Abstract
Regular non-steroidal anti-inflammatory drug (NSAID) use increases stress fracture risk, but the mechanisms remain unclear. Here, we used Ptgs2-Y385F mice, which lack cyclooxygenase 2 (COX2) enzyme activity, to test the hypothesis that naproxen decreases strain adaptive bone remodeling in a COX2-dependent manner and decreases bone toughness and fracture resistance through COX2-independent effects. MicroCT and mechanical testing showed minimal baseline differences between Ptgs2-Y385F and wild-type (WT) mice. Following non-damaging forelimb compression, naproxen decreased load-induced bone formation in WT, but not Ptgs2-Y385F mice, consistent with a COX2-dependent effect. In contrast, naproxen reduced bone toughness and post-yield deformation across genotypes and doses, supporting a COX2-independent mechanism. Histologically, naproxen increased empty osteocyte lacunae in both genotypes, while osteoblast number, total lacunae, and perilacunar labeling were increased only in WT mice. Naproxen pre-treatment before fatigue fracture produced mild, sex-specific effects on fracture initiation and healing. Analysis of osteocyte dendritic networks in uninjured femurs revealed sexually dimorphic changes in dendrite number and density in naproxen-treated mice as compared to vehicle. In total, naproxen influences bone through both COX2-dependent and COX2-independent mechanisms, with some sexual dimorphism. These findings confirm that regular NSAID usage compromises skeletal health and underscore the need for new pain management strategies.