VOL. 89-B, No. 9, SEPTEMBER 2007 1253 The effects of the short-term administration of low therapeutic doses of anti-COX-2 agents on the healing of fractures AN EXPERIMENTAL STUDY IN RABBITS T. Karachalios, L. Boursinos, L. Poultsides, L. Khaldi, K. N. Malizos From the University of Thessaly, Larissa, Greece  T. Karachalios, MD, DSc, Associate Professor  L. Boursinos, MD, Resident  L. Poultsides, MD, Resident  K. N. Malizos, MD, DSc, Professor and Chairman Orthopaedic Department  L. Khaldi, MD, Consultant Pathologist Department of Pathology School of Medicine, Faculty of Health Sciences, University of Thessaly, 22 Papakyriazi Street, Larisa 41222, Greece. Correspondence should be sent to Dr T. Karachalios; e-mail: kar@med.uth.gr ©2007 British Editorial Society of Bone and Joint Surgery doi:10.1302/0301-620X.89B9. 19050 $2.00 J Bone Joint Surg [Br] 2007;89-B:1253-60. Received 18 December 2006; Accepted after revision 16 May 2007 We have evaluated the effect of the short-term administration of low therapeutic doses of modern COX-2 inhibitors on the healing of fractures. A total of 40 adult male New Zealand rabbits were divided into five groups. A mid- diaphyseal osteotomy of the right ulna was performed and either normal saline, prednisolone, indometacin, meloxicam or rofecoxib was administered for five days. Radiological, biomechanical and histomorphometric evaluation was performed at six weeks. In the group in which the highly selective anti-COX-2 agent, rofecoxib, was used the incidence of radiologically-incomplete union was similar to that in the control group. All the biomechanical parameters were statistically significantly lower in both the prednisolone and indometacin (p = 0.01) and in the meloxicam (p = 0.04) groups compared with the control group. Only the fracture load values were found to be statistically significantly lower (p = 0.05) in the rofecoxib group. Histomorphometric parameters were adversely affected in all groups with the specimens of the rofecoxib group showing the least negative effect. Our findings indicated that the short-term administration of low therapeutic doses of a highly selective COX-2 inhibitor had a minor negative effect on bone healing. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for orthopaedic con- ditions such as osteoarthritis, soft-tissue inju- ries and fractures. 1-5 The new generation of NSAIDs, selective cyclo-oxygenase-2 (COX-2) inhibitors, have analgesic and anti-inflamma- tory effects equivalent or superior to those of conventional NSAIDs, while reducing the prevalence of adverse gastrointestinal events. 1-7 Several animal and in vitro studies have shown impaired bone healing in the presence of conventional NSAIDs, as measured by a variety of different parameters. 4,5,8-18 Initial studies investigating the effects of COX-2 selective inhibitors on bone healing yielded similar results, 5,16,19-22 but some have shown minor or no impairment of the healing pro- cess. 11,23,24 Since animal data suggest that the effects of COX-2 inhibitors are probably both dose- dependent and reversible, 1,3 we investigated the effect of the short-term administration of low therapeutic doses of corticosteroids, indometacin, meloxicam and rofecoxib on non-osteonal 25 (secondary) healing of frac- tures in rabbits. Materials and Methods We used 40 adult male New Zealand white rab- bits with a mean age of 3.0 months (2.3 to 3.1) and mean weight of 3.5 kg (3.4 to 3.6) at the start of the study. They were divided into five groups (A-E) of eight rabbits each and were kept under normal experimental conditions and allowed unrestricted access to standard stock diet and tap water. Six died during the induction of anaesthesia and a further 14, which were in groups B and C, developed superficial or deep infection. They were treated, withdrawn from the study and replaced by others. The experimental pro- cedures had been reviewed and approved by an institutional animal care committee in accor- dance with the current National policy for experimentation in animals. We performed an osteotomy at the mid- diaphysis of the right ulna on all the animals using a thin oscillating saw, 26,27 under general anaesthesia induced by cetamine, mitazolam and atropine. Special care was taken to protect and avoid disruption of the periosteum at the site of the osteotomy which was left without fixation. All the animals were left free to move as pain allowed. All received two prophylactic Research