Current and Future Concepts for the Treatment of Impaired Fracture Healing

Abstract

Bone regeneration represents a complex process, of which basic biologic principles have been evolutionarily conserved over a broad range of different species. Bone represents one of few tissues that can heal without forming a fibrous scar and, as such, resembles a unique form of tissue regeneration. Despite a tremendous improvement in surgical techniques in the past decades, impaired bone regeneration including non-unions still affect a significant number of patients with fractures. As impaired bone regeneration is associated with high socio-economic implications, it is an essential clinical need to gain a full understanding of the pathophysiology and identify novel treatment approaches. This review focuses on the clinical implications of impaired bone regeneration, including currently available treatment options. Moreover, recent advances in the understanding of fracture healing are discussed, which have resulted in the identification and development of novel therapeutic approaches for affected patients.

Keywords: biomaterials; fracture healing; non-union; osteoanabolic molecules.

Figure 1

Case example of infected non-union treated with Masquelet technique and Reamer–irrigator–aspirator. (a,b) Ap and lateral radiograph of a multi-fragmentary Gustilo–Anderson Type II open tibia and fibula fracture of a 74-year-old man. (c) Ap radiograph after surgical treatment. (d) 7 month after surgery: re-presentation of the patient with an infected non-union of the tibia with re-fracture and failure of the osteosynthesis material. (e,f) Postoperative Radiograph of the lower leg (ap and lateral): Condition after removal of the broken osteosynthesis material. Large, bone defect of the tibia after extensive debridement, reaming of the medullary canal, radical resection of the non-union and temporary immobilization with an external fixator. The microbiological samples taken intraoperatively revealed the presence of Staphylococcus caprae. Antibiotic therapy was carried out according to the recommendations of the interdisciplinary infection board. (g) Re-osteosynthesis of tibia and fibula after resolution of infection. Temporary treatment of the bone defect with a cement spacer to induce a vascularized foreign-body membrane (Masquelet membrane). (h) Intraoperative radiograph after removal of the cement spacer 2 months after implantation. (i–k) Harvest of autologous bone graft (bone marrow, morselized bone) from the femur using the Reamer–irrigator–aspirator (RIA). (l,m) Picture and intraoperative radiograph after filling of the bone defect with autologous bone. (n,o) Ap and lateral radiograph of the left lower leg demonstrate healing of the bone defect 4 month after surgery.

Figure 2

(a) Ap radiograph of the right lower leg of a 24-year-old man with an atrophic non-union of the tibia after an open fracture in Albania 5 years ago. (b,c) Enlargement of the non-union in an ap and lateral radiograph. According to the patient’s history: condition after 4 surgical trials in 3 countries. (d) Intraoperative ap radiograph after positioning of the Taylor Spatial Frame (TSF) external fixator and radical resection of the atrophic non-union. (e) Resected tibia non-union with atrophic bone over a length of 7 cm. (f) Intraoperative positioning of the tibia and the TSF for the planned bone segment transport by callus distraction. (g) Postoperative picture of the attached TSF. (h) Radiograph of the tibia during the distraction process (0.5 mm/day over a period of 140 days) with constant substitution of calcium and vitamin D. (i) X-ray of the tibia after the end of the distraction with already clearly visible bone formation. (j) Postoperative radiograph after removal of the ring fixator and angular stable plate osteosynthesis. (k) Radiological control at the end of treatment with healed bone defect 3 months after TSF removal.

Figure 3

Sequential need for growth hormones and their effect on fracture repair. Platelet derived growth factor (PDGF) acts in recruitment and proliferation of mesenchymal stem cells/osteoprogenitor cells (MSC/OPC), exerts positive effects on angiogenesis via vascular endothelial growth factor (VEGF) and acts chemotactic on immune cells. Platelet derived growth factor receptor β (PDGFRβ) signaling suppresses osteogenic differentiation. Bone morphogenic protein-2 (BMP-2) promotes osteoblastic and chondrocyte differentiation. Fibroblast growth factor-2 (FGF-2) acts mitogenic on MSC/OPC, osteoblasts, chondrocytes and osteoclasts, and enhances matrix synthesis and angiogenesis. Fibroblast growth factor 23 (FGF-23) inhibits osteoblast differentiation and matrix synthesis. Fibroblast growth factor receptor 3 (FGFR3) signaling inhibits osteoclastic bone resorption. Parathyroid hormone (PTH) enhances differentiation and proliferation of osteoblasts, enhances differentiation of chondrocytes, enhances matrix synthesis and activates osteoclasts and bone remodeling.

Figure 4

Synergy of parathyroid hormone (PTH), fibroblast growth factor 2 (FGF-2) and bone morphogenic protein-2 (BMP-2) in the activation of osteogenic gene transcription. PTH upregulates FGF-2, and PTH and FGF-2 synergistically activate Wnt signaling via lipoprotein receptor 5/6 (LPR5/6) and Frizzled receptor (Fz). Receptor activation inhibits the β-catenin destroy complex (DC) and β-catenin (β-cat) induces osteogenic gene transcription. FGF-2 enhances BMP-2 which activates transcription factor runt-related transcription factor 2 (Runx2), distal-less homebox 5 (Dlx5) and Osterix via Smad1/5/8 / Smad4 signaling. Osteocyte derived Sclerostin (Scl) inhibits Wnt signaling by LPR5 blockage and osteocyte Scl production is inhibited by PTH.