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.
1. Bo J, Sudmann E, Marton PF. Effect of indomethacin on fracture healing in rats. Acta Orthop Scand. 1976;47:588-99.
2. Allen HL, Wase A, Bear WT. Indomethacin and aspirin: effect of nonsteroidal anti-inflammatory agents on the rate of fracture repair in the rat. Acta Orthop Scand. 1980;51:595-600.
3. Altman RD, Latta LL, Keer R, Renfree K, Hornicek FJ, Banovac K. Effect of nonsteroidal anti-inflammatory drugs on fracture healing: a laboratory study in rats. J Orthop Trauma. 1995;9:392-400.
4. Giannoudis PV, MacDonald DA, Matthews SJ, Smith RM, Furlong AJ, De Boer P. Nonunion of the femoral diaphysis: the influence of reaming and non-steroidal anti-inflammatory drugs. J Bone Joint Surg Br. 2000;82:655-8.
5. Simon AM, Manigrasso MB, O'Connor JP. Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res. 2002;17:963-76.
6. Goodman S, Ma T, Trindade M, Ikenoue T, Matsuura I, Wong N, Fox N, Genovese M, Regula D, Smith RL. COX-2 selective NSAID decreases bone ingrowth in vivo. J Orthop Res. 2002;20:1164-9.
7. Gerstenfeld LC, Thiede M, Seibert K, Mielke C, Phippard D, Svagr B, Cullinane D, Einhorn TA. Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res. 2003;21:670-5.
8. Moore KD, Goss K, Anglen JO. Indomethacin versus radiation therapy for prophylaxis against heterotopic ossification in acetabular fractures: a randomised, prospective study. J Bone Joint Surg Br. 1998;80:259-63.
9. Reuben SS, Ekman EF. The effect of cyclooxygenase-2 inhibition on analgesia and spinal fusion. J Bone Joint Surg Am. 2005 Mar;87(3):536-42.
10. Gerstenfeld LC, Al-Ghawas M, Alkhiary YM, Cullinane DM, Krall EA, Fitch JL, Webb EG, Thiede MA, Einhorn TA. Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing. Reversibility of effects after short-term treatment. J Bone Joint Surg Am. 2007;89:114-25.
11. Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006;116:4-15.
12. Furberg CD, Psaty BM, FitzGerald GA. Parecoxib, valdecoxib, and cardiovascular risk. Circulation. 2005;111:249.
13. Egan KM, Wang M, Fries S, Lucitt MB, Zukas AM, Pure E, Lawson JA, FitzGerald GA. Cyclooxygenases, thromboxane, and atherosclerosis: plaque destabilization by cyclooxygenase-2 inhibition combined with thromboxane receptor antagonism. Circulation.2005;111:334-42.