successful analgesia, especially in male patients and in overweight patients associated with the metabolic phenotype Despite huge efforts invested in the development of new OA analgesics and although several candidates look promising and more and more potential drug targets are identified, pain reduction in OA is still relatively unsuccessful. The complex and diverse underlying mechanisms of OA pain, the timely and spatial alterations of pain types and sensitization, and the interaction of nerves and OA-related structural changes, immune reactions, and altered metabolic conditions still require more intense interdisciplinary research to achieve effective pain management. Metabolism can be altered in OA, and there are multiple metabolic components underlying metabolic dysregulation. The metabolic syndrome, characterized by excessive and long-term positive energy balance, is defined by several cardio-metabolic factors that commonly are found together with obesity, which are central adiposity, dyslipidemia, impaired fasting glucose levels, and hypertension. People with metabolic syndrome are prone to developing a variety of disorders, especially cardiovascular diseases, type 2 diabetes mellitus (T2DM), and some forms of tumor. The increase in prevalence of metabolic syndrome in industrialized nations, and an association with obesity, together with the fact that it was a rare disease in pre-industrial populations, leads to the hypothesis that the metabolic syndrome might be a major risk factor for OA nowadays. Besides hypertension, which seems to provide an elevated risk of knee OA 129, T2DM and knee OA often coexist and are known for common risk factors such as obesity and aging. The mechanical impact of excess body weight on joints may explain lower limb OA. However, it is unclear whether T2DM is linked to OA independently of excess weight and whether T2DM is involved in OA pathology. A coexistence between the occurrence of T2DM and OA was shown, but a causal link is not yet established 130. T2DM clearly has an unhealthy effect on OA via two pathways: (1) chronic hyperglycemia, which is connected to oxidative stress, abnormal production of pro-inflammatory cytokines and advanced glycation end products (AGEs) in joint tissues, and (2) insulin resistance, which may have local effects but may also maintain a systemic low-grade inflammatory state 131. Metabolic targets for osteoarthritis therapy So, are there metabolic targets known that are suitable for OA therapy? Some experimental studies show that mTOR signaling pathways can activate autophagy, which might be an effective approach for treating OA 119. OA chondrocytes where AMP kinase (AMPK) has been removed exhibit increased catabolic responses to pro-inflammatory cytokines and biochemical injury. These effects are attenuated by molecules that activate AMPK, indicating that decreased AMPK activity is associated with cartilage degradation 120, 121. Possibly, AMPK-activating drugs such as methotrexate, metformin, and sodium salicylate might be good candidates to combat OA progression. A Taiwanese study examined whether or not the use of a COX-2 inhibitor with metformin in OA patients with T2DM was related to fewer joint replacement surgeries than the use of a COX-2 inhibitor only 122. At the end of a 10-year follow up period, fewer joint replacement surgeries seemed to be needed in the case group compared to the control group. This outcome may be attributed to the fact that a combination therapy decreases pro-inflammatory factors associated with OA progression much more than one without metformin therapy . Statin usage and osteoarthritis Some pre-clinical and clinical data are available regarding the effects of statin usage on OA progression. Farnahgi et al. aimed to define the effects of hypercholesterolemia on the progression of OA in a murine OA model 132. Surgical destabilization of the medial meniscus in knees from mice which were fed a high-cholesterol