Ghaidaa Badabaan,Maxine Strickland,Steven R Singer,Adriana G. Creanga,Gayathri Subramanian
Novel modified quantitative index for cone-beam CT assessment of medication-related osteonecrosis of the jaw - comparative analysis with original index
Bisphosphonate-Associated Osteonecrosis of the Jaw,Cone-Beam Computed Tomography
Purpose The main research goal was to address the critical need for an objective and quantitative index to describe the nature and extent of radiographic features of medication-related osteonecrosis of the jaw (MRONJ) lesions and complement the descriptive radiographic interpretation of the lesion and its clinical assessment. Method and Materials A retrospective review of MRONJ patients assessed at our institution was performed to compare the Composite Radiographic Index (CRI), identified from a prior scoping review, with a proposed modification, the Modified CRI index (‘Mod-CRI’). The Mod-CRI index was weighted to assign a higher score for diffuse radiographic involvement of a given lesion, and delineated MRONJ lesions into those with ‘high’ and ‘low’ severity. Twenty-two MRONJ cases imaged with CBCT were retrospectively assessed with both CRI and Mod-CRI indices and the two indices were compared for their ability to quantitatively describe cone-beam computerized tomography (CBCT) radiographic features and complement the clinical staging of the MRONJ lesion. Results There was a statistically significant association between increased clinical stage and higher mod-CRI score (p = 0.040). The Mod-CRI index sorted the patients who scored intermediate scores with the CRI (n = 15) into either the low (n = 8) or high categories (n = 7). Conclusion The Mod-CRI index eliminated the ambiguous intermediate-category-scores in the previously published CRI index and provided greater clarity to the interpretation of a given index score. Adopting the Mod-CRI could improve MRONJ assessment and enhance communication between the radiologist and the clinician.
Novel modified quantitative index for cone-beam CT assessment of medication-related osteonecrosis of the jaw - comparative analysis with original index

The main research goal was to address the critical need for an objective and quantitative index to describe the nature and extent of radiographic features of medication-related osteonecrosis of the jaw (MRONJ) lesions and complement the descriptive radiographic interpretation of the lesion and its clinical assessment.

A retrospective review of MRONJ patients assessed at our institution was performed to compare the Composite Radiographic Index (CRI), identified from a prior scoping review, with a proposed modification, the Modified CRI index (‘Mod-CRI’). The Mod-CRI index was weighted to assign a higher score for diffuse radiographic involvement of a given lesion, and delineated MRONJ lesions into those with ‘high’ and ‘low’ severity. Twenty-two MRONJ cases imaged with CBCT were retrospectively assessed with both CRI and Mod-CRI indices and the two indices were compared for their ability to quantitatively describe cone-beam computerized tomography (CBCT) radiographic features and complement the clinical staging of the MRONJ lesion.

There was a statistically significant association between increased clinical stage and higher mod-CRI score (p = 0.040). The Mod-CRI index sorted the patients who scored intermediate scores with the CRI (n = 15) into either the low (n = 8) or high categories (n = 7).

The Mod-CRI index eliminated the ambiguous intermediate-category-scores in the previously published CRI index and provided greater clarity to the interpretation of a given index score. Adopting the Mod-CRI could improve MRONJ assessment and enhance communication between the radiologist and the clinician.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare and poorly understood condition (Ruggiero et al., 2014). It presents complexities in all phases of care, from diagnosis through management, as well as predicting response to treatment. Clinically similar appearing lesions may have dissimilar radiographic features and vice versa (Ruggiero et al., 2014, Walton et al., 2019, Ruggiero et al., 2022), (Bianchi et al., 2007, Bedogni et al., 2008, Bedogni et al., 2014, Kämmerer et al., 2016). A wide variety of radiographic features exist in MRONJ, including osteolytic defects, sequestration, trabecular sclerotic changes, cortical irregularity, and periosteal reaction (Treister et al., 2010, Aghaloo and Tetradis, 2017, Diniz-Freitas et al., 2018). Often, the clinical presentation under-represents the extent of the lesion seen radiographically (Raje et al., 2008, Fleisher et al., 2014, Subramanian et al., 2017). Such a wide variation in the nature and extent of such radiographic features of MRONJ lesions necessitates a comprehensive clinical as well as radiographic assessment, especially when gauging lesion severity or determining palliative and surgical treatment options. The most widely accepted staging system is the American Association of Oral and Maxillofacial Surgeons (AAOMS) staging (Ruggiero et al., 2014), (Ruggiero et al., 2022). The presence or absence of symptoms has a direct impact on stages I and II. Radiographic changes are less sensitively reflected in initial staging so long as they are confined to the dentoalveolar region, regardless of the anteroposterior extent of involvement. A staging system that simultaneously incorporates a more sensitive representation of the radiographic features of the MRONJ lesion may enhance assessment and guide management. A quantitative radiographic index may lend itself to easier incorporation into comprehensive staging of lesions. A scoping review (Badabaan et al., 2023) was undertaken to evaluate the published literature for any such quantitative radiographic indices used in assessing MRONJ lesions for changes seen in cone-beam computerized tomography (CBCT) imaging and identified the Composite Radiographic Index (CRI) as the single radiographic index that reflects both the nature and extent of radiographic characteristics (Walton et al., 2019). This scoping review also highlighted shortcomings with the CRI index. In a significant fraction of Stage 1 and 2 MRONJ lesions, the CRI score did not improve diagnostic clarity because larger diffuse lesions with small number of radiographic features were assigned similar scores as lesions which were localized to a narrow region of involvement but demonstrated a larger number of radiographic features. This raised the question whether it is possible to increase the clinical utility of the CRI index by providing a weighted score to diffuse changes. We chose to assign a weighted score of 3 instead of 2 for any diffuse radiographic change and surmised that any two diffuse radiographic changes might augment the severity of the lesion. This modified index (Mod-CRI index) is designed to generate scores of only binary significances- low and high scores signifying lesions of low and high severity, respectively, based on score 5 and below, or 6 and higher, implying greater morbidity to the likely surgical management of a lesion with a ‘high’ severity relative to that with a ‘low’ score. In order to compare the relative ability of the CRI and Mod-CRI indices to ‘sort’ MRONJ lesions of varying severity in a clinically meaningful manner, institutional retrospective and radiographic imaging reviews of MRONJ patients who received CBCT imaging as part of their diagnostic workup were conducted.

After obtaining protocol approval from the Institutional Review Board (IRB), an institutional retrospective review was conducted of patients who presented to the General Practice Residency program clinic at Rutgers School of Dental Medicine, subsequently diagnosed with MRONJ, and underwent CBCT imaging as part of their diagnostic work up (n = 22).

1. Patients above 18 years of age with a large volume (both maxilla and mandible) or small volume (a section of teeth either in maxilla or mandible) CBCT study in our database. 2. Previous history of identified medications taken either IV or orally for the management of osteoporotic/osteopenic disease or cancer bone disease. 3. Information in their patient record including past medical history, medications, duration, demographic data. 

1. History of or present osteoradionecrosis. 2. Insufficient chart information (missing diagnostic data). 3. No existing CBCT examination of the suspected area of MRONJ.  Scans included large volume (including maxilla and/or mandible) CBCT using our iCAT Next Generation Scanner, (Imaging Sciences International, Hatfield, USA) with DICOM files maintained in the RSDM iCAT computer database or our Planmeca Viso G7 (Planmeca, Helsinki Finland) with DICOM file maintained in the RSDM MiPACS database or our limited field of view CBCT Carestream 9000 scanner (Carestream, Rochester, USA) with DICOM file maintained in the RSDM MiPACS database. The CBCT scans were individually analyzed by two oral and maxillofacial radiologists (an OMFR board certified radiologist (AC) and a graduating resident in OMFR (GB)). Examiners were calibrated prior to examining the imaging studies to reduce Intra-Inter examiner variability.

Initial calibration, using pre-selected cases of MRONJ, was performed, with discussion and forced consensus of diagnosis, radiographic features and agreement on extent of lesions. A week later, the calibration was repeated using the same images and a forced consensus was reached where there was disagreement as to the findings. A second calibration was repeated a week later using 3 scans to confirm the forced consensus. Lesion assessment was standardized as follows. • If normal appearing bone was apparent between two nearby areas where diseased tissue could be readily ascertained, the total area will be considered affected, and measurement will include the entire region. • Images were viewed in a dimly lit room, using Anatomage Invivo Dental (Santa Clara, USA) advanced viewing software, in Standardized viewing setting. • Viewers had complete control over all parameters in viewing CBCT scans. They could manipulate and modify contrast, brightness, reduce scatter, crop, re-align and re-slice as deemed necessary to assess and score.

The diagnostic data collected included medical history and medications taken, radiographic presentation and treatments performed, as well as observations of the healing process were noted, and abstracted to a spreadsheet. Radiographic findings were graded using the Composite Radiographic Index score (CRI index) that was described by Walton et al, with four parameters (lytic changes, sclerotic changes, sequestration and periosteal reaction), assigning a score for each parameter based on absence (0), localized (1) and extensive or diffuse presence (2) (Walton et al., 2019). CRI index scores ranged from 0 to 8 and were assessed as low (1–2), medium (3–5), or high (6–8). All patient scans were anonymized and then exported to be viewed independently by each viewer; the impression of the OMFR board-certified radiologist (AC) prevailed in case of a disagreement. The Modified or Mod-CRI index: is similar to the CRI index. Each of four radiographic features, namely, lytic changes, sclerotic changes, sequestration and periosteal reaction, were scored for absence (0), localized (1) or extensive or diffuse presence (an arbitrarily weighted score of ‘3′ instead of ‘2′ per the original CRI index was assigned for extensive/diffuse radiographic changes). The definitions of localized and diffuse were identical to those of the CRI index (less than one tooth dimension antero-posteriorly, versus beyond). A Mod-CRI score of 5 or below was classified as ‘low’. A higher Mod-CRI score ranging from 6 to 12 was assessed as ‘high’. The scoring criteria using the Mod-CRI index (‘Mod-CRI’) are illustrated in Fig. 1. The scores obtained using the CRI and the Mod-CRI indices were compared. A separate spreadsheet was maintained for the radiographic interpretation. The Mod-CRI index score for each lesion was determined by collaborative assessments by the two examiners, given the exploratory nature of this exercise. Fisher’s exact test was used to evaluate correlation of categorical variables.

This section summarizes the retrospective review of patients with previously diagnosed MRONJ and imaged with CBCT. Table 1 summarizes the data abstracted for the review (n = 22, 17 female and 5 males). More than half of the patients were symptomatic at presentation. MRONJ occurred more frequently in the mandible than in the maxilla, 13 vs 9 respectively. Five MRONJ lesions involved localized bony changes, while 17 lesions involved nearly an entire quadrant. Reliability testing for the original CRI scoring was done between the inter-raters’ values for the 22 scans reviewed, the Kappa coefficient result was (0.83) demonstrating strong agreement, with a 69.5% percent agreement between the two examiners (Landis and Koch 1977). The reliability testing using the Mod-CRI scoring also scored 69.5% percent in agreement. A summary of pertinent results (Tables 2, Table 3): Use of the original CRI index (Walton et al., 2019) sorted the 22 patients identified in this study into three categories- five in the low category (CRI score of 0–2), 15 in the intermediate (CRI score 3–5) and two in the high category CRI score of 6–8) (Table 2, left). Use of the Mod-CRI index did not alter the assignment of patients who were earlier sorted to the ‘low’ and ‘high’ categories on the CRI index (Table 2, right). However, the Mod-CRI index sorted the patients who scored intermediate scores with the CRI (n = 15) into either the low (n = 8) or high categories (n = 7) (Table 3). Accordingly, a third of Stage 1, quarter of Stage 2 and all of Stage 3 patients were ‘upgraded’ to the ‘high’ category. Representative CBCT imaging slices of MRONJ lesions with intermediate CRI scores that were reassigned in either direction are depicted in Fig. 2. In contrast to re-scoring the lesions using the Mod-CRI criteria, merely ‘re-adjusting’ the score classification of the CRI index, i.e., 0–4 as ‘low’ and 5–8 as ‘high’, or, 0–3 as ‘low’ and 4–8 as ‘high’ will not aid in clarity, as both lesions depicted in Fig. 2 will sort into the same category and hence, no additional clarity will be provided. Fig. 2 Representative MRONJ lesion with medium CRI score that was 'downgraded' (top panel) and 'upgraded' (bottom panel) when assessed using Mod-CRI index. There appeared to be a statistical association between lower clinical staging and lower Mod-CRI scores, and between higher clinical staging and high Mod-CRI scores (p = 0.04, Fisher’s exact test, Table 2, right). This was to be expected because the Mod-CRI was designed to amplify the weightage of more diffuse radiographic changes, which, by definition, correlated with Stage 3 lesions. In contrast, there did not appear to be a significant correlation of CRI scores and clinical staging (p = 0.189), consistent with the need and rationale for developing the Mod-CRI index.

This study explored the use of the proposed modified-CRI index (Mod-CRI), which provides a higher weightage to diffuse radiographic changes when compared to localized changes, to amplify the distinction between localized and diffuse radiographic changes. In order to test the utility of the Mod-CRI index, a retrospective study was performed to assess the radiographic presentation of MRONJ lesions imaged at our institution, comparing the utility of the CRI and Mod-CRI indices in scoring the lesions. Using the Mod-CRI index did not alter the two ends of the spectrum, specifically cases identified by the CRI index as ‘low’ and ‘high’ severity scores. This was to be expected that the modifications to the original CRI index were only aimed to add more weightage to diffuse radiographic changes and thus differentiate lesions with multiple localized changes from those with diffuse involvement. Nearly 70% of the cases assessed in this retrospective study were assigned intermediate CRI scores. Using the Mod-CRI index resulted in the re-assignment of these cases into ‘low’ and ‘high’ severity. This assignment was verified by going back to the radiographic data to qualitatively assess this re-assignment (Fig. 2). It was striking that four ‘Stage 3′ lesions scored only in the intermediate category when graded using the CRI index, primarily because they had fewer than three parameters demonstrating diffuse changes. All four lesions received scores 6 or greater using the Mod-CRI index and were sorted into the ‘high’ severity group. In contrast, two-thirds of Stage 1 and 75% of Stage II lesions were sorted into the ‘low’ severity group. The need for a reliable and reproducible means to assess and grade the radiographic changes in MRONJ is well established (Bianchi et al., 2007, Walton et al., 2019). Such an index could have value in lesion assessment and outcome prognostication. MRONJ is a complex entity with four clinical stages (Stage 0–3). It is counterintuitive to view a simple index that provides a binary classification as an aid in deciding whether or not to surgically intervene. It must be emphasized that we recognize that the Mod-CRI score may serve as one of many factors in such a decision-making process. For instance, in the case of an MRONJ lesion that does not respond well to conservative management, a ‘low’ Mod-CRI score can support surgical debridement, irrespective of the systemic status of the patient (whether otherwise healthy or with a significant burden of illness from cancer-related cachexia or malnutrition), as long as it is anatomically favorable (no proximity to critical structures) (Fig. 2a, for instance). However, a ‘high’ Mod-CRI score may indicate need for caution, supporting debridement only if sequestration were evident, and conservative management if no sequestration was noted. (Fig. 2b, for instance). In either case, the Mod-CRI is expected to supplement and not supplant the traditional comprehensive CBCT radiographic report. It is speculated that describing MRONJ lesions simultaneously and dually with both the AAOMS staging and Mod-CRI criteria, for example, ‘Stage 2, high Mod-CRI’ or ‘Stage 2, low Mod-CRI’, and similarly for Stage 1 lesions, as well, may enhance the clarity of lesion assessment. Future studies are warranted to validate such a classification. In addition, while future studies are required to validate the Mod-CRI index as a prognosticator of outcome, this pilot study justifies such an effort, despite the small sample size. The Mod-CRI index could potentially serve to augment communication between the radiologist and the clinician, by appropriately reflecting the radiographic extent of the lesion and thus positively impact clinical decision making.

1. Being a cross-sectional assessment, this study cannot delineate between ‘early’ radiographic changes of an initial MRONJ from ‘delayed’ changes that accompany established lesions. 2. The inter-rater reliability for the CRI index was fair- this may reflect the difference in experience between the two examiners. However, this must be a consideration while interpreting the results of the study. 3. A score of 6 was arbitrarily designated to signify a ‘high’ Mod-CRI score. Thus, a lesion with just one radiographic change, no matter how diffuse, would not receive a Mod-CRI score in the ‘high’ category. However, it is unlikely to find a radiographic change such as diffuse lytic or sclerotic changes in isolation, without any other concomitant changes in radiographic density. Secondly, sequestration requires lytic changes to isolate bone of high radiodensity. Further, periosteal reaction is a rare radiographic finding with poorly understood diagnostic and prognostic significance. Thus, requiring at least two diffuse radiographic changes to constitute an MRONJ lesion of higher severity is a calculated designation. Nevertheless, this requires validation. 4. The sample size being small, this study is underpowered to answer more quantitative questions. Larger, rigorously designed studies are necessary to validate the Mod-CRI. 

This study proposes a modified index for assessing and describing the radiographic features and extent of the MRONJ lesion, generating a binary index of severity. Modifying the preexisting index appeared to provide greater clarity in lesion description and assessment. If validated, this modified index could enhance communication between the general dentist, radiologist and the surgeon and guide clinical decision-making and management. Further studies are required to evaluate the Mod-CRI index as a prognostic indicator and validate its use in surgical planning.

Ethical approval was obtained from the institutional review board at Rutgers University, New Jersey, USA.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.