Clinical and molecular factors associated with external apical root resorption by orthodontics: Umbrella review

INTRODUCTION

External apical root resorption (EARR) is one of the undesired biological effects of an orthodontic treatment.^[1-3] Permanent loss of root structure is originated by excessive pressure, which leads to capillary collapse, reduction in blood flow, and override of the repair capacity of supporting tissues. These, in turn, lead to the formation of necrotic areas, known as hyaline zones, and activation of the inflammatory response, activating cellular and molecular mechanisms that promote EARR.^[1,2,4-7]

Formation of hyaline areas during orthodontic treatment is unavoidable, but the incidence and severity of EARR are variable,^[7-9] ranging from 26% to 100% as a function of biological, mechanical, and molecular factors, as the orthodontic movements are not the only factor that influences the onset of EARR.^[7,10-13]

Different investigative approaches associate the following factors with a risk of developing EARR: age, gender, nutrition status, medication, systemic diseases, genetics, oral habits, malocclusion, tooth type, root morphology, history of dental trauma, previous orthodontic treatments, pulp vitality, infections, and inflammations are the most relevant biological factors.^{[2,3,6,11,14-18]} Mechanical factors include the type of orthodontic appliances, orthodontic movement type, extractions, treatment time, and level of force magnitude.^[6,19-27]

In addition, several biomarkers are related to the progress of EARR as a response to the orthodontic dental movement. Tissue tension generates tissue structural reorganization that releases neurotransmitters, growth factors, and cytokines, which have been attempted to study in-depth by analyzing the gingival crevicular fluid (GCF) that constitutes their releasing medium.^{[4,7,16,28-30]}

Interleukins (ILs) are a complex of cytokines or low-molecular weight proteins that act as messengers and are physiologically secreted during the bone remodeling process in response to local stress (IL 1 β, IL-6, IL-7, IL-8, TNFα, IL-4, IL-10, IL-13, IL18, and Interferon-γ). The human genome codifies around 50 ILs and associated proteins. However, their association with EARR has not been conclusive, as data convergence has not been obtained. ^{[7,8,10,16,29-34]}

Diagnosis of EARR depends on early detection using routine radiographies. Root shortening begins between the second and fifth treatment weeks, but such change will be only visible in panoramic or periapical radiographs 3 or 4 months after the beginning of the orthodontic treatment. As these diagnostic aids underestimate the extension and produce negative false cases, the “gold standard” to diagnose EARR is cone-beam computed tomography (CBCT) because it accurately detects EARR without the existing limitations of other techniques. CBCT offers high-resolution structural analysis in the three planes of space and superimposition elimination, which provide high sensitivity and specificity in the identification of these types of conditions. ^{[2,3,10,35-37]}

Consequently, multiple clinical and orthodontic variables are associated with EARR. However, investigations show contradictory results, so careful analysis is necessary due to the high heterogeneity within original studies. Therefore, the main objective of this umbrella review was to analyze current evidence on orthodontically induced EARR to identify clinical and molecular factors associated with this condition.

MATERIAL AND METHODS

Article selection

A total of 124 potentially eligible articles were identified. After duplicate elimination, 118 articles remained, which were then screened for title and abstract. One hundred articles were not related to the topic and were discarded. The remaining 18 articles were read and analyzed and eight were subsequently discarded because the studied population was animals. Ten articles (four systematic reviews and six systematic reviews with meta-analysis) were selected for data analysis and validation using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Admeasurement Tool to Assess Systematic Reviews (AMSTAR-2) guidelines. The flow of article selection is shown in [Figure 1].

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Figure 1:

Selection process of included articles.

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RESULTS

Quality assessment of systematic reviews and meta-analyses

Quality assessment of the ten included articles in this umbrella review is shown in [Table 1]. According to the AMSTAR-2 guideline, seven studies were classified as having moderate quality and 3 as low quality. According to the PRISMA guideline, the articles with the best scores were investigations performed by Nowrin et al.^[4], Gandhi et al.^[2], Yi et al.^[37], and Fang X. et al.^[38]. Out of the 27 items included in the PRISMA checklist, only one article matches all the criteria and the score is over 18 points. Besides, nine out of ten articles report high heterogeneity and the remaining article does not report it.

Quality assessment instruments reported in these studies are the Grading of Recommendations, Assessment, Development, and Evaluations, which was used in three articles; the Strengthening the Reporting of Genetic Association Studies statement in two articles; the Risk of bias in Non-randomized Studies-of Interventions tool in 1 study, the Methodological index for non-randomized studies index in 1 work, the Quality Assurance International certification in 1 article, the PRISMA guideline in 1 article, and the Methodologic Scoring System adopted by Roscoe et al. in 2015 in the remaining article.^[6]

Table 1: Assessment and quality control of selected articles

Article	Prisma guideline information qualification	Amstar-2 guideline general quality	Heterogeneity	Quality assessment instrument used in the study
Shifat A Nowrina[4] Saidi Jaafarb Norma Ab Rahmana Rehana Basric Mohammad Khursheed Alamd Fazal Shahida 2018	24/27	Low	CC vs. TT: p-value: 0.020 I2: 60.136 CT vs. TT: p-value: 0.019 I2: 60.371 CC + CT vs TT: p-value: 0.032 I2: 56.520 CC vs. CT + TT: p-value: 0.000 I2: 76.917	(STREGA) statement
Arwa Aldeeri, Lulu Alhammad, Amjad Alduham, Waad Ghassan, Sanaa Shafshak, Eman Fatani 2018 [5]	18/27	Moderate	NR	The Methodologic Scoring System Adopted from Roscoe MG et al, 2015.9[6]
Marina G. Roscoe, Josete B. C. Meira, and Paolo M. Cattaneo 2015[66]	21/27	Moderate	Heterogeneity in study design and treatment protocols	PRISMA 2009 checklist
Francesco TARALLO, Claudio CHIMENTI, Giordano PAIELLA, Massimo CORDARO and Michele TEPEDINO 2019[7]	20/27	Low	Heterogeneity in the studies	Quality Assessment Instrument (QAI)
Vaibhav Gandhi , Shivam Mehta, Marissa Gauthier, Jijian Mu, Chia-Ling Kuo, , Ravindra Nanda and Sumit Yadav 2020[2]	27/27	Moderate	Heterogeneity among studies was modeled by a the effect of a random study in the mixed-effects meta-regression model	Methodological index for non-randomized studies (MINORS)
Aikaterini Samandara, Spyridon N Papageorgiou, Ioulia Ioannidou-Marathiotou, Smaragda Kavvadia-Tsatala, Moschos A Papadopoulos 2018[3]	23/27	Moderate	P<0.10	Grading of Recommendations, Assessment, Development and Evaluations (GRADE) Downs and Black checklist
Scott Derek Currell, , Andrew Liaw, A y Alan Nimmo 2019[1]	21/27	Moderate	NR	Grading of Recommendations, Assessment, Development and Evaluations (GRADE)
Hatem A. Alhadainy, Carlos Flores, Jacqueline Crossman 2016[13]	18/27	Low	P<0,05; I2=69%). Because I2was 69%, a random effects model was performed that showed a funnel plot with asymmetric distribution of the included studies	Grading of Recommendations, Assessment, Development and Evaluations (GRADE)
Jianru Yi, Meile Li y Zhihe Zhao 2019[37]	23/27	Moderate	(I2> 50%) The hypothesis test was set at p<0.05	STREGA statement
Xuanwei Fang, Rui Qi, Chufeng Liu 2019[38]	22/27	Moderate	Chi2= 17,14 df= 12 (P=0,14) I2= 30%	Grading of Recommendations, Assessment, Development and Evaluations (GRADE)

CC: Control, TT: Treated, STREGA: Strengthening the reporting of genetic association studies, PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analysis, NR: Not reported

Cochrane evaluation of individual studies identified sources of bias [Table 2] and assessed the presence of a prism algorithm, the report of interobserver evaluation, and the presence of a funnel plot in each study. The results of this study showed that all investigations exposed the use of the prism algorithm, resulting in a low risk of selection bias. Assessment of interobserver concordance was reported in all articles, leading to a low risk of bias. Due to the presence of a funnel plot, only two studies showed a low risk of report bias, and it was undefined or unclear in the remaining articles as some doubts about the results arose.

Table 2: Cochrane assessment for individual studies

With the purpose of reducing systematic errors, possible bias in the included articles was identified. Due to the high variability among ethnic groups, a selection bias may be found in genetic studies, as genotypes vary according to ethnicity. Samples of fewer than 100 patients were considered a potential bias. The difference in precision among radiographies and measurement and quantification methods was also considered a measurement bias. The absence of control groups, lack of high-quality prospective studies, non-homogeneity at the GCF collection time, different methods to collect this fluid, and measurement of applied force magnitude were other biases.

DISCUSSION

Due to the absence of pathognomonic signs, EARR is casually detected in routine panoramic radiographs. However, underestimating its severity may lead to permanent loss of important root structure since other risks patients are subjected to from their biological background, their interaction with the environment, and factors related to the mechanics employed in orthodontic treatment are mostly unknown. Results presented in this umbrella review may be used as a foundation to develop more solid investigations on this topic.

In 2019, Currel et al.^[1] analyzed the degree of root resorption in teeth subjected to orthodontic treatment considering mechanical factors such as type of device and orthodontic force magnitude and direction. It was found that continuous forces increase EARR regardless of magnitude and direction. Bracket type, ligation, and archwire sequence did not influence the severity of EARR.^[1]

In 2019, Samandara reported that root shortening is significantly increased after orthodontic therapy and confirmed that heavy forces, extractions, and anterior teeth with abnormal root morphology are factors that increase the prevalence and severity of this condition. Similar results are reported by Fernandes stating that orthodontic therapy with extractions increases the risk of EARR by 70% and also considering other variables, such as increased overjet and long dilacerated roots.^[3,39]

Harris et al.,^[40] Barbagallo et al.,^[27] Cheng et al.,^[25] and Paetyangkul et al.^[36] concurred that there is a directly proportional relationship between force and EARR and that the type of orthodontic movement is a significant mechanical factor as forces intensify on certain areas of the root according to the orthodontic action. For instance, pressure accumulates on the root apex during intrusion movements, thus increasing the risk of EARR in that zone. During extrusion movements, EARR is more frequently found on the cervical third toward the mesial and distal, which are the areas where pressure accumulates. However, it is important to mention that extrusion movements have 4 times lower resorption probabilities than intrusions.^[41]

The type of appliance used in the orthodontic treatment is another variable that may influence the behavior of the root resorption process. Conventional brackets have been compared with self-ligating ones to determine whether significant differences are found between both bracket types in the incidence of EARR . Yi J. et al.^[37] established that self-ligating systems may produce lighter forces during aligning movements since no ligature is needed, which may produce a protective effect for maxillary central incisors that are most vulnerable. However, Aras et al. concluded that it is not possible to suggest the superiority of one system over another due to the lack of investigations that follow solid methodologies to identify the exact differences between both systems. ^[37,42]

Regarding molecular factors, articles suggest that EARR has an important genetic component. Homozygous patients for allele 1 of IL-1B exhibit 5–6 times higher risk of developing EARR >2 mm than other groups. Data show that allele 1 in the IL-1B gene, known for reducing the production of IL-1 cytokine, significantly increases the risk of resorption. In addition, it has been suggested that EARR is a complex condition influenced by many different factors that are important to know to understand the contribution of environmental factors, such as habits and biomechanics.^[4,43]

The search for EARR biomarkers intensified after finding dentin specific proteins (DPP-and DSP) that are byproducts found in the GCF, even though such proteins are not routinely released within the periodontal ligament space. ELISA immunoassays were analyzed by James et al. and later confirmed by Balducci et al.,^[44,45] who identified and quantified these proteins in patients under orthodontic treatment. Dentin matrix protein-1 (DMP-1) was found in large quantities in the GCF as it is eliminated from bone and dentin during resorption processes. However, based on the results of the current work, DMP-1 is not dentin-specific, and its presence may be explained not only because of EARR but also due to the remodeling process during the orthodontic movement. As such, it is not an adequate biomarker of this condition as it is not possible to differentiate between its normal and pathological activities. Likewise, DSP protein was found in control groups, so no consensus is reached in the scientific literature to classify them as exact molecular biomarkers of EARR as they are not exclusive of dentin and are expressed in the osseous tissue. Their presence in the GCF may be explained by physiological remodeling processes, which are increased in patients under orthodontic treatment.^[43,46]

Perinetti et al. assessed the activity of ALP in the GCF to evaluate its utility in the diagnosis of EARR during orthodontic treatment. These authors observed a significantly higher ALP activity in tension sites compared to compression zones, which increases as the force increases. However, this finding only reflects the biological activity of such compound in the periodontium during the dental movement and must be further studied, as proposed by Tarallo et al. in 2019.^[7,33,47]

As for dental pulp status and root resorption, Alhadainy et al. and Huzar et al. concurred that the endodontic treatment does not seem to increase root resorption as no significant differences are found between vital and endodontically-treated teeth.^[13,48]

CONCLUSION

Different factors or individual characteristics are paramount to define the risk of root resorption. The dental professional must carry out a comprehensive medical record of patients, including their background, to make the best treatment decision possible.

Biomarkers such as I-1B, I-6, I-4 ILs, and DPP are potential indicators of root resorption, and such molecules might be used to establish the individual risk and/or reach an early diagnosis of EARR to reduce the negative impact of this condition on orthodontic treatments.