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 F2a 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
F2a 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.