{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:52:51Z","timestamp":1785405171058,"version":"3.56.0"},"posted":{"date-parts":[[2025,8,25]]},"group-title":"Bioengineering","reference-count":101,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["AR052273"],"award-info":[{"award-number":["AR052273"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,25]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>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.<\/jats:p>","DOI":"10.1101\/2025.08.20.669939","type":"posted-content","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T16:45:12Z","timestamp":1756140312000},"source":"Crossref","is-referenced-by-count":0,"title":["COX2-independent and COX2-dependent effects of naproxen on bone quality, osteocytes, and fatigue fracture healing in male and female mice"],"prefix":"10.64898","author":[{"given":"Alexandra","family":"Ciuciu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"McLaughlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Ciuciu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly 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