Influence of statins locally applied from orthopedic implants on osseous integration

Abstract

Background: Simvastatin increases the expression of bone morphogenetic protein 2 (BMP-2) in osteoblasts, therefore it is important to investigate the influence of statins on bone formation, fracture healing and implant integration. The aim of the present study was to investigate the effect of simvastatin, locally applied from intramedullary coated and bioactive implants, on bone integration using biomechanical and histomorphometrical analyses.

Methods: Eighty rats received retrograde nailing of the femur with titanium implants: uncoated vs. polymer-only (poly(D,L-lactide)) vs. polymer plus drug coated (either simvastatin low- or high dosed; "SIM low/ high"). Femurs were harvested after 56 days for radiographic and histomorphometric or biomechanical analysis (push-out).

Results: Radiographic analysis revealed no pathological findings for animals of the control and SIM low dose group. However, n=2/10 animals of the SIM high group showed osteolysis next to the implant without evidence of bacterial infection determined by microbiological analysis. Biomechanical results showed a significant decrease in fixation strength for SIM high coated implants vs. the control groups (uncoated and PDLLA). Histomorphometry revealed a significantly reduced total as well as direct bone/implant contact for SIM high- implants vs. controls (uncoated and PDLLA-groups). Total contact was reduced for SIM low vs. uncoated controls. Significantly reduced new bone formation was measured around SIM high coated implants vs. both control groups.

Conclusions: This animal study suggests impaired implant integration with local application of simvastatin from intramedullary titanium implants after 8 weeks when compared to uncoated or carrier-only coated controls.

Figure 1

Histomorphometric overview and x-ray after 56 days, for animals from a) uncoated group, b) PDLLA, c) SIM low and d) SIM high. No macroscopic differences were obvious between all 4 groups with regard to implant integration, osteolysis, ectopic bone formation or implant loosening.

Figure 2

Microscopic and radiographic findings in one (out of n=2/20) SIM high-treated femur after 56 days, showing osteolysis around the implant. Bacterial infection was ruled out by means of microbiological diagnostics.

Figure 3

Biomechanical fixation strength of SIM high coated implants was significantly weaker than with uncoated- (p = 0.002) or PDLLA-coated implants (p = 0.005) (*).

Figure 4

a) Histomorphometric analysis. Total bone/implant contact was significantly decreased between the uncoated control and both experimental groups (SIM high: p < 0.001; SIM low: p = 0.006) as well as between PDLLA and SIM high (p < 0.001) (*). b) Direct bone/implant contact showed significant differences between SIM high and both control groups (vs. uncoated: p = 0.001; vs. PDLLA: p = 0.006) (*). c) Indirect bone/implant contact was reduced for both SIM coated groups, differing significantly between the PDLLA and SIM high group (p = 0.004) (*). d) Newly formed bone (within a 0.3mm range around the implants) was significantly reduced between uncoated controls and all other groups (vs. PDLLA: p = 0.002; vs. SIM low and –high: p < 0.001, respectively), as well as between PDLLA and SIM high implants (p = 0.002) (*).

Figure 5

Histological samples were analyzed following a 13.7 mm line (from the nutrient foramen to the distal femur) to determine bone/implant contact and new bone formation, within a 0.3 mm region of interest, on both sides of the implant[42].