ABSTRACTMechanical loading enhances bone strength and counteracts arthritis‐induced inflammation‐mediated bone loss in female mice. It is unknown whether nonsteroidal anti‐inflammatory drugs (NSAIDs; eg, COX‐2 inhibitors) can reduce inflammation without affecting the loading‐associated bone formation in male mice. The aim of this study was to investigate if loading combined with a COX‐2 inhibitor (NS‐398) could prevent arthritis‐induced bone loss and inflammation in male mice. Four‐month‐old male C57BL/6J mice were subjected to axial tibial mechanical loading three times/week for 2 weeks. Local mono‐arthritis was induced with a systemic injection of methylated bovine serum albumin on the first day of loading, followed by a local injection in one knee 1 week later. The arthritis induction, knee swelling, bone architecture, and osteoclast number were evaluated in the hind limbs. C‐terminal cross‐links as a marker for osteoclast activity was measured in serum. Compared with loading and arthritis alone, loading of the arthritic joint enhanced swelling that was partly counteracted by NS‐398. Loading of the arthritic joint enhanced synovitis and articular cartilage damage compared with loading alone. Loading increased cortical bone and counteracted the arthritis‐induced decrease in epiphyseal bone. NS‐398 did not alter the bone‐protective effects of loading. C‐terminal cross‐links, a bone resorption marker, was increased by arthritis but not loading. In conclusion, loading prevented arthritis‐induced epiphyseal and metaphyseal bone loss, and NS‐398 reduced knee swelling without affecting the bone‐protective effects of loading. If our results can be extrapolated to the human situation, specific COX‐2 inhibitors could be used in combination with loading exercise to prevent pain and swelling of the joint without influencing the bone‐protective effects of loading. © 2023 The Authors.JBMR Pluspublished by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.