Title: Controlled release of celecoxib inhibits inflammation and subchondral bone changes in a rat model of osteoarthritis
Abstract: Purpose: Osteoarthritis (OA) is a common musculoskeletal disease with considerable socioeconomical impact. Anti-inflammatory agents have been proven to be effective but have been associated with systemic side effects or limited duration of local activity. Local administration of controlled release systems combined with anti-inflammatory drugs for the long-term inhibition of inflammation, thereby facilitating regeneration, can pose a solution to this problem. Celecoxib, a selective COX-2 inhibitor, was the first drug to be approved for OA. Both in vitro and in vivo studies have found beneficial effects of celecoxib on cartilage, subchondral bone and synovial tissue. Clinical studies have already proven that celecoxib is effective in relieving OA pain. The aims of this study were to 1) confirm safety of the intra-articularly released celecoxib from a controlled release system based on polyesteramide microspheres (PEAMs) in a rat model with induced knee joint OA and 2) find the optimal loading dose of celecoxib. Methods: Six weeks after induction of OA by transecting the anterior cruciate ligament and removing the medial part of the medial meniscus, rats were randomly divided into four groups (n = 6 each) receiving either unloaded PEAMs or PEAMs loaded with celecoxib (0.03 mg; 0.2 mg or 0.4 mg in 25 μL). During the 16-week follow up limb function was monitored and blood was collected to measure plasma celecoxib concentrations. Systemic and local adverse effects of celecoxib were scored post mortem. μ-CT and histology of both the treated and untreated contralateral knee joints were utilized to measure disease progression and the effects of continued exposure to celecoxib. μ-CT was used to assess subchondral bone changes. OARSI scoring and immunohistochemistry for CD68 (macrophage marker) was performed to assess the severity of osteoarthritis and synovial inflammation. Results: Systemic and local adverse effects were absent on post mortem analysis. Celecoxib-loaded PEAMs reduced the formation of osteophytes, bone cysts and loose bodies on μ-CT in OA joints. There was less subchondral sclerosis in the groups treated with celecoxib-loaded PEAMs when compared to unloaded PEAMs. Furthermore, celecoxib counteracted osteoarthritis-related trabecular bone volume loss. On histology, synovial inflammation and synovial infiltration by macrophages was inhibited by celecoxib-loaded PEAMs. Cartilage degeneration, however, remained unchanged. Conclusions: Intra-articular injection of celecoxib-loaded microspheres in the dose range of 0.03-0.4 mg celecoxib was proven to be safe in osteoarthritic joints. Prolonged presence of celecoxib reduced subchondral bone changes and synovitis. As such, celecoxib-loaded PEAMs seem to be a promising platform for local treatment of osteoarthritis. Studies that evaluate the effect of celecoxib-loaded PEAMs on clinical parameters are warranted.