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


APR is a frequent side effect of ZOL treatment, and although it is transient and usually mild, it can be debilitating and reduce patient willingness to continue treatment. Predicting and preventing this adverse event may be helpful to maximize patient adherence with treatment.

Despite the limited number of patients, our cohort appears to be representative of the target population. First, APR was observed in 44.4% of OP subjects treated with ZOL, similar that in the HORIZON pivotal trial, which reported a 31% incidence of APR after first ZOL infusion.[17] Other reports describe an APR rate between 30% and 55% in patients treated with intravenous BPs for the first time.[18] Second, 25(OH)D levels in our population agreed with European and Italian epidemiologic data in terms of distribution between deficient or normal levels.[19,20]

Bertoldo et al[9] first described the association between 25(OH)D levels and APR development after the first ZOL infusion in BP-naïve patients, while Srivastava et al[21] confirmed the role of low serum 25(OH)D as risk factor for APR in children treated for the first time with intravenous BPs. Supporting these observations, 25(OH)D levels in our study were also significantly lower in APR+ patients than APR- patients. Sixty-five percent of APRs occurred in patients with insufficient 25(OH)D compared with only 31% of APR- patients. The risk of APR associated with ZOL was almost 4-fold higher in patients with deficient 25(OH)D, similar to previous reports.[12]

Although a causal relationship between 25(OH) D levels and APR has not been clearly proven, our findings and previous reports could be related to the possible immune-modulating properties of 25(OH)D. In fact, 25(OH)D seems to be able to inhibit adaptive immunity and promote innate immunity through antimicrobial peptide production. In particular, inhibition of T cells by 25(OH) D has been demonstrated in vitro,[22] and it also inhibits γδT cell receptor activation in vitro,[23] a subpopulation of T cells involved in the APR reaction after BPs (27). This could explain why low serum 25(OH)D levels are associated with a greater risk of APR after the first ZOL infusion. One limitation of our study but also a possible future aim would be to analyze levels of inflammatory markers (i.e., C-reactive protein, IL-6) and correlate them with 25(OH) D levels and prior BP that could influence the biochemical and clinical response.

Reid et al[8] identified previous treatment with BPs as an independent protective factor for APR, but they did not provide information on 25(OH)D status. Patients on prior pharmacologic BP treatment could be more likely to take vitamin D supplements and are therefore possibly protected. Nevertheless, another group reported that previous exposure to BPs alone was not sufficient to prevent APR.[18]

Furthermore, our observation suggests little or no protective role of previous oral BP treatment against APR, although it is possible that the lack of effect is due to the small sample size. Serum 25(OH)D levels and previous oral BP treatment were not independently associated with APR, which could be related to the higher 25(OH)D levels in patients previously treated with oral BPs. Moreover, this risk was not influenced by the specific type or duration of oral BP treatment, and we did not identify a time interval between cessation of oral BP intake and ZOL infusion that could ensure a significant reduction in APR risk. Several other mechanisms are probably involved in APR onset in patients previously treated with oral BPs. It is possible that a phenomenon similar to that involved in the progressive decrease of APR rate after subsequent drug administration is involved.

Strengths of our study include its prospective design and the enrollment of consecutive qualified patients. Limitations include a lack of information on APR severity and duration.