Fever After Zoledronic Acid Administration Is Due to Increase in TNF-αand IL-6

Abstract

The most common adverse event typically associated with bisphosphonate therapy is transient fever. The aim of this study was to define the role of the main cytokines of the acute-phase reaction interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) involved in the pathogenesis of zoledronic acid-induced fever. Eighteen consecutive cancer patients with bone metastases were treated, for the first time, with a single dose of 4 mg zoledronic acid infusion. They were prospectively evaluated for circulating TNF-alpha, interferon-gamma (IFN-gamma), and IL-6 levels at different times, just before and 1, 2, 7, and 21 days after diphosphonate infusion. Clinical and standard laboratory parameters were recorded at the same time points. TNF-alpha circulating levels increased significantly 1 and 2 days after zoledronic acid infusion (respectively, p = 0.002 and p < 0.001) and then decreased to levels similar to the basal levels. IL-6 levels increased significantly 1 day after the infusion (p = 0.007), returning to values similar to the median basal values 2 days after zoledronic acid administration. Moreover, in patients who experienced fever, the TNF-alpha and IL-6 increases were higher than in patients without fever. No statistically significant differences in IFN-gamma were identified at different time points in patients with and without fever. Our results show that zoledronic acid induces transient TNF-alpha and IL-6 increases and that these increases are higher in patients who have developed fever, suggesting that these cytokines could be responsible for fever pathogenesis. The sharp reduction in serum calcium levels observed in patients with fever may be related to zoledronic acid pharmacokinetic modifications.

Cytokines Behavior in Multiple Myeloma Patients during Zoledronic Acid Treatment

“…In our result, as documented also by other investigators we observed a sharp and statistically significant increase in IL-6 and TNF-α median values on days 1 and 2 after zoledronic acid infusion [19,20].…”

“…In conclusion, we described the modification in serum level of important cytokine in MM. About the anti-angiogenic effect recently demonstrated in vivo although the lack of long-lasting reduction of VEGF and PDGF that we noticed differently from what happen in solid cancer [10,20], we could not exclude that zoledronic acid express its anti-myeloma activity by inhibiting VEGF (reduced after day 7) and PDGF, even though zoledronic acid may not have an effect on the cytokine themselves. It is possible that this drug may have an impact on the effect of VEGF and PDGF on signalling that leads to blood vessel development or it also may have an impact on the effect of VEGF and PDGF on myeloma cells directly like hypothesized in some recent study, previously mentioned.…”

Adverse effects of zoledronic acid infusion in patients treated for postmenopausal osteoporosis

“…The exact mechanism underlying these reactions is unclear. However, it is thought to result from the activation of γδT cells which may lead to an increased circulating levels of interleukin-6 and tumor necrosis factor-α (10) . These reactions were the only ones by the patients in our study.…”

“…Often time, they were informed about the possible adverse effects and advised to contact the doctor in case of an emergency. Post-infusion adverse effects are common after zoledronic acid infusion and are thought to result from increased levels of inflammatory mediators in circulation as a response to infusion (10) . Therefore, we prescribed oral ibuprofen 800 mg/day for three daysto prevent post-infusion adverse effects that are induced by inflammatory mediators.…”

Adverse Effects of Bisphosphonates: Implications for Osteoporosis Management

“…nearly 3 mg/dL at 21 days after infusion of 4 mg of zoledronic acid. 12 Key point: All patients who are to begin receiving either oral or IV bisphosphonate therapy should have adequate calcium and vitamin D intake. If any concerns about nutritional status or absorptive capacity arise, serum levels of 25-hydroxyvitamin D, calcium phosphorus, and parathyroid hormone as well as urinary calcium excretion should be assessed and abnormalities addressed before initiating bisphosphonate therapy.…”