Identification of Risk Factors for Bisphosphonate-Associated Atypical Femoral Fractures and Osteonecrosis of the Jaw in a Pharmacovigilance Database

BACKGROUND: Atypical femoral fractures (AFs) and osteonecrosis of the jaw (ONJ) are well-known adverse drug reactions (ADRs) associated with bisphosphonates. To prevent these ADRs and to aid in the search for pathogenic mechanisms, knowledge of risk factors can be helpful. Objective: To identify risk factors for bisphosphonate-related ONJ and AF. Methods: In this case-control study of reports of bisphosphonate-related ADRs from February 16, 1984, to October 16, 2013, in the Swedish national database of ADRs, we compared characteristics for cases of ONJ (n = 167) and AF (n = 55) with all other bisphosphonate-related ADRs (n = 565) with regard to demographic variables, clinical characteristics, and concomitant drug treatments. We adjusted for multiple comparisons with Bonferroni correction. Results: Time to onset of ADRs differed statistically significantly between cases of AF and controls (2156 vs 111 days). For ONJ versus controls, differences were statistically significant for time to onset (1240 vs 111 days), intravenous administration (40% vs 20%), dental procedures (49% vs 0.2%) and prostheses (5% vs 0%), cancer disease (44% vs 12%), multiple myeloma (21% vs 1%), rheumatoid arthritis (14% vs 5%), and treatment with antineoplastic agents and oxycodone. Conclusion: These results lend further evidence to previously identified risk factors for ONJ—that is, intravenous bisphosphonate administration; invasive dental procedures and dental prostheses; cancer disease, in particular multiple myeloma; and possibly, long-term bisphosphonate treatment. A putative further risk factor is rheumatoid arthritis. Only long-term bisphosphonate treatment was more common among AF cases. The lack of overlap of risk factors between ONJ and AF suggests different pathogenic mechanisms.