Acute Phase Reactions After Zoledronic Acid Infusion

Protective Role of 25-hydroxyvitamin D and Previous Oral Bisphosphonate Therapy

Chiara Crotti, MD; Nelson B. Watts, MD; Maria De Santis, MD, PhD; Angela Ceribelli, MD, PhD; Gianluigi Fabbriciani, MD; Francesca Cavaciocchi, PhD; Bianca Marasini, MD; Carlo Selmi, MD, PhD; Marco Massarotti, MD


Endocr Pract. 2018;24(5):405-410. 

In This Article

Abstract and Introduction


Objective: The most common adverse reaction to zoledronic acid (ZOL) infusion is the acute phase reaction (APR), characterized by transient, usually mild, flu-like symptoms. Previous treatment with oral amino-bisphosphonates (BPs) was reported as an independent protective factor for APR, and an association between APR and 25-hydroxyvitamin D (25(OH)D) levels in BP-naïve patients treated with ZOL was identified. The aims of our study were to confirm this association and to see if it was different in patients previously treated with oral BPs compared with BP-naïve patients and to investigate the role of 25(OH)D for the time of APR onset.

Methods: We included 153 consecutive patients with postmenopausal osteoporosis undergoing their first ZOL infusion. Sixty-eight had been previously treated with oral BPs. Clinical, demographic, and serologic data were recorded.

Results: 25(OH)D levels were significantly lower in patients experiencing APR compared to patients without APR (26.3 ± 12.7 vs. 37.0 ± 13.5 ng/mL, respectively; P<.0001). Patients with 25(OH)D <30 ng/mL had a significantly higher risk of APR (odds ratio [OR] 4.2 [95% confidence interval [CI] 2.1–8.2]) occurring in 65%. APR was significantly less frequent in patients previously treated with oral BPs than in BP-naïve subjects (33.8% [23/68] vs 52.9% [45/85], P = .018), but only a weak association remained after correction for 25(OH)D (OR 0.5, 95% CI 0.3–1.1, P = .08).

Conclusion: Higher baseline 25(OH)D levels appear to be protective for APR post-ZOL infusion. The role of previous treatment with oral BPs as an independent protective factor for APR should be evaluated in a larger cohort.


Osteoporosis (OP) is a common condition affecting millions of women around the world, with significant financial and personal costs. Several therapeutic options are currently available for OP, in particular amino-bisphosphonates (BPs) because of their good cost-effectiveness profile.[1] Zoledronic acid (ZOL) was the first intravenous BP licensed for the treatment of OP. In placebo-controlled trials, up to 30% of patients treated with ZOL experienced an "acute phase reaction" (APR), characterized by a transient flu-like syndrome with fever, chills, flushes, fatigue, malaise, and musculoskeletal and gastrointestinal symptoms, usually mild, occurring 24 to 36 hours after infusion and resolving within 2 to 3 days.[2–6] This is a sterile acute inflammation due to the immunomodulatory action of this class of drugs, involving the activation of monocytes and γδ T cells and the production of pro-inflammatory cytokines as interleukin (IL)-6, interferon-γ, tumor necrosis factor-α; frequency and severity are markedly reduced after the first infusion.[7] The immunologic basis of this tolerance and the role of 25-hydroxyvitamin D (25(OH)D) in modulating the activation of both monocytes and γδ T cells are not well known. A multicenter, randomized, double-blind study identified some risk factors (i.e., younger age, nonsteroidal anti-inflammatory use, back pain) involved in the development of APR,[8] while previous oral BP treatment was reported as an independent protective factor for APR. Another study suggested an association between APR onset and 25(OH)D levels in BP-naïve patients.[9] The aim of our study was to recapitulate these observations and determine whether the association between APR and 25(OH)D differed in patients previously treated with oral BPs. We also investigated the level of 25(OH)D associated with the highest risk of APR.