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
Clinical Relevance: While animal studies have suggested that both
nonsteroidal anti-inflammatory drugs and coxibs inhibit bone repair, there
have been no clinical reports with Level-1 evidence to support these findings.
Because most patients discontinue these medications when pain has subsided, it
is important to determine whether the inhibitory effects are reversible. The
present animal study confirms that inhibition of cyclooxygenase 2 impairs
fracture-healing and that the effects are dependent on both the dose and
duration of treatment. However, the reduced prostaglandin levels in callus
rebound with drug withdrawal, and the impairment in the mechanical integrity
of the healing fractures is reversed after short-term treatment.