Glucosamine and chondroitin sulfate, components of normal cartilage that are marketed as dietary supplements in the United States, have been evaluated for their potential role in the treatment of osteoarthritis. Due to claims of efficacy, increased prevalence of osteoarthritis, and a lack of other effective therapies, there has been substantial interest in using these dietary supplements as therapeutic agents for osteoarthritis. Though pharmacokinetic and bioavailability data are limited, use of these supplements has been evaluated for management of osteoarthritis symptoms and modification of disease progression. Relevant clinical trial efficacy and safety data are reviewed and summarized.
Glucosamine is a hexosamine sugar that is naturally produced in humans. It is an important precursor in the biosynthesis of many connective tissue macromolecules such as hyaluronic acid, proteoglycans, glycosaminoglycans (GAGs), glycolipids, and glycoproteins. Chondroitin sulfate is a prominent GAG found in articular cartilage. Its hydrophilic properties enable the articular cartilage to absorb relatively large quantities of water thereby conveying and absorbing compressive forces on the cartilage. Glucosamine and chondroitin sulfate have gained popularity in recent years as potential therapeutic agents for osteoarthritis (OA), as a major manifestation of this disease is failure of articular hyaline cartilage.
OA is a chronic, progressive, degenerative, articular disease that is particularly common in weight-bearing joints. OA is the most prominent form of arthritis; its prevalence increases dramatically with age. OA can lead to significant pain, reduced range of motion, and increasing debility. As a result, it is considered a leading cause of disability in the United States and has become a central public health concern. OA affects approximately 20 million Americans, and the prevalence is predicted to double in the next 20 years. There is more to the pathogenesis of OA than normal aging; factors including genetics, sex, age, obesity, joint trauma, and muscle strength play a part in disease pathogenesis. Other mechanical aspects, such as joint instability and repetitive microtrauma, have also been implicated in perpetuating the disease process. Medical therapy, including weight management and physical therapy, has primarily been directed toward the treatment of joint pain related to OA. Analgesics (acetaminophen, paracetamol) and nonsteroidal anti-inflammatory drugs (NSAIDs) are mainstream agents used in the treatment of OA-related pain. However, simple analgesics may be less effective than NSAIDs in short-term pain control. Additionally, some studies have indicated that efficacy of NSAIDs for pain relief, including cyclo-oxygenase-2 inhibitors, is modest and can be associated with an increased risk of adverse events when used long-term.
Because available medical treatments for OA are modestly effective, at best, and most are directed at short-term pain control, the development of interventions that could relieve pain and potentially modify structural damage is very appealing. Substantial interest in glucosamine and chondroitin sulfate (often framed in lay literature as “cartilage precursors”) abounds regarding the potential efficacy of glucosamine and chondroitin sulfate alone or in combination. Both of these agents are sold in the United States as dietary supplements and, therefore, are not required to meet the same safety and efficacy thresholds as drugs before they are approved to be marketed. Studies demonstrating efficacy of either agent alone or in combination have been of variable quality and have yielded inconsistent results. This article summarizes the current literature on these agents and their utility in the treatment of OA.
Preparations, bioavailability, and pharmacokinetics of glucosamine
Glucosamine is commercially available in a number of preparations. Some glucosamine preparations are extracted commercially by the acid hydrolysis of chitin derived from crustacean shells and, thus, patients with shellfish allergies should be advised to avoid the use of glucosamine manufactured in this manner. Because glucosamine is a weak organic base, it must be stabilized as a salt. The two most common and commercially available forms of oral glucosamine are in the form of glucosamine hydrochloride (HCl) and cocrystals or coprecipitates of glucosamine sulfate with potassium or sodium chloride.
Glucosamine HCl ( Fig. 1 A) is a very stable salt form of glucosamine that is available as a pure, oral preparation with a long shelf life. Hydrochloride salts are frequently used in combination with weak organic bases due to their favorable stability and solubility characteristics. Because of these characteristics, glucosamine HCl has been readily available for many years. The sulfate salt of glucosamine (see Fig. 1 B) is extremely hygroscopic and readily deteriorates in ambient conditions making it impractical for oral ingestion. Over the years, methods to stabilize glucosamine hydrochloride as a cocrystal or coprecititate with either sodium chloride or potassium chloride were developed and patented that yielded a cocrystallized matrix of sodium chloride with glucosamine sulfate (see Fig. 1 C). This product is suitable for oral dosing, and has subsequently been used in many commercially-sponsored OA trials.
Absolute daily dosing of glucosamine varies between and within various preparations due to the molecular size of the associated salt. Although no dosing studies have been conducted, recommended dosages of the final salt product generally range from 1250 mg to 1500 mg daily.
There are several studies that address the absorption, distribution, and metabolism of glucosamine. Glucosamine HCl given orally at clinically significant doses was shown to be bioavailable in both serum and synovium of horses and beagles. Synovial concentrations of glucosamine remained elevated up to 12 hours, whereas serum levels were once again undetectable after 6 hours in the equine study. Uptake of radiolabeled glucosamine sulfate by articular cartilage after oral dosing was shown in both rats and dogs. These investigators also studied oral dosing in human volunteers. Though absorption of radiolabeled oral glucosamine sulfate was 90%, there was a significant first-pass effect in the liver resulting in 44% bioavailability. It is important to note that the specific methods for glucosamine detection in plasma were not sufficiently sensitive for monitoring its concentration in the unchanged form after oral dosing. A more recent study using liquid chromatography with mass spectrometry detection has been able to determine plasma concentrations more precisely, and has yielded an estimated half-life of 15 hours for oral-dose crystalline glucosamine sulfate. This same study showed that glucosamine sulfate pharmacokinetics were linear up to the standard dosing of 1500 mg once daily, and higher doses did not result in a proportionally higher increase in glucosamine maximum concentration. Further animal studies have helped in determining an estimated bioavailability of 25%. Interestingly, a recent human pharmacokinetic study revealed that combined dosing of glucosamine HCl with sodium chondroitin sulfate statistically significantly reduced circulating plasma levels of glucosamine compared with levels seen with glucosamine HCl dosed alone.
Preparations, bioavailability, and pharmacokinetics of chondroitin sulfate
Chondroitin 4-sulfate and chondroitin 6-sulfate are GAGs found in hyaline cartilage and differing structurally by the position of the monosaccharide that is sulfated ( Fig. 2 ). They are very large, complex molecules. The position of chondroitin sulfation is of unclear significance but may be associated with aging tissue. Older, more superficial cartilage, contains higher proportions of chondroitin 6-sulfate, whereas newer, deeper cartilage, contains more chondroitin 4-sulfate. In one study, ratios of chondroitin 6-sulfate to chondroitin 4-sulfate in cartilage affected by OA were substantially lower, but the clinical significance of this finding remains unclear.
Sodium chondroitin sulfate is available in a number of oral preparations produced by multiple manufacturers. It is typically harvested from bovine and porcine tracheal cartilage, or occasionally from fish or avian cartilage. It is sold in the United States as a dietary supplement and does not require a prescription for purchase. The production process is not as strictly regulated as drugs, and differences in potency and quality are variable. Although no formal dose finding studies have been conducted, commonly recommended dosages are between 800 and 1200 mg daily.
The oral bioavailability and pharmacokinetics of bovine-derived chondroitin sulfate were studied in healthy male volunteers by Volpi. Plasma levels of chondroitin were monitored at regular intervals from baseline to 48 hours after oral administration of 4 g. Levels of chondroitin sulfate peaked at 2 hours and were increased by 200% at 2 to 4 hours. In a second study by the same investigator, shark-derived chondroitin sulfate was administered instead, and similar peak plasma levels were documented at 8.7 hours. These observed discrepancies were attributed to the differences in molecular weights and charge densities of the two chondroitin sulfate molecules. Based on these studies and an additional study, oral bioavailability of chondroitin sulfate is estimated at 5% to 15% with an elimination half-life of 6 hours and a range of peak plasma levels from 2 to 28 hours after administration. A recent publication on the human pharmacokinetics of clinically relevant doses of glucosamine HCl and sodium chondroitin sulfate could not detect a difference above circulating endogenous plasma levels of chondroitin sulfate after a single 1200 mg oral dose at all time periods from 0.25 to 36 hours.
Preparations, bioavailability, and pharmacokinetics of chondroitin sulfate
Chondroitin 4-sulfate and chondroitin 6-sulfate are GAGs found in hyaline cartilage and differing structurally by the position of the monosaccharide that is sulfated ( Fig. 2 ). They are very large, complex molecules. The position of chondroitin sulfation is of unclear significance but may be associated with aging tissue. Older, more superficial cartilage, contains higher proportions of chondroitin 6-sulfate, whereas newer, deeper cartilage, contains more chondroitin 4-sulfate. In one study, ratios of chondroitin 6-sulfate to chondroitin 4-sulfate in cartilage affected by OA were substantially lower, but the clinical significance of this finding remains unclear.
Sodium chondroitin sulfate is available in a number of oral preparations produced by multiple manufacturers. It is typically harvested from bovine and porcine tracheal cartilage, or occasionally from fish or avian cartilage. It is sold in the United States as a dietary supplement and does not require a prescription for purchase. The production process is not as strictly regulated as drugs, and differences in potency and quality are variable. Although no formal dose finding studies have been conducted, commonly recommended dosages are between 800 and 1200 mg daily.
The oral bioavailability and pharmacokinetics of bovine-derived chondroitin sulfate were studied in healthy male volunteers by Volpi. Plasma levels of chondroitin were monitored at regular intervals from baseline to 48 hours after oral administration of 4 g. Levels of chondroitin sulfate peaked at 2 hours and were increased by 200% at 2 to 4 hours. In a second study by the same investigator, shark-derived chondroitin sulfate was administered instead, and similar peak plasma levels were documented at 8.7 hours. These observed discrepancies were attributed to the differences in molecular weights and charge densities of the two chondroitin sulfate molecules. Based on these studies and an additional study, oral bioavailability of chondroitin sulfate is estimated at 5% to 15% with an elimination half-life of 6 hours and a range of peak plasma levels from 2 to 28 hours after administration. A recent publication on the human pharmacokinetics of clinically relevant doses of glucosamine HCl and sodium chondroitin sulfate could not detect a difference above circulating endogenous plasma levels of chondroitin sulfate after a single 1200 mg oral dose at all time periods from 0.25 to 36 hours.
Possible mechanisms of action in osteoarthritis
Although there is conflicting evidence that orally supplemented glucosamine and chondroitin sulfate are bioavailable in the serum and synovial fluid, a defined mechanism of action by which they might alter the joint has not been demonstrated. The majority of in vitro studies addressing the effects of glucosamine on joints have been performed using concentrations of 50 to 5000 μM, which greatly exceeds the observed peak plasma concentration (Cmax) of 10 μM after clinically relevant glucosamine doses of 1500 mg per day in human studies. Therefore, studies evaluating concentrations of glucosamine that are physiologically pertinent to the in vivo action of the drug are important for providing insight into possible mechanisms of action on joint tissues. One study evaluated incubated human chondrocytes affected by OA with glucosamine sulfate at concentrations ranging from 0.2 to 200 μM. A significant increase in aggrecan core protein levels and its mRNA, as well as a reduction in matrix metalloproteinase-3, was noted at concentrations of glucosamine above 10 μM. Another study looked at the effects of glucosamine HCl on equine chondrocytes and synoviocytes. At concentrations of about 1 μM, glucosamine HCl appeared to interfere with interleukin-1 (IL-1) stimulation of prostaglandin E production in both types of cells.
Relevant in vivo studies in rabbits and mice with papain-induced joint injury have shown increased cartilage GAG content after oral glucosamine administration. One rabbit study used an anterior cruciate ligament deficient model of acute OA and daily oral administration of glucosamine HCl. Glucosamine HCl was administered for 8 weeks starting at 3 weeks after surgery and no significant change in cartilage composition was noted, though there did seem to be a mild reduction in GAG loss from the femoral condyles. A follow-up of this study observed that glucosamine HCl seemed to exert inhibitory effects on the bone turnover at the ligament resection site, noting the importance of studying all tissues pertaining to the joint rather than cartilage alone.
The in vitro effects of chondroitin sulfate alone, and in combination with glucosamine, have also been studied. Some studies have shown a reduction in the expression of various proinflammatory enzymes and molecules such as phospholipase A2, cyclooxygenase-2, and prostaglandin E2. One study found that the addition of chondroitin sulfate, in physiologic concentrations, to IL-1β-stimulated chondrocytes inhibited the nuclear translocation of nuclear factor-kappaB (NF-κB). NF-κB is a transcription factor known to play a key role in the initiation of various proinflammatory genes involved in the pathogenesis of OA. Data addressing the in vivo activity of chondroitin sulfate is limited, but a few animal studies using chondroitin sulfate with or without glucosamine have been published. One study gave DBA/1 J mice with a type II collagen-induced arthritis varying dosages of chondroitin sulfate for 9 weeks and found a partial reduction in cartilage destruction, synovitis, and inflammatory cell infiltration. It is important to note that these results were achieved at doses of 1000 mg/kg/d, which is significantly higher than typical doses taken by human subjects. Another study evaluated dogs previously treated with sodium chondroitin sulfate and glucosamine HCl who then underwent chymopapain injection of the radiocarpal joint to induce synovitis. This study indicated that prior treatment with sodium chondroitin sulfate resulted in less synovial inflammation.
In light of the many in vitro studies, and a few in vivo studies, suggesting potential therapeutic effects for oral glucosamine and chondroitin sulfate, several clinical trials have sought to study the effects of these dietary supplements in human patients. Studying the effect of therapeutic interventions in OA has been complicated by many factors, including slow progression of the disease, increased placebo effect in larger trials, use of agents of low therapeutic effect size, and difficulty in developing standardized outcome measures. In recent years, literature regarding the use of glucosamine and chondroitin sulfate alone, and in combination, for the treatment of OA has increased dramatically, yet clinical efficacy still remains controversial.
The surrogate markers for disease progression in clinical OA studies generally involve the assessment of pain and function or structural changes of the joint. The use of joint replacement as an endpoint for OA progression is complicated by the relatively small proportion of patients with OA that require this procedure, compared with the OA population at large. The two most common instruments used for measurement of pain and function in clinical OA trials are the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and the Lequesne index questionnaires that base OA severity on parameters such as pain, stiffness, and functional activity.
Radiologic changes of OA are the most commonly used surrogate markers for disease progression. Most trials evaluating structural progression of OA assess knee joint space width (JSW) with formal measuring techniques. Though changes in JSW do not consistently correlate with symptoms of OA of the knee, some studies have shown a correlation with knee arthroplasty. There are a number of important issues that must be considered when obtaining measurements of JSW radiographically. Differences in positioning and weight-bearing can affect joint space measurements at the knee. For example, the presence of knee pain can alter JSW measurement, by limiting the degree of extension achieved. The protocol published in 1996 by the Osteoarthritis Research Society International (OARSI) for knee imaging recommended weight-bearing anteroposterior (AP) fully extended knee views. However, subsequent studies have shown superior reliability and sensitivity to change with detailed protocols that employ 20 to 30 degrees of knee flexion. Most trials have now incorporated the use of automated systems for JSW measurement from digital images as a way of minimizing error in measurement.
Clinical studies of glucosamine in OA
Symptoms
Some of the earlier clinical trials investigating the treatment of OA with glucosamine used a glucosamine sulfate preparation provided by the patent holder, Rottapharm.
These studies generally demonstrated a positive effect of glucosamine therapy on OA, but were fraught with shortcomings due to small sample size, inadequate allocation concealment, lack of intention-to-treat principles, and the propensity for sponsor bias. Subsequently, Rottapharm sponsored two larger, placebo-controlled studies that demonstrated a benefit of glucosamine sulfate treatment in both the symptoms and the radiographic progression of OA. The first study evaluated 212 patients with knee OA over the 3 years and randomized one group to receive 1500 mg of oral glucosamine sulfate daily versus placebo. Though the primary outcome measure was radiographic progression, this study also looked at pain and function by WOMAC scores as percent change on a visual analog scale (VAS). This study found a statistically significant improvement in pain and function favoring glucosamine by WOMAC, but no improvement in stiffness. The second study evaluated 202 similarly ascertained patients with knee OA using the same doses of glucosamine over 3 years. This study reported a significant change in WOMAC scores for pain, function, and stiffness in the glucosamine treated group. A comprehensive meta-analysis, published in 2005, reviewed the available literature on the efficacy of glucosamine monotherapy in the management of OA pain and function. This review by Towheed and colleagues included nine trials using the Rotta preparation of glucosamine versus eight trials using non-Rotta preparations. Overall improvement in pain was noted with glucosamine versus placebo, and reported to be of clinical significance. However, results for efficacy in function were variable with significant changes reported for Lequesne index, but not for WOMAC total scores or subscores. Subgroup analysis in patients taking the Rotta glucosamine preparation demonstrated significant improvement in WOMAC total scores, but no significant change was reported in function outcomes for non-Rotta preparations. In the late 1990s, the National Institutes of Health (NIH) funded a large, double-blind, placebo- and celecoxib-controlled, multicenter clinical trial to more carefully evaluate the efficacy and safety of glucosamine and chondroitin sulfate alone and in combination in the treatment of OA of the knee. The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) enrolled 1583 patients with symptomatic knee OA and randomized them to receive glucosamine HCl 1500 mg daily, sodium chondroitin sulfate 1200 mg daily, both in combination at the same daily doses, celecoxib 200 mg daily, or placebo for 24 weeks. The primary outcome measure was a 20% decrease in WOMAC Pain at 24 weeks compared with baseline. The results demonstrated that glucosamine was not significantly better than placebo in the overall reduction of knee pain. Glucosamine showed a trend toward significance in the subgroup of patients with moderate to severe knee pain treated with glucosamine, but interpretation of this result was limited by the small number of patients in this subgroup. A GAIT ancillary study recently published 2-year results on 662 patients with knee OA randomized to the same treatments, and found no clinically important improvement in WOMAC pain or function compared with placebo. Although the glucosamine and celecoxib groups showed beneficial trends for pain and function, they did not reach statistical significance.
Structural Modification
The placebo-controlled studies evaluating the long-term effects of glucosamine on structural progression of knee OA are limited; three studies of reasonable quality evaluated glucosamine with a primary outcome of change in JSW. The results of the pain and function secondary outcome measures of two of these studies are reviewed above, and the third study was a GAIT ancillary study published in 2008. The first study evaluated 212 patients with knee OA for radiographic progression. Patients were randomized to receive 1500 mg of glucosamine sulfate daily versus placebo over 3 years. Standing, weight-bearing, AP knee radiographs were obtained sequentially to determine change in medial compartment JSW. The investigators noted progressive cartilage loss in patients receiving placebo and no joint space loss in patients taking glucosamine sulfate. The second study evaluated 202 patients randomized similarly and using the same radiographic techniques as the first study, and also found no joint space loss in the glucosamine group compared with the placebo group. The third study was a 24-month GAIT ancillary study that enrolled 572 patients with radiographic OA of the knees and randomized them to receive glucosamine HCl, sodium chondroitin sulfate, the combination of both, celecoxib, and placebo in the doses described earlier for GAIT. Radiographic data were obtained using the metatarsophalangeal (MTP) radiographic view of the knee joints at 12 and 24 months. No statistically significant difference in mean JSW measured at the medial tibiofemoral joint was observed for any group compared with placebo, though there was a trend toward improvement in patients with milder OA receiving glucosamine. One notable difference between the first two studies and the third study was the use of different imaging techniques. The first two studies obtained their measurements of JSW from AP extended views of the knee, whereas the third study used the semiflexed MTP view described by Buckland-Wright and colleagues. JSWmeasured on extended AP views may measure other structures such as the menisci and collateral ligaments, and not only articular cartilage. Additionally, the presence of joint pain at the time of imaging may alter the ability to achieve full extension, thereby giving the appearance of reduced JSW.
Related posts:
Perspectives About Complementary and Alternative Medicine in Rheumatology
Effectiveness of CAM Therapy: Understanding the Evidence
The Role and Effect of Complementary and Alternative Medicine in Systemic Lupus Erythematosus
The State of Research on Complementary and Alternative Medicine in Pediatric Rheumatology
Fish Oil in Rheumatic Diseases
Herbal Medicine in the Treatment of Rheumatic Diseases
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
