Copyright © 2007 by The Journal of Bone and Joint Surgery, Inc.
Commentary & Perspective
Commentary & Perspective by
Thomas A. Einhorn, MD*,
Boston Medical Center, Boston, Massachusetts
Posted March 2007
For over a quarter of a century, investigators have been asking
the question, "Does inhibition of prostaglandin synthesis by nonsteroidal anti-inflammatory
drugs inhibit the repair of bone?"1-4 Such research was originally
focused on the nonspecific cyclooxygenase inhibitors, but with the introduction
of cyclooxygenase-2 (COX-2) specific inhibitors in the 1990s and with the
recognition that COX-2 is a critical regulator of bone repair, the development
of these selective inhibitors led to a flurry of investigations to determine if
this class of drugs had any inhibitory effects on bone-healing. Indeed, studies
confirmed that they did5-7. As a result, many physicians now advise
their patients not to use these drugs as analgesic or anti-inflammatory agents following
a fracture or after operative procedures (e.g., spinal or long-bone arthrodesis
or cementless total joint arthroplasty) for which the success of the operation
depends on bone formation. Because no prospective, randomized clinical trials
had ever been performed to test the hypothesis that inhibitors of COX-2 impair
bone-healing, all clinical recommendations were made on the basis of the extrapolation
of findings from preclinical animal studies. Two clinical reports with less
than level-I evidence4,8 and one with level-I evidence9 have
been communicated, but the results of those studies have been inconclusive and
even contradictory.
In this month's issue of The Journal, Simon and O'Connor communicate another report on COX-2 inhibition of fracture-healing in an animal model. With use of female Sprague-Dawley rats, they determined how the healing of closed femoral fractures was affected by the dose of celecoxib (a COX-2-selective, nonsteroidal anti-inflammatory drug) or the timing of its introduction and administration. The results showed that doses as small as 2 mg/kg/day, begun four hours after fracture and continued for fifteen days, reduced the mechanical properties of the fracture calluses and caused a significant increase in the proportion of nonunions when the fractures were assessed at eight weeks. Treatment at a dose of 4 mg/kg/day, begun four hours after fracture and continued for only five days, led to a similar effect. Conversely, when the drug was introduced prior to fracture, or initiated fourteen days after fracture, this effect was not observed. The authors concluded that introduction of COX-2-selective nonsteroidal anti-inflammatory drug therapy during the early stages of fracture-healing can significantly reduce fracture callus mechanical properties at later stages of healing and can increase the proportion of nonunions. Moreover, to correlate the inhibitory effect of these drugs with the impaired synthesis of prostaglandins, the investigators demonstrated that celecoxib treatment at a dose of 4 mg/kg/day reduced fracture callus prostaglandin E2 and F2α levels by >60%.
The results of this investigation are interesting and
certainly raise questions concerning the safety of using inhibitors of COX-2 in
the setting of bone-healing. However, a recent report from my laboratory, published
in the January issue of The Journal, reported
different findings10. We showed, using valdecoxib as opposed to celecoxib,
and an ED50 dose (median effective dose), that if fracture-healing is assessed
as early as five weeks (thirty-five days) after fracture, and if inhibition of COX-2
is continued for up to twenty-one days after fracture, an inhibitory effect of
this treatment on fracture-healing detected at twenty-one days would disappear
by thirty-five days. Our studies were also correlated with evidence of a
rebound in the synthesis of prostaglandin fourteen days after drug withdrawal. Hence,
while the report by Simon and O'Connor suggests that treatment with celecoxib in
the first five days after fracture will lead to impaired fracture-healing and
an increase in nonunions when assessed at eight weeks, our results show that treatment
with valdecoxib for the first twenty-one days after fracture, if discontinued
for a period of fourteen days, will permit recovery of the healing responses
sufficiently so that neither fracture-healing nor nonunion rate will be
affected.
Although two different COX-2 inhibitors were used, the reasons
for the discrepancy in findings between the Simon and O'Connor report and ours
are unclear. While, in our study, male Sprague Dawley rats were used, Simon and
O'Connor studied female rats. However, there is no evidence that there is any
difference in fracture-healing between male and female animals of this species.
Simon and O'Connor used a high-dose and a low-dose of celecoxib while we used
an ED50 dose of valdecoxib. However, the ED50 dose of celecoxib is in the range
used by Simon and O'Connor, hence sufficient inhibition of COX-2 should have
been provided by either drug. The model of fracture-healing used in both
studies was the same, and the methods of data analysis were also quite similar.
Indeed, in both studies, prostaglandin levels were shown to be reduced by
exposure to either drug.
Perhaps an explanation for the differences in the findings
in these two reports is related to the selectivity of the two drugs against COX-2
and their effects on the synthesis of other prostaglandins besides
prostaglandin E2 and F2α.
The recent focus on the cardiac toxicity of COX-2 inhibitors has led to a number
of reports showing that different pharmacological agents have differential
inhibitory effects on COX-1 and COX-2 through selective alterations in the
production of other prostaglandin metabolites such as prostacyclin (PGI2)
and thromboxane A2 (TXA2)11. Selective COX-2 inhibitors
appear to depress PGI2 but not COX-1-derived TXA212,13.
Uncoupling of the balance of these effects by a selective inhibitor of COX-2
apparently leads to detrimental effects on coagulation control. It may
therefore be speculated that a similar type of uncoupled inhibition of these
enzymes may influence the process of bone repair through effects on the local
concentrations and ratios of different prostaglandins.
In vitro studies help us to understand the cellular
mechanisms of biological processes. With an understanding of those mechanisms,
experiments to determine the effects of interventions can be performed in animal
models. However, it is only with clinical investigations, particularly
prospective randomized controlled trials, that knowledge of the outcomes of an
intervention can be determined. On the basis of the findings of the study by
Simon and O'Connor, and in consideration of the findings of our report, it
seems that questions related to the use of COX-2 inhibitors in bone repair in patients
remain unresolved and that clarification can only come from well-done clinical
trials.
*The author did not receive any outside funding or grants in support of his research for or preparation of this work. The author or a member of his immediate family received, in any one year, payments or other benefits in excess of $10,000 or a commitment or agreement to provide such benefits from a commercial entity (Merck, Pfizer). Also, a commercial entity (Pfizer) paid or directed in any one year, or agreed to pay or direct, benefits in excess of $10,000 to a research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.
References
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