Distal tibial fracture repair in a neurofibromatosis type 1-deficient mouse treated with recombinant bone morphogenetic protein and a bisphosphonate.

Abstract

Congenital pseudarthrosis of the tibia is an uncommon manifestation of neurofibromatosis type 1 (NF1), but one that remains difficult to treat due to anabolic deficiency and catabolic excess. Bone grafting and more recently recombinant human bone morphogenetic proteins (rhBMPs) have been identified as pro-anabolic stimuli with the potential to improve the outcome after surgery. As an additional pharmaceutical intervention, we describe the combined use of rhBMP-2 and the bisphosphonate zoledronic acid in a mouse model of NF1-deficient fracture repair. Fractures were generated in the distal tibiae of neurofibromatosis type 1-deficient (Nf1(+/-)) mice and control mice. Fractures were open and featured periosteal stripping. All mice received 10 μg rhBMP-2 delivered in a carboxymethylcellulose carrier around the fracture as an anabolic stimulus. Bisphosphonate-treated mice also received five doses of 0.02 mg/kg zoledronic acid given by intraperitoneal injection. When only rhBMP but no zoledronic acid was used to promote repair, 75% of fractures in Nf1(+/-) mice remained ununited at three weeks compared with 7% of controls (p < 0.001). Systemic post-operative administration of zoledronic acid halved the rate of ununited fractures to 37.5% (p < 0.07). These data support the concept that preventing bone loss in combination with anabolic stimulation may improve the outcome following surgical treatment for children with congenital pseudarthosis of the tibia and NF1.

• Authors: A Schindeler, O Birke, N Y C Yu, A Morse, A Ruys, P A Baldock, D G Little
• Journal: The Journal of bone and joint surgery. British volume (J Bone Joint Surg Br) Vol. 93 Issue 8 Pg. 1134-9 (Aug 2011) ISSN: 2044-5377 [Electronic] England
• PMID: 21768643 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BMP2 protein, human
• Bone Density Conservation Agents
• Bone Morphogenetic Protein 2
• Diphosphonates
• Imidazoles
• Recombinant Proteins
• Zoledronic Acid

Topics

• Animals
• Bone Density Conservation Agents (therapeutic use)
• Bone Morphogenetic Protein 2 (therapeutic use)
• Combined Modality Therapy
• Diphosphonates (therapeutic use)
• Disease Models, Animal
• Drug Evaluation, Preclinical (methods)
• Drug Therapy, Combination
• Fracture Fixation, Internal (methods)
• Fracture Healing (drug effects)
• Fractures, Ununited (prevention & control)
• Imidazoles (therapeutic use)
• Mice
• Mice, Knockout
• Neurofibromatosis 1 (complications)
• Postoperative Care (methods)
• Pseudarthrosis (complications, congenital)
• Recombinant Proteins (therapeutic use)
• Tibial Fractures (diagnostic imaging, drug therapy, etiology, surgery)
• Treatment Outcome
• X-Ray Microtomography
• Zoledronic Acid