Skip to main content

Advertisement

SpringerLink
Log in

Influence of bisphosphonates on endothelial cells, fibroblasts, and osteogenic cells

  • Original Article
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript

Abstract

Bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) is a side effect primarily in patients receiving highly potent nitrogen-containing bisphosphonates. The exact etiopathology is unknown. In addition to reduced bone remodeling, there may also be an impact on soft tissues. The impact of nitrogen- (ibandronate, pamidronate, zoledronate) and non-nitrogen-containing bisphosphonates (clodronate) on human umbilicord vein endothelial cells (HUVEC), fibroblasts and osteogenic cells was analyzed employing cell viability testing and a scratch wound assay. The impact on the cell morphology of vital-stained osteogenic cells was investigated by cell visualization (confocal laser scanning microscopy). Pamidronate and zoledronate had the greatest negative impact on all cell lines, whereas the impact of ibandronate and clodronate was less distinct. The effect of clodronate on HUVEC and fibroblasts was particularly marginal. BP-ONJ could be a multifactorial event with multicellular impairments. This might result in altered wound healing. The increased impact of the highly potent bisphosphonates, particularly on non-bone cells, may explain the higher occurrence of BP-ONJ.

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
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Diel IJ, Bergner R, Grotz KA (2007) Adverse effects of bisphosphonates: current issues. J Support Oncol 5(10):475–482

    PubMed  Google Scholar 

  2. Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of jaws: a growing epidemic. J Oral Maxillofac Surg 61(9):1115–1117

    Article  PubMed  Google Scholar 

  3. Walter C, Grotz KA, Kunkel M et al (2007) Prevalence of bisphosphonate associated osteonecrosis of the jaw within the field of osteonecrosis. Support Care Cancer 15(2):197–202

    Article  PubMed  Google Scholar 

  4. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws AAoOaMS (2007) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 65(3):369–376

    Article  Google Scholar 

  5. Hoff AO, Toth BB, Altundag K et al (2008) Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 23(6):826–836

    Article  PubMed  Google Scholar 

  6. Aguiar Bujanda D, Bohn Sarmiento U, Cabrera Suarez MA et al (2007) Assessment of renal toxicity and osteonecrosis of the jaws in patients receiving zoledronic acid for bone metastasis. Ann Oncol 18(3):556–560

    Article  PubMed  Google Scholar 

  7. Boonyapakorn T, Schirmer I, Reichart PA et al (2008) Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 44(9):857–869

    Article  PubMed  Google Scholar 

  8. Wang EP, Kaban LB, Strewler GJ et al (2007) Incidence of osteonecrosis of the jaw in patients with multiple myeloma and breast or prostate cancer on intravenous bisphosphonate therapy. J Oral Maxillofac Surg 65(7):1328–1331

    Article  PubMed  Google Scholar 

  9. Walter C, Al-Nawas B, Grotz KA et al (2008) Prevalence and risk factors of bisphosphonate-associated osteonecrosis of the jaw in prostate cancer patients with advanced disease treated with zoledronate. Eur Urol 54(5):1066–1072

    Article  PubMed  Google Scholar 

  10. Rizzoli R, Burlet N, Cahall D et al (2008) Osteonecrosis of the jaw and bisphosphonate treatment for osteoporosis. Bone 42(5):841–847

    Article  PubMed  Google Scholar 

  11. Walter C, Al-Nawas B, Wagner W (2008) Implantology as a reason for bisphosphonate-associated-osteonecrosis of the jaws (BP-ONJ). Clin Oral Implants Res 19(9):850

    Google Scholar 

  12. Mashiba T, Mori S, Burr DB et al (2005) The effects of suppressed bone remodeling by bisphosphonates on microdamage accumulation and degree of mineralization in the cortical bone of dog rib. J Bone Miner Metab 23(Suppl):36–42

    Article  PubMed  Google Scholar 

  13. Santini D, Vincenzi B, Avvisati G et al (2002) Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 8(5):1080–1084

    PubMed  Google Scholar 

  14. Allegra A, Oteri G, Nastro E et al (2007) Patients with bisphosphonates-associated osteonecrosis of the jaw have reduced circulating endothelial cells. Hematol Oncol 25(4):164–169

    Article  PubMed  Google Scholar 

  15. Ziebart T, Yoon CH, Trepels T et al (2008) Sustained persistence of transplanted proangiogenic cells contributes to neovascularization and cardiac function after ischemia. Circ Res 103(11):1327–1334

    Article  PubMed  Google Scholar 

  16. Landesberg R, Cozin M, Cremers S et al (2008) Inhibition of oral mucosal cell wound healing by bisphosphonates. J Oral Maxillofac Surg 66(5):839–847

    Article  PubMed  Google Scholar 

  17. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63

    Article  PubMed  Google Scholar 

  18. Kim HJ, Kim SH, Kim MS et al (2005) Varying Ti-6Al-4V surface roughness induces different early morphologic and molecular responses in MG63 osteoblast-like cells. J Biomed Mater Res A 74(3):366–373

    PubMed  Google Scholar 

  19. Park BS, Heo SJ, Kim CS et al (2005) Effects of adhesion molecules on the behavior of osteoblast-like cells and normal human fibroblasts on different titanium surfaces. J Biomed Mater Res A 74(4):640–651

    PubMed  Google Scholar 

  20. Klein MO, Tapety F, Sandhöfer F et al (2006) Visualization of vital osteogenic cells on differently treated titanium surfaces using confocal laser scanning microscopy (CLSM)—a pilot study. Z Zahnärztl Implantol 21(4):145–153

    Google Scholar 

  21. Mashiba T, Hirano T, Turner CH et al (2000) Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 15(4):613–620

    Article  PubMed  Google Scholar 

  22. Rogers MJ, Watts DJ, Russell RG (1997) Overview of bisphosphonates. Cancer 80(8 Suppl):1652–1660

    Article  PubMed  Google Scholar 

  23. Marx RE, Sawatari Y, Fortin M et al (2005) Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63(11):1567–1575

    Article  PubMed  Google Scholar 

  24. Reszka AA, Halasy-Nagy J, Rodan GA (2001) Nitrogen-bisphosphonates block retinoblastoma phosphorylation and cell growth by inhibiting the cholesterol biosynthetic pathway in a keratinocyte model for esophageal irritation. Mol Pharmacol 59(2):193–202

    PubMed  Google Scholar 

  25. Reid IR, Bolland MJ, Grey AB (2007) Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone 41(3):318–320

    Article  PubMed  Google Scholar 

  26. Fleisch H (2003) Bisphosphonates in osteoporosis. Eur Spine J 12(Suppl 2):S142–S146

    Article  PubMed  Google Scholar 

  27. Rogers MJ, Gordon S, Benford HL et al (2000) Cellular and molecular mechanisms of action of bisphosphonates. Cancer 88(12 Suppl):2961–2978

    Article  PubMed  Google Scholar 

  28. Huja SS, Fernandez SA, Hill KJ et al (2006) Remodeling dynamics in the alveolar process in skeletally mature dogs. Anat Rec A Discov Mol Cell Evol Biol 288(12):1243–1249

    PubMed  Google Scholar 

  29. Ruggiero SL, Mehrotra B, Rosenberg TJ et al (2004) Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 62(5):527–534

    Article  PubMed  Google Scholar 

  30. Marx RE, Cillo JE Jr, Ulloa JJ (2007) Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 65(12):2397–2410

    Article  PubMed  Google Scholar 

  31. Montazeri AH, Erskine JG, McQuaker IG (2007) Oral sodium clodronate induced osteonecrosis of the jaw in a patient with myeloma. Eur J Haematol 79(1):69–71

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

The authors thank Johanna Adler for CLSM image acquisition.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, Johannes Gutenberg University—Mainz, Augustusplatz 2, 55131, Mainz, Germany

    C. Walter, M. O. Klein, A. Pabst, B. Al-Nawas & T. Ziebart

  2. Institute of Applied Structure and Microanalysis, Johannes Gutenberg University—Mainz, Obere Zahlbacher Str. 63, 55101, Mainz, Germany

    H. Duschner

Authors
  1. C. Walter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. O. Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Pabst
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B. Al-Nawas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. Duschner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. Ziebart
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Walter.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Walter, C., Klein, M.O., Pabst, A. et al. Influence of bisphosphonates on endothelial cells, fibroblasts, and osteogenic cells. Clin Oral Invest 14, 35–41 (2010). https://doi.org/10.1007/s00784-009-0266-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-009-0266-4

Keywords

Search

Navigation