Results

Literature search

The article selection process is illustrated in the flowchart (Fig. 1). The initial electronic search identified 627 potentially relevant records. After the removal of 255 duplicate records, 372 records remained for title and abstract screening. Following this step, 318 records were excluded. Twenty-seven articles were subsequently assessed for eligibility through full-text review and were included in the qualitative synthesis. Of these, ten met the criteria for inclusion in the meta-analysis. Data extracted from the included studies are summarized in Table 1.

Author | Study drawing | Groups | Radiotherapy regimen | Risk factors | ORM localization
Niewald et al. 1996 | Retrospective cohort | N: 168Age: 55,5y | 60 Gy:48/6 weeks70 Gy: 53/7 weeks72-80 Gy: 4/for minor interruptions2-58 Gy:10/ incomplete treatment | Deep paradontitis P = 0.039/0.004;BED(oc/jS) P = 0.002/0.001;Bone surgeryP = 0.032/0.002 | ND
Reuther et al., 2002 | Retrospective cohort | N: 830ORN:68Gender:F: 184 M:646Age: 52y | Cobalt-60 irradiation / radio-therapy with electrons or photons: 60 Gy | Gingivitis: 12Gingivitis with/without a mild marginal periodontitis:12Severe marginal periodontitis withseveral missing teeth: 46Could not be evaluated: 10Induced damage to the hard substancesof the teeth was detectable: 46 | Mandible: 1
Koga et al., 2008 | Retrospective cohort | N: 405G1: 365G2: 5G3: 57Gender:M: 365F: 49Age: 53y | RT: 63 Gy | Extraction:Before RT:Maxilla:I: 61C: 61PM: 136M: 304Mandible:I: 274C: 187PM: 298M: 326During RT:Maxilla:I: 6C: 2PM: 1M: 6Mandible:I: 3C: 2PM: 9M: 4After RT:Maxilla:I: 14C: 11PM: 23M: 70Mandible:I: 55C: 27PM: 47M: 43Spontaneous:5Primary oncologic surgery: 4Tooth extraction: 3Salvage surgery: 2Prosthetic trauma: 1Plate and screw infection: 1Root infection: 1 | Maxilla: 1Mandible:PM/M: 14I: 2
Chen et al., 2005 | Retrospective cohort | N: 1.758ORN: 48Gender:M: 27F: 21Age:51-60y | Tele-60 Counit or linearaccelerator that generated 6 -10 MV photons/ 70 Gy | No significant:Concomitant chemotherapyLesion locationInterval between end of radiotherapy and first sign of ORNUse of HBOSignificant:TNM stage Adiation doseTooth extractionSevere infectionBleedingBone exposure | Molars/premolars: 61Maxilla:31Both jaws: 17Mandibule:13
Lye et al., 2007 | Prospective cohort | N:40ORN: 3Gender:M: 28F: 12Age: 53.7yChinese: 37Malay: 3 | RT: 60/ 76 Gy | Periodontal status: Normal: 10;Gingivitis: 51Periodontitis: 92Abscessed:2Pulpal status:Normal: 7;Necrotic:136;Pulpitic: 8;Abscessed: 4;Teeth characteristics: 155;Location of tooth: Anterior Maxilla: 19Mid Maxilla: 15Posterior Maxilla: 32Anterior Mandible: 36Mid Mandible:24Posterior Mandible: 29 | Posterior maxila:1Posterior mandible: 2
Bagan et al., 2009 | Cross-sectionalstudy | N: 73Group 2 ORN: 20Age:Group 2: 62,2yGender: group 2M: 16F: 4 | RT: 64.85 Gy | Extraction: 8Prosthesis: 2Unknown etiology: 10 | Mandible: 16Upper jaw: 4
Lee et al., 2009 | Retrospective cohort | N: 198Gender:M: 159F: 39Age: 58 y | Co-60: 694MV: 129Dose:16-75 Gy | Systemic diseaseDiabetes mellitus: 19 Hypertension: 26Primary siteOral cavity: 89Oral tongue: 41Floor of mouth: 16Retro molar trigone: 8 Upper alveolar ridge: 7Buccal mucosa: 6Lower alveolar ridge: 5Hard palate: 4Mucosal lip: 1Oropharyn: 109Tonsil: 67Base of tongue: 33Soft palate: 7Stage:I: 14II: 26III: 29IV:129Mandible invasion: 20Pre-irradiation dental extraction: 82Surgery + Radiotherapy: 10Mandibular surgery: 59Radiotherapy alone: 97Induction chemotherapy: 54 | Maxilla: 5Mandible: 8
Chopra, et al., 2011 | Retrospective cohort | N: 46Gender:M:28F: 18;Age: 54yRace:White: 34; African american:11 | 3DCRT /2 Gy: 97% | Chemotherapy:Yes: 78% No: 22% Surgery:No: 28%Yes: 72%Full dentition:5%Partially edeniuious: 45%Edeniuious:50%Oral hygiene: Good: 23%; Fair: 18%; Poor: 59%;Fluoride prophyçaxis:No:44%,Yes: 56%;Secondary infection: Yes: 54%;No: 46%Pre-RT extraction: No 37%;Yes 63%;Post-RT extraction: No: 58%;Yes: 42% | Mandible: 43Maxillary, orbital, andcalvarial involvement: 1
Niewald et al., 2014 | Retrospective cohort | N: 204Group A: 90Group B: 114Mean age:Group A: 57.1y;Group B: 54.6y; | Group A: 73Group B: 74CT: 60–70 GyGroup A: 46- 72 GyGroup B: 41 -82.8 Gy | Dental status before starting radiotherapyNo significantAbsent, presente, deeply carious destroyed, loose,Root remaunders,Devital,Roots filed completely, Roots filedIncompletely,Aoical periodontitisCysts, RetainedDental treatment before radiotherapyEndodontic treatment,removal of roor remaders,tooth extraction, conserving treatment:, cystectomy,healthy teeth remaining after dental rehabilitation:Significant:Carious,N-stage,total dose,BED2,daily fraction, | Corpus mandible:Group A: 11/90Group B: 22/114
Studer et al., 2015 | Retrospective cohort | N: 715Age: 62y | IMRT:69,6 -70/2 Gy | Comorbid-ity: 43Carotid artery calcification:31Recurrent tumors: 3T1:5;T2:1;T3:6;T4: 13;Periosteal resection: 6/17;Marginal resection: 8/20;Segmental resection: 2/28 | ND
Thibault De Maesschalck et al., 2016 | Retrospective cohort | RT: 145;IMRT: 89Age:RT: 60.5 -69.6 y;IMRT: 61.1–69.8 y | RT: 69.9 Gy | Diabetes mellitus:RT: 8IMRT: 4Neck dissection: RT: 43 IMRT: 32Chemotherapy:RT: 112 IMRT: 81Good dental health: RT:20 IMRT: 16Edentulous: RT: 20/85 IMRT: 20/86Dental extraction pre-RT:RT 40/81 IMRT: 46/85 | RT: 16 mandibleIMRT: 9 mandible
Caparrotti et al., 2017 | Case–control | N:1196-ORN: 1125+ ORN: 71Age: 60.7yGender:F: 232M: 991 | 70 Gy/35/5/5 days: 69970 Gy/35/6/6 days: 27160 Gy/25/2,4/5 days: 11864 Gy/40/1.6/5 days: 11650 -74 Gy/1.2–2.6/5 days: 19 | HPV -: 288HPV + : 770Unknown: 138Systemic treatment:No: 501Yes: 695Chemotherapy:No: 614Yes: 81 | Mandible: 77
Kojima et al., 2017 | Retrospective cohort | N:392+ ORN:30-ORN:362Gender:M: 296F: 96Age: 66y | 3D CRTIMRTRT dose: 50-59 Gy | Tumor siteOralcavity/ oropharynx: 219Other: 173StageI-II: 71III-IV: 307DiabetesYes: 94No: 298Serum creatinine: Within normal range: 360 Higher than normal range: 32Serum albumin> 3.0 mg/dL:349< 3.0 mg/dL: 43Minimumn White blood cell Count during RT: > 3000/uL: 196< 3000/uL: 196Minimum lymphocyte Count during RT: > 800/uL: 99< 800/uL: 293Dental statusDentulous:361 Edentulous: 31Periapical periodontitisat first visit:Yes: 127No: 265PeriapicalPeriodontitis pre-RT:Yes: 85No: 307Pericoronitis at first visit:Yes: 6No: 386Pericoronitis pre-RT:Yes: 3No: 389Carious stump at first visit:Yes: 92No: 300Carious stump pre-RT:Yes: 39No: 353Severe marginal periodontitis at first visit:Yes:126No: 266Severe marginal periodontitis pre-RT:Yes: 59No: 333Tooth extraction before RT:Yes: 132No:270Tooth extraction after RT:Yes:38No:354 | Maxilla:C: 2M: 4Mandible:I: 1M: 23
Zhang et al2017 | Retrospective cohort | IMRT: 534IMPT: 50 | IMPT: 25,6 GyIMRT: 41,2 Gy | HPV status: + IMRT:364 + IMPT:35-IMRT 75 -IMPT:4Equivocal: IMRT: 18 IMPT: 2Not detected: IMRT: 77 IMPT:9 | ND
Liu et al., 2018 | Retrospective cohort | N: 213Gender:M: 168;F: 45Age: 56y | RT: 35 /144 Gy | ND | Mandibular body: 83Angulus mandible: 23Angulus/ramus/body mandible: 101Bilateral:99
Kristensena et al., 2019 | Retrospective cohort | N: 1224 + ORN: 56-ORN:1168Gender:M:+ ORN: 42-ORN:74F:+ ORN: 14-ORN: 38Age:+ ORN: 57.5-ORN: 59.5 | IMRT: 66–68 Gy/5–6/2 Gy | Dental extraction before radiotherapy: 100Cisplatin: + ORN + : 41, -ORN + : 84, + ORN-: 15, -ORN-: 28 | ND
Habib et al., 2020 | Retrospective cohort | ORN: 197Gender:M:141F: 56Age:60-70y | IMRT: 115RT: < 55/55–65/> 65 Gy | Primary cause:Spontaneous 65Induced:132Dental extraction: 59Pre-radiotherapy extraction site: 48Infection of exposed jaw plate: 17Dental infection 2Dental trauma: 5Dental implant:1HPV + : 37HPV-: 41Unknown: 20 | Mandible1/5:anterior region;Bilaterally: 12.1%
Liao et al., 2020 | Retrospective cohort | N: 5062+ ORN: 52-ORN: 5010Age: 50.3–50.8yGender:M: 4221F: 841Income level:Low income: 1451Moderate income: 1943High income: 1668 | RTIMRT | Hypertension:Yes: 1375No:3689Diabetes mellitus:Yes: 679No: 4383Depression: Yes: 192 No: 4870Number of pre-RT toothextraction: + ORN:4.33 -ORN: 4.16Timing of pre-RT tooth extraction: 1-7d: 17598-21d: 3303 | ND
Dumoulin et al., 2020 | Retrospective cohort | N: 415Gender:F:+ ORN 10-ORN:112 M:+ ORN: 21-ORN: 272Age:+ ORN: 55.5-ORN: 58 | IMRT: 50–70 Gy/5d/5-6w | Comorbidities:No:+ ORN: 23-ORN: 317Yes:+ ORN: 8-ORN: 67Dental cause:11Surgical: 11No cause: 9Tooth infection: 6Complications from pre- and post-radiotherapy extractions were found: 5 | Double location: 2Body mandibular: 23Angle/ramus: 5Symphysis: 5
Khoo et al.,2021 | Retrospective cohort | N: 73ORN: 16Gender:M:41F:32:Age: 47y | RT: < 60 Gy | Lower incisor/canine: 86Upper incisor/canine: 55Lower premolar: 42Upper premolar: 41Lower molar: 75Upper molar: 90Periapical periodontiti: 145Caries: 178Perio: 42Mixed caries-perio related: 8Others: 4No data: 12Time of extraction post radiotherapy3 m- 1y: 131–5y: 103> 5y: 273 | ND
Liao et al., 2021 | Retrospective cohort | N:16,701 + ORN: 903- ORN: 15,798Age:+ ORN: 51,9-ORN: 53Salary income:Low: + ORN: 273, -ORN: 5089Middle: + ORN: 393- ORN:6977High: + ORN: 237 -ORN: 3732 | RT convencional e IMRT: ≥ 60 Gy | Lip+ ORN:30-ORN: 496Tongue: + ORN:241-ORN: 566Gum: + ORN: 147-ORN: 1713Mouth foor: + ORN: 44-ORN: 468Buccal: + ORN: 417 -ORN: 7088Retromolar: + ORN: 24-ORN: 365DM: + ORN:170-ORN: 2999HTN: + ORN: 243 -ORN: 5025CVA: + ORN: 45-ORN: 1059Pre-RT tooth extraction: + ORN: 415-ORN: 6583During RT tooth extraction: + ORN: 107 -ORN: 1123 | Mandible
Rosenfeld, et al., 2021 | Retrospective cohort | N: 93ORN: 7Gender:M: 67F: 26Age: 61.95y | RT: 55.45 Gy | DM:17Diabetic uncontrolled:9 | ND
Lang, et al.,2022 | Case–control | N: 89+ ORN:44,-ORN:45;Age: + ORN: 70.5y-ORN: 71yGender:M:+ ORN: 35-ORN: 37F:+ ORN: 9-ORN: 8 | IMRT3D-CRT | Caries, periodontal disease: + ORN: 36-ORN: 17Pre-RT dental treatment: + ORN: 31-ORN: 12CHT: + ORN: 22-ORN: 28IT:+ ORN: 8-ORN: 1None: + ORN:14-ORN: 16 | Body/ jaw: 78%Angle/ ramus: 22%
Boromand., et al., 2023 | Retrospective cohort | N: 450+ ORN: 90Gender:M: 322F: 128Age: 61.3y | IMRT: 2723DCRT: 119VMAT: 7 | Brachytherapy:+ ORN: 68.9%Spontaneously:-ORN: 39.8%Tumor staging:T1 = 16T2 = 35T3 = 16T4 = 23 | Ipsilateral side of the primary tumor: 70Contralateral: 18No precise localization: 2
Watson et al., 2023 | Cross-sectional study | N: 2732ORN: 219Age: 61yGender:M: 2000F: 732 | IMRT:70 Gy/35 | Stage III-IV PC: 1410OCC: 490OPC: 969Pré-RT extraction: -:1776,+ : 956 | Mandible
Kovarik et al., 2024 | Retrospective cohort | N: 1608ORN:141Gender:M: 1194F: 414Age: 61y | IMRT:60-66 Gy/ 30f/6w; | Dental extraction: 25Mandibulotomy: 6Mandibulectomy: 11Maxillectomy: 3Interventions pre- and post-RT: 67Bone resection: 4RT Only: 37RT and cisplatin: 53RT and cetuximab: 6 | Mandible: 133Maxilla: 8
Renouf et al., 2024 | Case–control | N: 171-ORN:114 + ORN: 57Age: 59yGender:M:+ ORN 46-ORN: 91F:+ ORN: 11-ORN: 23 | IMRT: 70 Gy/ 35f | Dental hygiene:Poor: + ORN: 28-ORN: 47Healthy: + ORN: 11-ORN: 21 Missing: + ORN:18-ONR: 46Pre-IMRT dental evaluation:No:+ ORN: 6-ORN: 19Yes:+ ORN: 50-ORN: 83Missing: + ORN:1-ORN: 12Edentulous:No:+ ORN: 54-ORN: 94Yes:+ ORN: 3-ORN:11Missing: + ORN: 0-ORN: 9Pre-IMRT dental avulsions:No:+ ORN: 15-ORN: 31Yes:+ ORN: 38-ORN: 62Missing: + ORN:4-ORN: 21Post-IMRT dental avulsions:No:+ ORN:18-ORN: 62Yes:+ ORN:38-ORN: 34Missing: + ORN: 1-ORN:18Concurrent chemotherapy:No:+ ORN: 19-ORN: 33Yes:+ ORN: 38-ORN: 81Diabetes:No:+ ORN: 47-ORN:106Yes:+ ORN: 9-ORN: 8Missing: + ORN: 1-ORN:0 | Molar mandibularsectors (43.9% in 35–38[dental], 42.1% in 45–48 [dental]);Nearly 80% were ipsilateral to the tumor location
Author | ORM time | Imagens | Imagens features | Habitis | Follow-up | Level of evidence (Oxford)
Niewald et al. 1996 | 5.5 y: 60 Gy 2 y: 70 Gy | ND | ND | ND | 2.86y | II
Reuther et al., 2002 | 13 m | ND | ND | Smoker: 51Alcohol: 54 | 30y | II
Koga et al., 2008 | ND | ND | ND | ND | G1: 44.8 mG2: 53.7 mG3: 42.8 m | II
Chen et al., 2005 | < 24 m: 1024–60 m: 28 > 60 m: 10 | P;PR;CT | ND | ND | 4y | II
Lye et al., 2007 | ND | ND | ND | No-smoker: 85%No-alcohol: 82.5% | 1,4w / 12w | II
Bagan et al., 2009 | ND | ND | ND | Smoker: 12Alcohol: 8 | ND | IV
Lee et al., 2009 | 1-69 m | PanoramicTCBone scintigraphy | ND | ND | ND | II
Chopra, et al., 2011 | 7.5 m | ND | ND | Smoker:No:65% Yes: 35%Alcohol: Yes: 76%No:24% | 35.5 m | II
Niewald et al., 2014 | Group A: 11/74Group B: 8/73 | PR | ND | ND | Group A: 4.1 yGroup B: 5y | II
Studer et al., 2015 | 20 m | ND | ND | Smoker: 74Alcohol: 63 | 3–6 weeks;2–3 m/ 1º year3 m/ 2ª e 3º year6 m/ 4-5º year | II
Thibault De Maesschalck et al., 2016 | ND | CT;MRI | ND | Smoker:RT: 55 IMRT: 37 | 1.8y | II
Caparrotti et al., 2017 | 0.9 y | CT;MRI | ND | SmokerYes:385Ex: 495No: 315Unknown:1 | 3/3 months/ 1,2 years;4/4 months /3 years;6/6 months/ 4 years;1 years | III
Kojima et al., 2017 | Median: 20 m | Panoramic | ND | ND | ND | II
Zhang et al2017 | 3–6 m | ND | ND | ND | 1 month, then every 3/1 years;4–6/2 years, and annually | II
Liu et al., 2018 | 36 m | ND | ND | Alcohol:No: 145Yes: 68Smoker:No: 163Yes: 50 | 47.74 months | II
Kristensena et al., 2019 | 10.9 m | ND | ND | No Smoker:+ ORN: 17-ORN: 51Smoker: + ORN: 39-ORN: 61 | 3 month/2 years;6 month/5 years | II
Habib et al., 2020 | < 1 y: 71> 1 y: 126 | ND | ND | Smoker:Yes: 77No: 58Ex: 62Alcohol:Yes:137No: 14Ex:46 | ND | II
Liao et al., 2020 | 1y: 131st—2nd: 172- 3nd: 103rd- 4th: 65th: 6 | ND | ND | ND | 4.07y | II
Dumoulin et al., 2020 | ND | PR: 28;CT: 18 | ND | Smoker:Yes:+ ORN: 6-ORN: 105Alcohoal: + ORN: 0-ORN: 14Tobacco + alcohol:+ ORN: 22-ORN: 184 | 3y | II
Khoo et al.,2021 | ND | CTPR | WPLS;Irregularity, interruption or loss of lamina dura;Bone sclerosis;Bone resorption; | Smoker:Yes: 4No:59No data: 10Alcohol:Yes: 3No: 53No data: 17 | ND | II
Liao et al., 2021 | ND | ND | ND | ND | ND | II
Rosenfeld, et al., 2021 | ND | ND | ND | Smoker: 30 | ND | II
Lang, et al.,2022 | 18 m | CT | ND | Smoker:Yes:+ ORN: 29-ORN: 19No:+ ORN:15 -ORN: 26 | 28 m | III
Boromand., et al., 2023 | 3.9y | ND | ND | Smoker:417 | -ORN: 4,5y+ ORN: 3,9y | II
Watson et al., 2023 | ND | ND | Lytic or mixed sclerotic lesions of bone | Smoker:807 | ND | IV
Kovarik et al., 2024 | 6 m: 23,4% | CT | ND | Smoker:No: 483 Yes: 399Ex: 565 | 3y | II
Renouf et al., 2024 | 2y | CT | ND | Smoker:No:+ ORN: 5-ORN: 9Yes:+ ORN: 52 -ORN:105Smoking pack-years:+ ORN:35.4-ORN: 36.8Smoker after IMRT:No:+ ORN: 35 -ORN: 60Yes:+ ORN: 20 -ORN: 26Missing: + ORN: 2-ORN:28Alcohol:No:+ ORN: 17 -ORN: 40Yes:+ ORN: 40 -ORN: 73Missing: + ORN: 0 -ORN: 1 | + ORN: 5,2y-ORN:4.8y | III

Description of the studies

The included studies covered a 28-year period, from 1996 to 2024 [38–65]. Overall, the studies comprised two cross-sectional studies [43, 63], three case-control studies [49, 60, 64], twenty-one retrospective cohort studies [39, 40, 42, 44–48, 50–59, 61, 62, 65], and one prospective cohort study [41]. The study by Liao et al. [57] included the largest sample size, comprising 16,701 patients, and reported relevant demographic information, including mean age, sex, and income (Table 1). Chopra et al. [45] identified race as a variable that may be associated with the development of ORNJ and should be further explored in future investigations. The radiation dose reported across the included studies ranged from 60 to 70 Gy [39–65].

The most frequently reported radiotherapy modality was intensity-modulated radiotherapy (IMRT) [49, 50, 52, 53, 55–58, 60, 62–66], followed by conventional radiotherapy [38, 41, 42, 48, 54, 55, 58], three-dimensional conformal radiotherapy (3D-CRT) [46, 51, 61, 62], cobalt-60 irradiation or photon/electron radiotherapy [40, 45], volumetric modulated arc therapy (VMAT) [45, 62], telecobalt therapy or linear accelerator-based radiotherapy [41], and intensity-modulated proton therapy (IMPT) [52]. Six studies [44, 47, 50, 53, 58, 60] did not report the radiotherapy modality used.

Only 18 studies provided information on participants’ behavioral habits, including alcohol consumption and tobacco use [41, 42, 44, 46, 47, 49, 50, 53–55, 57, 58, 60–65]. The reported risk factors and clinical variables included gingivitis [40, 42, 47], periodontitis [40, 42, 47, 51, 58, 61], chemotherapy [41, 45, 46, 49, 50, 54, 61, 64, 65], lesion location [41, 45, 51, 59], hyperbaric oxygen therapy (HBOT) [41], tumor classification according to the TNM system [41, 45, 47, 48, 51, 62, 63], radiation dose [41, 47], tooth extraction [41–44, 55, 58, 59, 64], local infection [39, 41, 46, 55, 57], exposed bone [39, 41], unknown etiology [44, 61], use of dentures [44], oral hygiene [46, 47, 49], number of remaining teeth [46, 49, 65], pre-radiotherapy tooth extraction [43, 45, 46, 49, 51, 54–57, 63, 65], post-radiotherapy tooth extraction [43, 46, 51, 65], comorbidities such as hypertension, diabetes, and immunosuppression [45, 48–51, 56, 57, 59, 60, 65], serum creatinine [51], serum albumin [51], minimum white blood cell count during radiotherapy [51], minimum lymphocyte count during radiotherapy [51], type of surgical resection, including marginal, segmental, and periosteal resection [45, 48, 49], HPV infection [50, 52, 55], spontaneous onset [43, 55, 57, 62], induced onset [55], dental trauma [55], dental implants, post-extraction complications [57], brachytherapy [62], time after extraction [56, 58], salvage surgery [43], prosthetic trauma [43], plate and screw infection [42], and root infection [42, 43].

One study [53] did not report any risk factors or behavioral habit-related variables. The mandible was the most frequently affected site [40–47, 49–51, 53, 55, 57, 59, 61, 63–65], particularly the premolar and molar regions (Table 1). Less frequently affected sites included the maxilla [41–46, 51, 53, 61, 64], as well as the orbital and calvarial bones [46]. One study [62] did not specify the exact anatomical location.

The time interval between radiotherapy and ORNJ development varied considerably across the included studies, ranging from 3 to 6 months [52] to 5 years [39]. CT was the most frequently used imaging modality for ORNJ assessment, followed by panoramic radiography [41, 45, 47, 51, 57, 58], scintigraphy [45], and MRI [49, 50]. Detailed radiographic features were reported in only two studies [58, 63] and included widening of the periodontal ligament space, irregularity or loss of the lamina dura, bone sclerosis, bone resorption [58], and mixed lytic or sclerotic lesions involving the cortical bone [63]. The reported follow-up period ranged from 1.8 years [49] to 30 years [40]; one study followed patients until death [41] (Table 1).

Bias analysis of included studies

In case-control studies, selection was reduced in all three studies by the control definition variable, and in the outcomes, it was downgraded by the non-response rate [50; 61; 65]. In cohort studies, the selection was downgraded for demonstrating the outcome of interest at the beginning of the study [54; 62; 46; 57; 55; 58; 43; 51] Three studies did not have a well-defined cohort selection and were therefore downgraded [46; 43; 65]. All articles demonstrated good compatibility of cohorts on the basis of the design or analysis [54; 62; 46; 57; 55; 58; 43; 51; 64; 45; 56; 59; 53; 39; 60; 42; 41; 49; 47; 48; 52]. Most studies demonstrated good results in outcomes (Table 2). Risk of bias analysis revealed methodological variability among the included studies. The study by Bagan et al. [44] presented greater methodological rigor, with well-defined inclusion criteria, a detailed description of participant allocation, and valid and reliable measurement of exposure and outcomes. However, it did not identify confounding factors nor employ strategies for their control, which may compromise the internal validity of the findings.

Study | Study design | Assessment tool | Quality appraisal details
Caparrotti et al., 2017 | Case-control | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★
Lang et al., 2022 | Case-control | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★
Renouf et al., 2024 | Case-control | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★
Kristensen et al., 2019 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Boromand et al., 2024 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Chopra et al., 2011 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★; Compatibility: ★★; Outcome/Exposure: ★
Dumoulin et al., 2020 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★
Habib et al., 2020 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Khoo et al., 2021 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Koga et al., 2008 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★; Compatibility: ★★; Outcome/Exposure: ★★★
Kojima et al., 2017 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Kovarik et al., 2024 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★; Compatibility: ★★; Outcome/Exposure: ★★★
Lee et al., 2009 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Liao et al., 2020 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Liao et al., 2021 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Liu et al., 2018 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Maesschalck et al., 2016 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Nieward et al., 1996 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Nieward et al., 2014 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Reuther et al., 2002 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Rosenfeld et al., 2021 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Studer et al., 2016 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Zhang et al., 2017 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★★; Compatibility: ★★; Outcome/Exposure: ★★
Liy et al., 2007 | Prospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Chen et al., 2005 | Retrospective cohort | Newcastle–Ottawa Scale (NOS) | Selection: ★★★; Compatibility: ★★; Outcome/Exposure: ★★★
Bagan et al., 2009 | — | JBI Critical Appraisal Checklist | Inclusion criteria: Yes; Participants detail: Yes; Exposure valid/reliable: Yes; Standardized condition criteria: Yes; Confounders identified: No; Strategies for confounders: No; Results valid/reliable: Yes; Appropriate statistics: Yes
Watson et al., 2023 | — | JBI Critical Appraisal Checklist | Inclusion criteria: No; Participants detail: No; Exposure valid/reliable: No; Standardized condition criteria: Yes; Confounders identified: Yes; Strategies for confounders: Yes; Results valid/reliable: Yes; Appropriate statistics: No

On the other hand, Watson et al. [63] demonstrated significant methodological limitations, including a lack of clear definition of inclusion criteria, a lack of detail in participant allocation, and unvalidated measurement of exposure. Despite this, the study identified and applied strategies to control confounding factors and used objective criteria for assessing the condition. However, the statistical analysis was considered inadequate.

Synthesis of meta-analysis and sensitivity results

Meta-analyses were performed for dichotomous qualitative variables, and Peto’s method was used to estimate the pooled effects for diabetes and the N2a, N3, and T1 tumor stages. Oral cancer was significantly associated with an increased likelihood of ORNJ [54, 56, 57, 65] (OR = 4.00; 95% CI: 2.90–5.51; p < 0.0001) (Fig. 2a). However, substantial heterogeneity was detected among the included studies (I² = 92.3%), indicating that this result should be interpreted with caution. The trim-and-fill sensitivity analysis suggested that the association remained statistically significant after adjustment for potential publication bias or small-study effects (OR = 4.81; 95% CI: 1.56–14.90; p = 0.0064; I² = 92.3%) (Fig. 2b).

Fig. 2: Meta-analysis of clinical and tumor-related factors associated with ORNJ. Forest plots showing the pooled associations between ORNJ and (a) oral cancer, (c) tumors located in the tonsillar region, (d) tumors located at the base of the tongue, (e) oropharyngeal tumors, and (g) diabetes mellitus. Trim-and-fill sensitivity analyses for potential publication bias or small-study effects are presented for (b) oral cancer, (f) oropharyngeal tumors, and (h) diabetes mellitus. Effect estimates are expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Heterogeneity across studies was assessed using the I² statistic

Regarding tumor site, neither tumors located in the tonsillar region [48, 49] nor those located at the base of the tongue were significantly associated with ORNJ (tonsillar region: OR = 1.32; 95% CI: 0.87–2.01; p = 0.1938; I² = 0%; base of the tongue: OR = 0.75; 95% CI: 0.48–1.18; p = 0.2163; I² = 0%) (Fig. 2c, d). Conversely, oropharyngeal tumors [54, 57, 65] showed a statistically significant association with ORNJ (OR = 2.34; 95% CI: 1.63–3.34; p < 0.0001) (Fig. 2e). However, the very high heterogeneity observed among studies (I² = 97.1%) and the loss of statistical significance after trim-and-fill adjustment (OR = 2.61; 95% CI: 0.32–21.52; p = 0.3741) suggest that this finding should be interpreted with caution (Fig. 2f).

Diabetes mellitus [49, 51, 56–60, 65] showed no significant association with ORNJ (OR = 1.01; 95% CI: 0.86–1.19; p = 0.9029; I² = 39.5%) (Fig. 2g). The trim-and-fill sensitivity analysis did not indicate relevant evidence of publication bias or small-study effects, with no change in the pooled estimate (OR = 1.01; 95% CI: 0.86–1.19; p = 0.9029; I² = 39.5%) (Fig. 2h). Neck dissection [46, 47] was also not significantly associated with ORNJ (OR = 1.47; 95% CI: 0.88–2.45; p = 0.1463), although moderate-to-substantial heterogeneity was observed (I² = 61.1%) (Fig. 3a).

Fig. 3: Meta-analysis of neck dissection and tumor T stage associated with ORNJ. Forest plots showing the pooled associations between ORNJ and (a) neck dissection, (b) T1 tumors, (d) T2 tumors, (f) T1–T2 tumors, (g) T3 tumors, and (i) T4 tumors. Trim-and-fill sensitivity analyses for potential publication bias or small-study effects are presented for (c) T1 tumors, (e) T2 tumors, (h) T3 tumors, and (j) T4 tumors. Effect estimates are expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Heterogeneity across studies was assessed using the I² statistic

Analysis of TNM staging showed no significant association between T1 tumors and ORNJ [47, 48, 52, 63] (OR = 1.01; 95% CI: 0.62–1.65; p = 0.9576), with considerable heterogeneity among studies (I² = 95.6%) (Fig. 3b). The trim-and-fill sensitivity analysis yielded an imprecise adjusted estimate with a wide confidence interval (OR = 2.44; 95% CI: 0.12–48.28; p = 0.5589; I² = 95.6%) (Fig. 3c). T2 tumors were significantly associated with ORNJ (OR = 1.78; 95% CI: 1.32–2.41; p = 0.0002; I² = 96%) (Fig. 3d); however, this association was no longer significant after trim-and-fill adjustment (OR = 2.90; 95% CI: 0.71–11.81; p = 0.1366; I² = 95.6%) (Fig. 3e). T1–T2 tumors [51, 61] and T3 tumors were not significantly associated with ORNJ (T1–T2: OR = 0.89; 95% CI: 0.46–1.70; p = 0.7193; I² = 0%; T3: OR = 1.30; 95% CI: 0.91–1.86; p = 0.1526; I² = 92.2%) (Fig. 3f, g). The adjusted estimate for T3 tumors remained non-significant after trim-and-fill analysis (OR = 1.98; 95% CI: 0.44–8.81; p = 0.3700; I² = 92.2%) (Fig. 3h). T4 tumors were significantly associated with ORNJ (OR = 1.98; 95% CI: 1.38–2.84; p = 0.0002; I² = 77.6%) (Fig. 3i), but this association was no longer statistically significant after trim-and-fill adjustment (OR = 1.75; 95% CI: 0.69–4.45; p = 0.2406; I² = 84.2%) (Fig. 3j).

Regarding nodal staging, N0 disease [47, 48, 63] showed no significant association with ORNJ (OR = 1.01; 95% CI: 0.66–1.54; p = 0.9724; I² = 68.5%) (Fig. 4a). The association remained non-significant after trim-and-fill adjustment, although the adjusted estimate was less precise and heterogeneity increased (OR = 1.73; 95% CI: 0.73–4.08; p = 0.2106; I² = 82.6%) (Fig. 4b). Likewise, no significant associations were observed for the N1, N2, N2a, N2b, N2c, or N3 subcategories (Fig. 4c–k). However, the trim-and-fill analyses indicated potential publication bias or small-study effects in some subgroups, suggesting that these findings should be interpreted with caution.

Fig. 4: Meta-analysis of nodal staging and oral hygiene associated with ORNJ. Forest plots showing the pooled associations between ORNJ and (a) N0, (c) N1, (d) N2, (f) N2a, (g) N2b, (i) N2c, (k) N3 nodal stages, and (l) good oral hygiene. Trim-and-fill sensitivity analyses for potential publication bias or small-study effects are presented for selected nodal-stage subgroups, including (b) N0 and the corresponding adjusted analyses shown in the remaining panels. Effect estimates are expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Heterogeneity across studies was assessed using the I² statistic

Regarding clinical and behavioral variables, good oral hygiene [49, 65] was a significant protective factor for ORNJ (OR = 0.40; 95% CI: 0.21–0.76; p = 0.0057; I² = 0%) (Fig. 4l). Chemotherapy [49, 50, 54, 56, 59, 61, 65] showed a statistically significant inverse association with ORNJ (OR = 0.84; 95% CI: 0.74–0.94; p = 0.0036), although this result should be interpreted with caution due to the very high heterogeneity observed (I² = 96%) (Fig. 5a). Moreover, the association was no longer statistically significant after trim-and-fill adjustment (OR = 0.72; 95% CI: 0.19–2.72; p = 0.6275; I² = 97.4%) (Fig. 5b). Tobacco use [48, 49, 53, 56, 59, 60, 64], in turn, was significantly associated with an increased likelihood of ORNJ (OR = 2.56; 95% CI: 1.96–3.34; p < 0.0001; I² = 93.5%) (Fig. 5c). Although trim-and-fill analysis suggested possible publication bias or small-study effects, the association remained statistically significant after adjustment (OR = 3.44; 95% CI: 1.22–9.73; p = 0.0199; I² = 92.9%) (Fig. 5d).

Fig. 5: Fig. 5 Meta-analysis of treatment-related and behavioral factors associated with ORNJ. Forest plots showing the pooled associations between ORNJ and (a) chemotherapy, (c) tobacco use, (e) tooth extraction, (f) pre-radiotherapy tooth extraction, and (h) post-radiotherapy tooth extraction. Trim-and-fill sensitivity analyses for potential publication bias or small-study effects are presented for (b) chemotherapy, (d) tobacco use, (g) pre-radiotherapy tooth extraction, and (i) post-radiotherapy tooth extraction. Effect estimates are expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Heterogeneity across studies was assessed using the I² statistic

Finally, tooth extraction [54, 57] was strongly associated with ORNJ (OR = 12.31; 95% CI: 6.40–23.69; p < 0.0001), although this finding should be interpreted with caution due to the very high heterogeneity across studies (I² = 97.5%) (Fig. 5e). Pre-radiotherapy tooth extraction [48, 50, 56, 58] showed a statistically significant association with ORNJ (OR = 1.15; 95% CI: 1.01–1.31; p = 0.0294; I² = 40.5%) (Fig. 5f), but this result was no longer significant after trim-and-fill adjustment (OR = 1.09; 95% CI: 0.75–1.58; p = 0.6368; I² = 46.9%) (Fig. 5g). In contrast, post-radiotherapy tooth extraction [50, 56, 58] remained strongly associated with ORNJ (OR = 8.38; 95% CI: 7.20–9.77; p < 0.0001; I² = 0%) (Fig. 5h), and the adjusted trim-and-fill estimate remained very similar (OR = 8.50; 95% CI: 7.34–9.85; p < 0.0001; I² = 0%) (Fig. 5i).

Synthesis GRADE

The GRADE assessment demonstrated that the variables oral cancer, tonsil tumor, base of tongue, oropharynx, diabetes mellitus, stages T1–T2, N1, N2 (including N2a, N2b and N2c), N3, good oral hygiene, tobacco use, tooth extraction, as well as extractions performed before and after radiotherapy, presented a moderate level of evidence. No variable was classified as having a high level of evidence, while the others presented a low level of evidence. Additional details are described in Table 3.

Results | Illustrative comparative difference | Measurement effect (Odds ratio)[95% CI] | Sample population number | Quality of Evidence (GRADE) | Comments
 | Experimental group | Control group | 
Oral cancer | The average number of positive oral cancer events ranged from 19 to 33. | The average number of positive oral cancer events ranged from 48 to 1194. | OR = 4.00 [2.90; 5.51] | 6.872 | (-)(-)(+)(+)(+)Moderate | It was downgraded because the heterogeneity was I² = 92.3% and different study designs
Tonsil tumor | The average number of tonsil cancer cases ranged from 12 to 43 positive events. | The average number of tonsil cancer cases ranged from 97 to 584 positive events. | OR= 1.32 [0.87; 2.01] | 1.430 | (-)(+)(+)(-)(+)Moderate | It was downgraded because the confidence interval was too wide and different study designs
Tumor at the base of the tongue | The average number of cases of tongue base tumor ranged from 8 to 21 positive events. | The average number of cases of tongue base tumor ranged from 76 to 411 positive events. | OR= 0.75 [0.48; 1.18] | 1.430 | (-)(+)(+)(-)(+)Moderate | It was downgraded because the confidence interval was too wide and different study designs
Oropharyngeal tumor | The average number of oropharyngeal cancer cases ranged from 12 to 31 positive events. | The average number of oropharyngeal cancer cases ranged from 54 to 165 positive events. | OR = 2.34 [1.63; 3.34] | 1.810 | (-)(+)(+)(+)(+)Moderate | Different study designs
Diabetes Mellitus | The average number of positive events in patients with diabetes mellitus ranged from 0 to 170. | The average number of cases of patients with diabetes mellitus ranged from 8 to 2,999 positive events. | OR= 1.01 [0.86; 1.19] | 23.068 | (-)(+)(+)(+)(+)Moderate | Different study designs
Neck dissection | The average number of positive events among patients who underwent neck dissection ranged from 7 to 14. | The average number of positive events among patients who underwent neck dissection ranged from 67 to 121. | OR= 1.47 [0.88; 2.45] | 1.430 | (-)(-)(+)(-)(+)Low | It was downgraded because the heterogeneity was I² = 61.1%, different study designs and confidence interval was too wide
T1 | The average number of cases of patients with stage T1 ranged from 1 to 13 positive events. | The average number of cases of patients with stage T1 ranged from 7 to 207 positive events. | OR=1.01 [0.62; 1.65] | 2.825 | (-)(-)(+)(-)(+)Low | It was downgraded because the heterogeneity was I² = 95.6% and different study designs
T2 | The average number of positive events in patients with stage T2 ranged from 9 to 28. | The average number of patients with stage T2 ranged from 34 to 388 positive events. | OR= 1.78 [1.32; 2.41] | 2.825 | (-)(-)(+)(-)(-)Low | It was downgraded because it presents a publication risk, however, through the adjusted tri-and-fill test, it also presented heterogeneity of I²= 96%, different study designs and confidence interval was too wide
T1-2 | The average number of positive events for patients with stage T1-2 ranged from 6 to 28. | The average number of positive events for patients with stage T1-2 ranged from 32 to 65. | OR= 0.89 [0.46; 1.70] | 481 | (-)(+)(+)(-)(+)Moderate | It was downgraded because the confidence interval was too wide and different study designs
T3 | The average number of cases of patients with stage T3 ranged from 4 to 18 positive events. | The average number of positive events for patients with stage T3 ranged from 13 to 312. | OR= 1.30 [0.91; 1.86 | 2.825 | (-)(-)(+)(-)(+)Low | It was downgraded because the heterogeneity was I² = 92.2% and different study designs
T4 | The average number of positive events in patients with stage T4 ranged from 7 to 19. | The average number of patients with stage T4 ranged from 21 to 144 positive events. | OR= 1.98 [1.38; 2.84] | 2.825 | (-)(-)(+)(-)(-)Low | Reduction is made because it presents heterogeneity of I²= 77.6%, risk of publication, which was adjusted through the trim-and-fill test, different study designs and confidence interval was too wide.
N0 | The average number of cases of patients with N0 lymph nodes ranged from 4 to 16 positive events. | The average number of cases of patients with N0 lymph nodes ranged from 36 to 162 positive events. | OR= 1.01 [0.66; 1.54] | 1.601 | (-)(-)(+)(-)(-)Low | Reduction is made because it presents heterogeneity of I²= 68.5% and risk of publication, which was adjusted through the trim-and-fill test and it was downgraded because the confidence interval was too wide and different study designs
N1 | The average number of cases of patients with N1 lymph nodes ranged from 5 to 20 positive events. | The average number of cases of patients with N1 lymph nodes ranged from 30 to 96 positive events. | OR= 1.19 [0.74; 1.92] | 1.601 | (-)(+)(+)(+)(-)Moderate | Reduction is made because it presents a publication risk, which was adjusted through the trim-and-fill test and different study designs
N2 | The average number of cases of patients with N2 lymph nodes ranged from 16 to 21 positive events. | The average number of cases of patients with lymph nodes ranged from 29 to 789 positive events. | OR= 1.01 [0.87; 1.17] | 1.601 | (-)(+)(+)(+)(-)Moderate | Reduction is made because it presents a publication risk, which was adjusted through the trim-and-fill test and different study designs
N2a | The average number of cases of patients with N2a lymph nodes ranged from 1 to 2 positive events. | The average number of cases of patients with N2a lymph nodes ranged from 10 to 73 positive events. | OR= 0.58 [0.24; 1.41] | 1.430 | (-)(+)(+)(-)(+)Moderate | It was downgraded because the confidence interval was too wide and different study designs
N2b | The average number of cases of patients with N2b lymph nodes ranged from 7 to 23 positive events. | The average number of cases of patients with N2b lymph nodes ranged from 66 to 412 positive events. | OR= 0.89 [0.65; 1.20] | 1.430 | (-)(+)(+)(-)(+)Moderate | It was downgraded because the confidence interval was too wide and different study designs
N2c | The average number of cases of patients with N2c lymph nodes ranged from 7 to 21 positive events. | The average number of cases of patients with N2c lymph nodes ranged from 51 to 304 positive events. | OR= 1.15 [0.73; 1.82] | 1.430 | (-)(+)(+)(-)(+)Moderate | It was downgraded because the confidence interval was too wide.
N3 | The average number of cases of patients with N3 lymph nodes ranged from 0 to 5 positive events. | The average number of cases of patients with N3 lymph nodes ranged from 9 to 78 positive events. | OR= 0.60 [0.31; 1.19] | 1.601 | (-)(+)(+)(+)(-)Moderate | Reduction is made because it presents a publication risk, which was adjusted through the trim-and-fill test.
Good oral hygiene | The average number of cases of patients with good dental hygiene ranged from 3 to 11 positive events. | The average number of positive events in patients with good dental hygiene ranged from 33 to 47. | OR= 0.40 [0.21; 0.76] | 337 | (-)(+)(+)(-)(+)Moderate | It was downgraded because the confidence interval was too wide and different study designs
Chemotherapy | The average number of positive events among patients who underwent chemotherapy ranged from 22 to 517. | The average number of positive events among patients who underwent chemotherapy ranged from 28 to 10,442. | OR= 0.84 [0.74; 0.94] | 24.677 | (+)(-)(+)(-)(-)Low | Reduction is made because it presents heterogeneity of I²= 96% and risk of publication, which was adjusted through the trim-and-fill test and confidence interval was too wide
Tobbaco use | The average number of positive events among patients who smoked ranged from 2 to 52. | The average number of positive cases among patients who smoked ranged from 19 to 357. | OR= 2.56 [1.96; 3.34] | 3.422 | (+)(-)(+)(+)(-)Moderate | Reduction is made because it presents heterogeneity of I²= 93.5% and risk of publication, which was adjusted through the trim-and-fill test.
Tooth extraction | The average number of positive events among patients who underwent tooth extractions ranged from 25 to 43. | The average number of positive events among patients who underwent tooth extractions ranged from 57 to 255. | OR= 12.31 [6.40; 23.69] | 1.629 | (+)(-)(+)(+)(+)Moderate | It was downgraded because the heterogeneity was I² = 97.5%.
Tooth extraction prior to radiotherapy | The average number of positive events in patients who underwent dental extractions prior to radiotherapy ranged from 7 to 415. | The average number of positive events among patients who underwent dental extractions prior to radiotherapy ranged from 80 to 6,583. | OR= 1.15 [1.01; 1.31] | 17.674 | (+)(+)(+)(+)(-)Moderate | Reduction is made because it presents a publication risk, which was adjusted through the trim-and-fill test.
Dental extraction after radiotherapy | The average number of patients who underwent extractions after radiotherapy ranged from 11 to 692 positive events. | The average number of patients who underwent extractions after radiotherapy ranged from 27 to 4,398 positive events. | OR= 8.38 [7.20; 9.77] | 17.508 | (+)(+)(+)(+)(-)Moderate | Reduction is made because it presents a publication risk, which was adjusted through the trim-and-fill test.