Skip to main content

Advertisement

SpringerLink
Log in

Increased CD14+ and decreased CD14− populations of monocytes 48 h after zolendronic acid infusion in breast cancer patients

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

It has been proposed that bisphosphonates cause osteonecrosis of the jaws through impairment of the monocyte population function and proliferation. Such changes have been confirmed in jaw tissues, ex vivo. In this clinical study, we report for the first time a similar pattern of changes in peripheral blood monocytes.

Introduction

The aim of this study is to examine the effect of zolendronic acid administration in the peripheral blood white cell population, seeking a plausible pathophysiological link between bisphosphonates and osteonecrosis of the jaw.

Methods

Twenty-four breast cancer patients, under zolendronic acid treatment for bone metastasis, were included. Peripheral blood samples were obtained prior to and 48 h following zolendronic acid administration. Flow cytometry gated at leukocyte, monocyte, and the granulocyte populations for the CD4/CD8/CD3, CD3/CD16+56/CD45/CD19, CD14/CD123, and CD14/23 stainings were performed.

Results

We were able to record a number of changes in the white cell populations after 48 h of zolendronic acid administration. Most importantly, in the monocyte populations, we were able to detect statistically significant increased populations of CD14+/CD23+ (p = 0.038), CD14+/CD23− (p = 0.028), CD14+/CD123+ (p = 0.070, trend), and CD14+/CD123− (p = 0.043). In contrast, statistically significant decreased populations of CD14−/CD23+ (p = 0.037) and CD14−/CD123+ (p = 0.003) were detected.

Conclusions

Our results provide evidence supporting the hypothesis that bisphosphonate administration modifies the monocyte-mediated immune response. An increase of CD14+ peripheral blood monocyte (PBMC) populations along with a decrease of CD14− PBMC populations has been recorded. The latter finding is in accordance with limited—currently existing—evidence and warrants further elucidation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Khan AA, Morrison A, Hanley DA et al (2015) Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 30:3–23

    Article  PubMed  Google Scholar 

  2. Kyrgidis A, Triaridis S, Antoniades K (2009) Effects of bisphosphonates on keratinocytes and fibroblasts may have a role in the development of osteonecrosis of the jaw. Biosci Hypotheses 2:153–159

    Article  CAS  Google Scholar 

  3. Kyrgidis A, Triaridis S, Vahtsevanos K, Antoniades K (2009) Osteonecrosis of the jaw and bisphosphonate use in breast cancer patients. Expert Rev Anticancer Ther 9:1125–1134

    Article  PubMed  CAS  Google Scholar 

  4. Kyrgidis A, Yavropoulou M, Tilaveridis I, Andreadis C, Antoniades K, Kouvelas D (2015) A systematic review of bone anti-resorptive treatment toxicity in innate and adaptive immunity cells: osteonecrosis of the jaws and future implications. J Dentists 3:50–59

    Article  Google Scholar 

  5. Kyrgidis A, Tzellos T-G, Toulis K, Antoniades K (2011) The facial skeleton in patients with osteoporosis: a field for disease signs and treatment complications. Journal of Osteoporosis 2011:Article ID 147689, 147610 pages, doi:147610.144061/142011/147689

  6. Conwell LS, Chang AB (2014) Bisphosphonates for osteoporosis in people with cystic fibrosis. Cochrane Database of Syst Rev 3:CD002010

    Google Scholar 

  7. Sharma A, Einstein AJ, Vallakati A, Arbab-Zadeh A, Walker MD, Mukherjee D, Homel P, Borer JS, Lichstein E (2014) Risk of atrial fibrillation with use of oral and intravenous bisphosphonates. Am J Cardiol 113:1815–1821

    Article  PubMed  CAS  Google Scholar 

  8. Lee SH, Chang SS, Lee M, Chan RC, Lee CC (2013) Risk of osteonecrosis in patients taking bisphosphonates for prevention of osteoporosis: a systematic review and meta-analysis. Osteoporos Int 25:1131–1139

    Article  PubMed  CAS  Google Scholar 

  9. Kyrgidis A, Vahtsevanos K, Koloutsos G, Andreadis C, Boukovinas I, Teleioudis Z, Patrikidou A, Triaridis S (2008) Biphosphonate related osteonecrosis of the jaws: risk factors in breast cancer patients. A case control study. J Clin Oncol 26:4634–4638

    Article  PubMed  Google Scholar 

  10. Vahtsevanos K, Kyrgidis A, Verrou E et al (2009) Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 27:5356–5362

    Article  PubMed  CAS  Google Scholar 

  11. Hess LM, Jeter JM, Benham-Hutchins M, Alberts DS (2008) Factors associated with osteonecrosis of the jaw among bisphosphonate users. Am J Med 121(475–483):e473

    Google Scholar 

  12. Badros A, Terpos E, Katodritou E, Goloubeva O, Kastritis E, Verrou E, Zervas K, Baer MR, Meiller T, Dimopoulos MA (2008) Natural history of osteonecrosis of the jaw in patients with multiple myeloma. J Clin Oncol 26:5904–5909

    Article  PubMed  Google Scholar 

  13. Otto S, Marx RE, Tröltzsch M et al (2015) Comments on “diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus”. J Bone Miner Res 30:1113–1115

    Article  PubMed  Google Scholar 

  14. Cardona F, Bagán JV, Sáinz E, Figuerido J, Giner F, Vidán FJ (2009) Osteonecrosis de los maxilares por bisfosfonatos: Actualización y puesta al día. Anales del Sistema Sanitario de Navarra 32

  15. Khan AA, Morrison A, Hanley DA et al (2014) Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 30:3–23

    Article  Google Scholar 

  16. Kyrgidis A (2009) Novel hypotheses in the etiopathogenesis of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67:2554

    Article  PubMed  Google Scholar 

  17. Katsarelis H, Shah NP, Dhariwal DK, Pazianas M (2015) Infection and medication-related osteonecrosis of the jaw. J Dent Res 94:534–539

    Article  PubMed  CAS  Google Scholar 

  18. Pazianas M (2011) Osteonecrosis of the jaw and the role of macrophages. J Natl Cancer Inst 103:232–240

    Article  PubMed  Google Scholar 

  19. Reuter S, Lang D (2009) Life span of monocytes and platelets: importance of interactions. Front Biosci (Landmark Edition) 14:2432–2447

    Article  CAS  Google Scholar 

  20. Funda DP, Tuckova L, Farre MA, Iwase T, Moro I, Tlaskalova-Hogenova H (2001) CD14 is expressed and released as soluble CD14 by human intestinal epithelial cells in vitro: lipopolysaccharide activation of epithelial cells revisited. Infect Immun 69:3772–3781

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Ziegler-Heitbrock HW, Ulevitch RJ (1993) CD14: cell surface receptor and differentiation marker. Immunol Today 14:121–125

    Article  PubMed  CAS  Google Scholar 

  22. Jersmann HPA (2005) Time to abandon dogma: CD14 is expressed by non-myeloid lineage cells. Immunol Cell Biol 83:462–467

    Article  PubMed  CAS  Google Scholar 

  23. Zamani F, Zare Shahneh F, Aghebati-Maleki L, Baradaran B (2013) Induction of CD14 expression and differentiation to monocytes or mature macrophages in Promyelocytic cell lines: new approach. Adv Pharm Bull 3:329–332

    PubMed  PubMed Central  Google Scholar 

  24. Hoefert S, Schmitz I, Weichert F, Gaspar M, Eufinger H (2015) Macrophages and bisphosphonate-related osteonecrosis of the jaw (BRONJ): evidence of local immunosuppression of macrophages in contrast to other infectious jaw diseases. Clin Oral Investig 19:497–508

    Article  PubMed  Google Scholar 

  25. Marcu-Malina V, Balbir-Gurman A, Dardik R, Braun-Moscovici Y, Segel M, Bank I (2014) A novel prothrombotic pathway in systemic sclerosis patients: possible role of bisphosphonate activated γδ T cells. Front Immunol:5

  26. Biosciences B (2010) Human and mouse CD marker handbook. Becton, Dickinson and Company., San Jose, CA 95131

  27. Lecoanet-Henchoz S, Gauchat J-F, Aubry J-P et al (1995) CD23 regulates monocyte activation through a novel interaction with the adhesion molecules CD11b-CD18 and CD11c-CD18. Immunity 3:119–125

    Article  PubMed  CAS  Google Scholar 

  28. Armant M, Rubio M, Delespesse G, Sarfati M (1995) Soluble CD23 directly activates monocytes to contribute to the antigen-independent stimulation of resting T cells. J Immunol 155:4868–4875

    PubMed  CAS  Google Scholar 

  29. Bigley V, Haniffa M, Doulatov S et al (2011) The human syndrome of dendritic cell, monocyte, B and NK lymphoid deficiency. J Exp Med 208:227–234

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Roberts AW, He S, Ritchie D, Hertzberg MS, Kerridge I (2010) A phase I study of anti-CD123 monoclonal antibody (CD123) CSL360 targeting leukemia stem cells (LSC) in AML. J Clin Oncol 28

  31. Novak N, Allam JP, Hagemann T, Jenneck C, Laffer S, Valenta R, Kochan J, Bieber T (2004) Characterization of FcepsilonRI-bearing CD123 blood dendritic cell antigen-2 plasmacytoid dendritic cells in atopic dermatitis. J Allergy Clin Immunol 114:364–370

    Article  PubMed  CAS  Google Scholar 

  32. Ueda Y, Hagihara M, Okamoto A, Higuchi A, Tanabe A, Hirabayashi K, Izumi S, Makino T, Kato S, Hotta T (2003) Frequencies of dendritic cells (myeloid DC and plasmacytoid DC) and their ratio reduced in pregnant women: comparison with umbilical cord blood and normal healthy adults. Hum Immunol 64:1144–1151

    Article  PubMed  Google Scholar 

  33. Strobl H, Scheinecker C, Csmarits B, Majdic O, Knapp W (1995) Flow cytometric analysis of intracellular CD68 molecule expression in normal and malignant haemopoiesis. Br J Haematol 90:774–782

    Article  PubMed  CAS  Google Scholar 

  34. Gill S, Tasian S, Ruella M et al (2013) Anti-CD123 chimeric antigen receptor T cells (CART-123) provide a novel myeloablative conditioning regimen that eradicates human acute myeloid leukemia in preclinical models. Blood 122

  35. Mardiros A, Dos Santos C, McDonald T, et al (2013) T cells expressing CD123-specific cytolytic effector functions and anti-tumor effects against human acute myeloid leukemia. Blood.

  36. Skrzeczynska-Moncznik J, Bzowska M, Loseke S, Grage-Griebenow E, Zembala M, Pryjma J (2008) Peripheral blood CD14high CD16+ monocytes are main producers of IL-10. Scand J Immunol 67:152–159

    Article  PubMed  CAS  Google Scholar 

  37. Rossini M, Adami S, Viapiana O, Tripi G, Zanotti R, Ortolani R, Vella A, Troplini S, Gatti D (2013) Acute phase response after zoledronic acid is associated with long-term effects on white blood cells. Calcif Tissue Int 93:249–252

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  39. Thompson K, Roelofs AJ, Jauhiainen M, Monkkonen H, Monkkonen J, Rogers MJ (2010) Activation of gammadelta T cells by bisphosphonates. Adv Exp Med Biol 658:11–20

    Article  PubMed  CAS  Google Scholar 

  40. Kalyan S, Quabius ES, Wiltfang J, Monig H, Kabelitz D (2013) Can peripheral blood gammadelta 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 

  41. Kyrgidis A, Verrou E (2010) Fatigue in bone: a novel phenomenon attributable to bisphosphonate use. Bone 46:556

    Article  PubMed  CAS  Google Scholar 

  42. Anastasilakis AD, Toulis KA, Goulis DG, Polyzos SA, Delaroudis S, Giomisi A, Terpos E (2009) Efficacy and safety of denosumab in postmenopausal women with osteopenia or osteoporosis: a systematic review and a meta-analysis. Horm Metab Res 41:721–729

    Article  PubMed  CAS  Google Scholar 

  43. Zhou Z, Chen C, Zhang J, Ji X, Liu L, Zhang G, Cao X, Wang P (2014) Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis. Int J Clin Exp Pathol 7:2113–2122

    PubMed  PubMed Central  CAS  Google Scholar 

  44. Curtis JR, Xie F, Yun H, Saag KG, Chen L, Delzell E (2015) Risk of hospitalized infection among rheumatoid arthritis patients concurrently treated with a biologic agent and denosumab. Arthritis & Rheumatology 67:1456–1464

    Article  CAS  Google Scholar 

  45. Ji X, Pushalkar S, Li Y, Glickman R, Fleisher K, Saxena D (2012) Antibiotic effects on bacterial profile in osteonecrosis of the jaw. Oral Dis 18:85–95

    Article  PubMed  CAS  Google Scholar 

  46. Iwamoto S, Iwai S, Tsujiyama K, Kurahashi C, Takeshita K, Naoe M, Masunaga A, Ogawa Y, Oguchi K, Miyazaki A (2007) TNF-alpha drives human CD14+ monocytes to differentiate into CD70+ dendritic cells evoking Th1 and Th17 responses. J Immunol (Baltimore, Md : 1950) 179:1449–1457

    Article  CAS  Google Scholar 

  47. Tundup S, Srivastava L, Nagy T, Harn D (2012) CD14 deficiency enhances Th2 responses and alternative activation of macrophages in response to schistosome infection or IL-4. (117.10). The. J Immunol 188:117.110

    Google Scholar 

  48. WHITELAW DM, Bell M (1966) The intravascular lifespan of monocytes. Blood 28:455–464

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

AK, MY, and RL made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; AK, MY, RZ, CA, KA, and DK participated in drafting the manuscript or revising it critically for important intellectual content; AK, MY, RZ, CA, KA, and DK approved the final version of the submitted manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Clinical Pharmacology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

    A. Kyrgidis & D. Kouvelas

  2. Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Aristotle University of Thessaloniki, Thessaloniki, Greece

    A. Kyrgidis & K. Antoniades

  3. Laboratory of Clinical and Molecular Endocrinology, 1st Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece

    M. P. Yavropoulou

  4. Department of Neurology, AHEPA University Hospital, Thessaloniki, Greece

    R. Lagoudaki

  5. 3rd Department of Clinical Oncology, Theagenio Cancer Hospital, Thessaloniki, Greece

    C. Andreadis

Authors
  1. A. Kyrgidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. P. Yavropoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Lagoudaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Andreadis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. Antoniades
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D. Kouvelas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Kyrgidis.

Ethics declarations

The study was further approved by the Ethics Committee of the Theagenio Cancer Hospital.

Conflicts of interest

None.

Funding

The study was supported in part by the IKY Fellowships of Excellence for Postgraduate studies in Greece–Siemens Program, State Scholarships Foundation, Grant No. SR 229146. The funding source had no role in the study design, collection, analysis, and interpretation of the data, nor in the writing of the manuscript. A.K., M.Y., and R.L. had access to the raw data. The corresponding author had full access to all of the data and the final responsibility to submit for publication.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kyrgidis, A., Yavropoulou, M.P., Lagoudaki, R. et al. Increased CD14+ and decreased CD14− populations of monocytes 48 h after zolendronic acid infusion in breast cancer patients. Osteoporos Int 28, 991–999 (2017). https://doi.org/10.1007/s00198-016-3807-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-016-3807-0

Keywords

Search

Navigation