bone turnover in early OA to decreased bone turnover in the late stages or timely changes in the pain type requires precise knowledge of the underlying mechanistic alterations. Choosing appropriate medication for selective disease time-points might help tailor individual treatment regimens for each patient in the future. Additionally, OA might present itself with overlapping endotypes like, for instance, an inflammatory pain endotype that could benefit from a combination of pharmaceuticals addressing both pain and inflammation. Many clinical studies have been conducted in OA that address mainly structural targets like cartilage and bone in combination with reduction of inflammation and pain. In general, success was marginal, and only very few drugs, i.e. sprifermin or some BPs, resulted in improvement of joint structure and function. In addition, targeting TrkA or TRPV1 led to pain relief; however, no pharmacological treatment was able to halt or reverse OA progression long term. Data from the application of MSCs/ASCs generated some guarded optimism; however, so far, only cartilage lesions were addressed with cell-based therapies, whereas subchondral bone, tendons, and other joint tissues were not included. This is a crucial shortcoming, as OA is recognized as a whole-joint disease. One central point to be considered for all future therapeutic approaches, either regenerative or pharmacological, is the mechanical status of the joint. With this in mind, it is strongly suggested that the altered joint mechanics that cause OA are addressed in a first-line therapy. If altered OA joint mechanics are not normalized and original biomechanical pathways are not restored, it will be most likely that pharmacological or biological treatments of articular cartilage or inflammatory processes will not be efficacious. Furthermore, modulation of derailed cellular mechanoreceptive pathways might provide new opportunities to halt structural tissue deterioration. OA is not a single disease with a common pathophysiological pathway, as many pathways and risk factors lead to mechanical failure of the joint ( Figure 1), so identifying early OA stages would certainly be advantageous for the development of more efficient, targeted therapies. Therefore, the identification of reliable biomarkers and even more advanced imaging methods as well as stronger inter-disciplinary treatment regimens is indispensable. Considering these central points, personalized OA therapy is the ultimate goal, and recent advances in phenotype classification and targeted drug development might provide a pool of suitable therapeutic options in the future. F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions (any comments will already have been addressed in the published version). The referees who approved this article are: Osteoarthritis is a chronic degenerative disorder characterised by cartilage loss. It is extremely prevalent in society and is a major cause of disability. It is important to treat osteoarthritis effectively using a multidisciplinary approach tailored to the patient’s needs. This paper reviews current thinking on the aetiology, pathogenesis, investigations, and management of osteoarthritis. The paper also discusses the challenges for developing good quality outcome measures for use in large scale multicentre clinical trials for new osteoarthritis treatments, especially disease modifying osteoarthritis drugs. Osteoarthritis is a chronic, degenerative disorder of unknown cause characterised by gradual loss of articular cartilage. It is the most prevalent disease in our society, with a worldwide distribution. It ranks fourth in health impact in women and eighth in men in the