title: Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing. Reversibility of effects after short-term treatment.
abstract: BACKGROUND
  Cyclooxygenase-2-specific anti-inflammatory drugs (coxibs) and nonspecific nonsteroidal anti-inflammatory drugs have been shown to inhibit experimental fracture-healing. The present study tested the hypothesis that these effects are reversible after short-term treatment.
  
  
  METHODS
  With use of a standard model of fracture-healing, identical ED50 dosages of either a nonsteroidal anti-inflammatory drug (ketorolac), a coxib (valdecoxib), or vehicle (control) were orally administered to rats for either seven or twenty-one days and fracture-healing was assessed with biomechanical, histological, and biochemical analyses.
  
  
  RESULTS
  When healing was assessed at twenty-one days, the seven-day treatment produced only a trend for a higher rate of nonunion in valdecoxib and ketorolac-treated animals as compared with controls. No differences were observed at thirty-five days. The twenty-one-day treatment produced significantly more nonunions in valdecoxib-treated animals as compared with either ketorolac-treated or control animals (p < 0.05), but these differences disappeared by thirty-five days. The dose-specific inhibition of these drugs on prostaglandin E2 levels and the reversibility of the effects after drug withdrawal were assessed in fracture calluses and showed that ketorolac treatment led to twofold to threefold lower levels of prostaglandin E2 than did valdecoxib. Withdrawal of either drug after six days led to a twofold rebound in these levels by fourteen days. Histological analysis showed delayed remodeling of calcified cartilage and reduced bone formation in association with valdecoxib treatment.
  
  
  CONCLUSIONS
  Cyclooxygenase-2-specific drugs inhibit fracture-healing more than nonspecific nonsteroidal anti-inflammatory drugs, and the magnitude of the effect is related to the duration of treatment. However, after the discontinuation of treatment, prostaglandin E2 levels are gradually restored and the regain of strength returns to levels similar to control.
authors.affiliation: Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Boston University Medical Center, 715 Albany Street, R-205, Boston, MA 02118, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Gerstenfeld
authors.forename: M
authors.initials: M
authors.lastname: Al-Ghawas
authors.forename: Y M
authors.initials: YM
authors.lastname: Alkhiary
authors.forename: D M
authors.initials: DM
authors.lastname: Cullinane
authors.forename: E A
authors.initials: EA
authors.lastname: Krall
authors.forename: J L
authors.initials: JL
authors.lastname: Fitch
authors.forename: E G
authors.initials: EG
authors.lastname: Webb
authors.forename: M A
authors.initials: MA
authors.lastname: Thiede
authors.forename: T A
authors.initials: TA
authors.lastname: Einhorn
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002146:Bony Callus / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D005594:Fracture Fixation, Intramedullary; D017102:Fracture Healing / Q000187:drug effects*; D050723:Fractures, Bone / Q000628:therapy; D005599:Fractures, Ununited / Q000473:pathology; D007555:Isoxazoles / Q000494:pharmacology*; D020910:Ketorolac / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D007555:Isoxazoles; D020910:Ketorolac; D013449:Sulfonamides; C406224:valdecoxib; D000096926:Benzenesulfonamides