Selective and Non-Selective Cyclooxygenase Inhibitors Delay Stress Fracture Healing in the Rat Ulna
School of Veterinary Science, The University of Queensland, Gatton, QLD 4343, Australia.Journal of Orthopaedic Research (Impact Factor: 2.99). 02/2013; 31(2). DOI: 10.1002/jor.22203
Anti-inflammatory drugs are widely used to manage pain associated with stress fractures (SFxs), but little is known about their effects on healing of those injuries. We hypothesized that selective and non-selective anti-inflammatory treatments would retard the healing of SFx in the rat ulna. SFxs were created by cyclic loading of the ulna in Wistar rats. Ulnae were harvested 2, 4 or 6 weeks following loading. Rats were treated with non-selective NSAID, ibuprofen (30 mg/kg/day); selective COX-2 inhibition, [5,5-dimethyl-3-3 (3 fluorophenyl)-4-(4 methylsulfonal) phenyl-2 (5H)-furanone] (DFU) (2.0 mg/kg/day); or the novel c5a anatagonist PMX53 (10 mg/kg/day, 4 and 6 weeks only); with appropriate vehicle as control. Quantitative histomorphometric measurements of SFx healing were undertaken. Treatment with the selective COX-2 inhibitor, DFU, reduced the area of resorption along the fracture line at 2 weeks, without affecting bone formation at later stages. Treatment with the non-selective, NSAID, ibuprofen decreased both bone resorption and bone formation so that there was significantly reduced length and area of remodeling and lamellar bone formation within the remodeling unit at 6 weeks after fracture. The C5a receptor antagonist PMX53 had no effect on SFx healing at 4 or 6 weeks after loading, suggesting that PMX53 would not delay SFx healing. Both selective COX-2 inhibitors and non-selective NSAIDs have the potential to compromise SFx healing, and should be used with caution when SFx is diagnosed or suspected. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
Article: NSAIDs and fracture healing[Show abstract] [Hide abstract]
ABSTRACT: Purpose of review: Published data raise concerns about the use of nonselective NSAIDs and selective cyclo-oxygenase (COX)-2 inhibitors as anti-inflammatory or analgesic drugs in patients after a recent fracture or who are undergoing (uncemented) arthroplasty or osteotomy. However, clinical reports on the effect of COX-2 inhibition on fracture healing in humans have been variable and inconclusive. This review gives an overview of the published data and an advice when to avoid NSAIDs. Recent findings: Prostaglandins play an important role as mediators of inflammation and COX are required for their production. Inflammation is an essential step in the fracture healing process in which prostaglandin production by COX-2 is involved. Data from animal studies suggest that NSAIDs, which inhibit COX-2, can impair fracture healing due to the inhibition of the endochondral ossification pathway. Animal data suggest that the effects of COX-2 inhibitors are dependent on the timing, duration, and dose, and that these effects are reversible. Summary: These animal data, together with the view of limited scientifically robust clinical evidence in humans, indicate that physicians consider only short-term administration of COX-2 inhibitors or other drugs in the pain management of patients who are in the phase of fracture or other bone defect healing. COX-2-inhibitors should be considered a potential risk factor for fracture healing, and therefore to be avoided in patients at risk for delayed fracture healing.
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ABSTRACT: Synopsis: Bone stress injury (BSI) represents the inability of bone to withstand repetitive loading, which results in structural fatigue and localized bone pain and tenderness. A BSI occurs along a pathology continuum that begins with a stress reaction, which can progress to a stress fracture and, ultimately, a complete bone fracture. Bone stress injuries are a source of concern in long-distance runners, not only because of their frequency and the morbidity they cause but also because of their tendency to recur. While most BSIs readily heal following a period of modified loading and a progressive return to running activities, the high recurrence rate of BSIs signals a need to address their underlying causative factors. A BSI results from disruption of the homeostasis between microdamage formation and its removal. Microdamage accumulation and subsequent risk for development of a BSI are related both to the load applied to a bone and to the ability of the bone to resist load. The former is more amenable to intervention and may be modified by interventions aimed at training-program design, reducing impact-related forces (eg, instructing an athlete to run "softer" or with a higher stride rate), and increasing the strength and/or endurance of local musculature (eg, strengthening the calf for tibial BSIs and the foot intrinsics for BSIs of the metatarsals). Similarly, malalignments and abnormal movement patterns should be explored and addressed. The current commentary discusses management and prevention of BSIs in runners. In doing so, information is provided on the pathophysiology, epidemiology, risk factors, clinical diagnosis, and classification of BSIs. Level of evidence: Therapy, level 5.
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ABSTRACT: Stress fractures (SFxs) are debilitating injuries and exact mechanisms that initiate their repair incompletely understood. We hypothesised that osteocyte apoptosis and expression of cytokines and proteins such as sclerostin, VEGF, TGF-β, COX-2 and IL-6 were early signalling events to facilitate the formation of periosteal woven bone and recruitment of osteoclast precursors to the site of remodelling. A SFx was created in the right ulna of mature female wistar rats using cyclic end loading. Rats were killed 1, 4 and 7 days after loading (n=5 per group). Standard histological staining was used to examine SFx morphology and immunohistochemistry to detect the localisation of these proteins and in situ hybridisation to detect mRNA along the SFx line or gene expression to quantify the target genes. Unloaded ulnae served as controls. The labelling index of caspase-3, COX-2 and IL-6 was significantly elevated in the region of SFxs at all time points compared with controls (P<0.001). In addition, the labelling index of sclerostin protein was significantly reduced in osteocytes adjacent to the SFx region when compared with controls at all three time points (P<0.001). Both VEGF and TGF-β expressions were only localised in the woven bone. These data reinforce the involvement of osteocyte apoptosis in the healing of fatigue damage in bone, and demonstrate that local regulation of sclerostin, COX-2 and IL-6 are important signalling events associated with new bone formation and SFx remodelling.
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