Effects of an oral bisphosphonate and three intravenous bisphosphonates on several cell types in vitro
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To analyze the influence of an oral bisphosphonate and compare the potency to intravenous bisphosphonates on various cell types as regards the rarity of bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ) caused by oral bisphosphonate.
Materials and methods
A viability assay (MTT), a migration assay (Boyden chamber), and an apoptosis assay (Caspase-Glo® 3/7) were performed to analyze the effect of bisphosphonates on human fibroblasts, umbilical vein endothelial cells (HUVEC), and osteoblasts.
Alendronate and intravenous bisphosphonates suppressed cell viability and migration, and induced apoptosis in all tested cell types. Alendronate had a greater impact than ibandronate on the characteristics in fibroblasts and osteoblasts but not as strong as zoledronate.
The incidence of BP-ONJ in oral bisphosphonate treatment is reported to be much lower than that in intravenous bisphosphonates. However, the influences of alendronate on human cells were at least as strong as ibandronate, although it was lower than zoledronate.
Alendronate showed strong enough effects to suppress human somatic cells and was comparable to certain intravenous bisphosphonates in potency. This study suggests that the lower incidence of BP-ONJ in alendronate treatment is not originated by its potency, but might be due to the low bioavailability of alendronate, lower dosing on a daily basis, and having no additional therapies.
KeywordsBisphosphonate Alendronate Bisphosphonate-associated osteonecrosis of the jaw BP-ONJ HUVEC Fibroblasts Osteoblasts
The part of this work was presented in thesis form for the doctoral dissertation for Junho Jung from Johannes-Gutenberg University Mainz.
This study was funded by the International Team for Implantology (ITI) scholarship program (to the first author).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent is not required for this study.
- 2.Terpos E, Kleber M, Engelhardt M, Zweegman S, Gay F, Kastritis E, van de Donk NW, Bruno B, Sezer O, Broijl A, Bringhen S, Beksac M, Larocca A, Hajek R, Musto P, Johnsen HE, Morabito F, Ludwig H, Cavo M, Einsele H, Sonneveld P, Dimopoulos MA, Palumbo A, European Myeloma N (2015) European Myeloma Network guidelines for the management of multiple myeloma-related complications. Haematologica 100(10):1254–1266. https://doi.org/10.3324/haematol.2014.117176 CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Stresing V, Fournier PG, Bellahcene A, Benzaid I, Monkkonen H, Colombel M, Ebetino FH, Castronovo V, Clezardin P (2011) Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase. Bone 48(2):259–266. https://doi.org/10.1016/j.bone.2010.09.035 CrossRefPubMedGoogle Scholar
- 12.Acil Y, Moller B, Niehoff P, Rachko K, Gassling V, Wiltfang J, Simon MJ (2012) The cytotoxic effects of three different bisphosphonates in-vitro on human gingival fibroblasts, osteoblasts and osteogenic sarcoma cells. J Craniomaxillofac Surg 40(8):e229–e235. https://doi.org/10.1016/j.jcms.2011.10.024 CrossRefPubMedGoogle Scholar
- 18.Kyle RA, Yee GC, Somerfield MR, Flynn PJ, Halabi S, Jagannath S, Orlowski RZ, Roodman DG, Twilde P, Anderson K, American Society of Clinical O (2007) American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 25(17):2464–2472. https://doi.org/10.1200/JCO.2007.12.1269 CrossRefPubMedGoogle Scholar
- 19.Boonyapakorn T, Schirmer I, Reichart PA, Sturm I, Massenkeil G (2008) Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 44(9):857–869. https://doi.org/10.1016/j.oraloncology.2007.11.012 CrossRefPubMedGoogle Scholar
- 20.Walter C, Al-Nawas B, Grotz KA, Thomas C, Thuroff JW, Zinser V, Gamm H, Beck J, Wagner W (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. https://doi.org/10.1016/j.eururo.2008.06.070 CrossRefPubMedGoogle Scholar
- 22.Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, Koutsoukou V, Gika D, Anagnostopoulos A, Papadimitriou C, Terpos E, Dimopoulos MA (2005) Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23(34):8580–8587. https://doi.org/10.1200/JCO.2005.02.8670 CrossRefPubMedGoogle Scholar
- 23.Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, Nooka A, Sayegh G, Guarneri V, Desrouleaux K, Cui J, Adamus A, Gagel RF, Hortobagyi GN (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. https://doi.org/10.1359/jbmr.080205 CrossRefPubMedGoogle Scholar
- 24.Dimopoulos MA, Kastritis E, Anagnostopoulos A, Melakopoulos I, Gika D, Moulopoulos LA, Bamia C, Terpos E, Tsionos K, Bamias A (2006) Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: evidence of increased risk after treatment with zoledronic acid. Haematologica 91(7):968–971PubMedGoogle Scholar
- 28.Kwon JW, Park EJ, Jung SY, Sohn HS, Ryu H, Suh HS (2015) A large national cohort study of the association between bisphosphonates and osteonecrosis of the jaw in patients with osteoporosis: a nested case-control study. J Dent Res 94(9 Suppl):212S–219S. https://doi.org/10.1177/0022034515587862 CrossRefPubMedGoogle Scholar
- 30.Misso G, Porru M, Stoppacciaro A, Castellano M, De Cicco F, Leonetti C, Santini D, Caraglia M (2012) Evaluation of the in vitro and in vivo antiangiogenic effects of denosumab and zoledronic acid. Cancer Biol Ther 13(14):1491–1500. https://doi.org/10.4161/cbt.22274 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Manzano-Moreno FJ, Ramos-Torrecillas J, De Luna-Bertos E, Ruiz C, Garcia-Martinez O (2015) High doses of bisphosphonates reduce osteoblast-like cell proliferation by arresting the cell cycle and inducing apoptosis. J Craniomaxillofac Surg 43(3):396–401. https://doi.org/10.1016/j.jcms.2014.12.008 CrossRefPubMedGoogle Scholar
- 34.Fisher JE, Rosenberg E, Santora AC, Reszka AA (2013) In vitro and in vivo responses to high and low doses of nitrogen-containing bisphosphonates suggest engagement of different mechanisms for inhibition of osteoclastic bone resorption. Calcif Tissue Int 92(6):531–538. https://doi.org/10.1007/s00223-013-9711-0 CrossRefPubMedGoogle Scholar
- 35.Otto S, Pautke C, Opelz C, Westphal I, Drosse I, Schwager J, Bauss F, Ehrenfeld M, Schieker M (2010) Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism. J Oral Maxillofac Surg 68(11):2837–2845. https://doi.org/10.1016/j.joms.2010.07.017 CrossRefPubMedGoogle Scholar