Effect of Metformin as Add-on Therapy to Ibuprofen on Disease Activity in Knee Osteoarthritis Patients: A Randomized Controlled Trial.

Osteoarthritis (OA) is a worldwide highly prevalent chronic joint disease commonly affecting individuals of 40 years and older. OA is highly debilitating, encompassing various physical symptoms like pain, stiffness, swelling, disability and loss of normal joint function. Knee OA is one of the major causes of impaired function and disability of elderly population resulting in markedly reduced quality of life and increased socioeconomic burden.

(OA) is a progressive degenerative disorder characterized by degraded cartilage,low to moderate synovial inflammation, alteration of bony structure.The pathogenesis of OA is complex, combination of risk factors such as aging, obesity, being female, smoking, genetics, excessive joint load and injury, metabolic alterations and mechanical stress contribute to OA.These factors induce low-grade chronic inflammation and imbalance in oxidant-antioxidant levels, stimulating chondrocytes to produce reactive oxygen species (ROS) and pro-inflammatory cytokines. Overproduction of IL-1β, IL-6, TNF-α activate synoviocytes,macrophages, B and T lymphocytes, chondrocytes to play a role in the cartilage degradation, a central feature of OA.The infrapatellar fat pad (IFP) from knee OA patients secreted significantly higher levels of IL-6, but not TNF-α and IL-1β.

Decreased AMPK-α activity was found in human samples as well as mice OA knee joint chondrocytes which leads to increased mTOR activity,inhibition of autophagy, increased apoptosis and inflammatory activity of OA chondrocytes. Mitochondrial injury and a lowered expression of SIRT1 protein are often associated with the pathogenesis of OA.

Existing therapies such as Nonsteroidal Anti-inflammatory drugs (NSAIDs) and other analgesics are only used to reduce pain and swelling. With the chronic nature of knee OA, pharmacological approaches must be safe for long-term use. NSAIDs are the mainstay of management for knee OA but cause serious gastrointestinal, renal and cardiovascular adverse events with no beneficial effect on joint structures.Total knee replacement is the last option for patients with end-stage knee OA.

Metformin exerts a chondroprotective effect by inducing the SIRT1 expression and activating AMPK-α, leading to reduced inflammatory mediators and matrix degradation substances, inhibit the accumulation of RAGE, increase in autophagy as well as a decrease in catabolism and apoptosis, as evidenced by in vivo and in vitro studies. Metformin as an AMPK-α activator can protect inflammatory cell death of chondrocytes and attenuates cartilage degeneration and prevents or delays the development and progression of knee OA. Metformin is able to reduce RANKL and stimulates OPG expression in osteoblasts, further inhibit osteoclast differentiation and prevent bone loss. Data from human studies suggest that metformin could reduce knee OA progression by modifying inflammatory pathways and being considered as an alternative or adjuvant treatment of knee OA.