Reply

To the Editor: We read with interest the recent article by Reinhardt et al reporting on the abundance of activated g/d T cells in the enthesis, ciliary body, and aortic valve in Tcrd-H2BeGFP mice (1). The clinical implications of these findings might be relevant. We suggest, for example, that this particular localization of g/d T cells may explain the adverse effects of certain drugs. Zoledronic acid is a drug used to treat osteoporosis, Paget’s disease, and bone metastasis (2). The use of intravenous zoledronic acid is occasionally associated with the appearance of an acute-phase response within 24–36 hours, mainly characterized by fever, musculoskeletal symptoms (principally pain and stiffness of the joints, which suggest an inflammatory reaction, possibly enthesitis), and eye inflammation (3). In particular, in some cases, uveitis has been observed after infusion (4). Moreover, it is known that zoledronic acid might induce arrhythmias (atrial fibrillation, in particular) (5). Nitrogen-containing bisphosphonates, such as zoledronic acid, inhibit osteoclastic bone resorption by blocking farnesyl pyrophosphate synthase, an enzyme in the mevalonate pathway, leading to accumulation of isopentenyl diphosphate and dimethyl-allyl diphosphate in monocytes. This results in the activation of adjacent g/d T cells and the release of interferon-g and tumor necrosis factor (6). We have previously demonstrated that higher numbers of circulating g/d T cells before zoledronic acid infusion correlate with a higher risk of acute-phase reactions (7). In addition, g/d T cell numbers decrease after the infusion and were found to be lower than before zoledronic acid treatment, even at 12-month follow-up (8). This effect on circulating lymphocytes may be attributed to the activation, differentiation, and homing of these cells at tissue levels (9). Akitsu et al have found increased homing of g/d T cells in mice with inflammatory arthritis (10). Given their localization in the enthesis and ciliary body of mice, we hypothesize that g/d T cells, activated by zoledronic acid, might induce articular inflammation and uveitis. Moreover, the localization of activated g/d T cells in the aortic valve may suggest that they have a role even in arrhythmias, in particular, atrial fibrillation, which has been reported as an adverse effect of zoledronic acid infusion.