The Journal of Bone and Joint Surgery (American). 2007;89:500-511.
doi:10.2106/JBJS.F.00127
© 2007 The Journal of Bone and Joint Surgery, Inc.
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Dose and Time-Dependent Effects of Cyclooxygenase-2 Inhibition on Fracture-Healing

Ann Marie Simon, BS1 and J. Patrick O'Connor, PhD1

1 Department of Orthopaedics, UMDNJ-New Jersey Medical School, MSB G580/ORTHO, 185 South Orange Avenue, Newark, NJ 07103. E-mail address for J.P. O'Connor: oconnojp{at}umdnj.edu

Investigation performed at the Department of Orthopaedics, UMDNJ-New Jersey Medical School, Newark, New Jersey

Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the Arthritis Foundation and the Orthopaedic Research and Education Foundation. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

A commentary is available with the electronic versions of this article, on our web site (www.jbjs.org) and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM).

Background: Fracture-healing is impaired in mice lacking a functional cyclooxygenase-2 (COX-2) gene or in rats continuously treated with COX-2 inhibitors. These observations indicate that COX-2 is a critical regulator of fracture repair. Nonsteroidal anti-inflammatory drugs are commonly used to treat pain associated with musculoskeletal trauma and disease. Nonsteroidal anti-inflammatory drugs inhibit COX-2 function and in so doing can impair fracture-healing. The goal of the present study was to determine how variations in nonsteroidal anti-inflammatory drug therapy ultimately affect fracture-healing.

Methods: Closed femoral fractures were made in female Sprague-Dawley rats. The rats were treated with different doses of celecoxib (a COX-2-selective nonsteroidal anti-inflammatory drug) or were treated for different periods before or after fracture with celecoxib. Eight weeks after the fracture, healing was assessed with radiography and destructive torsional mechanical testing. The effect of celecoxib treatment on fracture callus prostaglandin E2 and F2{alpha} levels was determined as a measure of cyclooxygenase activity.

Results: Celecoxib doses as small as 2 mg/kg/day reduced fracture callus mechanical properties and caused a significant increase in the proportion of nonunions. Similarly, treatment with celecoxib at a dose of 4 mg/kg/day for just five days reduced fracture callus mechanical properties and significantly increased the proportion of nonunions. Conversely, celecoxib therapy prior to fracture or initiated fourteen days after fracture did not significantly increase the proportion of nonunions. Celecoxib treatment at a dose of 4 mg/kg/day reduced fracture callus prostaglandin E2 and F2{alpha} levels by >60%.

Conclusions: COX-2-selective nonsteroidal anti-inflammatory drug therapy during the early stages of fracture repair significantly reduced fracture callus mechanical properties at later stages of healing and increased the proportion of nonunions in this animal model.

Clinical Relevance: Celecoxib therapy in the therapeutic range used by humans significantly impaired fracture-healing if administered during the first two weeks after a fracture in this animal model. However, celecoxib therapy prior to fracture or after the early stages of fracture-healing did not impede healing. These observations indicate that nonsteroidal anti-inflammatory drug therapy during the early stages of fracture-healing probably should be avoided.


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