4 Mechanism Oxidative stress Apoptosis/autophagy Sarcopenia Loss of proprioception Joint laxity Synovitis Increased osteon density Matrix protein modiﬁcation (e.g., glycosylation) Nonenzymatic collagen cross-linking Reduced circulating progenitor cells (e.g., MSC) (a) (b) Figure 2: Tibial plateau of an elderly patient showing end- stage OA with complete cartilage loss (a). Computed tomography osteoabsorptiometry (CT-OAM) indicates high bone density in red (b). is in line with the observation that increased BMD measure- ment of the knee correlates with clinical OA. However, the relation between generalized bone loss or osteoporosis and OA is still controversial. The MOST study has shown that high femoral neck and whole-body BMD are associated with Table 1: Age-related mechanisms triggering OA. Journal of Aging Research Consequence Cell senescence Reduced regeneration capacity Reduced elasticity, ﬂuid content, stability Impaired crack-bridging potency Reduced joint stability Microtrauma, Charcot-like arthropathy Microtrauma Bone stiﬀness Inﬂammatory cytokine production Impaired regeneration capacity an increased risk of OA [36]. However, osteophytes alter BMD assessment, so it remains unclear whether increased BMD is a consequence, rather than a cause of OA. Clearly, the higher bone density in patients with OA is not associated with a lower risk of vertebral or nonvertebral fractures [37]. 6. Muscle Atrophy and Its Role on OA in the Elderly Muscle atrophy can have several causes. Immobilization, malnutrition, myopathy, neurologic disorders, comorbidity of several common diseases such as cancer, congestive heart failure, COPD, or any state of chronic inﬂammation aﬀect the muscle mass substantially. Also endocrinologic disorders which are generally more frequently observed in the elderly can trigger muscle atrophy, for example, low testosteron levels, diabetes mellitus, or hypothyroidism. In contrast to secondary muscle atrophy, the commonly observed loss of muscle mass in the elderly is a syndrome referred to as “sarcopenia” [38]. Reduced muscle tissue usu- ally starts at the age of 50 years and results in diminished muscle function. Subsequently, decreased muscle strength of the joints contribute to the pathogenesis of OA within the next decades. Fifty percent of all individuals aged over 75 suf- fer from sarcopenia. The mechanistic association between OA and muscle atrophy has been clearly demonstrated. Several factors such as reduced stability, joint immobilization, restriction of range of motion but also so called arthrogenous muscle inhibition or reﬂex atrophy are implicated in this process. The latter is due to abnormal nociceptive aﬀerent feedback processes, releasing neuromodulators in the spinal cord, which in turn cause a change in alpha-motoneuron excitability. In knee OA, it has been shown that quadriceps muscle strength is reduced between 20 and 40% for isometric and isokinetic contractions [39]. 7. Physical Activity Preventing OA Physiotherapy is the gold standard for OA treatment. The positive eﬀect of physiotherapy on knee OA has been clearly