This is a randomized controlled trial examining and compare the effects of open and closed kinetic chain exercises on pain, function, and cartilage synthesis and degradation biomarkers after an eight-week rehabilitation program for knee osteoarthritis (OA) patients.

Design and Subjects: A prospective, active control, three-parallel-group, assessor-blinded, randomized controlled trial. A sample of 120 subjects will be recruited and randomly assigned to one of three study groups at a 1:1:1 allocation ratio (40 participants per group): a) Standard care only, b) Closed kinetic chain exercises plus standard care, and c) Open kinetic chain plus standard care.

Intervention: participants will receive 24 treatment sessions (3 sessions/week) over 8 weeks. Participants will be allocated to the experimental groups will receive the standard care protocol in addition to either closed or open-chain exercises.

Outcome measures: The primary outcomes are physical function and pain assessed using the Western Ontario and McMaster Universities (WOMAC) scores. Secondary outcomes include the Numeric Pain Rating Scale, quadriceps and hamstring strength, joint range of motion (ROM), joint proprioception error, and serum and urine OA biomarkers including the Serum cartilage oligomeric matrix protein (COMP), Serum propeptide Type-II N-terminal (PIIANP), Serum C- reactive protein (CRP), and Urine type -II Collagen telopeptide (CTX-II).

Data Analysis: Data will be analyzed using the intension-to-treat (ITT) analysis with multiple imputations. The primary analysis of the primary outcomes at a two-month follow-up time point (after completing the intervention protocol for 8 weeks) will be carried out using a mixed-model analysis of variance (ANOVA) test with adjustment for a set of pre-specified baseline factors. Secondary analysis using the ANOVA test for the primary outcomes at a six-month follow-up time point, and secondary outcomes at all follow-up time points will also be carried out.

Inclusion Criteria:

• ≥40 years of age;
• having knee pain;
• having at least three of the following additional symptoms: a-morning stiffness ≤ 30 minutes, b-crepitation, c-bone margin tenderness, d-bony enlargement or e-no palpable warmth;
• willing to provide informed consent

Exclusion Criteria:

• Knee joints showing Kellgren and Lawrence (K-L) grades 1 or 4;
• rheumatoid arthritis;
• serious pathological conditions (inflammatory arthritis and malignancy); total or partial arthroplasty of the affected knee joint, or on a waiting list for joint replacement surgery;
• recent surgical procedure of the lower extremities in the previous 6 months;
• uncontrolled hypertension and unstable cardiovascular problems that could subject the participant to increased risk with exercise and physical exertion;
• physical incapability to safely perform exercises, walking or stationary cycling, as in debilitating visual defects, neurological problems, exaggerated low back pain, advanced osteoporosis, and inability to walk 10 meters without an assistive device;
• use of prescribed analgesics, corticosteroid or analgesic injection intervention for knee pain within the previous 30 days;
• lack of clear comprehension of study procedures or inability to comply with instructions;
• stated inability to attend or complete the proposed course of intervention and follow-up schedule.

Both the outcome assessors and the study statistician will be blinded to group allocation.