Non-steroidal anti-inflammatory drugs (NSAIDs) reduce pain, fever, and inflammation by inhibiting the cyclooxygenase (COX) enzymes. Increasing evidence shows a correlation between regular NSAID use and an increased incidence of bone stress fracture. Stress fractures are caused by repetitive, sub-fracture forces that form microcracks in bone that worsen if not allowed to heal. Populations most at risk of forming stress fractures are also likely to regularly take NSAIDs, thus this correlation must be investigated. Our investigation of NSAID effects on humans in the general population showed a correlation of increased stress fracture incidence in cohorts that had been taking NSAIDs regularly. To investigate this further, we used a model of COX2 inactivity, the Ptgs2-Y385F mouse, which harbors a point mutation in prostaglandin-endoperoxide synthase 2 (Ptgs2), which encodes a COX2 enzyme with inhibited cyclooxygenase activity. This mutation alone models a lifelong inhibition of COX2 cyclooxygenase activity. Through administration of both non-selective and COX2-selective NSAIDs to Ptgs2- Y385F mice, NSAID effects on bone that are independent or dependent on COX2 inhibition can be identified. Additionally, effects of acetaminophen (a non-NSAID analgesic) in rat bone, and celecoxib (a COX2-selective NSAID) in C57BL/6J and Ptgs2- Y385F mice are also included. The main aims of this work are:​ (1) evaluate the effects of NSAIDs on non-loaded bone in wild-type (WT) and Ptgs2-Y385F mice, and (2) identify NSAID effects on bone under non-damaging and damaging loading conditions. In the study of rats given acetaminophen, it was seen that a low dose of acetaminophen did not cause adverse effects on bone. The study of celecoxib in C57BL/6J mice showed that celecoxib decreased load-induced bone formation. In our follow-up study of celecoxib treatment in Ptgs2-Y385F, heterozygous, and WT mice, celecoxib had a significant effect on trabecular bone geometry and bone mechanical performance in both WT and Ptgs2- Y385F, but not heterozygous mice. Finally, in the study of naproxen’s effects on bone, it was found that naproxen decreased load-induced bone formation in only WT mice, but decreased bone toughness in both genotypes. Overall, these findings add to the overall understanding of NSAID mechanisms in bone through the identification of COX2-independent and -dependent effects.