Omnium-Gatherum: Running

As any of the millions of Americans tottering around on ramshackle cartilage and ruptured ligaments can attest, the knee rates as the most unsound joint in the body. Each year, surgeons condemn more than 260,000 dilapidated knee joints and rebuild them, cementing titanium and polyethylene plastic to their skeletal ruins. Despite meaty muscles to brace it, despite a scaffold of ropy ligaments and tendons to buttress it, despite the bony shingle of a kneecap to shelter it, this load-bearing hinge between the two longest columns of bone in the body is prone to injury. Once damaged, the timbers of a leg shiver with the ravages of osteoarthritis.

As I found out last winter, a patch of ice and a stairway can conspire as agents of ruin. While chasing my 5-year-old daughter, I slipped and what had been until that moment my "good knee" twisted out. Two weeks later, the MRI showed a mangled anterior cruciate ligament (ACL). Now I had a matched pair -- the new specimen plus the torn (and never repaired) ACL I owed to a long-ago racquetball injury. The MRI also showed mild osteoarthritis -- also called degenerative joint disease -- in both knees.

As is common in early osteoarthritis, my knees don't hurt. Not yet. But I know what lies ahead. As osteoarthritis progresses, cartilage, which acts as a cushion between the bones of a joint, grinds down. Bone scrapes against bone. That hurts -- a lot. The time for me to act to avoid the pain, debilitation and joint replacement surgery associated with the condition, I figure, is now.

Which is how I came to be standing in the dietary supplement aisle, squinting at the fine print on bottles of glucosamine, one of the building blocks of cartilage.

As a physician, I knew of two European studies that showed that the substance, made into supplement form from the ground-up shells of crabs, shrimp or lobsters, slowed cartilage erosion in the knee -- something no other medicine or supplement had been shown to do. I knew that the evidence wasn't perfect and that more study data would be available in a few years. But time and knee cartilage wait for no one. I wanted to weigh the evidence now.

There were other decisions to make as well. Assuming my research convinced me I might benefit from taking glucosamine, what form should I take: Liquid or tablets? Glucosamine sulfate, glucosamine hydrochloride, N-acetyl glucosamine, or some combination of the above? Should I take a formulation with chondroitin, another building block of cartilage, or without? Also, what was known about glucosamine's long-term safety?

Clearly, there was a lot to consider. Given my scientific background, I thought it would be easy to evaluate the evidence. Little did I know.

A Matter of View

I'm not the only one out there with a more than casual interest in glucosamine. Presumably driven by their effectiveness in relieving arthritis pain, glucosamine and chondroitin products topped $700 million in U.S. retail sales in 2002, according to the Nutrition Business Journal.

Glucosamine supplements owe their popularity in large part to Jason Theodosakis, also known as "Dr. Theo," a preventive and sports medicine specialist in Tucson. His 1997 bestseller "The Arthritis Cure" catapulted glucosamine into the public eye after he and others reported success in using it as part of an integrative treatment program for arthritis pain.

Studies show that both glucosamine and chondroitin, when taken as supplements, stimulate the synthesis of proteoglycans, substances that join into the rubbery matrix that forms cartilage, allowing it to bind water and give joints elasticity. Both glucosamine and chondroitin also work by dampening inflammation in joints. In laboratory studies using human cells that make cartilage, chondroitin inhibits the enzymes that chew away at cartilage as osteoarthritis progresses.

In the body, glucosamine is made in cartilage cells from the amino acid glutamine and glucose. But, theory goes, production may slow with age. Hence, the interest in supplementation.

Many folks are taking glucosamine with their doctors' blessing. While its ability to slow arthritis is debated, its ability to relieve arthritis pain is accepted by the American Academy of Orthopaedic Surgeons. (The AAOS takes no stance on the supplement's value for slowing disease progression, says a spokesman, Nicholas DiNubile.)

My own orthopedic surgeon did nothing to steer me away. As he flexed and palpated my knee, making my roughed-up cartilage creak like the Tin Man after a storm, I asked if he thought my taking glucosamine might help slow down the arthritis. He shrugged, then answered, "It probably can't hurt." He offered no further information.

As I left his office, he said, "You'll be back."

"Probably," I replied, "but hopefully not for another decade or two." My hope sprang from my regular, albeit low-impact, exercising -- part of the standard prescription for keeping joints healthy. Also weighing in my favor, I thought, was my 16-year hiatus from orthopedic surgeons after my first ACL tear, as well as my knowledge about glucosamine.

The two European studies, one published in The Lancet in 2001, the other in the Archives of Internal Medicine in 2002, showed that a three-year regimen of glucosamine relieved pain and increased ease of movement in the knees of osteoarthritis patients. Even more important, X-rays of participants who took glucosamine showed on average no loss of joint space -- a marker of cartilage loss -- objective evidence that osteoarthritis had been halted or slowed. Those on placebo, meanwhile, showed joint space narrowing. This narrowing -- about 0.1 millimeters each year, about equal to the thickness of a sheet of paper -- may sound like a wisp of a loss, but over years changes of this size can cause considerable pain and disability.

Both studies were randomized, double-blind, placebo-controlled trials -- the highest standard of clinical evidence -- involving more than 200 patients.

Despite this, critics in the United States have found soft spots: Both studies were funded by a glucosamine product maker (with an obvious interest in finding positive results), just as pharmaceutical companies fund most clinical trials for drugs. And the study methods are also subject to question.

For accurate X-ray measurements, consistent positioning of the knee is critical from year to year. But the X-ray view chosen for both studies -- that of the standing, fully extended knee -- according to Daniel Clegg, professor of medicine at the University of Utah School of Medicine, "cannot be controlled to assure that the same view is obtained at each data point."

Instead, as pain is relieved by glucosamine, critics say, the knee may be extended more. And the joint space measurements may look better simply on the basis of knee position change rather than cartilage preservation.

But wait, countered the researchers. If the X-ray method was inaccurate, then the joint space narrowing seen in the placebo groups should not have been consistent with the natural rate of narrowing found in population studies. (But consistent they were.)

Plus, noted investigator Lucio Rovati, from Rotta Research Laboratory in Milan, the X-rays of a placebo subgroup, whose members experienced a degree of pain relief comparable to that in the glucosamine group, still showed significantly greater joint space narrowing than those on glucosamine.

Case closed? Not in the world of science.

Even if I sided with the Europeans in this transatlantic food supplement fight, my next step was still unclear. Both studies used a liquid formulation of glucosamine sulfate marketed under a European brand name I couldn't find on local drug shelves. (Only later did I find it for sale on the web.) And among the mind-boggling array of other glucosamine products on the market, which was the best?

Form and Function

Let's start with the question of what form of glucosamine is best.

Several articles from top medical journals recommended the sulfate form -- the form used in the European studies -- because sulfur helps to maintain the structure of cartilage. Yet most of the products I found on drugstore shelves contained glucosamine hydrochloride, which apparently is cheaper to make.

Theodosakis, now an international authority on the treatment of osteoarthritis who serves as a consultant to several supplement and drug companies, told me that the hydrochloride and sulfate forms are identical in their effects. "Dr. Theo" doesn't recommend n-acetyl glucosamine; there's little evidence, he says, that it works.

"The sulfate form has the most research behind it," he said. "However," he added, "this is related to the fact that this form was patented by a company in Europe, and so more research money was available. . . . "

Harry Preuss, professor of physiology at Georgetown University Medical Center and an adviser to the Arthritis Foundation on its annual supplement guide, agreed: "The sulfate and hydrochloride forms are probably comparable, as there is plenty of sulfur in the body."

As for liquid or tablets, both are well absorbed and work equally well, according to the medical literature and several experts I consulted.

And what about chondroitin?

Several studies support chondroitin's effectiveness for relieving arthritis pain. And while X-ray evidence in humans is more preliminary than that for glucosamine, one study in the journal Clinical Rheumatology in 2002 showed less arthritis progression over three years in the finger joints of those taking chondroitin than of those on placebo.

Knees came into the chondroitin picture, too, as of last fall. A European study presented at the annual meeting of the American College of Rheumatology showed less joint space narrowing (and therefore less arthritis progression) in 150 patients on chondroitin compared with 150 on placebo over two years.

While no human trial has definitely shown that the combination of glucosamine and chondroitin helps with pain and mobility more than either supplement alone, animal and laboratory studies of cells that make cartilage indicate that the two work synergistically. Based on the benefits they see in their patients, Theodosakis and others believe in the effectiveness of the combined ingredients.

As for safety, scientists have studied glucosamine and chondroitin for more than 30 years. Sold as prescription medication in some European countries, they have been used to relieve aching joints for more than a decade. Significant side effects haven't been a problem.

In advice applicable to my case, Theodosakis recommends using glucosamine and chondroitin after joint damage, even if pain is not a problem.

"Supplements are especially effective for osteoarthritis that develops after trauma to a joint, as in sports injuries. I liken this to calcium and vitamin D for osteoporosis, which slow bone loss but have no noticeable effect on symptoms." He adds, "I have a career built now on keeping people from surgery, including joint replacement."

As someone who is very attached to her cartilage, I want to believe this.

Eyes on GAIT

In another two years, I should know more about whether my betting instincts were good or not. Results are due in 2006 from the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT), sponsored by the National Institutes of Health and directed by Utah's Clegg. The portion of the trial dealing with arthritis progression involves about 800 participants over a two-year period.

Like the European studies, the GAIT trial is using X-rays to evaluate the effects of glucosamine hydrochloride, chondroitin and a combination of the two. There is one crucial difference: the X-ray view. GAIT will use one of several semi-flexed views of the standing knee, although "nobody knows which one is best," as Rovati says.

AAOS spokesman DiNubile isn't waiting for the outcome to act. As orthopedic consultant to the Philadelphia 76ers basketball team and the Pennsylvania Ballet, DiNubile knows some knees that have come in for hard landings.

"I recommend glucosamine and chondroitin as part of a comprehensive approach against osteoarthritis," he says. "It's just as important or more important that people maintain an ideal weight, participate in low-impact exercise that doesn't stress joints, strengthen muscles through weight training, as well as take vitamin C [he recommends 1,000 milligrams] and a multivitamin to make sure they're getting enough vitamins E, D, and A."

Meanwhile, those persistent Europeans have some preliminary evidence that taking glucosamine each day keeps the orthopedic surgeon away. Last fall, at a meeting of the American College of Rheumatology, European scientists reported that five years after participating in a three-year glucosamine study, almost twice as many (17) from the placebo group as from the treatment group (nine) had undergone joint surgery, primarily total knee replacement. Probably because of the small number of cases involved, results didn't quite reach the statistical significance level, but came in just a scalpel's breadth away.

On further analysis of their data, the European scientists found indications that glucosamine may be most effective in slowing the progression of knee osteoarthritis early, before too much damage has occurred to joints. In a paper published a year ago in the journal Osteoarthritis and Cartilage, they wrote: "Patients with mild to moderate knee osteoarthritis should be treated not only for their symptoms but also to prevent cartilage loss."

All told, the evidence is still less conclusive than the science I would like to have guide my medical decisions.

But here was the kicker, so to speak, for me. This paper came out last January -- the very same month as my last injury.

I am definitely taking this stuff.

Susan Whiteman is a physician in Bethesda.

Click here for Dr. Theodosakis' Glucosamine Chondroitin product recomendations.