There are 600 million knees in the U.S. and most of them have outlived their warranty. In fact, each year there are 300,000 knee replacement surgeries. But that is just a drop in the ocean compared to the 20 million people with osteoarthritis (OA), the 100 million pain relief prescriptions written each year, and the even larger, very competitive market for over-the-counter (OTC) medications and supplements.
The American College of Rheumatology defines OA as a "heterogeneous group of conditions that leads to joint symptoms and signs, which are associated with defective integrity of articular cartilage, in addition to related changes in the underlying bone at the joint margins." A recent review of OA treatment strategies, albeit weak in covering alternative therapies, noted that the etiology of OA combines inflammatory, metabolic and mechanical causes. There is deterioration of articular cartilage, loss of synovial fluid, dysfunctional bone remodeling (bone spurs, etc.) and chronic inflammation. Treatment objectives are to control pain, improve function and reduce disability1.
For decades, mainstream medical care for OA has mostly been geared toward the use of pain relieving and anti-inflammatory drugs. Unfortunately, these address the pain and secondary inflammation, but not the underlying cause of OA, which is the progressive loss of the shock-absorbing cartilage and synovial fluid in the joint space. Novel medical and surgical methods approach the problem directly through such therapies as injecting a synthetic synovial fluid, or replacing bone and cartilage with steel and polyethylene.
The supplement industry also actively supports OA care. Products with anti-inflammatory properties co-exist with products intended to help maintain healthy joint tissues and fluids by providing the precursor compounds for repair and re-growth.
Medical Treatment for OA
The fictitious doctor in the FOX television series "House" pops Vicodin like M&M candies, but even he realizes using opiate pain relief for a chronic condition is akin to turning up the volume on a car radio to drown out bad engine noise. Nevertheless, the big money, as in billions of dollars, has been in the prescription anti-inflammatory drugs. Small money (still millions of dollars, but growing) is in replacing lost synovial fluid, re-growing cartilage cells and surgical joint replacement.
No steroidal anti-inflammatory drugs (NSAIDS) are the most commonly used class of arthritis medication. They function by blocking cyclooxygenase (COX) enzymes. Drugs that selectively inhibited the COX-2 enzyme (in theory less likely to provoke gastrointestinal bleeding) reached the market in 1998 and screeched to a near halt in 2004-05 when Vioxx (voluntarily) and Bextra (involuntarily) exited the U.S. market. Celebrex is still prescribed, however, more cautiously than before. Arcoxia and Prexige are approved in some countries, but not in the U.S.
In 2005, "Black Box" warnings were added to the labels of Celebrex and other prescription NSAIDS, which belatedly recognized that this class of drugs is responsible for hospitalizing more than 100,000 people and causing the deaths of more than 15,000 patients each year.
Next-generation NSAIDS—not yet approved—include compounds that block the lipoxygenase (LOX) enzymes, or perhaps function as dual COX/LOX inhibitors. Licofelone (Merckle GmbH) has successfully completed Phase III clinical trials showing OA treatment equivalence to other NSAIDS but with fewer adverse effects2. However, given the backlash to the COX-2 debacle, Licofelone will likely go through an arduous safety evaluation before approval is reached in any country.
Intense "flare-ups" can be treated with intra-joint injections of corticosteroids or synthetic hyaluronan to (respectively) suppress inflammation or restore lubrication. The former requires a single injection and provides several months of relief. The latter, however, requires an injection each week for three weeks; patients usually experience some improvement for six to 10 months. These therapies are meant for those suffering from severe OA, who have not benefited from less invasive therapies such as lifestyle modification, physiotherapy or oral pain relief treatments like supplements, NSAIDS or opiates.
When cartilage damage is trauma-related rather than osteoporotic there are a few novel treatments available. "Microfracture surgery" is used to treat younger patients (often professional athletes), who have full thickness damage to the cartilage that goes all the way down to the bone. Small holes are made in the bone ends, allowing bone marrow cells to seep out and a clot to form, which then matures into cartilage-like repair tissue eventually becoming smooth and durable. Genzyme Corp. has been active on this front. So far, it has developed two methods to take out cartilage cells, grow millions of copies in test tubes and replant the autologous cultured chondrocyte product into the knee joint.
"Bone on bone" is the description often used to describe the knees of someone who is a candidate for knee replacement surgery. The average age of a knee replacement candidate is 70 years, the average cost is $25,000, and 85% of knee replacements are expected to last 15-20 years. As mentioned previously, 300,000 knee replacement surgeries take place in the U.S. each year. That number includes approximately 25,000 "do-overs" to correct a failed first procedure.
Ingredients for OA
The following information represents a sampling of both well known and new ingredients with claims of benefits for OA, in addition to the clinical evidence that exists to support those claims. New products enter this field every year, but companies will need to rely on more than a "history of use" for joint ingredients to be successful going forward.
Boswellia/Boswellic Acid: 5-LOXIN is a product that was recently introduced to the supplement market. It cites an Ayurvedic heritage for Boswellia Serrata as evidence, while also claiming that it is much more potent than traditional products (mostly boswellic acid preparations) because the 3-O-acetyl-11-keto-beta-boswellic acid (AKBA) content is 10 to 15 times higher. To date, no human clinical trials have yet been performed on 5-LOXIN, however, trials are planned to start during the last quarter of 2005. All of the clinical evidence on boswellia has been performed with 700-1000 mg per day of low AKBA products (which are typically described as containing 50-70% total boswellic acids). 5-LOXIN, however, is recommended in only 100 mg per day doses due to its high AKBA content.
Without convincing clinicals, the OA case for any of the commercially available boswellic acid preparations is a work in progress. So far, in vitro work shows inhibition of 5-lipoxygenase and of metalloproteinase enzymes that are implicated in degeneration of joint tissues. Two rat studies with 5-LOXIN demonstrated anti-inflammatory activity in arthritis models. But the Sander 1998 clinical study, often cited as evidence for benefit of rheumatoid arthritis, actually reported "…no measurable efficacy3." And the Kimmatkar 2003 study4, reporting a benefit for OA from 1000 mg per day, suggested results this author finds suspiciously "too good to be true." However, the product studied in the Kimmatkar study, WokVel (a proprietary extract standardized to boswellic acids), is currently involved in a comparative clinical study, the results of which are due out before the end of the year. WokVel, sourced from a company based in India, is said to reduce the production of leukotrienes by inhibiting synthesis of 5-lipoxygenase. Toxicity studies in rats and primates showed no pathological changes in hematological, biochemical or histological parameters at doses of up to 1000 mg/kg.
Cetylated Fatty Acids: In controlled clinical trials, twice daily application of a topical cream containing cetylated fatty acids improved knee function in OA5, and twice daily oral consumption of the same product at 2100 mg per day produced similar results6. However, while the evidence is compelling, further investigation is warranted because the mechanisms of action "remain to be elucidated."
Chondroitin: Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of repeating disaccharide subunits. The source material is usually bovine cartilage. The chains vary in length from 20 to 80 disaccharides. Whether synthesized in the body or absorbed from a supplement, chondroitin sulfate chains are attached to proteins and then secreted by the cells as proteoglycans into the extracellular matrix. One of the properties of chondroitin is that it is strongly negatively charged, and this draws water into the extracellular matrix and maintains a high level of hydration. A meta-analysis of clinical trials found chondroitin sulfate to be safe and effective in providing pain relief. Daily intakes of 800 to 1200 mg per day were equally effective, and significant pain relief was seen as early as two weeks7.
Collagen Hydrolysate: The uses of hydrolyzed collagen (a protein extracted from animal cartilage) date back to the 1970s when it played an unfortunate part in the liquid, protein-sparing diet craze. The use of hydrolyzed collagen as the sole source of protein in these very low calorie weight loss plans contributed to illness and death because it is an incomplete protein, lacking some of the essential amino acids. In its current guise, hydrolyzed collagen is sold by numerous supplement companies touting a broad range of health claims, including relief from OA. Products claim to deliver 2 to 10 grams per day, either as capsules, powder or liquid.
The evidence behind hydrolyzed collagen comes from a collection of in vitro, animal and human clinical studies. With regard to the former, cartilage cells in culture increased collagen synthesis when hydrolyzed collagen was added8. In another study, mice fed a laboratory-prepared collagen hydrolysate incorporated 2.5 times as much proline into the cartilage compared to controls9. In the most often cited human study, 389 OA patients at 20 sites in three countries (U.S., U.K., Germany) took either 10 grams per day of collagen hydrolysate or a placebo for 24 weeks. There was no significant difference in changes to the pain or physical function scores between the treatments. However, when the data were analyzed country-by-country, the patients from Germany receiving collagen hydrolysate had significant improvements in pain and function compared to placebo—the U.S. and U.K. arms of the study showed non-significant trends of being worse than placebo10.
Unhydrolyzed/Undenatured Collagen (from chicken sternum): This is an ingredient worth mentioning, but there does not seem to be a lot of clinical evidence with regard to its benefits in OA. However, clinical trials are currently in progress.
Glucosamine: The raw material used to make glucosamine is shell chitin, which is typically sourced from crab or shrimp. Taken as glucosamine sulfate or glucosamine hydrochloride at 1500 mg per day, it increases blood concentrations by 50%, from 0.04 mmol/L to 0.06 mmol/L. Glucosamine is incorporated into the glycosaminoglycans that interact with collagen and elastic fibers to form a cushioning cartilage tissue between opposing bones of the knee joint. A comprehensive review of the safety and efficacy of glucosamine reported no adverse effects of glucosamine on blood, urine, fecal or cardiovascular performance parameters. Symptoms or side effects were typically reported to match or be lower than those reported for placebo, and much lower than seen with NSAIDS. The majority of clinical trials report significant pain relief. Two trials of three years duration reported a slowing of knee cartilage loss compared to placebo-treated controls11.
H. procumbens (Devil's Claw): A comprehensive review of Devil's Claw encompasses the European Scientific Cooperative on Phytotherapy (ESCOP) monograph and more than 10 published clinical trials for musculoskeletal pain relief12. The evidence is consistent for a benefit from aqueous extracts delivering a daily dose of 50 mg or more of harpagoside (the presumed active compound). The mechanism of action does not appear to involve prostaglandin synthesis. In other words, it is neither a COX nor a LOX inhibitor13.
Methylsulfonylmethane (MSM): This synthesized compound, chemically similar to dimethyl sulfoxide (DMSO), is often sold in combination with glucosamine and chondroitin, with MSM content ranging between 250-750 mg per day. Classic nutritional biochemistry identifies a requirement for the sulfur-containing amino acids methionine and cysteine as sufficient to meet all sulfur needs. Yet there is a large body of scientific evidence that suggests other sulfur compounds may be helpful, including alpha lipoic acid, S-adenosylmethionine (SAMe), N-acetylmethionine and taurine.
In an unpublished report from 2001, 10 OA patients received MSM at 2250 mg per day and reported pain relief by the fourth week14. A larger clinical trial conducted in India reported that MSM at 1500 mg per day, administered in three doses, for 12 weeks was effective for pain relief and inflammation. For the 27 patients who completed 12 weeks on MSM, there was a reported 51% reduction in the mean pain index, 33% reduction in self-reported pain on the visual analog scale, 70% reduction in swelling and 32% reduction in the Lequesne Index15 (author's note: this study's results seem "too good to be true"). Lastly, a recently presented but as yet unpublished study used MSM at 6000 mg per day for 12 weeks and researchers reported better pain relief compared to placebo16. While the current research on MSM is encouraging, more is necessary to substantiate its effects for pain relief and inflammation.
Milk Protein Concentrate: A small clinical trial (10-13 OA patients per group) of 6 weeks duration showed that a milk protein concentrate (MPC) taken at 4000 mg per day was similarly effective to glucosamine sulfate at 1500 mg per day for providing relief of pain and stiffness, and improving physical activity. Both were better than placebo. Based on previously published in vitro and animal work, the authors propose that the mechanism is anti-inflammatory via the inhibition of the migration of inflammatory neutrophils from the blood stream to the inflammation site17. MPC is generated by injecting dairy cows with a bacterial vaccine, which induces the secretion of antibodies and undefined low molecular weight substances into the milk. The concentrating process removes, casein, whey, fat, lactose, salt and water, leaving the active principle(s). This product is known commercially as MicroLactin.
Solubilized Keratin: A company based in New Zealand has approached the U.S. market with its soluble, digestible keratin protein extracted from the wool of sheep. It claims to have an intact amino acid profile, a high antioxidant content and the ability to improve joint function. Specifically, the company claims that its ingredient, Cynatine FLX, because of its 4.2% cysteine (CYS) content, will provide this essential amino acid for joint proteoglycan sulfation, taurine anti-inflammation, glutathione (antioxidant) biosynthesis and direct antioxidant activity. While all of this might be true in theory, there is no clinical proof that dietary CYS is inadequate, or that Cynatine FLX will provide useful amounts and exhibit these functions. Cynatine FLX is an interesting ingredient with some preliminary animal data, but it definitely needs more clinical proof of its benefits for it to be commercially successful.
Other Ingredients: Older, more established ingredients also tout claims for pain relief. Omega 3 fatty acids from fish oil have shown some benefit for rheumatoid arthritis (but not OA).
SAMe is best known as an antidepressant, but a meta-analysis of 11 clinical trials for OA found it as effective in reducing pain and improving functional limitations as NSAID therapy, without the NSAID adverse effects.
Four clinical trials of white willow bark extract (WWB) reported effective pain relief from OA and low back pain. As the salicin content of WWB is far below the amount found in pain-relieving Aspirin, researchers are of the opinion that there are as yet unidentified biologically active compounds in WWB that may be responsible for relieving pain.
A galactolipid compound called GOPO, which is found in rose hip, is claimed to be effective in treating OA. It only recently became commercially available in the U.S. through a product called LitoZin and it is promoted as being more effective than glucosamine. GOPO content varies considerably in different species of rose hip, but through years of analysis by a Danish company, a unique sub-species of the rose hip plant with the highest content of GOPO was produced. The company that has secured the rights to LitoZin in the U.S. claims that the product has been shown to be clinically effective in 82% of patients in reducing pain and increasing mobility.
Science as Marketing
A statement commonly heard from the cynical side of the R&D team is "I'd much rather have an effect and no mechanism than a mechanism and no effect." Historically, dietary supplement claims have been based on a combination of ancient use along with anecdotal quotes of efficacy. While these practices continue, they are now likely to be supplemented with scientific evidence of efficacy. But the science of these "scientific" claims is often no better. In a lot of cases, preliminary clinical evidence, or sometimes just a few animal studies, is paired with in vitro evidence for a mechanism, and the combination is held up as proof of function in a "market the mechanism" campaign.
Pharmaceutical companies use in vitro screening and animal tests as a sieve. Extensive pre-clinical work is completed on toxicology, absorption, distribution, mechanism of action, metabolic breakdown and excretion. After the foundation is built, a careful, progressive series of clinical (human) trials delve into safety, efficacy, adverse side effects and interactions with other drugs. While dietary supplement companies are not expected to drop hundreds of millions of dollars on research before bringing a product to market, they should show continuing progress until a valid clinical milestone is reached. This is usually defined as two or more carefully designed and conducted clinical trials with appropriate blinding, controls and clinically significant endpoints—either widely accepted biomarkers, such as blood pressure, or a direct measure of the disease state, such as pain relief. It is encouraging to see that some companies are headed down this path, but the vast majority of companies are still lagging behind.
Commerce, like nature, abhors a vacuum. Due to the withdrawal of Vioxx and Bextra, and the "black box" warnings added to the labels of Celebrex and the non-COX NSAIDS, the market for safe pain relief from OA remains open. If the GAIT study produces negative results for glucosamine and/or chondroitin (see sidebar), then the market is wide open indeed. Combining these circumstances with the fact that the Baby Boomers are reaching the age of arthritis means any supplement that can prove safety plus pain relief and/or maintenance of joint health has a strong future in the U.S. and worldwide. NW
About the author:
David Mark, PhD, is president of dmark consulting LLC, a provider of research management services to functional food and dietary supplement companies. He can be reached at 978-897-0890; E-mail: [email protected]; Website: www.dmarknutrition.com.
Dr. Mark has as clients dietary supplement companies that market products containing chondroitin, glucosamine, MSM and SAMe.
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