New life for cartilage compounds

New life for cartilage compounds

With the collapse of the cox-2 inhibitor pharmaceutical drug market, natural joint-health ingredients continue to innovate and amass research findings to vouch for their efficacy. Todd Runestad scans the field


Even without the celebrated cox-2 inhibitors like Vioxx being pulled from OTC shelves, good old glucosamine chugs along as the biggest selling dietary supplement in the US, with an incredible 55 per cent of nonbotanical supplements sales, according to Information Resources Inc.

What could truly make or break a buoyant market are results from the $12 million, 24-week, 1,500-subject National Institutes of Health GAIT study. The trial is completed, data is currently being analysed and results will likely be published this autumn. If the results come out positively, that could mean an even bigger boom for the supplements market. (And if they come out negatively, critics can point out that the form used, glucosamine HCl, has been studied far less than the crystallised sulfate salt.)

The five-arm clinical trial followed 1,588 volunteers across 13 clinical centres. Glucosamine alone (1,500mg), chondroitin alone (1,200mg) and a combination of the two were used to treat knee pain. The fourth arm was the cox-2 inhibitor celecoxib (Celebrex), and the final arm was placebo.

The glucosamine HCl was manufactured by Pfanstiehl Laboratories in Illinois and donated by Wilke Resources. The chondroitin sulfate was manufactured and donated by Bioiber-ica SA in Spain.

Regardless of the results of the GAIT study, natural products suppliers and manufacturers are assiduously researching and developing innovative products to address the burgeoning joint health arena of health care.

Combination products are the latest step in moving beyond glucosamine and chondroitin, which have almost become commodity products at this point. Shrimp duties and the tsunami have driven up the price of glucosamine, though Indian glucosamine supplier Pharmed Medicare, which supplies most of the European market, is building a new facility that will increase production by 50 per cent.

Other new delivery systems include beverages, effervescent drinks and chews. Manufacturers are amending glucosamine/chondroitin combinations to include fish oils, MSM, botanicals and more. The only thing apparently holding back the entire sector is research — and even there some gains are being made. But many of these innovative or novel ingredients boast one or two studies, whereas glucosamine and chondroitin enjoy hundreds.

"In a lot of ways glucosamine and chondroitin are the best studied," says Daniel Clegg, MD, who is heading up the GAIT study. "For these other supplments, the scientific data are so small that you can't form a rational conclusion on them."

GAG reflex

The success of glucosamine can be traced to its roots in the body. Glycosaminoglycans (GAGs) are concentrated in connective tissues and are the building blocks of cartilage and joint fluid. Glucosamine is a GAG, as are chondroitin, hyaluronic acid and various sulfates. Indeed, some researchers believe that glucosamine sulfate is effective more because of its sulfate than the glucosamine. It is thought that glucosamine also stimulates the secretion of GAGs in the cartilage and chondroitin also inhibits the enzymes that destroy cartilage. Hyaluronic acid provides the moisture-filled cushioning in the joint synovial fluid.

Chondroitin is the most abundant GAG in cartilage and is responsible for the resiliency of cartilage. Treatment with these joint supplements is based on the theory that oral consumption of glucosamine, chondroitin and hyaluronic acid may increase the rate of formation of new cartilage by providing more of the necessary building blocks.1

GAGs are obtained from shark or beef cartilage or chitin from crustacean shells — and here is another area of innovation differentiation, as Cargill has recently launched a vegetarian-source glucosamine, Regenasure, derived from corn through a fermentation process.

Glucosamine and chondroitin appear to offer certain advantages over such standard arthritis treatments as acetaminophen and ibuprofen. These drugs can quickly relieve osteoarthritis pain and stiffness, but they do nothing to stop joint damage. There is at least some evidence that glucosamine and chondroitin do — inexpensively and safely.

Fatty acids

The hallmark of omega-3 fatty acids is their ability to modulate inflammation by decreasing levels of interleukin-1 (IL-1), a proinflammatory cytokine, and reducing the release of leukotriene B(4) from stimulated neutrophils.2 Indeed, one placebo-controlled clinical trial demonstrated that supplementing 66 rheumatoid arthritis patients with 130mg/kg/day of omega-3s significantly decreased IL-1 levels from baseline, decreased the number of tender joints and enabled some patients to discontinue NSAIDs.3

Taking off from this preliminary research on fatty acids, a proprietary esterified fatty acid complex, Celadrin, has demonstrated efficacy for range of motion and function improvement of osteoarthritic joints.

In one placebo-controlled trial with 64 patients with osteoarthritis of the knee, after 68 days those supplementing with Celadrin experienced significant increases in knee flexion (10.1 degrees vs 1.1 degrees for placebo) as well as perceived functional improvement.4 However, WOMAC scores — the gold standard in osteoarthritis measurements — were not used in the study.

Interestingly, a topical formulation of this same cetylated fatty acid brought about significant improvements in 40 patients with knee osteoarthritis. Patients were tested 30 minutes after initial application and after 30 days of cream application twice daily. Cetylated fatty acid patients in this placebo-controlled study experienced significantly decreased time to climb stairs and increased range of motion (no difference in placebo group).5


Some manufacturers formulate combination products using a variety of joint-health ingredients. In the case of BioCell Collagen II, a bevy of ingredients is found naturally in the matrix. BioCell Collagen II naturally contains Type II collagen proteins (60-65 per cent), chondroitin sulfate (20 per cent), hyaluronic acid (10 per cent), glucosamine and other proteoglycans. A serving of 1,500mg BioCell Collagen II supplies 900mg collagen type II protein (amino acids), 300mg chondroitin, 150mg hyaluronic acid and traces of glucosamine and other elements.

One randomised, double-blind trial involved 60 patients with severe, active rheumatoid arthritis. After three months, the supplementing group experienced a decrease in the number of swollen joints and tender joints compared to placebo. Of note, four patients in the collagen group had complete remission of the disease, and no side effects were seen.6

A more recent randomised controlled clinical trial with 274 patients with active rheumatoid arthritis examined the effects of four dosages of type II collagen — 20, 100, 500 or 2,500mcg/day. The researchers used three criteria to measure results, and only the smallest dosage — 20mcg/day — found any significant results, and only in one of the three criteria categories.7 Another six-month trial with type II collagen among 60 patients found no significant results, with the notable exception of two collagen-treated patients who experienced clinical remission according to the criteria of the American Rheumatism Association.8

Novel anti-inflammatory

New ingredients that compete with glucosamine and chondroitin need to demonstrate better performance or fewer adverse effects. A formulation of concentrated milk proteins, MicroLactin, is comprised of antibodies and other bioactives which are then isolated and concentrated.

MicroLactin was compared to both placebo and glucosamine in a double-blind, randomised, placebo-controlled, six-week trial with 35 subjects. Although the MicroLactin group experienced three adverse effects, compared with one for the glucosamine group, and both ingredients demonstrated significant improvements in all categories of the WOMAC osteoarthritis index, the MicroLactin group was 60 per cent better than glucosamine in the composite WOMAC analysis.9

Earlier research into its mechanism of action discerned that MicroLactin inhibits inflammation by decreasing the emigration of neutrophils from the vascular space, by up to 75 per cent.10 It seems to do this by restricting the slow leakage of neutrophils through vascular tight junctions.11 A method of isolation and use patent was issued for the anti-inflammatory factor in MicroLactin.


In the Ayurvedic medical model of India, boswellia (Boswellia serrata) has been used extensively for joint support. Himalayas USA's JointCare formula contains boswellia, as well as guggul (Commiphora mukul), guduchi (Tinospora cordifolia) and licorice (Glycyrrhiza glabra).

Two human trials support its safety and efficacy. In a double-blind, placebo-controlled study of 57 patients with osteoarthritis of the knee, the botanical group experienced a significant 79.2 per cent decrease in pain scores and 87.6 per cent decline in swelling scores, compared to placebo.12 Another clinical trial of 50 osteoarthritis patients found a 56.8 per cent decrease in symptoms after six months, compared to 29.1 per cent in the placebo group.13

In indigenous Peru, cat's claw (Uncaria guianensis) is used to treat arthritis, among other maladies. New research shows that it slightly improves the performance of a novel mineral supplement, SierraSil, made up of a blend of 65 macro and trace minerals. The in vitro study used human cartilage tissue and cells obtained from knee-surgery patients and examined cartilage degredation caused by the pro-inflammatory IL-1. SierraSil alone significantly reduced cartilage structural integrity breakdown by 68-73 per cent, while a combination of SierraSil with Vincaria brand cat's claw showed reductions of 58-77 per cent.14 A 120-patient clinical trial is underway to validate these results in a human model.

Unigen Pharmaceuticals brings to its joint health product the usual slate of ingredients — glucosamine, chondroitin, MSM, cetyl myristoleate — with a patented botanical formulation called Protectin, comprised of Accacia catechu extract and Scutelleria bicalensis root. The botanicals are said to act as anti-inflammatory agents. A double-blind, placebo-controlled, randomised human trial of 60 patients is currently in peer review and could be published later this year.

Many up-and-coming ingredients are striving to scientifically validate their products and make inroads against glucosamine and chondroitin. The collapse of cox-2 drugs means the supplements market for joint health is wide open, regardless of the results of the GAIT trial. If the GAIT results are positive, expect a renewed wave of product launches — likely housed not just with glucosamine and chondroitin, but with some of the ingredients mentioned here.

Osteoarthritis treatments


Level of evidence based on literature search, and strength of recommendation based on evidence and expert opinion


Level of evidence

Effect size range

Strength of recommendation



1.23 - 1.5




0.43 - 1.02




0.47 - 0.96










Opiod analgesics












Herbal remedies


0.23 - 1.32



1. Conn D, et al. Alternative treatments and rheumatic disease. Bull Rheumat Dis 1999; 48:1-4.
2. Kremer JM. N-3 fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr 2000 Jan; 71(1 Supp):349S-51S.
3. Kremer JM, et al. Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal anti-inflammatory drugs. Clinical and immune correlates. Arthritis Rheum 1995 Aug; 38(8):1107-14.
4. Hesslink R Jr, et al. Cetylated fatty acids improve knee function in patients with osteoarthritis. J Rheumatol 2002 Aug; 29(8):1708-12.
5. Kraemer WJ, et al. Effect of a cetylated fatty acid topical cream on functional mobility and quality of life of patients with osteoarthritis. J Rheumatology 2004; 31(4):767-74.
6. Trendham DE, et al. Effects of oral administration of type II collagen on rheumatoid arthritis. Science 1993 Sep 24; 261(5129):1727-30.
7. Barnett ML, et al. Treatment of rheumatoid arthritis with oral type II collagen. Results of a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 1998 Feb; 41(2):290-7.
8. Cazzola M, et al. Oral type II collagen in the treatment of rheumatoid arthritis. A six-month double-blind, placebo-controlled study. Clin Exp Rheumatol 2000 Sept-Oct; 18(5):571-7.
9. Zenk JL, et al. The effects of milk protein concentrate on the symptoms of osteoarthritis in adults: an exploratory, randomized, double-blind, placebo-controlled trial. Curr Therap Res 2002 Jul; 63(7):430-42.
10. Ormrod DJ, Miller TE. A low molecular weight component derived from the milk of hyperimmunized cows suppresses inflammation by inhibiting neutrophil emigration. Agents Actions 1992; 35:1-10.
11. Ormrod DJ, Miller TE. The anti-inflammatory activity of a low molecular weight component derived from the milk of hyperimmunized cows. Agents Actions 1991; 32:160-6.
12. Chandanwale AS, Kulkarni K. Clinical evaluation of Rumalaya forte in osteoarthrosis. Med Update 2003; 10(9):23-6.
13. Rastogi S, et al. Evaluating the safety and efficacy of Rumalaya forte: a double-blind clinical trial. Orthopaedics Today 2003; V(1):63-5.
14. Miller M, et al. Suppression of human cartilage degradation and chondrocyte activation by a unique mineral supplement SierraSil and a cat's claw extract, Vincaria. J Am Nutraceut Assoc 2004; 7(2):32-8.

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