application in a surgical rat OA model 69. Its effectivity is currently being evaluated in a phase II trial of knee OA (NCT03072147). Dietary supplementation of vitamin D 3 Additional dietary supplementation of vitamin D 3 (cholecalciferol) might be an option to target and strengthen bone in OA owing to its ability to increase calcium and phosphate uptake from the gut and its direct effect on bone cell metabolism 70. Numerous trials for vitamin D 3 supplementation in OA patients can be found at clinicaltrials.gov, but there are contradictory reports about a relationship between vitamin D levels and a higher risk for OA incidence and progression 71. A meta-analysis of randomized controlled trials revealed a reduction in WOMAC pain and improved joint function in OA patients after vitamin D 3 intake, but only at a concentration of 2,000 IU 72. Cartilage degradation was not affected. Generally, vitamin D 3 intake might be beneficial for a large proportion of the population, as its deficiency is a worldwide problem and elderly people, who are also at an increased risk of OA, are often affected 73. Restoration of bone metabolism and structure might be a worthwhile goal because of the huge importance of this structure as a mechanic buffer for proper load perception and distribution. A detailed knowledge of timely changes in OA-related bone metabolism might enable a more precise use of bone anabolic and anti-catabolic therapies to restore or prevent bone degradation. Maintenance of bone structure and shock-absorbing abilities might prevent cartilage alterations and therefore put a hold on subsequent degradative events culminating in joint failure. It is now commonly accepted that OA has an inflammatory component that might be more dominant in specific patient subgroups and joint tissues. The release of various pro-inflammatory mediators like prostaglandins, cytokines, and chemokines has been demonstrated in numerous pre-clinical OA animal models and in patients 74. Synovitis is a common feature of inflammatory OA, and technical progress in imaging technologies like ultrasound and MRI revealed synovitis in a large number of patients at different disease stages 75, 76. A plethora of triggers including aberrant mechanical forces, metabolic syndrome, increased age, and fragments of cartilage extracellular matrix (ECM) or crystals might induce the release of these mediators from various responsive joint tissue cell types. A large number of recent review articles address cells and components of the innate immune system as the main drivers of OA inflammatory processes 77, 78. Non-steroidal anti-inflammatory drugs and glucocorticoids are commonly used to treat OA but are not optimal owing to moderate effectiveness and serious side-effects in long-term use 79, 80. Anti-cytokine therapy Most biologics used to treat OA-related inflammation were developed for rheumatoid arthritis (RA), a disease associated with more pronounced inflammation. So far, biologics targeting the inflammatory cytokines interleukin (IL)-1 and -6 as well as TNF-α have not been useful in the prevention of pain or structural progression of OA ( Table 1C). Granulocyte/macrophage colony-stimulating factor (GM-CSF) was associated with inflammatory pain in a mouse OA model 81 and was associated with hip OA over knee OA in a study analyzing mononuclear cell contribution to synovial inflammation 82. The anti-GM-CSF antibody otilimab (GSK3196165) was enrolled in a study for erosive hand OA and yielded promising results (NCT02683785) 83. Mavrilimumab, a GM-CSF receptor inhibitory antibody effective in RA 84, might therefore also have potential as an OA drug. The predominantly low-grade and non-systemic inflammation observed in OA might explain the limited success of single cytokine blockade. Concentration on specific OA subsets like erosive hand OA associated with more pronounced inflammation potentially presents a responsive patient group for anti-cytokine biologics. Identification of a single potent