Abstract
With an aging population the frequency of postmenopausal fractures is increasing. Methods to enhance the repair of osteoporotic bone repair therefore become more important to reduce the society burden of care. We asked if absorbable collagen sponges containing recombinant human bone morphogenetic protein-2 (rhBMP-2) have the potential to enhance bone repair. We randomly assigned 40 rats into the ovariectomy and sham operation groups. A segmental defect was created in the right tibia 12 weeks after ovariectomy. rhBMP-2-containing absorbable collagen sponges were implanted into the defect in half of the animals in each group. We analyzed radiographs and histological sections and performed three-point bending tests to assess repair. Radiological scores in the rhBMP-2 applied rats were higher than those in controls at the end of 8 weeks after tibial osteotomy. The specimens failed under higher loads in the rhBMP-2-applied groups and histology revealed a higher fracture healing score, including callus formation, bone union, marrow changes, and cortex remodeling. We observed no adverse tissue responses such as fibrous connective tissue formation and inflammatory cellular infiltration. rhBMP-2 in absorbable collagen sponges enhanced bone repair in segmental tibial defects of ovariectomized rats. The sponges with rhBMP-2 appeared to enhance bone repair.
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Akkus O, Korkusuz F, Akin S, Akkas N. Relation between mechanical stiffness and vibration transmission of fracture callus: an experimental study on rabbit tibia. Proc Instn Mech Eng. 1998;212:327–336.
Alanay A, Chen C, Lee S, Murray SS, Brochmann EJ, Miyazaki M, Napoli A, Wang JC. The adjunctive effect of a binding peptide on bone morphogenetic protein enhanced bone healing in a rodent model of spinal fusion. Spine. 2008;33:1709–1713.
An YH, Friedman RJ. Animal models of bone defect repair. In: An YH, Friedman RJ, eds. Animal Models in Orthopedic Research. Boca Raton, FL: CRC Press LLC; 1999:241–260.
Atik OS. FRAX™ and Turkey: osteoporotic fracture risk assessment. Joint Dis Relat Surg. 2008;19:100.
Atik OS, Gunal I, Korkusuz F. Burden of osteoporosis. Clin Orthop Relat Res. 2006;443:19–24.
Blythe JG, Buchsbaum HJ. Fracture healing in estrogen-treated and castrated rats. Obstet Gynecol. 1976;48:351–352.
Bostrom M, Lane J, Tomin E, Browne M, Berberian W, Turek T, Smith J, Wozney J, Schildhauer T. Use of bone morphogenetic protein-2 in the rabbit ulna nonunion model. Clin Orthop Rel Res. 1996;327:272–282.
Chao EY, Inoue N, Koo TK, Kim YH. Biomechanical considerations of fracture treatment and bone quality maintenance in elderly patients and patients with osteoporosis. Clin Orthop Relat Res. 2004;425:12–25.
Chu TM, Warden SJ, Turner CH, Stewart RL. Segmental bone repair using a load-bearing biodegradable carrier of bone morphogenetic protein-2. Biomaterials. 2007;28:459–467.
Egermann M, Baltzer AW, Adamaszek S, Evans C, Robbins P, Schneider E, Lill CA. Direct adenoviral transfer of bone morphogenetic protein-2 cDNA enhances fracture healing in osteoporotic sheep. Hum Gene Ther. 2006;17:507–517.
Egermann M, Schneider E, Evans CH, Baltzer AW. The potential of gene therapy for fracture healing in osteoporosis. Osteoporos Int. 2005;16(Suppl 2):S120–S128.
Giannoudis P, Tzioupis C, Almalki T, Buckley R. Fracture healing in osteoporotic fractures: is it really different? A basic science perspective. Injury. 2007;38(Suppl 1):S90–S99.
Gürkan L, Ekeland A, Gautvik KM, Langeland N, Rønningen H, Solheim LF. Bone changes after castration in rats. A model for osteoporosis. Acta Orthop Scand. 1986;57:67–70.
Hollinger JO, Onikepe AO, MacKrell J, Einhorn T, Bradica G, Lynch S, Hart CE. Accelerated fracture healing in the geriatric, osteoporotic rat with recombinant human platelet-derived growth factor-BB and an injectable beta-tricalcium phosphate/collagen matrix. J Orthop Res. 2008;26:83–90.
Johnson KD, Frierson KE, Keller TS, Cook C, Scheinberg R, Zerwekh J, Meyers L, Sciadini MF. Porous ceramics as bone graft substitutes in long bone defects: a biomechanical, histological, and radiographic analysis. J Orthop Res. 1996;14:351–369.
Keskin DS, Tezcaner A, Korkusuz P, Korkusuz F, Hasirci V. Collagen-chondroitin sulfate-based PLLA-SAIB-coated rhBMP-2 delivery system for bone repair. Biomaterials. 2005;26:4023–4034.
Kirker-Head C, Karageorgiou V, Hofmann S, Fajardo R, Betz O, Merkle HP, Hilbe M, von Rechenberg B, McCool J, Abrahamsen L, Nazarian A, Cory E, Curtis M, Kaplan D, Meinel L. BMP-silk composite matrices heal critically sized femoral defects. Bone. 2007;41:247–255.
Lindholm TS. Studies of the skeletal mass and bone formation of tibial fracture callus and femoral bone in growing osteopenic rats. Acta Chir Scand Suppl. 1974;449:37–42.
Maeda H, Sano A, Fujioka K. Controlled release of rhBMP-2 from collagen minipellet and the relationship between release profile and ectopic bone formation. Int J Pharm. 2004;275:109–122.
Melhus G, Solberg LB, Dimmen S, Madsen JE, Nordsletten L, Reinholt FP. Experimental osteoporosis induced by ovariectomy and vitamin D deficiency does not markedly affect fracture healing in rats. Acta Orthop. 2007;78:393–403.
Namkung-Matthai H, Appleyard R, Jansen J, Hao Lin J, Maastricht S, Swain M, Mason RS, Murrell GA, Diwan AD, Diamond T. Osteoporosis influences the early period of fracture healing in a rat osteoporotic model. Bone. 2001;281:80–86.
Nordsletten L, Madsen JE. The effect of bone morphogenetic proteins in fracture healing. Scand J Surg. 2006;95:91–94.
Rosier RN, O’Keefe RJ, Hicks DG. The potential role of transforming growth factor beta in fracture healing. Clin Orthop Relat Res. 1998;355 Suppl:S294–S300.
Royals MA, Fujita SM, Yevey GL, Rodriguez J, Schultheiss PC, Dunn RL. Biocompatibility of a biodegradable in situ forming implant system in Rhesus monkeys. J Biomed Mater Res. 1999;45:231–239.
Schliephake H, Weich HA, Dullin C, Gruber R, Frahse S. Mandibular bone repair by implantation of rhBMP-2 in a slow release carrier of polylactic acid–an experimental study in rats. Biomaterials. 2008;29:103–110.
Schmidmaier G, Schwabe P, Wildemann B, Haas NP. Use of bone morphogenetic proteins for treatment of non-unions and future perspectives. Injury. 2007;38-S4:S35–S41.
Sciadini MF, Johnson KD. Evaluation of recombinant human bone morphogenetic protein-2 as a bone-graft substitute in a canine segmental defect model. J Orthop Res. 2000;18:289–302.
Sener M, Onar V, Kazimoglu C, Yagdi S. Mortality and morbidity in elderly patients who underwent partial prosthesis replacement for proximal femoral fractures. Joint Dis Relat Surg. 2009;20:11–17.
Swiontkowski MF, Aro HT, Donell S, Esterhai JL, Goulet J, Jones A, Kregor PJ, Nordsletten L, Paiement G, Patel A. Recombinant human bone morphogenetic protein-2 in open tibial fractures. A subgroup analysis of data combined from two prospective randomized studies. J Bone Joint Surg Am. 2006;88:1258–1265.
Tang Y, Tang W, Lin Y, Long J, Wang H, Liu L, Tian W. Combination of bone tissue engineering and BMP-2 gene transfection promotes bone healing in osteoporotic rats. Cell Biol Int. 2008;32:1150–1157.
Tou JC, Foley A, Yuan YV, Arnaud S, Wade CE, Brown M, Tou JC, Foley A, Yuan YV, Arnaud S, Wade CE, Brown M. The effect of ovariectomy combined with hindlimb unloading and reloading on the long bones of mature Sprague-Dawley rats. Menopause. 2008;15:494–502.
Xu SW, Yu R, Zhao GF, Wang JW. Early period of fracture healing in ovariectomized rats. Chin J Traumatol. 2003;6:160–166.
Yang CY, Simmons DJ, Lozano R. The healing of grafts combining freeze-dried and demineralized allogeneic bone in rabbits. Clin Orthop Relat Res. 1994;298:286–295.
Acknowledgments
We thank Dr. Hasan Bilgili of Ankara University for conducting the ovariectomies; Dr. Sedat Ulger for evaluating the radiological images; Dr. Tevfik Sabuncu, Dr. Müge Harma, and Dr. Mehmet Harma of Harran University for their help in creating the osteoporosis rat model; Arzu Tasci of Middle East Technical University for assisting with the biomechanical tests and Dr. Sedat Isikli of Hacettepe University for statistical analysis. Orhan Resit Cubukcu MD and Celal Aydin MD of Middle East Technical University Medical Center Radiodiagnostic Unit independently evaluated and scored the xray pictures. Dilara Zeybek MD of Hacettepe University Faculty of Medicine, Department of Histology and Embryology, assisted blinded evaluation and scoring of the histological sections.
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This project was partly supported by Harran University Research Fund (HUBAK 436). Kurtsan Inc. (Istanbul, Turkey) supplied the absorbable collagen sponges for this study.
Each author certifies that his or her institution has approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.
This work was performed at the Middle East Technical University.
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Sarban, S., Senkoylu, A., Isikan, U.E. et al. Can rhBMP-2 Containing Collagen Sponges Enhance Bone Repair in Ovariectomized Rats?: A Preliminary Study. Clin Orthop Relat Res 467, 3113–3120 (2009). https://doi.org/10.1007/s11999-009-1004-6
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DOI: https://doi.org/10.1007/s11999-009-1004-6