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.
This study is a double-blind, randomized, placebo-controlled trial in knee OA patients. This
study will be conducted to evaluate the effect of metformin as add-on therapy on disease
progression and inflammatory indicator in knee OA patients.The intervention group will
receive metformin 500mg extended release tablet once daily for 8 weeks, with standard of
care(ibuprofen and rabeprazole) as prescribed by the physician whereas control group will
receive placebo oral tablet once daily with standard of care(ibuprofen and rabeprazole)
during the same study period. The investigator will compare changes in five dimensions (pain,
symptoms, activities of daily living, sport and recreation function, and knee-related quality
of life) of KOOS score (out of 100) and serum interleukin-6 (IL-6) level, at the time of
recruitment with after 8 weeks of intervention in both the intervention and placebo
controlled groups.
Adding Metformin with the conventional treatment of Ibuprofen could potentially have a
substantial impact on disease activity in patients with Knee Osteoarthritis(OA).