Material and method

Protocol and registration

The present systematic review and meta-analysis was carried out following the methodological guidelines of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [25] and Cochrane handbook [26]. In addition, the protocol was registered in the Open Science Framework (OSF) platform (registration doi: 10.17605/OSF.IO/4ZK9B).

Search

Electronic searches were performed in PubMed/MEDLINE, Scopus, Embase, Web of Science, Cochrane Library, SciELO, and LILACS. The search strategy was developed by combining keywords related to the research question with database-specific controlled vocabulary terms. For PubMed/MEDLINE, Medical Subject Headings (MeSH) terms were applied when appropriate. Grey literature was also searched using OpenGrey, and handsearching was conducted in key journals within the field. The search strategy included the terms “osteoradionecrosis of the jaws” AND “risk factors”. The reference lists of all articles included in the systematic review were screened to identify additional eligible studies. When potentially relevant studies were not available in full text, the corresponding authors were contacted by email or through scientific networking platforms, such as ResearchGate.

Eligibility criteria

Cross-sectional observational, cohort, and case-control studies including patients diagnosed with ORNJ who underwent imaging examinations for diagnostic evaluation were eligible for inclusion. Studies were excluded when the sample included only patients with a history of using medications associated with osteonecrosis of the jaws, such as bisphosphonates; patients with systemic diseases affecting bone or dental tissue structure, including osteoporosis, hyperparathyroidism, hypothyroidism, and hypophosphatasia; patients with metastatic tumors of extraoral origin involving the maxilla and/or mandible; or patients with a recent history of surgical procedures involving bone or dental structures. Additionally, studies with designs other than those specified in the eligibility criteria, including animal studies, case reports, case series, review articles, expert opinions, and letters to the editor, were excluded. No restrictions were imposed on language or year of publication.

Research question and PECOS

The research question was: “In patients undergoing radiotherapy for the treatment of head and neck cancer,_ what are the risk factors associated with the development of osteoradionecrosis of the jaw (ORNJ), compared with patients who did not develop ORNJ?”_ Accordingly:

P (Population): Patients diagnosed with head and neck cancer.E (Intervention): Head and neck cancer patients who received radiotherapy.C (Comparison): Patients who developed ORNJ compared with those who did not.O (Outcomes): Risk factors for the development of osteoradionecrosis and imaging characteristics.S (study design): cross-sectional, cohort and case-control studies.

Study selection

All identified references were imported into the free online software Rayyan [27], followed by the removal of duplicate records. Two previously calibrated independent reviewers screened the retrieved articles according to the pre-established eligibility criteria based on titles and abstracts. Thereafter, the same reviewers independently assessed the full-text articles to determine eligibility for inclusion in the systematic review. Disagreements were resolved by consultation with a third reviewer experienced in dental radiology and systematic review methodology. The study selection process, including included and excluded records, is presented in a flowchart (Fig. 1).

Fig. 1: PRISMA flow diagram of the study selection process for the present systematic review

Data extraction

After completion of the study selection process, data were extracted and recorded in a standardized data extraction table. The following information was collected: first author’s name and year of publication, sample size, sex distribution, mean age, presence of systemic diseases, potential local risk factors for ORNJ development, including periodontal and endodontic diseases, tooth extractions, smoking status, daily tobacco consumption, and cumulative smoking exposure, as well as the classification and frequency of radiographic findings and treatment modalities. In addition, the included studies were classified according to the Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence to determine the level of scientific evidence of each study design [28].

Assessment of the risk of bias of the included studies

The methodological quality of non-randomized studies, including case-control and cohort designs, was assessed using the Newcastle-Ottawa Scale (NOS). The NOS evaluates three domains: selection of the study groups, comparability of the groups, and ascertainment of exposure for case-control studies or outcome for cohort studies. A maximum of four stars can be assigned to the selection domain, two to comparability, and three to exposure or outcome. The overall NOS ratings was used to support the interpretation of the results of the meta-analyses [29].

The risk of bias of the included cross-sectional studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Analytical Cross-Sectional Studies. This tool has been validated and is widely used to evaluate methodological quality in observational studies [30, 31]. The checklist comprises eight items addressing potential sources of bias related to study design, conduct, and outcome analysis. Each item was rated as “yes,” “no,” “unclear,” or “not applicable.” All assessments were independently performed by two previously calibrated reviewers.

Meta-analysis

For all comparative analyses, the experimental group consisted of patients who had received radiotherapy and developed ORNJ, whereas the control group consisted of patients who had received radiotherapy but did not develop ORNJ. For the evaluation of categorical variables, including smoking, diabetes, chemotherapy, tumor staging (TNM), neck dissection, good dental health, tooth extraction, pre-radiotherapy tooth extraction, post-radiotherapy tooth extraction, and tumor site, the odds ratio (OR) was used as the effect measure. Meta-analyses were performed using a fixed-effect model with the inverse-variance method. In cases of sparse data or rare events, Peto’s method was used [32]. The results of the meta-analyses were illustrated using forest plots. Statistical analyses were performed using R software (version 3.6.3) with the meta package, adopting a significance level of α = 0.05. Heterogeneity was assessed using the I² statistic and was considered high when I² exceeded 50% [33–35]. Quantitative synthesis was conducted only for variables reported in at least two studies with sufficient data to enable pooling in the meta-analysis.

Sensitivity analysis, publication bias and meta-analysis

Potential publication bias was evaluated using the trim-and-fill method, a non-parametric sensitivity analysis designed to assess funnel plot asymmetry and estimate the potential impact of unpublished or missing studies on the pooled effect estimate. This approach imputes potentially missing studies and provides an adjusted overall effect estimate, allowing evaluation of whether the meta-analytic results are robust to potential publication bias [36].

Assessment of the certainty of scientific evidence

The certainty of evidence for each meta-analysis outcome was assessed using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation) [37]. This framework evaluates five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias [37]. Based on these domains, the certainty of evidence was classified as very low, low, moderate, or high.