title: Can peripheral blood γδ T cells predict osteonecrosis of the jaw? An immunological perspective on the adverse drug effects of aminobisphosphonate therapy.
abstract: Nitrogen-bisphosphonates (n-BP), often referred to as aminobisphosphonates, are the most commonly prescribed drugs for the treatment of disorders of bone fragility. However, long-term continuous treatment predisposes certain individuals to serious rare side effects, such as bisphosphonate-associated osteonecrosis of the jaw (BAONJ). n-BP use is known to unintentionally activate a subset of innate T cells called Vγ9Vδ2 T cells, but the consequence of this chronic immune stimulation has remained unexplored. The primary objectives of this study were to 1) determine the fate of Vγ9Vδ2 T cells in osteoporotic patients on n-BP therapy as a function of time and type of therapy; 2) evaluate the proportion of Vγ9Vδ2 T cells in patients who had recently experienced n-BP-associated ONJ. We found there is a notable loss of Vγ9Vδ2 T cells over time in osteoporotic patients on n-BP therapy, particularly those on intravenous (iv) therapy (Spearman r = -0.55, p < 0.0001 iv; r = -0.3, p < 0.03 oral) (n = 68); no difference was observed in total T cells, monocytes, or granulocytes. Importantly, the observed negative effect on Vγ9Vδ2 T cells coincides with the reported route of administration and timing of the rare occurrence of BAONJ. Patients (n = 6) who had experienced BAONJ were all found to be significantly deficient in Vγ9Vδ2 T cells (median = 0.07%) in comparison to age- and sex-matched treatment-naïve controls (N = 11; median = 2.40%), U = 0, p = 0.001; this was the only consistent difference in the leukocytes assessed. All BAONJ cases had an underlying condition that further contributed to impaired immunity. We propose Vγ9Vδ2 T cells show a strong potential to serve as harbingers of possible adverse immune effects of n-BP therapy, particularly in those patients already having a compromised immune system as they may be most vulnerable to the development of conditions such as BAONJ.
authors.affiliation: Institute of Immunology, Christian-Albrechts University Kiel, Kiel, Germany. kalyan@immunologie.uni-kiel.de
authors.forename: Shirin
authors.initials: S
authors.lastname: Kalyan
authors.forename: Elgar Susanne
authors.initials: ES
authors.lastname: Quabius
authors.forename: Jörg
authors.initials: J
authors.lastname: Wiltfang
authors.forename: Heiner
authors.initials: H
authors.lastname: Mönig
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000368:Aged; D000369:Aged, 80 and over; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000097:blood* / Q000276:immunology*; D048429:Cell Size; D015331:Cohort Studies; D004164:Diphosphonates / Q000009:adverse effects*; D005260:Female; D006801:Humans; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010024:Osteoporosis / Q000188:drug therapy; D010641:Phenotype; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors
chemical_list: D004164:Diphosphonates; D016692:Receptors, Antigen, T-Cell, gamma-delta