Acute-Phase Reaction to Zoledronic Acid and Bone Fracture Risk Reduction

Female patient in hospital bed looking at xray with clincian
Female patient in hospital bed looking at xray with clincian
Zoledronic acid, an annual intravenous therapy for osteoporosis, sometimes causes acute-phase reactions such as fever, myalgia, and flu-like symptoms after infusion. Researchers wondered if these initial transient reactions could be used as a predictor of the drug’s efficacy in people at risk for fractures.

Postmenopausal women with osteoporosis treated with zoledronic acid who have an acute-phase reaction (APR) after their first infusion have a significantly greater reduction in risk of morphometric vertebral fracture compared with those who do not have an APR, according to a study in the Journal of Bone and Mineral Research.

Investigators used data from the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) to evaluate whether APR occurrence after an initial zoledronic acid infusion was predictive of drug efficacy regarding change in bone mineral density (BMD) or fracture reduction with treatment.

The 3-year, international, multicenter, randomized, double-blind, placebo-controlled phase 3 study enrolled postmenopausal women with osteoporosis. The participants were randomized from February 2002 to June 2003 to receive either zoledronic acid (5 mg as an intravenous infusion over 15 minutes) or a placebo infusion at baseline, year 1, and year 2. All participants received oral daily calcium (1000 to 1500 mg) and vitamin D (400 to 1200 IU) and were monitored for 3 years.

A total of 7714 women were included in the analysis—3852 received placebo and 3862 received zoledronic acid. The mean ± SD age of the women was 73.1±5.4 years, and 14.1% were Asian.

The study authors found that the occurrence of any APR within 3 days of the first study drug infusion was significantly increased in women who received zoledronic acid compared those who received placebo (42.4% vs 11.8%, respectively, P < .0001). The difference in mean change in BMD for the zoledronic acid group compared with the placebo group was comparable for women with an APR and those without (all P for interaction > .10).

The incidence of vertebral fracture was 2.2% in women with an APR compared with 4.3% in those without an APR (odds ratio [OR] = 0.49; 95% CI, 0.33-0.74; P = .0007).

A nonsignificant trend also was observed regarding a lower risk for nonvertebral and hip fracture in women who had an APR (nonvertebral fracture relative hazard [RH] = 0.82; 95% CI, 0.65-1.04; P = .10; hip fracture RH = 0.70; 95% CI, 0.40-1.24; P = .22). A greater treatment-related reduction in vertebral fracture risk occurred in participants with an APR (unadjusted OR = 0.19; 95% CI, 0.12-0.31) vs those without (unadjusted OR = 0.38; 95% CI, 0.30-0.49) (P for interaction = .01).

The researchers noted limitations to their findings. APRs were self-reported and could not be objectively verified, and some of the covariables, such as previous use of bisphosphonates and NSAIDs, were also based only on self-report. In addition, because HORIZON-PFT only assessed bone turnover markers (BTMs) in a small number of patients, the study authors could not include BTMs as covariables and reliably compare their change as an outcome in women with and without APR or include BTMs in the multivariable analyses.

“These results may be reassuring to patients who experience an APR, because it indicates that the treatment, which is highly effective at reducing risk of vertebral fractures, may be even more efficacious in them,” the investigators commented.


Black DM, Reid IR, Napoli N, et al. The interaction of acute-phase reaction and efficacy for osteoporosis after zoledronic acid: HORIZON pivotal fracture trial. J Bone Miner Res. Published online September 28, 2021. doi:10.1002/jbmr.4434