Naproxen Impairs Load-induced Bone Formation, Reduces Bone Toughness, and Delays Stress Fracture Rep
Geisinger Commonwealth School of Medicine
INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) are effective in reducing pain and inflammation by the blockade of cyclooxygenases (COX) enzymes and prostaglandin E2 (PGE2). In addition, prostaglandins are part of the signaling pathway for strain adaptive bone remodeling. Therefore, we reasoned that regular use of NSAIDs in periods of repetitive mechanical loading may result in an increased risk of skeletal fatigue injuries such as stress fracture. METHODS: Mice were randomly assigned to receive aspirin, naproxen, or vehicle in drinking water. One group received non-damaging axial forelimb compressions over two weeks before sacrifice. A separate group received an ulnar stress fracture, healed for one week, then sacrificed. Lamellar bone formation was measured via dynamic histomorphometry. Bones were scanned using a Bruker Skyscan 1275 microCT system. Standard three-point bending was performed on non-loaded bone. Hydroxyproline assays, picrosirius red staining, and second harmonic generation (SHG) imaging were performed for collagen analysis. Behavioral tests were performed to examine analgesic efficacy. Analyses were performed in Prism 7 with an adjusted p-value < 0.05 considered significant. RESULTS: Mice treated with naproxen had significantly decreased periosteal bone formation parameters, including decreases in rPs.MS/BS (-65%), rPs.MAR (-77%), and rPs.BFR/BS (-76%). We observed a significant decrease (-35%) in toughness in bones from mice treated with naproxen as compared to vehicle. The effects of aspirin was not statistically significant. The percentage of thin collagen fibrils was significantly increased (+201%) in the naproxen treated mice compared to vehicle. This increase in thinner fibrils was at the expense of thick fibrils, which were significantly decreased (-49%) in naproxen treated mice. Consistent with these results, we found a significant decrease in SHG signal in bones from mice treated with naproxen (-32%). In the separate group, we observed that vehicle-treated mice used their loaded forelimb significantly less (-25% to -34%) on days 3 to 6 as compared to baseline, while aspirin and naproxen treated mice did not. the amount of woven bone formed 7 days after stress fracture was significantly diminished (-27%) in bones harvested from mice treated with naproxen, but not aspirin. SIGNIFICANCE: Routine use of naproxen may increase the risk of stress fracture in active individuals and extend the time required for healing.