Undenatured Collagen in Osteoarthritis Management: Practitioner's Review in 2025

Undenatured Collagen: Multimodal Cartilage Preserving Agent

Undenatured type II collagen (UC-II) retains its triple helix structure and glycosylation, unlike denatured forms. This preserved structure enables effective interaction with immune cells in the gut, inducing oral tolerance through regulatory T cells, IL-10, and TGF-β. It reduces IL-17/IL-22 expression, rewires gut immune networks, and protects against joint inflammation and cartilage damage. Studies show UC-II inhibits IL-2 and IL-6, increases IL-4 and Treg cells, and suppresses MMP-13 production, offering anti-inflammatory, immune-modulating, and cartilage-protective benefits in osteoarthritis management. (3,4) UC-II is absorbed via Peyer’s patches in the gut-associated lymphoid tissue (GALT), where it promotes the differentiation of naïve T cells into collagen-specific regulatory Treg cells. These Tregs migrate to joints, suppress TNF-α and IL-6, and release IL-10, IL-4, and TGF-β to reduce inflammation and preserve cartilage integrity. [Figure] (5)

Figure: UC-II induces oral tolerance via Peyer’s patches in the GALT, activating Tregs that modulate joint inflammation in osteoarthritis. Adapted from: Gupta & Maffulli, Annals of Medicine, 2025. doi:10.1080/07853890.2025.2493306

Clinical Evidence- Undenatured Collagen (UC-II) Benefits Osteoarthritis Care:

Undenatured Collagen(UC-II) Improved Pain & QoL in Osteoarthritis: A randomized, double-blind, placebo-controlled study enrolled 48 adults with osteoarthritis to assess the efficacy of UC-II (40 mg/day) versus placebo for 90 days. Outcomes were measured using the WOMAC score (assesses pain, stiffness, and physical function in osteoarthritis), Pain NRS, QoL (EQ-5D-5L), and GROC (X-ray). After 90 days, the UC-II group showed a 20.39% reduction in WOMAC score (vs. 7.24% placebo), 37.77% pain reduction on NRS (vs. 8.70%), and 90.32% QoL improvement (vs. 7.14%). On X-ray, 87.5% showed improvement vs. none in placebo, showing ​​the safety and effectiveness of UC-II for improving pain, function, and quality of life in osteoarthritis. (6)

Undenatured Collagen Type II (UC-II) Provides Symptom Relief & Functional Improvement in Early OA Knee: A systematic review included 8 RCTs involving 243 patients with early knee osteoarthritis. Patients received oral UC-II, typically at a dose of 40 mg/day, and were followed for 3 to 6 months. The primary outcomes assessed were VAS (measures pain intensity on a visual scale), WOMAC, Lequesne Index, TUG test, 6-minute walk test, and knee ROM. The analysis showed a significant reduction in WOMAC scores (MD: -8.91; 95% CI: -13.74 to -4.08) and VAS scores (MD: -1.65; 95% CI: -2.77 to -0.54), favoring UC-II over placebo. TUG and 6MWT also improved in several studies. This demonstrates UC-II's potential as a safe, effective supplement for symptom relief and functional improvement in early knee osteoarthritis. (7)

Undenatured Collagen Type II (UC-II) Compared to Glucosamine-Chondroitin in OA Knee: An Indian Experience: A prospective interventional study involving 50 patients with mild to moderate knee osteoarthritis compared UC-II and glucosamine-chondroitin over 90 days. Both groups started with identical VAS pain scores of 5.5, but by day 90, the UDC II group achieved superior improvement (1.5 vs 3.0). WOMAC functional scores similarly favored UDC II, improving from 56% to 31% compared to glucosamine-chondroitin's improvement from 60% to 51%. The study demonstrated UDC II's superior efficacy in providing pain relief and functional improvement in osteoarthritic patients. (8)

Undenatured Collagen Type II (UC-II) - Safety and Practical Use in Indian Practice

Undenatured collagen type II (UC-II) has consistently shown a favorable safety profile, with a low incidence of mild, non-serious adverse events such as nausea and headache. Across clinical studies, no serious events or treatment discontinuations have been reported, supporting its overall good tolerability. (7)

Further supporting its clinical use, the Food Safety and Standards Authority of India (FSSAI) recognizes undenatured collagen type II as a permitted nutraceutical ingredient listed under Schedule VI, with a recommended maximum daily dosage of 40 mg, affirming its regulatory acceptance for use in health supplements in India. (9)

Integrating with lifestyle modifications and structured physiotherapy, including muscle strengthening exercises, enhances its therapeutic potential, reinforcing a comprehensive approach to osteoarthritis management focused on both symptom relief and long-term joint health. (10)

Conclusion

• Osteoarthritis remains the most prevalent musculoskeletal disorder, driving chronic pain and disability.
• Current pharmacological therapies offer only palliative relief, failing to halt cartilage degeneration or address the underlying disease progression.
• Undenatured collagen provides anti-inflammatory, immune-modulating, and cartilage-protective benefits by preserving its triple helix structure and inducing oral tolerance.
• Clinical studies support its safe, low-dose use as an effective adjunct to standard care, with regulatory approval from FSSAI in India.

References

1. Singh, A et al. “Burden of osteoarthritis in India and its states, 1990-2019: findings from the Global Burden of disease study 2019.” Osteoarthritis and cartilage vol. 30,8 (2022): 1070-1078. doi:10.1016/j.joca.2022.05.004

2. Alad, M.; Yousef, F.; Epure, L.M.; Lui, A.; Grant, M.P.; Merle, G.; Eliopoulos, N.; Barralet, J.; Antoniou, J.; Mwale, F. Unraveling Osteoarthritis: Mechanistic Insights and Emerging Therapies Targeting Pain and Inflammation. Biomolecules 2025, 15, 874. https://doi.org/10.3390/biom15060874

3. Xu, Rong et al. “Undenatured type II collagen and its role in improving osteoarthritis.” Ageing research reviews vol. 91 (2023): 102080. doi:10.1016/j.arr.2023.102080

4. Pan, P., Wang, Y., Nyirenda, M.H. et al. Undenatured type II collagen protects against collagen-induced arthritis by restoring gut-joint homeostasis and immunity. Commun Biol 7, 804 (2024). https://doi.org/10.1038/s42003-024-06476-z

5. Gupta A, Maffulli N. Undenatured type II collagen for knee osteoarthritis. Annals of Medicine. 2025;57(1):2493306. doi:10.1080/07853890.2025.2493306

6. Sriraam VT, Pillai S, Singla R, Singla S. Clinical benefits of undenatured chicken collagen type II Unstergen® as a nutritional therapy in the management of osteoarthritis: a double-blind, placebo controlled clinical study. Int J Res Orthop 2025;11:505-12.

7. Kumar, Prasoon et al. “Efficacy of undenatured collagen in knee osteoarthritis: review of the literature with limited meta-analysis.” American journal of translational research vol. 15,9 5545-5555. 15 Sep. 2023

8. Babu S, Elangovan P, Kumar DS. Role of undenatured collagen type ii in management of osteoarthritis: A hospital based study. International Journal of Orthopaedics Sciences. 2020;6(4):747-750. doi: 10.22271/ortho.2020.v6.i4k.2414

9. Food Safety and Standards Authority of India. Food Safety and Standards (Health Supplements, Nutraceuticals, Food for Special Dietary Use, Food for Special Medical Purpose, Functional Food and Novel Food) Regulations, 2016. Version-I, Government of India, Ministry of Health and Family Welfare, 29 Sept. 2021.

10. Indian Council of Medical Research. (2024, July). Standard Treatment Workflow (STW): Osteoarthritis of knee joint (ICD-10-M19.9). Department of Health Research, Ministry of Health and Family Welfare, Government of India. https://www.icmr.gov.in/icmrobject/uploads/STWs/1726645313_10_osteoarthritis.pdf

Abbreviations: NSAIDs: Nonsteroidal Anti-Inflammatory Drugs, IL: Interleukin, TGF-β: Transforming Growth Factor Beta, MMP: Matrix Metalloproteinase, Treg: Regulatory T Cells, RCT: Randomized Controlled Trial, VAS: Visual Analog Scale, WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index, NRS: Numeric Rating Scale, QoL: Quality of Life, EQ-5D-5L: EuroQol 5 Dimensions 5 Levels Questionnaire, GROC: Global Rating of Change, TUG: Timed Up and Go Test, 6MWT: 6-Minute Walk Test, ROM: Range of Motion, FSSAI: Food Safety and Standards Authority of India, TEAE: Treatment-Emergent Adverse Event