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

Abstract

Based on preclinical evidence in animal models, the present study examined the clinical efficacy and safety of recombinant human fibroblast growth factor-2 (rhFGF-2) to accelerate bone repair in a dose-escalation prospective trial. One of three dosages (200, 400 or 800 mg) of rhFGF-2 in a biodegradable gelatin hydrogel was injected during surgery into the osteotomy site of 59 knee osteoarthritis patients undergoing high tibial osteotomy, and 57 of them were monitored for 16 weeks. The rhFGF-2 dose dependently increased the percentage of patients with radiographic bone union, and decreased the average time needed for such union. The percentages of patients with an absence of pain and full-weight bearing were also greater in the higher dosage groups than in the low dosage group, especially in the clinically critical periods 6, 8, and 10 weeks. Neither blood chemistries nor clinical adverse events were associated with the rhFGF-2 dosages. We therefore conclude that the rhFGF-2 in gelatin hydrogel dose dependently accelerated radiographic bone union of a surgical osteotomy with a safety profile at least at the dosages used, suggesting the clinical efficacy of this agent for bone repair. ß

A pilot study of regenerative therapy using controlled release of recombinant human fibroblast growth factor for patients with pre-collapse osteonecrosis of the femoral head

“…Release of rhFGF-2 from the hydrogel at the site of implantation was measurable for more than 2 weeks, a period that correlates strongly with the patterns of in vivo rhFGF-2 release and hydrogel degradation [18]. One human application that merits attention is a report on single injections of rhFGF-2-impregnated hydrogel at doses of 200, 400, and 800 μg in cut bone surfaces of the lower leg, which produced rapid synostosis in a dosedependent manner [19,20].…”

A local application of recombinant human fibroblast growth factor 2 for tibial shaft fractures: A randomized, placebo-controlled trial

“…Based on the evidence of animal studies and a preparatory doseescalation clinical trial, (12)(13)(14)(15)(16)(17)(18) this prospective, randomized, double-blind, placebo-controlled multicenter trial for the first time revealed that local application of a synthetic material, rhFGF-2 hydrogel, accelerated healing of fresh fractures. The hydrogel alone was not likely to affect the healing process because the time to bone union in our placebo group was similar to that without any intervention but the nailing surgery in a previous report.…”

“…The hydrogel alone was not likely to affect the healing process because the time to bone union in our placebo group was similar to that without any intervention but the nailing surgery in a previous report. (2) In our previous dose-escalation trial, (18) we selected 0.2, 0.4, and 0.8 mg as the dosages of rhFGF-2 based on results of animal experiments (12,14,17) and found dose-dependent effects on bone union of the tibial osteotomy. (18) To further determine the dosage with maximal efficacy, this study added a dosage of 2.4 mg because our preparatory toxicity tests in dogs with daily intramuscular administration of the rhFGF-2 hydrogel predicted the nontoxic dosage of rhFGF-2 to be 40 mg/kg per day (Supplemental Table S1).…”

“…(12)(13)(14)(15)(16)(17) Aiming at clinical application, we recently performed a dose-escalation trial of a local injection of rhFGF-2 in the gelatin hydrogel into the surgical high tibial osteotomy site of knee osteoarthritis patients and found that rhFGF-2 (0.2, 0.4, or 0.8 mg) dose dependently accelerated bone union of the osteotomy with a safety profile. (18) Considering that delayed union or nonunion generally can be determined on radiographs in less than 6 months after the fracture, (19) we performed a prospective, randomized, double-blind, placebocontrolled multicenter trial based on the hypothesis that a local application of the rhFGF-2 hydrogel increases the number of patients who achieve bone union of tibial shaft fractures within 24 weeks of intramedullary nailing surgery.…”

Results of high tibial osteotomy: review of the literature

“…Encouraging results have been reported with the use of PRP, bone marrow stromal cells and growth factors [9,19,28], associated both with bone grafting and with bone substitute augmentation. Nevertheless, the use of plasma products still remains experimental and their efficacy compared to autologous iliac crest graft has not been demonstrated yet [9].…”