title: Dose and time-dependent effects of cyclooxygenase-2 inhibition on fracture-healing.
abstract: 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 F(2alpha) 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 F(2alpha) 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.
authors.affiliation: Department of Orthopaedics, UMDNJ-New Jersey Medical School, MSB G580/ORTHO, 185 South Orange Avenue, Newark, NJ 07103, USA.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Simon
authors.forename: J Patrick
authors.initials: JP
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000494:pharmacology; D002146:Bony Callus / Q000187:drug effects / Q000378:metabolism; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy*; D017102:Fracture Healing / Q000187:drug effects* / Q000502:physiology; D005596:Fractures, Closed / Q000000981:diagnostic imaging / Q000188:drug therapy*; D011453:Prostaglandins / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D011453:Prostaglandins; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib