Effects of Different Collagen Formulations on Knee Osteoarthritis

Background and Rationale Knee osteoarthritis (OA) is a prevalent joint disorder characterized by progressive cartilage degeneration, chronic pain, and loss of function. While conservative management often includes dietary supplements such as hydrolyzed collagen and bioactive collagen peptides to support joint biology, clinical evaluations of these supplements are typically limited to traditional, unidimensional pain and function scales. Recent literature, however, emphasizes that OA pain is highly complex, involving peripheral nociceptive mechanisms, constant and intermittent pain patterns, and central neurological sensitization. Addressing a significant methodological gap in the literature, this study extends beyond standard scales by incorporating comprehensive Patient-Reported Outcome Measures (PROMs) to capture the holistic pain experience, including central sensitization, in patients with knee OA.

Study Procedures and Blinding This is a single-center, randomized, double-blind, placebo-controlled, parallel-group clinical trial. Following the baseline clinical and radiographic evaluation (Kellgren-Lawrence grading performed by an experienced orthopedic surgeon), eligible participants will be randomly allocated to one of three intervention arms using computer-assisted block randomization.

To ensure strict quadruple blinding (participant, care provider, investigator, and outcomes assessor), allocation concealment will be achieved using independently coded, opaque packaging. The active interventions (two different collagen formulations) and the placebo (maltodextrin-based) will be formulated to be entirely identical in appearance, color, smell, taste, and volume.

Intervention Administration and Monitoring Participants will be instructed to consume their assigned single-use sachet once daily between 13:00 and 15:00 for the entire 8-week intervention period. Patients will be advised to maintain their habitual physical activity levels throughout the study. Rescue analgesics are permitted if necessary for severe pain; however, the use of these medications must be strictly suspended at least 48 hours prior to any clinical evaluation session to avoid masking the outcomes. Adherence to the supplement regimen, rescue medication usage, and any potential adverse events will be continuously monitored via daily follow-up cards filled out by the participants. A minimum adherence rate of 95% is mandatory; participants failing to meet this threshold will be excluded from the final analysis.

Sample Size and Statistical Analysis Plan An a priori power analysis was conducted using G*Power software to determine the required sample size. Based on a Mixed-Design ANOVA model (group × time interaction) aiming for a moderate effect size (Cohen's f = 0.25), an alpha level of 0.05, and 80% statistical power, a minimum of 42 participants was required. To account for potential dropouts, a total of 45 patients (15 per group) will be enrolled.

Statistical analyses will be executed using R software under a Per-Protocol (PP) framework. Data normality will be assessed using the Shapiro-Wilk test. A Mixed-Design ANOVA will be employed to evaluate the main effects and the group-by-time interactions. Significant interactions will be further analyzed with post-hoc pairwise comparisons utilizing the Bonferroni correction. Effect sizes will be reported using Cohen's d for pairwise comparisons and partial eta squared (reported as η²p) for variance analyses, along with corresponding lower and upper bounds (LB/UB). Statistical significance is set at p < 0.05.

Inclusion criteria

• Adults aged between 35 and 65 years.
• Clinical and radiographic diagnosis of primary knee osteoarthritis according to the American College of Rheumatology (ACR) criteria.
• Radiographic severity of Kellgren-Lawrence grade 2 or 3 in the affected knee.
• Experiencing chronic knee pain for at least the last 3 months.
• Willingness to refrain from starting any new dietary supplements or physical therapy programs during the 8-week study period.
• Ability to read, understand, and provide written informed consent, as well as independently complete the patient-reported outcome questionnaires.

Exclusion criteria

• Severe knee osteoarthritis (Kellgren-Lawrence grade 4) or mild/doubtful osteoarthritis (Kellgren-Lawrence grade 0-1).
• History of intra-articular injections (corticosteroid, hyaluronic acid, PRP, stem cell, etc.) to the affected knee within the last 6 months.
• Routine use of other joint health supplements (e.g., glucosamine, chondroitin, MSM, other collagen products) within the last 3 months.
• History of major lower extremity surgery, major trauma, or previous ligament reconstruction (e.g., ACL reconstruction) on the affected knee.
• Presence of systemic inflammatory joint diseases (e.g., rheumatoid arthritis, ankylosing spondylitis, gout).
• Known allergy, hypersensitivity, or intolerance to bovine (beef) products or maltodextrin.
• Current pregnancy or lactation.
• Severe neurological, psychiatric, or cognitive disorders that would prevent accurate completion of the pain and central sensitization questionnaires.