Purpose Zoledronic acid (ZOL) as an annual infusion is effective in reducing risk of vertebral, hip and other fractures. However, an acute phase reaction (APR), consisting of fever and/or flu-like symptoms for up to 3 days after an infusion is common. Previous analyses of APR have examined APR prevalence and predictors. The objective of this analysis was to investigate whether the occurrence of an APR influences drug efficacy.

Methods This analysis uses data from the 3-year, international, randomized, double-blind, placebo-controlled phase 3 study, Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT). APR’s were identified as adverse events (AE’s) occurring at a higher frequency in ZOL vs. placebo participants within 3 days of the first infusion. Multivariate logistic or Cox regression were used to examine the relationship between APR and change in BMD as well as 3 categories of fractures: morphometric vertebral (VFx), non-vertebral and hip.

Results There were 3862 postmenopausal women in the zoledronic acid group and 3852 in the placebo group included in the analyses. 42.4% in ZOL vs. 11.8% in placebo experienced an APR after the first infusion. Within women randomized to ZOL, those who had an APR had a 51% lower risk of vertebral fracture than those who did not have an APR (Odds Ratio=0.49,p<0.001). The vertebral fracture results were only slightly attenuated after adjustment for factors associated with either APR or vertebral fracture. A similar but non-significant trend was observed for non-vertebral and hip fracture (Relative Hazard=0.82, p=0.105;RH=0.70,p=0.225, respectively). When the analysis included the placebo, as well as ZOL groups, there was a significant interaction between treatment and APR for vertebral fractures.

Conclusions

Our results suggest women who experience an APR have a larger reduction in vertebral fracture risk. These results may be reassuring to patients who experience an APR.