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Naturally Improving Joint StructureNaturally Improving Joint Structure

Steve Myers

December 13, 2012

9 Min Read
Naturally Improving Joint Structure

Where addressing inflammation and pain is a common thread in many diseases and condition, including arthritis, methods to improve the structural integrity of joints, including cartilage and synovial fluid, typify the joint health category.

As a primary component of synovial fluid, hyaluronic acid (HA) has been studied as a therapeutic compound for arthritis treatment. While available as an oral supplement, most research on HA involves injections to the synovial cavity.1,2 However, these indirectly show if a patient gets supplemental HA into the joint, it can improve symptoms. Without a clear track via blood vessels, HA takes a slower path to the joint. Unfortunately for sufferers of joint problems, this is the reason most supplements targeting structural improvements in the joint take so long to generate noticeable benefit.

There are some results on oral HA supplementation. An unpublished trial from Miami Associates showed 80 mg/d of oral HA supplementation (as Hyal-Joint, from Bioiberica) in patients with knee OA reduced knee pain and improved quality of life. Similarly, a randomized, controlled trial involving eight weeks of 200 mg/d oral HA supplementation (as HyaBest, from Kewpie Corp.) in knee OA patients significantly improved pain scores among those with the most severe pain, compared to placebo.3 In 2012, a Japan study of older adults taking 200 mg/d HyaBest for 12 months found significant improvement in knee OA symptoms, compared to placebo, as indicated by Japan Knee Osteoarthritis Measurement (JOM) scores.4

Natural sources of collagen are increasingly studied for benefit to cartilage. In addition to unpublished research indicating hydrolyzed chicken sternum type-2 collagen (as BioCell Collagen®, from BioCell Technology) reduced pain and improved quality of life in OA patients, research has also shown the treatment can increase HA levels.5 Results from a study conducted by AIMBR were published in early 2012, detailing how BioCell Collagen improved OA symptoms and quality of life.6  In the randomized, double blind, placebo-controlled trial, 80 patients with physician-verified evidence of progressive OA in their hip and/or knee joint took either 2 g/d BioCell Collagen or placebo for 70 days. WOMAC scores significantly improved in the treatment group at 35 and 70 days, compared to placebo, as did reports of improved physical activity.

Undernatured type-2 collagen (as UC-II®, from InterHealth Nutraceuticals) was also supported by unpublished research showing improvements to pain, mobility and joint flexibility, but more recent published human trials confirmed the benefits. Knee OA patients participating in a pilot study reported reduced pain, morning stiffness and post-rest stiffness after taking  40 mg/d UC-II for 90 days.7 The trial compared UC-II to glucosamine/chondroitin, finding a 33-percent reduction in WOMAC scores for UC-II users and a 14-percent score reduction for the glucosamine/chondroitin group.

Glucosamine is a precursor for glycosaminoglycans (GAGs), which are viscous enough to help lubricate joints, but rigid enough to provide structural integrity to cartilage. Hyaluronic acid is a GAG, but it is non-proteolytic due to a lack of sulfate. HA possesses the biophysical ability of GAGs to lubricate and hydrate. Other GAGs also attach to proteins to become proteoglycans, which play a role in cell and tissue development.

Early research investigated glucosamine supplementation's ability to protect the cartilage from damage. Glucosamine, which is found in the exoskeletons of numerous shellfish and in animal bones and marrow,  was found to preserve cartilage capillary permeability,  stimulate synovial HA production and protect the joint chondrocytes that help produce cartilage matrix.8,9,10

Glucosamine has been most often studied in combination with chondroitin sulfate, a GAG found naturally cartilage as a proteglycan. Chondroitin helps the cartilage resist compressive forces and has been shown to stimulate extracellular matrix production by chondrocytes, inhibit inflammatory mediators and protect against cartilage degeneration.11

The dominant research on glucosamine-chondroitin has been the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT), a large National Institutes of Health (NIH)-funded multicenter trial on knee OA. The research involved 1,583 OA patients randomized to receive either a combination of 500 mg/tid glucosamine hydrochloride (HCL) form along with 400 mg/tid Bioiberica chondroitin sulfate taken on its own or in tandem with 200 mg/d of the NSAID celecoxib, or a placebo treatment for 24 weeks.

Initial results showed no significant benefit from glucosamine-chondroitin supplementation across the entire patient spectrum, however there was a significant benefit from this combo in a subset of patients with moderate-to-severe OA pain.12 A similar analysis of the GAIT data found no benefit to joint space narrowing across the study population, but there was an improvement trend among a subset of patients with moderate knee pain.13

Beyond GAIT, researchers have conducted meta-analyses of prior studies on both glucosamine and chondroitin, finding positive effects over a longer term. A 2009 review of six studies involving more than 1,500 cases discovered one year of glucosamine treatment failed to improve joint space narrowing, but there was a small-to-moderate benefit after three years of supplementation.14 It took two years of chondroitin supplementation to show a small, but significant, benefit to joint space narrowing, according to researchers.

A subsequent review by World Health Organization (WHO) researchers suggested glucosamine in sulfate form is more effective on OA than in the HCL form used in the GAIT trial.15 To prove their theory, the scientists conducted a follow-up study on patients from two prior trials that involved the sulfate form and total joint replacement (TJR).16 More than twice as many patients receiving placebo ended up having TJR than did those taking glucosamine sulfate. The researchers suggested one to three years of glucosamine sulfate supplementation may delay TJR for an average of five years after patients stop drug treatments.

Glucosamine and chondroitin are often combined with methylsulfonylmethane (MSM), a sulfur-containing compound. Analgesic and anti-inflammatory effects were attributed to a combination of glucosamine and MSM in a 2004 study of OA patients.17 The trial looked at each ingredient on its own as well as in combination, finding reduced pain and swelling and improved joint function with all treatment variations.

In 2006, a randomized, double blind, placebo-controlled study conducted by the Southwest College of Naturopathic Medicine and Health Sciences, Tempe, AZ, showed MSM supplementation in knee OA patients significantly reduced WOMAC scores for pain and physical function impairment, as well as improvement in performing daily living activities, compared to placebo.18 WOMAC scores did not significantly change for stiffness and aggregated total symptoms.

Eggshells and eggshell membrane are sources of naturally occurring GAGs including HA and chondroitin, as well as collagen. Human clinical study showed 500 mg/d NEM supplementation in OA patients improved scores for pain and stiffness after 10, 30 and 60 days, compared to placebo, but not on function and overall WOMAC scores.19

Research from NIS Labs published in 2012 highlighted the mechanism of natural eggshell membrane (as NEM®, from ESM technologies) in joint inflammation management.20 They reported NEM suppresses pro-inflammatory cytokines, namely TNFalpha, in peripheral blood mononuclear cell cultures.

Read the previous articles in this series, "When Bones Collide" and "Omega-3s, Botanicals for Joint Health."

Find more information in the INSIDER Joint Health Content Library.

References Listed on next page.


1. McNeil JD. Intra-articular hyaluronic acid preparations for use in the treatment of osteoarthritis." Int J Evid Based Healthc. 2011 Sep;9(3):261-4.

2. Strand V et al. "A multicenter, randomized controlled trial comparing a single intra-articular injection of Gel-200, a new cross-linked formulation of hyaluronic acid, to phosphate buffered saline for treatment of osteoarthritis of the knee."Osteoarthritis Cartilage. 2012 May;20(5):350-6

3. Sato T and Iwaso H. "An effectiveness study of hyaluronic acid [HyaBest®(J)] in the treatment of osteoarthritis of the knee on patients in the United States." J New Rem and Clin. 2009;58(3).

4. Tashiro T et al. "Oral administration of polymer hyaluronic acid alleviates symptoms of knee osteoarthritis: a double-blind, placebo-controlled study over a 12-month period." Sci World J. 2012 Oct. 16; Online ahead of print.

5. Schauss AG et al. Acute and subchronic oral toxicity studies in rats of a hydrolyzed chicken sternal collagen preparation." Food Chem Toxicol. 2007;45(2):315-21.

6. Schauss AG et al. "Effect of the novel low molecular weight hydrolyzed chicken sternal cartilage extract, BioCell Collagen, on improving osteoarthritis-related symptoms: a randomized, double-blind, placebo-controlled trial." J Agric Food Chem. 2012 Apr 25;60(16):4096-101.

7. Bagchi M, Lau FC, Bagchi D. Beneficial effects of oral administration of undenatured type II collagen on osteoarthritis: a human clinical trial." Presented at: J Am Coll Nutr 49th Annual Meeting; Oct. 2008; Abstract No. 30.

8. Martí-Bonmatí L et al. " Glucosamine sulfate effect on the degenerated patellar cartilage: preliminary findings by pharmacokinetic magnetic resonance modeling." Eur Radiol. 2009 Jun;19(6):1512-8.

9. Uitterlinden EJ et al. Glucosamine increases hyaluronic acid production in human osteoarthritic synovium explants." BMC Musculoskelet Disord. 2008 Sep 11;9:120.

10. Ilic MZ et al. " Effects of long-term exposure to glucosamine and mannosamine on aggrecan degradation in articular cartilage." Osteoarthritis Cartilage. 2003 Aug;11(8):613-22.

11. Kubo M et al. Chondroitin sulfate for the treatment of hip and knee osteoarthritis: current status and future trends. Life Sci. 2009 Sep 23;85(13-14):477-83.

12. Clegg D et al. Glucosamine, Chondroitin Sulfate, and the Two in Combination for Painful Knee Osteoarthritis." New Engl J Med. 2006;354:795-808.

13. Sawitzke AD et al. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial." Arthritis Rheum. 2008 Oct;58(10):3183-91.

14. Lee YH et al. Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis." Rheumatol Int. 2010 Jan;30(3):357-63.

15. Bruyere O, Reginster JY. Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis." Drugs Aging. 2007;24(7):573-80.

16. Bruyere O et al. Total joint replacement after glucosamine sulphate treatment in knee osteoarthritis: results of a mean 8-year observation of patients from two previous 3-year, randomised, placebo-controlled trials." Osteoarthritis Cartilage. 2008 Feb;16(2):254-60.

17. Usha PR, Naidu MU. "Randomised, Double-Blind, Parallel, Placebo-Controlled Study of Oral Glucosamine, Methylsulfonylmethane and their Combination in Osteoarthritis." Clin Drug Investig. 2004;24(6):353-63.

18. Kim LS et al. "Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial." Osteoarthritis Cartilage. 2006 Mar;14(3):286-94.

18. Ruff KJ et al. Eggshell membrane in the treatment of pain and stiffness from osteoarthritis of the knee: a randomized, multicenter, double-blind, placebo-controlled clinical study." Clin Rheumatol. 2009;28:907-14.

20. Benson KF et al. "Effects of natural eggshell membrane (NEM) on cytokine production in cultures of peripheral blood mononuclear cells: increased suppression of tumor necrosis factor-α levels after in vitro digestion." J Med Food. 2012 Apr;15(4):360-8.

About the Author(s)

Steve Myers

Senior Editor

Steve Myers is a graduate of the English program at Arizona State University. He first entered the natural products industry and Virgo Publishing in 1997, right out of college, but escaped the searing Arizona heat by relocating to the East Coast. He left Informa Markets in 2022, after a formidable career focused on financial, regulatory and quality control issues, in addition to writing stories ranging research results to manufacturing. In his final years with the company, he spearheaded the editorial direction of Natural Products Insider.

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