Local Application of Alendronate on β-Tricalcium Phosphate Accelerated Induction of Osteogenesis with Formation of Giant Osteoclast-Like Cell

DOI: 10.4236/jbnb.2012.32023   PDF   HTML     5,200 Downloads   7,681 Views   Citations


Intrinsic osteoinductivity—the ability to induce bone formation in ectopic sites without addition of osteogenic factors has been reported in various porous materials. Tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells are thought to play an important role in material-induced osteoinduction. To investigate the influence of osteoclastic activity on intrinsic osteoinduction, we loaded alendronate (10–2 , 10–4 , and 10–6 M) onto porous β-tricalcium phosphate (β-TCP) blocks to inhibit osteoclastic activity, and evaluated osteoinductivity by implantation of the blocks into the dorsal muscles of adult beagle dogs. Alendronate-loaded porous β-TCP blocks increased both speed and amount of osteoinduction, as measured 4 weeks after implantation, with the 10–4 M alendronate-loaded β-TCP being especially active. This finding indicates that β-TCP loaded with 10–4 M alendronate might prove crucial in providing the desirable balance between the degradation rate of bone scaffolds and their osteoinductive replacement. Thus, material-induced osteoinduction may be controlled by local application of alendronate, establishing alendronate loading as a promising therapeutic approach.

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C. Fukuda, N. Akiyama, M. Takemoto, S. Fujibayashi, M. Neo and T. Nakamura, "Local Application of Alendronate on β-Tricalcium Phosphate Accelerated Induction of Osteogenesis with Formation of Giant Osteoclast-Like Cell," Journal of Biomaterials and Nanobiotechnology, Vol. 3 No. 2, 2012, pp. 169-177. doi: 10.4236/jbnb.2012.32023.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] G. D. Winter and B. J. Simpson, “Heterotopic Bone Formed in a Synthetic Sponge in the Skin of Young Pigs,” Nature, Vol. 223, 1969, pp. 88-90. doi:10.1038/223088a0
[2] U. Ripamonti, “The Morphogenesis of Bone in Replicas of Porous Hydroxyapatite Obtained from Conversion of Calcium Carbonate Exoskeletons of Coral,” Journal of Bone and Joint Surgery, Vol. 73, No. 5, 1991, pp. 692- 703.
[3] H. Yamasaki and H. Sakai, “Osteogenic Response to Porous Hydroxyapatite Ceramics under the Skin of Dogs,” Biomaterials, Vol. 13, No. 5, 1992, pp. 308-312. doi:10.1016/0142-9612(92)90054-R
[4] U. Ripamonti, “Osteoinduction in Porous Hydroxyapatite Implanted in Heterotopic Sites of Different Animal Models,” Biomaterials, Vol. 17, No. 1, 1996, pp. 31-35. doi:10.1016/0142-9612(96)80752-6
[5] H. Yuan, Z. Yang, Y. Li, X. Zhang, J. D. De Bruijn and K. De Groot, “Osteoinduction by Calcium Phosphate Biomaterials,” Journal of Materials Science: Materials in Medicine , Vol. 9, No. , 1998, pp. 723-726. doi:10.1023/A:1008950902047
[6] H. Yuan, Y. Li, J. D. de Bruijn, K. de Groot and X. Zhang, “Tissue Responses of Calcium Phosphate Cement: A Study in Dogs,” Biomaterials, Vol. 21, No. 12, 2000 pp. 1283-1290. doi:10.1016/S0142-9612(00)00016-8
[7] H. Yuan, J. D. de Bruijn, X. Zhang, C. A. van Blitterswijk and K. de Groot, “Bone Induction by Porous Glass Ceramic Made from Bioglass (45S5),” Journal of Biomedical Materials Research, Vol. 58, No. 3, 2001, pp. 270-276. doi:10.1002/1097-4636(2001)58:3<270::AID-JBM1016>3.0.CO;2-2
[8] P. Habibovic, C. M. van der Valk, C. A. van Blitterswijk, K. De Groot and G. Meijer, ”Influence of Octacalcium Phosphate Coating on Osteoinductive Properties of Biomaterials,” Journal of Materials Science: Materials in Medicine, Vol. 15, No. 4, 2004, pp. 373-380. doi:10.1023/B:JMSM.0000021104.42685.9f
[9] D. Le Nihouannen, G. Daculsi, A. Saffarzadeh, O. Gauthier, S. Delplace, P. Pilet, et al., “Ectopic Bone Formation by Microporous Calcium Phosphate Ceramic Particles in Sheep Muscles,” Bone, Vol. 36, No. 6, 2005, pp. 1086-1093. doi:10.1016/j.bone.2005.02.017
[10] S. Fujibayashi, M. Neo, H. M. Kimb, T. Kokubo and T. Nakamura, “Osteoinduction of Porous Bioactive Titanium Metal,” Biomaterials, Vol. 25, No. 3, 2004, pp. 443-450. doi:10.1016/S0142-9612(03)00551-9
[11] Z. Zhang, H. Kurita, H. Kobayashi and K. Kurashina, “Osteoinduction with HA/TCP Ceramics of Different Composition and Porous Structure in Rabbits,” Oral Science International, Vol. 2, No. 2, 2005, pp. 85-95.
[12] H. Yuan, K. Kurashina, J. D. de Bruijn, Y. Li, K. de Groot and X. Zhang, “A Preliminary Study on Osteoinduction of Two Kinds of Calcium Phosphate Ceramics,” Biomaterials, Vol. 20, No. 19, 1999, pp. 1799-1806. doi:10.1016/S0142-9612(99)00075-7
[13] M. C. Kruyt, W. J. Dhert, C. Oner, C. A. van Blitterswijk and A. J. Verbout, J. D. de Bruijn, “Optimization of Bone—Tissue Engineering in Goats,” Journal of Biomedical Materials Research Part B: Applied Biomaterials, Vol. 69, 2004, No. 2, pp. 113-120. doi:10.1002/jbm.b.10073
[14] A. Fukuda, M. Takemoto, T. Saito, S. Fujibayashi, M. Neo, D. K. Pattanayak, et al., “Osteoinduction of Porous Ti Implants with a Channel Structure Fabricated by Selective Laser Melting,” Acta Biomaterialia, Vol. 7, No. 5, 2011, pp. 2327-2336. doi:10.1016/j.actbio.2011.01.037
[15] P. Habibovic, H. Yuan, C. M. van der Valk, G. Meijer, C. A. van Blitterswijk and K. de Groot, “3D Micro-environment as Essential Element for Osteoinduction by Biomaterials,” Biomaterials, Vol. 26, No. 17, 2005, pp. 3565-3575. doi:10.1016/j.biomaterials.2004.09.056
[16] Z. Yang, H. Yuan, W. Tong, P. Zou, W. Chen and X. Zhang, “Osteogenesis in Extraskeletally Implanted Porous Calcium Phosphate Ceramics: Variability among Different Kinds of Animals,” Biomaterials, Vol. 17, No. 22, 1996, pp. 2131-2137. doi:org/10.1016/0142-9612(96)00044-0
[17] N. Akiyama, M. Takemoto, S. Fujibayashi, M. Neo, M. Hirano and T. Nakamura, “Difference between Dogs and Rats with Regard to Osteoclast-Like Cells in Calcium- Deficient Hydroxyapatite-Induced Osteoinduction,” Journal of Bio-medical Materials Research Part A, Vol. 96, No. , 2011, pp. 402-412. doi:org/10.1002/jbm.a.32995
[18] N. Kondo, A. Ogose, K. Tokunaga, H. Umezu, K. Arai, N. Kudo, et al., “Osteoinduction with Highly Purified β- Tricalcium Phosphate in dog Dorsal Muscles and the Proliferation of Osteoclasts before Heterotopic Bone For- mation,” Biomaterials, Vol. 27, No. 25, 2006, pp. 4419- 4427. doi:10.1016/j.biomaterials.2006.04.016
[19] T. Nasu, M. Takemoto, N. Akiyama, S. Fujibayashi, M. Neo and T. Nakamura, “EP4 Agonist Accelerates Osteo-induction and Degradation of Beta-Tricalcium Phosphate by Stimulating Osteoclastogenesis,” Journal of Biomedical Materials Research Part A, Vol. 89, No. 3, 2009, pp. 601- 608.
[20] F. P. Coxon, M. H. Helfrich, R. Van’t Hof , S. Sebti, S. H. Ralston, A. Hamilton, et al., “Protein Geranylgeranylation is Required for Osteoclast Formation, Function, and Survival: Inhibition by Bisphosphonates and GGTI-298,” Journal of Bone and Mineral Research, Vol. 15, No. 8, 2000, pp. 1467-1476. doi:10.1359/jbmr.2000.15.8.1467
[21] R. G. Russell, “Bisphosphonates: From Bench to Bedside,” Annals of the New York Academy of Sciences, Vol. 1068, 2006, pp. 367-401. doi:10.1196/annals.1346.041
[22] R. Balena, B. C. Toolan, M. Shea, A. Markatos, E. R Myers, S. C. Lee, et al., “The Effects of 2-Year Treatment with the Aminobisphosphonate Alendronate on Bone Metabolism, Bone Histomorphometry, and Bone Strength in Ovariectomized Nonhuman Primates,” Journal of Clinical Investigation, Vol. 92, No. 6, 1993, pp. 2577- 2586. doi:10.1172/JCI116872
[23] R. S. Weinstein, P. K. Roberson and S. C. Manolagas, “Giant Osteoclast Formation and Long-Term Oral Bisphosphonate Therapy,” New England Journal of Medicine, Vol. 360, 2009, pp. 53-62. doi:10.1056/NEJMoa0802633
[24] T. Tanaka, M. Saito, M. Chazono, Y. Kumagae, T. Kikuchi, S. Kitasato and K. Marumo, “Effects of Alendronate on Bone Formation and Osteoclastic Resorption after Implantation of Beta-Tricalcium Phosphate,” Journal of Biomedical Materials Research Part A, Vol. 93, No. 2, 2010, pp. 469-474. doi:10.1002/jbm.a.32560
[25] J. D. Bobyn, S. A. Hacking, J. J. Krygier, E. J. Harvey, D. G. Little and M. Tanzer, “Zoledronic Acid Causes Enhancement of Bone Growth into Porous Implants,” Journal of Bone and Joint Surgery British, Vol. 87, No. 3, 2005, pp. 416-420.
[26] U. Ripamonti, R. M. Klar, L. F. Renton and C. Ferretti, “Synergistic Induction of Bone Formation by hOP-1, hTGF-β3 and Inhibition by Zoledronate in Macroporous Coral-Derived Hydroxyapatites,” Biomaterials, Vol. 31, No. 25, 2010, pp. 6400-6410. doi:10.1016/j.biomaterials.2010.04.037
[27] N. Gjorevski and C. M. Nelson, “Bidirectional Extra- cellular Matrix Signaling during Tissue Morphogenesis,” Cytokine & Growth Factor Reviews, Vol. 20, No. 5-6, 2009, pp. 459-465. doi:10.1016/j.cytogfr.2009.10.013
[28] F. Lorget, S. Kamel, R. Mentaverri, A. Wattel, M. Naassila, M. Maamer, et al., “High Extracellular Calcium Concentrations Directly Stimulate Osteoclast Apoptosis,” Biochemical and Biophysical Research Communications, Vol. 268, No. 3, 2000, pp. 899-903. doi:10.1006/bbrc.2000.2229
[29] R. H. Nielsen, M. A. Karsdal, M. G. Sorensen, M. H. Dziegiel and K. Henriksen, “Dissolution of the Inorganic Phase of Bone Leading to Release of Calcium Regulates Osteoclast Survival,” Biochemical and Biophysical Research Communications, Vol. 360, No. 4, 2007, pp. 834- 839. doi:10.1016/j.bbrc.2007.06.145
[30] G. Duque1 and D. Rivas, “Alendronate has an Anabolic Effect on Bone through the Differentiation of Mesen- chymal Stem Cells,” Journal of Bone and Mineral Re- search, Vol. 22, No. , 2007, pp. 1603-1611. doi:10.1359/jbmr.070701
[31] A. I. Idris, J. Rojas, I. R. Greig, R. J. Van’t Hof and S. H. Ralston, “Aminobisphosphonates Cause Osteoblast Apoptosis and Inhibit Bone Nodule Formation in Vitro,” Calcified Tissue International, Vol. 82, No. 3, 2008, pp. 191-201. doi:10.1007/s00223-008-9104-y
[32] I. R. Orriss, M. L. Key, K. W. Colston and T. R. Arnett, “Inhibition of Osteoblast Function in Vitro by Amino-bisphosphonates,” Journal of Cellular Biochemistry, Vol. 106, No. 1, 2009, pp. 109-118. doi:10.1002/jcb.21983
[33] G. Duque1, C. Vidal and D. Rivas, “Protein Isopreny-lation Regulates Osteogenic Differentiation of Mesen- chymal Stem Cells: Effect of Alendronate, and Farnesyl and Geranylgeranyl Transferase Inhibitors,” British Jour- nal of Pharmacology, Vol. 162, No. 5, 2011, pp. 1109-1118. doi:10.1111/j.1476-5381.2010.01111.x
[34] E. Kohn, R. Alessandro, J. Spoonster, R. P. Wersto and L. A. Liotta, “Angiogenesis: Role of Calcium—Mediated Signal Transduction,” Proceedings of the National Academy of Sciences of USA, Vol. 92, No. 5, 1995, pp. 1307-1311. doi:10.1073/pnas.92.5.1307
[35] M. Zayzafoon, “Calcium/Calmodulin Signaling Controls Osteoblast Growth and Differentiation,” Journal of Cellular Biochemistry, Vol. 97, No. 1, 2006, pp. 56-70. doi:10.1002/jcb.20675
[36] H. Yuan, J. D. De Bruijn, Y. Li, J. Feng, Z. Yang, K. De Groot, et al., “Bone Formation Induced by calcium Phosphate Ceramics in Soft Tissue of Dogs: A Comparative Study between Porous α-TCP and β-TCP,” Journal of Materials Science: Materials In Medicine, Vol. 12, No. 1, 2001, pp. 7-13. doi:10.1023/A:1026792615665

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