The effect of biologic factors and adjunctive therapies on orthodontically induced inflammatory root resorption: a systematic review and meta-analysis

The effect of biologic factors and adjunctive therapies on orthodontically induced inflammatory... Summary Objective Biologic factors and adjunctive therapies are known to affect the degree of orthodontically induced inflammatory root resorption (OIIRR). However, a systematic overall assessment of their impact on OIIRR has not previously been reported. We, therefore, aimed to systematically assess effects on OIIRR of biologic factors and adjunctive therapies in human and animal subjects. Methods A comprehensive search strategy was performed for all major electronic databases. Two reviewers independently selected studies, undertook data extraction and assessed the risk of bias for all included studies according to a pre-specified protocol inspired by Cochrane and the PRISMA guidelines. Eligible studies compared the effect of intervention(s) in an experimental and a control group. Results A total of 9 human and 36 animal trials met the inclusion criteria. Where appropriate, random-effect meta-analyses were carried out to determine the outcome measure OIIRR. The random-effect meta-analysis demonstrated that OIIRR was inhibited by fluoride (ES = −2.08 [−3.02, −1.14]), thyroxine (ES = −1.91 [−3.20, −0.61]), and steroids (ES = −2.79 [−4.26, −1.33]). In contrast, corticotomy (ES = 0.38 [0.05, 0.71]) significantly enhanced OIIRR. Conclusion In animals, administration of fluoride, thyroxine and steroids decreased OIIRR, whereas corticotomy increased OIIRR. In general, the effect on OIIRR increased with higher dosage and/or exposure time. Despite methodological limitations of the included studies, this systematic review provides an important overview of the effect of biologic factors and adjunctive therapies on OIIRR. Introduction Orthodontic force application induces local inflammation that is essential for tooth movement and a fundamental component in root resorption. Brezniak and Wasserstein (1), therefore, advised that the term orthodontic force-induced root resorption be coined orthodontically induced inflammatory root resorption (OIIRR) for increased precision. OIIRR has a multifactorial aetiology involving both environmental and host factors (2–4). Administration of medications, hormones, specific diet regimen or any substances that might interfere directly or indirectly with bone metabolism were defined as biologic factors. Furthermore, interventions like low-level laser therapy, ultrasound therapy and corticotomy that similarly could induce a local or systemic effect and thus influence orthodontic treatment induced root resorption were defined adjunctive therapies. The effect of biologic factors and adjunctive therapies on root resorption is complex and not fully understood (2,5–7). Information about possible adverse effects is important for the orthodontist because many patients use prescribed and/or over the counter medications, dietary supplements and some undergo adjunctive therapies. This might increase or decrease the velocity of tooth movement, but also lead to undesired side effects such as increased root resorption (8,9). Although the average orthodontic patient experiences about 2.5 mm of root shortening, around 1–5% of the teeth will show severe OIIRR exceeding 5 mm (10–12). Some of the above-mentioned patient-related biologic factors may increase and others may reduce the degree of OIIRR. Therefore, a comprehensive review of the literature investigating potential OIIRR risk factors is warranted. To our knowledge, all previous reviews have focused on the effect of such interventions on orthodontic tooth movement and not on OIIRR, thus no systematic review of the effect of biologic factors or adjunctive therapies on the degree of OIIRR exists (4,13). Therefore, we aimed to systematically assess the effect of biologic factors and adjunctive therapies on OIIRR in both human subjects and animals. Material and methods Protocol and registration A detailed study protocol inspired by the PRISMA and Cochrane guidelines was constructed before the study was initiated. The protocol was published online on the SYRCLE website (Supplementary Table 1), http://www.syrcle.nl/ (14–17). Eligibility criteria, information sources, search strategy and study selection A search strategy was performed for each of the selected databases in collaboration with an experienced librarian. Table 1 presents the PICOS question and outline (Population, Intervention, Comparison, Outcome and Study design) of this review. Exclusion criteria were dual publications, studies with groups of fewer than 5 subjects, and studies that measured OIIRR qualitatively. The included biologic factors and adjunctive therapies were systemic disorders, specific dietary regimens, LLLT, ultrasound therapy and any systemic or local administration of substances that might interfere directly or indirectly with bone physiology. The search terms were developed for MEDLINE and modified to operate in all of the major international research databases (Supplementary Table 2). The corresponding author was contacted when there was need for additional or clarifying information. The reference lists of the selected studies were hand-searched to identify any additional relevant studies. Two of the authors (LH and VVR), who were not blinded to the authors or the result of the study, independently selected studies that were eligible for inclusion in the review, assessed the risk of bias and extracted data. Disagreements were resolved by discussion and consultation with a third author (KDK). Table 1. PICOS question, outline, search strategy. How do biologic factors and adjunctive therapies affect OIIRR in human subjects and animals?  Population: Patients and animals with fixed orthodontic appliances.  Intervention: Patients or animals in the experiment group with biologic factor or adjunctive intervention.  Comparison: A matched control group with fixed appliances but without intervention.  Outcome: OIIRR quantitatively measured on histological sections, quantitatively by radiographs or tomographic imaging  Study design: Randomized and controlled clinical trials, cohort studies, case–control studies and animal experiments. Split-mouth designs were included.  Databases included (October 9, 2017)  • MEDLINE via PubMed  • EMBASE  • Cochrane Central Register of Controlled Trials  • WEB OF SCIENCE  • EBM Reviews (Cochrane database of systematic reviews)  • LILACS (Latin American and Caribbean Center on Health Sciences)  • SCOPUS  • Google Scholar  • Clinical Trials (searched at www.clinicaltrials.gov)  How do biologic factors and adjunctive therapies affect OIIRR in human subjects and animals?  Population: Patients and animals with fixed orthodontic appliances.  Intervention: Patients or animals in the experiment group with biologic factor or adjunctive intervention.  Comparison: A matched control group with fixed appliances but without intervention.  Outcome: OIIRR quantitatively measured on histological sections, quantitatively by radiographs or tomographic imaging  Study design: Randomized and controlled clinical trials, cohort studies, case–control studies and animal experiments. Split-mouth designs were included.  Databases included (October 9, 2017)  • MEDLINE via PubMed  • EMBASE  • Cochrane Central Register of Controlled Trials  • WEB OF SCIENCE  • EBM Reviews (Cochrane database of systematic reviews)  • LILACS (Latin American and Caribbean Center on Health Sciences)  • SCOPUS  • Google Scholar  • Clinical Trials (searched at www.clinicaltrials.gov)  View Large Table 1. PICOS question, outline, search strategy. How do biologic factors and adjunctive therapies affect OIIRR in human subjects and animals?  Population: Patients and animals with fixed orthodontic appliances.  Intervention: Patients or animals in the experiment group with biologic factor or adjunctive intervention.  Comparison: A matched control group with fixed appliances but without intervention.  Outcome: OIIRR quantitatively measured on histological sections, quantitatively by radiographs or tomographic imaging  Study design: Randomized and controlled clinical trials, cohort studies, case–control studies and animal experiments. Split-mouth designs were included.  Databases included (October 9, 2017)  • MEDLINE via PubMed  • EMBASE  • Cochrane Central Register of Controlled Trials  • WEB OF SCIENCE  • EBM Reviews (Cochrane database of systematic reviews)  • LILACS (Latin American and Caribbean Center on Health Sciences)  • SCOPUS  • Google Scholar  • Clinical Trials (searched at www.clinicaltrials.gov)  How do biologic factors and adjunctive therapies affect OIIRR in human subjects and animals?  Population: Patients and animals with fixed orthodontic appliances.  Intervention: Patients or animals in the experiment group with biologic factor or adjunctive intervention.  Comparison: A matched control group with fixed appliances but without intervention.  Outcome: OIIRR quantitatively measured on histological sections, quantitatively by radiographs or tomographic imaging  Study design: Randomized and controlled clinical trials, cohort studies, case–control studies and animal experiments. Split-mouth designs were included.  Databases included (October 9, 2017)  • MEDLINE via PubMed  • EMBASE  • Cochrane Central Register of Controlled Trials  • WEB OF SCIENCE  • EBM Reviews (Cochrane database of systematic reviews)  • LILACS (Latin American and Caribbean Center on Health Sciences)  • SCOPUS  • Google Scholar  • Clinical Trials (searched at www.clinicaltrials.gov)  View Large Data items and collection Data extraction forms were developed to record the study design, number of subjects and characteristics, interventions, administration route, dosage and duration of interventions, timing and observation period with fixed appliance and intervention, number of teeth and tooth number for assessment of OIIRR, method of outcome assessment and outcome. Risk of bias assessment in individual studies Bias was defined and classified in accordance with the Oxford Centre for Evidence-Based Medicine as any tendency to influence the research results (or their interpretation) other than the experimental intervention (18). Seven criteria were analysed to grade the risk of inherent bias in each study with human subjects and ten criteria for studies with animal subjects. Risk of bias (high, unclear, low) was assessed using the Cochrane Collaboration risk of bias tool for the human studies and the SYRCLE’s risk of bias tool for the animal studies (17,19). Summary measures and approach to synthesis Statistical heterogeneity was assessed by inspecting a graphic display of the estimated treatment effects (ES) from the trials in conjunction with 95% confidence intervals (CIs). The chi-square test was used to assess for heterogeneity; a P value below 0.1 was considered statistically significant for heterogeneity (20). I2 tests for homogeneity were undertaken to quantify the extent of heterogeneity before each meta-analysis. I2 values above 50% signify moderate-to-high heterogeneity. A weighted treatment effect was calculated. The results for OIIRR were expressed as effect sizes with 95% CIs. Results were combined using random-effect meta-analyses, which was considered appropriate in view of the variations in populations and settings. In order to perform meta-analysis of the different categories of biologic factors and adjunctive therapies, a minimum of two studies were required. The number of exposed subjects was reported as n1 and the number of control subjects was reported as n2. Additional analyses Meta-regression was performed to study differences in outcome related to specific biologic factors and adjunctive therapies (20–22). Meta-analysis and sensitivity analyses were undertaken using the Stata statistical software package (version 13.1; StataCorp, College Station, Texas, USA) applying the ‘metan’ and ‘metareg’ commands (20,23). Results Study selection and characteristics A total of 2,392 trials were initially considered potentially relevant for the review. Evaluation of the titles and abstracts identified 99 potential candidates for inclusion. After reading the full text of these articles, 9 human studies and 36 animal studies satisfied the inclusion criteria (Tables 2 and 3, Supplementary Tables 3 and 4). The search was preformed including articles published until October 2017, primary without any language restrictions. However, the search yielded one article written in Chinese. Although we tried to contact the corresponding author, he did not reply. Unfortunately, we did not have resources to have the article translated and it was excluded. Table 2. Description of human studies.   DiBiase 2016  Raza 2016  Sousa 2011  Abbas 2016  Charavet 2016  Patterson 2017  Shoreibah 2012  Wang 2013  McNab 1999  Group  Intraoral intervention  Intraoral intervention  Intraoral intervention  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Mechanical vibration  LIPUS  LLLT  Piezocision and corticotomy  Piezocision  Piezocision  Corticotomy  Corticotomy  Asthma  Study design  Multicenter RCT  RCT, split mouth  Prospective, cohort study, split mouth  RCT, split mouth  RCT  Prospective, cohort study, split mouth  Prospective cohort study  Prospective cohort study  Retrospective case–control study  OIIRR assessment method  PR  μCT  PR  CBCT  CT  μCT  PR  CBCT  OPG  OIIRR finding  No difference  Decreased percentage, number and total volume  No difference  No difference  No difference  Increased OIIRR  Decreased OIIRR  Decreased OIIRR  Increased OIIRR  BF outcome  Neutral  Protective  Neutral  Neutral  Neutral  Exacerbating  Protective  Protective  Exacerbating    DiBiase 2016  Raza 2016  Sousa 2011  Abbas 2016  Charavet 2016  Patterson 2017  Shoreibah 2012  Wang 2013  McNab 1999  Group  Intraoral intervention  Intraoral intervention  Intraoral intervention  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Mechanical vibration  LIPUS  LLLT  Piezocision and corticotomy  Piezocision  Piezocision  Corticotomy  Corticotomy  Asthma  Study design  Multicenter RCT  RCT, split mouth  Prospective, cohort study, split mouth  RCT, split mouth  RCT  Prospective, cohort study, split mouth  Prospective cohort study  Prospective cohort study  Retrospective case–control study  OIIRR assessment method  PR  μCT  PR  CBCT  CT  μCT  PR  CBCT  OPG  OIIRR finding  No difference  Decreased percentage, number and total volume  No difference  No difference  No difference  Increased OIIRR  Decreased OIIRR  Decreased OIIRR  Increased OIIRR  BF outcome  Neutral  Protective  Neutral  Neutral  Neutral  Exacerbating  Protective  Protective  Exacerbating  CBCT: Cone-beam computed tomography; CT: Computerized tomography; LIPUS: Low-intensity pulsed ultrasound LLLT: Low-level laser therapy; OIIRR: Orthodontically induced inflammatory root resorption; OPG: Orthopantomogram PR: Periapical radiograph; RCT: Randomized clinical trial; μCT: Micro computed tomography. View Large Table 2. Description of human studies.   DiBiase 2016  Raza 2016  Sousa 2011  Abbas 2016  Charavet 2016  Patterson 2017  Shoreibah 2012  Wang 2013  McNab 1999  Group  Intraoral intervention  Intraoral intervention  Intraoral intervention  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Mechanical vibration  LIPUS  LLLT  Piezocision and corticotomy  Piezocision  Piezocision  Corticotomy  Corticotomy  Asthma  Study design  Multicenter RCT  RCT, split mouth  Prospective, cohort study, split mouth  RCT, split mouth  RCT  Prospective, cohort study, split mouth  Prospective cohort study  Prospective cohort study  Retrospective case–control study  OIIRR assessment method  PR  μCT  PR  CBCT  CT  μCT  PR  CBCT  OPG  OIIRR finding  No difference  Decreased percentage, number and total volume  No difference  No difference  No difference  Increased OIIRR  Decreased OIIRR  Decreased OIIRR  Increased OIIRR  BF outcome  Neutral  Protective  Neutral  Neutral  Neutral  Exacerbating  Protective  Protective  Exacerbating    DiBiase 2016  Raza 2016  Sousa 2011  Abbas 2016  Charavet 2016  Patterson 2017  Shoreibah 2012  Wang 2013  McNab 1999  Group  Intraoral intervention  Intraoral intervention  Intraoral intervention  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Mechanical vibration  LIPUS  LLLT  Piezocision and corticotomy  Piezocision  Piezocision  Corticotomy  Corticotomy  Asthma  Study design  Multicenter RCT  RCT, split mouth  Prospective, cohort study, split mouth  RCT, split mouth  RCT  Prospective, cohort study, split mouth  Prospective cohort study  Prospective cohort study  Retrospective case–control study  OIIRR assessment method  PR  μCT  PR  CBCT  CT  μCT  PR  CBCT  OPG  OIIRR finding  No difference  Decreased percentage, number and total volume  No difference  No difference  No difference  Increased OIIRR  Decreased OIIRR  Decreased OIIRR  Increased OIIRR  BF outcome  Neutral  Protective  Neutral  Neutral  Neutral  Exacerbating  Protective  Protective  Exacerbating  CBCT: Cone-beam computed tomography; CT: Computerized tomography; LIPUS: Low-intensity pulsed ultrasound LLLT: Low-level laser therapy; OIIRR: Orthodontically induced inflammatory root resorption; OPG: Orthopantomogram PR: Periapical radiograph; RCT: Randomized clinical trial; μCT: Micro computed tomography. View Large Table 3. Description of animal studies.   Crowther 2017  Foo 2007  Gonzales 2011  Sadegh 2016  Seifi 2003  Seifi 2016  Sekhavat 2002  Shirazi 2017  Al-Daghreer 2014  Group  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Intraoral interventions  Biologic factor (BF)  Casein phosphopeptide (CPP)  Fluoride  Fluoride  Zinc  Calsium gluconat (CaG), PGE2  Angiogenic cytokine  PGE1: Misoprostol  Caffeine  LIPUS  Strain/Species  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Sprague-Dawley rats  Beagle dog  EG  CPP  Fluoride  2, 4, 12 weeks Fluoride  1.5, 20, 50 ppm Zinc  PGE2, CaG+PGE2  E10, E100, E1000  6 various doses PGE1  1, 2 or 3 g/l caffeine  Split mouth: LIPUS  n(CG)/n(EG)  20/20  10/10  10/10  11/11  8/8  10/10  8/8  10/10  10/10  Duration of BF  28 days  14 days  2, 4, 12 weeks  60 days  21 days  21 days  14 days  3 days  4 weeks  Duration of fixed appliance  14 days  14 days  14 days  20 days  21 days  21 days  14 days  14 days  4 weeks  OIIRR assessment method  μCT  μCT  SEM, LSM  Histology  Histology  Histology  Histology  Histology  Histology, μCT  OIIRR definition (measure)  Volume (mm3)  Volume (×10−4 mm3), cube-root volume (×10−4 mm3)  Surface area (%), volume (×106 μm3), depth (μm)  Number (n), width (μm), depth (μm)  Surface area (mm2)  Number (n), surface area (mm2)  Depth (mm)  Depth (mm)  Number (n), volume (μm3), percentage (%)  BF outcome  Neutral  Protective  Protective for depth and volume  Neutral  Neutral  Protective for E100  Neutral  Protective  Protective    Ekizer 2015  Fonseca 2013  Higashi 2017  Seifi 2014  Yadav 2016  Arita 2016  Hauber Gamiero 2008  Hu 2014  Ong 2000  Group  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Hormones  Hormones  Hormones  Hormones  Biologic factor (BF)  LLLT (LED)  LLLT (LED)  LLLT (LED)  LLLT  Mechanical vibration  Diabetes  Stress, restrain  rHGH  Prednisolone  Strain/Species  Wistar rats  Wistar rats  Wistar rats  New Zealand rabbits  CD1 mice  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  EG  LLLT  LLLT  LLLT for 1, 2 or 3 days  LLLT  5, 10, 20 HZ vibration  Diabetes+saline (n = 9); Diabetes+insulin (n = 7)  Short- and long- term stress  rHGH 7, 14 days  Prednisolone  n(CG)/n(EG)  10/10  7/7  8/8  8/8  8/8  9/7, 7/7  10/10  5/5  6/6  Duration of BF  10 days  7 days  14 days  48 days  14 days  4 weeks  3 or 40 days  1,3, 7 and 14 days  24 days  Duration of fixed appliance  10 days  7 days  14 days  48 days  14 days  14 days  14 days  1, 3, 7 or 14 days  12 days  OIIRR assessment method  Histology  Histology  μCT  Histology  μCT  SEM, LSM  Histology  μCT  Histology  OIIRR definition (measure)  Surface area (%)  Number (n)  Number (n), diameter (μm), depth (μm), volume (μm3)  Surface area (mm2)  Volume (mm3)  Surface area (×104 μm2), depth (μm), volume (×106 μm3)  Index of resorption (%)  Index of resorption (%)  Length (μm)  BF outcome  Protective  Protective  Neutral  Protective  Neutral  Diabetes protective; diabetes and insulin neutral  Neutral  Protective  Protective    Poumpros 1994  Seifi 2015  Sirisoontorn 2011  Sirisoontorn 2012  Vazquez-Landaverde 2002  Verna 2006  Gameiro 2008  Gonzales 2009  Kirschneck 2017  Group  Hormones  Hormones  Hormones  Hormones  Hormones  Hormones  Medications  Medications  Medications  Biologic factor (BF)  TH  OVX, ORX  OVX  Zoledronic acid, OVX  TH  Methylprednisolone  Celecoxib  Asp., Ace., Mel., Cel., Pre.  Meloxicam  Strain/Species  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Fischer-344 rats  EG  TH  OVX, ORX  OVX  OVX, OVX+Za.  Oral or injected TH  Chronic group: meth. for 7 weeks (n = 23); Acute group: meth. for 3 weeks (n = 22)  For 3 (n = 9), or 14 days (n = 7)  High or low dose; Asp., acet., mel., cel., pre.  OTM+meloxicam  n(CG)/n(EG)  16/15  10/10  5/5  5/5  16/16  23/19; 22/19  9/9; 7/7  5/5  7/7  Duration of BF  10 days  7 weeks  8 weeks  Za. for 5 weeks  10 days  Chronic group: 7 weeks. Acute group: 2 weeks  For 3 or 14 days  14 days  24 days  Duration of fixed appliance  10 days  3 weeks  28 days  21 days  8 days  21 days  14 days  14 days  14 days  OIIRR assessment method  Histology  Histology  SEM, LSM  SEM, LSM  Histology  Histology  Histology  SEM, LSM  Histology  OIIRR definition (measure)  Index of resorption (%)  Surface area (mm2)  Surface area (×102 μm2), depth (μm), volume (×104 μm3)  Surface area (×102 μm2), depth (μm), volume (104 μm3)  Index of resorption (%)  Number (n)  Index of resorption (%)  Surface area (%), depth (mm), volume (x106μm3)  Index of resorption (%)  BF outcome  Protective  Protective  Exacerbating  OVX exacerbating. Za. protective with OVX  Protective  Exacerbatin: acute group. Neutral: chronic group  Neutral  Protective: pre., high and low dose, and cel. high dose. Otherwise neutral  Protective    Liu 2004  MirHashemi 2013  Rafiei 2015  Sodagar 2013  Wang 2014  Zhou 1997  Kurohama 2016  Murphy 2016  Murata 2013  Group  Medications  Medications  Medications  Medications  Medications  Medications  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Clodronate  Atorvastatin  Fluoxetine  Celecoxib  Lithium Chloride  Indomethacin  Corticotomy  Corticotomy  OVA allergen sensitization and asp.  Strain/Species  Wistar rats  Sprague-Dawley rats  *  Sprague-Dawley rats  Sprague-Dawley rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Brown-Norway rats  EG  Split mouth: clodronate  Atorvastatin  Fluoxetine  Celecoxib  LiCl  Indomethacin  4 different types of corticotomy  Corticotomy with low or high force  OVA and asp.. OVA  n(CG)/n(EG)  26/26  12/12  15/15  7/7  5/5  12/12  10/10  11/11  7/7  Duration of BF  21 days  21 days  7 weeks  18 days  14 days  For 1, 3, 6 or 10 days  Corticotomy at app. insertion  Corticotomy at app. insertion and at day 7  Asp for 14 days  Duration of fixed appliance  21 days  21 days  21 days  14 days  14 days  14 days  14 or 21 days  14 days  14 days  OIIRR assessment method  Histology  Histology  Histology  Histology  SEM  Histology  SEM, LSM  Histology, μCT  Histology  OIIRR definition (measure)  Surface area (μm2)  Length (μm), depth (μm)  Index of resorption (%)  Depth (mm)  Surface area ratio  Index of resorption (%)  Surface area (×103 μm2), depth (μm)  Volume (mm3)  Surface area (×103 μm2)  BF outcome  Protective  Neutral  Neutral  Neutral  Neutral  Exacerbating after 10 days  Exacerbating for 3 parameters, otherwise neutral  Exacerbating with high force, neutral with low force  Exacerbating for OVA    Crowther 2017  Foo 2007  Gonzales 2011  Sadegh 2016  Seifi 2003  Seifi 2016  Sekhavat 2002  Shirazi 2017  Al-Daghreer 2014  Group  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Intraoral interventions  Biologic factor (BF)  Casein phosphopeptide (CPP)  Fluoride  Fluoride  Zinc  Calsium gluconat (CaG), PGE2  Angiogenic cytokine  PGE1: Misoprostol  Caffeine  LIPUS  Strain/Species  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Sprague-Dawley rats  Beagle dog  EG  CPP  Fluoride  2, 4, 12 weeks Fluoride  1.5, 20, 50 ppm Zinc  PGE2, CaG+PGE2  E10, E100, E1000  6 various doses PGE1  1, 2 or 3 g/l caffeine  Split mouth: LIPUS  n(CG)/n(EG)  20/20  10/10  10/10  11/11  8/8  10/10  8/8  10/10  10/10  Duration of BF  28 days  14 days  2, 4, 12 weeks  60 days  21 days  21 days  14 days  3 days  4 weeks  Duration of fixed appliance  14 days  14 days  14 days  20 days  21 days  21 days  14 days  14 days  4 weeks  OIIRR assessment method  μCT  μCT  SEM, LSM  Histology  Histology  Histology  Histology  Histology  Histology, μCT  OIIRR definition (measure)  Volume (mm3)  Volume (×10−4 mm3), cube-root volume (×10−4 mm3)  Surface area (%), volume (×106 μm3), depth (μm)  Number (n), width (μm), depth (μm)  Surface area (mm2)  Number (n), surface area (mm2)  Depth (mm)  Depth (mm)  Number (n), volume (μm3), percentage (%)  BF outcome  Neutral  Protective  Protective for depth and volume  Neutral  Neutral  Protective for E100  Neutral  Protective  Protective    Ekizer 2015  Fonseca 2013  Higashi 2017  Seifi 2014  Yadav 2016  Arita 2016  Hauber Gamiero 2008  Hu 2014  Ong 2000  Group  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Hormones  Hormones  Hormones  Hormones  Biologic factor (BF)  LLLT (LED)  LLLT (LED)  LLLT (LED)  LLLT  Mechanical vibration  Diabetes  Stress, restrain  rHGH  Prednisolone  Strain/Species  Wistar rats  Wistar rats  Wistar rats  New Zealand rabbits  CD1 mice  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  EG  LLLT  LLLT  LLLT for 1, 2 or 3 days  LLLT  5, 10, 20 HZ vibration  Diabetes+saline (n = 9); Diabetes+insulin (n = 7)  Short- and long- term stress  rHGH 7, 14 days  Prednisolone  n(CG)/n(EG)  10/10  7/7  8/8  8/8  8/8  9/7, 7/7  10/10  5/5  6/6  Duration of BF  10 days  7 days  14 days  48 days  14 days  4 weeks  3 or 40 days  1,3, 7 and 14 days  24 days  Duration of fixed appliance  10 days  7 days  14 days  48 days  14 days  14 days  14 days  1, 3, 7 or 14 days  12 days  OIIRR assessment method  Histology  Histology  μCT  Histology  μCT  SEM, LSM  Histology  μCT  Histology  OIIRR definition (measure)  Surface area (%)  Number (n)  Number (n), diameter (μm), depth (μm), volume (μm3)  Surface area (mm2)  Volume (mm3)  Surface area (×104 μm2), depth (μm), volume (×106 μm3)  Index of resorption (%)  Index of resorption (%)  Length (μm)  BF outcome  Protective  Protective  Neutral  Protective  Neutral  Diabetes protective; diabetes and insulin neutral  Neutral  Protective  Protective    Poumpros 1994  Seifi 2015  Sirisoontorn 2011  Sirisoontorn 2012  Vazquez-Landaverde 2002  Verna 2006  Gameiro 2008  Gonzales 2009  Kirschneck 2017  Group  Hormones  Hormones  Hormones  Hormones  Hormones  Hormones  Medications  Medications  Medications  Biologic factor (BF)  TH  OVX, ORX  OVX  Zoledronic acid, OVX  TH  Methylprednisolone  Celecoxib  Asp., Ace., Mel., Cel., Pre.  Meloxicam  Strain/Species  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Fischer-344 rats  EG  TH  OVX, ORX  OVX  OVX, OVX+Za.  Oral or injected TH  Chronic group: meth. for 7 weeks (n = 23); Acute group: meth. for 3 weeks (n = 22)  For 3 (n = 9), or 14 days (n = 7)  High or low dose; Asp., acet., mel., cel., pre.  OTM+meloxicam  n(CG)/n(EG)  16/15  10/10  5/5  5/5  16/16  23/19; 22/19  9/9; 7/7  5/5  7/7  Duration of BF  10 days  7 weeks  8 weeks  Za. for 5 weeks  10 days  Chronic group: 7 weeks. Acute group: 2 weeks  For 3 or 14 days  14 days  24 days  Duration of fixed appliance  10 days  3 weeks  28 days  21 days  8 days  21 days  14 days  14 days  14 days  OIIRR assessment method  Histology  Histology  SEM, LSM  SEM, LSM  Histology  Histology  Histology  SEM, LSM  Histology  OIIRR definition (measure)  Index of resorption (%)  Surface area (mm2)  Surface area (×102 μm2), depth (μm), volume (×104 μm3)  Surface area (×102 μm2), depth (μm), volume (104 μm3)  Index of resorption (%)  Number (n)  Index of resorption (%)  Surface area (%), depth (mm), volume (x106μm3)  Index of resorption (%)  BF outcome  Protective  Protective  Exacerbating  OVX exacerbating. Za. protective with OVX  Protective  Exacerbatin: acute group. Neutral: chronic group  Neutral  Protective: pre., high and low dose, and cel. high dose. Otherwise neutral  Protective    Liu 2004  MirHashemi 2013  Rafiei 2015  Sodagar 2013  Wang 2014  Zhou 1997  Kurohama 2016  Murphy 2016  Murata 2013  Group  Medications  Medications  Medications  Medications  Medications  Medications  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Clodronate  Atorvastatin  Fluoxetine  Celecoxib  Lithium Chloride  Indomethacin  Corticotomy  Corticotomy  OVA allergen sensitization and asp.  Strain/Species  Wistar rats  Sprague-Dawley rats  *  Sprague-Dawley rats  Sprague-Dawley rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Brown-Norway rats  EG  Split mouth: clodronate  Atorvastatin  Fluoxetine  Celecoxib  LiCl  Indomethacin  4 different types of corticotomy  Corticotomy with low or high force  OVA and asp.. OVA  n(CG)/n(EG)  26/26  12/12  15/15  7/7  5/5  12/12  10/10  11/11  7/7  Duration of BF  21 days  21 days  7 weeks  18 days  14 days  For 1, 3, 6 or 10 days  Corticotomy at app. insertion  Corticotomy at app. insertion and at day 7  Asp for 14 days  Duration of fixed appliance  21 days  21 days  21 days  14 days  14 days  14 days  14 or 21 days  14 days  14 days  OIIRR assessment method  Histology  Histology  Histology  Histology  SEM  Histology  SEM, LSM  Histology, μCT  Histology  OIIRR definition (measure)  Surface area (μm2)  Length (μm), depth (μm)  Index of resorption (%)  Depth (mm)  Surface area ratio  Index of resorption (%)  Surface area (×103 μm2), depth (μm)  Volume (mm3)  Surface area (×103 μm2)  BF outcome  Protective  Neutral  Neutral  Neutral  Neutral  Exacerbating after 10 days  Exacerbating for 3 parameters, otherwise neutral  Exacerbating with high force, neutral with low force  Exacerbating for OVA  *: Not stated; Ace: Acetaminophen; App.: orthodontic appliance; Asp: Aspirin, Acetylsalicylic Acid; BF: Biologic factor; CaG: Calcium gluconate; Cel: Celecoxib; CG: Control group; EG: Experiment group; E10: 10 ng basic fibroblast growth factor; E100: 100 ng basic fibroblast growth factor; E1000: 1000 ng basic fibroblast growth factor; LED: Light emitting diode therapy; LiCl: Lithium Chloride; LIPUS: Low-intensity pulsed ultrasound; LLLT: Low-level laser therapy; LSM: Laser scanning microscope; Mel: Meloxicam; Meth: Methylprednisolone; OIIRR: Orthodontically induced inflammatory root resorption; ORX: Orchiectomy; OTM: Orthodontic tooth movement; OVA: Ovalbumin; OVX: Ovariectomy; PG: Prostaglandin; Pre: Prednisolone; rHGH: Recombinant human growth hormone; SEM: Scanning electron microscope; TH: Thyroid hormone; Za: Zoledronic acid; μCT: Micro computed tomography. View Large Table 3. Description of animal studies.   Crowther 2017  Foo 2007  Gonzales 2011  Sadegh 2016  Seifi 2003  Seifi 2016  Sekhavat 2002  Shirazi 2017  Al-Daghreer 2014  Group  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Intraoral interventions  Biologic factor (BF)  Casein phosphopeptide (CPP)  Fluoride  Fluoride  Zinc  Calsium gluconat (CaG), PGE2  Angiogenic cytokine  PGE1: Misoprostol  Caffeine  LIPUS  Strain/Species  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Sprague-Dawley rats  Beagle dog  EG  CPP  Fluoride  2, 4, 12 weeks Fluoride  1.5, 20, 50 ppm Zinc  PGE2, CaG+PGE2  E10, E100, E1000  6 various doses PGE1  1, 2 or 3 g/l caffeine  Split mouth: LIPUS  n(CG)/n(EG)  20/20  10/10  10/10  11/11  8/8  10/10  8/8  10/10  10/10  Duration of BF  28 days  14 days  2, 4, 12 weeks  60 days  21 days  21 days  14 days  3 days  4 weeks  Duration of fixed appliance  14 days  14 days  14 days  20 days  21 days  21 days  14 days  14 days  4 weeks  OIIRR assessment method  μCT  μCT  SEM, LSM  Histology  Histology  Histology  Histology  Histology  Histology, μCT  OIIRR definition (measure)  Volume (mm3)  Volume (×10−4 mm3), cube-root volume (×10−4 mm3)  Surface area (%), volume (×106 μm3), depth (μm)  Number (n), width (μm), depth (μm)  Surface area (mm2)  Number (n), surface area (mm2)  Depth (mm)  Depth (mm)  Number (n), volume (μm3), percentage (%)  BF outcome  Neutral  Protective  Protective for depth and volume  Neutral  Neutral  Protective for E100  Neutral  Protective  Protective    Ekizer 2015  Fonseca 2013  Higashi 2017  Seifi 2014  Yadav 2016  Arita 2016  Hauber Gamiero 2008  Hu 2014  Ong 2000  Group  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Hormones  Hormones  Hormones  Hormones  Biologic factor (BF)  LLLT (LED)  LLLT (LED)  LLLT (LED)  LLLT  Mechanical vibration  Diabetes  Stress, restrain  rHGH  Prednisolone  Strain/Species  Wistar rats  Wistar rats  Wistar rats  New Zealand rabbits  CD1 mice  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  EG  LLLT  LLLT  LLLT for 1, 2 or 3 days  LLLT  5, 10, 20 HZ vibration  Diabetes+saline (n = 9); Diabetes+insulin (n = 7)  Short- and long- term stress  rHGH 7, 14 days  Prednisolone  n(CG)/n(EG)  10/10  7/7  8/8  8/8  8/8  9/7, 7/7  10/10  5/5  6/6  Duration of BF  10 days  7 days  14 days  48 days  14 days  4 weeks  3 or 40 days  1,3, 7 and 14 days  24 days  Duration of fixed appliance  10 days  7 days  14 days  48 days  14 days  14 days  14 days  1, 3, 7 or 14 days  12 days  OIIRR assessment method  Histology  Histology  μCT  Histology  μCT  SEM, LSM  Histology  μCT  Histology  OIIRR definition (measure)  Surface area (%)  Number (n)  Number (n), diameter (μm), depth (μm), volume (μm3)  Surface area (mm2)  Volume (mm3)  Surface area (×104 μm2), depth (μm), volume (×106 μm3)  Index of resorption (%)  Index of resorption (%)  Length (μm)  BF outcome  Protective  Protective  Neutral  Protective  Neutral  Diabetes protective; diabetes and insulin neutral  Neutral  Protective  Protective    Poumpros 1994  Seifi 2015  Sirisoontorn 2011  Sirisoontorn 2012  Vazquez-Landaverde 2002  Verna 2006  Gameiro 2008  Gonzales 2009  Kirschneck 2017  Group  Hormones  Hormones  Hormones  Hormones  Hormones  Hormones  Medications  Medications  Medications  Biologic factor (BF)  TH  OVX, ORX  OVX  Zoledronic acid, OVX  TH  Methylprednisolone  Celecoxib  Asp., Ace., Mel., Cel., Pre.  Meloxicam  Strain/Species  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Fischer-344 rats  EG  TH  OVX, ORX  OVX  OVX, OVX+Za.  Oral or injected TH  Chronic group: meth. for 7 weeks (n = 23); Acute group: meth. for 3 weeks (n = 22)  For 3 (n = 9), or 14 days (n = 7)  High or low dose; Asp., acet., mel., cel., pre.  OTM+meloxicam  n(CG)/n(EG)  16/15  10/10  5/5  5/5  16/16  23/19; 22/19  9/9; 7/7  5/5  7/7  Duration of BF  10 days  7 weeks  8 weeks  Za. for 5 weeks  10 days  Chronic group: 7 weeks. Acute group: 2 weeks  For 3 or 14 days  14 days  24 days  Duration of fixed appliance  10 days  3 weeks  28 days  21 days  8 days  21 days  14 days  14 days  14 days  OIIRR assessment method  Histology  Histology  SEM, LSM  SEM, LSM  Histology  Histology  Histology  SEM, LSM  Histology  OIIRR definition (measure)  Index of resorption (%)  Surface area (mm2)  Surface area (×102 μm2), depth (μm), volume (×104 μm3)  Surface area (×102 μm2), depth (μm), volume (104 μm3)  Index of resorption (%)  Number (n)  Index of resorption (%)  Surface area (%), depth (mm), volume (x106μm3)  Index of resorption (%)  BF outcome  Protective  Protective  Exacerbating  OVX exacerbating. Za. protective with OVX  Protective  Exacerbatin: acute group. Neutral: chronic group  Neutral  Protective: pre., high and low dose, and cel. high dose. Otherwise neutral  Protective    Liu 2004  MirHashemi 2013  Rafiei 2015  Sodagar 2013  Wang 2014  Zhou 1997  Kurohama 2016  Murphy 2016  Murata 2013  Group  Medications  Medications  Medications  Medications  Medications  Medications  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Clodronate  Atorvastatin  Fluoxetine  Celecoxib  Lithium Chloride  Indomethacin  Corticotomy  Corticotomy  OVA allergen sensitization and asp.  Strain/Species  Wistar rats  Sprague-Dawley rats  *  Sprague-Dawley rats  Sprague-Dawley rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Brown-Norway rats  EG  Split mouth: clodronate  Atorvastatin  Fluoxetine  Celecoxib  LiCl  Indomethacin  4 different types of corticotomy  Corticotomy with low or high force  OVA and asp.. OVA  n(CG)/n(EG)  26/26  12/12  15/15  7/7  5/5  12/12  10/10  11/11  7/7  Duration of BF  21 days  21 days  7 weeks  18 days  14 days  For 1, 3, 6 or 10 days  Corticotomy at app. insertion  Corticotomy at app. insertion and at day 7  Asp for 14 days  Duration of fixed appliance  21 days  21 days  21 days  14 days  14 days  14 days  14 or 21 days  14 days  14 days  OIIRR assessment method  Histology  Histology  Histology  Histology  SEM  Histology  SEM, LSM  Histology, μCT  Histology  OIIRR definition (measure)  Surface area (μm2)  Length (μm), depth (μm)  Index of resorption (%)  Depth (mm)  Surface area ratio  Index of resorption (%)  Surface area (×103 μm2), depth (μm)  Volume (mm3)  Surface area (×103 μm2)  BF outcome  Protective  Neutral  Neutral  Neutral  Neutral  Exacerbating after 10 days  Exacerbating for 3 parameters, otherwise neutral  Exacerbating with high force, neutral with low force  Exacerbating for OVA    Crowther 2017  Foo 2007  Gonzales 2011  Sadegh 2016  Seifi 2003  Seifi 2016  Sekhavat 2002  Shirazi 2017  Al-Daghreer 2014  Group  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Intraoral interventions  Biologic factor (BF)  Casein phosphopeptide (CPP)  Fluoride  Fluoride  Zinc  Calsium gluconat (CaG), PGE2  Angiogenic cytokine  PGE1: Misoprostol  Caffeine  LIPUS  Strain/Species  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Sprague-Dawley rats  Beagle dog  EG  CPP  Fluoride  2, 4, 12 weeks Fluoride  1.5, 20, 50 ppm Zinc  PGE2, CaG+PGE2  E10, E100, E1000  6 various doses PGE1  1, 2 or 3 g/l caffeine  Split mouth: LIPUS  n(CG)/n(EG)  20/20  10/10  10/10  11/11  8/8  10/10  8/8  10/10  10/10  Duration of BF  28 days  14 days  2, 4, 12 weeks  60 days  21 days  21 days  14 days  3 days  4 weeks  Duration of fixed appliance  14 days  14 days  14 days  20 days  21 days  21 days  14 days  14 days  4 weeks  OIIRR assessment method  μCT  μCT  SEM, LSM  Histology  Histology  Histology  Histology  Histology  Histology, μCT  OIIRR definition (measure)  Volume (mm3)  Volume (×10−4 mm3), cube-root volume (×10−4 mm3)  Surface area (%), volume (×106 μm3), depth (μm)  Number (n), width (μm), depth (μm)  Surface area (mm2)  Number (n), surface area (mm2)  Depth (mm)  Depth (mm)  Number (n), volume (μm3), percentage (%)  BF outcome  Neutral  Protective  Protective for depth and volume  Neutral  Neutral  Protective for E100  Neutral  Protective  Protective    Ekizer 2015  Fonseca 2013  Higashi 2017  Seifi 2014  Yadav 2016  Arita 2016  Hauber Gamiero 2008  Hu 2014  Ong 2000  Group  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Hormones  Hormones  Hormones  Hormones  Biologic factor (BF)  LLLT (LED)  LLLT (LED)  LLLT (LED)  LLLT  Mechanical vibration  Diabetes  Stress, restrain  rHGH  Prednisolone  Strain/Species  Wistar rats  Wistar rats  Wistar rats  New Zealand rabbits  CD1 mice  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  EG  LLLT  LLLT  LLLT for 1, 2 or 3 days  LLLT  5, 10, 20 HZ vibration  Diabetes+saline (n = 9); Diabetes+insulin (n = 7)  Short- and long- term stress  rHGH 7, 14 days  Prednisolone  n(CG)/n(EG)  10/10  7/7  8/8  8/8  8/8  9/7, 7/7  10/10  5/5  6/6  Duration of BF  10 days  7 days  14 days  48 days  14 days  4 weeks  3 or 40 days  1,3, 7 and 14 days  24 days  Duration of fixed appliance  10 days  7 days  14 days  48 days  14 days  14 days  14 days  1, 3, 7 or 14 days  12 days  OIIRR assessment method  Histology  Histology  μCT  Histology  μCT  SEM, LSM  Histology  μCT  Histology  OIIRR definition (measure)  Surface area (%)  Number (n)  Number (n), diameter (μm), depth (μm), volume (μm3)  Surface area (mm2)  Volume (mm3)  Surface area (×104 μm2), depth (μm), volume (×106 μm3)  Index of resorption (%)  Index of resorption (%)  Length (μm)  BF outcome  Protective  Protective  Neutral  Protective  Neutral  Diabetes protective; diabetes and insulin neutral  Neutral  Protective  Protective    Poumpros 1994  Seifi 2015  Sirisoontorn 2011  Sirisoontorn 2012  Vazquez-Landaverde 2002  Verna 2006  Gameiro 2008  Gonzales 2009  Kirschneck 2017  Group  Hormones  Hormones  Hormones  Hormones  Hormones  Hormones  Medications  Medications  Medications  Biologic factor (BF)  TH  OVX, ORX  OVX  Zoledronic acid, OVX  TH  Methylprednisolone  Celecoxib  Asp., Ace., Mel., Cel., Pre.  Meloxicam  Strain/Species  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Fischer-344 rats  EG  TH  OVX, ORX  OVX  OVX, OVX+Za.  Oral or injected TH  Chronic group: meth. for 7 weeks (n = 23); Acute group: meth. for 3 weeks (n = 22)  For 3 (n = 9), or 14 days (n = 7)  High or low dose; Asp., acet., mel., cel., pre.  OTM+meloxicam  n(CG)/n(EG)  16/15  10/10  5/5  5/5  16/16  23/19; 22/19  9/9; 7/7  5/5  7/7  Duration of BF  10 days  7 weeks  8 weeks  Za. for 5 weeks  10 days  Chronic group: 7 weeks. Acute group: 2 weeks  For 3 or 14 days  14 days  24 days  Duration of fixed appliance  10 days  3 weeks  28 days  21 days  8 days  21 days  14 days  14 days  14 days  OIIRR assessment method  Histology  Histology  SEM, LSM  SEM, LSM  Histology  Histology  Histology  SEM, LSM  Histology  OIIRR definition (measure)  Index of resorption (%)  Surface area (mm2)  Surface area (×102 μm2), depth (μm), volume (×104 μm3)  Surface area (×102 μm2), depth (μm), volume (104 μm3)  Index of resorption (%)  Number (n)  Index of resorption (%)  Surface area (%), depth (mm), volume (x106μm3)  Index of resorption (%)  BF outcome  Protective  Protective  Exacerbating  OVX exacerbating. Za. protective with OVX  Protective  Exacerbatin: acute group. Neutral: chronic group  Neutral  Protective: pre., high and low dose, and cel. high dose. Otherwise neutral  Protective    Liu 2004  MirHashemi 2013  Rafiei 2015  Sodagar 2013  Wang 2014  Zhou 1997  Kurohama 2016  Murphy 2016  Murata 2013  Group  Medications  Medications  Medications  Medications  Medications  Medications  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Clodronate  Atorvastatin  Fluoxetine  Celecoxib  Lithium Chloride  Indomethacin  Corticotomy  Corticotomy  OVA allergen sensitization and asp.  Strain/Species  Wistar rats  Sprague-Dawley rats  *  Sprague-Dawley rats  Sprague-Dawley rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Brown-Norway rats  EG  Split mouth: clodronate  Atorvastatin  Fluoxetine  Celecoxib  LiCl  Indomethacin  4 different types of corticotomy  Corticotomy with low or high force  OVA and asp.. OVA  n(CG)/n(EG)  26/26  12/12  15/15  7/7  5/5  12/12  10/10  11/11  7/7  Duration of BF  21 days  21 days  7 weeks  18 days  14 days  For 1, 3, 6 or 10 days  Corticotomy at app. insertion  Corticotomy at app. insertion and at day 7  Asp for 14 days  Duration of fixed appliance  21 days  21 days  21 days  14 days  14 days  14 days  14 or 21 days  14 days  14 days  OIIRR assessment method  Histology  Histology  Histology  Histology  SEM  Histology  SEM, LSM  Histology, μCT  Histology  OIIRR definition (measure)  Surface area (μm2)  Length (μm), depth (μm)  Index of resorption (%)  Depth (mm)  Surface area ratio  Index of resorption (%)  Surface area (×103 μm2), depth (μm)  Volume (mm3)  Surface area (×103 μm2)  BF outcome  Protective  Neutral  Neutral  Neutral  Neutral  Exacerbating after 10 days  Exacerbating for 3 parameters, otherwise neutral  Exacerbating with high force, neutral with low force  Exacerbating for OVA  *: Not stated; Ace: Acetaminophen; App.: orthodontic appliance; Asp: Aspirin, Acetylsalicylic Acid; BF: Biologic factor; CaG: Calcium gluconate; Cel: Celecoxib; CG: Control group; EG: Experiment group; E10: 10 ng basic fibroblast growth factor; E100: 100 ng basic fibroblast growth factor; E1000: 1000 ng basic fibroblast growth factor; LED: Light emitting diode therapy; LiCl: Lithium Chloride; LIPUS: Low-intensity pulsed ultrasound; LLLT: Low-level laser therapy; LSM: Laser scanning microscope; Mel: Meloxicam; Meth: Methylprednisolone; OIIRR: Orthodontically induced inflammatory root resorption; ORX: Orchiectomy; OTM: Orthodontic tooth movement; OVA: Ovalbumin; OVX: Ovariectomy; PG: Prostaglandin; Pre: Prednisolone; rHGH: Recombinant human growth hormone; SEM: Scanning electron microscope; TH: Thyroid hormone; Za: Zoledronic acid; μCT: Micro computed tomography. View Large The nine human studies included four studies with a randomized controlled clinical trial (RCT) design (24–27), two of which used a split-mouth design (24,25). One study had a retrospective case–control design (6), and four were prospective cohort studies (28–31), two of which used a split-mouth design (28,31) (Table 2). All 36 included animal studies were prospective clinical trials (Table 3). Although all of these studies were generally described as randomized controlled trials, the randomization procedure was considered sufficient for two studies only, whereas it was inadequate in five studies and unclear for the remaining 29 studies because of lacking description of the randomization process. Two were based on split-mouth designs (32,33), and 34 were considered parallel-group randomized controlled trials (34–67). Risk of bias within studies All included studies were assessed for risk of bias (Supplementary Tables 3 and 4). Overall, many items were scored as ‘high’ or ‘unclear’, indicating poor reporting and experimental design of these studies. Test for publication bias was not undertaken as no more than five studies were included in any of the individual meta-analysis (17). Results of individual studies The included studies were categorized as follows: systemic supplement, intraoral intervention, hormone, medication, corticotomy, asthma and allergy. We compared experimental groups with biologic factor intervention and control group without intervention. Furthermore, control groups were sometimes given sham injection(s) or a placebo drug (Supplementary Tables 5 and 6). Due to considerable heterogeneity in methodology and variation in study design for the human studies, meta-analysis was considered appropriate only for the animal studies. Systemic supplements Neither casein phosphopeptide (CPP) (64), nor zinc (57) displayed any significant difference in effect on OIIRR. Injections of Calsium and PGE2 in rats reduced OIIRR as opposed to administering PGE2 only (46). However, reduced level of OIIRR was reported with caffeine (65) and with high doses of angiogenic cytokine (58). Meta-analysis detected no effect of prostaglandin on OIIRR (ES = 0.26 [−0.14, 0.66]) (46,47) (Figure 1). Moreover, meta-analysis showed significant reduction of OIIRR with fluoride (ES = −2.08 [−3.02, −1.14]) (35,37) (Figure 1). Meta-regression showed an average decrease in the effect size of OIIRR of −0.26 per week with fluoride treatment (P = 0.034). The reduction of OIIRR from 2 to 4 weeks was, however, not statistically significant. In contrast, a statistically significant decrease was observed from 2 to 12 weeks. Figure 1. View largeDownload slide Random-effects meta-analysis of the effect of prostaglandin, fluoride per week and LLLT on OIIRR. (1) 2.5 g/kg; (2) 10.0 g/kg; (3) 5.0 g/kg; (4) 25.0 g/kg; (5) 50.0 g/kg; (6) 100.0 g/kg; (7) Resorption lacunae volume; (8) resorption lacunae cube-root volume; (9) resorption lacunae surface area; (10) resorption lacunae depth; (11) resorption lacunae diameter, (a) 1 day exposure and (b) 2 days exposure. Figure 1. View largeDownload slide Random-effects meta-analysis of the effect of prostaglandin, fluoride per week and LLLT on OIIRR. (1) 2.5 g/kg; (2) 10.0 g/kg; (3) 5.0 g/kg; (4) 25.0 g/kg; (5) 50.0 g/kg; (6) 100.0 g/kg; (7) Resorption lacunae volume; (8) resorption lacunae cube-root volume; (9) resorption lacunae surface area; (10) resorption lacunae depth; (11) resorption lacunae diameter, (a) 1 day exposure and (b) 2 days exposure. Intraoral interventions Nine studies evaluated intraoral interventions being LLLT (28,34,45,55,66), low-intensity pulsed ultrasound (LIPUS) (24,32) and mechanical vibration (27,59). Six of the studies were animal experiments (32,34,45,55,59,66). Neither LLLT (28) nor mechanical vibration (27) significantly altered OIIRR in human subjects. On the other hand, LIPUS resulted in significant OIIRR reduction when irradiating human premolars (24); same effect was shown in beagle dogs (32). Mechanical vibration had insignificant effect on OIIRR in rats, but the decreasing trend varied with different frequencies (59). LLLT in rabbits significantly reduced OIIRR (45), however, meta-analysis of the three studies examining LLLT in rats showed no difference (34,55,66) (Figure 1). Hormones Diabetic rats had significantly reduced OIIRR after 2 weeks with orthodontic treatment, but the effect diminished with insulin administration (63). The same effect was registered after 7 and 14 days of treatment with recombinant human growth hormone (rHGH) (56). Long- and short-term stress increased plasma corticosterone levels in rats, but OIIRR scores did not differ (39). Meta-analysis of the studies evaluating the effect of thyroxine administration revealed that OIIRR was significantly inhibited in rats (44,54) (Figure 2). Figure 2. View largeDownload slide Random-effects meta-analysis of the effect of hormones, medications (NSAID) and corticotomy on OIIRR. (1) oral administration; (2) administration by subcutaneous injection; (3) resorption lacunae surface area; (4) resorption lacunae depth; (5) resorption lacunae volume; (a) high dosage; (b) low dosage; (6) acute group: 3 weeks; (7) chronic group: 7 weeks; (8–9) administration for 3 and 14 days; (10–12) administration for 1, 3 and 6 days; (13) high force level; (14) low force level. Experiment 1: (A) corticotomy technique 1; (B) corticotomy technique 2; (C) corticotomy technique 3. Experiment 2: (D) corticotomy technique 1; (C) corticotomy technique 2. *(C) The technique was repeated in the two experiments. Figure 2. View largeDownload slide Random-effects meta-analysis of the effect of hormones, medications (NSAID) and corticotomy on OIIRR. (1) oral administration; (2) administration by subcutaneous injection; (3) resorption lacunae surface area; (4) resorption lacunae depth; (5) resorption lacunae volume; (a) high dosage; (b) low dosage; (6) acute group: 3 weeks; (7) chronic group: 7 weeks; (8–9) administration for 3 and 14 days; (10–12) administration for 1, 3 and 6 days; (13) high force level; (14) low force level. Experiment 1: (A) corticotomy technique 1; (B) corticotomy technique 2; (C) corticotomy technique 3. Experiment 2: (D) corticotomy technique 1; (C) corticotomy technique 2. *(C) The technique was repeated in the two experiments. The effect of ovariectomy (OVX) in rats was contradictory. Although some reports showed significantly increased OIIRR (48,49), others show an opposite effect of both OVX and orchiectomy (ORX) (ES = 0.38 [0.05, 0.71]) (60) (Figure 2). Meta-analysis displayed significant reduction of OIIRR with prednisolone administration (38,43) (Figure 2). On the other hand, administrating methylprednisolone to acute (3 weeks) and chronic (7 weeks) groups of rats demonstrated increased OIIRR for the acute group only (51). Overall, the meta-analysis showed reduction of OIIRR with steroids (ES = −2.79 [−4.26, −1.33]) (Figure 2). Medications Bisphosphonates Liu et al. (33) administered clodronate and Sirisoontorn et al. (49) administered zoledronic acid after ovariectomy. The animals with OVX and zoledronic acid showed almost the same amount of OIIRR as the control group, as opposed to the effect by OVX alone. Similar, inhibitory effect on OIIRR was reported with the administration of clodronate in rats (33). Nonsteroidal anti-inflammatory drugs (NSAIDs) Aspirin, administered in both high and low doses, did not have any significant effect on OIIRR in a rat model (38). However, when aspirin was administered to allergy-sensitized animals, it significantly reduced OIIRR. The reduction was not significant when compared to control animals (41). Indomethacin, when administered at appliance reactivation for 10 days in a rat model, enhanced OIIRR compared to a control group (52). Three studies considered selective COX-2 inhibitor NSAIDs (36,38,50), whereas two studies evaluated meloxicam (38,67), and meta-analysis showed significant reduction of OIIRR (Figure 2). Overall, meta-analysis on the effect of NSAIDs showed no significant difference in OIIRR (ES = −0.49 [−1.00, 0.01]) (Figure 2). Acetaminophen High and low doses of acetaminophen had no significant effect on OIIRR in rats (38). Others Statins, atorvastatin more specifically, had no significant effect on OIIRR (40). Likewise, neither lithium chloride (LiCl) nor fluoxetine were found to have significant effect on OIIRR (53,61). Corticotomy Seven studies assessed corticotomy, five of which were human trials (25,26,29–31) and two were animal experiments (42,62). The human trials differed with respect to study design; two being RCTs (25,26) and the other three were prospective cohort studies (29–31). The two RCTs found no significant difference in the effect of corticotomy on OIIRR (25,26); however, two prospective cohort studies found reduction of OIIRR (29,30), while the other prospective study reported increased root resorption with piezocision (31). Meta-analysis showed significantly increased OIIRR when assessing the effect of corticotomy on OIIRR in rats (ES = 0.38 [0.05, 0.71]) (42,62) (Figure 2). Asthma and allergy McNab et al. (6) retrospectively evaluated control and asthmatic orthodontic patients and found that the asthmatic patients had significantly increased OIIRR; the upper first molar being most susceptible. Allergic sensitization in animals was reported to significantly increase OIIRR compared with the control group (41). Discussion The aetiology of OIIRR is multifactorial and shaped by a combination of environmental and host factors (2,3). The aim of this systematic review was to assess the risk of any biologic or adjunctive intervention that might affect OIIRR. Although several reviews on OIIRR have been published previously (2,68,69), no systematic review concerning the influence of biologic factors on OIIRR exists. In the present study, we summarize the available literature and present information that may help clinicians identify and treat high-risk patients. Systemic supplements Fluoride increases bone mass and mineral density and has been used in the treatment of metabolic bone diseases such as osteoporosis (70). Fluoridated water has been shown to reduce OIIRR in dose-dependent manner: longer exposure and higher doses of fluoride seem to promote OIIRR inhibition (71). Furthermore, sodium fluoride has been shown to inhibit the osteoclastic activity and reduce the number of active osteoclasts (72). Prostaglandins (PGs) and various growth factors have been successfully tested to accelerate orthodontic tooth movement, but side effects such as OIIRR have also been reported. The two included studies that evaluated the effect of PGs showed no increase in OIIRR (46,47). However, the angiogenic cytokine basic fibroblast growth factor (bFGF) reduced OIIRR in a rat model, but only when high doses were administered (58). It thus appears important to notice that similar dose-dependent effect might exist in other factors or interventions. Intraoral interventions Several included studies examining the effect of LLLT and ultrasound therapy in animals reported a significant reduction of OIIRR (32,34,45,55), but the meta-analysis of the rat studies found no overall differences between lased and non-lased animals. Raza et al. (24) further underpinned the protective effect of ultrasound therapy in human subjects by reporting significant reduction of OIIRR. However, Higashi et al. (66) measured significant reduction of OIIRR after 3 days with laser therapy in a dose-dependent manner. Moreover, a possible reason that no significant effect was seen with LLLT when irradiating human canines could be that humans require higher doses and longer exposure to irradiation than were given in this study (28). Mechanical vibration did not seem to have significant effect on OIIRR, neither in humans nor in rats, although the results showed a trend towards decreased resorption with different frequencies of vibration (27,59). Again, despite no significant differences between the experimental groups, different application modalities seem to have varied effects (27,59). Hormones As diabetes affects bone metabolism, it may also have an impact on OIIRR (73). Significantly, lower OIIRR was measured in diabetic rats, but the effect was diminished by insulin administration (63). It is well known that thyroxine (T4) affects intestinal calcium absorption and therefore is indirectly involved in bone turnover (13). The meta-analysis reported significant reduction of OIIRR in animal subjects exposed to thyroxine (44,54), indicating its involvement in the aetiology of forced-induced root resorption. Some authors suggest administration of thyroxine to patients susceptible to OIIRR, however, this may cause other adverse effects, and more research on this issue is, therefore, needed (44). Administration of rHGH significantly inhibited OIIRR in rats after 7 and 14 days of treatment, but the authors used higher and more frequent dosages than would normally be required for growth-hormone-deficient patients (56). Nevertheless, it confirms the importance of time and dosage exposure for different factors. The relationship between the reduction in oestrogen after menopause and the development of osteoporosis is well established. Using a post-menopausal model, Sirisoontorn et al. (48,49) reported significantly increased OIIRR when comparing OVX rats with controls. They suggested that the loss of oestrogen could modulate osteoclastogenesis via the OPG/RANK/RANKL system. In contrast, Seifi et al. (60) found markedly reduced OIIRR in both OVX and ORX rats. The latter evaluated OIIRR in the mesial root of maxillary first molars only, while Sirisoontorn et al. (48,49) evaluated both the mesial and distal roots. Differences in root angulation, morphology and force distribution could have contributed to the opposing results, but despite that, an increased risk for OIIRR should be considered when planning orthodontic treatment for post-menopausal women. The two studies evaluating the effects of prednisolone showed a significant reduction of OIIRR (38,43), whereas the study on methylprednisolone (51) showed significant increase in the acute phase but no difference in the chronic stage. The reduction of OIIRR was explained by suppression of clastic-inflammatory activity that was reflected in the lower TRAP cell counts in the steroid-treated animals (43). On the other hand, the increased OIIRR in the acute methylprednisolone group was explained by a lack of balance between blastic activities, inhibited by the drug and the clastic activities, enhanced or unchanged by drug administration (51). Overall, meta-analysis showed significant reduction of OIIRR with steroid administration. To date, no human investigations have evaluated the effect of stress hormones on OIIRR, but existing animal studies show that stress experience leads to increased blood corticosterone levels (5,39). This increase had no significant impact on OIIRR as animals subjected to both short- and long-term stress displayed similar amounts of OIIRR. Medications Both studies examining the effect of bisphosphonates reported significant inhibition of OIIRR in rats (33,49). However, meta-analysis was not performed since one of the studies examined ovariectomized rats in which bisphosphonates were administered (49). NSAIDs are the most widely used analgesics and are commonly prescribed for orthodontic patients. All included studies evaluating the effect of NSAIDs on OIIRR used rats (36,38,50,52). The overall meta-analysis showed no significant difference in OIIRR when NSAIDs were used (36,38,50,52). Although not all of the results were significant, the findings suggest that NSAIDs may reduce OIIRR, however, the clinical relevance of this effect must be considered low. Corticotomy Corticotomy is one of the many strategies invoked to increase alveolar bone remodelling, increase the speed of orthodontic tooth movement, and potentially reduce OIIRR (74). Clinical reports indicate that bone remodelling is temporarily accelerated by corticotomy, with increased tooth movement and decreased OIIRR (75,76); the most desired effect for an orthodontist. Still, reports from animal studies show increased OIIRR and the meta-analysis confirms these findings (42,62). A possible explanation for the increased OIIRR is that corticotomy may induce an inflammatory reaction and release of biochemical mediators that enhance osteoclastic activity. The risk of corticotomy-related iatrogenic root damage must also be considered (31). Asthma and allergy The relationship between OIIRR and asthmatic and allergic conditions is poorly understood; but from the few, low evidence studies, asthma and allergy seem to increase OIIRR (6,41). Increased osteoclastogenesis during allergen-induced inflammation may be a possible pathway for increased bone and root resorption; however, clinical studies are needed to support these suppositions. Limitations The employed bias assessment tools showed that all the included studies were characterized by an unclear or high risk of bias; thus, the methodological quality of the studies is poor. It is therefore obvious that an improvement of current methodology is needed. The meta-analysis for fluoride, prostaglandin and corticotomy consisted only of two studies, which should be considered in the interpretation of the results. Therefore, this systematic review provides a reference for future high-quality preclinical animal and human clinical trials aiming to evaluate the effect of biologic factors and adjunctive therapies on OIIRR. Vast majority of the included studies are experimental, and these findings cannot be directly extrapolated to humans. Furthermore, the existing literature is unclear about appropriate dosage, timing and duration for the various biologic factors and therapies and in what way these variables may affect OIIRR. For example, administration of supplements or medications could be oral via drinking water or stomach tube, submucosal, intraperitoneal or subcutaneous injection, among others. It is uncertain if these administration routes have any influence on the viability of the used agents. Another limitation is that very few of the included studies reported adverse effects from respective treatments, which is important when considering the therapeutic efficacy of various agents, and also when designing new studies. Implications for practice In patients in whom biologic agents are used, it is important to adjust the treatment goals and treatment mechanics to minimize OIIRR. For example, findings indicate that asthma may increase the risk of OIIRR, and asthma patients must, therefore, be informed about the risk before commencing treatment, and the clinician should do more intense follow-up during the course of treatment. Thus, in cases where certain factors are known to increase the risk of OIIRR, the orthodontic treatment plan should be modified accordingly. Conclusion In summary, fluoride, thyroxine and steroids reduce OIIRR, whereas corticotomy enhances OIIRR. Identifying increased-risk patients is important to avoid excessive OIIRR. Additionally, the evidence afforded by this systematic review identifies several adjunctive treatments that may help reduce OIIRR in high-risk patients. Clinicians may consider implementing these treatments in patients showing signs of OIIRR early in their treatment course. Supplementary material Supplementary material is available at European Journal of Orthodontics online. 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For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The European Journal of Orthodontics Oxford University Press

The effect of biologic factors and adjunctive therapies on orthodontically induced inflammatory root resorption: a systematic review and meta-analysis

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com
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0141-5387
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1460-2210
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10.1093/ejo/cjy003
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Abstract

Summary Objective Biologic factors and adjunctive therapies are known to affect the degree of orthodontically induced inflammatory root resorption (OIIRR). However, a systematic overall assessment of their impact on OIIRR has not previously been reported. We, therefore, aimed to systematically assess effects on OIIRR of biologic factors and adjunctive therapies in human and animal subjects. Methods A comprehensive search strategy was performed for all major electronic databases. Two reviewers independently selected studies, undertook data extraction and assessed the risk of bias for all included studies according to a pre-specified protocol inspired by Cochrane and the PRISMA guidelines. Eligible studies compared the effect of intervention(s) in an experimental and a control group. Results A total of 9 human and 36 animal trials met the inclusion criteria. Where appropriate, random-effect meta-analyses were carried out to determine the outcome measure OIIRR. The random-effect meta-analysis demonstrated that OIIRR was inhibited by fluoride (ES = −2.08 [−3.02, −1.14]), thyroxine (ES = −1.91 [−3.20, −0.61]), and steroids (ES = −2.79 [−4.26, −1.33]). In contrast, corticotomy (ES = 0.38 [0.05, 0.71]) significantly enhanced OIIRR. Conclusion In animals, administration of fluoride, thyroxine and steroids decreased OIIRR, whereas corticotomy increased OIIRR. In general, the effect on OIIRR increased with higher dosage and/or exposure time. Despite methodological limitations of the included studies, this systematic review provides an important overview of the effect of biologic factors and adjunctive therapies on OIIRR. Introduction Orthodontic force application induces local inflammation that is essential for tooth movement and a fundamental component in root resorption. Brezniak and Wasserstein (1), therefore, advised that the term orthodontic force-induced root resorption be coined orthodontically induced inflammatory root resorption (OIIRR) for increased precision. OIIRR has a multifactorial aetiology involving both environmental and host factors (2–4). Administration of medications, hormones, specific diet regimen or any substances that might interfere directly or indirectly with bone metabolism were defined as biologic factors. Furthermore, interventions like low-level laser therapy, ultrasound therapy and corticotomy that similarly could induce a local or systemic effect and thus influence orthodontic treatment induced root resorption were defined adjunctive therapies. The effect of biologic factors and adjunctive therapies on root resorption is complex and not fully understood (2,5–7). Information about possible adverse effects is important for the orthodontist because many patients use prescribed and/or over the counter medications, dietary supplements and some undergo adjunctive therapies. This might increase or decrease the velocity of tooth movement, but also lead to undesired side effects such as increased root resorption (8,9). Although the average orthodontic patient experiences about 2.5 mm of root shortening, around 1–5% of the teeth will show severe OIIRR exceeding 5 mm (10–12). Some of the above-mentioned patient-related biologic factors may increase and others may reduce the degree of OIIRR. Therefore, a comprehensive review of the literature investigating potential OIIRR risk factors is warranted. To our knowledge, all previous reviews have focused on the effect of such interventions on orthodontic tooth movement and not on OIIRR, thus no systematic review of the effect of biologic factors or adjunctive therapies on the degree of OIIRR exists (4,13). Therefore, we aimed to systematically assess the effect of biologic factors and adjunctive therapies on OIIRR in both human subjects and animals. Material and methods Protocol and registration A detailed study protocol inspired by the PRISMA and Cochrane guidelines was constructed before the study was initiated. The protocol was published online on the SYRCLE website (Supplementary Table 1), http://www.syrcle.nl/ (14–17). Eligibility criteria, information sources, search strategy and study selection A search strategy was performed for each of the selected databases in collaboration with an experienced librarian. Table 1 presents the PICOS question and outline (Population, Intervention, Comparison, Outcome and Study design) of this review. Exclusion criteria were dual publications, studies with groups of fewer than 5 subjects, and studies that measured OIIRR qualitatively. The included biologic factors and adjunctive therapies were systemic disorders, specific dietary regimens, LLLT, ultrasound therapy and any systemic or local administration of substances that might interfere directly or indirectly with bone physiology. The search terms were developed for MEDLINE and modified to operate in all of the major international research databases (Supplementary Table 2). The corresponding author was contacted when there was need for additional or clarifying information. The reference lists of the selected studies were hand-searched to identify any additional relevant studies. Two of the authors (LH and VVR), who were not blinded to the authors or the result of the study, independently selected studies that were eligible for inclusion in the review, assessed the risk of bias and extracted data. Disagreements were resolved by discussion and consultation with a third author (KDK). Table 1. PICOS question, outline, search strategy. How do biologic factors and adjunctive therapies affect OIIRR in human subjects and animals?  Population: Patients and animals with fixed orthodontic appliances.  Intervention: Patients or animals in the experiment group with biologic factor or adjunctive intervention.  Comparison: A matched control group with fixed appliances but without intervention.  Outcome: OIIRR quantitatively measured on histological sections, quantitatively by radiographs or tomographic imaging  Study design: Randomized and controlled clinical trials, cohort studies, case–control studies and animal experiments. Split-mouth designs were included.  Databases included (October 9, 2017)  • MEDLINE via PubMed  • EMBASE  • Cochrane Central Register of Controlled Trials  • WEB OF SCIENCE  • EBM Reviews (Cochrane database of systematic reviews)  • LILACS (Latin American and Caribbean Center on Health Sciences)  • SCOPUS  • Google Scholar  • Clinical Trials (searched at www.clinicaltrials.gov)  How do biologic factors and adjunctive therapies affect OIIRR in human subjects and animals?  Population: Patients and animals with fixed orthodontic appliances.  Intervention: Patients or animals in the experiment group with biologic factor or adjunctive intervention.  Comparison: A matched control group with fixed appliances but without intervention.  Outcome: OIIRR quantitatively measured on histological sections, quantitatively by radiographs or tomographic imaging  Study design: Randomized and controlled clinical trials, cohort studies, case–control studies and animal experiments. Split-mouth designs were included.  Databases included (October 9, 2017)  • MEDLINE via PubMed  • EMBASE  • Cochrane Central Register of Controlled Trials  • WEB OF SCIENCE  • EBM Reviews (Cochrane database of systematic reviews)  • LILACS (Latin American and Caribbean Center on Health Sciences)  • SCOPUS  • Google Scholar  • Clinical Trials (searched at www.clinicaltrials.gov)  View Large Table 1. PICOS question, outline, search strategy. How do biologic factors and adjunctive therapies affect OIIRR in human subjects and animals?  Population: Patients and animals with fixed orthodontic appliances.  Intervention: Patients or animals in the experiment group with biologic factor or adjunctive intervention.  Comparison: A matched control group with fixed appliances but without intervention.  Outcome: OIIRR quantitatively measured on histological sections, quantitatively by radiographs or tomographic imaging  Study design: Randomized and controlled clinical trials, cohort studies, case–control studies and animal experiments. Split-mouth designs were included.  Databases included (October 9, 2017)  • MEDLINE via PubMed  • EMBASE  • Cochrane Central Register of Controlled Trials  • WEB OF SCIENCE  • EBM Reviews (Cochrane database of systematic reviews)  • LILACS (Latin American and Caribbean Center on Health Sciences)  • SCOPUS  • Google Scholar  • Clinical Trials (searched at www.clinicaltrials.gov)  How do biologic factors and adjunctive therapies affect OIIRR in human subjects and animals?  Population: Patients and animals with fixed orthodontic appliances.  Intervention: Patients or animals in the experiment group with biologic factor or adjunctive intervention.  Comparison: A matched control group with fixed appliances but without intervention.  Outcome: OIIRR quantitatively measured on histological sections, quantitatively by radiographs or tomographic imaging  Study design: Randomized and controlled clinical trials, cohort studies, case–control studies and animal experiments. Split-mouth designs were included.  Databases included (October 9, 2017)  • MEDLINE via PubMed  • EMBASE  • Cochrane Central Register of Controlled Trials  • WEB OF SCIENCE  • EBM Reviews (Cochrane database of systematic reviews)  • LILACS (Latin American and Caribbean Center on Health Sciences)  • SCOPUS  • Google Scholar  • Clinical Trials (searched at www.clinicaltrials.gov)  View Large Data items and collection Data extraction forms were developed to record the study design, number of subjects and characteristics, interventions, administration route, dosage and duration of interventions, timing and observation period with fixed appliance and intervention, number of teeth and tooth number for assessment of OIIRR, method of outcome assessment and outcome. Risk of bias assessment in individual studies Bias was defined and classified in accordance with the Oxford Centre for Evidence-Based Medicine as any tendency to influence the research results (or their interpretation) other than the experimental intervention (18). Seven criteria were analysed to grade the risk of inherent bias in each study with human subjects and ten criteria for studies with animal subjects. Risk of bias (high, unclear, low) was assessed using the Cochrane Collaboration risk of bias tool for the human studies and the SYRCLE’s risk of bias tool for the animal studies (17,19). Summary measures and approach to synthesis Statistical heterogeneity was assessed by inspecting a graphic display of the estimated treatment effects (ES) from the trials in conjunction with 95% confidence intervals (CIs). The chi-square test was used to assess for heterogeneity; a P value below 0.1 was considered statistically significant for heterogeneity (20). I2 tests for homogeneity were undertaken to quantify the extent of heterogeneity before each meta-analysis. I2 values above 50% signify moderate-to-high heterogeneity. A weighted treatment effect was calculated. The results for OIIRR were expressed as effect sizes with 95% CIs. Results were combined using random-effect meta-analyses, which was considered appropriate in view of the variations in populations and settings. In order to perform meta-analysis of the different categories of biologic factors and adjunctive therapies, a minimum of two studies were required. The number of exposed subjects was reported as n1 and the number of control subjects was reported as n2. Additional analyses Meta-regression was performed to study differences in outcome related to specific biologic factors and adjunctive therapies (20–22). Meta-analysis and sensitivity analyses were undertaken using the Stata statistical software package (version 13.1; StataCorp, College Station, Texas, USA) applying the ‘metan’ and ‘metareg’ commands (20,23). Results Study selection and characteristics A total of 2,392 trials were initially considered potentially relevant for the review. Evaluation of the titles and abstracts identified 99 potential candidates for inclusion. After reading the full text of these articles, 9 human studies and 36 animal studies satisfied the inclusion criteria (Tables 2 and 3, Supplementary Tables 3 and 4). The search was preformed including articles published until October 2017, primary without any language restrictions. However, the search yielded one article written in Chinese. Although we tried to contact the corresponding author, he did not reply. Unfortunately, we did not have resources to have the article translated and it was excluded. Table 2. Description of human studies.   DiBiase 2016  Raza 2016  Sousa 2011  Abbas 2016  Charavet 2016  Patterson 2017  Shoreibah 2012  Wang 2013  McNab 1999  Group  Intraoral intervention  Intraoral intervention  Intraoral intervention  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Mechanical vibration  LIPUS  LLLT  Piezocision and corticotomy  Piezocision  Piezocision  Corticotomy  Corticotomy  Asthma  Study design  Multicenter RCT  RCT, split mouth  Prospective, cohort study, split mouth  RCT, split mouth  RCT  Prospective, cohort study, split mouth  Prospective cohort study  Prospective cohort study  Retrospective case–control study  OIIRR assessment method  PR  μCT  PR  CBCT  CT  μCT  PR  CBCT  OPG  OIIRR finding  No difference  Decreased percentage, number and total volume  No difference  No difference  No difference  Increased OIIRR  Decreased OIIRR  Decreased OIIRR  Increased OIIRR  BF outcome  Neutral  Protective  Neutral  Neutral  Neutral  Exacerbating  Protective  Protective  Exacerbating    DiBiase 2016  Raza 2016  Sousa 2011  Abbas 2016  Charavet 2016  Patterson 2017  Shoreibah 2012  Wang 2013  McNab 1999  Group  Intraoral intervention  Intraoral intervention  Intraoral intervention  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Mechanical vibration  LIPUS  LLLT  Piezocision and corticotomy  Piezocision  Piezocision  Corticotomy  Corticotomy  Asthma  Study design  Multicenter RCT  RCT, split mouth  Prospective, cohort study, split mouth  RCT, split mouth  RCT  Prospective, cohort study, split mouth  Prospective cohort study  Prospective cohort study  Retrospective case–control study  OIIRR assessment method  PR  μCT  PR  CBCT  CT  μCT  PR  CBCT  OPG  OIIRR finding  No difference  Decreased percentage, number and total volume  No difference  No difference  No difference  Increased OIIRR  Decreased OIIRR  Decreased OIIRR  Increased OIIRR  BF outcome  Neutral  Protective  Neutral  Neutral  Neutral  Exacerbating  Protective  Protective  Exacerbating  CBCT: Cone-beam computed tomography; CT: Computerized tomography; LIPUS: Low-intensity pulsed ultrasound LLLT: Low-level laser therapy; OIIRR: Orthodontically induced inflammatory root resorption; OPG: Orthopantomogram PR: Periapical radiograph; RCT: Randomized clinical trial; μCT: Micro computed tomography. View Large Table 2. Description of human studies.   DiBiase 2016  Raza 2016  Sousa 2011  Abbas 2016  Charavet 2016  Patterson 2017  Shoreibah 2012  Wang 2013  McNab 1999  Group  Intraoral intervention  Intraoral intervention  Intraoral intervention  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Mechanical vibration  LIPUS  LLLT  Piezocision and corticotomy  Piezocision  Piezocision  Corticotomy  Corticotomy  Asthma  Study design  Multicenter RCT  RCT, split mouth  Prospective, cohort study, split mouth  RCT, split mouth  RCT  Prospective, cohort study, split mouth  Prospective cohort study  Prospective cohort study  Retrospective case–control study  OIIRR assessment method  PR  μCT  PR  CBCT  CT  μCT  PR  CBCT  OPG  OIIRR finding  No difference  Decreased percentage, number and total volume  No difference  No difference  No difference  Increased OIIRR  Decreased OIIRR  Decreased OIIRR  Increased OIIRR  BF outcome  Neutral  Protective  Neutral  Neutral  Neutral  Exacerbating  Protective  Protective  Exacerbating    DiBiase 2016  Raza 2016  Sousa 2011  Abbas 2016  Charavet 2016  Patterson 2017  Shoreibah 2012  Wang 2013  McNab 1999  Group  Intraoral intervention  Intraoral intervention  Intraoral intervention  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Mechanical vibration  LIPUS  LLLT  Piezocision and corticotomy  Piezocision  Piezocision  Corticotomy  Corticotomy  Asthma  Study design  Multicenter RCT  RCT, split mouth  Prospective, cohort study, split mouth  RCT, split mouth  RCT  Prospective, cohort study, split mouth  Prospective cohort study  Prospective cohort study  Retrospective case–control study  OIIRR assessment method  PR  μCT  PR  CBCT  CT  μCT  PR  CBCT  OPG  OIIRR finding  No difference  Decreased percentage, number and total volume  No difference  No difference  No difference  Increased OIIRR  Decreased OIIRR  Decreased OIIRR  Increased OIIRR  BF outcome  Neutral  Protective  Neutral  Neutral  Neutral  Exacerbating  Protective  Protective  Exacerbating  CBCT: Cone-beam computed tomography; CT: Computerized tomography; LIPUS: Low-intensity pulsed ultrasound LLLT: Low-level laser therapy; OIIRR: Orthodontically induced inflammatory root resorption; OPG: Orthopantomogram PR: Periapical radiograph; RCT: Randomized clinical trial; μCT: Micro computed tomography. View Large Table 3. Description of animal studies.   Crowther 2017  Foo 2007  Gonzales 2011  Sadegh 2016  Seifi 2003  Seifi 2016  Sekhavat 2002  Shirazi 2017  Al-Daghreer 2014  Group  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Intraoral interventions  Biologic factor (BF)  Casein phosphopeptide (CPP)  Fluoride  Fluoride  Zinc  Calsium gluconat (CaG), PGE2  Angiogenic cytokine  PGE1: Misoprostol  Caffeine  LIPUS  Strain/Species  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Sprague-Dawley rats  Beagle dog  EG  CPP  Fluoride  2, 4, 12 weeks Fluoride  1.5, 20, 50 ppm Zinc  PGE2, CaG+PGE2  E10, E100, E1000  6 various doses PGE1  1, 2 or 3 g/l caffeine  Split mouth: LIPUS  n(CG)/n(EG)  20/20  10/10  10/10  11/11  8/8  10/10  8/8  10/10  10/10  Duration of BF  28 days  14 days  2, 4, 12 weeks  60 days  21 days  21 days  14 days  3 days  4 weeks  Duration of fixed appliance  14 days  14 days  14 days  20 days  21 days  21 days  14 days  14 days  4 weeks  OIIRR assessment method  μCT  μCT  SEM, LSM  Histology  Histology  Histology  Histology  Histology  Histology, μCT  OIIRR definition (measure)  Volume (mm3)  Volume (×10−4 mm3), cube-root volume (×10−4 mm3)  Surface area (%), volume (×106 μm3), depth (μm)  Number (n), width (μm), depth (μm)  Surface area (mm2)  Number (n), surface area (mm2)  Depth (mm)  Depth (mm)  Number (n), volume (μm3), percentage (%)  BF outcome  Neutral  Protective  Protective for depth and volume  Neutral  Neutral  Protective for E100  Neutral  Protective  Protective    Ekizer 2015  Fonseca 2013  Higashi 2017  Seifi 2014  Yadav 2016  Arita 2016  Hauber Gamiero 2008  Hu 2014  Ong 2000  Group  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Hormones  Hormones  Hormones  Hormones  Biologic factor (BF)  LLLT (LED)  LLLT (LED)  LLLT (LED)  LLLT  Mechanical vibration  Diabetes  Stress, restrain  rHGH  Prednisolone  Strain/Species  Wistar rats  Wistar rats  Wistar rats  New Zealand rabbits  CD1 mice  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  EG  LLLT  LLLT  LLLT for 1, 2 or 3 days  LLLT  5, 10, 20 HZ vibration  Diabetes+saline (n = 9); Diabetes+insulin (n = 7)  Short- and long- term stress  rHGH 7, 14 days  Prednisolone  n(CG)/n(EG)  10/10  7/7  8/8  8/8  8/8  9/7, 7/7  10/10  5/5  6/6  Duration of BF  10 days  7 days  14 days  48 days  14 days  4 weeks  3 or 40 days  1,3, 7 and 14 days  24 days  Duration of fixed appliance  10 days  7 days  14 days  48 days  14 days  14 days  14 days  1, 3, 7 or 14 days  12 days  OIIRR assessment method  Histology  Histology  μCT  Histology  μCT  SEM, LSM  Histology  μCT  Histology  OIIRR definition (measure)  Surface area (%)  Number (n)  Number (n), diameter (μm), depth (μm), volume (μm3)  Surface area (mm2)  Volume (mm3)  Surface area (×104 μm2), depth (μm), volume (×106 μm3)  Index of resorption (%)  Index of resorption (%)  Length (μm)  BF outcome  Protective  Protective  Neutral  Protective  Neutral  Diabetes protective; diabetes and insulin neutral  Neutral  Protective  Protective    Poumpros 1994  Seifi 2015  Sirisoontorn 2011  Sirisoontorn 2012  Vazquez-Landaverde 2002  Verna 2006  Gameiro 2008  Gonzales 2009  Kirschneck 2017  Group  Hormones  Hormones  Hormones  Hormones  Hormones  Hormones  Medications  Medications  Medications  Biologic factor (BF)  TH  OVX, ORX  OVX  Zoledronic acid, OVX  TH  Methylprednisolone  Celecoxib  Asp., Ace., Mel., Cel., Pre.  Meloxicam  Strain/Species  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Fischer-344 rats  EG  TH  OVX, ORX  OVX  OVX, OVX+Za.  Oral or injected TH  Chronic group: meth. for 7 weeks (n = 23); Acute group: meth. for 3 weeks (n = 22)  For 3 (n = 9), or 14 days (n = 7)  High or low dose; Asp., acet., mel., cel., pre.  OTM+meloxicam  n(CG)/n(EG)  16/15  10/10  5/5  5/5  16/16  23/19; 22/19  9/9; 7/7  5/5  7/7  Duration of BF  10 days  7 weeks  8 weeks  Za. for 5 weeks  10 days  Chronic group: 7 weeks. Acute group: 2 weeks  For 3 or 14 days  14 days  24 days  Duration of fixed appliance  10 days  3 weeks  28 days  21 days  8 days  21 days  14 days  14 days  14 days  OIIRR assessment method  Histology  Histology  SEM, LSM  SEM, LSM  Histology  Histology  Histology  SEM, LSM  Histology  OIIRR definition (measure)  Index of resorption (%)  Surface area (mm2)  Surface area (×102 μm2), depth (μm), volume (×104 μm3)  Surface area (×102 μm2), depth (μm), volume (104 μm3)  Index of resorption (%)  Number (n)  Index of resorption (%)  Surface area (%), depth (mm), volume (x106μm3)  Index of resorption (%)  BF outcome  Protective  Protective  Exacerbating  OVX exacerbating. Za. protective with OVX  Protective  Exacerbatin: acute group. Neutral: chronic group  Neutral  Protective: pre., high and low dose, and cel. high dose. Otherwise neutral  Protective    Liu 2004  MirHashemi 2013  Rafiei 2015  Sodagar 2013  Wang 2014  Zhou 1997  Kurohama 2016  Murphy 2016  Murata 2013  Group  Medications  Medications  Medications  Medications  Medications  Medications  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Clodronate  Atorvastatin  Fluoxetine  Celecoxib  Lithium Chloride  Indomethacin  Corticotomy  Corticotomy  OVA allergen sensitization and asp.  Strain/Species  Wistar rats  Sprague-Dawley rats  *  Sprague-Dawley rats  Sprague-Dawley rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Brown-Norway rats  EG  Split mouth: clodronate  Atorvastatin  Fluoxetine  Celecoxib  LiCl  Indomethacin  4 different types of corticotomy  Corticotomy with low or high force  OVA and asp.. OVA  n(CG)/n(EG)  26/26  12/12  15/15  7/7  5/5  12/12  10/10  11/11  7/7  Duration of BF  21 days  21 days  7 weeks  18 days  14 days  For 1, 3, 6 or 10 days  Corticotomy at app. insertion  Corticotomy at app. insertion and at day 7  Asp for 14 days  Duration of fixed appliance  21 days  21 days  21 days  14 days  14 days  14 days  14 or 21 days  14 days  14 days  OIIRR assessment method  Histology  Histology  Histology  Histology  SEM  Histology  SEM, LSM  Histology, μCT  Histology  OIIRR definition (measure)  Surface area (μm2)  Length (μm), depth (μm)  Index of resorption (%)  Depth (mm)  Surface area ratio  Index of resorption (%)  Surface area (×103 μm2), depth (μm)  Volume (mm3)  Surface area (×103 μm2)  BF outcome  Protective  Neutral  Neutral  Neutral  Neutral  Exacerbating after 10 days  Exacerbating for 3 parameters, otherwise neutral  Exacerbating with high force, neutral with low force  Exacerbating for OVA    Crowther 2017  Foo 2007  Gonzales 2011  Sadegh 2016  Seifi 2003  Seifi 2016  Sekhavat 2002  Shirazi 2017  Al-Daghreer 2014  Group  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Intraoral interventions  Biologic factor (BF)  Casein phosphopeptide (CPP)  Fluoride  Fluoride  Zinc  Calsium gluconat (CaG), PGE2  Angiogenic cytokine  PGE1: Misoprostol  Caffeine  LIPUS  Strain/Species  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Sprague-Dawley rats  Beagle dog  EG  CPP  Fluoride  2, 4, 12 weeks Fluoride  1.5, 20, 50 ppm Zinc  PGE2, CaG+PGE2  E10, E100, E1000  6 various doses PGE1  1, 2 or 3 g/l caffeine  Split mouth: LIPUS  n(CG)/n(EG)  20/20  10/10  10/10  11/11  8/8  10/10  8/8  10/10  10/10  Duration of BF  28 days  14 days  2, 4, 12 weeks  60 days  21 days  21 days  14 days  3 days  4 weeks  Duration of fixed appliance  14 days  14 days  14 days  20 days  21 days  21 days  14 days  14 days  4 weeks  OIIRR assessment method  μCT  μCT  SEM, LSM  Histology  Histology  Histology  Histology  Histology  Histology, μCT  OIIRR definition (measure)  Volume (mm3)  Volume (×10−4 mm3), cube-root volume (×10−4 mm3)  Surface area (%), volume (×106 μm3), depth (μm)  Number (n), width (μm), depth (μm)  Surface area (mm2)  Number (n), surface area (mm2)  Depth (mm)  Depth (mm)  Number (n), volume (μm3), percentage (%)  BF outcome  Neutral  Protective  Protective for depth and volume  Neutral  Neutral  Protective for E100  Neutral  Protective  Protective    Ekizer 2015  Fonseca 2013  Higashi 2017  Seifi 2014  Yadav 2016  Arita 2016  Hauber Gamiero 2008  Hu 2014  Ong 2000  Group  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Hormones  Hormones  Hormones  Hormones  Biologic factor (BF)  LLLT (LED)  LLLT (LED)  LLLT (LED)  LLLT  Mechanical vibration  Diabetes  Stress, restrain  rHGH  Prednisolone  Strain/Species  Wistar rats  Wistar rats  Wistar rats  New Zealand rabbits  CD1 mice  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  EG  LLLT  LLLT  LLLT for 1, 2 or 3 days  LLLT  5, 10, 20 HZ vibration  Diabetes+saline (n = 9); Diabetes+insulin (n = 7)  Short- and long- term stress  rHGH 7, 14 days  Prednisolone  n(CG)/n(EG)  10/10  7/7  8/8  8/8  8/8  9/7, 7/7  10/10  5/5  6/6  Duration of BF  10 days  7 days  14 days  48 days  14 days  4 weeks  3 or 40 days  1,3, 7 and 14 days  24 days  Duration of fixed appliance  10 days  7 days  14 days  48 days  14 days  14 days  14 days  1, 3, 7 or 14 days  12 days  OIIRR assessment method  Histology  Histology  μCT  Histology  μCT  SEM, LSM  Histology  μCT  Histology  OIIRR definition (measure)  Surface area (%)  Number (n)  Number (n), diameter (μm), depth (μm), volume (μm3)  Surface area (mm2)  Volume (mm3)  Surface area (×104 μm2), depth (μm), volume (×106 μm3)  Index of resorption (%)  Index of resorption (%)  Length (μm)  BF outcome  Protective  Protective  Neutral  Protective  Neutral  Diabetes protective; diabetes and insulin neutral  Neutral  Protective  Protective    Poumpros 1994  Seifi 2015  Sirisoontorn 2011  Sirisoontorn 2012  Vazquez-Landaverde 2002  Verna 2006  Gameiro 2008  Gonzales 2009  Kirschneck 2017  Group  Hormones  Hormones  Hormones  Hormones  Hormones  Hormones  Medications  Medications  Medications  Biologic factor (BF)  TH  OVX, ORX  OVX  Zoledronic acid, OVX  TH  Methylprednisolone  Celecoxib  Asp., Ace., Mel., Cel., Pre.  Meloxicam  Strain/Species  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Fischer-344 rats  EG  TH  OVX, ORX  OVX  OVX, OVX+Za.  Oral or injected TH  Chronic group: meth. for 7 weeks (n = 23); Acute group: meth. for 3 weeks (n = 22)  For 3 (n = 9), or 14 days (n = 7)  High or low dose; Asp., acet., mel., cel., pre.  OTM+meloxicam  n(CG)/n(EG)  16/15  10/10  5/5  5/5  16/16  23/19; 22/19  9/9; 7/7  5/5  7/7  Duration of BF  10 days  7 weeks  8 weeks  Za. for 5 weeks  10 days  Chronic group: 7 weeks. Acute group: 2 weeks  For 3 or 14 days  14 days  24 days  Duration of fixed appliance  10 days  3 weeks  28 days  21 days  8 days  21 days  14 days  14 days  14 days  OIIRR assessment method  Histology  Histology  SEM, LSM  SEM, LSM  Histology  Histology  Histology  SEM, LSM  Histology  OIIRR definition (measure)  Index of resorption (%)  Surface area (mm2)  Surface area (×102 μm2), depth (μm), volume (×104 μm3)  Surface area (×102 μm2), depth (μm), volume (104 μm3)  Index of resorption (%)  Number (n)  Index of resorption (%)  Surface area (%), depth (mm), volume (x106μm3)  Index of resorption (%)  BF outcome  Protective  Protective  Exacerbating  OVX exacerbating. Za. protective with OVX  Protective  Exacerbatin: acute group. Neutral: chronic group  Neutral  Protective: pre., high and low dose, and cel. high dose. Otherwise neutral  Protective    Liu 2004  MirHashemi 2013  Rafiei 2015  Sodagar 2013  Wang 2014  Zhou 1997  Kurohama 2016  Murphy 2016  Murata 2013  Group  Medications  Medications  Medications  Medications  Medications  Medications  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Clodronate  Atorvastatin  Fluoxetine  Celecoxib  Lithium Chloride  Indomethacin  Corticotomy  Corticotomy  OVA allergen sensitization and asp.  Strain/Species  Wistar rats  Sprague-Dawley rats  *  Sprague-Dawley rats  Sprague-Dawley rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Brown-Norway rats  EG  Split mouth: clodronate  Atorvastatin  Fluoxetine  Celecoxib  LiCl  Indomethacin  4 different types of corticotomy  Corticotomy with low or high force  OVA and asp.. OVA  n(CG)/n(EG)  26/26  12/12  15/15  7/7  5/5  12/12  10/10  11/11  7/7  Duration of BF  21 days  21 days  7 weeks  18 days  14 days  For 1, 3, 6 or 10 days  Corticotomy at app. insertion  Corticotomy at app. insertion and at day 7  Asp for 14 days  Duration of fixed appliance  21 days  21 days  21 days  14 days  14 days  14 days  14 or 21 days  14 days  14 days  OIIRR assessment method  Histology  Histology  Histology  Histology  SEM  Histology  SEM, LSM  Histology, μCT  Histology  OIIRR definition (measure)  Surface area (μm2)  Length (μm), depth (μm)  Index of resorption (%)  Depth (mm)  Surface area ratio  Index of resorption (%)  Surface area (×103 μm2), depth (μm)  Volume (mm3)  Surface area (×103 μm2)  BF outcome  Protective  Neutral  Neutral  Neutral  Neutral  Exacerbating after 10 days  Exacerbating for 3 parameters, otherwise neutral  Exacerbating with high force, neutral with low force  Exacerbating for OVA  *: Not stated; Ace: Acetaminophen; App.: orthodontic appliance; Asp: Aspirin, Acetylsalicylic Acid; BF: Biologic factor; CaG: Calcium gluconate; Cel: Celecoxib; CG: Control group; EG: Experiment group; E10: 10 ng basic fibroblast growth factor; E100: 100 ng basic fibroblast growth factor; E1000: 1000 ng basic fibroblast growth factor; LED: Light emitting diode therapy; LiCl: Lithium Chloride; LIPUS: Low-intensity pulsed ultrasound; LLLT: Low-level laser therapy; LSM: Laser scanning microscope; Mel: Meloxicam; Meth: Methylprednisolone; OIIRR: Orthodontically induced inflammatory root resorption; ORX: Orchiectomy; OTM: Orthodontic tooth movement; OVA: Ovalbumin; OVX: Ovariectomy; PG: Prostaglandin; Pre: Prednisolone; rHGH: Recombinant human growth hormone; SEM: Scanning electron microscope; TH: Thyroid hormone; Za: Zoledronic acid; μCT: Micro computed tomography. View Large Table 3. Description of animal studies.   Crowther 2017  Foo 2007  Gonzales 2011  Sadegh 2016  Seifi 2003  Seifi 2016  Sekhavat 2002  Shirazi 2017  Al-Daghreer 2014  Group  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Intraoral interventions  Biologic factor (BF)  Casein phosphopeptide (CPP)  Fluoride  Fluoride  Zinc  Calsium gluconat (CaG), PGE2  Angiogenic cytokine  PGE1: Misoprostol  Caffeine  LIPUS  Strain/Species  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Sprague-Dawley rats  Beagle dog  EG  CPP  Fluoride  2, 4, 12 weeks Fluoride  1.5, 20, 50 ppm Zinc  PGE2, CaG+PGE2  E10, E100, E1000  6 various doses PGE1  1, 2 or 3 g/l caffeine  Split mouth: LIPUS  n(CG)/n(EG)  20/20  10/10  10/10  11/11  8/8  10/10  8/8  10/10  10/10  Duration of BF  28 days  14 days  2, 4, 12 weeks  60 days  21 days  21 days  14 days  3 days  4 weeks  Duration of fixed appliance  14 days  14 days  14 days  20 days  21 days  21 days  14 days  14 days  4 weeks  OIIRR assessment method  μCT  μCT  SEM, LSM  Histology  Histology  Histology  Histology  Histology  Histology, μCT  OIIRR definition (measure)  Volume (mm3)  Volume (×10−4 mm3), cube-root volume (×10−4 mm3)  Surface area (%), volume (×106 μm3), depth (μm)  Number (n), width (μm), depth (μm)  Surface area (mm2)  Number (n), surface area (mm2)  Depth (mm)  Depth (mm)  Number (n), volume (μm3), percentage (%)  BF outcome  Neutral  Protective  Protective for depth and volume  Neutral  Neutral  Protective for E100  Neutral  Protective  Protective    Ekizer 2015  Fonseca 2013  Higashi 2017  Seifi 2014  Yadav 2016  Arita 2016  Hauber Gamiero 2008  Hu 2014  Ong 2000  Group  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Hormones  Hormones  Hormones  Hormones  Biologic factor (BF)  LLLT (LED)  LLLT (LED)  LLLT (LED)  LLLT  Mechanical vibration  Diabetes  Stress, restrain  rHGH  Prednisolone  Strain/Species  Wistar rats  Wistar rats  Wistar rats  New Zealand rabbits  CD1 mice  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  EG  LLLT  LLLT  LLLT for 1, 2 or 3 days  LLLT  5, 10, 20 HZ vibration  Diabetes+saline (n = 9); Diabetes+insulin (n = 7)  Short- and long- term stress  rHGH 7, 14 days  Prednisolone  n(CG)/n(EG)  10/10  7/7  8/8  8/8  8/8  9/7, 7/7  10/10  5/5  6/6  Duration of BF  10 days  7 days  14 days  48 days  14 days  4 weeks  3 or 40 days  1,3, 7 and 14 days  24 days  Duration of fixed appliance  10 days  7 days  14 days  48 days  14 days  14 days  14 days  1, 3, 7 or 14 days  12 days  OIIRR assessment method  Histology  Histology  μCT  Histology  μCT  SEM, LSM  Histology  μCT  Histology  OIIRR definition (measure)  Surface area (%)  Number (n)  Number (n), diameter (μm), depth (μm), volume (μm3)  Surface area (mm2)  Volume (mm3)  Surface area (×104 μm2), depth (μm), volume (×106 μm3)  Index of resorption (%)  Index of resorption (%)  Length (μm)  BF outcome  Protective  Protective  Neutral  Protective  Neutral  Diabetes protective; diabetes and insulin neutral  Neutral  Protective  Protective    Poumpros 1994  Seifi 2015  Sirisoontorn 2011  Sirisoontorn 2012  Vazquez-Landaverde 2002  Verna 2006  Gameiro 2008  Gonzales 2009  Kirschneck 2017  Group  Hormones  Hormones  Hormones  Hormones  Hormones  Hormones  Medications  Medications  Medications  Biologic factor (BF)  TH  OVX, ORX  OVX  Zoledronic acid, OVX  TH  Methylprednisolone  Celecoxib  Asp., Ace., Mel., Cel., Pre.  Meloxicam  Strain/Species  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Fischer-344 rats  EG  TH  OVX, ORX  OVX  OVX, OVX+Za.  Oral or injected TH  Chronic group: meth. for 7 weeks (n = 23); Acute group: meth. for 3 weeks (n = 22)  For 3 (n = 9), or 14 days (n = 7)  High or low dose; Asp., acet., mel., cel., pre.  OTM+meloxicam  n(CG)/n(EG)  16/15  10/10  5/5  5/5  16/16  23/19; 22/19  9/9; 7/7  5/5  7/7  Duration of BF  10 days  7 weeks  8 weeks  Za. for 5 weeks  10 days  Chronic group: 7 weeks. Acute group: 2 weeks  For 3 or 14 days  14 days  24 days  Duration of fixed appliance  10 days  3 weeks  28 days  21 days  8 days  21 days  14 days  14 days  14 days  OIIRR assessment method  Histology  Histology  SEM, LSM  SEM, LSM  Histology  Histology  Histology  SEM, LSM  Histology  OIIRR definition (measure)  Index of resorption (%)  Surface area (mm2)  Surface area (×102 μm2), depth (μm), volume (×104 μm3)  Surface area (×102 μm2), depth (μm), volume (104 μm3)  Index of resorption (%)  Number (n)  Index of resorption (%)  Surface area (%), depth (mm), volume (x106μm3)  Index of resorption (%)  BF outcome  Protective  Protective  Exacerbating  OVX exacerbating. Za. protective with OVX  Protective  Exacerbatin: acute group. Neutral: chronic group  Neutral  Protective: pre., high and low dose, and cel. high dose. Otherwise neutral  Protective    Liu 2004  MirHashemi 2013  Rafiei 2015  Sodagar 2013  Wang 2014  Zhou 1997  Kurohama 2016  Murphy 2016  Murata 2013  Group  Medications  Medications  Medications  Medications  Medications  Medications  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Clodronate  Atorvastatin  Fluoxetine  Celecoxib  Lithium Chloride  Indomethacin  Corticotomy  Corticotomy  OVA allergen sensitization and asp.  Strain/Species  Wistar rats  Sprague-Dawley rats  *  Sprague-Dawley rats  Sprague-Dawley rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Brown-Norway rats  EG  Split mouth: clodronate  Atorvastatin  Fluoxetine  Celecoxib  LiCl  Indomethacin  4 different types of corticotomy  Corticotomy with low or high force  OVA and asp.. OVA  n(CG)/n(EG)  26/26  12/12  15/15  7/7  5/5  12/12  10/10  11/11  7/7  Duration of BF  21 days  21 days  7 weeks  18 days  14 days  For 1, 3, 6 or 10 days  Corticotomy at app. insertion  Corticotomy at app. insertion and at day 7  Asp for 14 days  Duration of fixed appliance  21 days  21 days  21 days  14 days  14 days  14 days  14 or 21 days  14 days  14 days  OIIRR assessment method  Histology  Histology  Histology  Histology  SEM  Histology  SEM, LSM  Histology, μCT  Histology  OIIRR definition (measure)  Surface area (μm2)  Length (μm), depth (μm)  Index of resorption (%)  Depth (mm)  Surface area ratio  Index of resorption (%)  Surface area (×103 μm2), depth (μm)  Volume (mm3)  Surface area (×103 μm2)  BF outcome  Protective  Neutral  Neutral  Neutral  Neutral  Exacerbating after 10 days  Exacerbating for 3 parameters, otherwise neutral  Exacerbating with high force, neutral with low force  Exacerbating for OVA    Crowther 2017  Foo 2007  Gonzales 2011  Sadegh 2016  Seifi 2003  Seifi 2016  Sekhavat 2002  Shirazi 2017  Al-Daghreer 2014  Group  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Systemic supplements  Intraoral interventions  Biologic factor (BF)  Casein phosphopeptide (CPP)  Fluoride  Fluoride  Zinc  Calsium gluconat (CaG), PGE2  Angiogenic cytokine  PGE1: Misoprostol  Caffeine  LIPUS  Strain/Species  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Sprague-Dawley rats  Beagle dog  EG  CPP  Fluoride  2, 4, 12 weeks Fluoride  1.5, 20, 50 ppm Zinc  PGE2, CaG+PGE2  E10, E100, E1000  6 various doses PGE1  1, 2 or 3 g/l caffeine  Split mouth: LIPUS  n(CG)/n(EG)  20/20  10/10  10/10  11/11  8/8  10/10  8/8  10/10  10/10  Duration of BF  28 days  14 days  2, 4, 12 weeks  60 days  21 days  21 days  14 days  3 days  4 weeks  Duration of fixed appliance  14 days  14 days  14 days  20 days  21 days  21 days  14 days  14 days  4 weeks  OIIRR assessment method  μCT  μCT  SEM, LSM  Histology  Histology  Histology  Histology  Histology  Histology, μCT  OIIRR definition (measure)  Volume (mm3)  Volume (×10−4 mm3), cube-root volume (×10−4 mm3)  Surface area (%), volume (×106 μm3), depth (μm)  Number (n), width (μm), depth (μm)  Surface area (mm2)  Number (n), surface area (mm2)  Depth (mm)  Depth (mm)  Number (n), volume (μm3), percentage (%)  BF outcome  Neutral  Protective  Protective for depth and volume  Neutral  Neutral  Protective for E100  Neutral  Protective  Protective    Ekizer 2015  Fonseca 2013  Higashi 2017  Seifi 2014  Yadav 2016  Arita 2016  Hauber Gamiero 2008  Hu 2014  Ong 2000  Group  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Intraoral interventions  Hormones  Hormones  Hormones  Hormones  Biologic factor (BF)  LLLT (LED)  LLLT (LED)  LLLT (LED)  LLLT  Mechanical vibration  Diabetes  Stress, restrain  rHGH  Prednisolone  Strain/Species  Wistar rats  Wistar rats  Wistar rats  New Zealand rabbits  CD1 mice  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  EG  LLLT  LLLT  LLLT for 1, 2 or 3 days  LLLT  5, 10, 20 HZ vibration  Diabetes+saline (n = 9); Diabetes+insulin (n = 7)  Short- and long- term stress  rHGH 7, 14 days  Prednisolone  n(CG)/n(EG)  10/10  7/7  8/8  8/8  8/8  9/7, 7/7  10/10  5/5  6/6  Duration of BF  10 days  7 days  14 days  48 days  14 days  4 weeks  3 or 40 days  1,3, 7 and 14 days  24 days  Duration of fixed appliance  10 days  7 days  14 days  48 days  14 days  14 days  14 days  1, 3, 7 or 14 days  12 days  OIIRR assessment method  Histology  Histology  μCT  Histology  μCT  SEM, LSM  Histology  μCT  Histology  OIIRR definition (measure)  Surface area (%)  Number (n)  Number (n), diameter (μm), depth (μm), volume (μm3)  Surface area (mm2)  Volume (mm3)  Surface area (×104 μm2), depth (μm), volume (×106 μm3)  Index of resorption (%)  Index of resorption (%)  Length (μm)  BF outcome  Protective  Protective  Neutral  Protective  Neutral  Diabetes protective; diabetes and insulin neutral  Neutral  Protective  Protective    Poumpros 1994  Seifi 2015  Sirisoontorn 2011  Sirisoontorn 2012  Vazquez-Landaverde 2002  Verna 2006  Gameiro 2008  Gonzales 2009  Kirschneck 2017  Group  Hormones  Hormones  Hormones  Hormones  Hormones  Hormones  Medications  Medications  Medications  Biologic factor (BF)  TH  OVX, ORX  OVX  Zoledronic acid, OVX  TH  Methylprednisolone  Celecoxib  Asp., Ace., Mel., Cel., Pre.  Meloxicam  Strain/Species  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Wistar rats  Fischer-344 rats  EG  TH  OVX, ORX  OVX  OVX, OVX+Za.  Oral or injected TH  Chronic group: meth. for 7 weeks (n = 23); Acute group: meth. for 3 weeks (n = 22)  For 3 (n = 9), or 14 days (n = 7)  High or low dose; Asp., acet., mel., cel., pre.  OTM+meloxicam  n(CG)/n(EG)  16/15  10/10  5/5  5/5  16/16  23/19; 22/19  9/9; 7/7  5/5  7/7  Duration of BF  10 days  7 weeks  8 weeks  Za. for 5 weeks  10 days  Chronic group: 7 weeks. Acute group: 2 weeks  For 3 or 14 days  14 days  24 days  Duration of fixed appliance  10 days  3 weeks  28 days  21 days  8 days  21 days  14 days  14 days  14 days  OIIRR assessment method  Histology  Histology  SEM, LSM  SEM, LSM  Histology  Histology  Histology  SEM, LSM  Histology  OIIRR definition (measure)  Index of resorption (%)  Surface area (mm2)  Surface area (×102 μm2), depth (μm), volume (×104 μm3)  Surface area (×102 μm2), depth (μm), volume (104 μm3)  Index of resorption (%)  Number (n)  Index of resorption (%)  Surface area (%), depth (mm), volume (x106μm3)  Index of resorption (%)  BF outcome  Protective  Protective  Exacerbating  OVX exacerbating. Za. protective with OVX  Protective  Exacerbatin: acute group. Neutral: chronic group  Neutral  Protective: pre., high and low dose, and cel. high dose. Otherwise neutral  Protective    Liu 2004  MirHashemi 2013  Rafiei 2015  Sodagar 2013  Wang 2014  Zhou 1997  Kurohama 2016  Murphy 2016  Murata 2013  Group  Medications  Medications  Medications  Medications  Medications  Medications  Corticotomy  Corticotomy  Asthma and allergy  Biologic factor (BF)  Clodronate  Atorvastatin  Fluoxetine  Celecoxib  Lithium Chloride  Indomethacin  Corticotomy  Corticotomy  OVA allergen sensitization and asp.  Strain/Species  Wistar rats  Sprague-Dawley rats  *  Sprague-Dawley rats  Sprague-Dawley rats  Sprague-Dawley rats  Wistar rats  Wistar rats  Brown-Norway rats  EG  Split mouth: clodronate  Atorvastatin  Fluoxetine  Celecoxib  LiCl  Indomethacin  4 different types of corticotomy  Corticotomy with low or high force  OVA and asp.. OVA  n(CG)/n(EG)  26/26  12/12  15/15  7/7  5/5  12/12  10/10  11/11  7/7  Duration of BF  21 days  21 days  7 weeks  18 days  14 days  For 1, 3, 6 or 10 days  Corticotomy at app. insertion  Corticotomy at app. insertion and at day 7  Asp for 14 days  Duration of fixed appliance  21 days  21 days  21 days  14 days  14 days  14 days  14 or 21 days  14 days  14 days  OIIRR assessment method  Histology  Histology  Histology  Histology  SEM  Histology  SEM, LSM  Histology, μCT  Histology  OIIRR definition (measure)  Surface area (μm2)  Length (μm), depth (μm)  Index of resorption (%)  Depth (mm)  Surface area ratio  Index of resorption (%)  Surface area (×103 μm2), depth (μm)  Volume (mm3)  Surface area (×103 μm2)  BF outcome  Protective  Neutral  Neutral  Neutral  Neutral  Exacerbating after 10 days  Exacerbating for 3 parameters, otherwise neutral  Exacerbating with high force, neutral with low force  Exacerbating for OVA  *: Not stated; Ace: Acetaminophen; App.: orthodontic appliance; Asp: Aspirin, Acetylsalicylic Acid; BF: Biologic factor; CaG: Calcium gluconate; Cel: Celecoxib; CG: Control group; EG: Experiment group; E10: 10 ng basic fibroblast growth factor; E100: 100 ng basic fibroblast growth factor; E1000: 1000 ng basic fibroblast growth factor; LED: Light emitting diode therapy; LiCl: Lithium Chloride; LIPUS: Low-intensity pulsed ultrasound; LLLT: Low-level laser therapy; LSM: Laser scanning microscope; Mel: Meloxicam; Meth: Methylprednisolone; OIIRR: Orthodontically induced inflammatory root resorption; ORX: Orchiectomy; OTM: Orthodontic tooth movement; OVA: Ovalbumin; OVX: Ovariectomy; PG: Prostaglandin; Pre: Prednisolone; rHGH: Recombinant human growth hormone; SEM: Scanning electron microscope; TH: Thyroid hormone; Za: Zoledronic acid; μCT: Micro computed tomography. View Large The nine human studies included four studies with a randomized controlled clinical trial (RCT) design (24–27), two of which used a split-mouth design (24,25). One study had a retrospective case–control design (6), and four were prospective cohort studies (28–31), two of which used a split-mouth design (28,31) (Table 2). All 36 included animal studies were prospective clinical trials (Table 3). Although all of these studies were generally described as randomized controlled trials, the randomization procedure was considered sufficient for two studies only, whereas it was inadequate in five studies and unclear for the remaining 29 studies because of lacking description of the randomization process. Two were based on split-mouth designs (32,33), and 34 were considered parallel-group randomized controlled trials (34–67). Risk of bias within studies All included studies were assessed for risk of bias (Supplementary Tables 3 and 4). Overall, many items were scored as ‘high’ or ‘unclear’, indicating poor reporting and experimental design of these studies. Test for publication bias was not undertaken as no more than five studies were included in any of the individual meta-analysis (17). Results of individual studies The included studies were categorized as follows: systemic supplement, intraoral intervention, hormone, medication, corticotomy, asthma and allergy. We compared experimental groups with biologic factor intervention and control group without intervention. Furthermore, control groups were sometimes given sham injection(s) or a placebo drug (Supplementary Tables 5 and 6). Due to considerable heterogeneity in methodology and variation in study design for the human studies, meta-analysis was considered appropriate only for the animal studies. Systemic supplements Neither casein phosphopeptide (CPP) (64), nor zinc (57) displayed any significant difference in effect on OIIRR. Injections of Calsium and PGE2 in rats reduced OIIRR as opposed to administering PGE2 only (46). However, reduced level of OIIRR was reported with caffeine (65) and with high doses of angiogenic cytokine (58). Meta-analysis detected no effect of prostaglandin on OIIRR (ES = 0.26 [−0.14, 0.66]) (46,47) (Figure 1). Moreover, meta-analysis showed significant reduction of OIIRR with fluoride (ES = −2.08 [−3.02, −1.14]) (35,37) (Figure 1). Meta-regression showed an average decrease in the effect size of OIIRR of −0.26 per week with fluoride treatment (P = 0.034). The reduction of OIIRR from 2 to 4 weeks was, however, not statistically significant. In contrast, a statistically significant decrease was observed from 2 to 12 weeks. Figure 1. View largeDownload slide Random-effects meta-analysis of the effect of prostaglandin, fluoride per week and LLLT on OIIRR. (1) 2.5 g/kg; (2) 10.0 g/kg; (3) 5.0 g/kg; (4) 25.0 g/kg; (5) 50.0 g/kg; (6) 100.0 g/kg; (7) Resorption lacunae volume; (8) resorption lacunae cube-root volume; (9) resorption lacunae surface area; (10) resorption lacunae depth; (11) resorption lacunae diameter, (a) 1 day exposure and (b) 2 days exposure. Figure 1. View largeDownload slide Random-effects meta-analysis of the effect of prostaglandin, fluoride per week and LLLT on OIIRR. (1) 2.5 g/kg; (2) 10.0 g/kg; (3) 5.0 g/kg; (4) 25.0 g/kg; (5) 50.0 g/kg; (6) 100.0 g/kg; (7) Resorption lacunae volume; (8) resorption lacunae cube-root volume; (9) resorption lacunae surface area; (10) resorption lacunae depth; (11) resorption lacunae diameter, (a) 1 day exposure and (b) 2 days exposure. Intraoral interventions Nine studies evaluated intraoral interventions being LLLT (28,34,45,55,66), low-intensity pulsed ultrasound (LIPUS) (24,32) and mechanical vibration (27,59). Six of the studies were animal experiments (32,34,45,55,59,66). Neither LLLT (28) nor mechanical vibration (27) significantly altered OIIRR in human subjects. On the other hand, LIPUS resulted in significant OIIRR reduction when irradiating human premolars (24); same effect was shown in beagle dogs (32). Mechanical vibration had insignificant effect on OIIRR in rats, but the decreasing trend varied with different frequencies (59). LLLT in rabbits significantly reduced OIIRR (45), however, meta-analysis of the three studies examining LLLT in rats showed no difference (34,55,66) (Figure 1). Hormones Diabetic rats had significantly reduced OIIRR after 2 weeks with orthodontic treatment, but the effect diminished with insulin administration (63). The same effect was registered after 7 and 14 days of treatment with recombinant human growth hormone (rHGH) (56). Long- and short-term stress increased plasma corticosterone levels in rats, but OIIRR scores did not differ (39). Meta-analysis of the studies evaluating the effect of thyroxine administration revealed that OIIRR was significantly inhibited in rats (44,54) (Figure 2). Figure 2. View largeDownload slide Random-effects meta-analysis of the effect of hormones, medications (NSAID) and corticotomy on OIIRR. (1) oral administration; (2) administration by subcutaneous injection; (3) resorption lacunae surface area; (4) resorption lacunae depth; (5) resorption lacunae volume; (a) high dosage; (b) low dosage; (6) acute group: 3 weeks; (7) chronic group: 7 weeks; (8–9) administration for 3 and 14 days; (10–12) administration for 1, 3 and 6 days; (13) high force level; (14) low force level. Experiment 1: (A) corticotomy technique 1; (B) corticotomy technique 2; (C) corticotomy technique 3. Experiment 2: (D) corticotomy technique 1; (C) corticotomy technique 2. *(C) The technique was repeated in the two experiments. Figure 2. View largeDownload slide Random-effects meta-analysis of the effect of hormones, medications (NSAID) and corticotomy on OIIRR. (1) oral administration; (2) administration by subcutaneous injection; (3) resorption lacunae surface area; (4) resorption lacunae depth; (5) resorption lacunae volume; (a) high dosage; (b) low dosage; (6) acute group: 3 weeks; (7) chronic group: 7 weeks; (8–9) administration for 3 and 14 days; (10–12) administration for 1, 3 and 6 days; (13) high force level; (14) low force level. Experiment 1: (A) corticotomy technique 1; (B) corticotomy technique 2; (C) corticotomy technique 3. Experiment 2: (D) corticotomy technique 1; (C) corticotomy technique 2. *(C) The technique was repeated in the two experiments. The effect of ovariectomy (OVX) in rats was contradictory. Although some reports showed significantly increased OIIRR (48,49), others show an opposite effect of both OVX and orchiectomy (ORX) (ES = 0.38 [0.05, 0.71]) (60) (Figure 2). Meta-analysis displayed significant reduction of OIIRR with prednisolone administration (38,43) (Figure 2). On the other hand, administrating methylprednisolone to acute (3 weeks) and chronic (7 weeks) groups of rats demonstrated increased OIIRR for the acute group only (51). Overall, the meta-analysis showed reduction of OIIRR with steroids (ES = −2.79 [−4.26, −1.33]) (Figure 2). Medications Bisphosphonates Liu et al. (33) administered clodronate and Sirisoontorn et al. (49) administered zoledronic acid after ovariectomy. The animals with OVX and zoledronic acid showed almost the same amount of OIIRR as the control group, as opposed to the effect by OVX alone. Similar, inhibitory effect on OIIRR was reported with the administration of clodronate in rats (33). Nonsteroidal anti-inflammatory drugs (NSAIDs) Aspirin, administered in both high and low doses, did not have any significant effect on OIIRR in a rat model (38). However, when aspirin was administered to allergy-sensitized animals, it significantly reduced OIIRR. The reduction was not significant when compared to control animals (41). Indomethacin, when administered at appliance reactivation for 10 days in a rat model, enhanced OIIRR compared to a control group (52). Three studies considered selective COX-2 inhibitor NSAIDs (36,38,50), whereas two studies evaluated meloxicam (38,67), and meta-analysis showed significant reduction of OIIRR (Figure 2). Overall, meta-analysis on the effect of NSAIDs showed no significant difference in OIIRR (ES = −0.49 [−1.00, 0.01]) (Figure 2). Acetaminophen High and low doses of acetaminophen had no significant effect on OIIRR in rats (38). Others Statins, atorvastatin more specifically, had no significant effect on OIIRR (40). Likewise, neither lithium chloride (LiCl) nor fluoxetine were found to have significant effect on OIIRR (53,61). Corticotomy Seven studies assessed corticotomy, five of which were human trials (25,26,29–31) and two were animal experiments (42,62). The human trials differed with respect to study design; two being RCTs (25,26) and the other three were prospective cohort studies (29–31). The two RCTs found no significant difference in the effect of corticotomy on OIIRR (25,26); however, two prospective cohort studies found reduction of OIIRR (29,30), while the other prospective study reported increased root resorption with piezocision (31). Meta-analysis showed significantly increased OIIRR when assessing the effect of corticotomy on OIIRR in rats (ES = 0.38 [0.05, 0.71]) (42,62) (Figure 2). Asthma and allergy McNab et al. (6) retrospectively evaluated control and asthmatic orthodontic patients and found that the asthmatic patients had significantly increased OIIRR; the upper first molar being most susceptible. Allergic sensitization in animals was reported to significantly increase OIIRR compared with the control group (41). Discussion The aetiology of OIIRR is multifactorial and shaped by a combination of environmental and host factors (2,3). The aim of this systematic review was to assess the risk of any biologic or adjunctive intervention that might affect OIIRR. Although several reviews on OIIRR have been published previously (2,68,69), no systematic review concerning the influence of biologic factors on OIIRR exists. In the present study, we summarize the available literature and present information that may help clinicians identify and treat high-risk patients. Systemic supplements Fluoride increases bone mass and mineral density and has been used in the treatment of metabolic bone diseases such as osteoporosis (70). Fluoridated water has been shown to reduce OIIRR in dose-dependent manner: longer exposure and higher doses of fluoride seem to promote OIIRR inhibition (71). Furthermore, sodium fluoride has been shown to inhibit the osteoclastic activity and reduce the number of active osteoclasts (72). Prostaglandins (PGs) and various growth factors have been successfully tested to accelerate orthodontic tooth movement, but side effects such as OIIRR have also been reported. The two included studies that evaluated the effect of PGs showed no increase in OIIRR (46,47). However, the angiogenic cytokine basic fibroblast growth factor (bFGF) reduced OIIRR in a rat model, but only when high doses were administered (58). It thus appears important to notice that similar dose-dependent effect might exist in other factors or interventions. Intraoral interventions Several included studies examining the effect of LLLT and ultrasound therapy in animals reported a significant reduction of OIIRR (32,34,45,55), but the meta-analysis of the rat studies found no overall differences between lased and non-lased animals. Raza et al. (24) further underpinned the protective effect of ultrasound therapy in human subjects by reporting significant reduction of OIIRR. However, Higashi et al. (66) measured significant reduction of OIIRR after 3 days with laser therapy in a dose-dependent manner. Moreover, a possible reason that no significant effect was seen with LLLT when irradiating human canines could be that humans require higher doses and longer exposure to irradiation than were given in this study (28). Mechanical vibration did not seem to have significant effect on OIIRR, neither in humans nor in rats, although the results showed a trend towards decreased resorption with different frequencies of vibration (27,59). Again, despite no significant differences between the experimental groups, different application modalities seem to have varied effects (27,59). Hormones As diabetes affects bone metabolism, it may also have an impact on OIIRR (73). Significantly, lower OIIRR was measured in diabetic rats, but the effect was diminished by insulin administration (63). It is well known that thyroxine (T4) affects intestinal calcium absorption and therefore is indirectly involved in bone turnover (13). The meta-analysis reported significant reduction of OIIRR in animal subjects exposed to thyroxine (44,54), indicating its involvement in the aetiology of forced-induced root resorption. Some authors suggest administration of thyroxine to patients susceptible to OIIRR, however, this may cause other adverse effects, and more research on this issue is, therefore, needed (44). Administration of rHGH significantly inhibited OIIRR in rats after 7 and 14 days of treatment, but the authors used higher and more frequent dosages than would normally be required for growth-hormone-deficient patients (56). Nevertheless, it confirms the importance of time and dosage exposure for different factors. The relationship between the reduction in oestrogen after menopause and the development of osteoporosis is well established. Using a post-menopausal model, Sirisoontorn et al. (48,49) reported significantly increased OIIRR when comparing OVX rats with controls. They suggested that the loss of oestrogen could modulate osteoclastogenesis via the OPG/RANK/RANKL system. In contrast, Seifi et al. (60) found markedly reduced OIIRR in both OVX and ORX rats. The latter evaluated OIIRR in the mesial root of maxillary first molars only, while Sirisoontorn et al. (48,49) evaluated both the mesial and distal roots. Differences in root angulation, morphology and force distribution could have contributed to the opposing results, but despite that, an increased risk for OIIRR should be considered when planning orthodontic treatment for post-menopausal women. The two studies evaluating the effects of prednisolone showed a significant reduction of OIIRR (38,43), whereas the study on methylprednisolone (51) showed significant increase in the acute phase but no difference in the chronic stage. The reduction of OIIRR was explained by suppression of clastic-inflammatory activity that was reflected in the lower TRAP cell counts in the steroid-treated animals (43). On the other hand, the increased OIIRR in the acute methylprednisolone group was explained by a lack of balance between blastic activities, inhibited by the drug and the clastic activities, enhanced or unchanged by drug administration (51). Overall, meta-analysis showed significant reduction of OIIRR with steroid administration. To date, no human investigations have evaluated the effect of stress hormones on OIIRR, but existing animal studies show that stress experience leads to increased blood corticosterone levels (5,39). This increase had no significant impact on OIIRR as animals subjected to both short- and long-term stress displayed similar amounts of OIIRR. Medications Both studies examining the effect of bisphosphonates reported significant inhibition of OIIRR in rats (33,49). However, meta-analysis was not performed since one of the studies examined ovariectomized rats in which bisphosphonates were administered (49). NSAIDs are the most widely used analgesics and are commonly prescribed for orthodontic patients. All included studies evaluating the effect of NSAIDs on OIIRR used rats (36,38,50,52). The overall meta-analysis showed no significant difference in OIIRR when NSAIDs were used (36,38,50,52). Although not all of the results were significant, the findings suggest that NSAIDs may reduce OIIRR, however, the clinical relevance of this effect must be considered low. Corticotomy Corticotomy is one of the many strategies invoked to increase alveolar bone remodelling, increase the speed of orthodontic tooth movement, and potentially reduce OIIRR (74). Clinical reports indicate that bone remodelling is temporarily accelerated by corticotomy, with increased tooth movement and decreased OIIRR (75,76); the most desired effect for an orthodontist. Still, reports from animal studies show increased OIIRR and the meta-analysis confirms these findings (42,62). A possible explanation for the increased OIIRR is that corticotomy may induce an inflammatory reaction and release of biochemical mediators that enhance osteoclastic activity. The risk of corticotomy-related iatrogenic root damage must also be considered (31). Asthma and allergy The relationship between OIIRR and asthmatic and allergic conditions is poorly understood; but from the few, low evidence studies, asthma and allergy seem to increase OIIRR (6,41). Increased osteoclastogenesis during allergen-induced inflammation may be a possible pathway for increased bone and root resorption; however, clinical studies are needed to support these suppositions. Limitations The employed bias assessment tools showed that all the included studies were characterized by an unclear or high risk of bias; thus, the methodological quality of the studies is poor. It is therefore obvious that an improvement of current methodology is needed. The meta-analysis for fluoride, prostaglandin and corticotomy consisted only of two studies, which should be considered in the interpretation of the results. Therefore, this systematic review provides a reference for future high-quality preclinical animal and human clinical trials aiming to evaluate the effect of biologic factors and adjunctive therapies on OIIRR. Vast majority of the included studies are experimental, and these findings cannot be directly extrapolated to humans. Furthermore, the existing literature is unclear about appropriate dosage, timing and duration for the various biologic factors and therapies and in what way these variables may affect OIIRR. For example, administration of supplements or medications could be oral via drinking water or stomach tube, submucosal, intraperitoneal or subcutaneous injection, among others. It is uncertain if these administration routes have any influence on the viability of the used agents. Another limitation is that very few of the included studies reported adverse effects from respective treatments, which is important when considering the therapeutic efficacy of various agents, and also when designing new studies. Implications for practice In patients in whom biologic agents are used, it is important to adjust the treatment goals and treatment mechanics to minimize OIIRR. For example, findings indicate that asthma may increase the risk of OIIRR, and asthma patients must, therefore, be informed about the risk before commencing treatment, and the clinician should do more intense follow-up during the course of treatment. Thus, in cases where certain factors are known to increase the risk of OIIRR, the orthodontic treatment plan should be modified accordingly. Conclusion In summary, fluoride, thyroxine and steroids reduce OIIRR, whereas corticotomy enhances OIIRR. Identifying increased-risk patients is important to avoid excessive OIIRR. Additionally, the evidence afforded by this systematic review identifies several adjunctive treatments that may help reduce OIIRR in high-risk patients. Clinicians may consider implementing these treatments in patients showing signs of OIIRR early in their treatment course. Supplementary material Supplementary material is available at European Journal of Orthodontics online. 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The European Journal of OrthodonticsOxford University Press

Published: Mar 29, 2018

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