The Next Generation's Supplement for Improved Joint and Cartilage Support

Chondroitin & Glucosamine:
New Forms Stand Up to Arthritis 

By Will Block

Celebrex^® prescriptions continue to surge - so reads the press wire on GD Serle's new COX-2 inhibitor pain-relief drug as out-of-the-gate sales continue to soar. Celebrex is really a good name for indicating what its manufacturers are doing, celebrating a blockbuster as big as - or bigger than - Viagra^®. At this time, it is thought that Celebrex will top Viagra's first year with sales expected to exceed $1 billion in 1999. Celebrex may be the most successful new drug launch ever. What does it relieve, you may ask? If you don't already know the answer and you've got the ailment at which it is aimed, you probably need to raise your antennas.

Celebrex helps relieve the pain of arthritis. Yet Celebrex does not treat the cause of arthritis. You would think that the market for a new drug, especially one that deals only with symptoms, could not burn so brightly. Speaking of antennas (for increased reception), were you aware of the popularity of several best-selling books such as The Arthritis Cure over the last few years? Perhaps the media's justifiable excitement for the stars of these books, glucosamine and chondroitin, got you to act. Nevertheless, most people have still not heard the good words on these natural alternatives to drugs. They have not heard about glucosamine and chondroitin because treating arthritis is a major business, and the roar of Celebrex has muffled the clamor of the alternatives.

Unfortunately, new non-steroidal anti-inflammatory drugs (NSAIDs) such as Celebrex, or older ones such as aspirin and ibuprofen, do not deal with the cause of arthritis, the most common form of which is osteoarthritis. Instead, these drugs reduce inflammation and pain, which by itself is good, but not without inflicting the price of unacceptable side effects such as: stomach pain, ulcers, nausea, cramps, diarrhea, kidney damage, and possibly high blood pressure. These side effects might be acceptable tradeoffs if NSAIDs could stop and/or repair the damage caused by arthritis. But they don't. In fact, there is some evidence that NSAIDs may make matters worse i.e., some of these drugs may even exacerbate osteoarthritis.¹

New and Improved Chondroitin and Glucosamine
The real news is that recent studies have found both glucosamine and chondroitin to be even better than expected, pioneering a whole new category beyond pain relief, known as chondroprotection (chondro means cartilage related). It is entirely possible that "chondroprotection" is the "magic bullet" that addresses the core problem of arthritis which is cartilage degradation. Glucosamine-chondriotin nutrients go beyond preserving joint health and maintaining function. They are more than just cartilage protectors. Glucosamine-chondroitin can restore proper joint function. They are indeed chondro-restoratives.

To date, all of the attention has been given to the first available nutrients of this type, glucosamine sulfate and chondroitin sulfate, which until now have been the most studied forms. And while their benefits have been studied independently of each other, together these precursors to the production of cartilage matrix biomaterials appear to be nearly everything one could ask for . . . building and protecting the cartilage matrix.

When you consider the new forms, specifically N-acetyl D-glucosamine and balanced chondroitin 4- and 6-sulfate, you begin to realize that if we knew something about glucosamine and chondroitin before the most recent research, it pales by comparison to what we are now learning. As you will see, the new chondroitin-glucosamine nutrients tend to optimize both short- and long-term results; they enhance bioavailability, increase efficiency. The new forms of glucosamine and chondroitin offer what we have been yearning for - the retrieval of young-adult joint functionality.

What is Osteoarthritis?
Osteoarthritis is an infirmity that affects approximately 12% of the U.S. population (more than 32 million people). It is an ailment, the incidence of which increases with age.² As the most common form of arthritis, osteoarthritis causes degradation of the cartilage matrix biomaterials that enable your joints to work properly. The result is inflammation, pain, and loss of movement. If not addressed, osteoarthritis can eventually lead to joint deformities and total loss of mobility. For humans, mobility is at the core of independent living.

Cartilage is the primary bio-material that helps cushion and dissipate the friction caused by the rubbing together of your bones where they meet at the joints. At these junctures, cartilage is attached to the end of your bones. Serving to absorb shock, the protective activity of cartilage diminishes with wear, tear, and age if not properly maintained. This breakdown may result in stiffness, pain, and many other problems that prevent mobility. This may occur in the joints of the hands, neck, feet, knees, elbows, hips, and even the spine. It may occur anywhere in the body where bones rub together. Normally, osteoarthritis is age related and doesn't start to occur until the 40's, but undue stress, or injury, or a number of other conditions may bring it on sooner.

Europe Has Led the Way For Glucosamine
Until recently in this country, there appeared to be little that could be done to alleviate the chronic and progressive damage of osteoarthritis. However, this was not the case in Europe where, starting in the early 1970's, studies started to appear indicating that a natural-occurring substance comprised of a sugar and an amino acid (known as a glucosaminoglycan, or GAG for short) could help slow, stop, and even reverse the progression of osteoarthritis.^3,4 The name of the substance is glucosamine.

Several decades earlier, in the 1940's, there was a readily-available solution for joint pain, a supposed "miracle" drug, first synthesized in the 1930's, called cortisone. As a corticosteroid, like the hormones produced and secreted by the adrenals, cortisone certainly took care of pain fast enough, but it had serious unacceptable side effects, often making the cure worse than the disease.⁵ These side effects include: adrenal insufficiency, mineral metabolism and calcium absorption malfunctioning, atherosclerosis, cataracts, and immunosuppression. And that's not all. Today we know that corticosteroids even decrease bone growth often making osteoarthritis worse.⁶ The desire to avoid these side effects led to the development of non-steroidal anti-inflammatory drugs (NSAIDs). While NSAIDs are not as powerful anti-inflammatories (and therefore pain relieving) as are corticosteroids, they are considered to have less serious side effects. However, NSAIDs are not without their own inherent, worrisome side effects. So fortunately, along came glucosamine, which soon proved to be at least one leg up over NSAIDs.

By 1980, Italian researchers evaluating the results of a double-blind placebo study could say that glucosamine tends to rebuild damaged cartilage, thus restoring articular function in the most chronic osteoarthritic patients.⁷ The same year, three other double-blind studies reporting on glucosamine were published. One study suggested that oral treatment with glucosamine sulfate should be considered basic therapy for the management of primary or secondary degenerative osteoarthrosis disorders.⁸ Another found that oral treatment with glucosamine sulfate could restore articular function to a certain extent.⁹ Also in 1980, a study of glucosamine found that osteoarthritic subjects experienced significant reductions in articular pain, joint tenderness, and restricted movement within the trial period. The subjects took 500 mg of glucosamine sulfate three times daily over a period of six to eight weeks. There were no adverse reactions.¹⁰

Healthy knee joint (top). Knee joint suffering from osteoarthritis(bottom).

Restoring Cartilage Balance
In healthy individuals a balance exists between the building and dismantling of cartilage (the synthesis and degradation of proteoglycans, the macromolecules of the cartilage matrix). This is much like the brake linings or shock absorbers of your car. With continued use, these parts wear out and you need to replace them. Inside your body you don't replace cartilage or synovial fluid (the liquid in the space between your bones that lubricates the joints and helps dampen the stress of movement). Instead, you rely on the inner mechanics of your body to dismantle and rebuild worn parts.

Studies using different experimental models have demonstrated that NSAIDs inhibit the synthesis of the glucosaminoglycans, such as glucosamine and chondroitin, which are needed to rebuild the worn parts of your joints. The result can be the intensification of any already-existing metabolic disorder, and the prevention of a return to normal cartilage composition. Thus, proper cartilage function can be impaired. In a dose-dependent way, glucosamine increases the ability of cartilage to synthesize needed glucoproteins, and in the process, restore the buildup-breakdown balance.¹¹

In a study involving 40 subjects with osteoarthrosis of the knee, glucosamine was compared to the NSAID ibuprofen (also known by such brand names as Advil^®).¹² After eight weeks of treatment at 1,500 mg of glucosamine or 1,200 mg of ibuprofen, the double-blind study found that the NSAID pulled out in front with a somewhat faster onset of pain relief, but by the end of the study, glucosamine was in the lead, providing more pain relief. All other parameters were similar, with a greater number of side effects attributed to the NSAID.

The use of glucosamine for the treatment of osteoarthritis has been based on its anti-inflammatory properties and a growing recognition that it promotes the metabolic activity of chondrocytes (cartilage-producing cells). A study completed in 1994 looked at the effect of glucosamine on the symptoms of 252 patients with osteoarthritis of the knee. Using 1,500 mg of oral glucosamine for four weeks, respondents' improvement (as measured by weekly assessments) exceeded those receiving placebo by 40%. Glucosamine was well tolerated throughout the study. There was no difference in side effects between the glucosamine and placebo-treated groups.¹³ Another similar study found glucosamine comparable to ibuprofen (an NSAID) for treatment of osteoarthritis of the knee. There were six times as many adverse reactions to ibuprofen versus glucosamine.¹⁴ What we continue to encounter in the research literature is the idea that glucosamine is not only safe but an active supporter of proteoglycan synthesis (i.e., a producer of cartilage macromolecules consisting of a protein bound to a glucosaminoglycan). This means that glucosamine is a metabolic enhancer offering a practical means to postpone and even prevent the onset of osteoarthritis in older people or those whose joints are "prematurely" stressed.¹⁵

Conventional Medicine Gives the Go-Ahead for Glucosamine
At this time, there's enough solid scientific information for even the Old Guard medical establishment to come around. At a recent symposium of the American Academy of Orthopaedic Surgeons in Anaheim, California, the official "green light" was given to glucosamine as a valid therapeutic alternative when NSAIDs such as aspirin and ibuprofen are ineffective or contraindicated.¹⁶ Other clinicians at the symposium even thought that glucosamine could be recommended as first-line therapy in selected patients with osteoarthritis. When you consider that glucosamine (in either the sulfate, HCL, or acetylated forms) is a dietary supplement not subject to FDA approval, you realize "the times, they are a changin'."

The new forms of glucosamine and chondroitin offer what we have been yearning for - the retrieval of young-adult joint functionality. 

Not as well received at the symposium, because of claims that the data is simply not as good, was evidence for the efficacy of oral chondroitin sulfate. Even though both glucosamine and chondroitin sulfate are components of the cartilage matrix, as per Dr Randy N. Rosier of the University of Rochester, New York, ". . . there is some question about how much chondroitin sulfate gets to the cartilage, even though studies have shown beneficial symptomatic effects with both agents."

Misinterpreted Evidence About Chondroitin
Until just this last year, the number of studies on chondroitin have been split: some in favor and some against. A significant part of the problem has been an inadequate understanding of the difference between how glucosamine and chondroitin work. This misunderstanding has confounded the evidence, leading to misinterpretation. In essence, glucosamine is rapidly taken up by your system,¹⁷ increasing its availability as a key element for production of the proteoglycans of the cartilage matrix. This leads to better repair mechanisms of cartilage erosion and helps restore proper joint function. Moreover, there can be a positive response to glucosamine within only a few days or a few weeks.

Chondroitin achieves its benefits much more slowly than glucosamine. Chondroitin bioavailability following oral administration has been calculated at only 12-13.2%,^18,19 the equivalent of about 1/2 that of glucosamine.²⁰ For this reason scientists have coined a term to emphasize this. They have named chondroitin a symptomatic slow-acting drug for osteoarthritis (SYSADOA).²¹ [Of course, it should be SYSANOA because natural-occurring chondroitin is not a drug but a nutrient.] When the studies are carried out over longer time periods, the benefits become clear. Although it's been thought not to possess the anti-inflammatory benefits of NSAIDs, chondroitin does have anti-inflammatory effects, but it often takes longer to show.²² Chondroitin also improves joint fluidity by drawing water to the cartilage tissue;²³ additionally, it helps fight enzymes that inhibit transportation of nutrients into these tissues as it prevents other enzymes from tearing down cartilage tissue.²⁴ Furthermore, chondroitin, like glucosamine, promotes the production of key cartilage components such as proteoglycans²⁵ and it also prevents abnormal cell death.²⁶

Chondroitin's Benefits Continue Even After Discontinuation
The first major study of chondroitin involved 120 subjects with osteoarthritis of the knees and hips.²⁷ After three months of treatment with chondroitin, the subjects were followed for two months. Taking 1,200 mg of chondroitin daily for three months significantly reduced the need for NSAIDs. This reduced need persisted throughout the two-month, treatment-free, follow-up phase. In other words, it appears likely that chondroitin changes cartilage structure and/or function for the better. Within the study, physician and patient assessment also showed a significant similar tendency. Both objective and subjective criteria were consistent with each other. Tolerance was outstanding.

In an open multi-center trial conducted in Austria, 61 patients, with osteoarthritis of the hip, knee and/or finger joints were treated with chondroitin sulfate for three months.²⁸ NSAID therapy, given along with chondroitin with the amount determined by the subject, was reduced by 72%, indicating that chondroitin provided significant pain relief. There were no serious side effects during the study. Overall pain reduction was thought to be additive, with contributions from both NSAIDs and chondroitin.

Chondroitin sulfate was compared with the NSAID diclofenac in a longer-term clinical study in patients with osteoarthritis of the knee.²⁹ One hundred forty-six subjects were randomized and split into two groups, one group took chondroitin and placebo at various times over a six-month period and the other group took the NSAID and placebo. Both groups ended taking only placebo the last two months. The study found that the NSAID group showed prompt reduction of clinical symptoms. However, the pain returned at the end of the treatment period when the NSAID users stopped. Pain relief had a slower onset in the chondroitin group but relief lasted for up to three months after the end of treatment.

At a recent symposium of the American Academy of Orthopaedic Surgeons in Anaheim, California, the official "green light" was given to glucosamine as a valid therapeutic alternative when NSAIDs such as aspirin and ibuprofen are ineffective or contraindicated. 

Special Chondroitin Studies Are Impressive
A bumper year for chondroitin studies was 1998. It was also the year for a different kind of chondroitin to clearly make its presence felt - a chondroitin based on a very specific admixture of 4-sulfate and 6-sulfate isoforms. In one of the longer studies to date, lasting one year, researchers assessed the effect of chondroitin on 42 subjects with osteoarthritis of the knee.³⁰ Comprised of both men and women, in the age range of 35-78, 800 mg of chondroitin per day was supplied. Most prior studies had used 1,200 mg/day.

The results clearly indicated significant reduction in joint pain and significant increases in overall mobility. This study went further than others, measuring the actual joint space and levels of various biochemical markers associated with bone and joint metabolism. Some of the subjects were shown to stabilize the space narrowing of their knee joints compared with progressive space narrowing (due to deterioration of cartilage) in those subjects receiving only placebo. Additionally, abnormal bone and joint metabolism stabilized in those taking chondroitin, whereas in the placebo group it remained as abnormal as at the beginning of the study. To date, this study has been the most hopeful, indicating the ability of chondroitin to alter the "natural" age-related, downward course of osteoarthritis.

Another major area of arthritic pain is the finger joint, the subject of a study involving 119 Belgian men and women in a double-blind, placebo-controlled trial using 1,200 mg/day of chondroitin per day over the course of three years.³¹ Helping to assess the progress were radiological readings at yearly intervals.

Five categories were used to assess the results on the finger joints: subjects who were not affected, and subjects who had classical osteoarthritis, loss of joint space, erosive osteoarthritis, and remodeled (deformed) joints. In the chondroitin group, the scientists observed a significant decrease in the number of osteoarthritic patients with new "erosive" finger joints. This result was particularly important since the next step in degradation is nodular deformities. In protecting against erosive evolution - that can lead to crooked and enlarged finger joints - chondroitin alters the structure-function modifying aspects of osteoarthritis. In other words, chondroitin helps prevent joint degeneration.

Walking More Ably With Chondroitin
Hungary was the site of another investigation of the value of chondroitin for arthritis of the knee.³² Six months of daily intake of 800 mg of chondroitin by 80 patients found that spontaneous joint pain constantly decreased, but little benefit was seen in the placebo takers. The time needed to walk 20 meters was significantly reduced only among chondroitin takers. Efficacy evaluations, when compared to placebo, were rated high for chondroitin by both double-blinded physician researchers and the subjects.

Chondroitin may have the ability to alter the "natural" age-related downward course of osteoarthritis. 

Yet another knee study was conducted in France.³³ A mixture of chondroitin 4- and 6-sulfate was given orally to 104 subjects at the dose of 800 mg/day. Clinical manifestations and anatomic progression showed positive after one year. Functional impairment was reduced by approximately 50%, representing a significant improvement over placebo for all clinical criteria. As with most other studies, tolerance was excellent or good in most cases. This was one more study demonstrating that chondroitin is a structure modulator, helping to alter cartilage structure for the better. Chondroitin use resulted in a measurable improvement of the interarticular joint space as read by x-rays.

Glucosamine and Chondroitin Together: 2 Glucosaminoglycans Are Better Than 1
What would an ideal chondroprotective/restorative agent do? According to a book on "second-line" agents for osteoarthritis, such a compound would need to accomplish the following goals:³⁴

1. Enhance chondrocyte synthesis (chondrocytes produce cartilage cells)
2. Enhance synthesis of hyaluronic acid (a prime component of synovial fluid, the lubricant of the joint)
3. Inhibit enzymes that degrade cartilage
4. Strengthen and enhance vessels that feed joints or supply them with nutrients
5. Reduce joint pain
6. Reduce synovitis (inflammation of the membrane surrounding synovial fluid)

Currently there is no one agent that can achieve all of these goals, especially not drugs (owing to the unacceptable side effects). However, glucosamine and chondroitin together may be able to hit the bull's eye. Separately, glucosamine has been shown to exhibit four of the six stated objectives; namely, items 1, 2, 5 and 6. Glucosamine enhances chondrocyte synthesis of glycosaminoglycans, collagen, and DNA (item 1). It also, especially in the form of acetylglucosamine, helps synthesize hyaluronic synovial fluid (item 2). Studies have also found that it exhibits anti-inflammatory effects and pain relief (item 5) including those attributable to synovitis (item 6).

Similarly, chondroitin sulfates have been shown in cultures to help with chondrocyte synthesis (item 1). Further, chondroitin has been found to inhibit degradative enzymes in cartilage (item 3). Many studies have shown that chondroitin helps reduce arterial plaque and also clear cholesterol deposits (item 4). In human studies, chondroitin reduces joint pain and improves joint mobility (item 5). Also, in mice, it reduces the incidence of synovitis associated with joint arthritis (item 6).

Altogether, chondroitin rings the bell on items 1, 3, 4, 5, and 6 - a near-ideal chondroprotective-restorative agent. Neither glucosamine nor chondroitin fulfills the quest for the ideal separately. When combined, they appear to provide coverage for everything on the list - and judging from the newly compiled evidence, they can provide even more.

It is incontrovertible that the results of recent studies are superior when they shift back to a youthful mix of chondroitin 4- and 6-sulfates. 

The Synergy of Glucosamine and Chondroitin
Thirty-four U.S. Navy divers and special warfare subjects, suffering chronic pain and degenerative joint disease of the knee or low back, were randomized and given either placebo or glucosamine HCl (1,500 mg/day) and mixed chondroitin 4,6 sulfates (1,200 mg/day).³⁵ The study lasted for 16 weeks and involved a crossover, in which those taking placebo and those taking the glucosamine-chondroitin regimen switched regimens. While the study was short-term, knee-osteoarthritic symptoms were significantly relieved for subjects taking the glucosamine-chondroitin. However, when running times (as in sprinting) were measured, there were no increases in speed. Formally, no benefit could be cited for spinal degenerative joint disease. However, the researchers were hopeful that longer studies would prove benefits for spinal degenerative joint disease.

Billed as the first North American study of compounds that accelerate glycosaminoglycan synthesis, a combined study of the effects of glucosamine and mixed chondroitin 4,6 sulfate taken together was just published.³⁶ Ninety-three patients with osteoarthritis of the knee were given oral glucosamine at 1,000 mg and chondroitin sulfate at 800 mg, both twice a day. At 2,000 mg and 1,600 mg, this constitutes 1/3 more than the highest levels in prior studies for each of the nutrients separately. But it appears to be worth it. There was a significant increase in the joint functionality of the experimental group taking glucosamine and chondroitin compared to those taking placebo. Joint functionality improved twice as much as those taking placebo. As well, there was a significant drop in the use of pain medication by the glucosamine-chondroitin group. Side effects were equal to placebo; in other words, there were none. The excitement was rendered by the authors stating that glucosamine and chondroitin may be disease-modifying agents.

Which Glucosamine and Which Chondroitin to Take
All the different qualities, amounts and forms of glucosamine and chondroitin may leave the reader confused about what is best. One thing seems quite clear: there is a different and complementary role for the two isoforms of chondroitin, 4-sulfate and 6-sulfate.³⁷ Studies have found that the activity of chondroitin depends upon the structure. For example, chondroitin 6-sulfate has been found to be more efficient than chondroitin 4-sulfate for inhibiting detrimental enzyme activity. It works better at blocking enzyme-associated degradation of cartilage.³⁸ For example, chondroitin 6-sulfate has been found to better inhibit elastase activity. Elastase is a potent mediator for the degradation of cartilage. Chondroitin 4-sulfate is far more effective for glucosamine synthesis by chondrocytes.³⁹ Thus 4-sulfate appears to be critical for synthesis of cartilage matrix.

In young rabbits, the synthesis of 4-sulfate exceeds that of 6-sulfate, but this reverses with age.⁴⁰ Indeed, other studies strongly suggest that different ratios of chondroitin 4-sulfate and 6-sulfate in joint fluid reflect the degree of joint health. When 6-sulfate increases too much, proteoglycan metabolism of joint tissues declines. This is particularly true of articular cartilage. This knowledge could be used to diagnose joint diseases and predict joint cartilage destruction from such joint diseases, and also to design a superior nutrient supplement.⁴¹ As humans age, the mix of 4- and 6-sulfates in human cartilage shifts almost entirely to 6-sulfate.⁴² With DHEA, we seek to maintain youthful levels and ratios to other hormones; we should also seek to do the same with chondroitins.

It is unquestionable that the results of recent studies are superior when these studies used "youthful" mixtures of 4- and 6-sulfates. It is possible to say that ratio should favor chondroitin 4-sulfate over chondroitin 6-sulfate by about 1.45 (or approximately 3 parts of chondroitin 4-sulfate to 2 parts of chondroitin 6-sulfate). Sixty percent should be 4-sulfate and 40% should be 6-sulfate.

Unlike other forms of glucosamine, acetylglucosamine appears to be converted to glucosamine in vivo on an as-needed basis and those levels may be increased and maintained. 

Unfortunately, commercially-available products containing chondroitin are comprised of either chondroitin 4-sulfate or chondroitin 6-sulfate, not a mixture. And existing mixtures are non-rational combinations for human physiology. Now, intelligent, rational, and scientific mixtures are available.

Acetylglucosamine's Superiority
Glucosamine and its derivatives, such as glucosamine sulfate and N-acetyl D-glucosamine (a.k.a. acetylglucosamine), have been shown to be effective in restoring proper joint function.⁴³ Yet it is unfortunate that both of the most widely used versions of glucosamine, the sulfate form and the HCL form, have relatively short half-lives in the bloodstream, meaning they don't stay in the bloodstream very long. Longer and continuous bloodstream presence ensures continuous utilization and better protection. When ten healthy subjects were given 1 gram/day of acetylglucosamine for three days, followed by a four-day abstinence (a washout period), the results showed a prolonged half-life. Levels of acetylglucosamine were still strong, even two full days (48 hours) after ingestion had ended. Acetylglucosamine levels were still above baseline.

Unlike other forms of glucosamine, acetylglucosamine appears to be converted to glucosamine in vivo on an as-needed basis and those levels may be increased and maintained. Acetylglucosamine has other unique benefits and like chondroitin can inhibit the release of the leukocyte-elastase enzyme, thus reducing cartilage degradation.⁴⁴ Hyaluronic acid, an all-important component of synovial fluid, is readily formed from acetylglucosamine.⁴⁵ Acetylglucosamine is the best choice as a glucosamine source.

How to Take Acetylglucosamine and Chondroitin 4,6 Sulfate
In keeping with most of the major studies done on glucosamine, and proportioned for the essential amount of glucosamine contained in acetylglucosamine (there is 50% less glucosamine in acetylglucosamine than in glucosamine sulfate), oral ingestion of up to 3,000 mg/day is warranted. Mixed chondroitin sulfates (60% 4-sulfate and 40% 6-sulfate) are probably best taken at the same amounts used in most recent studies: 1,200 mg/day. These nutrients should be taken together, in divided amounts, three times and preferably four times per day, for optimal joint-function improvement.

Together - A Real Celebration
Unlike the palliative promises of Celebrex, the nutritional road of using N-acetyl D-glucosamine together with a youthful mixture of chondroitin 4- or 6-sulfate is a real cause for celebration. And that is - the ability to recover the freedom of motion you probably thought you'd never again enjoy.

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