Mylène Jansen

Clinical evidence and molecular mechanisms of KJD 189 10 Introduction With an aging and increasingly obese population, there is a growing demand for joint- preserving treatments for osteoarthritis (OA), a degenerative joint disease characterized by pain and disability due to joint tissue damage. OA gives rise to a huge societal problem, as the disease affects over 10% of the adult population. 1 Joint preservation is especially relevant in case of relatively young, middle aged, physically still active patients, as it postpones irreversible surgical treatments such as joint arthroplasty. With that, it prevents complex and costly revision surgery later in life. More and more options for joint-preserving treatments are subject of study, with multiple reviews addressing joint distraction specifically as one of these options. 2–4 Over the past 30 years, joint distraction has emerged as a joint-preserving treatment for (end- stage; considered for joint replacement surgery) OA, with a gradually growing promise for implementation in regular clinical practice. For joint distraction, the two bony ends of a joint are placed at a certain distance, for a certain time, using an external fixation frame. 5 In the 1990s, this treatment was first described for the hip, ankle, and foot joints. 6–9 Since then, joint distraction has been applied for the knee and thumb-base as well. 10–12 In 2013, an evaluation of distraction studies was covered in a review on cartilage repair strategies in this journal. 2 Data showed predominantly positive results, with patients experiencing significant improvements in pain and mobility, as well as evidence of cartilage and bone tissue repair activity. 2 Despite this clinical promise, the mechanisms behind the observed quite unique tissue regenerative process were still unknown. Over the past years, more research has been performed on these (molecular) mechanisms behind distraction treatment, specifically for the knee, to support the structural changes seen upon treatment. This includes research into synovial fluid markers, stem cell involvement, and animal studies showing tissue repair mechanisms. Moreover, since 2013 more extensive clinical trials have been performed, with distraction also being applied in regular care for the knee, although still in small numbers. 13 Compared to other joints, more extensive research has been performed on distraction on the knee, especially with respect to the working mechanisms. This review therefore focuses specifically on distraction of the knee, with the first part describing the increased clinical evidence with respect to patient-reported symptomatic outcomes as well as cartilaginous tissue repair. This part is followed by discussing different concepts of potential underlying molecular mechanisms. Finally, the overall picture emerging from the combined evidence and the possible future approaches, with regard to joint distraction and translation to other joint- preserving techniques is discussed. Clinical evidence Several clinical trials have been performed in which patients were treated with knee joint distraction (KJD), in some cases combined with other treatment modalities. While there are