Safety study: is there a pathologic IGF-1, PDGF and TGF-β cytokine expression caused by adjunct BMP-7 in tibial and femoral non-union therapy?

Abstract

Background: In this prospective safety study, we investigated if the characteristic cytokine expression during bone regeneration is manipulated by the local application of bone morphogenetic protein-7 (BMP-7) in non-union surgery. Therefore, the levels of insulin like growth factor 1 (IGF-1), platelet-derived growth factor AB (PDGF-AB) and transforming growth factor beta (TGF-β) were compared between patients with the gold standard use of autologous bone graft (ABG) and those with additional application of BMP-7 as part of the diamond concept.

Patients and methods: Between 2009 and 2014, of the 153 patients with tibial and femoral non-unions, a matched pair analysis was performed to compare the serological cytokine expressions. Blood samples were collected preoperatively, 1, 2 and 6 weeks as well as 3 and 6 months after non-union surgery. Matching criteria were smoking status, fracture location, gender, age and body mass index (BMI). Patients in G1 (n=10) were treated with ABG and local BMP-7 while their matching partners in G2 (n=10) received ABG only. The routine clinical and radiologic follow-up was 1 year.

Results: Although the IGF-1 quantification in G2 showed higher pre- and postoperative values compared to G1 (p<0.05), the courses of both groups were similar. Likewise, PDGF-AB and TGF-β expressions appeared similar in G1 and G2 with peaks in both groups at 2 weeks follow-up. Osseous consolidation was assessed in all operated non-unions. The adjunct application of BMP-7 did not cause any pathologic cytokine expression.

Conclusion: Similar expressions of the serum cytokines IGF-1, PDGF-AB and TGF-β were demonstrated in non-union patients treated with ABG and additional application of BMP-7 according to the diamond concept. Our findings indicate that the local application of BMP-7, which imitates the physiologic secretion of growth factors during bone regeneration, is safe and without the risk of abnormal systemic cytokine expression. Studies with higher patient numbers will have to validate these assumptions.

Keywords: bone morphogenetic protein; cytokine; non-union; safety.

Figure 1

Perioperative X-rays of a femoral non-union. Notes: Before non-union treatment according to the diamond concept (A) and 6 months postoperatively when consolidation was achieved (B). The intramedullary nail was removed, the non-union resected and the gap was filled with ABG (autologous bone graft), 3.3 mg BMP-7 and a tricalcium phosphate bone graft (Vitoss; Stryker, Duisburg, Germany). Re-osteosynthesis was performed with an angled blade plate.

Figure 2

Groups of matched patients: G1 – treatment with BMP-7 and autologous bone graft (ABG) according to the diamond concept, G2 – treatment with ABG alone.

Figure 3

Timeline of sample acquisition according to a standardized cytokine protocol.

Figure 4

Analysis of sequential IGF-1 (A), PDGF-AB (B) and TGF-β (C) expression levels of G1 (autologous bone graft with additional BMP-7) and G2 (autologous bone graft alone) groups expressed as absolute mean concentrations ± standard deviation. Notes: Serum concentration was measured in picograms per milliliter (pg/mL). The Wilcoxon’s signed-rank test assessed significant differences between both groups at each particular time point (*indicates significant differences, p<0.05).