Since its initial description¹, the incidence of medication-related osteonecrosis of the jaw (MRONJ) and the number of related publications have increased rapidly. As this serious disease² has been studied by clinicians and scientists, controversies have arisen between medical societies^3-6.

The Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaw from the American Association of Oral and Maxillofacial Surgeons (AAOMS) has made great efforts to present an accepted and widely used definition of MRONJ^7-9. The following definition is the current gold standard for MRONJ worldwide: the presence of exposed jawbone or bone that can be probed for at least 8 weeks in a patient receiving antiresorptive therapy who has not received radiotherapy to the head or neck. Furthermore, AAOMS developed a four-stage disease classification scale (stage 0 to III) that is regarded as the standard for deriving treatment recommendations and creating comparability in the nomenclature of epidemiological data⁹.

However, the AAOMS staging system has also been the subject of controversy. The absolute goal of a staging system should be to depict the extent of the disease, derive suitable therapeutic options, and make prognostic assessments. However, the AAOMS staging system, which is driven by clinical inspectorial examinations, might fail to detect the actual extent of bone involvement in MRONJ, raising the risk of assigning patients to inappropriate treatments^10,11. In particular, AAOMS stage I⁹ is misleading. Because an early stage implies a good prognosis, the AAOMS recommends that stage I patients be treated with a non-surgical, conservative approach. However, the size of the mucosal defect (sinus tract or bones exposed over a large area) does not allow conclusions to be drawn about the true extent of the necrosis or the appropriate therapy recommendation or prognosis. Indeed, few data are available to support MRONJ staging or the concerns about it. Therefore, it is not surprising that many working groups have attempted to investigate the relationship between the staging and the true extent of necrosis by using radiological diagnostics to detect early signs of MRONJ or assess the real extent of the disease^12-16. Unfortunately, there is no consensus on the efficacy of different imaging modalities in assessing the real extent of necrotic bone area^17,18. Furthermore, inconsistent results have been found, including both over- and underestimation of the extent of MRONJ when comparing the AAOMS stages with various imaging modalities¹⁹. At present, it seems that determining the true extent of necrosis is only possible intraoperatively using the judgment of experienced surgeons or fluorescence-based methods^20-22.

To date, no clinical data investigating the connection between the size of a mucosal defect and the extent of necrosis have been published. Before it makes sense to question a clinically established classification to improve it, it is urgently necessary to provide evidence that the classification is clinically relevant. Therefore, our aims in this study were to determine whether the extent of a mucosal lesion correlates with the bony lesion in stage I patients. We also wanted to assess possible intragroup differences in the clinical manifestation of necrosis (probeable vs visible bone). We hypothesize that the extent of the mucosal lesion bears no relationship to the bony lesion and that whether the necrotic bone is visible or probeable is clinically irrelevant.

Even though great progress has been made in diagnosing and treating MRONJ in recent years, diagnosis (especially early cases) and staging remain challenging, partly because the diagnostic procedure is not standardized, and the AAOMS classification does not cover all manifestations of MRONJ^11,19.

Compared with the 2009 version^7,8, the most recent version of the AAOMS consensus paper has widened the definition of MRONJ⁹. This amendment was triggered by several studies that found that patients can suffer from MRONJ without visually detectable necrotic bone (non-exposed MRONJ, including intraoral fistula, mandibular fracture, dentally unexplained pain, and swelling) and would therefore not fulfill the initial definition of MRONJ^{10,12,13,24,25}. Therefore, the modified definition in the latest AAOMS consensus paper includes patients who present with bone probeable through a sinus tract⁹. This change is an important step forward because different interpretations of “bone exposure” had led some authors to diagnose probeable bone as MRONJ, whereas others did not. That disagreement might partly explain the different prevalence figures in recent epidemiological studies¹⁹.

However, the current staging system still suffers from several inconsistencies. In its 2009 consensus paper⁸, AAOMS added a “stage 0” to its classification system for subjects with the non-exposed variant of MRONJ (no clinical evidence of necrotic bone but nonspecific clinical findings, radiographic changes, and symptoms). This stage is accompanied by nonspecific symptoms (odontalgia, bone pain in the jaw, loosening of teeth, and others). Unfortunately, the core definition of MRONJ remains unchanged, and AAOMS continues to focus on the clinical evidence of long-standing bony exposure¹¹. Consequently, patients with non-exposed MRONJ without probeable bone do not have MRONJ as it is currently defined. This paradox has been highlighted by many authors calling for urgent change^13,26-28.

In a hierarchical staging system such as the AAOMS classification (stage 0-III), both clinicians and patients should be able to assume that the stages differ in terms of the extent or severity of disease they represent. However, AAOMS has made no statement about whether their stages correlate with differences in the extent of necrotic bone area⁹. That failure was precisely the starting point for this study.

In this study, we have shown that the intraoperatively detected areas of necrotic bone were significantly larger than the preoperative visible mucosal lesions in both the visible and probeable bone groups. However, we also showed that the intraoperatively detected necrotic osseous lesions in stage I patients⁹ with mucosal defects and visible bone were significantly larger than those in patients with preoperative probeable bone. Furthermore, our linear regression model shows a weak but significant correlation between the extent of the mucosal lesion and the necrotic bone area in the anteroposterior direction in patients who presented with visible bone preoperatively.

However, the very low correlation coefficients (R²<0.2) indicate that our regression models cannot be used to predict the exact extent of a necrotic bony lesion from the extent of a mucosal lesion. The scattering around the regression line is far too large for that. Instead, it must be assumed that other factors influence the extent of both the necrotic and mucosal lesions. Furthermore, the direction of influence is unclear. For future studies, we highly recommend the use of multivariate regression analyses in a larger population.

A further linear regression model between the preoperative extent of the mucosal lesion and the resection defect did not show significant results. In other words, preoperative patient presentation with visible or probeable bone does not predict the extent of the underlying necrotic osseous lesion. However, large areas of exposed bone might indicate that necrosis is extensive, perhaps because a small mucosal lesion protects necrotic bone from prolonged exposure to bacteria, which limits secondary infections and disease progression.

Furthermore, we have shown that the resection defects were significantly larger than the mucosal lesions, although no regression was detected between the extent of the mucosal lesion and the surgically induced defect. That the resection defect is obviously larger than the mucosal and osseous lesions is not surprising; it is a result of the necessary extraction of adjacent teeth and the smoothing of sharp bone edges after the removal of the necrotic bone. However, our results suggest that it is impossible to use mucosal defects and AAOMS stages⁹ to predict the effort needed for the surgical management of MRONJ.

Furthermore, for 6 lesions classified as stage I preoperatively, resections beyond the alveolar bone were needed, meaning that those lesions were postoperatively classified as stage III.

To the best of our knowledge, no previous study has investigated the questions addressed herein. A partly comparable study was conducted by Assaf et al.²⁹, who compared the extent of MRONJ, as detected by Tc-99m-methylene diphosphonate bone scintigraphy, with the intraoperative extent of the disease. They found that the true extent of osseous lesions, as determined by surgery, was significantly underestimated by clinical examination but not by bone scintigraphy²⁹. Their results underline the importance of imaging in diagnosing and managing MRONJ.

A criticism from surgeons who treat according to the AAOMS treatment recommendations for MRONJ will certainly be that the patients in the present study who presented with MRONJ stage I⁹ were surgically treated. There is currently great controversy between international professional societies regarding the AAOMS treatment recommendations⁹. For stages I and II, AAOMS recommends non-surgical treatment⁹ such as symptomatic treatment with oral antibiotics, oral antibacterial mouth rinse, pain control, and regular clinical follow-up. Surgical debridement or resection of necrotic bone is recommended for stage II MRONJ patients⁹. Similar recommendations were also made by Khan et al.³⁰ on behalf of the International Osteonecrosis of the Jaw Task Force. They based their treatment recommendations on the disease stage and size of the lesion. In their view, conservative therapy should be continued until obvious progression of the disease occurs, pain cannot be controlled by conservative means, or antiresorptive therapy is discontinued by the treating oncologist³⁰. However, as the results of this study show, neither the severity nor progression of the disease can be measured or interpreted using the current clinically driven staging system⁹. Therefore, we assert that therapy recommendations based on those criteria must be critically reviewed and interpreted.

Furthermore, it must not go unmentioned that non-surgical management in cases of infection (AAOMS stage II⁹) through the use of antibacterial treatment usually leads to a stage downshift (to AAOMS stage I)^31,32, which is interpreted as a treatment success by many authors³³. Such a fluent transition between those lower stages does not produce any clear information about the real osseous lesion. In addition to freedom from infection, some authors describe a decline in the mucosal lesion and sometimes even the total rehabilitation of mucosal integrity^33-35. In this study, we observed a reduction in the size of the mucosal lesion between the time of study inclusion (T0) and the day of surgery (T1), but that improvement in the mucosal situation should not be misinterpreted as evidence that the disease has resolved. As can be seen from our intraoperative evaluation, the necrotic lesion was significantly larger than the mucosal lesion, with only a tenuous relationship between their sizes. In other words, the successful elimination of infection and restoration of mucosal integrity neither resolves nor revitalizes the necrotic bone.

Data from a recent longitudinal study by our working group even suggests that necrotic bone defects show a tendency to enlarge rather than diminish³². In that study, 92 patients with stage I MRONJ⁹ were initially treated using a standardized conservative (non-surgical) protocol of antimicrobial mouth rinsing and gel application (with chlorhexidine). Only 8 patients (8.7%) showed complete mucosal healing and resolution of symptoms, whereas the remaining 84 (91.3%) had persistent exposed jawbone at the end of the observation period (15.6 months). Among those 84 patients, 67 (79.8%) showed an upshift in AAOMS stage from I to II or III, which inevitably led to operations, with extensive bone loss in 28 cases³².

Considering that the management of stage III patients is known to be a major challenge and that outcomes are often worse than in earlier stages³⁶, the AAOMS treatment recommendations are even more questionable. In a large retrospective cohort using data from more than 10 years, Ruggiero and Kohn³⁶ observed a significant difference in outcomes with respect to the disease stage, with stage I and II disease showing a higher likelihood of better outcomes than stage III. In addition, they showed that a positive result in stage III was 28 times more likely to be achieved by surgical treatment than by non-surgical treatment³⁶. Those results stand in total contrast to the recommendations published a year before by that same author⁹.

A closer look at our data shows that the necrotic lesion is 2 to 3 times larger than the mucosal lesion. The extent of the necrotic lesion in patients with only probeable bone was also comparable to that in patients with visible bone. Surgically induced resection defects of up to 53 mm in this trial argue in favor of early surgical treatment and against postponing surgical therapy until stage III⁹ has been reached. Given that MRONJ patients are usually already seriously ill and in need of rapid continuation of their antiresorptive or oncological therapy, which is delayed by conservative, non-surgical therapy^37,38, several working groups and international guidelines argue in favor of early surgical treatment.

To summarize our findings, the clinically driven AAOMS staging system fails to reflect the actual extent of MRONJ. As a logical consequence, it is not possible to derive correct treatment recommendations from it¹¹. Knowledge about the extent of necrosis is indispensable to surgical treatment planning for MRONJ. Consequently, some authors recommend the use of different imaging modalities to accurately assess the extent of MRONJ preoperatively¹².

Unfortunately, no consensus has been reached on the efficacy of different radiological imaging modalities in assessing the extent of a necrotic osseous lesion³⁹. The latest meta-analysis to examine the prevalence of radiographic findings on jaws exposed to antiresorptive therapy, including jaws with MRONJ, identified only 29 studies with a total of 1,133 patients. The most frequent radiological findings were mixed lytic-sclerotic areas (73.88%), osteolytic changes (66.18%), osteosclerosis (65.75%), cortical bone erosion (50.83%), and persisting alveolar socket (45.77%)³⁹. Those authors emphasized that the overall level of evidence in the studies identified was very low. They also pointed out that no imaging modality currently allows clear differentiation between necrotic and vital bone³⁹. That is why we assessed the extent of MRONJ in this study using an intraoperative measurement technique.

Certainly, auto-fluorescence-guided resection of necrotic bone has some drawbacks. For instance, bleeding in the operating area makes the fluorescence properties difficult to obtain, which might distort the measurements. It is also difficult to use this technique in a sterile operating theater because no currently available devices allow thermic sterilization²². However, this technique can assess the extent of necrotic bone with great clinical accuracy^21,22.

Nonetheless, further efforts must be made to find radiographic modalities that can clearly differentiate between necrotic and vital bone. Such modalities could enable early diagnosis, significantly affecting the management of the underlying disease and enabling better treatment and the prevention of new potential cases^39,40. By assessing the real extent of the lesion and detecting asymptomatic necrotic areas, high-resolution imaging could be helpful in individualized treatment planning⁴¹. Such imaging is necessary to define a new classification for MRONJ.

The main limitation of this study is the relatively small number of patients involved, which inevitably limits its statistical power to detect significant associations. Furthermore, only patients with stage I MRONJ⁹ were included in the trial. Therefore, these results can only be generalized to other patients to a limited degree. In assessing the extent of mucosal or necrotic lesions or resection defects, the measurement methods allowed only two-dimensional measurements. Because MRONJ is truly a three-dimensional problem, future studies should find a way to make three-dimensional measurements. The heterogeneous intake of antiresorptive drugs, as well anti-angiogenetic or immunomodulatory medications, might also be a limitation because our sample size was too small to allow subgroup analyses that could highlight potential differences caused by the type and administration of medications. Indeed, subgroup analyses in multifactorial regression models might be the aim of future prospective clinical trials. This research has brought to light many questions that need further investigation. Future studies should use a prospective approach to analyze a larger group of patients with all stages of MRONJ.

In this retrospective study, we have shown that preoperative mucosal defects (visible or probeable) in MRONJ patients do not allow exact conclusions to be drawn about the intraoperative extent of bone necrosis, and thus they provide inadequate information about disease severity. In comparing the visible bone and probeable bone groups, the extent of the osseous necrotic lesion in the anteroposterior direction was significantly larger in patients with a visible mucosal defect. In the transversal direction, no significant differences between those groups were found. Therefore, therapy recommendations that are partly based on the size of the mucosal defect must be critically reviewed. Therapy decisions should be made on a patient-specific basis, and they should combine clinical examination and radiological findings, always taking into account the general condition of the patient and consultation with the treating oncologist or osteologist.