Abstract
Introduction: 5–10% of all fractures end in delayed or non-union. It has been reported for 3 decades that NSAIDs have an inhibitory action on fracture repair, yet GPs still prescribe these drugs in up to 50% of fracture patients. Not all fracture patients who are treated with this class of medication go on to develop non-union, yet a strong correlation has been shown in clinical studies between long bone fractures and development of delayed and non-union. The mechanism behind this effect has yet to be elucidated. In cancer research it has been shown that NSAIDs, primarily by a COX-2 pathway, can exert an inhibitory action on cell proliferation by inhibiting angiogenesis. It is proposed that a similar mechanism occurs in the induction of NSAID induced delayed fracture repair. We have investigated this hypothesis using an externally fixated murine model of femoral fracture.
Methods: 158 animals were randomised into either treatment (Rofecoxib 5mg/kg/day in a 0.5% methylcellulose carrier) or control (carrier alone). All had a standard surgical regimen involving creating of an open femoral fracture with treatment using a 4-pin external fixator under the isoflurane inhalational anaesthesia. Outcome measures included standardised x-rays (Faxitron MX-20) and Laser Doppler Flow (Oxford Optronics) measurements taken at days 0, 4, 8, 16, 24 and 32, along with biomechanical testing (Lloyd Instruments Ltd) at days 24 and 32. Data was entered into a spreadsheet and analysed using Mann-Whitney U and Wilcoxon Tests for statistical differences (SPSS, Version 9), with statistical significance being attained when p< 0.05.
Results: A greater number of animals in the NSAID group had a failure of treatment with loss fixation due to pin pullout from poor osseointegration (53% NSAID compared to 26% controls). Of those animals that completed the studies, x-ray analysis showed a change in pixel density at the fracture gap suggesting poorer healing of the NSAID animals that was statistically different at days 16, 24 and 32. Biomechanical testing suggested treatment animals had attained statistically less peak loads and stiffness at day 32. Laser Doppler Flow measurements across the fracture gap showed generally less flow at all time points in the NSAID group. This was statistically significant at days 4 and 24.
Conclusions: The new selective and specific COX-2 inhibitors are marketed as having a cleaner side effect profile and are being widely used by primary care practitioners in trauma patients. Not all animals that are treated with NSAIDs go on to develop a delayed union and some are able to heal with similar mechanical properties to animals in a control group. However, we have illustrated that the highly specific COX-2 inhibitor rofexcoxib has a significant negative effect on maintenance of fracture fixation and fracture repair in this model, both in terms of x-ray and biomechanical analysis. We have also shown that the inhibition of fracture healing is associated with a decrease in blood flow at the fracture site leading to the hypothesis that the mechanism behind the effect is via an inhibition of angiogenesis.
The abstracts were prepared by Emer Agnew. Correspondence should be addressed to Irish Orthopaedic Association, Secretariat, c/o Cappagh National Orthopaedic Hospital, Finglas, Dublin 11, Ireland.
