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Aminobisphosphonates, particularly zoledronate, have a long-term effect on T cells


Two recent studies have investigated why an acute phase reaction (APR) occurs in some patients but not others after administration of intravenous zoledronate (ivZOL).

Rossini et al. studied five men and 63 women with osteoporosis given a single dose of 5 mg ivZOL. Twenty-three of those patients had never been treated with aminobisphosphonates (NBPs), 25 had been previously treated with oral NBPs other than ZOL and 15 patients had been given ivZOL 12 months earlier.

Blood analysis showed that patients who were NBP naive had significantly higher levels of circulating γδ T cells compared to patients previously treated with oral NBPs or ivZOL. More people in this group had an APR in response to ivZOL (57%) than in the oral NBP group (22%), while no patient in the group previously given ivZOL showed signs of an APR. Follow up one year after the ivZOL injection administered in this study showed that patients who had previously received oral NBPs or ivZOL had lower levels of circulating γδ T cells that patients given only the ivZOL injection.

Welton et al. performed a phase IV safety study on 19 female osteoporotic patients, which provides further insights. All patients, who were otherwise healthy and had no prior history of NBP use, were given ivZOL for the first time. Most patients (15/19) experienced signs of an APR, including elevated oral temperature, an increased pulse rate and raised levels of creatinine reactive protein. Administration of ivZOL caused a transient drop in γδ T cells of around 30% and an increase in monocytes.

It is suggested that ivZOL is presented to γδ T cells by monocytes, and this interaction and crosstalk leads to the changes that result in an APR. Although changes in the levels of γδ T cells and monocytes were found to be temporary in this study, long-term changes in other T-cell populations did occur; cenral memory T-cells were significantly reduced, which would lead to reduced production of interferon γ. This may explain why non-naive ZOL patients have a lower incidence of APR when they are given a subsequent dose of ivZOL, even a year later.

Editor’s comment: These two studies clarify the mechanisms of APR and desensitization that arise after administration of ivZOL and, more broadly, NBPs.

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