Objectives: Medication‐related osteonecrosis of the jaws (MRONJ) is a serious condition developed in up to 15% of patients who take antiresorptive medications. Its underlying pathogenesis remains unclear. The association between systemic comorbidities and MRONJ was investigated.

Subjects and Methods: A case–control study was conducted in Brisbane, Australia. Hospital records were used to identify 68 cases of MRONJ between January 2003 and March 2017. Each case was individually matched to three controls (204 in total) according to sex, age, primary disease, and type and duration of antiresorptive therapy. Data on patient demographic, social and clinical characteristics were collected. Systemic comorbidities and medications were quantified as a comorbidity–polypharmacy score (CPS). Associations were investigated using conditional logistic regression.

Results: The CPS calculated for patients who developed MRONJ (mean ± SD = 20.2 ± 5.1) was significantly higher than for controls (12.9 ± 4.6). Multivariable analysis determined a significant relationship between CPS and the presence of MRONJ (OR = 1.5; 95% CI = 1.3, 1.8, p < 0.001).

Conclusions: Patients with multiple systemic comorbidities and high levels of polypharmacy were more likely to develop MRONJ. The CPS is a simple and effective tool to quantify the risk of MRONJ attributed to a patient's systemic condition and should be considered in conjunction with the patient's oral health to assess the overall risk of MRONJ.