Simvastatin locally applied from a biodegradable coating of osteosynthetic implants improves fracture healing comparable to BMP-2 application.
Many clinical and experimental investigations address the influence of statins on bone formation and fracture healing. Simvastatin was shown to increase the expression of Bone morphogenetic protein (BMP-2), which is one of the most potent growth factors targeting bone formation. In this study, the effect of simvastatin locally applied from a bioactive polymer coating of implants on fracture healing was investigated. A closed fracture of the right tibia of 5-month-old Sprague-Dawley rats was performed. Intramedullary stabilization was achieved with uncoated vs. polymer-only coated vs. polymer plus drug coated titanium Kirschner wires. Test substances (either simvastatin low- or high dosed or BMP-2) were incorporated into a biodegradable layer of poly(d,l-lactide). Tibiae were harvested after 28 or 42 days, respectively and underwent biomechanical testing (torsional stiffness and maximum load) and histomorphometric analysis. Radiographic results demonstrated progressed callus consolidation in the BMP-2- and simvastatin-treated groups compared to the uncoated group at both timepoints. The simvastatin-high-dosed group revealed an increased torsional stiffness and significantly elevated maximum load (d 28) compared to control group as well as a significant increase in both parameters at d 42. BMP-2-treated animals showed significantly elevated maximum load and stiffness at the early timepoint and elevated torsional stiffness after d 42. The histomorphometric analysis revealed a significantly decreased cartilage area for BMP-2 treated animals at d 28. Even though an increase of mineralized areas among periosteal callus was found at d 42 for simvastatin-high as well as BMP-2 treated animals, no significant difference could be detected at both timepoints compared to the uncoated group. However, simvastatin-high treated animals revealed significantly reduced cartilage areas within the periosteal callus at d 42. The present study revealed a dose-dependent effect and improved fracture healing under local application of simvastatin. Biomechanical, radiographic and histomorphometric properties showed comparable results to BMP-2- treated animals in this study.
Pauly
S
S
Center for Musculoskeletal Surgery, Julius Wolff Institut, Charité-Universitaetsmedizin Berlin, Germany.
Luttosch
F
F
Morawski
M
M
Haas
N P
NP
Schmidmaier
G
G
Wildemann
B
B
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage / Q000494:pharmacology*; D002146:Bony Callus / Q000473:pathology; D020099:Coated Materials, Biocompatible; D005260:Female; D017102:Fracture Healing / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011091:Polyesters; D019736:Prostheses and Implants; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*
D055396:Bone Morphogenetic Protein 2; D020099:Coated Materials, Biocompatible; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011091:Polyesters; C033616:poly(lactide); D019821:Simvastatin