Dissertation committee:
Αικατερίνη Καραγιάννη, Ομότιμη Καθηγήτρια, Τμήμα Οδοντιατρικής, Σχολή Επιστημών Υγείας, ΕΚΠΑ
Χρίστος Αγγελόπουλος, Καθηγητής, Τμήμα Οδοντιατρικής, Σχολή Επιστημών Υγείας, ΕΚΠΑ
Αμάντα Ψυρρή, Καθηγήτρια, Τμήμα Ιατρικής, Σχολή Επιστημών Υγείας, ΕΚΠΑ
Κώστας Τσιχλάκης, Ομότιμος Καθηγητής, Τμήμα Οδοντιατρικής, Σχολή Επιστημών Υγείας, ΕΚΠΑ
Νικόλαος Νικητάκης, Καθηγητής, Τμήμα Οδοντιατρικής, Σχολή Επιστημών Υγείας, ΕΚΠΑ
Φοίβος Μαδιανός, Καθηγητής, Τμήμα Οδοντιατρικής, Σχολή Επιστημών Υγείας, ΕΚΠΑ
Εμμανουήλ Βάρδας, Επίκουρος Καθηγητής, Τμήμα Οδοντιατρικής, Σχολή Επιστημών Υγείας, ΕΚΠΑ
Summary:
Medication-Related Osteonecrosis of the Jaw (MRONJ) is defined as a complication, which affects the jawbone of patients that meet all of the following criteria: (a) patients were in the past or are now on treatment with bone targeting agents (BTAs) and/or antiangiogenics, (b) they have exposed bone or bone that can be probed through an intraoral or extraoral fistula in the maxillofacial region for more than 8 weeks, and (c) they have no history of radiation therapy or obvious metastatic disease to the jaws. More than 90% of the MRONJ cases occur in cancer patients, who receive high doses of BTAs, with an incidence between 1.1% to 1.3% for the first year of administration.
Imaging characteristics of the jaws support the clinical diagnosis and are recommended to determine the stage and to effectively manage the MRONJ. The International Task Force on MRONJ suggests that intraoral and panoramic radiographs are useful in evaluating the presence of changes of MRONJ, such as thickening of lamina dura, increased trabecular density of the alveolar bone or widening of the periodontal ligament space. Moreover, they suggest that computed tomography (CT) offers the advantages of assessing maxilla and mandible trabecular architecture, cortical integrity, periosteal bone and early fistula formation. Cone-beam CT (CBCT) is recommended as being particularly useful displaying with higher resolution the jawbone. CBCT is advantageous over ΠΑΝΟΡΑΜΙΚΉ, as panoramic radiographs produce a two-dimension image and do not allow for a full evaluation of the extent of the lesion. However, only a few articles have been published regarding the imaging characteristics of MRONJ and are mostly based on findings from small and retrospective studies with a mixed population of osteoporosis and cancer patients and with MRONJ staging based on clinical criteria.
A prospective, 30-month follow-up, observational study was conducted between June 2017 and October 2019, aiming to include a convenient sample of 100 patients. The study was approved by the Committee of Research and Ethics of the Dental School, National and Kapodistrian University of Athens, Reference number 391.
Eligible participants for this analysis were cancer patients diagnosed with MRONJ. Patients with MRONJ and with an insufficient, non-evaluable, ΠΑΝΟΡΑΜΙΚΉ or CBCT were excluded. All study participants received information about the study, agreed to participate and signed the informed consent.
The goal of this study was to prospectively evaluate and compare the imaging characteristics of medication-related osteonecrosis of the jaw, observed in the Orthopantomogram (OPG) and in Cone Beam Computed Tomography (CBCT), in patients with cancer.
Cancer patients, who received Bone Targeting Agents and developed MRONJ, were prospectively included in the study. The demographic and underlying disease characteristics were recorded. MRONJ was staged following the American Association of Oral and Maxillofacial Surgery (AAOMS) 2014 criteria. Four predefined radiological findings, osteolytic changes, sclerosis, periosteal reaction, and sequestration were assessed and were scored as “absent”, when no changes were observed, as “localized”, when changes were confined within the alveolar bone and within one tooth dimension mesiodistally from the site of bone exposure, as “extensive”, when changes were confined within the alveolar bone and involved the bone of two teeth or multiple sites, and as “beyond the alveolar bone”, when changes extended “beyond the alveolar bone” and included the involvement of the sinus floor, nasal walls, inferior alveolar canal, inferior mandibular border, and mandibular fracture. Initial analysis was based on descriptive statistics. Absolute and relative frequencies were provided for categorical variables, while continuous were described by median, minimum and maximum. The difference in distribution of OPG and CBCT findings in patients who had both types of examination was assessed using the Wilcoxon Signed Rank Test. All tests were 2-sided, and the level of significance was set to α = 0.05. The entire statistical analysis was conducted with Stata 15.1 IC.
Ninety-eight cancer patients were enrolled. The median age of our patients was 71 years, with a, though non-significant, female predilection. Breast and prostate cancers were most common diagnoses, 35.7% of patients were receiving cytotoxic therapies and 42.9 received targeted therapies. Eighty patients (81.6%) received BTAs for over a year; 19 (19.4%) received BTAs between 13-24 months and 61 patients (62.2%) received BTAs for over 24 months. Mandible was the most common location of MRONJ, followed by maxilla. Few patients (14 patients, 14.3%) had MRONJ in both jaws.
Almost half of the study participants reported tooth extraction (48.0% of patients), a known preceding event, prior to the development of MRONJ. In our study, periodontal disease was the second most frequently reported local risk factor (18 patients, 18.4%), after tooth extraction and tooth pain was reported in almost one out of three patients. This comes in accordance with previous evidence that shows that periodontal infection and pain are significantly associated with jawbone necrosis, prior to the dental extraction, and subsequent MRONJ development.
The majority of the patients (n=58, 59.2%) had stage 2 MRONJ and 35 (35.7%) were at MRONJ stage 3. No stage 0 was observed. MRONJ stage 0 was neither reported in the multicenter case registry study on MRONJ. The AAOMS 2014 description of stage 0 does not fulfill the definition of MRONJ of exposed bone, and this is the reason for its lack of inclusion in clinical trials and studies. MASCC/ISOO/ASCO expert panel shared those concerns and suggested considering stage 0 as an indicator for increased MRONJ risk.
Fifty-two (53.06%) patients were assessed with OPG and 89 (90.81%) with CBCT.
Forty-three (43.87%) patients were assessed with both OPG and CBCT and were available for comparisons between OPG and CBCT. CBCT was significantly more accurate than OPG in interpreting the “beyond the alveolar bone” osteolytic changes, sclerosis, periosteal reaction, and sequestration in all MRONJ stages. P-value was 0.0002, <0.0001, 0.0027 and 0.0009 respectively. Furthermore, CBCT was significantly more accurate than OPG in interpreting the “extensive” and “beyond the alveolar bone” imaging characteristics, when comparisons included the patients with early stages of MRONJ, 1 and 2 and the patients with stage 3 of MRONJ.
Bone sclerosis, lytic changes, periosteal reaction and sequestration, in both OPG and CBCT, were observed more often, as the MRONJ stage advanced, by other investigators, too.
Conclusions: CBCT is superior and more stage-sensitive to OPG in interpreting and staging MRONJ and can be particularly useful to achieve an early diagnosis of MRONJ.
The strengths of this study were the prospective nature, the inclusion of a homogeneous patient group with cancer, the staging with assessment of both the clinical and radiological characteristics, according to the recommendations of the American Association of Oral and Maxillofacial Surgeons, and the comparative assessment of the imaging characteristics in 43 patents, who were examined with both OPG and CBCT.
The evaluation of the available OPG and CBCT by one of the researchers, beyond the regular assessment by the radiologist-faculty member of the Clinic of Oral Diagnosis and Radiology of the Dental School or the private radiologist of the patient was a weakness of the study.
