A real-world study on the prevalence and risk factors of medication related osteonecrosis of the jaw in cancer patients with bone metastases treated with Denosumab.

AIM: Assessing the incidence of Medication Related Osteonecrosis of the Jaw (MRONJ) in cancer patients with bone metastases receiving Denosumab (Dmab) and identifying potential risk factors. METHODS: A retrospective observational study on consecutive cancer patients with bone metastases, who received at least one dose of Dmab and one follow-up visit. MRONJ crude cumulative incidence (CCI) was estimated considering death without MRONJ as competing event. Multiple regression models were used to study the association between MRONJ incidence and potential risk factors: age, cancer diagnosis, previous bisphosphonates, dental treatments before starting Dmab, extraction or other dental treatment during Dmab, chemotherapy, hormone therapy, and antiangiogenic (AA) agents concurrent use. RESULTS: On 780 patients included (median follow-up 17 months), 54% and 18% had, respectively, breast and prostate cancer. The mean number of Dmab administration was 12. Fifty-six patients developed MRONJ with a 24- and a 48-month crude cumulative incidence of 5.7% (95% Cl: 4.2%-7.8%) and 9.8% (95% CI: 7.6%-12.7%), respectively. Higher MRONJ incidence was significantly associated with middle aged group (>56 and ≤73), both at univariate and multivariate analysis (p = 0.029 and 0.0106). Dental treatments (Hazard Ratio [HR] = 3.67; p = 0.0001), dental extractions (HR = 23.40; p < 0.0001), and previous BP administration (HR = 2.62; p = 0.0024) were significantly associated with higher MRONJ incidence at multivariate Cox analysis. Although not statistically significant, MRONJ incidence was lower for patients receiving chemotherapy or hormone therapy and higher for those receiving AAs. CONCLUSIONS: The results confirm a clinically relevant incidence of Dmab-induced MRONJ. Dental treatments, especially extraction, during and before Dmab, constitute a serious risk factor. The role of AA concurrent administration deserves further investigations.

Rechallenge of denosumab in jaw osteonecrosis of patients with unresectable giant cell tumour of bone: a case series analysis and literature review.

OBJECTIVES: Giant cell tumour of bone (GCTB) is a rare tumour, generally managed with surgery. Treatment of the very rare unresectable advanced/metastatic GCTB is challenging and denosumab is the only current available medical option, an anti-RANKL monoclonal antibody inhibiting osteolysis. An uncommon but severe and treatment-limiting adverse event of denosumab is the osteonecrosis of the jaw (ONJ). The clinical management of GCTB patients stopping denosumab for medication-related (MR)-ONJ and the possible reintroduction of denosumab after MR-ONJ resolution is matter of debate. We performed a retrospective study to describe the incidence, clinical features and outcome of MR-ONJ in unresectable GCTB patients treated with denosumab at our Institution. DESIGN AND SETTING: Retrospective, single-institutional study. PARTICIPANTS: Adult patients receiving denosumab as antineoplastic therapy for GCTB and experiencing MR-ONJ at Fondazione IRCCS Istituto Nazionale Tumori of Milan between January 2008 and July 2019. MAIN OUTCOME MEASURES: Incidence, time of onset and clinical features of MR-ONJ. RESULTS: 29 patients with locally advanced and/or metastatic GCTB treated with denosumab were identified. At a median follow-up of 70 months (range 1-125), 4 (13.8%) patients experienced MR-ONJ while on treatment, after 125, 119, 85 and 41 months of denosumab, respectively. All patients showed an ongoing tumour stabilisation with denosumab at the MR-ONJ onset and in all cases denosumab was stopped. All four patients were treated with ozone therapy. Two are waiting for surgery, two were already operated on. Both of them experienced disease progression and were thus rechallenged with denosumab. One is still on therapy after 25 months. The other had an MR-ONJ relapse after 39 months and was treated again with ozone therapy and surgery. She is under surveillance, GCTB being currently stable. CONCLUSION: A clinical algorithm of denosumab rechallenge after complete resolution of MR-ONJ in progressing GCTB patients should be prospectively validated.

Treatment of osteonecrosis of the jaw (ONJ) by medical ozone gas insufflation. A case report.

Osteonecrosis of the jaw (ONJ) is an adverse event reported in patients receiving cancer treatment, especially bisphosphonates and denosumab. A patient with multiple myeloma who underwent up to 22 intravenous zoledronic acid infusions without previous dental examination developed a devastating ONJ lesion in the right horizontal mandibular ramus. He was treated with local ozone gas applications every third day by means of a special bell to avoid O(3) diffusion. Azithromycin 500 mg/day was administered for 10 days prior to the O(3) applications. O(3) therapy resulted in sequestration of the necrotic bone after a median of 15 applications, following which surgery was necessary to remove it. Interestingly, removal was possible without the resection of the healthy mandible edge because of the presence of the bone sequestrum. Medical O(3) gas administration was effective and safe in a patient treated with bisphosphonates who developed a >2.5 cm ONJ lesion. Future research is needed to demonstrate the efficacy and tolerability of such treatment in a larger number of patients.

Efficacy and safety of medical ozone (O(3)) delivered in oil suspension applications for the treatment of osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: Preliminary results of a phase I-II study.

Osteonecrosis of the jaw (ONJ) is an adverse event that has been reported in patients receiving cancer treatment regimens, including bevacizumab, bisphosphonates, and denosumab. We performed a preliminary open label, prospective phase I-II study in patients treated with bisphosphonate to evaluate the treatment effect and tolerability of medical ozone (O(3)) delivered in an oil suspension on BONJ lesions ≤2.5cm. Ten consecutive patients with BONJ lesions not responsive to conservative treatment were pre-treated with 10days of antibiotics to reduce purulent secretions on the gum. The exposed bone lesion and osteomucosal edge was cleaned with an ultrasonic scaler. The BONJ lesion was treated with 10 local applications of medical O(3) delivered in an oil suspension for 10min. In all patients, mucosal lesions resolved with complete reconstitution of oral and jaw tissue, with 3-10 applications. No toxicity was reported. Unexpectedly, total sequestration of the necrotic bone, with spontaneous expulsion in eight patients and new bone formation around the necrotic area in two patients was observed. No patient required surgical intervention. In two patients with pre-and post-treatment X-rays, no residual bone lesions were observed after treatment. These preliminary results show the efficacy and tolerability of O(3) delivered in an oil suspension applied directly to BONJ lesions ≤2.5cm, thus indicating that BONJ can be a manageable and potentially curable condition.

Antibiotic prophylaxis before dental procedures may reduce the incidence of osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates.

Osteonecrosis of the jaw (ONJ) can be a severe complication of patients with multiple myeloma (MM) treated with bisphosphonates. Dental procedures are a major risk factor for ONJ occurrence. We retrospectively analysed the data of 178 patients with MM to evaluate if antibiotic prophylaxis before dental procedures may prevent ONJ. A correlation between dental procedures, antibiotic prophylaxis, incidence of ONJ and relevant clinical features was performed. Overall nine out of 178 patients developed ONJ (5 year crude cumulative incidence: 7.7%). Only one case of ONJ was not correlated with dental procedures. Seventy-five patients received at least one dental procedure and 43 received antibiotic prophylaxis. Eight cases of ONJ were observed, all in the group of patients without antibiotic prophylaxis. The only variable significantly associated with ONJ was antibiotic prophylaxis (p = 0.012), which had a protective effect. Thus, we speculated that antibiotic prophylaxis may prevent ONJ occurrence after dental procedures.