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Selective and Nonselective Cyclooxygenase-2 Inhibitors and Experimental Fracture-Healing

Reversibility of Effects After Short-Term Treatment

¹ Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Boston University Medical Center, 715 Albany Street, R-205, Boston, MA 02118
² Pfizer Corporation, 700 Chesterfield Parkway, Chesterfield, MO 63198
³ Department of Orthopaedic Surgery, Boston University Medical Center, Doctors Office Building, Suite 808, 720 Harrison Avenue, Boston, MA 02118. E-mail address: Thomas.Einhorn{at}bmc.org

Investigation performed at Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Boston University Medical Center, Boston, Massachusetts

Disclosure: In support of their research for or preparation of this manuscript, one or more of the authors received grants or outside funding from Pfizer Corporation. None of the authors 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, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

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.

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.

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