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Acute Phase Response After Zoledronic Acid is Associated with Long-Term Effects on White Blood Cells

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Abstract

We have recently reported a long-lasting decrease in circulating γδ T cells in osteoporotic patients on oral amino-bisphosphonates (N-BPs). Here we verify whether these changes are associated with the occurrence of acute phase response (APR) to intravenous (IV) zoledronic acid (ZOL) or changes of other circulating white blood cells (WBC). WBC count was obtained before and 1 year after a single IV administration of 5 mg ZOL in 36 osteoporotic patients (mean age 72 ± 9, range 45–86 years) without other relevant diseases; 12 of 36 patients developed the classical APR. After 1 year in the patients who experienced an APR, but not in the others, a significant decrease not only of γδ T cells (−30 %), but also of total lymphocytes (−11 %) and eosinophils (−27 %), was observed. The mechanism leading to the observed decrease of circulating lymphocytes and eosinophils remains unclear, but our observation opens a new frontier for the understanding of the immunoeffects of N-BPs.

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References

  1. Adami S, Bhalla AK, Dorizzi R, Montesanti F, Rosini S, Salvagno G, Lo Cascio V (1987) The acute-phase response after bisphoshonate administration. Calcif Tissue Int 41:326–333

    Article  PubMed  CAS  Google Scholar 

  2. Schweitzer DH, Oostendorp-van de Ruit M, Van der Pluijm G, Lowik CW, Papapoulos SE (1995) Interleukin-6 and the acute phase response during treatment of patients with Paget’s disease with the nitrogen-containing bisphosphonate dimethyl-amino-hydroxy-propylidene bisphosphonate. J Bone Miner Res 10:956–962

    Article  PubMed  CAS  Google Scholar 

  3. Kunzmann V, Bauer E, Wilhelm M (1999) Gamma/delta T-cell stimulation by pamidronate. N Engl J Med 340:737–738

    Article  PubMed  CAS  Google Scholar 

  4. Roelofs AJ, Jauhiainen M, Monkkonen H, Rogers MJ, Monkkonen J, Thompson K (2009) Peripheral blood monocytes are responsible for gamma delta T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br J Haematol 144:245–250

    Article  PubMed  Google Scholar 

  5. Miyagawa F, Tanaka Y, Yamashita S, Minato N (2001) Essential requirement of antigen presentation by monocyte lineage cells for the activation of primary human gamma delta T cells by aminobisphosphonate antigen. J Immunol 166:5508–5514

    PubMed  CAS  Google Scholar 

  6. Rossini M, Adami S, Viapiana O, Ortolani R, Vella A, Fracassi E, Gatti D (2012) Circulating γδ T cells and the risk of acute-phase response after zoledronic acid administration. J Bone Miner Res 27:227–230

    Article  PubMed  CAS  Google Scholar 

  7. Welton JL, Morgan MP, Martí S, Stone MD, Moser B, Sewell AK, Turton J, Eberl M (2013) Monocytes and γδ T cells control the acute phase response to intravenous zoledronate: insights from a phase IV safety trial. J Bone Miner Res 28:464–471

    Article  PubMed  CAS  Google Scholar 

  8. Rossini M, Adami S, Viapiana O, Fracassi E, Ortolani R, Vella A, Zanotti R, Tripi G, Idolazzi L, Gatti D (2012) Long-term effects of amino-bisphosphonates on circulating gammadelta T cells. Calcif Tissue Int 91:395–399

    Article  PubMed  CAS  Google Scholar 

  9. Kalyan S, Quabius ES, Wiltfang J, Mönig H, Kabelitz D (2013) Can peripheral blood γδ T cells predict osteonecrosis of the jaw? An immunological perspective on the adverse drug-effects of aminobisphosphonate therapy. J Bone Miner Res 28:728–735

    Article  PubMed  CAS  Google Scholar 

  10. Hayday AC (2009) Gammadelta T cells and the lymphoid stress–surveillance response. Immunity 31:184–196

    Article  PubMed  CAS  Google Scholar 

  11. Strid J, Roberts SJ, Filler RB, Lewis JM, Kwong BY, Schpero W, Kaplan DH, Hayday AC, Girardi M (2008) Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis. Nat Immunol 9:146–154

    Article  PubMed  CAS  Google Scholar 

  12. Tanaka Y, Morita CT, Tanaka Y, Nieves E, Brenner MB, Bloom BR (1995) Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature 375:155–158

    Article  PubMed  CAS  Google Scholar 

  13. Dieli F, Gebbia N, Poccia F, Caccamo N, Montesano C, Fulfaro F, Arcara C, Valerio MR, Meraviglia S, Di Sano C, Sireci G, Salerno A (2003) Induction of γδ T-lymphocyte effector functions by bisphosphonate zoledronic acid in cancer patients in vivo. Blood 102:2310–2311

    Article  PubMed  CAS  Google Scholar 

  14. Lymperi S, Ersek A, Ferraro F, Dazzi F, Horwood NJ (2011) Inhibition of osteoclast function reduces hematopoietic stem cell numbers in vivo. Blood 117:1540–1549

    Article  PubMed  CAS  Google Scholar 

  15. Van den Wyngaert T, Wouters K, Huizing MT, Vermorken JB (2011) RANK ligand inhibition in bone metastatic cancer and risk of osteonecrosis of the jaw (ONJ): non bis in idem? Support Care Cancer 19:2035–2040

    Article  PubMed  Google Scholar 

  16. Humbles AA, Lloyd CM, McMillan SJ, Friend DS, Xanthou G, McKenna EE, Ghiran S, Gerard NP, Yu C, Orkin SH, Gerard C (2004) A critical role for eosinophils in allergic airways remodeling. Science 305:1776–1779

    Article  PubMed  CAS  Google Scholar 

  17. Cheung PF, Wong CK, Lam CW (2008) Molecular mechanisms of cytokine and chemokine release from eosinophils activated by IL-17A, IL-17F, and IL-23: implication for Th17 lymphocytes-mediated allergic inflammation. J Immunol 180:5625–5635

    PubMed  CAS  Google Scholar 

  18. Kamiya N, Suzuki H, Endo T, Takano M, Yano M, Naoi M, Nishimi D, Kawamura K, Imamoto T, Ichikawa T (2011) Additive effect of zoledronic acid on serum prostate-specific antigen changes for hormone-sensitive prostate cancer patients with bone metastasis treated by combined androgen blockade. Int J Urol 19:169–173

    Article  PubMed  Google Scholar 

  19. Rennert G, Pinchev M, Rennert HS, Gruber SB (2011) Use of bisphosphonate and reduced risk of colorectal cancer. J Clin Oncol 29:1146–1150

    Article  PubMed  Google Scholar 

  20. Colón-Emeric CS, Mesenbrink P, Lyles KW, Pieper CF, Boonen S, Delmas P, Eriksen EF, Magaziner J (2010) Potential mediators of the mortality reduction with zoledronic acid after hip fracture. J Bone Miner Res 25:91–97

    Article  PubMed  Google Scholar 

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Correspondence to Silvano Adami.

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Rossini, M., Adami, S., Viapiana, O. et al. Acute Phase Response After Zoledronic Acid is Associated with Long-Term Effects on White Blood Cells. Calcif Tissue Int 93, 249–252 (2013). https://doi.org/10.1007/s00223-013-9750-6

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  • DOI: https://doi.org/10.1007/s00223-013-9750-6

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