Selective and non-selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna
Kidd LJ, Cowling NR, Wu AC, Kelly WL, Forwood MR. J Orthop Res. 2012 Jul 30. doi: 10.1002/jor.22203. [Epub ahead of print]
Non-steroidal anti-inflammatory drugs (NSAIDs) are a commonly used medication for pain related to musculoskeletal injuries that can be obtained both over the counter and with a prescription. They act by inhibiting the effects of cyclooxygenase (COX) enzymes, which play a role in bone biology, specifically bone resorption by COX-2. Stress fractures are common injuries that affect many people of all ages and level of activity. There are studies that show negative effects of NSAIDs on complete fracture healing, but there is little data on the relationship of NSAIDs and stress fractures. Kidd et al, set out to determine the effects of three different NSAIDs on stress fracture healing and woven bone consolidation in an animal model using the rat ulna. Their hypothesis was that a COX-2 inhibitor would have a greater effect on fracture line remodeling and consolidation of periosteal woven bone than ibuprofen (non-selective COX inhibitor) and PMX53 (a C5a receptor antagonist that targets the complement system; a key component of the immune system). A total of 170 rats underwent repetitive cyclic loading of their right ulna under anesthesia until a 10% increase in displacement was reached (all treatments were approved by the authors’ animal ethics committee). Sixty rats were given either a selective COX-2 inhibitor or a control daily over six weeks. Eighty rats received ibuprofen or distilled water over six weeks. Thirty rats were given PMX-53 and used the same control group as the rats given ibuprofen. The rats were then euthanized at 2 (except PMX-53 group), 4, or 6 weeks after the repetitive loading to examine the ulna using histomorphometry (microscopic examination of the cortical and woven bone area, as well as the area of bone resorption). The authors found that ibuprofen significantly reduced bone resorption and cortical formation 6 weeks after loading and that the selective COX-2 inhibitor significantly reduced resorption along the fracture line at 2 weeks only. There were no significant differences between the selective COX-2 inhibitor or PMX-53 treated groups and control groups at 6 weeks. There was no difference in woven bone area among any of the medications and control groups.
Stress fractures are a painful injury and patients often look for some type of medication for pain control, commonly an NSAID. The authors were surprised that ibuprofen caused a greater reduction in bone healing than the COX-2 inhibitor because there have been many studies that showed COX-2 plays the greatest role in fracture repair and resorption through the production of a prostaglandin (PGE2). They conclude that maybe both COX-1 and COX-2 enzymes are needed for the maximal amount of PGE2 production. The authors noted that one possible limitation that may have led to a lower than expected result with the COX-2 inhibitor was the use of a different vehicle than the ibuprofen. This may have created inconsistent drug levels with peaks and troughs. Although human studies would be needed to make a definite recommendation against the daily use of NSAIDs in stress fractures, we should be cautious when we prescribe a daily dose of these pain medications to our patients. Ibuprofen and other non-selective NSAIDs are available over the counter and thus are more commonly used than the COX-2 inhibitors, since they require a prescription. When an athlete or any patient is looking for every possible way to return to play as soon as possible, suggesting that they refrain from daily NSAIDs may be beneficial. This study does not address the impact of intermittent use of NSAIDs. Have you noticed any changes in healing rates in your patients with stress fractures that use NSAIDs? How do you counsel patients and athletes for pain control with stress fractures?
Written by: Kris Fayock, MD
Reviewed by: Jeffrey Driban
Related Posts:Kidd LJ, Cowling NR, Wu AC, Kelly WL, & Forwood MR (2012). Selective and non-selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna. Journal of Orthopaedic Research PMID: 22847634