Elsevier

Bone

Volume 49, Issue 1, July 2011, Pages 140-145
Bone

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

https://doi.org/10.1016/j.bone.2010.10.177Get rights and content

Abstract

The acute-phase response (APR) to aminobisphosphonates is triggered by activation of γδ T cells, resulting in pro-inflammatory cytokine release. Statins prevent aminobisphosphonate-induced γδ 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 γδ T cell levels, pro-inflammatory cytokines (TNFα, IFNγ, 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 TNFα, IFNγ, 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 Vγ9Vδ2 T cell levels at 48 hr, consistent with Vγ9Vδ2 T cell activation. Concurrent fluvastatin administration did not prevent zoledronic acid-induced cytokine release, alter circulating Vγ9Vδ2 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.

Research Highlights

► Study investigated if statins prevent acute-phase response to aminobisphosphonates. ► Zoledronic acid increased pro-inflammatory cytokine levels in post-menopausal women. ► Zoledronic acid induced flu-like symptoms in >50% study participants. ► Fluvastatin did not prevent symptoms or cytokine release induced by zoledronic acid. ► Fluvastatin does not prevent the acute-phase response to zoledronic acid.

Introduction

Bisphosphonates (BPs) are currently the most common treatment for a variety of disorders characterised by excessive osteoclastic bone resorption, such as post-menopausal osteoporosis [1], Paget's disease of bone [2] and tumour-associated osteolysis [3]. A common side-effect of intravenous administration of nitrogen-containing BP (N-BP), such as pamidronate or zoledronate (ZOL), is the development of a transient flu-like syndrome called the acute-phase response (APR). An APR typically occurs in 10–50% of patients receiving their first infusion [4], [5], [6] and is characterised by symptoms such as pyrexia and musculoskeletal aches and pains. These symptoms are frequently associated with increased circulating levels of pro-inflammatory cytokines such as IFNγ, TNFα and IL-6 [5], [7], [8], [9]. Whilst the exact molecular mechanism underlying this phenomenon is not fully understood, it is becoming clear that activation of a specific subset of T cells, so-called γδ T cells, plays a central role.

γδ T cells were first identified as possible initiators of the APR to N-BPs by Kunzmann et al., who observed marked increases in the number of circulating γδ T cells in PAM-treated multiple myeloma patients up to 28 days post-infusion, which correlated with the severity of the APR [10]. Subsequent studies revealed that N-BPs specifically activate the major subset of γδ T cells in peripheral blood, Vγ9Vδ2 T cells [11]. N-BP-induced activation of Vγ9Vδ2 T cells in peripheral blood mononuclear cell cultures in vitro results in production of IFNγ, TNFα and IL-6 [5], [12], [13], which closely mirrors cytokine production triggered by N-BP administration in vivo. This suggests that strategies to minimise or prevent Vγ9Vδ2 T cell activation by N-BPs in vivo may prevent the APR.

We and others have previously shown that activation of Vγ9Vδ2 T cells by N-BPs occurs via an indirect mechanism [12], [14], requiring intracellular uptake of N-BP to inhibit its molecular target, farnesyl diphosphate (FPP) synthase [15], [16], [17], [18]. Recently, we proposed that peripheral blood monocytes play a crucial role in Vγ9Vδ2 T cell activation due to selective internalisation of the N-BP by highly endocytic CD14+ monocytes [19]. We demonstrated that, following a clinically relevant pulse of ZOL, inhibition of FPP synthase in monocytes causes the accumulation of the enzyme substrates, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), both of which are agonists of the Vγ9Vδ2-T cell receptor (TCR) [20].

Consistent with a central role for IPP and DMAPP accumulation in triggering Vγ9Vδ2 T cell activation, we and others have previously shown that the stimulatory effects of N-BPs on Vγ9Vδ2 T cell activation and proliferation in peripheral blood mononuclear cell cultures can be prevented by simultaneous treatment with a statin [12], [13], [14]. These widely-used cholesterol-lowering drugs inhibit HMG-CoA reductase, an enzyme upstream of FPP synthase, and thus prevent N-BP-induced IPP/DMAPP accumulation. We therefore investigated in this study whether co-administration of a statin could prevent ZOL-induced cytokine release and flu-like symptoms of the APR in healthy post-menopausal women.

Section snippets

Study population and design

All research was conducted at Aberdeen Royal Infirmary, Aberdeen, UK. Ethical approval for this study was granted by the Grampian Local Research Ethics Committee. A total of 61 healthy women aged 50–70, who were > 12 months post-menopause and had a T-score ≥2.5 (i.e. non-osteoporotic), were recruited into the double-blind, placebo-controlled study. Participants were BP-naïve and had not received hormone replacement therapy within 6 months of inclusion. Subjects receiving statin therapy were not

Patient information and determination of FLU treatment protocol

Sixty female volunteers completed the study. The mean age was 60.6 ± 4.0 years. All volunteers were post-menopausal and presented with a T-score of ≥2.5. The subject disposition is shown in Fig. 1.

The proposed timing and dosage of FLU for the study was determined based on our findings in an in vitro model of the APR to N-BPs (Suppl. Fig. 1) using IFNγ release as a measure of N-BP-induced γδ T cell activation in PBMC cultures [12]. This showed that treatment of PBMCs with 1 μΜ FLU for 2 hr (which

Conclusions

We investigated whether FLU could prevent the most common adverse event associated with intravenous ZOL administration, the development of an APR, in a placebo-controlled, double-blind study in a healthy cohort of post-menopausal women. Our results show that, despite the inhibitory effect of FLU on N-BP-induced Vγ9Vδ2 T cell activation in vitro (Suppl. Fig. 1 & [13]), co-administration of FLU at the dosing regimens used did not prevent ZOL-induced Vγ9Vδ2 T cell activation, pro-inflammatory

Acknowledgments

We gratefully acknowledge the technical assistance provided by Mrs Denise Tosh, Mrs Kelly Deans and Mrs Linda Duncan. We would also like to thank Dr. Anke Roelofs for critical comments on the manuscript. The study was funded by an unrestricted educational grant by Novartis. DMR and KT are grateful to Arthritis Research UK for continued infrastructure support. DMR has received additional research funding from Novartis, participates in Advisory Boards for the company and is a member of their

References (30)

  • S. Adami et al.

    The acute-phase response after bisphosphonate administration

    Calcif Tissue Int

    (1987)
  • D. Thiebaud et al.

    An in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates

    Calcif Tissue Int

    (1997)
  • W. Strampel et al.

    Safety considerations with bisphosphonates for the treatment of osteoporosis

    Drug Saf

    (2007)
  • D.H. Schweitzer et al.

    Interleukin-6 and the acute phase response during treatment of patients with Paget's disease with the nitrogen-containing bisphosphonate dimethylaminohydroxypropylidene bisphosphonate

    J Bone Miner Res

    (1995)
  • G. Dicuonzo et al.

    Fever after zoledronic acid administration is due to increase in TNF-alpha and IL-6

    J Interferon Cytokine Res

    (2003)
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