Osteoarthritis (OA) is one of the most common diseases affecting individuals worldwide and is a leading cause of disability.1 The economic burden of managing and treating OA is significant and continues to rise.2 To date, there is no cure. Many factors, such as genetics, nutritional status, obesity, and joint injuries related to youth sports and recreational activities, can play a role in the development of OA.3 The end result is a population that is living longer with progressive degenerative changes to the joints. In an analysis drawing data from the 2010 to 2012 National Health Interview Survey, Hootman et al4 reported that 52.5 million adults in the United States (22.7% of all adults) had physician-diagnosed arthritis and 22.7 million (9.8%) had limitation of activity attributable to arthritis. The prevalence of self-reported, physician-diagnosed arthritis is projected to increase from the 47.8 million reported in 2005 to nearly 67 million by 2030 (25% of the adult population). By 2030, it is projected that 25 million adults (9.3% of the adult population) will report arthritis-attributable activity limitations. By 2030, more than 50% of arthritis cases will be among adults older than 65 years. However, a younger demographic of working-age adults (45 to 64 years old) will account for almost one-third of cases.5 Osteoarthritis is being diagnosed in younger age groups in part because of sports-related injuries6 and also as a sequela of the ever-increasing obesity epidemic.7,8
Current OA therapies include pharmaceutical and over-the-counter medications for the management of pain, stiffness, and joint inflammation, as well as weight loss and exercise. Additional treatment possibilities include the use of steroid injections, viscosupplementation, and bracing. Ultimately, when conservative measures fail to provide significant relief, total joint replacement surgery is an excellent option with predictably good results. Many of these therapies, however, are not without risk. Intentional and accidental acetaminophen overdose is one of the most common drug-related toxicities reported and is the leading cause of acute liver failure in the United States and the United Kingdom.9 Nonsteroidal anti-inflammatory drugs are among the most prescribed and used analgesics/anti-inflammatories worldwide.10 Gastrointestinal hemorrhage,11 hepatic damage,12 renal damage, renal failure,13,14 blood pressure destabilization,15,16 and an increased risk of catastrophic cardiovascular events17–19 are potential adverse events associated with various members of this class of pharmaceuticals. Studies have shown that the elderly are at a greater risk for adverse events with all analgesics because of physiological changes associated with age and drug–drug interactions associated with the polypharmacy of the management of multiple conditions.20,21 Nonsteroidal anti-inflammatory drugs and aspirin are contraindicated with most anticoagulation medications, and even acetaminophen can be problematic in patients receiving anticoagulant therapy with warfarin.22,23 Total joint replacement surgery is highly successful for relieving pain and improving function among individuals with OA, but it is not without significant risk.24 This is by no means a condemnation of these therapies, as I find all of them to be of great benefit to patients in my orthopedic practice. Although providing patient comfort and improving both function and mobility are of paramount importance, risk vs benefit should always be weighed and discussed with patients when determining the need for these therapies.25
Concerns over these risks are driving many patients to seek complementary and alternative medical approaches to manage the pain and discomfort of OA. This is also true of relatively younger patients who are rightfully looking for ways to try to postpone or altogether avoid joint replacement surgery. According to industry analysts, “Bone and joint health” dietary supplements were predicted to grow globally to a $9 billion industry in 2017.26 However, it is also an industry populated by both well-researched supplements and those of questionable quality, purity, and scientific support.27–31 Without condescension, physicians should encourage their patients to discuss what supplements they are using or thinking of using. This approach encourages open communication so that patients are alerted to any potential supplement–drug interactions or side effects that could arise. The best advice to offer patients who wish to use a dietary supplement is to recommend that they choose a brand used in published, peer-reviewed clinical trials.32,33
The 2 most researched and widely used joint health supplements are glucosamine and chondroitin sulfate. They have been studied extensively in many countries around the world, alone and in combination, through in vitro, in vivo, and human clinical trials with and without industry support. A large body of literature reporting on in vitro, in vivo, and human clinical trials of these compounds, individually or in combination, exists. This review focuses on only the randomized, controlled, human clinical trials published from 2006 to December 2016. PubMed, with search criteria including the keywords glucosamine, chondroitin sulfate, OA, cartilage, and inflammation, was used to identify these studies.
The most widely cited study of glucosamine and chondroitin sulfate is the National Institutes of Health–sponsored, multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT), published in 2006. The GAIT was designed as a placebo-controlled trial to assess the efficacy of the dietary supplements glucosamine and chondroitin sulfate, both alone and in combination, for the management of knee OA pain. Celecoxib served as a positive control arm for the study. Participants were randomly assigned to receive either 500 mg of glucosamine hydrochloride 3 times daily, 400 mg of chondroitin sulfate 3 times daily, the 2 in combination 3 times daily, an identical placebo capsule 3 times daily, or 200 mg of celecoxib disguised in a capsule once daily and an identical placebo capsule twice daily to satisfy the 3 times per day regimen. The GAIT was plagued by an exceptionally large overall placebo response rate that greatly dampened a meaningful interpretation of the data.34,35 One important finding, however, was in the predefined subset of patients (n=354) with moderate-to-severe OA knee pain who had a statistically significant response in the cohort receiving the glucosamine hydrochloride/chondroitin sulfate combination treatment compared with placebo (79.2% vs 54.3%, respectively; P=.002).35
Because the findings of the GAIT were inconclusive as a result of the small moderate-to-severe OA pain cohort, additional research with a larger population providing sufficient statistical power was deemed necessary. To further investigate these findings, the randomized, double-blind, Multicentre Osteoarthritis interVEntion trial with SYSADOA (MOVES) was conducted by Hochberg et al.36 This was a 6-month, phase IV, noninferiority study of the combination of 500 mg of glucosamine hydrochloride and 400 mg of sodium chondroitin sulfate (CS b-Bioactive; Bioiberica SA, Barcelona, Spain) taken 3 times daily vs 200 mg of celecoxib (Celebrex; Pfizer Inc, New York, New York) taken once daily along with 2 identical placebos matching the dosing regimen of glucosamine/chondroitin sulfate. The 606 patients enrolled matched the inclusion criteria of the moderate-to-severe pain subset of the GAIT: Kellgren–Lawrence grades 2 to 3 OA and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score of 301 or greater on a scale of 0 to 500. As with the GAIT, the primary outcome was the mean decrease in WOMAC pain score from baseline to 6 months. Secondary outcomes included WOMAC function and stiffness scores, visual analog scale (VAS) score for pain, presence of joint swelling/effusion, rescue medication consumption, and Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT–OARSI) criteria. This study also included the EuroQol-5D, a 2-page self-evaluation consisting of 5 state-of-health and ability to perform activities of daily living questions and a VAS to record the respondent's overall feeling of health at that moment. Being a noninferiority study and for ethical reasons, a placebo arm was not incorporated into the study. Because the inclusion/exclusion criteria and measurement tools were the same as those used for the moderate-to-severe subset in the placebo-controlled GAIT, MOVES was considered an extension and expansion of the previous study by the investigators.
The MOVES showed comparable efficacy of glucosamine hydrochloride/chondroitin sulfate and celecoxib at 6 months in all of the measured criteria. At the completion of the 6-month patient participation, the WOMAC pain score showed a 50.1% decrease in the glucosamine hydrochloride/chondroitin sulfate cohort and a 50.2% decrease in those receiving celecoxib (Figure 1). The WOMAC stiffness scores decreased by 46.9% and 49.2%, the WOMAC function scores decreased by 45.5% and 46.4%, and the VAS scores decreased by 48.0% and 48.8%, respectively. By OMERACT–OARSI criteria measured at 6 months, both treatment groups achieved a 79% response rate. Additionally, a greater than 50% reduction from baseline was observed for joint effusion and joint swelling in both groups. Similar improvements were also noted for both treatment groups as measured by the EuroQol-5D. Apart from the first month of study participation, during which, as would be expected, the use of rescue medication (acetaminophen) was higher in the glucosamine hydrochloride/chondroitin sulfate group, the consumption of rescue medication was low and similar between the 2 groups. In this study, patients with cardiovascular or gastrointestinal risk factors were appropriately excluded because of concerns over potential complications related to longer-term nonsteroidal anti-inflammatory drug use. Glucosamine and chondroitin sulfate have been shown to be safe for long-term use.37 These results are in agreement with and confirm the data analysis of the moderate-to-severe OA knee pain subset of the GAIT. Statistical P values cannot be directly compared between the 2 studies because in placebo-controlled studies, the null hypothesis seeks P≤.05; for noninferiority studies, P becomes greater as the equivalence of the 2 interventions is approached.
At 6 months, the Multicentre Osteoarthritis interVEntion trial with SYSADOA showed comparable efficacy of the chondroitin sulfate/glucosamine hydrochloride combination (CS+GH) and celecoxib (CE). The P values at 30, 60, and 120 days compare pain with baseline. The P value at 180 days compares efficacy of CS+GH with that of CE. Abbreviations: CI, confidence interval; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index. [Reproduced from the Annals of the Rheumatic Diseases, Hochberg MC, Martel-Pelletier J, Monfort J, et al, Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. 75(1), 37–44, 2016, with permission from BMJ Publishing Group Ltd.]
In vitro chondrocyte research with glucosamine and chondroitin sulfate, both individually and in combination, has suggested a potential for modulation of OA progression by decreasing the gene expression of prostaglandin E2, nitric oxide, and metalloproteinase enzymes associated with cartilage matrix destruction and increasing proteoglycan synthesis activity.38–40 Two randomized, double-blinded, placebo-controlled studies have been identified that radiographically evaluated modulation of joint space narrowing by glucosamine, chondroitin sulfate, or the combination over time. The first, by Sawitzke et al41 of the GAIT, enrolled 572 participants who had been randomized to 1 of the 5 arms of the GAIT and continued to receive either glucosamine, chondroitin sulfate, the 2 in combination, placebo, or celecoxib as defined in the original GAIT protocol for 24 months. Measurements of the minimal medial tibiofemoral joint space width were performed at baseline and at 12 and 24 months. As with the initial population of GAIT enrollees, most participants in this phase of the study had mild OA symptoms (Kellgren–Lawrence grade 2). At the end of 24 months, 357 subjects (of whom 66% had both knees qualifying for evaluation) had met the minimum of a baseline and at least 1 radiographic follow-up measurement. No statistically significant measurement difference from the placebo group was found for any of the groups; however, the joint space width loss in the placebo cohort was only 0.166 mm, much less than the 0.2-mm loss that would have been considered clinically meaningful for the 2-year period. As would be expected, joint space width loss was greater and increased with time in the subjects with Kellgren–Lawrence grade 3 compared with Kellgren–Lawrence grade 2 radiographic OA for all groups.41 An additional primary outcome measure of this 24-month study was the number of participants showing a 20% reduction in WOMAC pain scores with secondary outcomes of improvements in WOMAC pain and function scores from baseline and OMERACT–OARSI responses. Although all of the groups, including placebo, showed a clinically detectable symptomatic improvement in the first 24 weeks, the improvements leveled off but persisted for the remainder of the study. None of the interventions, including celecoxib, reached significance compared with placebo at 24 months. The authors of this study cited that this is similar to what has been reported in long-term studies of nonsteroidal anti-inflammatory drugs in general. As with the original 6-month GAIT, low levels of baseline pain for the participants, a continued high placebo response throughout the study that matched those of the interventions, and nearly three-fourths of the participants classified as overweight or obese minimized the ability to measure significant change.42
The second study, conducted and reported by Fransen et al,43 was a 2-year, randomized, double-blinded, placebo-controlled clinical trial of 605 participants with chronic knee pain and medial tibiofemoral joint space width narrowing with at least 2 mm of medial joint space width remaining. Approximately half of the participants had a Kellgren–Lawrence grade of less than 2 in the studied knee. Enrollees were randomly assigned to receive, once daily, either 1500 mg of glucosamine sulfate, 800 mg of chondroitin sulfate, both 1500 mg of glucosamine and 800 mg of chondroitin sulfate, or matching placebo capsules. The primary outcome measures were medial tibiofemoral joint space narrowing at 2 years and a symptomatic 0 to 10 points pain scale change during 12 months. At the 2-year follow-up, 303 sets of knee radiographs from baseline to year 2 were considered valid for evaluation. After accounting for all confounding factors, only those assigned to the glucosamine sulfate–chondroitin sulfate group showed a statistically significant decrease in joint space narrowing compared with placebo (P=.046). For the primary symptomatic outcome, no group showed a significant decrease in maximum knee pain compared with placebo (P=.57); however, because most participants in this study had mild OA symptoms (only 5% had Kellgren–Lawrence grade 3 scores), a significant change in mild pain score measurement was unlikely due to floor effect.43
Considerable debate has persisted over the years as to the superiority of one glucosamine salt form over the other. The National Institutes of Health researchers tasked with selecting the investigational agents for GAIT chose a glucosamine hydrochloride salt. Their reasoning was that because both salt forms dissociate into free glucosamine cations when in solution or taken orally, there is no advantage of one salt over the other when based on equivalent amounts of the glucosamine moiety.44 The sulfate anion, however, can contribute slightly to the extracellular inorganic sulfate pool. More than adequate amounts of inorganic sulfates are normally obtained from food, beverages, drinking water, and biodegradation of sulfur-bearing amino acids such as cysteine and methionine.45 The pharmacokinetics of the 2 glucosamine salts have also been shown to be identical in both animals and humans.46
In this regard, a comparator trial evaluated the clinical response to the glucosamine hydrochloride salt and chondroitin sulfate in combination vs the glucosamine sulfate salt and chondroitin sulfate in combination. In this 16-week, controlled, multicenter clinical trial conducted by Provenza et al,47 more than 900 patients with Kellgren–Lawrence grades 2 to 3 knee OA were recruited. The study compared the efficacy of a pharmaceutical glucosamine sulfate/chondroitin sulfate combination (Artrolive; Aché Laboratórios Farmacêuticos S.A., São Paulo, Brazil) with that of the combination of FCHG49 glucosamine hydrochloride/TRH122 sodium chondroitin sulfate (Cosamin DS; Nutramax Laboratories Consumer Care, Inc, Edgewood, Maryland). Enrollees were randomly assigned to 1 of 3 groups to receive either 1500 mg of glucosamine sulfate/1200 mg of chondroitin sulfate to be taken as capsules in a divided dose 3 times daily, as a sachet once daily, or the 1500 mg of glucosamine hydrochloride/1200 mg of chondroitin sulfate combination in capsules divided 3 times daily. Primary outcome measurements used a change from baseline of patient-reported pain as measured by the VAS and response to change in pain, function, and activities of everyday living on the Lequesne index questionnaire (Figure 2). The 2 formulations were found to be equally effective in providing clinically meaningful analgesia in this comparator study, regardless of the administration protocol followed (P<.001). An overall reduction in pain from baseline levels as measured by the VAS and the use of acetaminophen as rescue medication was also significant and equal in all 3 cohorts (P<.005).47 The results of this trial suggest no significant difference between the formulations of glucosamine hydrochloride and glucosamine sulfate in terms of efficacy.
The open label clinical trial by Provenza et al47 evaluated the efficacy of the combination of glucosamine sulfate plus chondroitin sulfate administered as a single dose once daily (group I), divided 3 times daily (group II), and glucosamine hydrochloride plus chondroitin sulfate divided 3 times daily (group III). Graph showing data from the mean pain intensity visual analog scale (VAS) scores of the 3 groups during the 16-week evaluation (A). Graph showing data from the mean scores of the Lequesne index (B). [Reprinted by permission from Springer Nature, Clinical Rheumatology, Combined glucosamine and chondroitin sulfate, once or three times daily, provides clinically relevant analgesia in knee osteoarthritis. Provenza JR, Shinjo SK, Silva JM, et al, 2015.]
These trials indicate that glucosamine/chondroitin sulfate is more efficacious for chondroprotection when initiated early in the course of OA despite a lack of significant pain. The most measurable reduction of OA knee pain can be seen in patients with moderate-to-severe knee OA (Kellgren–Lawrence grades 2 to 3).
The most recent study, by Roman-Blas et al,48 incorporating a placebo arm was a small, 6-month, randomized, placebo-controlled, double-blind clinical trial of a combination of pharmaceutical-quality crystalline glucosamine sulfate and chondroitin sulfate. This trial recruited 164 participants with Kellgren–Lawrence grades 2 to 3 radiographic OA and moderate-to-severe knee pain (using a self-reported VAS score of 40 to 80 mm on a 100-mm scale) prior to actual enrollment. Participants were randomized to receive either a sachet containing 1500 mg of glucosamine sulfate and 1200 mg of chondroitin sulfate or a matching placebo once daily. The primary outcome measure in this study was the mean change from baseline for the VAS measuring global pain. The secondary outcome measures included WOMAC pain and function subscale scores, OMERACT–OARSI response criteria, and rescue medication use. The 2 groups showed similar improvements in scores and rescue medication use, having no significant differences. Although this study indicated the importance of a placebo arm in the interpretation of results, it also pointed out the limitations to the use of subjective measurement tools when a significant placebo effect is combined with rescue analgesic use. It is conceivable that the use of even a mild analgesic such as acetaminophen can add to the level of placebo response, as the study participants are knowingly taking a drug active against pain and thus narrowing the difference in measurable response between intervention and placebo groups.48
Mechanism of Action
Several in vitro studies have confirmed that inhibition of the nuclear factor-kappa B signaling pathway is an important, if not the major, mechanism of action of glucosamine and chondroitin sulfate.49–52 Modulation of gene expression of cytokines and chemokines involved with inflammatory processes, as in synovitis, can decrease the expression of the metalloproteinase and aggrecanase enzymes involved with cartilage matrix destruction.53,54 Nuclear factor-kappa B is composed of a family of transcription proteins located in the cytoplasm, bound to and kept inactive by the inhibitor protein IkB. These transcription factors, when activated by proinflammatory cytokines, lipopolysaccharides, and other agents, translocate into the nucleus. There they increase the expression of genes influencing a wide range of biological processes, such as innate and adaptive immunity, inflammation, injury, and a multitude of stress responses affecting homeostasis.55
To investigate the effects of glucosamine and chondroitin sulfate on biomarkers of inflammation in a controlled setting, Navarro et al56 conducted a randomized, placebo-controlled, double-blind crossover trial using 1500 mg of FCHG49 glucosamine hydrochloride and 1200 mg of TRH122 sodium chondroitin sulfate daily or placebo for 28 days followed by a 28-day washout period before the crossover. After 27 respondents had been screened, 18 healthy, overweight, nonsmoking, 20- to 55-year-old men and women (9 of each) were accepted into the study. Because body mass index is a strong predictor of certain inflammatory markers, subjects were selected from applicants with a body mass index of greater than 25 to no more than 32.5 kg/m2. The primary outcome measurements examined were changes in serum and urine biomarkers of inflammation. Secondary outcome measurements evaluated changes in plasma proteomic patterns by means of pathway analysis using a customized microarray. On biomarker analysis, serum high-sensitivity C-reactive protein, a biomarker for systemic inflammation, was shown to have significantly decreased (by 23%) after the glucosamine hydrochloride/chondroitin sulfate intervention compared with placebo (P=.048). Although all but one of the other serum and urine biomarkers of inflammation and oxidative stress slightly decreased, no significant changes were found. The secondary outcomes using the plasma proteomic analyses indicated that cytokine activity and other inflammation-related pathways were significantly decreased, which supports the findings of other glucosamine and chondroitin sulfate in vitro and in vivo research.57,58 Inflammatory cytokines such as interleukin-6, interleukin-1ß, and tumor necrosis factor-α stimulate the production of C-reactive protein by hepatocytes.59 Therefore, modulation of these and other cytokines can impact C-reactive protein levels as well. On studying otherwise healthy women with mild OA or no OA, Spector et al60 reported that C-reactive protein levels were modestly, but significantly, increased in those with early OA and that higher C-reactive protein levels were predictive of OA progression during the following 4 years.
With the publication of the GAIT in 2006, more questions were raised than answered, creating a need for further research. The clinical, proteomic, and in vitro studies discussed in this article have added significantly to the body of evidence supporting the use of high-quality glucosamine and chondroitin sulfate for the management of OA. This should encourage clinicians to keep an open mind regarding the benefits these compounds can provide for their patients. Uncontrolled studies that cannot account for the quality of the supplements being taken or participant compliance, and using only subjective measurements, add nothing more than what can be considered as anecdotal information; therefore, they were not included in this review. Choosing a high-quality supplement brand can be a challenge. Supplements do not need to meet label claims in the United States, resulting in potential suboptimal supplements in terms of quantity, quality, and purity of ingredients being sold to consumers. Also, additional additives that are not listed on the label may be included in the product. Additives can result in unwanted side effects or even potential drug interactions. Unlisted additives might even include a banned substance, which would be an issue for athletes. Choosing products that have been independently tested by third-party organizations such as NSF International, Consumer Labs, and US Pharmacopeia can help ensure higher quality and purity of ingredients and that there are no unlisted additives. The seal of NSF International and/or US Pharmacopeia can be found on the label of products meeting their rigorous standards. Also, patients and physicians should research which supplement brands have been used in well-designed clinical trials with positive outcomes. The expanding discovery of biomarkers, allowing researchers to objectively identify and measure changes in inflammation and OA progression, is providing new and important tools for clinical investigators. These new tools should be used to correlate important data with the validated subjective measurement tools currently used in clinical studies to provide information that is not confounded by placebo response or rescue analgesic use. Although OA pain reduction is paramount to the patient and should be a primary endpoint of a clinical study, so should the measurement of the modulation of mediators associated with OA progression and structural change for long-term patient benefit.
Osteoarthritis remains a major challenge. There is no cure, and treatment options are relatively limited and focused on symptom relief rather than on modifying or altering the course of disease. Osteoarthritis is the leading cause of disability in the United States. Its incidence is increasing, including among younger individuals. The direct and indirect costs are high, as is the cost of managing the complications of treatment. I believe that the body of scientific evidence, especially in conjunction with the newer studies presented and summarized in this article, warrants consideration of glucosamine and chondroitin sulfate for the management of OA. I am surprised that newer joint supplement research is rarely covered in orthopedic publications and news. I am hopeful that the American Academy of Orthopaedic Surgeons will take into consideration these well-designed studies when upgrading its treatment guidelines for the management of OA.61
In terms of my practice, I continue to routinely recommend glucosamine and chondroitin sulfate, along with exercise, activity modification, and weight loss (when indicated), as a first-line intervention for individuals with OA. I suggest a high-quality brand. I ask patients to allow, at a minimum, a 2-month trial, as the onset of the clinical response can be slow. I also use the same supplement combination when patients undergo any cartilage regeneration knee surgery, such as micro-fracture or autologous chondrocyte transplantation.
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