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bioRxiv · 10.1101/2025.08.20.669939

COX2-independent and COX2-dependent effects of naproxen on bone quality, osteocytes, and fatigue fracture healing in male and female mice

Ciuciu, A.·McLaughlin, E.·Barrientos, K. C.·LaPoint, T.·Tomlinson, R. E.
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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.

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Ciuciu, A., McLaughlin, E., Barrientos, K. C., LaPoint, T., Tomlinson, R. E.. 2025-08-25. COX2-independent and COX2-dependent effects of naproxen on bone quality, osteocytes, and fatigue fracture healing in male and female mice. https://doi.org/10.1101/2025.08.20.669939

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