• Open Access

Monocytes and γδ T cells control the acute-phase response to intravenous zoledronate: Insights from a phase IV safety trial

Authors

  • Joanne L Welton,

    1. Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
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  • Matt P Morgan,

    1. Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
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  • Salvador Martí,

    1. Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
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  • Michael D Stone,

    1. Bone Research Unit, Cardiff University Academic Centre, Llandough Hospital, Penarth, United Kingdom
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  • Bernhard Moser,

    1. Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
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  • Andrew K Sewell,

    1. Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
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  • Jane Turton,

    Corresponding author
    1. Bone Research Unit, Cardiff University Academic Centre, Llandough Hospital, Penarth, United Kingdom
    • Cardiff and Vale University Health Board, Bone Research Unit, Cardiff University Academic Centre, Llandough Hospital, Penlan Road, Penarth, Vale of Glamorgan CF64 2XX, United Kingdom.
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    • JT and ME contributed equally to this work.

  • Matthias Eberl

    Corresponding author
    1. Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
    • Cardiff Institute of Infection and Immunity, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom.
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    • JT and ME contributed equally to this work.


Abstract

Aminobisphosphonates (NBPs) are used widely against excessive bone resorption in osteoporosis and Paget's disease as well as in metastatic bone disease and multiple myeloma. Intravenous NBP administration often causes mild to severe acute-phase responses (APRs) that may require intervention with analgesics and antipyretics and lead to treatment noncompliance and nonadherence. We here undertook a phase IV safety trial in patients with osteoporosis to investigate the APR of otherwise healthy individuals to first-time intravenous treatment with the NBP zoledronate. This study provides unique insight into sterile acute inflammatory responses in vivo, in the absence of confounding factors such as infection or cancer. Our data show that both peripheral γδ T cells and monocytes become rapidly activated after treatment with zoledronate, which ultimately determines the clinical severity of the APR. Our study highlights a key role for IFN-γ in the zoledronate-induced APR and identifies pretreatment levels of monocytes and central/memory Vγ9/Vδ2 T cells as well as their responsiveness to zoledronate in vitro as predictive risk factors for the occurrence of subclinical and clinical symptoms. These findings have diagnostic and prognostic implications for patients with and without malignancy and are relevant for Vγ9/Vδ2 T-cell–based immunotherapy approaches. © 2012 American Society for Bone and Mineral Research. © 2013 American Society for Bone and Mineral Research.

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