Italian position paper (SIPMO-SICMF) on medication-related osteonecrosis of the jaw (MRONJ).

OBJECTIVE: This paper aims to describe the 2023 update position paper on MRONJ developed by the Italian Societies of Oral Pathology and Medicine (SIPMO) and of Maxillofacial Surgery (SICMF). METHODS: This is the second update following the 2013 and 2020 Italian position papers by the Expert panel, which is a representation of the two scientific societies (SIPMO and SICMF). The paper is based on an extensive analysis of the available literature from January 2003 to February 2020, and the subsequent review of literature conducted between March 2020 and December 2022 to include all new relevant published papers to confirm or modify the previous set of recommendations. RESULTS: This position paper highlights the main issues of MRONJ on risk estimates, disease definition, diagnostic pathway, individual risk assessment, and the fundamental role of imaging in the diagnosis, classification, and management of MRONJ. CONCLUSION: The Expert Panel confirmed the MRONJ definition, the diagnostic work-up, the clinical-radiological staging system and the prophylactic drug holiday, as recognized by SIPMO-SICMF; while, it presented novel indications regarding the categories at risk of MRONJ, the prevention strategies, and the treatment strategies associated with the therapeutic drug holiday.

SIMPEDVR: using VR in teaching pediatric emergencies to undergraduate students-a pilot study.

The objective of this work was to provide pilot data on feasibility of using virtual reality (VR) to train undergraduate students in pediatric emergency scenarios. We staged VR sessions for a total of 45 medical and nursing students; in every session, each student managed two pediatric emergency virtual scenarios. At the end of the sessions, students completed a Technology Assessment Questionnaire to evaluate the perceived usefulness and perceived ease-of-use of their VR training experience and rated their perceived level of competence in managing the two clinical scenarios. The median perceived usefulness was 91.7/100 (interquartile range (IQR) 80.6-100), while the median perceived ease-of-use was 77.8/100 (IQR 63.9-88.9). The perceived level of competence increased from 2 (IQR 1-3) to 4 (IQR 3-4) on a 5-point Likert scale, for both scenarios (p < 0.001, Wilcoxon test for paired samples).       Conclusions: The staged VR sessions had a good perceived usefulness and resulted in an increase in the perceived level of competence. The results on the ease-of-use, however, show that an assumption that millennials and younger students can navigate with confidence VR hardware in a healthcare training setting should not be made; further work is required to ease the integration of VR into curricula. What is Known: • Virtual reality (VR) is a rising simulation training methodology in Pediatric Emergency Medicine (PEM), however little experience is reported about its use for undergraduate students What is New: • VR PEM trainiing was found useful by undergraduate students and its use increased their perceived level of competence, although ease-of-use received lower ratings. • Despite the young age, an assumption that millennials and younger students can navigate with confidence VR hardware in a healthcare training setting should not be made.

Safety of boneless reconstruction of the mandible with a CAD/CAM designed titanium device: The replica cohort study.

OBJECTIVE: We evaluated the safety of REPLICA, a CAD/CAM-designed patient-specific titanium mandible, in patients with mandibular defects not suitable for reconstruction with traditional techniques. PATIENTS AND METHODS: We performed a cohort study with a composite primary outcome assigned at the end of a 1-year follow-up. The outcome was assigned in the presence of all the following: 1) absence of intraoral or skin extrusion of REPLICA; 2) decrease or cessation of oral pain; 3) stability or increase in mouth opening; 4) resumption of oral feeding without the need of nasogastric tube; 5) absence of fracture at multidetector computer tomography (MDCT); 6) absence of displacement (MDCT); 7) absence of screw loosening (MDCT). The secondary outcome was the patient-reported QOL at 6 months of follow-up as detected by the EORTC QLQ-C30 and QLQ-H&N35 questionnaires. RESULTS: Between March 2012 and June 2017, 18 consecutive patients, with a median (IQR) age of 67 (65;74) underwent reconstruction of mandibular defects with REPLICA at our Unit. The primary outcome was reached by 14 of the 18 patients. QOL data were available for 15 patients at the 6-month follow-up, showing a good profile of general and disease-specific QOL. CONCLUSION: REPLICA offered a safe solution at 1-year for the treatment of mandibular defects not suitable for reconstruction with traditional techniques, and was associated with subjective well-being and satisfaction. Further studies are needed to assess the full range of indications of REPLICA.

Is vitamin D deficiency a risk factor for osteonecrosis of the jaw in patients with cancer? A matched case-control study.

PURPOSE: A previous case-control histomorphometric study showed higher odds of osteomalacia in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ). Vitamin D deficiency causes osteomalacia and may therefore be involved in the pathogenesis of BRONJ. The present case-control study aimed at testing such hypothesis. MATERIALS AND METHODS: BRONJ+ and BRONJ- patients treated with bisphosphonates were matched by sex (same) and age (within 5 years). Serum 25-hydroxy-vitamin D (25-OH-D), parathyroid hormone, bone alkaline phosphatase, total procollagen type 1 amino-terminal propeptide, carboxy-terminal collagen crosslinks, Dickkopf WNT signaling pathway inhibitor 1 and sclerostin were measured. RESULTS: The main outcome was vitamin D deficiency defined as 25-OH-D < 50 nmol/l. A total of 51 BRONJ+ and 73 BRONJ- patients were studied. The frequency (95% CI) of vitamin D deficiency was 59% (45%-72%) in BRONJ+ and 62% (48%-75%) in BRONJ- patients. This amounts to a difference of -3% (-22%-16%, p = 0.77) for BRONJ+ patients. Serum 25-hydroxy-vitamin D and parathyroid hormone were similar in BRONJ+ and BRONJ- patients. Among the bone metabolism markers, only sclerostin differed between the two groups, being higher in BRONJ+ patients. CONCLUSION: The present matched case-control study suggests that vitamin D deficiency is not a risk factor for BRONJ.

Displaced Dental Materials in the Maxillary Sinus: An Original Series. Analysis and Definition of a Surgical Decision-Making Process.

OBJECTIVES: Displacement of dental materials into the maxillary sinus occurs in daily dental practice; dental implants have become a new common foreign body (FB), as implantation has become routine. The main goal of the present study was to analyze an original series of patients consecutively treated for maxillary sinus FBs. A secondary goal was to propose a decision-making flowchart on the basis of the authors' experience and a critical analysis of literature to select the most appropriate surgical approach. METHODS: Eleven consecutive patients evaluated for maxillary sinus FBs consisting of dental material were considered. RESULTS: For removal of the FBs, a nasal endoscopic approach was preferred in 5 cases, a nasal combined approach in 2 cases, an oronasal combined approach in 2 cases, and a lateral window approach in 2 cases. In 2 of 11 cases, complications were reported. A decision-making flowchart to select the best surgical approach is reported. CONCLUSIONS: The correct choice and application of FB removal techniques allow minimization of unfavorable outcomes and creation of an appropriate environment for new dental treatment. Prospective, large series-based studies will be necessary to confirm the safety and clinical efficacy of the proposed decision-making flowchart.

A novel nasal endoscopic approach for removing displaced dental implants from the maxillary sinus.

INTRODUCTION: Over the last 30years, dental implants have become widespread all over the world. Though the implantation procedure is standardized and safe, the displacement of implants into the maxillary sinus can occur. The aim of the study has been to describe a novel combined nasal endoscopic approach through the middle and lower meatus for managing dental implants displaced into the maxillary sinus. METHODS/RESULTS: A 40-year-old man was examined for a titanium osteo-integrated implant displaced within the alveolar recess of the left maxillary sinus. The indications and procedure are reported in detail. The pros and cons of this approach are compared with those of other standard surgical methods. CONCLUSIONS: The main strength of the technique described here lies in the ample view and ideal control of the displaced dental implant achieved by fashioning a second window at the lower meatus that enables enlargement of the natural ostium to be minimized, thereby ensuring an anatomically and functionally better result.

Osteonecrosis of the Jaw in Patients With Metastatic Renal Cell Cancer Treated With Bisphosphonates and Targeted Agents: Results of an Italian Multicenter Study and Review of the Literature.

Osteonecrosis of the jaw (ONJ) associated with the use of bisphosphonates has been rarely reported in metastatic renal cell cancer (RCC) patients. Since the introduction of combined therapies consisting of nitrogen-containing bisphosphonates (NBPs) and targeted agents, an increasing number of RCC patients were reported to develop ONJ, suggesting that therapeutic angiogenesis suppression might increase the risk of ONJ in NBPs users. We performed a multicenter retrospective study and reviewed literature data to assess the occurrence and to investigate the nature of ONJ in RCC patients taking NBPs and targeted agents. Nine Italian Centers contributed to the data collection. Patients with exposed and nonexposed ONJ were eligible for the study if they had been taking NBPs and were receiving targeted agents at the time of ONJ diagnosis. Forty-four RCC patients were studied. Patients were mostly male (82%), with a median age of 63 years (range, 45-85 years). Zoledronic acid (93%) and sunitinib (80%) were the most frequently used NBP and antiangiogenic agent, respectively. Other agents included Pamidronate, ibandronate, sorafenib, bevacizumab, mammalian target of rapamycin inhibitors. Forty-nine sites of ONJ were encountered, with the mandible being the preferred site of ONJ (52%); both jaws were affected in 5 cases (12%). The most common precipitating event was dental/periodontal infection (34%), followed by tooth extraction (30%). Oral triggers of ONJ were missing in 10 cases (23%). This unexpectedly high number of ONJ cases, in comparison with literature data, suggests that frequency of ONJ in RCC patients might be largely underestimated and suggests a potential role for targeted agents in the incremental risk of ONJ.

Up to a quarter of patients with osteonecrosis of the jaw associated with antiresorptive agents remain undiagnosed.

Recent data suggest that the traditional definition of bisphosphonate-associated osteonecrosis of the jaw (ONJ) may exclude patients who present with the non-exposed variant of the condition. To test the hypothesis that a proportion of patients with ONJ remain undiagnosed because their symptoms do not conform to the traditional case definition, we did a secondary analysis of data from MISSION (Multicentre study on phenotype, definition and classification of osteonecrosis of the jaws associated with bisphosphonates), a cross-sectional study of a large population of patients with bisphosphonate-associated ONJ who were recruited in 13 European centres. Patients with exposed and non-exposed ONJ were included. The main aim was to quantify the proportion of those who, according to the traditional case definition, would not be diagnosed with ONJ because they had no exposed necrotic bone. Data analysis included descriptive statistics, median regression, and Fisher's exact test. A total of 886 consecutive patients were recruited and 799 were studied after data cleaning (removal or correction of inaccurate data). Of these, 607 (76%) were diagnosed according to the traditional definition. Diagnosis in the remaining 192 (24%) could not be adjudicated, as they had several abnormal features relating to the jaws but no visible necrotic bone. The groups were similar for most of the phenotypic variables tested. To our knowledge this is the first study in a large population that shows that use of the traditional definition may result in one quarter of patients remaining undiagnosed. Those not considered to have ONJ had the non-exposed variant. These findings show the importance of adding this description to the traditional case definition.

Staging of osteonecrosis of the jaw requires computed tomography for accurate definition of the extent of bony disease.

Management of osteonecrosis of the jaw associated with antiresorptive agents is challenging, and outcomes are unpredictable. The severity of disease is the main guide to management, and can help to predict prognosis. Most available staging systems for osteonecrosis, including the widely-used American Association of Oral and Maxillofacial Surgeons (AAOMS) system, classify severity on the basis of clinical and radiographic findings. However, clinical inspection and radiography are limited in their ability to identify the extent of necrotic bone disease compared with computed tomography (CT). We have organised a large multicentre retrospective study (known as MISSION) to investigate the agreement between the AAOMS staging system and the extent of osteonecrosis of the jaw (focal compared with diffuse involvement of bone) as detected on CT. We studied 799 patients with detailed clinical phenotyping who had CT images taken. Features of diffuse bone disease were identified on CT within all AAOMS stages (20%, 8%, 48%, and 24% of patients in stages 0, 1, 2, and 3, respectively). Of the patients classified as stage 0, 110/192 (57%) had diffuse disease on CT, and about 1 in 3 with CT evidence of diffuse bone disease was misclassified by the AAOMS system as having stages 0 and 1 osteonecrosis. In addition, more than a third of patients with AAOMS stage 2 (142/405, 35%) had focal bone disease on CT. We conclude that the AAOMS staging system does not correctly identify the extent of bony disease in patients with osteonecrosis of the jaw.

Bevacizumab-related osteonecrosis of the mandible is a self-limiting disease process.

A female patient with non-small-cell lung cancer presented with a huge area of exposed bone in the mandible following spontaneous teeth loss. She was receiving multimodal chemotherapy containing bevacizumab. No previous treatment with bisphosphonates or comorbid conditions was reported. Pain medications and infection control were offered to the patient who was closely followed up. Initial imaging and histology of bone and surrounding mucosa (8 weeks after bevacizumab cessation) confirmed the clinical suspicion of avascular osteonecrosis of the mandible. Subsequent imaging and histology of bone and gingiva (12 weeks after bevacizumab cessation) revealed the initial sequestration of the mandible with a marked expansion of the mucosal vascular network. Spontaneous bone sequestration eventually occurred few months later, followed by stable and painless mucosal coverage of the mandibular bone. The patient remained disease-free up to 3 years of follow-up.

Osteomalacia: the missing link in the pathogenesis of bisphosphonate-related osteonecrosis of the jaws?

BACKGROUND: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-documented adverse event from treatment with nitrogen-containing bisphosphonates (NBPs). During a preliminary histomorphometric study aimed at assessing the rate of bone remodeling in the jaws of patients with surgically resected BRONJ, we found a defect of bone mineralization (unpublished data). We hypothesized that osteomalacia could be a risk factor for BRONJ in patients taking NBPs. Therefore, we looked for static and dynamic histomorphometric evidence of osteomalacia in biopsies from subjects with and without BRONJ. METHODS: This case-control study used histomorphometric analysis of bone specimens of patients using NBPs (22 patients with BRONJ and 21 patients without BRONJ) who required oral surgical interventions for the treatment/prevention of osteonecrosis. Patients were given tetracycline hydrochloride according to a standardized protocol before taking bone biopsies from their jaws. Biopsies with evidence of osteomyelitis or necrosis at histology were excluded from the study. Osteomalacia was defined as a mineralization lag time >100 days, a corrected mean osteoid thickness >12.5 mm, and an osteoid volume >10%. RESULTS: In all, 77% of patients with BRONJ were osteomalacic compared with 5% of patients without BRONJ, according to histomorphometry. Because osteomalacia was found almost exclusively in NBP users with BRONJ, this is likely to be a generalized process in which the use of NBPs further deteriorates mechanisms of bone repair. CONCLUSIONS: Osteomalacia represents a new and previously unreported risk factor for disease development. This finding may contribute to a better understanding of the pathogenesis of this disease and help with the development of strategies to increase the safety of NBP administration.

Long-term outcomes of surgical resection of the jaws in cancer patients with bisphosphonate-related osteonecrosis.

Surgical treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is controversial. Current recommendations contraindicate aggressive surgery because its results are unpredictable and may trigger disease progression. In this prospective study, we assessed the effectiveness of surgical resection of the jaws in cancer patients with BRONJ. Between June 2004 and July 2009, 30 cancer patients with refractory BRONJ underwent surgical resection of the jaws at our Units. They were followed-up weekly for the first month, at 3-month intervals up to 1 year, and at 6-month intervals up to 2 years. Panoramic radiographs and CT-scan were obtained at 3, 6, 12, 18 and 24 months. Primary outcomes were the 24-month recurrence rate of BRONJ and the 24-month mortality rate. Secondary outcomes were post-operative complications, duration of hospital stay after surgery, time to return to oral diet, and degree of oral pain. The 30 patients had a median age of 66 years and were mostly females (80%). Twenty-eight underwent a single resection and two had both jaws resected, for a total of 32 resected jaws. The cumulative recurrence rate of BRONJ in resected jaws 3.1% and 9.4% at 3 and 6 months, respectively. All the jaws with recurrent BRONJ had osteomyelitis at the margins of bone resection. The cumulative incidence of death was 3%, 12% and 16% at 12, 18 and 24 months. Surgical resection of BRONJ was highly effective, with few post-operative complications and were not associated with long-term mortality.

Oral bisphosphonate-associated osteonecrosis of the jaw after implant surgery: a case report and literature review.

This report documents a case of bisphosphonate-related osteonecrosis of the jaw (BRONJ) after dental implant placement in an osteoporotic patient treated with alendronate for 6 years. A 63-year-old patient underwent rehabilitation of the posterior mandible with 2 dental implants in 2006 while taking alendronate to treat osteoporosis. The surgical procedure was uneventful. Both implants integrated well, and in November 2006 the patient wore a fixed partial prosthesis. Alendronate was never discontinued. In June 2008 a painful cheek swelling of the left mandible developed, associated with gingival bleeding. Since then, the patient underwent several courses of antibiotics, without relief of symptoms. In June 2009 the patient was referred to our department. An area of infected and exposed necrotic bone in the left mandible enclosed 1 dental implant. A panoramic radiograph and computed tomography scan showed an increased bone marrow density with peri-implant bone sequestration. The technetium Tc 99m scintigraphy-labeled granulocytes were positive for active bone infection. Bone exposure persisted for 8 weeks, and diagnosis of oral nitrogen-containing bisphosphonate (N-BP)-related osteonecrosis was made. On the basis of a review of the literature, this is the 10th case of BRONJ after implant placement in patients taking oral N-BPs. Despite the low risk of BRONJ occurrence after implant surgery in oral N-BP users, the fate of dental implants in these patients remains uncertain. Therefore patients at risk must be given a full explanation of the potential risks of implant failure and BRONJ development. Because the potential role of infection is still debated, great attention should be paid to the long-term oral hygiene of implant-prosthetic restorations.

Occurrence of bisphosphonate-related osteonecrosis of the jaw after surgical tooth extraction.

PURPOSE: To evaluate the occurrence of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in patients exposed to nitrogen-containing bisphosphonates (NBPs) requiring surgical tooth extraction. PATIENTS AND METHODS: Sixty high-risk patients exposed to NBPs underwent surgical tooth extraction with bone biopsy and were treated with a 7-day cycle of oral antibiotics and discontinuation of NBPs for 1 month. BRONJ was defined as the occurrence of any BRONJ stage (0-3) at 3, 6, or 12 months of follow-up. Inferential analysis was performed on a per-bone (maxilla and/or mandible) basis (n = 72). The time to BRONJ was calculated, and age, gender, cancer diagnosis, and baseline osteomyelitis were evaluated as potential predictors. Exact logistic regression was used to model the time-to-outcome relationship, and hazard rates were calculated from logistic probabilities. RESULTS: BRONJ was detected at 3 months' follow-up in 4 bones and at 6 months in 1 further bone. In the whole cohort of bones, the hazard rate of BRONJ was 5.6% at 3 months and 1.5% at 6 months. Baseline osteomyelitis was a strong risk factor for BRONJ development (odds ratio, 156.96; exact 95% confidence interval, 18.99 to infinity; exact P < .0001). CONCLUSION: In this 12-month follow-up study, BRONJ was a rare outcome in high-risk NBP users who underwent surgical tooth extraction. Moreover, baseline osteomyelitis was a very strong risk factor for BRONJ development.

Worsening of osteonecrosis of the jaw during treatment with sunitinib in a patient with metastatic renal cell carcinoma.

We report on the potential association of suspected bisphosphonate-associated osteonecrosis of the jaw (BRONJ) recurrence with the use of the novel antiangiogenic drug sunitinib. A 59 year-old patient affected by metastatic renal cell carcinoma (RCC) and established BRONJ experienced consecutive episodes of painful jaw infection with cutaneous fistula and bone sequestration which occurred during active treatment with sunitinib, improved after discontinuation and antibiotic therapy, then rapidly worsened with resumption of sunitinib. We hypothesize that the potent antiangiogenic activity of sunitinib may amplify the inhibition of bone remodeling exerted by aminobisphosphonates entrapped within the osteonecrotic mineral matrix, antagonize mucosal healing and expose to infections during treatment. This supports the emerging role of soft-tissue damage in the pathogenesis of osteonecrosis of the jaw.

Bisphosphonate-associated jawbone osteonecrosis: a correlation between imaging techniques and histopathology.

OBJECTIVES: Recently, jawbone osteonecrosis has been reported as a potential adverse effect of bisphosphonates administration. This paper considers and highlights histopathologic and radiologic features of this condition. STUDY DESIGN: Eleven patients, owing to unresponsiveness to conservative treatment and uncontrollable pain, underwent surgical resection of diseased jawbone after extensive hyperbaric oxygen therapy. A thorough clinical, laboratory, and imaging study was performed. Surgical specimens underwent histopathologic and immunohistochemical evaluation. RESULTS: Computerized tomography (CT) scans showed increased bone density, periosteal reaction, and bone sequestration in advanced stages. With magnetic resonance imaging (MRI), exposed areas showed a low signal in T1- and T2-weighted and inversion recovery images, which suggests low water content and is histopathologically correlated with paucity in cells and vessels (osteonecrotic pattern). Unexposed diseased bone was characterized by T1 hypointensity and T2 and IR hyperintensity, which suggests high water content and inflammation, associated with hypercellularity, osteogenesis, and hypervascularity (osteomyelitic pattern). CONCLUSIONS: Diseased bone extends beyond the limits of the bone exposed in the oral cavity. Histopathologic examination correlated well with CT and MRI, which are the choice for the evaluation of bisphosphonate-associated jawbone osteonecrosis.