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. The adverse event profile following infusion of zoledronic acid, novel components of the acute phase response, and risk factors for its occurrence are described.