Periodontal tissue regeneration using fibroblast growth factor-2: randomized controlled phase II clinical trial

Abstract

Background: The options for medical use of signaling molecules as stimulators of tissue regeneration are currently limited. Preclinical evidence suggests that fibroblast growth factor (FGF)-2 can promote periodontal regeneration. This study aimed to clarify the activity of FGF-2 in stimulating regeneration of periodontal tissue lost by periodontitis and to evaluate the safety of such stimulation.

Methodology/principal findings: We used recombinant human FGF-2 with 3% hydroxypropylcellulose (HPC) as vehicle and conducted a randomized double-blinded controlled trial involving 13 facilities. Subjects comprised 74 patients displaying a 2- or 3-walled vertical bone defect as measured > or = 3 mm apical to the bone crest. Patients were randomly assigned to 4 groups: Group P, given HPC with no FGF-2; Group L, given HPC containing 0.03% FGF-2; Group M, given HPC containing 0.1% FGF-2; and Group H, given HPC containing 0.3% FGF-2. Each patient underwent flap operation during which we administered 200 microL of the appropriate investigational drug to the bone defect. Before and for 36 weeks following administration, patients underwent periodontal tissue inspections and standardized radiography of the region under investigation. As a result, a significant difference (p = 0.021) in rate of increase in alveolar bone height was identified between Group P (23.92%) and Group H (58.62%) at 36 weeks. The linear increase in alveolar bone height at 36 weeks in Group P and H was 0.95 mm and 1.85 mm, respectively (p = 0.132). No serious adverse events attributable to the investigational drug were identified.

Conclusions: Although no statistically significant differences were noted for gains in clinical attachment level and alveolar bone gain for FGF-2 groups versus Group P, the significant difference in rate of increase in alveolar bone height (p = 0.021) between Groups P and H at 36 weeks suggests that some efficacy could be expected from FGF-2 in stimulating regeneration of periodontal tissue in patients with periodontitis.

Trial registration: ClinicalTrials.gov NCT00514657.

Conflict of interest statement

Competing Interests: SM received research grants from Kaken Pharmaceutical Co., Ltd. MW is an employee and stockholder of Kaken Pharmaceutical Co., Ltd.

Figures

Figure 1. Schedule of the clinical trial.

We randomly allocated the 80 patients into 4 groups (n = 20 each): 1) a placebo group (Group P); 2) a group administered 0.03% FGF-2 (Group L); 3) a group administered 0.1% FGF-2 (Group M); and 4) a group administered 0.3% of FGF-2 (Group H). The clinical trial was then conducted in accordance with the clinical trial schedule. We also measured FGF-2 concentrations in the blood serum of 6 patients randomly chosen from each of the 4 groups, before and then 1 h, 2 h and 4 h after administration of the investigational drug.

Figure 2. Measured points of alveolar bone height using standardized radiographs.

Standardized dental radiographs taken before and after FGF-2 administration in one subject (a 29-year-old man) given 0.3% FGF-2. Points A, B, C and D represent the cementoenamel junction, apex, remaining alveolar bone crest and bottom of the bone defect, respectively. The examiners measured tooth axis heights between Points A and B, Points A and C, and Points A and D on the X-ray for each patient. To adjust for slight errors due to imaging, measurements for 5 examiners were multiplied by A-B ratio of before to after administration to correct A-B, A-C and A-D after administration (adjusted A-B, A-C and A-D, respectively). Rate of increase in alveolar bone height was derived from the following calculation formula. [(A-D before administration) - (adjusted A-D after administration)] by C-D before administration. On this radiography, C-D before administration, A-D before administration and, adjusted A-D after administration measured 9.00 mm, 12.80 mm and 5.93 mm, respectively. These values assigned to the above formula, we obtained the rate of increase in alveolar bone height as follows. The rate of increase in alveolar bone height (%) = 100(12.80–5.93)/9.00 = 76.35.

Figure 3. Flow of patients through the study.

Figure 4. Rates of increase in alveolar bone height in cases of 2- and 3-walled intrabony defects.

We compared rates of increase in alveolar bone height at 36 weeks after FGF-2 administration among Group P (19 placebo cases), Group L (19 cases administered 0.03% FGF-2), Group M (19 cases administered 0.1% FGF-2) and Group H (17 cases administered 0.3% FGF-2). This figure shows mean increase rates (%) and standard deviations of alveolar bone height. While no significant difference was observed between Groups L and M and P, Group H showed significantly increased (p = 0.021) alveolar bone height in the bone defect region compared to Group P.