Variable association of atypical femur fracture and osteonecrosis of jaw with bisphosphonates and denosumab use: Drug-safety surveillance study

Abstract In the United States, there are over ten million adults diagnosed with osteoporosis and many more are at risk of developing the condition. Osteoporosis affects both males and females, mostly post-menopausal. Bisphosphonates and denosumab have been widely used globally to treat the condition. The use of bisphosphonates and denosumab had been associated with rare adverse effects including osteonecrosis of the jaw, ONJ, and atypical femur fracture, AFF. However, it remained unclear whether those side effects were class-wide or drug-specific. By analyzing over 230,000 osteoporosis patient reports from the FDA adverse event reporting system, FAERS, we confirmed the association of bisphosphonates and denosumab use with AFF and ONJ. Additionally, comparing each of the four frequently used bisphosphonates with denosumab-treated patients used as a control, we identified: (i) varying significance of association with ONJ and AFF for alendronate, risedronate, ibandronate and zoledronic acid, (ii) over two fold increase in risk of both side effects in alendronate patients, particularly in females, (iii) over a six fold increase in AFF risk in both males and females taking risedronate, and (iv) lower risk of both AFF and ONJ, for zoledronic acid patients compared to denosumab. Key points We performed a disproportionality analysis of over 230,000 post-marketing reports of patients treated for osteoporosis to measure the risk of developing atypical femur fracture (AFF) and osteonecrosis of the jaw (ONJ). Alendronate, ibandronate, risedronate, zoledronic acid, and denosumab were all significantly associated with AFF and ONJ when compared to teriparatide. When compared to denosumab, patients taking alendronate, ibandronate, risedronate, or zoledronic acid had a variable risk of ONJ and AFF, which correlated with the frequency of drug administration. The trend in variable risk was observed in both females and males.