSLs on the labial surfaces of the maxillary incisors, canines, and
premolars as scored from high-resolution pre- and post-treatment digital photos with aid of a four-
level score.
Results:  One hundred forty-eight patients completed the trial, 75 in the test group and 73 in the
placebo group (dropout rate 10.8%). The total prevalence of WSL’s on subject level after debonding
was 41.8% in the test group and 43.8% in the placebo group. The number of patients exhibiting
more severe lesions (score 3  +  4) was higher in the placebo group (P  <  0.05); the absolute risk
reduction was 14% and the number needed to treat was 7.1.
Limitations:  The multicentre design with somewhat diverging routines at the different clinics may
have increased risk for performance bias. No health-economic evaluation was carried out. 
Conclusions:  Regular applications of an ammonium fluoride varnish reduced the prevalence of
advanced WSL during treatment with fixed orthodontic appliances.
Clinical trial registration:  ClinicalTrials.gov (NCT03725020).
Protocol:  The protocol was not published before trial commencement.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Orthodontic Society.
1
All rights reserved. For permissions, please email: [email protected]
2 European Journal of Orthodontics, 2019

Introduction private clinics) located in the Scania region, Sweden. The enrolment
started in January 2015 and ended in November 2017. The inclusion
Enamel demineralization, often called white spot lesions (WSLs), is a
criterion was a scheduled treatment with direct bonded fixed maxil-
frequently diagnosed unwanted side-effect during orthodontic treat-
lary appliances (slot 0.022 inches) according to a standard straight-
ment with fixed appliances. The lesions are commonly observed on
wire concept (21) during a period of at least 12 months. Exclusion
the labial surfaces of the maxillary incisors and have been reported
criteria were severe chronic conditions such as asthma and allergy,
to affect up to 96% of orthodontic patients (1–10). WSL have lim-
neuropsychiatric disorders, and regular use of oral antiseptics and
ited ability to improve after bracket removal, thus seriously jeopard-
previous orthodontic treatment with fixed appliances. In the event

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izing the final aesthetic result of the treatment (11, 12).
of long-term prescriptions of general antibiotics during the course
Professional applications of fluoride varnish constitute a corner-
of the study, this was recorded separately. All enrolled subjects were
stone in primary and secondary caries prevention and the efficacy
inhabitants in communities with a low natural fluoride content in
has been established in several systematic reviews (13–15). In a
the piped water (<0.3 ppm). 
Cochrane Library update, the prevented fraction of fluoride varnish
applications was 43% for permanent teeth and 37% in the primary
dentition when compared with placebo or no treatment (16). It is Intervention
generally thought that the risk for WSL is significantly enhanced The test varnish was a commercially available product, Fluor
during treatment with fixed orthodontic appliances (17) and, there- Protector S (Ivoclar Vivadent AG, Schaan, Liechtenstein). The active
fore, extended preventive efforts are required. In a previous rand- ingredient was 7700 ppm fluoride, delivered as ammonium fluoride,
omized placebo-controlled trial, the effect of a 1% fluorosilane dissolved in ethanol, water, and acrylate polymer. All patients were
varnish (Fluor Protector, Ivoclar Vivadent, Schaan, Liechtenstein) seen every sixth week for wire adjustments and mechanical biofilm
was investigated when regularly applied around the bracket base in removal. At the end of each visit, the clinical staff applied either the
adolescents undergoing orthodontic therapy (5). The incidence of test or the placebo varnish with a small brush in a thin layer around
WSL during the treatment with fixed appliances was 7.4% in the the base of the braces on the maxillary teeth. The varnishes were let
fluoride varnish group compared with 25.3% in the placebo group, to dry for 1 minute and the subjects were instructed not to eat or
a difference that was statistically significant (5). The systematic drink within 60 minutes after the application. Both varnishes had
review by Benson and co-workers (18) displayed moderate-quality a mild mint flavour and the placebo varnish had an identical com-
evidence for this intervention because it had not yet been replicated position except for the ammonium fluoride. Thus, taste, colour, and
by further studies in orthodontic participants. Thus, additional ran- handling properties were the same. The number of actual varnish
domized controlled trials are required to determine the best fluo- applications was recorded in the digital records of each patient in
ride technology to prevent WSLs in patients undergoing orthodontic order to keep track of the compliance with the protocol. All partici-
treatment. Recently, a new fluoride varnish formula (Fluor Protector pants were strongly encouraged to brush their teeth twice daily with
S, Ivoclar Vivadent, Schaan, Liechtenstein) has been developed with 1450 ppm fluoride toothpaste during the entire project. No dietary
1.5% ammonium fluoride as the main active ingredient. In addition restrictions or any other fluoride supplements such as fluoride rinses
to affecting the local balance between enamel demineralization and were recommended or prescribed during the study duration.
remineralization, the topical presence of fluoride in the biofilm can
hamper the metabolic activity of oral bacteria and reduce the eco- Randomization
logical stress (19, 20). The aim of the present trial was to investigate Informed consent was obtained from 166 patients (and their par-
the effect of this novel product in preventing WSL development in ents) and they were randomly allocated to the test or the placebo
adolescents undergoing treatment with fixed appliances. The null group with aid of a computer program, generating sequence num-
hypothesis was that the prevalence of WSL in the test group would bers in blocks of 15 in order to ensure that equal numbers of patients
not differ from the prevalence in a control group treated with pla- were allocated to both study groups within each clinic. The alloca-
cebo varnish.  tion sequence was performed by one of the authors not involved in
the treatments.

Subjects and methods

Blinding
Study design The study was triple blind; neither the patients, clinicians nor the
The project employed a randomized, triple-blind placebo-controlled investigators were aware of the allocated interventions. The varnishes
design with two parallel arms. The primary outcome was prevalence were separated by a colour code that was kept by an independent
and severity of WSLs on the labial surfaces of the maxillary incisors, monitor at the university and the allocation was not unveiled until
canines, and premolars after orthodontic treatment with fixed appli- after the statistical calculations. 
ance, as assessed from high-resolution pre- and post-treatment digi-
tal photos. Secondary endpoints were possible harms and patient’s Clinical procedures
perception of the post-treatment outcome of which the latter will All subjects were thoroughly examined prior to the onset of the
be reported separately. The study was ethically approved by the fixed appliances. After polishing with a rubber cup and fluoride-free
Regional Ethical Research Board (Dnr 2014/183) and registered in pumice paste, three standardized digital photos (one frontal and two
Clinical Trials.gov Identifier (NCT03725020). laterals) on the buccal surfaces of the maxillary premolars, canines,
and incisors were exposed (Nikon D7100, Macro Speedlight SB-21,
Participants Japan). The pictures were stored on USB device for future com-
182 healthy adolescents (12–18  years) were eligible and consecu- parisons with the post-treatment status. At the time of debonding,
tively invited to participate in the study. They were referred to one the remaining composite material on the surfaces was carefully
of three orthodontic specialist clinics (one university clinic and two removed with a slowly rotating carbide bur followed by polishing
M. Sonesson et al. 3

with a rubber cup and pumice paste. After drying with air and visual (5, 22). With alpha (α) set at 0.05 (Type I error) and beta (β) to 0.20
inspection, a new series of standardized frontal and lateral digital (Type II error), 154 subjects (77 in each group) were estimated to
photos was taken and stored on the device.  be needed to disclose a 15% difference between the groups. With
an expected attrition of approximately 15% (patient dropouts and
Outcome imaging errors), it was considered appropriate to enrol a total num-
The primary outcome was the prevalence and severity of WSL on ber of 180 subjects to the project.
patient level assessed from digital photos. The pre- and post-treat-

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ment photos were projected on a screen (Hewlett Packard ProBook
Results
6650b, Palo Alto, CA, USA) in a dark room and the prevalence and
severity of enamel demineralization were scored independently by The mean age in the test group was 14.1 years [standard deviation
two experienced and calibrated specialists (MS and ST) according (SD) 1.7 years; range 11.3–18.7] and 13.8 years (SD 1.8 years; range
to the four-step index of Gorelick and co-workers (2). The labial 10.1–18.0) in the placebo group. The majority was girls, 56% in the
surfaces of the maxillary incisors, cuspids, and premolars were test group and 59% in the placebo group. Eight patients, equally
the experimental sites and scored as: 1 = no white spot formation; distributed between the groups, were diagnosed with hypomineral-
2 = slight white spot formation (thin rim); 3 = excessive white spot ized white ‘cloudy’ enamel areas (n = 3) on the anterior teeth or mild
formation (thicker bands); 4 = white spot formation with cavitation. enamel fluorosis (n  =  5) at the onset of the fixed appliances. The
When in doubt, the lower score was chosen. In case of disagree- mean duration of the orthodontic treatment was 1.7 years (SD 0.5)
ment, the photos were re-examined until consensus was reached. in both groups, giving an average number of 13.2 varnish applica-
Unreadable follow-up photos (i.e. poor contrast, technical errors) tions per patient. The attrition rate was 10.8% with a similar distri-
were considered as dropouts. The examiners scoring the outcome bution in the two groups. A flow chart with the reasons for dropping
measures were not involved in the treatment of the patients. A ran- out is presented in Figure 1. None of the patients was prescribed
dom sample of 25 cases were re-assessed after 1 month in order to long-term antibiotics during the course of the study.
check and calculate the inter- and intra-examiner reliability.
WSLs on patient level
Side-effects At the onset of the fixed appliances, six patients in the test group and
All possible perceived side-effects (objective as well as subjective) in seven patients in the control group displayed slight WSLs (Score 2) on
connection to the interventions were reported to the clinical investi- one or more teeth. The prevalence of WSLs on subject level after the
gator and the participants had the opportunity to discontinue their treatment was similar in the test group (41.8%) and the placebo group
participation at any time without further motivation. (43.8%). The number of patients with more advanced lesions (Scores
3 and 4) differed however significantly (P < 0.05) between the groups
Statistical methods as presented in Table 1. Fewer patients in the test group had advanced
lesions at debonding; the absolute risk reduction was 14% and the num-
All data were processed with the IBM-SPSS software (version 25.0,
ber needed to treat was 7.1. This indicated that seven patients had to
Chicago, Illinois, USA). We compared proportions and categorized
be treated according to the protocol in order to gain one free of WSLs.
scores between the groups with chi-square tests. Continuous data
(age and treatment duration) were processed by t-tests. Inter- and
intra-examiner agreement was calculated with Cohen’s Kappa cor- WSLs on surface level
relation. The level of significance was set to 5% (P < 0.05). In all, 1.493 buccal tooth surfaces were scored immediately after
The sample size was determined through a power calculation debonding. The prevalence of WSLs on surface level was 21.3% with
based on WSL data from our previous trials with a similar design no difference between the groups. The lateral incisors and the first
premolars were most commonly affected. The mean number of new
lesions per patient was 2.0 (SD 2.6) and 1.9 (SD 2.5) in the test and
Invited (n=182) the placebo group, respectively. The percentage distribution of scores
is shown in Table 2. The difference between the groups concerning
Excluded (n=16)
WSL Score 3 was statistically significant (P < 0.05).
No consent

Inter- and intra-examiner agreement

Included and randomized (n=166) The agreement between the two evaluations of lesion scores was
82.5%. The weighted inter-examiner Kappa value was 0.60 [95%

Test group onset (n=85) Placebo group onset (n=81)

Table 1. Two-by-two table showing the prevalence of advanced
(score 3 + 4) post-orthodontic white spot lesions (WSLs) at debond-
ing in the test and the placebo group 

Relocated (n=1) Dropped out (n=4) Group WSL score 3 + 4 WSL score 1 + 2
Dropped out (n=6) Not debonded (n=4)
Not debonded (n=3)
Test 9 66
Placebo 19* 54

Test debonded (n=75) Placebo debonded (n=73)

Values in the table denote number of patients. 
*Statistically significant difference; odds ratio = 0.39, 95% confidence
Figure 1.  Flow chart for participants and dropouts in the trial. interval: 0.16–0.93, P < 0.05.
4 European Journal of Orthodontics, 2019

Table 2.  Percent distribution of white spot lesions on surface level lesions in previous studies (25, 26), the method may somewhat
immediately after debonding of fixed orthodontic appliances underestimate the true occurrence of enamel demineralization due
to remnants of bonding materials, contamination of moisture, and
Group Score 1 Score 2 Score 3 Score 4
unsharp/overexposed images. On the other hand, it allowed a blind,
Test 76.9% 19.6% 3.5% — unbiased, and independent evaluation of the scores by investiga-
Placebo 78.0% 15.8% 6.2%* — tors not involved in the clinical work, a benefit often overlooked
in clinical trials. The inter-examiner agreement was almost perfect
*Statistically significant different distribution compared with test group concerning the pre-treatment scores, while the Kappa value for the

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(chi-square test, P < 0.05). post-treatment readings indicated a larger variability; the debonding
photos were sometimes confounded by composite material, exces-
confidence interval (CI) 0.49–0.72], indicating a moderate to good sive enamel grinding, and gingival swelling/epulides.
reliability of the readings. The intra-rater reliability showed a good The strength of this study was its randomized, placebo-con-
agreement with 0.79 for examiner ‘one’ and 0.72 for examiner ‘two’.  trolled triple-blind design. By the use of parallel groups, we avoided
the problem with crossover effects associated with spilt-mouth stud-
Harm ies. Moreover, the professionally performed intervention linked to
the regular follow-ups and wire adjustments secured an almost per-
One patient in the test group dropped out from the study due to a
fect compliance with the protocol. The attrition rate of 10.8% was
feeling of slight nausea. No other adverse effects from the interven-
explained and acceptable considering the long duration of the multi-
tions were reported.
bracket treatments. There were no differences in the background
variables or in clinical appearance between those that dropped out
Discussion and those that remained in the study. 

Main findings
Generalizability
Several systematic reviews have examined and graded the effective-
It is well known that the prevalence of WSL in connection to fixed
ness of professional fluorides in preventing WSLs during treatment
orthodontic appliances varies largely with the general burden of
with fixed appliances (18, 23, 24). There is evidence of moderate
caries in the society and factors such as oral hygiene, preventive
certainty that fluoride varnishes applied regularly during treatment
measures, oral health awareness, scoring methods, and time after
is effective but the number of studies with adequate design and per-
debonding (6, 10). Since the present study displayed an average mid-
formance is limited (24). To our best knowledge, no previous trial
range WSL prevalence, we consider the external validity of our find-
has investigated the current varnish formula in a clinical trial with
ings as high and representative for orthodontic care in industrialized
caries lesion development as endpoint. The varnish contains 1.5%
countries.
ammonium fluoride (Ivoclar Vivadent AG, Schaan, Liechtenstein),
equivalent to 7700 ppm fluoride, in a homogenous colourless solu-
tion, but the concentration increases up to four times after setting. Limitations
The main finding of the present study was that the fluoride varnish The use of clinical photos excluded molar teeth from the evaluations.
under study could alleviate but not totally prevent the development The fact that a number of dental teams at three different clinics, two
of WSLs during treatment with fixed orthodontic appliances com- private clinics and one university clinic, with somewhat diverging
pared with placebo. The null hypothesis could, therefore, not be routines were involved in the project may have introduced a risk for
rejected. Nevertheless, the obtained results were clearly of clinical performance bias. Another limitation was that no formal health-eco-
importance. Most of the thin white rims (Score 2) visible adjacent nomic evaluation was included in the planning of the study. A post-
to the bracket base immediately after debonding are remineralized trial estimation of the direct and tangible costs of the intervention can
by nature and non-detectable after 3 months (7). Although the more certainly be made but the indirect costs are uncertain. For example,
advanced lesions can improve with time, most of them seem to a 20 month treatment with fixed appliances implied approximately
remain visible up to a decade after debonding (7). Thus, preventing 13 varnish applications taking 5 minutes each, and these costs must
severe WSLs during treatment is an important strategy in order to be weighed against the subjective and objective long-term benefits.
avoid cosmetic and caries-related problems for many orthodontic Professional varnishes have the advantage over self-applied fluorides
patients, and our present findings reinforce the usefulness of repeated through the extended slow-release of fluoride to the oral biofilm up to
fluoride varnish applications for this purpose. An interesting inciden- several weeks after application (27). The frequently repeated applica-
tal finding beyond the aim was that five patients in the project were tions of the fluoride varnish during the treatment was most likely a
diagnosed with a very mild fluorosis prior to bonding and none of key factor for efficacy since it has been shown that a one-time varnish
them exhibited any form of WSL development during treatment. application at the onset of orthodontic appliances did not provide
In this study, the prevalence of WSLs at debonding was 42.8% any advantages (28). In order to further explore the long-term effects
on subject level (patient with at least one WSL) and 21.3% on sur- of the intervention, the present study group will be clinically re-exam-
face level. Interestingly, these levels were more or less identical with ined 1 year after debonding and the patient’s perception and satisfac-
those from previous studies conducted in Sweden with fluoride var- tion with the treatment will be addressed through a questionnaire.
nish (5) and high fluoride toothpaste (22). To some extent, this may
be explained by the fact that the same scoring method from digital
photos was used in all the trials. This indirect scoring method was
Conclusion
selected for practical reasons since the clinics were located in dif- Application of an ammonium fluoride varnish around the bracket
ferent areas of the region. Although digital photographs have been base every sixth week during orthodontic treatment with fixed
proven a reliable and valid tool for the assessment of buccal caries appliances could prevent the development of advanced WSLs in
M. Sonesson et al. 5

adolescents when compared with placebo. The result reinforces the 11. Norevall, L.I., Marcusson, A. and Persson, M. (1996) A clinical evaluation
use of professional fluorides in orthodontic care in order to avoid of a glass ionomer cement as an orthodontic bonding adhesive compared
cosmetic and caries-related problems for patients with multi-bracket with an acrylic resin. European Journal of Orthodontics, 18, 373–384.
12. Mattousch, T.J., van der Veen, M.H. and Zentner, A. (2007) Caries lesions
treatment.
after orthodontic treatment followed by quantitative light-induced fluo-
rescence: a 2-year follow-up. European Journal of Orthodontics, 29, 294–
Funding 298.
13. Petersson, L.G., et al. (2004) Professional fluoride varnish treatment for
This study was mainly funded by the author’s institutions and partly

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caries control: a systematic review of clinical trials. Acta Odontologica
supported by Ivoclar Vivadent AG, Schaan, Liechtenstein. The com- Scandinavica, 62, 170–176. Review.
pany provided the varnishes and supported educational activities at 14. Azarpazhooh,  A. and Main,  P.A. (2009) Efficacy of dental prophylaxis
the participating clinics. The company played however no part in the (rubber cup) for the prevention of caries and gingivitis: a systematic review
design of the trial, in the statistical analysis, drafting of the manu- of literature. British Dental Journal, 207, E14; discussion 328–E14; dis-
script, or in the approval of the final wording. cussion 329.
15. Marinho, V.C. (2009) Cochrane reviews of randomized trials of fluoride
therapies for preventing dental caries. European Archives of Paediatric
Acknowledgements Dentistry, 10, 183–191.
16. Marinho,  V.C., Worthington,  H.V., Walsh,  T. and Clarkson,  J.E. (2013)
The authors thank the clinical staff at Bernhold Ortodonti AB,
Fluoride varnishes for preventing dental caries in children and ado-
Ortodonti Syd, and the Department of Orthodontics, Malmö
lescents. Cochrane Database Systematic Review, 11, CD002279. doi:
University for excellent cooperation.  10.1002/14651858.CD002279.pub2
17. Benson, P.E., Parkin, N., Dyer, F., Millett, D.T., Furness, S. and Germain, P.
(2013) Fluorides for the prevention of early tooth decay (demineralised
Conflict of interest
white lesions) during fixed brace treatment. Cochrane Database System-
The authors have no conflict of interest to declare. atic Review, 12, CD003809.
18. Bergstrand, F., and Twetman, S. (2011) A review on prevention and treat-
ment of post-orthodontic white spot lesions - evidence-based methods and
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