Characterization of and risk factors for the acute-phase response after zoledronic acid

Context: Intravenous aminobisphosphonates often cause an acute-phase response (APR), but the precise components of this, its frequency, and the risk factors for its development have not been systematically studied. Objective: The objective of the study was to characterize the APR and determine its frequency and the risk factors for its development. Design: The study was an analysis of adverse events from a large randomized trial. Setting: This was a multicenter international trial. Patients: Patients included 7765 postmenopausal women with osteoporosis. Intervention: Zoledronic acid 5 mg annually or placebo was the intervention. Main Outcome Measure: Adverse events occurring within 3 d of zoledronic acid infusion were measured. Results: More than 30 adverse events were significantly more common in the zoledronic acid group and were regarded collectively as constituting an APR. These were clustered into five groups: fever; musculoskeletal (pain and joint swelling); gastrointestinal (abdominal pain, vomiting, diarrhea); eye inflammation; and general (including fatigue, nasopharyngitis, edema). A total of 42.4% of the zoledronic acid group had an APR after the first infusion, compared with 11.7% of the placebo group. All APR components had their peak onset within 1 d, the median duration of the APR was 3 d, and severity was rated as mild or moderate in 90%. Stepwise regression showed that APR was more common in non-Japanese Asians, younger subjects, and nonsteroidal antiinflammatory drug users and was less common in smokers, patients with diabetes, previous users of oral bisphosphonates, and Latin Americans (P < 0.05 for all). Conclusion: This analysis identifies new components of the APR and provides the first assessment of risk factors for it. Despite its frequency, APR rarely resulted in treatment discontinuation in this study.