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.

MRONJ in breast cancer patients under bone modifying agents for cancer treatment-induced bone loss (CTIBL): a multi-hospital-based case series.

BACKGROUND: Cancer treatment-induced bone loss (CTIBL) is the most common adverse event experienced by patients affected by breast cancer (BC) patients, without bone metastases. Bone modifying agents (BMAs) therapy is prescribed for the prevention of CTIBL, but it exposes patients to the risk of MRONJ. METHODS: This multicentre hospital-based retrospective study included consecutive non-metastatic BC patients affected by MRONJ related to exposure to low-dose BMAs for CTIBL prevention. Patients' data were retrospectively collected from the clinical charts of seven recruiting Italian centres. RESULTS: MRONJ lesions were found in fifteen females (mean age 67.5 years), mainly in the mandible (73.3%). The mean duration of BMAs therapy at MRONJ presentation was 34.9 months. The more frequent BMAs was denosumab (53.3%). Ten patients (66.7%) showed the following local risk factors associated to MRONJ development: periodontal disease (PD) in three cases (20%) and the remaining six (40%) have undergone PD-related tooth extractions. One patient presented an implant presence-triggered MRONJ (6.7%). In five patients (33.3%) no local risk factors were observed. CONCLUSIONS: This is the first case series that investigated BC patients under BMAs for CTIBL prevention suffering from MRONJ. These patients seem to have similar probabilities of developing MRONJ as osteo-metabolic ones. Breast cancer patients under BMAs for CTIBL prevention need a regular prevention program for MRONJ, since they may develop bone metastases and be treated with higher doses of BMAs, potentially leading to a high-risk of MRONJ.

Chronic oroantral fistula: combined endoscopic and intraoral approach under local anesthesia.

OBJECTIVE: To evaluate the outcome of combined surgical treatment of oroantral communications associated with chronic maxillary sinusitis. PATIENTS AND METHODS: 8 consecutive patients affected by complicated oroantral fistula were included in the study. The protocol consisted of: clinical, endoscopic and radiological preoperative evaluation (panoramic tomogram and computed tomography); systemic antibiotic and steroid therapy 2 weeks before surgery; one-stage surgical procedure under local anaesthesia consisting in uncinectomy with enlargement of the osteomeatal complex through endoscopic nasal approach associated with the closure of the oroantral communication by means of a mucoperiosteal flap; postoperative antibiotic and cortisone-based therapy. Follow-up consisted of weekly clinical evaluation during the first month, and nasal endoscopy at 3, 8 and 24 weeks after surgery. RESULTS: After surgical treatment, all patients were symptom-free and had no endoscopic and radiological evidences of maxillary sinusitis at the 6-month follow-up. No recurrent oroantral fistulas were found. CONCLUSIONS: The current prospective study showed that a one-stage, combined endoscopic and intraoral approach under local anaesthesia represents a feasible and minimally invasive procedure for the long-term effective treatment of chronic complicated oroantral communications. Moreover, it represents an easily applicable approach also in outpatient clinics with minor patient discomfort.

Microsurgical reconstruction of the mandible in a patient with evans syndrome: a case report and review of the literature.

In this report, we describe the first successful case of microvascular free tissue transfer in a patient with Evans Syndrome (ES), a rare form of idiopathic thrombocytopenic purpura (ITP) and associated autoimmune hemolytic anemia (AIHA). Microvascular surgery in the setting of ES is likely to have higher complication rates because of the increased risk of postoperative bleeding and free flap thrombosis. The case presented here opens up to the feasibility of microvascular reconstruction of patients with coagulation disorders like ES. Every effort should be made to control for hemolytic, thrombocytopenic, and thrombophilic states associated with ES. In the absence of evidence-based treatment guidelines for ES, personalized treatment protocols with high-dose corticosteroids, immunoglobulin, and postoperative anticoagulation regimen are highly recommended.

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.

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.

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.

Medication-Related Osteonecrosis of Jaws (MRONJ) Prevention and Diagnosis: Italian Consensus Update 2020.

The Medication-Related Osteonecrosis of Jaws (MRONJ) diagnosis process and its prevention play a role of great and rising importance, not only on the Quality of Life (QoL) of patients, but also on the decision-making process by the majority of dentists and oral surgeons involved in MRONJ prevention (primary and secondary). The present paper reports the update of the conclusions from the Consensus Conference-held at the Symposium of the Italian Society of Oral Pathology and Medicine (SIPMO) (20 October 2018, Ancona, Italy)-after the newest recommendations (2020) on MRONJ were published by two scientific societies (Italian Societies of Maxillofacial Surgery and Oral Pathology and Medicine, SICMF and SIPMO), written on the inputs of the experts of the Italian Allied Committee on ONJ (IAC-ONJ). The conference focused on the topic of MRONJ, and in particular on the common practices at risk of inappropriateness in MRONJ diagnosis and therapy, as well as on MRONJ prevention and the dental management of patients at risk of MRONJ. It is a matter of cancer and osteometabolic patients that are at risk since being exposed to several drugs with antiresorptive (i.e., bisphosphonates and denosumab) or, more recently, antiangiogenic activities. At the same time, the Conference traced for dentists and oral surgeons some easy applicable indications and procedures to reduce MRONJ onset risk and to diagnose it early. Continuous updating on these issues, so important for the patient community, is recommended.

Soccer-related facial fractures: postoperative management with facial protective shields.

Facial fractures are one of the most common orofacial injury sustained during participation in sporting events.The frequency of maxillofacial lesions varies according to the popularity that each sport has in a particular country. Soccer is the most popular sport in Italy, and it is responsible for a large number of facial traumas.Traumas and fractures in soccer mainly involve the zygomatic and nasal regions and are especially caused by direct contact that takes place mainly when the ball is played with the forehead. In particular, elbow-head and head-head impacts are the most frequent dangerous contacts.Soccer is not a violent sport, and the use of protective helmets is not allowed because it could be dangerous especially when players play the ball with the head. The use of protective facial shields are exclusively permitted to preserve players who underwent surgery for facial fractures.The use of a facial protection mask after a facial fracture treatment has already been reported. This article describes a clinical experience of management of 4 soccer-related facial fractures by means of fabrication of individual facial protective shields.

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.

Bisphosphonate-associated osteonecrosis can hide jaw metastases.

BACKGROUND: Osteonecrosis of the jaw is a well known potential complication of bisphosphonate treatment but its pathogenesis is poorly understood. The current management of patients with bisphosphonate-associated osteonecrosis (BON) is based on "expert recommendations" and there is a recognized need of better evidence. We report two cases where BON hid jaw metastases and use them to discuss some limitations of the current recommendations. PATIENTS: Two patients undergoing long-term I.V. amino-bisphosphonate treatment for metastatic cancer presented with areas of intraorally exposed jawbone. Bisphosphonate-associated osteonecrosis was diagnosed on the basis of medical history, clinical and radiological features. They underwent surgical resection of the affected jaw due to unrelenting pain and lack of response to conservative treatments. RESULTS: Histological examination of the surgical specimen revealed cancer cells at the margins of the site of osteonecrosis. Our patients did not undergo bone biopsy according to current recommendations, due to lack of clinical and radiological signs suggestive of jaw metastases. CONCLUSIONS: Our findings show that: i) patients with BON may also have jaw metastases; ii) there may not be clinical or imaging hints to this fact and; iii) that a biopsy based on careful selection of the site (with inclusion of necrotic margins) may be needed to reach the correct diagnosis. Further studies should be performed on this topic because of its very important prognostic implications.

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.

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.