Sunitinib is commonly used in the treatment of patients with renal cell carcinoma and is associated with serious side-effects. We present the first report of a recurrent submandibular fistula in a patient treated with sunitinib. A 68-year-old man was referred to our clinic for a cutaneous fistula situated on the right side of his lower jaw. The patient had been diagnosed with bone metastases from a renal carcinoma 2 years ago and had received a single 4 mg dose of zoledronic acid and subsequent treatment with sunitinib 37.5 mg once daily for the past 4 weeks. The patient was treated surgically by a perilesional incision and primary closure with sutures, advised on meticulous oral hygiene and was kept on an antimicrobial agent in the form of clindamycin. After reinitiating his oncological treatment with sunitinib the cutaneous fistula re-appeared and bone abnormalities were also detected on his X-ray. After 18 months a contralateral cutaneous fistula was observed along with a spontaneous avulsion of the patient\'s left molar. Repeat surgical treatment and sequestrectomy was performed with the subsequent histopathological examination revealing a suspicion of osteonecrosis of the jaw and an associated Actinomyces infection.

OBJECTIVE: Medication-related osteonecrosis of the jaw (MRONJ) is characterized by necrosis of the jawbone with intraoral bacterial infection and has a significant negative impact on oral health-related quality of life. Risk factors for the onset are unknown, and definitive therapeutic approaches have not yet been defined. A case-control study at a single institution in Mishima City was conducted. The purpose of this study was to examine in detail the factors that contribute to the development of MRONJ.
METHODS: Medical records of MRONJ patients who visited Mishima Dental Center, Nihon University School of Dentistry, during the period 2015-2021 were extracted. Counter-matched sampling design was used to select participants matched for sex, age, and smoking for this nested case-control study. The incidence factors were statistically examined by logistic regression analysis.
RESULTS: Twelve MRONJ patients were used as cases and 32 controls were matched. After adjustment for potential confounders, injectable bisphosphonates (aOR = 24.5; 95% CI = 1.05, 575.0; P < 0.05) were significantly associated with the development of MRONJ.
CONCLUSIONS: High-dose bisphosphonates may be a risk factor for the development of MRONJ. Patients who use these products require careful prophylactic dental treatment against inflammatory diseases, and dentists and physicians should maintain close communication.

BACKGROUND: Cases of osteonecrosis of the jaw have been reported by dental surgeons to the pharmacovigilance center in Rennes, France, occurring among patients treated with palbociclib, a cyclin-dependent kinase 4/6 inhibitor. Although this event was not expected with the drug, a safety signal was raised. Describing a local case series, the aim of our study was to identify specific patterns that might suggest a triggering role for these drugs, and to discuss pathophysiological hypotheses.
METHODS: A retrospective case series of patients exposed to cyclin-dependent kinase 4/6 inhibitors between 2016 and 2020 with a diagnosis of osteonecrosis of the jaw at the Rennes Dental Care Center was analyzed. The descriptive analysis was conducted on patient demographics, breast cancer characteristics, osteonecrosis of the jaw, biological data, and exposure to cyclin-dependent kinase 4/6 inhibitors.
RESULTS: We identified eight cases, most of them at stages 0-1 (62.5%). Four patients were still exposed to palbociclib at the time of diagnosis and four had discontinued the treatment before the diagnosis. Chronological imputability could not be excluded given the drug\'s half-life and the variable intervals of dental monitoring from one patient to another. All patients had at least one dental osteonecrosis risk factor (including dental extraction, dentures, and denosumab exposure at the time of diagnosis). Neutropenia and mucositis were not systematically reported at the time of diagnosis. The anatomopathological characteristics were nonspecific.
CONCLUSIONS: We did not identify a specific pattern that could suggest a triggering role of palbociclib in the development of ONJ.

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.
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.
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.
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.

UNASSIGNED: Prior studies of the pharmacogenomics of osteonecrosis of the jaw (ONJ) have had various methodological limitations, including using candidate gene selection as their sole strategy, a small number of ONJ cases, or a study population based on an oncology setting.
UNASSIGNED: The aim of our case-control study was to evaluate previously reported associations between genetic factors and ONJ, which were based on either genome-wide association studies (GWAS) or candidate gene approaches. Furthermore, we aimed to identify genetic risk factors for ONJ by using GWAS to determine single-nucleotide polymorphisms (SNPs) with statistically significant differences in frequency between ONJ patients and osteoporosis controls.
UNASSIGNED: Patients with medically confirmed ONJ and who were registered in the Scandinavian Cohort of ONJ patients were included. Controls from the general population were matched on age (±5 years), sex, and cumulative antiresorptive drug exposure. The ONJ diagnosis date for cases corresponded to the index date for matched controls. DNA isolation, genotyping, and data analyses were performed by Q2/EA Genomics using standard protocols and best practices. Blood or tissue samples for 55 ONJ cases and 125 controls were collected. Due to the low quality of the tissue samples, final analyses were based on blood samples of 40 ONJ cases and 124 controls.
UNASSIGNED: We detected no significant genome-wide associations. Of the 43 SNPs with ONJ association in prior studies, none were replicated in our study.
UNASSIGNED: Even though our study sample is the largest to date, we had limited statistical power for GWAS but adequate power for replication analyses. Our study provides no evidence for any genetic predisposition to ONJ. Future studies could increase their statistical power by combining ONJ GWAS datasets and by performing a meta-analysis or pursuing a sequencing strategy in order to identify rare variants.

Desomorphine is a composite of the self-made illicit drug \"krokodil\", which is popular in Eastern Europe and other parts of the world. It causes toxic damage of different organs including bones. In this paper, a clinical portrait of the patient with drug-induced osteonecrosis of mandible who refused surgical treatment in the early stages of the disease, is presented. At the time of first presentation, the patient displayed swelling of oral soft tissues and purulent discharge in the molar area of the right mandible. Radiographic examination demonstrated several small radiolucent lesions in the body of the mandible. The patient gave consent for surgical treatment and rehabilitation only after 12 months of the diagnosis. During this period of time, the necrosis of the mandibular bone progressed and a pathological fracture of the jaw was developed. Patient underwent surgical treatment - resection of the mandible. Management of drug-induced jaw osteonecrosis is challenging as the necessity of dental and surgical treatment as well as treatment and rehabilitation of substance use disorder arises. Involvement of a multidisciplinary healthcare professionals team is essential in successful treatment of this pathology. The latter includes early surgical intervention/medical treatment and rehabilitation from drug addiction.

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse reaction, mainly due to bone-modifying agents (BMA), and it is a potentially painful and debilitating condition. To date, the literature has reported a 90% rate of successful outcomes for MRONJ patients undergoing surgical treatment. Particularly for patients with advanced disease stages who are unsuitable for surgery, prolonged medical treatment is required, with a consequent risk of the overuse of antibiotics and antibiotic resistance. The aim of this study is to evaluate the efficiency and safety of ozone, via oral mucosal infiltrations, in seven cancer patients with MRONJ, who are not eligible for surgery. The protocol (OZOPROMAF) consists of intratissue injections of an oxygen ozone (O2O3) mixture, which is applied until formation of a sequestrum and clinical healing. Follow-up was scheduled to confirm the healing of MRONJ and radiological evaluations by CBCT were planned. In order to assess the level of pain, a questionnaire including the Numeric Rating Scale for Pain (NRS Pain) was administered on the first visit, one day after treatment, and one week after treatment. After an application of OZOPROMAF, all patients reported discomfort for some hours, probably due to soft tissue pressure around the infiltration site. Thereafter, the discomfort subsided within 6-8 h. Complete mucosal healing of MRONJ occurred within a number of cycles ranging from 7 to 16. Complete resolution with an improvement in bone condition was observed in all patients. The MRONJ lesions of all patients healed after 18-24 months. The authors of this study contend that these preliminary results suggest the efficiency and safety of the O2O3 mixture. However, further research is required to confirm the efficacy of the O2O3 mixtures in MRONJ treatment, at least for patients who are unsuitable for surgery.

Oral rehabilitation can be a challenge in patients on high-dose antiresorptive medication (HDAR), especially if the alveolar anatomy has changed due to previous medication-related osteonecrosis of the jaw (MRONJ) resection. In healthy patients, dental implant treatment has found wide acceptance in prosthetic rehabilitation as it increases the patient\'s oral health-related quality of life. However, it is considered contraindicated in patients on HDAR due to the risk of MRONJ, although a recent feasibility study indicates that implant treatment may indeed be an option in these patients. The aim of the present case report is to illustrate the risk of MRONJ in a patient with cancer on HDAR and to discuss the reasons behind the outcomes of the implant treatment.
A patient with prostate cancer with bone metastases on high-dose denosumab therapy with previous MRONJ had four implants inserted bilaterally in the maxilla (14, 13, 23, 24). Two identical implant-supported screw-retained cantilever bridges were fabricated. The patient was followed for more than 1 year.
Peri-implantitis, and/or MRONJ, was diagnosed around two of the implants (23, 24), probably induced by crestal bone trauma from a healing abutment and/or a misfitting prosthetic reconstruction. A peri-implantitis operation was performed, but without the desired response, and the two implants (23, 24) were later removed in an MRONJ resection. The implants on the other side of the maxilla (14, 13) remained without complications. Dental implant treatment is feasible in patients on HDAR, but comorbidities (e.g., diabetes mellitus) and polypharmacy (e.g., chemotherapy and steroids) may add to the risk of implant failure. Minimal trauma surgery and prosthodontics are crucial to increase the chance of successful healing in an HDAR patient.

Pain is a problematic symptom in patients with osteonecrosis of the jaws (ONJ). Effective pain management in patients with advanced ONJ still remains an unresolved issue. This case series report presents three patients who were referred to the pain clinic for treatment of intractable pain caused by ONJ. Two patients received mandibular nerve blocks and achieved pain relief. After referral to the pain clinic, these two patients underwent segmental mandibulectomy for ONJ. In the third patient, the effect of pain control was limited. Appropriate cooperation between the oral and maxillofacial surgeon and the pain specialist is essential for pain management in patients with advanced ONJ who experience intense pain.

Medication-related osteonecrosis of the jaw (MRONJ) is a serious pathological condition that usually results from anti-resorptive or anti-angiogenic drugs. We aimed to report an unusual MRONJ in a female patient due to long-term simvastatin administration. A 48-year female was referred to the Department of Oral and Maxillofacial, Mashhad Dental School, Mashhad, Iran in Dec 2019. She complained of pain, swelling, and infection in the right mandibular area with a history of extraction. Based on medical history, the patient received 40 mg of simvastatin daily for ten years to control hypercholesterolemia. According to clinical and radiographic examinations, as well as previous medical and dental records, the lesion diagnosis was detected as MRONJ. Moreover, histopathological examination of the lesion confirmed our clinical diagnosis. The necrotic bone was removed with caution. The PRF was then inserted, and the flap was sutured without any tension. No complications were observed on following-up, and all symptoms were discontinued. There was a correlation between the administration of high-dose simvastatin and MRONJ. Moreover, more clinical investigation with larger sample sizes is suggested.