Glucosamine and Chondroitin Sulfate

Arthritis affects millions of people worldwide and about 1 in 3 adults living in the US today.  Traditionally, this disease has been regarded as incurable and the pain and disability associated with it as inevitable.  Today, however, a growing body of evidence exists in support of the use of specific supplements to reduce the pain and progression of this disease.  Glucosamine and chondroitin are two products that have been increasingly studied as therapeutic agents in the treatment of arthritis. 

            Historically, glucosamine was first used in Europe in the 1960s in its injectable form for the treatment of osteoarthritis.  Since then, studies in both Europe and the US have substantiated its benefits in the treatment of OA, and more specifically, have identified several possible mechanisms of action.  In clinical studies, glucosamine has been shown to stimulate proteoglycan synthesis, incorporate into the glycosaminoglycan chains of cartilage and decrease the activity of degradative enzymes.  As opposed to traditional NSAIDs, glucosamine and chondroitin have been shown to safely delay the progression of osteoarthritis both structurally and symptomatically over the short and long term.  Randomized clinical trials have shown radiographic evidence of reduction of knee joint space narrowing over three years in patients treated with glucosamine vs. placebo.

            To understand the role of glucosamine and chondroitin in osteoarthritis, it is first necessary to understand better how our joints work.  Our joints provide us with mobility over short distances much as a car provides us with mobility over longer distances.  To keep our vehicles performing efficiently, we bring them in for periodic tune-ups and repairs.  Similarly, our joints have their own internal, self-regulated mechanism of repair.  Joints repair themselves differently than other body parts.  Take skin and muscles, for instance.  When injured, skin tears, starts to bleed and ultimately forms a clot, followed by a scar.  When a muscle tears, it heals by fiber hypertrophy (enlargement) and regrowth.  If joints, however, were to form scars or hypertrophy, our range of motion and shock absorption of impact would be reduced.  We would not be able to move as easily or smoothly as we usually do.  Imagine, instead, the joints of the Tin Man, limited, crude and creaky. 

            The cartilage lining our joints has evolved without a vascular supply to avoid scar formation following injury.  Instead, when a joint is injured, a fragment of cartilage tears or breaks off.  The torn fragments of cartilage are degraded into smaller components and washed away from the joint.  The problem in osteoarthritis arises with faulty regulation of this degradation process.  When the cells that make cartilage (chondrocytes) sense injury to the joint, they begin to produce enzymes that can break down cartilage.  The chondrocytes know when to start but not when to stop.  They also have difficulty distinguishing between healthy and injured cartilage and end up gradually breaking down perfectly healthy cartilage.  In addition to uncontrolled breakdown, the chondrocytes are also building new cartilage, however, this new cartilage is different from the original.  It is weaker, less organized and more brittle.  As a result, it is more likely to be injured. This process underlies the cartilage breakdown that characterizes OA.  Destruction occurs faster than repair and the new, repaired cartilage is worse than the original. 

            How does glucosamine affect OA? 

   Glucosamine is made of the two components that form its name – glucose, which is the sugar our bodies burn for fuel, and glutamine, an amino acid building block of protein that helps build bone, cartilage, skin, nails and hair.  Glucosamine helps form proteoglycans, which are water-loving molecules that attract and hold water in healthy cartilage.  Proteoglycans, in turn, are 1 of the 3 essential components needed to build healthy cartilage.  Water and collagen are the other necessary ingredients.  Water brings nutrients to and lubricates the cartilage, as well as acts as a shock absorber to protect joints from the everyday impact of walking, running, jumping, etc.  Its role is crucial given that the cartilage found normally lining the joints is avascular, or without a blood supply.  All of its nourishment and lubrication is derived from the fluid that bathes it.  Collagen, on the other hand, provides the rope-like network around which the proteoglycans wrap themselves, much like ivy does a tree.  Together with the cushions of water, these three components form the woven framework known as cartilage.  When cartilage is damaged following injury to a joint, the network unravels and the proteoglycan threads are washed away.  As a result, cartilage loses its nourishment and lubrication source. 

In addition to glucosamine, another component contributing to the nourishment and lubrication of cartilage is the compound chondroitin.  Chondroitin is a protein made up of negatively charged chains of sugar molecules that attract fluid into the proteoglycan molecules and repel each other.  This fluid helps absorb the impact of movement like a sponge.  Chondroitin also has mild anti-inflammatory properties and has been shown to inhibit the destructive effects of inflammatory compounds including interleukin-1 and TNFalpha on cartilage. 

            In combination with glucosamine, a synergistic effect has been shown whereby new cartilage is stimulated to grow while at the same time is prevented from premature and uncontrolled degradation.  Together, both compounds have also been shown to decrease joint pain and stimulate the production of cartilage building blocks, including proteoglycans, collagen, glycosaminoglycans as well as the substance that makes joint fluid viscous – hyaluronan.

Efficacy in humans:  Recently, here in the US, the GAIT trial, a large, multi-center prospective controlled trial funded by the NIH, has evaluated the effects of glucosamine and chondroitin alone and in combination versus placebo and the NSAID Celebrex over a 2 year period.  The results of this large study revealed that glucosamine alone or chondroitin alone were more effective than placebo in reducing symptoms.  When taken in combination, glucosamine and chondroitin were found to be even more effective than Celebrex when taken for moderate-to-severe osteoarthritis.  In addition, the side effect profile of glucosamine and chondroitin is favorable when compared with that of Celebrex or any NSAID.  Every year, NSAIDs are believed to be responsible for 10,000 to 20,000 deaths and 100,000 to 200,000 hospitalizations in the United States alone.  Furthermore, despite their negative side effect profile, NSAIDs remain the most widely used anti-inflammatory medications for osteoarthritis even though they have also been shown to detrimentally affect disease progression.  Glucosamine and chondroitin, by contrast, are generally well tolerated and have been shown to reduce symptoms similar to NSAIDs and slow disease progression. 

Choosing supplements:  When choosing supplements, it is important to remember that not all supplements advertised as such are equal in quality.  As with any product, it is important to be aware of what one is actually buying.  In the US, glucosamine and chondroitin are available over the counter and are not federally regulated for quality control.  As a result, companies will often advertise poorly manufactured products with deceptive labeling claiming higher quantities of active ingredients than are actually in the bottle.  In Europe, on the other hand, glucosamine is available as a prescription drug and the composition most often used in the research literature is crystalloid glucosamine sulfate 1500 mg taken orally daily. 

Duration of usage:  When taking glucosamine and chondroitin supplements, there is often a question of how long is necessary for the medication to take effect.  Although each individual’s response to therapy varies, on average, one can expect effects anywhere from a few days to about eight weeks.  If improvement in pain and/or function is not seen after 8-12 weeks, the supplements may not be effective for you.

Side effects:  When taking glucosamine and chondroitin, it is also important to consider possible side effects, although rare.  In order of decreasing frequency, the most commonly reported side effects include indigestion, flatulence, high cholesterol levels, constipation, high blood pressure, rash, headache, diarrhea, itching and high blood sugar (though in at least one study patients’ blood sugars actually decreased mildly with glucosamine).  Long term side effects of glucosamine and chondroitin have not been adequately studied beyond 3 years, though the medication has been used for decades in Europe.  Also, it is important to keep in mind possible drug interactions with other medications when taking glucosamine and chondroitin supplements.  Fortunately, to date, no drug interactions have been reported.  Furthermore, glucosamine, chondroitin sulfate and the similar sounding “sulfa” drugs, such as Bactrim, have no reported cross reactions.  The sulfur contained in glucosamine and chondroitin sulfate is elemental and is otherwise found in every cell in the body as a required nutrient.  Most of our food contains sulfur as well. 

Special considerations:  While millions of people have used glucosamine and chondroitin supplements safely and effectively, it is worthwhile to consider conditions that would warrant caution while taking these supplements, such as shellfish allergy and diabetes.  People who are allergic to shellfish react to a protein in the meat portion of fish.  Most glucosamine products, however, are made from the shells of different fish, including crab, lobster and shrimp, which should lack the meat portion.  It is always possible that meat particles are retained, missed or not adequately removed, especially in lower quality products.  For this reason, it would be prudent for individuals with shellfish allergies to avoid glucosamine unless otherwise advised by a doctor or to consider vegetarian alternatives to glucosamine that are not derived from shellfish.  There has been some concern regarding glucosamine raising blood sugar levels, although this claim has not been substantiated.  It is important to be informed so that you have a full discussion with your physician about all the possible pros and cons of any new supplement before you start taking it.

Author: Ana Bracilovic, M.D., New York-Presbyterian Hospital, The University Hospital of Columbia and Cornell, New York, NY