Recombinant Human Basic Fibroblast Growth Factor Accelerates Fracture Healing by Enhancing Callus Remodeling in Experimental Dog Tibial Fracture

Abstract

Effect of recombinant human basic fibroblast growth factor (bFGF) on fracture healing was investigated using a tibial fracture in beagle dogs. Transverse fractures in the middle of the diaphyses were created in the right tibiae and bFGF was injected into the fracture sites at a single dose of 200 g. The time course of changes in callus volume and morphology of the fracture sites were evaluated at weeks 2, 4, 8, 16, and 32 after treatment, and the fracture strength was analyzed at weeks 16 and 32. At week 2, a radiogram of the fracture site showed obvious membranous ossification in the group injected with bFGF. Basic FGF extended the callus area at week 4 and increased the bone mineral content (BMC) in the callus at week 8. bFGF also increased the osteoclast number in the periosteal callus at weeks 2 and 4. In the bFGF group, a maximal increase in the osteoclast index was found at week 4, and an identical increase was recognized in the control group at weeks 8 and 16. These findings strongly suggested that bFGF stimulated not only callus formation but osteoclastic callus resorption. BMC in the bFGF group was followed by a rapid decrease from week 8, while that in the control group was identical from week 4. Fracture strength of the bFGF group showed significant recovery by week 16, and recovery was still evident by week 32. We conclude that bFGF promotes the fracture healing in dogs by the stimulation of bone remodeling. (J Bone Miner Res 1998;13:942-949)

Local application of recombinant human fibroblast growth factor‐2 on bone repair: A dose–escalation prospective trial on patients with osteotomy

“…Based on the evidence of extensive studies using various animal models, [6][7][8][9][10][11][12][13][14][15] this study for the first time showed clinical evidence that rhFGF-2 in gelatin hydrogel accelerated radiographic bone union of the closing wedge high tibial osteotomy. Because most osteotomies can heal only with appropriate fixations, and in fact, all patients even of the low dosage group eventually achieved radiographic bone union in the present study, the rhFGF-2 application may not have yielded bone union by preventing nonunion, but just accelerated bone union.…”

“…Instead of the control group, we determined the three dosages of rhFGF-2 based on previous preclinical results of osteotomy experiments on animals. [7][8][9]12 When the dosages in the animal studies were converted to the area of the human proximal tibiae, 800 mg of rhFGF-2 was expected to show a significant anabolic function, while 200 mg exerted little effect. In fact, the high dosage of rhFGF-2 showed significant bone anabolic function over the low dosage in the present clinical study.…”

“…After approval of the protocol by the Institutional Review Boards (IRB) at all participating institutions and after the patients had provided written informed consent, patients were assigned in order of enrollment to one of three investigational groups that received a total dosage of 200, 400, or 800 mg of rhFGF-2 in a biodegradable gelatin hydrogel carrier (the total reconstituted volume was 1 mL). The rhFGF-2 dosages were determined based on previous preclinical results of osteotomy experiments on rats, rabbits, dogs, and monkeys [7][8][9]12 through normalizing by the cross section area of the bones. Safety of a dosage was assessed and confirmed before proceeding to a higher trial dosage.…”

“…We and others have reported the anabolic effect of local and systemic administrations of FGF-2 on bone formation using several animal models including nonhuman primates. [6][7][8][9][10][11][12][13][14][15] A single local application of FGF-2 facilitated the healing of bone fracture and segmental bone defect in normal and diabetic rats, rabbits, dogs, and monkeys; [6][7][8][9][10][11][12] stimulated bone formation in callotasis bone lengthening in rabbits; 13 and increased bone mass intraosseously in normal and ovariectomized rats and rabbits. 14 In addition, a daily systemic administration of FGF-2 facilitated endosteal bone formation.…”

Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery

“…54 Several biological factors, such as TGFb, BMP, FGF, PDGF, IGF, and LMP-1, have been investigated for their potential use in bone regeneration and skeletal repair. [55][56][57][58][59][60][61][62][63][64][65][66][67][68][69] BMPs have been shown to be the most promising, and clinical trials with recombinant BMP-2 and -7 are ongoing. 54,[70][71][72][73] These BMPs have shown varying degrees of success in the clinical setting and further study on their mechanisms of action and optimal formulations is required to optimize effectiveness of this strategy for promoting osteogenesis.…”