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Published in: BMC Musculoskeletal Disorders 1/2015

Open Access 01-12-2015 | Research article

The effects of zoledronate on the survival and function of human osteoblast-like cells

Authors: Kuo-Chin Huang, Chin-Chang Cheng, Po-Yao Chuang, Tien-Yu Yang

Published in: BMC Musculoskeletal Disorders | Issue 1/2015

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Abstract

Background

Prolonged bisphosphonate treatment might suppress bone remodeling to the extent that normal bone repair is impaired. While this adverse side effect is usually ascribed to the negative effects of bisphosphonates on osteoclast survival and function, these effects on osteoblasts are still unclear.

Methods

In the current study, we hypothesized that zoledronate (ZOL) at the μM level might present negative effects on osteoblast survival and function. In vitro analyses of proliferation, migration and differentiation were performed on human osteoblast-like cells.

Results

Our results revealed that ZOL treatment dose- and time-dependently induced apoptosis of osteoblasts after concentrations had reached 10 μM (p < 0.001). The concentrations at which ZOL inhibited osteoblast migration by 50 % were between 10 and 15 μM. Moreover, there was a dose-dependent reduction in the extent of matrix mineralization, but without a concomitant inhibition of osteogenic differentiation in terms of secreted type I collagen and osteocalcin and of alkaline phosphatase activity per viable cell. Analyses of the expression of osteogenic genes confirmed that ZOL at the μM level had no effects on osteogenic differentiation of osteoblasts.

Conclusion

We concluded that ZOL at the μM level affected osteoblast survival and migration, but did not affect differentiation. The pathophysiological implications of ZOL at the μM level on skeletal disorders need to be investigated and clarified in the future researches.
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Literature
1.
2.
go back to reference Coxon FP, Thompson K, Rogers MJ. Recent advances in understanding the mechanism of action of bisphosphonates. Curr Opin Pharmacol. 2006;6:307–12.CrossRefPubMed Coxon FP, Thompson K, Rogers MJ. Recent advances in understanding the mechanism of action of bisphosphonates. Curr Opin Pharmacol. 2006;6:307–12.CrossRefPubMed
4.
go back to reference Jung A, Bisaz S, Fleisch H. The binding of pyrophosphate and two diphosphonates by hydroxyapatite crystals. Calcif Tissue Res. 1973;11:269–80.CrossRefPubMed Jung A, Bisaz S, Fleisch H. The binding of pyrophosphate and two diphosphonates by hydroxyapatite crystals. Calcif Tissue Res. 1973;11:269–80.CrossRefPubMed
5.
go back to reference van Beek E, Pieterman E, Cohen L, Löwik C, Papapoulos S. Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun. 1999;264:108–11.CrossRefPubMed van Beek E, Pieterman E, Cohen L, Löwik C, Papapoulos S. Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biochem Biophys Res Commun. 1999;264:108–11.CrossRefPubMed
6.
go back to reference Rousselle AV, Heymann D. Osteoclastic acidification pathways during bone resorption. Bone. 2002;30:533–40.CrossRefPubMed Rousselle AV, Heymann D. Osteoclastic acidification pathways during bone resorption. Bone. 2002;30:533–40.CrossRefPubMed
7.
go back to reference Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799–809.CrossRefPubMed Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799–809.CrossRefPubMed
8.
go back to reference Chesnutt III CH, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241–9.CrossRef Chesnutt III CH, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241–9.CrossRef
9.
go back to reference Duque G, Rivas D. Alendronate has an anabolic effect on bone through the differentiation of mesenchymal stem cells. J Bone Miner Res. 2007;22:1603–11.CrossRefPubMed Duque G, Rivas D. Alendronate has an anabolic effect on bone through the differentiation of mesenchymal stem cells. J Bone Miner Res. 2007;22:1603–11.CrossRefPubMed
10.
go back to reference Plotkin LI, Manolagas SC, Bellido T. Dissociation of the pro-apoptotic effects of bisphosphonates on osteoclasts from their anti-apoptotic effects on osteoblast/osteocytes with novel analogs. Bone. 2006;39:443–52.CrossRefPubMed Plotkin LI, Manolagas SC, Bellido T. Dissociation of the pro-apoptotic effects of bisphosphonates on osteoclasts from their anti-apoptotic effects on osteoblast/osteocytes with novel analogs. Bone. 2006;39:443–52.CrossRefPubMed
11.
go back to reference Park-Wyllie LY, Mamdani MM, Juurlink DN, Hawker GA, Gunraj N, Austin PC, et al. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA. 2011;305:783–9.CrossRefPubMed Park-Wyllie LY, Mamdani MM, Juurlink DN, Hawker GA, Gunraj N, Austin PC, et al. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA. 2011;305:783–9.CrossRefPubMed
12.
go back to reference Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90:1294–301.CrossRefPubMed Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90:1294–301.CrossRefPubMed
13.
go back to reference Tobias JH, Chow JW, Chambers TJ. 3-Amino-1-hydroxypropylidine-1-bisphosphonate (AHPrBP) suppresses not only the induction of new, but also the persistence of existing bone-forming surfaces in rat cancellous bone. Bone. 1993;14:619–23.CrossRefPubMed Tobias JH, Chow JW, Chambers TJ. 3-Amino-1-hydroxypropylidine-1-bisphosphonate (AHPrBP) suppresses not only the induction of new, but also the persistence of existing bone-forming surfaces in rat cancellous bone. Bone. 1993;14:619–23.CrossRefPubMed
14.
go back to reference Kozloff KM, Volakis LI, Marini JC, Caird MS. Near-infrared fluorescent probe traces bisphosphonate delivery and retention in vivo. J Bone Miner Res. 2010;25:1748–58.CrossRefPubMed Kozloff KM, Volakis LI, Marini JC, Caird MS. Near-infrared fluorescent probe traces bisphosphonate delivery and retention in vivo. J Bone Miner Res. 2010;25:1748–58.CrossRefPubMed
15.
go back to reference Otto S, Pautke C, Opelz C, Westphal I, Drosse I, Schwager J, et al. Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism. J Oral Maxillofacial Surg. 2010;68:2837–45.CrossRef Otto S, Pautke C, Opelz C, Westphal I, Drosse I, Schwager J, et al. Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism. J Oral Maxillofacial Surg. 2010;68:2837–45.CrossRef
16.
go back to reference Liberman UA. Long-term safety of bisphosphonate therapy for osteoporosis: a review of the evidence. Drugs Aging. 2006;23:289–98.CrossRefPubMed Liberman UA. Long-term safety of bisphosphonate therapy for osteoporosis: a review of the evidence. Drugs Aging. 2006;23:289–98.CrossRefPubMed
17.
go back to reference Ebert R, Zeck S, Krug R, Meissner-Weigl J, Schneider D, Seefried L, et al. Pulse treatment with zoledronic acid causes sustained commitment of bone marrow derived mesenchymal stem cells for osteogenic differentiation. Bone. 2009;44:858–64.CrossRefPubMed Ebert R, Zeck S, Krug R, Meissner-Weigl J, Schneider D, Seefried L, et al. Pulse treatment with zoledronic acid causes sustained commitment of bone marrow derived mesenchymal stem cells for osteogenic differentiation. Bone. 2009;44:858–64.CrossRefPubMed
18.
go back to reference Issack PS, Lauerman MH, Helfet DL, Doty SB, Lane JM. Alendronate inhibits PTH (1–34)-induced bone morphogenetic protein expression in MC3T3-E1 preosteoblastic cells. HSS J. 2007;3:169–72.PubMedCentralCrossRefPubMed Issack PS, Lauerman MH, Helfet DL, Doty SB, Lane JM. Alendronate inhibits PTH (1–34)-induced bone morphogenetic protein expression in MC3T3-E1 preosteoblastic cells. HSS J. 2007;3:169–72.PubMedCentralCrossRefPubMed
19.
go back to reference Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006;38:617–27.CrossRefPubMed Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006;38:617–27.CrossRefPubMed
20.
go back to reference Chapurlat RD, Delmas PD. Bone microdamage: a clinical perspective. Osteoporos Int. 2009;20:1299–308.CrossRefPubMed Chapurlat RD, Delmas PD. Bone microdamage: a clinical perspective. Osteoporos Int. 2009;20:1299–308.CrossRefPubMed
21.
go back to reference Norman TL, Wang Z. Microdamage of human cortical bone: incidence and morphology in long bones. Bone. 1997;20:375–9.CrossRefPubMed Norman TL, Wang Z. Microdamage of human cortical bone: incidence and morphology in long bones. Bone. 1997;20:375–9.CrossRefPubMed
Metadata
Title
The effects of zoledronate on the survival and function of human osteoblast-like cells
Authors
Kuo-Chin Huang
Chin-Chang Cheng
Po-Yao Chuang
Tien-Yu Yang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2015
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-015-0818-5

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