title: Fever after zoledronic acid administration is due to increase in TNF-alpha and 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.
authors.affiliation: Università Campus Bio-Medico, Rome, Italy. b.vincenzi@unicampus.it
authors.forename: Giordano
authors.initials: G
authors.lastname: Dicuonzo
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincenzi
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Avvisati
authors.forename: Laura
authors.initials: L
authors.lastname: Rocci
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Battistoni
authors.forename: Michele
authors.initials: M
authors.lastname: Gavasci
authors.forename: Domenico
authors.initials: D
authors.lastname: Borzomati
authors.forename: Roberto
authors.initials: R
authors.lastname: Coppola
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tonini
mesh_terms: D000210:Acute-Phase Reaction; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000150:complications / Q000503:physiopathology; D001862:Bone Resorption / Q000188:drug therapy; D002118:Calcium / Q000097:blood; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005334:Fever / Q000139:chemically induced* / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects*; D007371:Interferon-gamma / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000077211:Zoledronic Acid; D007371:Interferon-gamma; D002118:Calcium