Fluvastatin does not prevent the acute-phase response to intravenous zoledronic acid in post-menopausal women

The acute-phase response (APR) to aminobisphosphonates is triggered by activation of gamma delta T cells, resulting in pro-inflammatory cytokine release. Statins prevent aminobisphosphonate-induced gamma delta T cell activation in vitro, raising the possibility that statins might prevent the APR in vivo. The objective of this study was to determine whether fluvastatin prevents the APR to zoledronic acid in post-menopausal women. A double-blind, randomised, placebo-controlled study was conducted in 60 healthy, post-menopausal, female volunteers (mean age 60.6 +/- 4.0). Volunteers received 5 mg zoledronic acid by intravenous infusion, and either three times 40 mg fluvastatin (0 hr, 24 hr and 48 hr), 40 mg fluvastatin (0 hr) plus placebo (24 hr and 48 hr), or placebo (0 hr, 24 hr and 48 hr), orally. Post-infusion symptoms were assessed by questionnaire. Changes in gamma delta T cell levels, pro-inflammatory cytokines (TNF alpha, IFN gamma, IL-6) and C-reactive protein (CRP) were measured in peripheral blood at various time-points post-infusion. Zoledronic acid administration triggered increased serum levels of TNF alpha, IFN gamma, IL-6 and CRP in >= 70% of study volunteers, whilst characteristic APR symptoms were observed in >50% of participants. Zoledronic acid also induced a transient fall in circulating V gamma 9V delta 2 T cell levels at 48 hr, consistent with V gamma 9V delta 2 T cell activation. Concurrent fluvastatin administration did not prevent zoledronic acid-induced cytokine release, alter circulating V gamma 9V delta 2 T cell levels, nor diminish the frequency or severity of APR symptoms. In conclusion, intravenous zoledronic acid induced pro-inflammatory cytokine release and APR symptoms in the majority of study participants, which was not prevented by co-administration of fluvastatin. This article is part of a Special Issue entitled Bisphosphonates. (C) 2010 Elsevier Inc. All rights reserved.