EXAMINATION OF THE RELATIONSHIP BETWEEN FRACTURE REPAIR AND ANGIOGENESIS IN AN NSAID TREATED ANIMAL MODEL

Abstract

Introduction: Ten percent of fractures end in delayed or non-union. NSAIDs have been linked to an inhibitory action on fracture repair for three decades yet the mechanism of action remains to be elucidated. Cancer research has identified that NSAIDs impede cell proliferation by inhibiting angiogenesis. It is proposed that a similar mechanism occurs in the induction of NSAID induced non-unions. We have investigated this hypothesis in a randomized placebo control trial of the NSAID rofecoxib using a murine femoral fracture model.

Material and Methods: All animals had an open femoral fracture treated using an external fixator. Outcomes measures included x-ray, histology, and biomechanical testing, with laser Doppler used to assess blood flow across the fracture gap.

Results: Radiology showed similar healing patterns in both groups, however at the later stages (day 32) the NSAID group had significantly poorer healing. Histological analysis showed that controls healed quicker (days 24 and 32), with more callus (day 8) and less fibrous tissue (day 32). Biomechanical testing showed that controls were stronger at day 32. Both groups exhibited a similar pattern of blood flow; however NSAIDs exhibited a lower median flow from day 4 onwards (significant at days 4, 16 and 24).

Discussion: Positive correlations were demonstrated between both histological and radiographic assessments of healing, with increasing blood flow. NSAID animals exhibited lower flows, and poorer healing by all outcomes. Regression analysis demonstrates however that the negative effect of NSAIDs on fracture repair is independent of its inhibitory action on blood flow. In conclusion, COX-2 inhibitors are marketed as having cleaner side effect profiles and are widely used in trauma patients. Following development of a novel method of analyzing functional vascularity across a fracture gap, we have demonstrated that the COX-2 inhibitor rofecoxib has a significant negative effect on blood flow at the fracture gap as well as inhibiting fracture repair.