BACKGROUND Medication-related osteonecrosis of the jaws (MRONJ) is a serious condition that develops in up to 15% of patients who take antiresorptive or antiangiogenic medications. Despite extensive research into MRONJ since it was first reported in 2003, it is not clear why a minority of patients will develop this complication, and no gold standard treatment currently exists. A number of possible risk factors for MRONJ have been reported, but the existing evidence is weak and often contradictory. Preventative dentistry has been shown to reduce the incidence of MRONJ, but current guidelines are based on expert opinion and clinical experience. There is a need to better understand the factors that predispose a patient to MRONJ, and define the role of preventative dental care in reducing the incidence of this disease. AIMS The purpose of this research was to investigate the contributing risk factors for MRONJ and identify targets and strategies for MRONJ prevention. The intention was to develop an evidence-base for the dental management of patients taking antiresorptive and antiangiogenic medications. METHODS The first stage of this project was to conduct a systematic review of patient populations susceptible to MRONJ and previously reported risk factors. These data were used to define three risk categories for further investigation: dental risk factors, systemic risk factors, and haematological abnormalities as putative risk markers. A survey of patients treated at Royal Brisbane and Women’s Hospital (RBWH) and Gold Coast University Hospital (GCUH) between January 2003 and March 2017 was conducted to identify eligible cases of MRONJ and to determine whether the number of cases had changed over time with increasing awareness and understanding of MRONJ. Three casecontrol studies were used to compare the presence or absence of dental and systemic risk factors and haematological abnormalities between patients with a clinical diagnosis of MRONJ and disease-free controls. Three controls were individually matched to each case according to sex, age, primary disease, and antiresorptive type, dose, and duration. Associations between risk factors and MRONJ were investigated using conditional logistic regression. FINDINGS The systematic review identified 4106 cases of MRONJ, which included patients being treated for 39 different systemic diseases. There was very low level evidence for 25 possible dental and systemic disease indicators, and haematological risk markers. A clear need for more research into risk factors for MRONJ was identified. Since the first case of MRONJ was reported in 2003, the number of patients diagnosed with MRONJ at RBWH and GCUH has steadily increased. This suggests that improved awareness of MRONJ and the importance of preventative dental care has not translated into a reduction in disease. A number of comorbidities were found to be significant risk factors for MRONJ, including diabetes, cardiovascular disease, kidney disease, and tobacco use. The Comorbidity Polypharmacy Score (CPS) was determined to be a valid measure of MRONJ risk, and provides clinicians with a simple method of quantifying the cumulative severity of systemic risk factors. Two-thirds of all patients did not receive a dental examination in the 12 months prior to starting antiresorptives, and participants averaged less than one dental exam every three years during antiresorptive therapy. Cases averaged approximately one extraction and one filling per year during their antiresorptive therapy, which was significantly higher than treatment rates in the control group. Dental extractions and non-surgical dental care (fillings and dentures) increased the risk of MRONJ eight and six times, respectively. Cases who developed MRONJ and disease-free controls reported blood test results outside of laboratory reference ranges in similar frequencies. The most commonly reported abnormal results were low haemoglobin, low haematocrit, and low lymphocyte counts. The results of a full blood count do not appear to relate to the risk of MRONJ, but this does not preclude the role of immune function in the development of MRONJ. MRONJ appears to be a complex multifactorial disease. The underlying pathogenesis remains unclear, but there appears to be a significant opportunity to reduce the incidence of MRONJ by improving access to dental care before starting, and during, antiresorptive therapy. This will require a coordinated and collaborative approach from patients, doctors, and oral health professionals.