Conservative non‐surgical management in medication related osteonecrosis of the jaw: A retrospective study

Abstract Objectives To date, the best treatment for Medication Related Osteonecrosis of the jaw (MRONJ) is controversial. Recent studies suggest different therapies, considering the stage of MRONJ; however, sometimes patients, although with remarkable extension of disease, cannot undergo surgery. The purpose of present preliminary study was to evaluate the efficacy of conservative non‐surgical treatment of MRONJ lesions in a cohort of patients ineligible for surgery or refusing any surgical treatment for stage II and III of MRONJ. Materials and methods Patients with MRONJ (staging II or III) ineligible for surgical treatment were selected for a retrospective study. A conservative non‐surgical therapy (antibiotics and antiseptic) was administered for 1 year. Five scheduled checks were performed to assess changes in signs and symptoms during the observational period. Results Our observation was carried out on 12 patients. Improvement of signs and symptoms of disease were observed in population. Conclusion This study suggests that non‐surgical treatment may be a valid therapeutic option in patients ineligible for surgery. The sample size is small, further studies should be carried out to satisfy the aim of a conservative non‐surgical treatment protocol establishment.


| INTRODUCTION
Medication-related osteonecrosis of the jaw (MRONJ) is an adverse drug reaction, characterized by progressive destruction of bone in patients who underwent to bone-targeting agents associated with the risk of MRONJ, in the absence of a previous radiation treatment (Campisi et al., 2014;Fusco, Bedogni, Addeo, & Campisi, 2017).
To date, two main categories of drugs associated MRONJs are recognized, acting differently to bone metabolism: antiresorptive drugs (Bisphosphonates and Denosumab) and Antiangiogenic (eg Vascular Endothelial Growth Factor inhibitors such as Bevacizumab, Tyrosine Kinase inhibitors such as Sunitinib and mammalian Target of Rapamycin inhibitors such as Everolimus) (Di Fede, Panzarella, Mauceri, et al., 2018).
Etiology of MRONJ is multifactorial and pathogenesis remains unknown (Ruggiero, Saxena, Tetradis, Aghaloo, & Ioannidou, 2018); the patient's medical history, clinical examination, and radiological data are the only diagnostic and staging tools to approach and to face this condition (Di Fede et al., 2018).
The surgical treatments can be divided into conservative approaches (e.g., bone debridement, sequestrectomy) or more aggressive therapy so surgical resections and jaw bone reconstruction, where necessary (Ruggiero et al., 2018).
The best treatment for MRONJ is controversial, and there is not yet an agreement about the recommended method; however, the crucial point to face is the disease's progression by using infection control means (Vescovi & Nammour, 2010 (Bedogni, Fusco, Agrillo, & Campisi, 2012;Campisi et al., 2014) described in Table 2) could not be considered the best treatment, not only for operative risk but also because often they refused any surgical treatment for primary pathology.
Therefore, the purpose of present preliminary retrospective study was to evaluate the efficacy of conservative non-surgical treatment of MRONJ lesions in a cohort of patients with high operative risk (ASA 3) or for refused any surgical treatment and stage II and III of MRONJ (following SIPMO/SICMF staging [Bedogni et al., 2012;Campisi et al., 2014]).

| MATERIALS AND METHODS
A retrospective analysis was carried out on patients referred to the Section of Dentistry and Maxillofacial Surgery of University of Verona (Italy), during the period 2012 to 2015; patients were selected for the present study if they had (a) II and III stage MRONJ (following SIPMO/SICMF staging [Bedogni et al., 2012;Campisi et al., 2014]), (b) they refused surgical treatments or they were not eligible for them; and (c) high operative risk (ASA 2-3 [Doyle et al., 2020] ASA 5 A moribund patient who is not expected to survive without the operation. The patient is not expected to survive beyond the next 24 hours without surgery. ASA 6 A brain-dead patient whose organs are being removed with the intention of transplanting them into another patient. In all cases, MRONJ diagnoses and staging were made combining medical history, clinical and radiological examination performed by local multidisciplinary teams of specialists in oral medicine, oral and maxillofacial surgery and radiology (following SIPMO/SICMF staging [Bedogni et al., 2012;Campisi et al., 2014]). All patients signed informed written consent about risks and benefits of treatment proposed.
-t 0 : first visit included general health assessment, accurate general anamnesis about previous pathologies, allergies, previous surgeries, radiotherapy, and current and past drug treatments (exclusion criteria). Clinical symptoms were investigated and clinical evidences and risk factors of MRONJ (e.g., diabetes, concurrent use of steroid) were deeply assessed as suggested by present day guidelines (Campisi et al., 2014;Iorio-Siciliano et al., 2018).
Descriptive analysis of radiological data collected in t 0 was carried out. Clinical and radiological signs and symptoms were evaluated and MRONJ was staged following SIPMO/SICMF recommendations (Bedogni et al., 2012;Campisi et al., 2014) (Table 2).
When gastrointestinal disease related to the prolonged antibiotic therapy was present, ciprofloxacin (500 mg) therapy two times per day for 5 days was prescribed instead of amoxicillin+ clavulanic acid (Moretti, Pelliccioni, Montebugnoli, & Marchetti, 2011).
-t 1 , t 2 , t 3 , t 4 : Visits at each time-point provided complete intra and extra oral examination performed by the same surgeon. Clinical signs and symptoms evaluated in t 0 were scored at each time-point.

| RESULTS
For our study, we selected 12 patients ( Some clinical and radiological images are showed in Figures 1 and 2. MRONJ of all 12 patients was staged II and III, according to the SICMF-SIPMO clinical and radiological staging system (Bedogni et al., 2012).
No dropout from prescriptions were reported, further no patients needed to change to ciprofloxacin. All patients were treated with only antibiotic with amoxicillin + clavulanic acid (875 mg + 125 mg) and metronidazole (500 mg) three times per day and antiseptic therapies.
During the observation period, bone exposure slightly reduced and it was found to be present in 33.3% of the sample at t 4 . Differences in terms of bone exposure at different time-points were found to be not statistically significant (p = .544); furthermore one patient expelled the bone sequestrum spontaneously.
Rubor and edema found to be improved: at t 2 16.6% reported them, whereas in t 4 signs were completely disappeared (p = .00001).
Halitosis was present in 41.6% at t 1 and in 8.3% at t 2 , no longer detectable at t 3 and t 4 . (p = .00001).
Mucous fistulas progressively recovered during the observation period, found in 8.3% of the patients at t 4 . (p = .001); also cutaneous fistulas were lowered to 2 cases (p = .6567). Pain showed a great enhancement: it was never reported at t 4 .

All our patients presented in t 4 Stage 0 or Stage I following
Vescovi's classification (Vescovi & Nammour, 2010).
A summary of these results were reported in Table 4.

| DISCUSSIONS
To date, the best management of MRONJ is controversial; literature In this retrospective study, we reported patients with II and III stage of MRONJ and two of these were classified ASA 2. In itself, ASA 2 does not represent a contraindication for surgical intervention, indeed the real motivation for excluding these patients was their unwillingness of undergoing a further surgery. They were affected by cancers (breast and prostate) and stage II and III of MRONJ require mild invasive surgical procedures, these issues were responsible for inclusion of ASA 2 patients conservative treatment protocol for MRONJ.
Conservative non-surgical treatment (maintaining good oral hygiene, mouthwash, intraoral gels, analgesics, and antibiotics for dis- Moreover, in this study, patients treated were suffering from other diseases (especially cancers in advanced stadium) and they were of advanced age: therefore, conservative therapy seemed to be the most suitable treatment in order to maintain a stable condition, avoiding worsening of signs and symptoms, and ensuring an acceptable quality of life.
Some authors demonstrated that non-surgical conservative therapy may not necessarily lead to complete resolution of MRONJ, but it may symptomatically provide long-term relief.
We are well aware about the heterogeneity of sample and we can explain this because the aim of this preliminary study was to assess the viability of this protocol in maintaining the signs and symptoms of MRONJ under control without worsening of them. In good conscience, this protocol represents for us the last one chance to ensure a better quality of life to these patients, whenever it is possible, we would look to recommend the surgical treatment.
Nevertheless, literature suggests that chlorhexidine mouthwashes and an appropriate oral hygiene may reduce mouth bacterial count, moreover reducing halitosis (Brignardello-Petersen, 2017;Erovic Ademovski, Lingström, & Renvert, 2016). These results highlight the importance of the use of chlorohexidine mouthwashes and professional dental hygiene in a prevention and conservative non-surgical treatment protocol for MRONJ.
In addition, it has been documented in the literature that broadspectrum antibiotics as amoxicillin/clavulanic acid and metronidazole are the first-line drugs (Campisi et al., 2014).
MRONJ-associated sinusitis usually requires a multidisciplinary treatment (Procacci et al., 2018) antrostomy (Datta, Viswanatha, & Shree, 2016). Although our data of rhinosinusitis remission are not statistically significant because of poor sample, we might assume that also this symptom may benefit by this conservative treatment protocol. Opportunity of avoiding surgical procedures in ineligible patients is a great chance in their management; nevertheless, a larger sample is surely advisable.
Therefore, using this protocol, satisfying results were observed in subjects affected by advanced MRONJ (stage II and III). All our patients presented in t 4 Stage 0 or Stage I following Vescovi's classification (Vescovi & Nammour, 2010) and pain was never reported at t 4 .
These results suggest that many symptoms and signs, such as mucosal inflammation and pain, could improve or remit with the therapy administrated. This is encouraging for patients that cannot undergo surgery, and they should be stressed during pre-protocol talks and follow-up to improve compliance. Furthermore, regarding such parameters, our results are highly statistically significant: this is a great opportunity to improve the living conditions of patients affected by MRONJ but non-suitable for surgery. However, the results of this dosing regimen in the reduction of signs and symptoms of MRONJ are encouraging, especially concerning the improvement of the quality of life in palliative care.
Then, this study shows that non-surgical treatment may be a valid option for MRONJ in patients ineligible for surgery, but sample size is small; further studies on larger samples are required to define a protocol for conservative non-surgical treatment in MRONJ. Clinical protocol was carried out, in accordance with up-to-date literature, with the understanding and written consent of each subject and according to the above mentioned principles.

AKNOWLEDGEMENTS
For this study was not needed to collect an approval of IRB or ethical committee because the protocol is routinely used in our clinical practice, moreover we analyzed data and we did not perform a clnical trial neither an observational study.