Medication-related osteonecrosis of the jaw : occurence, risk factors, pathogenesis & treatment

Abstract: The antiresorptive drugs bisphosphonates and denosumab arewidely used to preserve bone strength by inhibiting osteoclast mediatedbone resorption. High dose intravenous bisphosphonatesand high dose denosumab are mainly used to treat skeletal relatedevents in patients with metastatic bone disease such as metastaticbreast cancer and metastatic prostate cancer or in patients withmultiple myeloma. In patients with osteoporosis, oral bisphosphonatesare mostly used. Medication-related osteonecrosis of the jaw(MRONJ) is a serious side effect associated both with bisphosphonatesand denosumab treatment. The first report on MRONJ waspublished in 2003. At first, the condition was believed to be a newdisease, but it was later proved to be the same disease, which existedmore than 100 years ago in match factory workers, and phosphateminers, in whom the disease was recognized as phossy jaw. The overall aim of this thesis was to study the occurrence, risk factors,pathogenesis and treatment of MRONJ.Study I describes prevalence, trigger factors and treatment outcomesof MRONJ retrospectively between the years 2003-2010 inRegion Skåne. During this time, 55 patients had been diagnosedwith MRONJ. Of these patients, 31 patients with a malignant diseasewere treated with high dose intravenous bisphosphonates and24 patients with osteoporosis were treated with oral bisphosphonates.The prevalence of MRONJ was estimated to be 0.024% forpatient on oral bisphosphonates and 2.8% for patients on high dose intravenous bisphosphonates. Tooth extraction was the mostcommon trigger factor. After treatment of MRONJ, healing occurredmore frequently in patients with osteoporosis treated withoral bisphosphonates than in patients with a malignant diseasetreated with high dose intravenous bisphosphonates.Study II investigated the association between microflora andMRONJ by using 16S rRNA pyrosequencing technique for the detectionof bacteria in necrotic bone lesions. Included were 18 consecutivepatients with MRONJ, ten with osteoporosis and eightwith metastatic disease. Bone biopsies were retrieved with two separate3 mm sterile trepan burrs from the centre of the necroticbone and from visible healthy bone. The necrotic bone lesions containedmainly anaerobic bacteria, representative for periodontalmicroflora, suggesting that a periodontal infection in combinationwith antiresorptive treatment could initiate the osteonecrosis. Study III is a prospective cohort study where the prevalence andinitiating factors of MRONJ and the outcome of surgical therapywere analysed. All new cases of MRONJ between 2012 and 2015in Region Skåne were included. Fifty-five patients with MRONJwere identified. The prevalence of MRONJ for patients on oralbisphosphonates was 0.043%, on high dose intravenous bisphosphonates1.03% and on high dose denosumab 3.64%. Periodontaldisease preceded development of MRONJ in 41 patients. Fifty patientswere treated surgically and followed up for at least 2months. Lesions progressed to remission or healing in 80.0% ofpatients treated with sequestrectomy and in 92.5% of patientstreated with block resection. In study IV, the aim was to prospectively determine the incidenceand define risk factors for MRONJ in patients with metastaticbreast cancer treated with zoledronic acid and/or denosumab.Breast cancer patients diagnosed between 2012 and 2015 in the regionof Skåne with one or several bone metastases and treated withzoledronic acid or denosumab were included. Systemic risk factors(age, zoledronic acid or denosumab use, treatment time, chemo-therapy or corticosteroid use, diabetes and smoking habits) wererecorded. Sixteen patients of 242 (6.6%) developed MRONJ duringthe 77 months study period (from 1st of January 2012 to 31stof May 2018). The incidence of MRONJ in patients treated withhigh dose zoledronic acid was 4.1%, and for patients with highdose denosumab 13.6%. The risk of developing MRONJ in patientson denosumab was significantly higher compared to patientstreated with zoledronic acid. Corticosteroid use was associatedwith a significant decreased risk of MRONJ and diabetes was associatedwith a significantly increased risk of MRONJ. Chemotherapyor smoking was not associated with a significant increasedrisk of MRONJ. In conclusion, the incidence of MRONJ is more than three timeshigher in breast cancer patients treated with denosumab comparedto breast cancer patients treated with zoledronic acid. The prevalencein patients with osteoporosis on oral bisphosphonates is low,< 0.05%. Corticosteroid use decreases the risk of developingMRONJ whilst diabetes increases the risk. The most common localrisk factor is a periodontal disease. Periodontal bacteria play a centralrole in the pathogenesis and development of MRONJ. Thetreatment outcome of MRONJ demonstrates healing in most patientstreated surgically.