Acute-phase reaction and fracture outcomes from zoledronic acid: a systematic review and meta-analysis

Zoledronic acid (ZOL), an intravenous bisphosphonate used to treat osteoporosis, is frequently associated with the development of an acute-phase reaction (APR). Although some studies have reported that the APR may correlate with fracture outcomes, the evidence remains inconsistent. This systematic review and meta-analysis aimed to investigate the association between the occurrence of an APR and fracture outcomes following ZOL therapy.

We searched MEDLINE, EMBASE, CENTRAL, International Clinical Trials Registry Platform, and ClinicalTrials.gov through April 2025 for observational studies and secondary analyses of randomized controlled trials in adults with osteoporosis. The primary outcome was the incidence of osteoporotic fractures. Secondary outcomes were mortality and changes in bone mineral density (BMD) and bone turnover markers (BTMs). The meta-analyses were performed using random-effects models and the certainty of evidence was assessed using the GRADE approach.

Seven studies were included in the final analysis. No significant association was observed between APR and fracture risk (all fractures: odds ratio (OR) 0.79, 95% confidence interval (CI) 0.19-3.26; vertebral fractures: OR 0.76, 95%CI 0.17-3.32). Similarly, no significant association was found between developing an APR and all-cause mortality, or changes in BMD, or BTMs. The certainty of the evidence ranged from very low to moderate.

Current evidence is insufficient to establish a clear association between ZOL-induced APR and fracture risk, mortality, or BMD outcomes among patients with osteoporosis. To accurately capture potential associations, future large-scale prospective studies should enroll high-risk patients, including bisphosphonate-naïve individuals, and evaluate baseline BTMs and short-term mortality.