Treatment and prevention of post-orthodontic white spot lesions

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Michael Palachi

5th year, group 12

Treatment and prevention of post-orthodontic white spot lesions:

Systematic Review

Master’s Thesis

Supervisor

Prof. Dr. Kristina Lopatienė

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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY

FACULTY OF ODONTOLOGY CLINIC OF ORTHODONTICS

Treatment and prevention of post-orthodontic white spot lesions : Systematic Review

Master’s Thesis

The thesis was done

by student ……… Supervisor ……….

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………20... ……….20…….

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EVALUATION TABLE OF THE MASTER’S THESIS OF THE

TYPE OF SYSTEMATIC REVIEW OF SCIENTIFIC LITERATURE

Evaluation: ... Reviewer: ...

(scientific degree. name and surname)

Reviewing date: ...

No. MT parts MT evaluation aspects

Compliance with MT requirements and evaluation Yes Partially No 1 Summa ry (0.5 point)

Is summary informative and in compliance with the

thesis content and requirements? 0.3 0.1 0

2 Are keywords in compliance with the thesis

essence? 0.2 0.1 0 3 Introductio n, aim and tasks (1 point)

Are the novelty, relevance and significance of the

work justified in the introduction of the thesis? 0.4 0.2 0 4 Are the problem, hypothesis, aim and tasks formed

clearly and properly? 0.4 0.2 0

5 Are the aim and tasks interrelated? 0.2 0.1 0

6 Selection criteria of the studies, search methods and strategy (3.4 points)

Is the protocol of systemic review present? 0.6 0.3 0 7

Were the eligibility criteria of articles for the selected protocol determined (e.g., year, language, publication condition, etc.)

0.4 0.2 0

8

Are all the information sources (databases with dates of coverage, contact with study authors to identify additional studies) described and is the last search day indicated?

0.2 0.1 0

9

Is the electronic search strategy described in such a way that it could be repeated (year of search, the last search day; keywords and their combinations; number of found and selected articles according to the combinations of keywords)?

0.4 0.1 0

10

Is the selection process of studies (screening, eligibility, included in systemic review or, if applicable, included in the meta-analysis) described?

0.4 0.2 0

11

Is the data extraction method from the articles (types of investigations, participants, interventions,

analyzed factors, indexes) described? 0.4 0.2 0

12

Are all the variables (for which data were sought and any assumptions and simplifications made) listed and defined?

0.4 0.2 0

13

Are the methods, which were used to evaluate the risk of bias of individual studies and how this

information is to be used in data synthesis, described?

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14 Were the principal summary measures (risk ratio, difference in means) stated?

0.4 0.2 0

15

Systemization and analysis of data (2.2 points)

Is the number of studies screened: included upon assessment for eligibility and excluded upon giving the reasons in each stage of exclusion presented?

0.6 0.3 0

16

Are the characteristics of studies presented in the included articles, according to which the data were extracted (e.g., study size, follow-up period, type of respondents) presented?

0.6 0.3 0

17

Are the evaluations of beneficial or harmful outcomes for each study presented? (a) simple summary data for each intervention group; b) effect estimates and confidence intervals)

0.4 0.2 0

18

Are the extracted and systemized data from studies presented in the tables according to individual tasks?

0.6 0.3 0

19

Discussion (1.4 points)

Are the main findings summarized and is their relevance indicated?

0.4 0.2 0

20 Are the limitations of the performed systemic review discussed?

0.4 0.2 0

21 Does author present the interpretation of the results?

0.4 0.2 0

22

Conclusions (0.5 points)

Do the conclusions reflect the topic, aim and tasks

of the Master’s thesis? 0.2 0.1 0

23 Are the conclusions based on the analyzed material?

0.2 0.1 0

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25

References (1 point)

Is the references list formed according to the requirements?

0.4 0.2 0

26

Are the links of the references to the text correct? Are the literature sources cited correctly and precisely?

0.2 0.1 0

27 Is the scientific level of references suitable for

Master’s thesis? 0.2 0.1 0

28

Do the cited sources not older than 10 years old form at least 70% of sources, and the not older than 5 years – at least 40%?

0.2 0.1 0

Additional sections, which may increase the collected number of points

29 Annexes Do the presented annexes help to understand the

analyzed topic? +0.2 +0.1 0

30 Practical Are the practical recommendations suggested and

are they related to the received results? +0.4 +0.2 0

Recommend ations

31

Were additional methods of data analysis and their results used and described (sensitivity analyses,

meta-regression)? +1 +0.5 0

32

Was meta-analysis applied? Are the selected statistical methods indicated? Are the results of

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*Remark: the amount of collected points may exceed 10 points. Reviewer’s comments:

Reviewer’s name and surname Reviewer’s signature

General requirements, non-compliance with which reduce the number of points

33

General requirements

Is the thesis volume sufficient (excluding annexes)?

15-20 pages (-2 points)

<15 pages (-5 points) 34 Is the thesis volume increased artificially? -2

points -1 point 35 Does the thesis structure satisfy the

requirements of Master’s thesis? -1 point -2 points 36 Is the thesis written in correct language,

scientifically, logically and laconically? -0.5 point -1 points 37 Are there any grammatical, style or

computer literacy-related mistakes? -2 points -1 points 38 Is text consistent, integral, and are the

volumes of its structural parts balanced? -0.2 point -0.5 points 39 Amount of plagiarism in the thesis. >20% (not evaluated)

40

Is the content (names of sections and sub- sections and enumeration of pages) in compliance with the thesis structure and aims?

-0.2 point -0.5 points

41

Are the names of the thesis parts in compliance with the text? Are the titles of sections and sub-sections distinguished logically and correctly?

42 Are there explanations of the key terms and

abbreviations (if needed)? -0.2 point -0.5 points

43

Is the quality of the thesis typography (quality of printing, visual aids, binding) good?

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Treatment and prevention of post-orthodontic

white spot lesions:

SUMMARY

Background: WSLs are a common, hardly manageable phenomenon with a consistent high

prevalence among patients, especially those admitted of inadequate routine of oral hygiene, that submitted to orthodontic care.

Objective: this review aims evaluating and updating the remineralization potential of today’s

available popular remineralization preparations and methods, and their efficacy to provide a

means of control or preventions of WSLs.

Search methods: Relevant randomized in-vivo clinical trials information search was conducted

from December 2018 till February 2019 and was performed on PubMed and PMC electronic databases which were chosen to be most adequate.

Type of studies: English languish studies, constructed on humans. Selection criteria: Clinical trials, consist 30 and above participating patients, investigating:

CPP-ACFP, or MI paste plus (CCP-ACFP) or fluoride varnish or of any combinations, in order to treat Patients of any age, just completed or are undergoing orthodontic treatment with fixed

appliances and are experiencing WSLs appearance on teeth surface.

Data collection and analysis: Qualitative assessment was chosen due to study heterogeneity,

and it was accordingly performed across 9 clinical studies were study selection, data extraction and risk of bias assessment according Cochrane.

Results: a total of 295 articles were reviewed after duplicates removal. Of which 9 selected

studies met the inclusion criteria.

Conclusions: Comparing to baseline, interventions mostly capable of WSLs remineralization of

some level, yet without reliable evidence of efficacy extent. Comparative results shown for synergy or dominant proficiency among interventions.

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1. INTRODUCTION

White spot lesions (WSLs), which are caries primary markers, are frequently apparent in patients submitted to orthodontic fixed appliances wear (more than 50%)[24,16], while most frequently

sites, prone to attain WSL are mainly labio-gingival surface of maxillary lateral incisors,

following canines and premolars. Least prone area considered maxillary posterior segments [26,6]. Damaging surface enamel may lead to subsurface porosity responsible for the given

appearance of chalky white areas [23,12]. The presence of orthodontic fixed appliances in the oral cavity and the biological and physical

processes that lead to the formation of biofilm around it [2], has an important impact on the progression of tooth surface lesions for several reasons. Especially for individuals of which oral hygiene is inadequate. One reason is the immense mechanical difficulty and uncomfortableness for patients to keep and maintain proper daily oral hygiene [19,6]. Furthermore, there is a

significant reduction and a critical negative bearing on the physiological self-cleansing ability of saliva and the oral musculature as they are restricted and disrupted by the characteristically rough surface of the orthodontic appliances‘ components [14]. Individuals of which their oral saliva and plaque sustain elevated levels of aciduric bacteria, as Streptococcus mutans, Lactobacillus

spp. and Candida albicans would be considered as levelled at high risk [1,3,6]. The formation of white spot lesions may show reversible pattern, spontaneous and

unspontaneous. Though seldom and unpredictably [19]. In addition, at some worsen circumstances, this process may formulate more substantial outcome

of carious lesions [19]. At this point, a more invasive treatment approach may be unavoidable. Unfortunately, literature denotes for early caries reveal, might be presented very shortly after

treatment; as soon as 1month post bonding. Whereas, for non-orthodontic patients, at least 6

months would pass for a resemble outcome to form [21,1]. A quick recognition of WSLs is

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[1].In the demineralization process calcium and phosphate ions are remove from hydroxyapatite [17]. Proposed preventive care agents; should present ions as calcium, phosphate and fluoride at their bioavailable form and under cariogenic conditions, to be subjected to oral cavity at

adequate amounts (Reynolds et al ,2008) [17], later to be incorporated into tooth dental biofilm. Aim for the deposition of fluoroapatite lattice into surface enamel [3]. In the aftermath,

demineralization could be prevented; halted and reversed.

Topical application of fluoride varnish is advised in high-risk patients [1]. At given preliminary excessive dose, fluoride escalates enamel resistance capacity and may prevent WSL

development. Whereas, when applied with fluoride varnish at low concentrations doses, enamel

remineralization and counteracting of lesion progression is more apparent [22]. The resultant fluoroapatite lattice, is most likely to be a longer lasting one, and deeper

incorporated. Since the mode of action consist of formulating fluoride ions reservoir while

guaranteeing their slow release [25,9]. Throughout the varies studies and researches that have been conducted on this subject, the

remineralization agents that have been previously mentioned, have yet shown a substantial lack of empirical evidence for efficacy in concurrently enhancing remineralization while reducing WSLs continuous demineralization[20,17,11].

1.1 Aim:

The purpose of this review is to evaluate the potential of three most widely used preventive remineralization agents, for the treatment of WSLs in patients submitted of orthodontic fixed appliances.

1.2 Tasks:

1. To review treatment protocols in the prevention and treatment of WSLs in patients undergoing orthodontic treatment

2. To compare effectiveness of treatment protocols with fluoride or casein supplements for WSLs mineralization and improvement

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2. SELECTION CRITERIA OF THE STUDIES, SEARCH METHODS

AND STRATEGY

2.1 Protocol

Protocol was conducted according PRIZMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement. While utilizing 9 randomised clinical trials, enquiry the efficacy of the remineralization potential of preventive care agents, for White Spot Lesions manifested in patients submitted to orthodontic fixed appliances wear; fluoride varnish, CPP-ACP, and CPP-ACFP.

2.2 Focus Question

The focus question was constructed according the problem, intervention, comparison, and outcome and study design PICOS (table 1).

Table 1 PICOS table

Component Description

Population Patients that are or were submitted to orthodontic treatment with fixed appliances and exhibit the formation of WSLs, and are being evaluated for the treatment with fluoride varnish, or CPP-ACP/ CPP-ACFP supplement products

Intervention Remineralization agents as fluoride varnish, or CPP-ACP/ CPP-ACFP are applied on suspectable areas for WSLs on teeth surfaces in patients undergoing orthodontic treatment

Comparison Remineralization effect between fluoride varnish to CPP-ACP/ CPP-ACFP products, comparison to baseline and to controlled groups

Outcome Improvement of WSLs seeing in visual appearance and in clinical parameters measurements. Encouragement of remineralization process, and reversing or halting enamel demineralization.

Study design Controlled Randomised trails, may be double blinded single blinded or not.

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2.3 Type of studies

The systemic review incorporates randomized clinical studies and /or follow-up studies, published in the period starting from September 2015 till February 2019;

Studies aim to examine the efficacy of selected remineralization methods and agents for the treatment and prevention of WSLs, in patients submitted to, during or post orthodontic treatment associated with fixed orthodontic appliances. The preventive remineralization measures, which were selected following short individual screening, appeared to reviewer of most currently notable and relevant. Furthermore, additional articles were utilized for supplementary, clearer view on the topic at hand. This articles array comprises of systemic reviews, randomised clinical trials and in-vitro studies. Out of total references 30 % are older than 5 years.

2.4 Literature search and screening

The search for relevant clinical papers included an overview of electronic databases, those that were chosen to be adequate are the PubMed (National Library of Medicine, NCBI), and PMC (PubMed Central®, the U.S. National Institutes of Health's National Library of Medicine

(NIH/NLM).) Strategy: electronic databases search was conducted from December 2018 till end of February 2019. The use of relevant key words was applied for each database:

1. Orthodontic treatment + cpp-acp or MI paste plus 2. WSLs +fluoride varnish

3. Fluoride varnish +orthodontic +remineralization

The initial search identified a total of 295 articles subsequent the removal of duplicates.

Following of the abstract examination, 62 of full-length articles were assessed for eligibility and 9 randomized clinical trials RCTs were accepted for revision (Fig.1).

2.5 Eligibility criteria of articles

Included studies eligible for evaluation in this review should present the following characteristics:

1) Full text articles, Language: English written

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Figure 2. PRIZMA flow diagram

S cr ee n in g

Records identified through PMC database searching (n =243) In clu d ed E li gib il ity Id en tif icat ion

Additional records identified PUBMED database searching

(n = 192)

Records after duplicates removed (n =295)

Articles excluded after assessment title and

abstract (n =233) Full-text articles

assessed for eligibility (n = 62)

Full-text articles excluded, not meeting inclusion criteria

(n =53) Causes: Other reviews

Invitro trials Older than 5 years

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4) General informative articles, systemic reviews, sole abstracts and case reports were

excluded and disregarded.

2.6 Inclusion and exclusion criteria

Inclusion criteria for studies were: 1) Clinical trials, study on humans;

2) Number of participating Patients is no less than 30.

3) Patients just completed orthodontic treatment or are undergoing orthodontic treatment with fixed appliances

 Patients of any age

 Patients teeth obtain WSLs on teeth surfaces

 Treatment conducted incorporates the use of CPP-ACFP, MI paste plus (CCP-AFPC) or fluoride varnish or combined methods

Exclusion criteria for studies were: 1) Invitro studies

2) trials older than 5 year 3) Non-human trails

4) Treatment methods conducted in trial has not incorporated at least one of remineralization agents being reviewed : MI paste plus, CPP-ACP crème and fluoride varnish.

2.7 Data items

Data in this review, was extracted and obtained from each of the 9 RCTs, for the benefit of comparison, according to the following characteristics: Participants’ number (study size), age, study design, materials chosen, follow up period, examination methods, conclusions and main findings.

2.8 Assessment of Risk of bias in individual Studies

The studies were examined individually and throughout in order to detect related phrases and comments of the authors that will aid in assessing bias in 7 domains according to the Cochrane guidelines.

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2.9 Outcome Measures

Traditional methods for detection of WSLs probably be most reliable if will combine technological, visual and tactile inspections.

Optical techniques utilized are such:

1. Quantitative laser DIAGNOdent: quantifies enamel demineralization(DDpen) 2. Digital photographs: for measuring WSLs incidence

3. QLF quantitative light induced fluorescence (parameters ∆q,∆F), Dental light reflector for WSLs visual inspection.

Indexes and parameters evaluated were: 1. Dental plaque index (DPI)

2. Index of gingival inflammation (GI)

3. White spot lesion (WSL) index, Gorelick Index, Nyvad NY criteria: WSLprogression and regression

4. CRT bacteria test

5. ICDAS : International Caries Detection and Assessment System,

6. DMFT, DMFS, scores and criteria according to Boyd for WSLs evaluation 7. Ekstrand criteria : lesions activity scores

8. The WHO criteria for carious status 9. EDI enamel decalcification index

10. Turesky modification of the Quigley and Hein plaque index; Turesky QHPI assess plaque level.

2.10 Types of interventions

Included RCTs were assess, in which the relevant treatment interventions were under inspection: 1. Explored synergistic remineralization ability of CPP-ACP along with fluoride releasing

products.

2. Explored remineralization capacity of CPP-ACP and CPP-ACFP products in comparison to fluoride varnish and control.

3. Explored remineralization by fluoride varnish, fluoride film and the antibacterial effect of chlorhexidine (CHX) gel.

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3. SYSTEMIZATION AND ANALYSIS OF DATA

3.1 Study selection

Article review was obtained according to the PRISMA flow diagram. At the initial search 435 article references were identified, subsequently 295 potential Studies were screened, obtained following record duplicate removal. The applied criteria for inclusion and exclusion was

screened across publications’ abstract, excluding 233 individuals and yield a total of 62 full text articles to be assessed for eligibility, of which 9 RCTs were selected to be revised.

3.2 Exclusion of studies Following full-text assessment, criteria for excluded studies were according to:

In vitro studies and non-human studies (n = 23). Case reports and review studies (n =10).

Older than 5 years (n = 16 +). Trials with bleaching therapy (n = 0) After carefully assessment reading (n=4)

3.3 Study design and performance Regarding the RCTs; four are doubled blinded trials [17,3,16,23], one was single blinded [22],

other two were partially blinded [9, 25] and for two trial blinding was not specified [1,15]. Five mixed trials were examined:

1) Singh S et al. (2016) [25]: inspected impact of fluoride varnish vs. CPP-ACP plus crème and regularly home care OH

2) Alavi S et al. (2018) [1]: inspected impact of chlorhexidine (CHX) gel vs fluoride varnish, a placebo-controlled study (3 armed)

3) Llena C et al. (2015) [17]: inspected impact of CPP - ACP and CPP-amorphous calcium fluoride phosphate (CPP-ACFP) versus fluoride varnish.

4) Kau CH et al. (2019) [15]: inspected impact of Clinpro 5000, Clinpro Crème, and MI paste Plus.

5) Restrepo M et al. (2016) [23]: inspected impact of chlorhexidine (CHX) gel vs fluoride varnish and regularly home care OH.

Two trials performed on casein supplements:

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2) Rechmann P et al. (2018) [22]: inspected impact of treatment combining MI (minimally invasive) Paste Plus (MIPP) and MI Varnish. (contains both casein and fluoride)

Two trials performed on fluoride supplements;

1) He T et al. (2016) [9]: inspected impact of Fluoride varnish vs fluoride film.

2) Kirschneck C et al. (2016) [16]: inspected Fluoride varnish (one-time application)

3.4 Participants

A total of 664 participants met the inclusion criteria and were evaluated across the selected trials. Regarding the range of ages: the minimum threshold: was set in most of trials from 12 years old or older [15,9,22,3,23,1,25]. Two of the nine trials set it from 6 and from 10 [17,16 respectively] years of age. The maximum threshold range has not exceeded 34. Though, one trial did not specify [15], The youngest age range was 6-14 [17], the most adult range was 18-34 [1].

3.5 Synthesis of results

Due to heterogeneity in study design across the performed trials, qualitative assessment has been

chosen for this review and meta- analysis will not be performed

3.6 Quality assessment and Risk of bias within and across studies

the quality assessment will be evaluated according to the risk of bias examination summery, (table 3). For each study bias evaluation has been performed for each domain (table 2).

Random sequence generation Allocation concealment Perform-ance bias Incomplete outcome data Selective reporting Blinding of outcome assessment Other sources of bias

Singh S et al. (2016) [25] Low Low Low Low Low Low Low

A’lavi S et al. (2018) [1] High High High Low Low High ?

Llena C et al. (2015) [17] Low Low High ? ? ? ?

Restrepo MW et al. (2016) [23]

Low Low Low ? Low Low Low

Beerens MW et al. (2019)[3] Low Low Low High Low Low Low

Rechmann P et al. (2018) [22]

Low Low ? Low ? ? Low

He T et al.(2016) [9] Low Low ? ? Low Low Low

Kirschneck C et al. (2016) [16]

Low Low Low Low Low Low Low

Kau CH et al. (2019) [15] Low Low High Low ? High ?

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0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

randome sequence Allocation concealment

Performance bias Incomplete outcome data Selective reporting Blinding of outcome assessment Other sources of bias

89% 89% 45% 56% 67% 56% 67% 0 0 22% 33% 11% 22% 33% 11% 11% 33% 11% 0 22% 0

Figure 2. Risk of bias acroos studies

low risk unclear high risk

High risk of bias (low evidence) Moderate risk of bias (moderate

evidence )

Low risk of bias (high evidence)

Did not recorded low in 3 or more categories.

Did not record low for two out of categories

All categories recorded low

Four studies Three studies Two studies

1. Alavi S, Yaraghi N. The effect of fluoride varnish and chlorhexidine gel on white spots and gingival and plaque indices in fixed orthodontic patients:

1. He et al. Comparative assessment of fluoride varnish and fluoride film for remineralization of

postorthodontic WSLs

1. Singh S et al. Effects of various remineralizing agents on the outcome of post-orthodontic white spot lesions (WSLs)

2. Beerens et al. Long-term

remineralizing effect of MI Paste Plus on regression of early..: a 12-month follow-up

2.Rechmann et al.. MI Varnish and MI Paste Plus in a caries prevention and remineralization

2. Kirschneck C et al. Efficacy of fluoride varnish for preventing white spot lesions and gingivitis during orthodontic treatment 3.Llena C, et al. ACP an

CPP-ACFP versus fluoride varnish

3.Restrepo et al. Control of White Spot Lesions with Use of Fluoride Varnish or Chlorhexidine

4. Kau et al. Effect of fluoride dentifrices on WSLs during orthodontic treatment

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3.7

Systemization of data and characteristics of studies

Findings and main characteristics of each of the allocated studies were obtained for the purpose of efficient comparison. Gathered information was exhibited in the following table 4.

Study Year Number Examination methods Treatment Study design Main findings Singh S et al. 2016 [25] 2016 45 ages 16-25

Mean of DIAGNO dent and mean visual

Immediate after debonding and after 1,3,6, months

3 groups 1) Control: twice daily with 1000

ppm fluoride toothpaste 2) Fluoride varnish (5 % NaF), with 1000 ppm F toothpaste twice daily 3)CPP-ACP : daily, pea size (900 ppm fluoride with CPP-ACP crème) with 1000 ppm fluoride toothpaste three arm group clinical trial follow-up: up to 6 months

The use of fluoride varnish and CPP-ACP plus crème in addition to twice daily use of fluoride toothpaste had no additional benefit in the remineralization of post-orthodontic WSLs A’lavi S et al. 2018 [1] 2018 40 ages 18-34

Visual inspection and tactile Clinical parameters were DPI and GI of Silness and Loe

WSL index according ICDAS

3 groups

1)CHX varnish (0.2%) 2)Fluoride varnish alcohol free (5%NaF) 4)placebo :70% Wt% sorbitol solution Records at 0,3,6,9 months Randomise d placebo controlled Clinical trial with 3 parallel groups Combination of CHX gel and fluoride varnish can reduce the development of gingivitis and decrease WSLs Llena C et al. 2015 [17] 2015 60 Ages 6-14 WSL index according ICDAS Mineralisation changes according Bonferronis Laser fluorescence DIAGNOdent at 0,4,8,12 weeks 3 groups.

A: daily topical GC Tooth Mouse (CPP-ACP) B: Mi Paste Plus (CPP-ACFP), C: fluoride varnish monthly professional application (Duraphat)

Double-blind prospective study At 4 weeks, CPP-ACFP is superior to fluoride varnish at remineralising smooth-surface WSLs. CPP-ACP is not superior Restrepo MW et al. 2016 [23] 2016 35 ages 13-20 Laser fluorescence DIAGNOdent pen (DD) WSLs progression and regression by Nyvad NY criteria at baseline and 3 months S-OHI oral hygiene index at initial and end treatment points and after 3 months

3 groups 1) Fluoride varnish: two

applications of 5% NaF 2) CHX: two applications of 2%

chlorhexidine gel 3) home care control group, saline

sol. was applied 1-week interval between

applications. all patients were instructed of diet and oral hygiene with fluoride toothpaste 1450ppmF

Randomize d blind 3-armed and controlled clinical trial

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2 groups A :MPP (CPP-ACP + NaF 0.2%

w/w; 900 ppm B: fluoride-free control paste +

calcium prospective , double-blinded, randomized , placebo-controlled trial The additional MPP for subsurface enamel lesions post

orthodontic fixed appliance treatment did not improve 1 year following Rechman-n P et al.2018 [22] 2018 40 (3 were lost) ages – 13-26 EDI- enamel decalcification ICDAS At baseline, 3,6,12 months 2 groups A :Experimental: in-office

application (4 times every 3 months )of MI Varnish (10% CPP-ACP, 5% NaF) And fluoride toothpaste (1100 ppm F) twice a day. And MI Paste PlusTM (MIPP, 10% CPP-ACP, 0.2% NaF, 900 ppm F). B: standard-of-care control identical fluoride toothpaste twice a day and recommended fluoride mouth rinse randomize, single-blind, prospectiv, controlled clinical trial

Daily MIPP and quarterly MIV resulted in no statistically significant differences in EDI sum and ICDAS scores. High salivary fluoride levels

He T et al.(2016) [9] 2016 240 (29 lost) ages 12-25 QLF at baseline and 3,6, months

Mixed effect linear model was used for analyse

3 groups A:fluoride varnish (Duraphat; 5% NaF) B: Fluoride film (5% acidulated sodium fluoride) C: placebo :fluoride-free toothpastes single-centre, randomize, active- controlled, examiner-blinded parallel

After removal of the brackets, daily use of fluoride toothpaste may be helpful - Not on a general scale,

fluoride varnish may be slightly more effective Kirschne-ck C et al.(2016) [16] 2016 90 ages 10-17 Extent of enamel demineralisation by ICDAS and GI at baseline and after 4,12,20 weeks. CRT bacteria test for the counts of mutans strep. lactobacilli

3 groups A) control: dental hygiene with

fluoride toothpaste and one-time placebo varnish application

B)elmex® fluid varnish C) Fluor Protector S varnish

All interventions from treatment starting point Single-centre randomized double-blind placebo-controlled A one-time , initial application of fluoride varnish not superior over sufficient dental hygiene with fluoride toothpaste Kau CH et al. (2019) [15] 2019 100 age older than 12

EDI was recorded following Banks and Rich- Mond’s method at the tooth level, all four areas, creating an EDI ranging from 0 to 8. At each visit, three intraoral photos to determine the presence of the WSLs

Three prospective groups (Clinpro 5000, Clinpro Tooth Crème, MI-Paste Plus)

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4. DISSCUSSION

The non-invasive, sought out WSLs remineralization management is accountable for an array of performed trials and for dental researcher’s effort. Nowadays popularity of fluoride and CPP-ACP constituents may be explicable, considering the ongoing endeavour for uncovering non-conventional and newer measures [24]. And yet assured dominance seems to be not yet applicable. Findings introduced in this review may raise some concerns, especially regarding

any claim for CPP-ACP and CPP-ACFP additional remineralization efficacy; According to revised studies, [25,17] when assessing CPP-ACP plus crème (Table IV), at no

point it showed superiority; while was compared with either fluoride varnish or MPP.

Singh S et al. Study’s (2016)[25] combined treatment of CPP-ACP and 1000 ppm fluoride tooth paste showed comparative results with control group for the mean of DIAGNOdent at p>0.05. However, compare to baseline it showed significant statistical difference in remineralization p <0.05. Llena C (2015)[17] compared CPP-ACP to CPP-ACFP and fluoride varnish. All

showed remineralization at DIAGNOdent at significant statistical level comparing to baseline p<0.01. Of four studies investigating MPP [3,22,15,17] , only one trial [17] implied encouraging results with notable superiority of CPPACFP over fluoride varnish and over CPPACP at 4 -week point, (while comparing their statistically significant difference from baseline results of DIAGNOdent scores decline). However, a concern should be regarded while evaluating following trials : Llena C et al.[17], Beerens MW et al.[3] and Kau CH et al. [15]. As are all considered attaining high risk of bias, hence any interpretation of findings originating from these studies should be made with caution.

Beerens MW et al. [3] has not shown WSLs additional improvement following application of MPP over the control group p >0.05. Yet comparing to baseline improvement was notable for

both groups regarding fluorescence loss p<0.001. Kau CH et al.[15] implied Clinpro 5000, was efficient in remineralization comparing

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that of the control group and even to baseline. Results of the main outcomes: ICDAS

scores, %ICDAS score surface and mean EDI level sum showed p>0.05. Yet, increase in oral environment fluoride ions concentration was noticeable: p<0.01 following MIV application. Now, one may question, for the highly dissimilar and unreliable nature of suggested results obtained from laboratory and in-vitro studies in comparison to those noticed in in-vivo RCTs. For instance, in reviews conducted by Chen H et al.[7] 2013 and Kalha AS et al. 2013[13], no reliable evidence was found for efficacy in WSLs mineralization of casein supplements and

fluoride interventions. Kalha though, obtained the notion that the latter may yet promote it. The answer might lie in the element of high complexity of the oral environment, which is hard to

mimic, [24] as well as in the process’ own complexity and its sensitivity to those elements. Nevertheless, while comparing to baseline, often aspired remineralization ability of some amount is achieved. There has been found an association between the distribution of biofilm to the distribution of gingivitis. Furthermore, it has been shown that the gingival bleeding index has

a positive linear correlation to the amount accumulated of biofilm [19]. The build-up of plaque and biofilm, along with the likely subsequent increase of acidogenic

strains of bacteria reside within, their harmful acidic aftermath, and the reduction in salivary flow, may impair tooth surface integrity, leading to enamel demineralization process by which white spot lesions may be apparent [19]. However, it is feasible for some WSLs, if superficial, to exhibit a spontaneous remineralization and improvement [19]. Kalha AS et al. 2013[13] proclaimed for the need in a caries risk assessment protocol throughout treatments in order to allow spontaneous, natural WSLs remineralization.

Previously, laboratory and non-clinical studies had claimed and demonstrated for the ability of fluoride and CPP-ACP with their derivatives based on products to gain significant

improvements in WSLs remineralization [22].

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originating from saliva [14]. As well, it indorses for the resultant increased concentration of bioavailable ions; calcium and phosphate [1]. When Ph descents, two things may occur: one is that CPP-bound ACP preform as a buffer influencing plaque Ph. Second, fluoride ions will be able of being presented at closed proximity, as they are liberated from their superficial tooth surface reserve created due a fluoride preparation [17]. Nano-complexes will formulate; an ions concentration gradient will result in the structured fluoro-hydroxyapatite, located at subsurface lesion area, substituting for the hydroxyapatite crystalline [1,17]. This will result in the

preferment of enamel remineralization [22].

According literature, fluoride supplements are a well-recognised beneficiary in the struggle of enamel remineralization. It has been suggested that its mode of action convey for a rise in enamel resistance. Furthermore, during changes in Ph it acts as an inhibitor for enamel mineral loss [10]. Reviews by HӦchli D et al. 2011[10] and Benson PE et al. 2013 [4] concluded

similarly, suggested fluoride varnish to portraits effectiveness [10] and it be a suitable alternative while compared with various forms of fluoride as interventions for DWLs [4], while nevertheless a further, more elaborate research should be made.

However, there is a dispute in literature regarding the recommended fluoride concentration given. Some support the claim that in order of preventing WSL progress, an efficient enamel protection and resistance can be establish by fluoride varnish, if conveys a preliminary high concentration fluoride dose [22]. In contrary, some warn about the possibility that it may

obstacle and limit deep remineralization capacity of calcium and phosphate ions. In the aftermath remineralization may be provided mainly to superficial layer [8].

Regarding CHX and fluoride varnish applications, if oral hygiene is maintained regularly, the success rates have been recorded in literature for reducing dental plaque and orthodontic WSLs prevalence. CHX may perform in conjugation with other preventive agents, by so providing a boosting effect, which can be very beneficial for patients which are of high risk. Moreover, its innate mode of action by itself has been concurred (though not proven) to obtain antiplaque and

antigingivitic outcomes [1].

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Llena C et al. (2015)[17] disclosed results supported for fluoride varnish remineralization efficacy of smooth surface WSLs, comparing to baseline at statistically significant change p<0.01. In more sever lesions it also showed positive results at 8-week point.

A’lavi et al.(2018) [1] implied that when comparing applied Fluoride varnish and CHX gel to control and placebo groups promising results transpire. A statistically significant improvement was noted in reducing both gingivitis and WSLs, with regarding DPI, gingival and WSLs indexes at p<0.05. Study by Baygin O et al. 2013 [2], suggested similar results for CHX

containing compounds; chlorhexidine varnish and chlorhexidine-fluoride -dentifrice, working in conjugation.

Restrepo M et al.(2016)[23] also conducted a controlled study comparing CHX gel (2% Chlorhexidine gel) and Fluoride varnish (5%NaF varnish). Right initially both showed significantly statistical change in fluorescence values while compared to baseline p<0.01. At third month fluoride group exhibited results comparable with those of CHX p>0.05 but significantly different to control p<0.05 (implying for a quick onset). However, at the end of study no significant difference between groups p>0.05 portraited.

Singh S et al.(2016)[25] performed study as well displayed constructive results. While

comparing to baseline (efficiency was comparative with that of control), treatment comprised of twice daily use of fluoride toothpaste and one time 1 ml fluoride varnish, will induce

remineralization effect with regard to the mean visual and DIAGNOdent scores at significant statistical evident p<0.01. Kirschneck P et al.(2016) [16] on the other hand, was unsuccessful in demonstrating the competence of the initial, one-time application of fluoride varnish; For the primary outcomes; mean ICDAS and GI index no significant difference p>0.05 was shown. He T et al.(2016)[9] compared fluoride varnish efficiency to that of fluoride film. Results suggested a very slim remineralization effect. Primary measure outcome decrease means of ∆Q showed no inter-grouped statistical difference p>0.05. Study utilized a mixed-effects linear model, and further pair wise comparison showed that both when comparing to baseline, are of remineralization efficacy, while fluoride varnish may portraits slightly larger remineralization ability at statistical significance of p<0.05. According Pithon MM et al. 2015 [21], while

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showed independence in that field. Explanation can regard the characteristics attachment properties difference between the two. Although, MI Varnish may show different result if excessive mechanical cleaning will be applied.

Review by Bergstrand F et al. 2011 [5] distinguished between mineralization treatment efficacies employed during and after the orthodontic treatment. For the former, regular professional

applications of fluoride varnish was rendered evidentially beneficial. For the latter, home-care CPP-ACP Crème applications combined fluoridated toothpaste showed no strong evidence to be beneficial.

Lopatiene K et al. 2016 [18], however, disclosed for a significantly achievable employment of interventions of fluoride and casein supplement for the control and prevention of WSLs. Along with that an early detection, is to be paramount for high probability of treatment success.

One may argue that mere entanglement, provided by introducing a patient with new materials for oral cleaning or by applicating periodically an in-office professional (%5 NaF fluoride, MI) varnish, not only it may very well induce protection of some level for tooth enamel, but also may emphasize and encourage for proper oral hygiene habits. It can assist in acquiring the well

needed long term commitment, collaboration and high awareness of the orthodontic patient, which is imperative in the effort of restricting and preventing WSLs initial prevalence. Since prevention and control at initial stages are most likely more attainable than that of already formulated lesions.

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4.1 Limitation

Within the limitations of this review one concerns a seemable drawback, which is the lack in a characteristic protocol able of reducing the diversity of study design, model analysis, study size and outcome measures through trials. Guidelines would be beneficiary in choosing specific, most reliable outcomes comprise both of technological optical and tactical methods, and may lessen of any misreading. Such protocol would have allowed a feasible meta-analysis or at least a more precise qualitative analysis in order of obtaining the most accurate comparison of results. Another limitation relates to the validity of trials in the aspect of risk of bias assessment according the Cochrane guidelines. Bias assessment is subjective and may appear unclear at times. Hence, the assessment for bias by reviewer might be inaccurate. At the outcome level four out of nine trials were evaluated as high risk of bias (table 3) and only two were considered of low risk, the rest unclear.

Across studies, (Fig.2) the domains that showed a tendency for cumulative risk of bias were those associated of blinding, and incomplete data. Risk of bias at review-level may be pondered considering only nine trials are allocated from a vast pool of research, the reviewer is aware for the probability of incomplete retrieval of studies.

5. CONCLUSIONS

1. In literature, following treatment protocols for WSLs’ improvement are found: fluoride varnish, CHX 2% ,casein supplements; both MIPP and CPP-ACP plus crème, and fluoride varnish combined casein supplements. Comparing to baseline protocols able of remineralization of some level, but no reliable evidence for proficiency extent achieved.

2. Evaluating efficiency of MI plus paste, CPP-ACP crème and fluoride varnish, none of treatment protocols provided with a reliable evidence for dominant efficacy

3. Even though treatment of WSLs protocols combined fluoride and casein supplements, they have not provided with a reliable evidence of a synergistic effect capable of enamel

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6. PRACTICAL RECOMMENDATIONS

Since it is not feasible for an orthodontic practitioner of insuring or compelling patients for collaboration in performing the sufficient oral hygiene routine required in aiding WSLs control, mineralization agents such as fluoride varnish, MI varnish, MI plus paste, and CPP-ACP crème should be highly considered. As are yet currently providing a probability for a pleasabile, though not complete solution, although no decisive, distinctive protocol could be clearly established for efficiency at this point.

ACKNOWLEDGEMENT

Author is extremely appreciative and would like to thank the dedicated support of her supervisor Prof. Dr. Kristina Lopatienė. Gratitude as well expands to the department of orthodontic

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Treatment and prevention of post-orthodontic white spot lesions

Michael Palachi

Treatment and prevention of post-orthodontic white spot lesions:

Systematic Review

EVALUATION TABLE OF THE MASTER’S THESIS OF THE

TYPE OF SYSTEMATIC REVIEW OF SCIENTIFIC LITERATURE

TABLE OF CONTENTS

Treatment and prevention of post-orthodontic

white spot lesions:

SUMMARY

1. INTRODUCTION

2. SELECTION CRITERIA OF THE STUDIES, SEARCH METHODS

AND STRATEGY

3. SYSTEMIZATION AND ANALYSIS OF DATA

3.7

4. DISSCUSSION

5. CONCLUSIONS

6. PRACTICAL RECOMMENDATIONS

ACKNOWLEDGEMENT