Having been in the dietary supplement industry for 40 years, I’ve seen a lot of nutraceuticals come and go. Comparatively few have had staying power, and even fewer have stood the test of time and continued to gain credibility. One of those is undenatured type II collagen—and since there is a fairly recent new study on it, I thought it was worthy of a review article.

Defining Undenatured Type II Collagen

Let’s start with an explanation of the term “denatured.” When discussing a protein, the term refers to any nonproteolytic change in the chemistry, composition, or structure of a native protein that causes it to lose some or all of its unique or specific characteristics. Conversely, an undenatured protein is one that retains its unique or specific characteristics. In the case of undenatured type II collagen, being undenatured appears to be an important element with regard to the quality and efficacy of the material.

Now regarding collagen, the five most common forms in the body are collagen types I-V. Type II is the main collagenous component of cartilage, making up 5 percent of all protein in cartilage and 85 to 90 percent of collagen of articular cartilage. Research on rheumatoid and osteoarthritis patients has demonstrated that undenatured type II collagen has benefits for joint health. The form used in most of the research is UC-II undenatured type II collagen derived from chicken sternum cartilage, so that is the form I’ll be discussing in this article.

Mechanism of Action

Type II collagen administered orally works with the immune system to promote healthy joints by a process called oral tolerance. This process helps the body to differentiate between foreign invaders, such as bacteria, and elements that are good for the body, such as nutrients. The process of oral tolerance takes place in the small intestine where food is absorbed. Through a complex series of immunological events, patches of lymphoid tissue surrounding the small intestine screen incoming compounds and serve as a “switch” to turn the body’s immune response to foreign substances on or off, depending upon what that substance is.1 In the case of the UC-II ingredient, small amounts (typically 40 mg) taken orally at bedtime have been shown to turn off the immune response targeted at the type II collagen present in bone joint cartilage.3,4 This suppresses the action of cells involved in the normal breakdown of collagen and other extracellular matrix proteins,5 which in turn gives the body a better chance to repair joint damage. Now, let’s take a look at the clinical research on the UC-II product.

Early Studies: Rheumatoid Arthritis

The early studies on UC-II undenatured type II collagen were conducted on rheumatoid arthritis patients. The American College of Rheumatology reports that rheumatoid arthritis (RA) is a chronic disease that causes pain, stiffness, swelling and loss of function in the joints and inflammation in other body organs. Unlike osteoarthritis, RA is an autoimmune disease where the body’s immune system attacks its own joint tissue. That being the case, the mechanism of action for UC-II undenatured type II collagen turned out to be ideal for RA. Here is a brief overview of three of those studies.

• In a 90-day, double-blind, placebo-controlled follow-up study on patients with severe rheumatoid arthritis, Harvard scientists found that 28 patients taking undenatured type II collagen showed significant improvement compared to the placebo group, while four patients recovered completely.6

• In another double-blind, placebo-controlled trial, Harvard Medical School researchers showed that following treatment with undenatured type II collagen, 21 of 54 rheumatoid arthritis patients (39 percent) demonstrated significant improvement, while only 11 of 57 patients (19 percent) taking a placebo showed improvement.7

• A human clinical study at Harvard Medical School showed that after three months of treatment with undenatured type II collagen, eight out of 10 patients with juvenile rheumatoid arthritis had a reduction in both swollen and tender joints. The average changes a 61 percent and 54 percent respective reduction in swollen and tender joint counts for the eight responders at the end of the study. Six patients had greater than a 33 percent reduction in both swelling and tender joint counts.8

Later Studies: Osteoarthritis and a Healthy Population

The later studies on UC-II undenatured type II collagen were conducted on osteoarthritis patients and a healthy population. Also according to the American College of Rheumatology, osteoarthritis (OA) is the most common form of arthritis. Most often affecting middle-aged and older people, OA results from degeneration of the joint cartilage. The causes of cartilage loss are multiple. Some kinds of OA are known to be hereditary, including the common form that causes enlargement of the knuckles. In most people, cartilage breakdown is due to both mechanical (“wear and tear”) effects and biochemical effects.

The 2009 Study

In 2009, a human clinical trial9 was published, evaluating the safety and efficacy of 40 mg UC-II undenatured type II collagen compared to a combination of glucosamine HCl 1,500 mg and chondroitin sulfate 1,200 mg (G+C) in people with OA of the knee over 90 days. The methods used to assess effectiveness included the WOMAC index (a measurement of physical function, stiffness and pain), the VAS score (a measurement of resting and moving pain), and the Lequesne score (a measurement of the effect of pain on daily activities. The results indicated:

• Supplementation with UC-II undenatured type II collagen reduced the WOMAC score by 33 percent as compared to 14 percent in G+C supplemented group after 90 days. Statistically significant differences included:

• Pain walking on flat surface (p=0.034)

• Difficulty walking on flat surface (p=0.038)

• Performing heavy domestic duties (p=0.031)

• UC-II supplementation decreased VAS score by 40 percent after 90 days as compared to 15.4 percent in G+C treated group. Statistically significant differences included:

• Night pain (p=0.040)

• Pain during climbing up and down stairs (p=0.014)

• Resting pain (p=0.034)

• Supplementation with UC-II undenatured type II collagen reduced Lequesne’s functional index score by 20 percent as compared to 6 percent in G+C treated group at the end of 90-day supplementation. Statistically significant differences included:

• Pain while up from sitting (p=0.036)

• Maximum distance walked (p=0.002)

The 2013 Study

In 2013 the results of a randomized, double-blind, placebo-controlled study,10 were presented during a conference at the Scripts Center for Integrative Medicine and then published in the Journal of International Society of Sports Nutrition. Fifty-five subjects reporting joint discomfort associated with strenuous exercise received either a placebo or UC-II undenatured type II collagen (40 mg a day) for 120 days. The results were that, compared to placebo, UC-II supplementation significantly improved joint flexibility, allowed subjects to exercise longer before experiencing initial joint discomfort, and allowed subjects to exercise longer before experiencing maximum joint discomfort. There were no significant changes in the placebo group.

The 2016 Study

Similar to the 2009 study, but this time with a placebo group added, a multicenter randomized, double-blind, placebo-controlled study was published in 2016.11 This study consisted of 191 volunteers with knee osteoarthritis (OA) pain and associated symptoms, who were randomized into three groups receiving a daily dose of UC-II supplementation (40 mg), glucosamine hydrochloride plus chondroitin sulfate (GC) (1,500 mg G & 1,200 mg C), or placebo for a 180-day period. The methods used to assess effectiveness included WOMAC, the Lequesne Functional Index (LFI), and VAS. At 180 days, the results were as follows:

• UC-II supplementation demonstrated a significant reduction in overall WOMAC score compared to placebo (p = 0.002) and GC (p = 0.04)

• UC-II supplementation resulted in significant changes for all three WOMAC subscales: pain (p = 0.0003 vs. placebo; p = 0.016 vs. GC); stiffness (p = 0.004 vs. placebo; p = 0.044 vs. GC); physical function (p = 0.007 vs. placebo)

• UC-II supplementation demonstrated a significant reduction in the LFI score compared to placebo (p = 0.009) and GC (p = 0.008)

• UC-II demonstrated a significant decrease in mean VAS score compared to placebo (p = 0.002) and GC (p = 0.025)

No significant change was observed between the GC and placebo cohorts. The researchers concluded that UC-II supplementation improved knee joint symptoms in knee OA subjects and was well-tolerated.

Animal Studies

In addition to the human studies, there have also been studies demonstrating the efficacy of UC-II supplementation in animals. In 2009, a blinded placebo-controlled study was conducted to examine the effectiveness of UC-II supplementation in promoting canine joint health as determined by a using Ground Force Plate analysis. This measures the amount of weight the dog is bearing on a given limb and impulse area measures the amount of force applied by the limb onto the plate. A daily dose of 40 mg of UC-II supplementation significantly increased peak force by 18 percent and impulse area by 44 percent after 120 days. Subjective parameters measured after limb manipulation and exercise also demonstrated a significant increase in joint comfort. Dogs on placebo exhibited no significant change in arthritic conditions.12

In another blinded placebo-controlled study, 20 osteoarthritic dogs were given 40 mg of UC-II supplementation, 2,000 mg of glucosamine + 1,600 mg of chondroitin, UC-II supplementation combined with glucosamine and chondroitin or placebo daily for 120 days. Results were that UC-II supplementation alone decreased overall pain by 62 percent, while painful limb movement and lameness decreased by 91 percent and 78 percent, respectively.13

Likewise, osteoarthritic horses (five to six per group) received placebo, 320 mg of UC-II supplementation, 480 mg of UC-II, 640 mg of UC-II or 5,400 mg of glucosamine + 1,800 mg of chondroitin. Horses receiving 320, 480 or 640 mg of UC-II ingredient exhibited significant reduction in arthritic pain. UC-II supplementation at 480 or 640 mg dose provided similar effects, and therefore, 480 mg was considered optimal. There was an 88 percent decrease in overall pain and a 78 percent decrease in pain upon limb manipulation.14

Safety of Undenatured Type II Collagen

It should be noted that undenatured type II collagen has an excellent safety profile. The toxicological research on UC-II ingredient suggests a very low potential for toxicity.15 Additionally, research conducted on dogs, horses and humans have shown no adverse effects.16-19 Also, an expert panel of toxicologists concluded that UC-II supplementation is safe for human consumption and is generally recognized as safe (GRAS).20

Conclusion

Undenatured type II collagen, as provided by the UC-II product, has a unique mechanism of action involving suppressing the action of cells involved in the normal breakdown of collagen and other extracellular matrix proteins. Furthermore, multiple studies over a 20-year period has demonstrated the safety and efficacy of this nutraceutical for joint mobility, flexibility and joint discomfort associated with strenuous exercise. UC-II supplementation has application for humans and for domestic animals as well.

References:

1 Weiner HL, da Cunha AP, Quintana F, Wu H. Oral tolerance. Immunol Rev. 2011;241(1):241-59.

2 Sieper J, Kary S, Sorensen H, Alten R, Eggens U, Huge W, Hiepe F, Kuhne A, Listing J, Ulbrich N, Braun J, Zink A, Mitchison NA. Oral Type II Collagen Treatment in Early Rheumatoid Arthritis. A Double-Blind, Placebo-Controlled, Randomized Trial. Arthritis and Rheumatism 1996; 39:41-51.

3 UCII FAQ, 2004 InterHealth Nutraceuticals, Inc. Accessed October 14, 2004 from www.interhealthusa.com/faqs/UCII_faqs.aspx.

4 Bagchi D, Misner B, Bagchi M, Kothari SC, Downs BW, Fafard RD, Pruess HG. Effects of Orally Administered Undenatured Type II Collagen Against Arthritic Inflammatory Diseases: A Mechanistic Exploration. International Journal of Clinical Pharmacology Research. 2002; 22:101-110.

5 Gupta RC, Canerdy TD, Lindley J, et al. Comparative therapeutic efficacy and safety of type-II collagen (UC-II), glucosamine and chondroitin in arthritic dogs: pain evaluation by ground force plate. J Anim Physiol Anim Nutr 2012;96(5):770-7.

6 Trentham DE, Dynesius-Trentham RA, Orav EJ, Combitchi-D, Lorenzo C, Sewell KL, Hafler DA, Weiner HL. Effects of Oral Administration of Type II Collagen on Rheumatoid Arthritis. Science 1993; 261:1727-1730.

7 Barnett ML, Kremer JM, St Clair EW, Clegg DO, Furst D, Weisman M, Fletcher MJF, Chasan-Taber S, Finger E, Morales A, Le-CH, Trentham DE. Treatment of Rheumatoid Arthritis with Oral Type II Collagen. Results of a Multicenter, Double-Blind, Placebo-Controlled Trial. Arthritis and Rheumatism 1998; 41:290-297.

8 Barnett ML Combitchi D, Trentham DE. A Pilot Trial of Oral Type II Collagen in the Treatment of Juvenile Rheumatoid Arthritis. Arthritis and Rheumatism 1996; 39:623-628.

9 Crowley DC, Lau FC, Sharma P, Evans M, Guthrie N, Bagchi M, Bagchi D, Dey DK, Raychaudhuri SP. Safety and efficacy of undenatured type II collagen in the treatment of osteoarthritis of the knee: a clinical trial. Int J Med Sci. 2009 Oct 9;6(6):312-21.

10 Lugo JP, Saiyed ZM, Lau FC, et al. Undenatured type II collagen (UC-II) for joint support: a randomized, double-blind, placebo-controlled study in healthy volunteers. J Int Soc Sports Nutr. 2013;10:40.

11 Lugo JP, Saiyed ZM, Lane NE. Efficacy and tolerability of an undenatured type II collagen supplement in modulating knee osteoarthritis symptoms: a multicenter randomized, double-blind, placebo-controlled study. Nutr J. 2016 Jan 29;15:14.

12 Gupta RC, Barnes M, Minniear J, et al. Pain reduction measured by ground force plate in arthritic dogs treated with type-II collagen. Presented at: Society of Toxicology 48th Annual Meeting; March 2009.

13 D’Altilio M, Peal A, Alvey M, et al. Therapeutic efficacy and safety of undenatured type II collagen singly or in combination with glucosamine and chondroitin in arthritic dogs. Toxicol Mech Methods. 2007;17:189-196.

14 Gupta RC, Skaggs P, Stocker A, et al. Therapeutic efficacy of undenatured type-II collagen (UC-II) in comparison to glucosamine and chondroitin in arthritic horses. J Vet Pharmacol Therap. 2009;32:577-584.

15 Marone PA, Lau FC, Gupta RC, Bagchi M, Bagchi D. Safety and toxicological evaluations of undenatured type II collagen. Toxicol Mech Meth. 2010;20:175-189.

16 Crowley DC, Lau FC, Sharma P, et al. Safety and efficacy of undenatured type II collagen in the treatment of osteoarthritis of the knee: a clinical trial. Int J Med Sci. 2009;6:312-321.

17 Bagchi D, Misner B, Bagchi M, et al. Effects of orally administered undenatured type II collagen against arthritic inflammatory diseases: a mechanistic exploration. Int J Clin Pharm Res. 2002;22:101-110.

18 D’Altilio M, Peal A, Alvey M, et al. Therapeutic efficacy and safety of undenatured type II collagen singly or in combination with glucosamine and chondroitin in arthritic dogs. Toxicol Mech Methods. 2007;17:189-196.

19 Gupta RC, Skaggs P, Stocker A, et al. Therapeutic efficacy of undenatured type-II collagen (UC-II) in comparison to glucosamine and chondroitin in arthritic horses. J Vet Pharmacol Therap. 2009;32:577-584.

20 Burdock Group. Dossier in Support of the Generally Recognized As Safe (GRAS) Status of UC-II as a Food Ingredient. Internal data, 2009.

Gene Bruno, MS, MHS, the dean of academics for Huntington University of Health Sciences, is a nutritionist, herbalist, writer and educator. For more than 30 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. He can be reached at [email protected].