Long-Term Effects of Amino-Bisphosphonates on Circulating γδ T Cells

Abstract

The aim of this study was to explore whether desensitization to the occurrence of the acute-phase response (APR) in patients previously treated with amino-bisphosphonates (N-BPs) is due to a long-lasting reduction in the number of circulating γδ T cells. Circulating lymphocyte subpopulation counts were obtained from 63 patients with postmenopausal or senile osteoporosis at baseline and after 2 days and 12 months of the first intravenous (IV) 5 mg zoledronic acid (ZOL) infusion. At baseline both the proportion and absolute number of circulating γδ T cells were significantly higher in patients who had never used N-BPs vs. previous users, either oral or IV. A typical APR was observed in none of the patients given IV ZOL a year earlier, in 6 (22 %) of the patients previously treated with oral N-BPs, and in 13 (57 %) of the patients naive to any N-BP treatment. In patients naive to N-BPs, a significant reduction in both total lymphocytes and their subsets was observed 2 days after ZOL infusion; all these changes returned to baseline values 1 year later with the exception of γδ T cells, which remained significantly lower in terms of both proportion and absolute number. These results indicate for the first time that both IV and oral N-BP treatments are associated with a long-lasting decrease in circulating γδ T cells, and this may explain the lower incidence of APR in patients previously exposed to N-BPs. Other clinical implications of this sustained effect of N-BPs on immune-regulatory cells might be important.

Osteonecrosis of the Jaw Developed in Mice

“…The repeated BP injections are postulated to result in the repeated activation of V␥9V␦2 T cells leading to eventual ␥␦ T cell depletion (17,18). It is tempting to speculate that the decreased circulating V␥9V␦2 T cells may causally associate with the development of nonexposure and fistula phenotype of ONJ in humans.…”

“…A deficiency in circulating ␥␦ T cells has been reported in patients with long term and repeated BP administrations (17,18), and BP-induced ␥␦ T cell deficiency was postulated to promote an underlying susceptibility to the development of ONJ (17). Because ␥␦ T cells are preferentially involved in barrier immunity (19,20), we hypothesized that the ␥␦ T cells in the oral barrier tissue play an important role in the development of ONJ.…”

Effect of different doses of zoledronic acid in establishing of bisphosphonate-related osteonecrosis

“…Knowing that ZA is myelotoxic 12 and has effects on the number of circulating leukocytes (acutely and chronically) 20,21 we performed haematological analysis throughout the experimental protocol. Each week, beginning on the 6th day of the first dose of ZA, 2 mL of blood (retro-orbital plexus) was collected.…”

Rheumatoid arthritis, γδ T cells and bisphosphonates

“…The latter is referred to as the acute phase response (APR) and it is linked to the activation of γδ T cells (in particular their major subpopulation of Vδ2 T cells) and the release of the pyrogenic cytokines such as IFN-γ and TNF-α 8. We observed that the proportion of circulating γδ T cells is an important determinant of the occurrence of APR after administration of N-BPs,9 and that N-BP treatment is associated with a decrease in circulating γδ T cells for at least 1 year,10 in particular in the patients with APR 11. The decrease in circulating γδ T cells could be attributed to the differentiation and homing at tissue levels of these cells 12.…”