Skip to main content
Top
Published in: Journal of Orthopaedic Surgery and Research 1/2019

Open Access 01-12-2019 | Femoral Fracture | Research article

Enhancement of the effects of intermittent parathyroid hormone (1-34) by bone morphogenetic protein in a rat femoral open fracture model

Authors: Shozo Kanezaki, Masashi Miyazaki, Toshinobu Ishihara, Naoki Notani, Tetsutaro Abe, Yuhta Tsubouchi, Masashi Kataoka, Hiroshi Tsumura

Published in: Journal of Orthopaedic Surgery and Research | Issue 1/2019

Login to get access

Abstract

Background

Nonunion in cases of open fracture is common. Both bone morphogenetic protein 2 (BMP-2) and parathyroid hormone (PTH) have been used to enhance bone healing. We investigated the combination of BMP-2 and PTH and examined the effects on a rat model of open femoral fractures.

Methods

Group I (n = 11) was implanted with control carrier. Group II (n = 12) was implanted with carrier containing 1 μg of recombinant human BMP-2 (rhBMP-2). Group III (n = 12) was implanted with carrier alone, followed by injections of PTH 1-34. Group IV (n = 11) was implanted with carrier containing 1 μg of rhBMP-2, followed by injections of PTH 1-34. Group V (n = 11) was implanted with carrier containing 10 μg of rhBMP-2. Group VI (n = 11) was implanted with carrier containing 10 μg of rhBMP-2, followed by injections of PTH 1-34. Rats were euthanized after 8 weeks, and their fractured femurs were explanted and assessed by manual palpation, radiographs, micro-computerized tomography, and histological analysis.

Results

Manual palpation tests showed that the fusion rates of groups III (66.7%), IV (63.6%), V (81.8%), and VI (81.8%) were considerably higher than those of group I. Groups V and VI had higher radiographic scores compared to group I. Micro-CT analysis revealed enhanced bone marrow density expressed as bone volume/tissue volume in groups V (61.88 ± 3.16%) and VI (71.14 ± 3.89%) versus group I (58.26 ± 1.86%). A histological analysis indicated that group VI had enhanced remodeling.

Conclusion

The combination of abundant rhBMP-2 and PTH enhanced bone healing and remodeling of newly formed bone in a rat femoral open fracture model.
Literature
1.
go back to reference Gustilo RB, Merkow RL, Templeman D. The management of open fractures. J Bone Joint Surg Am. 1990;72:299–304.CrossRef Gustilo RB, Merkow RL, Templeman D. The management of open fractures. J Bone Joint Surg Am. 1990;72:299–304.CrossRef
2.
go back to reference Okike K, Bhattacharyya T. Trends in the management of open fractures. A critical analysis. J Bone Joint Surg Am. 2006;88:2739–48.CrossRef Okike K, Bhattacharyya T. Trends in the management of open fractures. A critical analysis. J Bone Joint Surg Am. 2006;88:2739–48.CrossRef
3.
go back to reference Dailey HL, Wu KA, Wu PS, McQueen MM, Court-Brown CM. Tibial fracture nonunion and time to healing after reamed intramedullary nailing: risk factors based on a single-center review of 1003 patients. J Orthop Trauma. 2018;32:e263–9.CrossRef Dailey HL, Wu KA, Wu PS, McQueen MM, Court-Brown CM. Tibial fracture nonunion and time to healing after reamed intramedullary nailing: risk factors based on a single-center review of 1003 patients. J Orthop Trauma. 2018;32:e263–9.CrossRef
4.
go back to reference Dickson K, Katzman S, Delgado E, Contreras D. Delayed unions and nonunions of open tibial fractures. Correlation with arteriography results. Clin Orthop Relat Res. 1994 1994;May;:189-93. Dickson K, Katzman S, Delgado E, Contreras D. Delayed unions and nonunions of open tibial fractures. Correlation with arteriography results. Clin Orthop Relat Res. 1994 1994;May;:189-93.
5.
go back to reference Welch RD, Jones AL, Bucholz RW, Reinert CM, Tjia JS, Pierce WA, Wozney JM, Li XJ. Effect of recombinant human bone morphogenetic protein-2 on fracture healing in a goat tibial fracture model. J Bone Miner Res. 1998;13:1483–90.CrossRef Welch RD, Jones AL, Bucholz RW, Reinert CM, Tjia JS, Pierce WA, Wozney JM, Li XJ. Effect of recombinant human bone morphogenetic protein-2 on fracture healing in a goat tibial fracture model. J Bone Miner Res. 1998;13:1483–90.CrossRef
6.
go back to reference Jones AL, Bucholz RW, Bosse MJ, Mirza SK, Lyon TR, Webb LX, Pollak AN, Golden JD, Valentin-Opran A. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial. J Bone Joint Surg Am. 2006;88:1431–41.CrossRef Jones AL, Bucholz RW, Bosse MJ, Mirza SK, Lyon TR, Webb LX, Pollak AN, Golden JD, Valentin-Opran A. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial. J Bone Joint Surg Am. 2006;88:1431–41.CrossRef
7.
go back to reference Garrison KR, Shemilt I, Donell S, Ryder JJ, Mugford M, Harvey I, Song F, Alt V. Bone morphogenetic protein (BMP) for fracture healing in adults. Cochrane Database Syst Rev. 2010;16:CD006950. Garrison KR, Shemilt I, Donell S, Ryder JJ, Mugford M, Harvey I, Song F, Alt V. Bone morphogenetic protein (BMP) for fracture healing in adults. Cochrane Database Syst Rev. 2010;16:CD006950.
8.
go back to reference Louis-Ugbo J, Kim HS, Boden SD, Mayr MT, Li RC, Seeherman H, D'Augusta D, Blake C, Jiao A, Peckham S. Retention of 125I-labeled recombinant human bone morphogenetic protein-2 by biphasic calcium phosphate or a composite sponge in a rabbit posterolateral spine arthrodesis model. J Orthop Res. 2002;20:1050–9.CrossRef Louis-Ugbo J, Kim HS, Boden SD, Mayr MT, Li RC, Seeherman H, D'Augusta D, Blake C, Jiao A, Peckham S. Retention of 125I-labeled recombinant human bone morphogenetic protein-2 by biphasic calcium phosphate or a composite sponge in a rabbit posterolateral spine arthrodesis model. J Orthop Res. 2002;20:1050–9.CrossRef
9.
go back to reference Miyazaki M, Morishita Y, He W, Hu M, Sintuu C, Hymanson HJ, Falakassa J, Tsumura H, Wang JC. A porcine collagen-derived matrix as a carrier for recombinant human bone morphogenetic protein-2 enhances spinal fusion in rats. Spine J. 2009;9:22–30.CrossRef Miyazaki M, Morishita Y, He W, Hu M, Sintuu C, Hymanson HJ, Falakassa J, Tsumura H, Wang JC. A porcine collagen-derived matrix as a carrier for recombinant human bone morphogenetic protein-2 enhances spinal fusion in rats. Spine J. 2009;9:22–30.CrossRef
10.
go back to reference Doi Y, Miyazaki M, Yoshiiwa T, Hara K, Kataoka M, Tsumura H. Manipulation of the anabolic and catabolic responses with BMP-2 and zoledronic acid in a rat femoral fracture model. Bone. 2011;49:777–82.CrossRef Doi Y, Miyazaki M, Yoshiiwa T, Hara K, Kataoka M, Tsumura H. Manipulation of the anabolic and catabolic responses with BMP-2 and zoledronic acid in a rat femoral fracture model. Bone. 2011;49:777–82.CrossRef
11.
go back to reference Miyazaki M, Toyoda M, Yoshiiwa T, Kawano M, Kaku N, Tsumura H. Enhancement of the effects of exfoliated carbon nanofibers by bone morphogenetic protein in a rat femoral fracture model. J Orthop Res. 2015;33:185–92.CrossRef Miyazaki M, Toyoda M, Yoshiiwa T, Kawano M, Kaku N, Tsumura H. Enhancement of the effects of exfoliated carbon nanofibers by bone morphogenetic protein in a rat femoral fracture model. J Orthop Res. 2015;33:185–92.CrossRef
12.
go back to reference Morishita Y, Naito M, Miyazaki M, He W, Wu G, Wei F, Sintuu C, Hymanson H, Brochmann EJ, Murray SS, Wang JC. Enhanced effects of BMP-binding peptide combined with recombinant human BMP-2 on the healing of a rodent segmental femoral defect. J Orthop Res. 2010;28:258–64.PubMed Morishita Y, Naito M, Miyazaki M, He W, Wu G, Wei F, Sintuu C, Hymanson H, Brochmann EJ, Murray SS, Wang JC. Enhanced effects of BMP-binding peptide combined with recombinant human BMP-2 on the healing of a rodent segmental femoral defect. J Orthop Res. 2010;28:258–64.PubMed
13.
go back to reference Hock JM, Gera I, Fonseca J, Raisz LG. Human parathyroid hormone-(1-34) increases bone mass in ovariectomized and orchidectomized rats. Endocrinology. 1988;122:2899–904.CrossRef Hock JM, Gera I, Fonseca J, Raisz LG. Human parathyroid hormone-(1-34) increases bone mass in ovariectomized and orchidectomized rats. Endocrinology. 1988;122:2899–904.CrossRef
14.
go back to reference Watson P, Lazowski D, Han V, Fraher L, Steer B, Hodsman A. Parathyroid hormone restores bone mass and enhances osteoblast insulin-like growth factor I gene expression in ovariectomized rats. Bone. 1995;16:357–65.CrossRef Watson P, Lazowski D, Han V, Fraher L, Steer B, Hodsman A. Parathyroid hormone restores bone mass and enhances osteoblast insulin-like growth factor I gene expression in ovariectomized rats. Bone. 1995;16:357–65.CrossRef
15.
go back to reference Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434–41.CrossRef Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434–41.CrossRef
16.
go back to reference Nakamura T, Sugimoto T, Nakano T, Kishimoto H, Ito M, Fukunaga M, Hagino H, Sone T, Yoshikawa H, Nishizawa Y, Fujita T, Shiraki M. Randomized Teriparatide [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy Research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk. J Clin Endocrinol Metab. 2012;97:3097–106.CrossRef Nakamura T, Sugimoto T, Nakano T, Kishimoto H, Ito M, Fukunaga M, Hagino H, Sone T, Yoshikawa H, Nishizawa Y, Fujita T, Shiraki M. Randomized Teriparatide [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy Research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk. J Clin Endocrinol Metab. 2012;97:3097–106.CrossRef
17.
go back to reference Andreassen TT, Ejersted C, Oxlund H. Intermittent parathyroid hormone (1-34) treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res. 1999;14:960–8.CrossRef Andreassen TT, Ejersted C, Oxlund H. Intermittent parathyroid hormone (1-34) treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res. 1999;14:960–8.CrossRef
18.
go back to reference Alkhiary YM, Gerstenfeld LC, Krall E, Westmore M, Sato M, Mitlak BH, Einhorn TA. Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34). J Bone Joint Surg Am. 2005;87:731–41.PubMed Alkhiary YM, Gerstenfeld LC, Krall E, Westmore M, Sato M, Mitlak BH, Einhorn TA. Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34). J Bone Joint Surg Am. 2005;87:731–41.PubMed
19.
go back to reference Babu S, Sandiford NA, Vrahas M. Use of Teriparatide to improve fracture healing: what is the evidence? World J Orthop. 2015;6:457–61.CrossRef Babu S, Sandiford NA, Vrahas M. Use of Teriparatide to improve fracture healing: what is the evidence? World J Orthop. 2015;6:457–61.CrossRef
20.
go back to reference Yamamoto M, Takahashi Y, Tabata Y. Controlled release by biodegradable hydrogels enhances the ectopic bone formation of bone morphogenetic protein. Biomaterials. 2003;24:4375–83.CrossRef Yamamoto M, Takahashi Y, Tabata Y. Controlled release by biodegradable hydrogels enhances the ectopic bone formation of bone morphogenetic protein. Biomaterials. 2003;24:4375–83.CrossRef
21.
go back to reference Shields LB, Raque GH, Glassman SD, Campbell M, Vitaz T, Harpring J, Shields CB. Adverse effects associated with high-dose recombinant human bone morphogenetic protein-2 use in anterior cervical spine fusion. Spine (Phila Pa 1976). 2006;31:542–7.CrossRef Shields LB, Raque GH, Glassman SD, Campbell M, Vitaz T, Harpring J, Shields CB. Adverse effects associated with high-dose recombinant human bone morphogenetic protein-2 use in anterior cervical spine fusion. Spine (Phila Pa 1976). 2006;31:542–7.CrossRef
22.
go back to reference Morimoto T, Kaito T, Kashii M, Matsuo Y, Sugiura T, Iwasaki M, Yoshikawa H. Effect of intermittent administration of teriparatide (parathyroid hormone 1-34) on bone morphogenetic protein-induced bone formation in a rat model of spinal fusion. J Bone Joint Surg Am. 2014;96:e107.CrossRef Morimoto T, Kaito T, Kashii M, Matsuo Y, Sugiura T, Iwasaki M, Yoshikawa H. Effect of intermittent administration of teriparatide (parathyroid hormone 1-34) on bone morphogenetic protein-induced bone formation in a rat model of spinal fusion. J Bone Joint Surg Am. 2014;96:e107.CrossRef
23.
go back to reference Yu B, Zhao X, Yang C, Crane J, Xian L, Lu W, Wan M, Cao X. Parathyroid hormone induces differentiation of mesenchymal stromal/stem cells by enhancing bone morphogenetic protein signaling. J Bone Miner Res. 2012;27:2001–14.CrossRef Yu B, Zhao X, Yang C, Crane J, Xian L, Lu W, Wan M, Cao X. Parathyroid hormone induces differentiation of mesenchymal stromal/stem cells by enhancing bone morphogenetic protein signaling. J Bone Miner Res. 2012;27:2001–14.CrossRef
24.
go back to reference Tagil M, McDonald MM, Morse A, Peacock L, Mikulec K, Amanat N, Godfrey C, Little DG. Intermittent PTH(1-34) does not increase union rates in open rat femoral fractures and exhibits attenuated anabolic effects compared to closed fractures. Bone. 2010;46:852–9.CrossRef Tagil M, McDonald MM, Morse A, Peacock L, Mikulec K, Amanat N, Godfrey C, Little DG. Intermittent PTH(1-34) does not increase union rates in open rat femoral fractures and exhibits attenuated anabolic effects compared to closed fractures. Bone. 2010;46:852–9.CrossRef
Metadata
Title
Enhancement of the effects of intermittent parathyroid hormone (1-34) by bone morphogenetic protein in a rat femoral open fracture model
Authors
Shozo Kanezaki
Masashi Miyazaki
Toshinobu Ishihara
Naoki Notani
Tetsutaro Abe
Yuhta Tsubouchi
Masashi Kataoka
Hiroshi Tsumura
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Orthopaedic Surgery and Research / Issue 1/2019
Electronic ISSN: 1749-799X
DOI
https://doi.org/10.1186/s13018-019-1470-9

Other articles of this Issue 1/2019

Journal of Orthopaedic Surgery and Research 1/2019 Go to the issue