Musculoskeletal
The Effectiveness of Two COX-2 Inhibitors in the Prophylaxis Against Heterotopic New Bone Formation: An Experimental Study in Rabbits

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The purpose of this study was to present the effectiveness of 2 cyclooxygenase-2 inhibitors, meloxicam and parecoxib, in the prevention of heterotopic ossification.

Eighteen white mature male rabbits were divided into 3 groups of 6 animals. One was the control group; 1 group was administered meloxicam subcutaneously, and 1 group was administered parecoxib subcutaneously. For the induction of heterotopic new bone, the Michelsson model was used. The extent of heterotopic new bone development was assessed according to Scott's classification.

The meloxicam and parecoxib groups developed significantly less heterotopic bone when compared to the control group. There was no significant difference between the meloxicam and parecoxib group.

We concluded that meloxicam and parecoxib are capable of preventing the development of heterotopic new bone in rabbits. The clinical relevance of this study is that meloxicam and parecoxib may be helpful in reducing heterotopic ossification in humans.

Introduction

The incidence of heterotopic ossification (HO) is variable, affecting mainly total hip arthroplasty (6–50%) [1, 2, 3], internal fixation of acetabular fractures (14–90%) [4, 5], as well as patients with head (10–20%) [6] or spinal cord injuries (20–30%) [7]. Since there is no current medical treatment for the established HO, prophylaxis is the only way to avoid the consequences of this serious complication. Over the past years it has been shown that radiotherapy [8] and nonsteroidal anti-inflammatory drugs (NSAIDs) [9] are both effective in preventing the development of HO. Postoperative radiotherapy may not always be available and poses concerns regarding wound healing, loosening of implants, or even malignancy [10]. A wide range of NSAIDs have been proposed as an effective prophylactic modality, with indomethasin being the most extensively studied drug [11]. Nevertheless, NSAIDs have been associated with a high incidence of gastrointestinal complications and low patient compliance [12].

The advantages offered by the cyclooxygenase-2 (COX-2) inhibitors are that these drugs are equally effective in their anti-inflammatory action, while demonstrating lower incidence of gastrointestinal side effects [13, 14, 15] compared to the traditional NSAIDs. There are also reports that COX-2 inhibitors might not affect bone union as negatively as other NSAIDs [16, 17].

Although COX-2 inhibitors have been available for some time, there are few reports that they can prevent HO like other nonselective NSAIDS [12, 18, 19, 20, 21, 22].

The purpose of this study was to present the effectiveness of 2 COX-2 inhibitors, the “preferential” COX-2 inhibitor meloxicam, as well as the injectable COX-2-specific inhibitor parecoxib, in the prevention of HO. A historical comparison with indomethacin was also performed.

Section snippets

Materials and Methods

For the purposes of the experiment, the Michelsson [23] model for mechanical induction of heterotopic new bone formation was applied. The experiment was held in the Laboratory for Research of the Musculoskeletal System “Th. Garofalidis” (University of Athens, KAT Hospital, Athens, Greece). Once approval was obtained from the Veterinary Directorate of the Prefecture of Athens, Greece (protocol Number K/1898), 18 male sexually mature New Zealand white rabbits of similar age and weight were used.

Results

All of the radiographs were evaluated using the method of Scott et al. [24]. The graded results (Table 1) of the 10th wk were analyzed using the Wilcoxon's rank-sum test, which is a nonparametric test for assessing whether the difference in means between 2 independent samples of observations is statistically significant. The radiographic rating scale represents a variable that has been organized into ranked categories. Two-tailed P values less than 0.05 were considered to be significant. The

Discussion

The results from this study were compared to those from a similar experiment by Moed et al. [25], where it was shown that indomethasin was effective in decreasing the formation of heterotopic new bone. In this comparison we found no statistical difference between the results of the indomethasin group and the meloxicam (P = 0.12) or parecoxib (P = 0.08) groups of animals.

The Michelsson model was selected because it consistently leads to the formation of heterotopic new bone in rabbits, which is

Acknowledgments

All authors certify that they have not signed any agreement with any commercial interest, related to this study, that would in any way limit publication of any and all data generated by the study.

References (51)

  • M.J. Bosse et al.

    Heterotopic ossification as a complication of acetabular fractureProphylaxis with low-dose irradiation

    J Bone Joint Surg Am

    (1988)
  • B.R. Moed et al.

    The effect of indomethacin on heterotopic ossification following acetabular fracture surgery

    J Orthop Trauma

    (1993)
  • D.E. Garland et al.

    Periarticular heterotopic ossification in head-injured adultsIncidence and location

    J Bone Joint Surg Am

    (1980)
  • S.L. Stover et al.

    Experience with surgical resection of heterotopic bone in spinal cord injury patients

    Clin Orthop Relat Res

    (1991)
  • M.B. Coventry et al.

    The use of radiation to discourage ectopic boneA nine-year study in surgery about the hip

    J Bone Joint Surg Am

    (1981)
  • M. Fransen et al.

    Non-steroidal anti-inflammatory drugs for preventing heterotopic bone formation after hip arthroplasty

    Cochrane Database Syst Rev

    (2004)
  • M.H. Seegenschmiedt et al.

    Preoperative versus postoperative radiotherapy for prevention of heterotopic ossification (HO): First results of a randomized trial in high-risk patients

    Int J Radiat Oncol Biol Phys

    (1994)
  • M.A. Ritter et al.

    The effect of indomethacin on para-articular ectopic ossification following total hip arthroplasty

    Clin Orthop Relat Res

    (1982)
  • C. Bombardier et al.

    Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritisVIGOR Study Group

    N Engl J Med

    (2000)
  • F.E. Silverstein et al.

    Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trialCelecoxib Long-term Arthritis Safety Study

    JAMA

    (2000)
  • M. Mamdani et al.

    Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs

    BMJ

    (2002)
  • S.S. Reuben

    Considerations in the use of COX-2 inhibitors in spinal fusion surgery

    Anesth Analg

    (2001)
  • S.S. Reuben

    Effect of nonsteroidal anti-inflammatory drugs on osteogenesis and spinal fusion

    Reg Anesth Pain Med

    (2001)
  • T. Barthel et al.

    Prophylaxis of heterotopic ossification after total hip arthroplasty: A prospective randomized study comparing indomethacin and meloxicam

    Acta Orthop Scand

    (2002)
  • R. Legenstein et al.

    Indomethacin versus meloxicam for prevention of heterotopic ossification after total hip arthroplasty

    Arch Orthop Trauma Surg

    (2003)
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