Continuing Education Activity

Glucosamine sulfate is an oral supplement used in the management and treatment of osteoarthritis. This activity outlines the indications, hypothesized action, and contraindications for glucosamine sulfate as a valuable agent in managing osteoarthritis. This activity will highlight the hypothesized mechanism of action, adverse event profile, suggested dosing, monitoring for relevant interactions, and other key elements of glucosamine sulfate supplementation in the clinical setting pertinent for members of an interprofessional team managing the care of patients with osteoarthritis.

Objectives:

• Review the treatment considerations for osteoarthritic patients requesting to add glucosamine sulfate supplements to their treatment strategy.
• Describe the management considerations for patients taking glucosamine sulfate supplements.
• Summarize the risks associated with initiating glucosamine sulfate supplementation and related key patient counseling points.
• Explain the importance of collaboration and communication amongst the interprofessional team to ensure the appropriate screening of patients requesting glucosamine sulfate supplements as a part of their osteoarthritis management to improve patient outcomes by identifying contraindications and thus decreasing adverse events.

Indications

There is currently no FDA-approved indication for glucosamine sulfate, despite its popularity as a supplement in the treatment of osteoarthritis.

Osteoarthritis (OA), a common degenerative joint disease affecting 240 million worldwide, is a progressive condition most frequently affecting the larger weight-bearing joints of the body.[1] Despite the prevalence of this debilitating disorder, there persists a lack of OA-targeted pharmacotherapeutics. Available options largely focus on decreasing OA-associated pain, with NSAIDs and other analgesics being the most commonly used.[2] Supplements theorized to support joint health, such as glucosamine sulfate formulations, have maintained popularity as adjunct therapies in osteoarthritis management.[3] Literature to date has not proven glucosamine sulfate supplements to slow disease progression or effectively decrease OA-associated pain, with randomized control studies showing conflicting results.[4][5]

Although in vitro studies have demonstrated that glucosamine formulations significantly downregulate and upregulate catabolic and anabolic processes, respectively, human clinical trials completed to date have been unable to demonstrate these effects in vivo effectively. Although various studies have attempted to evaluate the effectiveness of glucosamine sulfate as a therapeutic agent in the treatment of OA, the majority of these have been of poor quality and/or at high risk of sponsorship bias. Most studies showing symptomatic improvement secondary to glucosamine sulfate treatment were generally of lower quality and small sample size, making it difficult to draw conclusions. The remaining, larger studies hold a high probability of bias, as the majority appears to have been sponsored by corporations manufacturing these formulations. Moreover, the heterogeneity between studies examining the capacity of oral glucosamine sulfate as an OA therapy is prohibitive of pooling data and validating conclusions. The verdict regarding the use of the supplement as an adjunct osteoarthritis therapy remains unclear.[6] 

As a result, there are no current guidelines on its use for osteoarthritis for the majority of joints due to lack of definitive evidence except for the knee; The American Academy of Orthopaedic Surgeons (AAOS) recommends against the use of glucosamine sulfate as a treatment for knee arthritis specifically following AHRQ report presents a high-quality systematic review of level I evidence covering the best available evidence and does not support the prescribing of glucosamine and/or chondroitin symptomatic OA of the knee.[7]

Other possible indications for glucosamine sulfate include temporomandibular joint disorder and rheumatoid arthritis. However, similar to osteoarthritis, there is no evidence to date supporting the effectiveness of glucosamine sulfate as an agent for symptomatic relief or as a modifier of disease progression.[8]

Mechanism of Action

Researchers have not identified the mechanisms of action for glucosamine sulfate in vivo, despite being the focus of various studies. However, what does seem certain is that glucosamine sulfate shows notable bioavailability following oral administration and decreased clearance compared to alternative formulations of glucosamine supplements such as glucosamine hydrochloride.[9] In light of this known bioavailability, the theorized therapeutic benefits of orally administered, exogenous glucosamine sulfate supplements are based on the hypothesized functions of endogenous glucosamine. Glucosamine is a naturally occurring amino sugar that serves as a fundamental building block of glycosaminoglycans, one of the structural components found in cartilage and other connective tissues. Glycosaminoglycans are key contributors to cartilaginous properties, such as elasticity, strength, and flexibility.[10][11]

The theorized mechanism of action of glucosamine, and thus, glucosamine sulfate, is largely based on in vitro studies analyzing its interaction with cell types found in the joint space. The proposed mechanism of action of glucosamine sulfate is thus two-fold. First, the theory is that glucosamine sulfate stimulates the synthesis of glycosaminoglycans and augments type II collagen expression in chondrocytes. Secondly, it is believed that glucosamine sulfate prevents glycosaminoglycan and collagen degradation by down-regulating the production of inflammatory cytokines via decreased prostaglandin E2 synthesis, inhibition of nuclear factor kappa B (NFkB), and decreased expression of catabolic enzymes such as metalloproteinases (MPs).[11][12]

The mechanism of action of glucosamine sulfate is often discussed in reference to the derangements in joint pathophysiology seen in osteoarthritis. Osteoarthritis characteristically manifests an imbalance between the synthesis of structural proteins of articular cartilage such as proteoglycans and collagen and their degradation by matrix metalloproteinases (MMPs).  In patients affected by this disease, chondrocytes can become activated to release pro-inflammatory cytokines due to environmental stress.[13] Due to these postulated effects on cartilage turnover processes, the hypothesis is that glucosamine sulfate may serve a role in managing osteoarthritis. 

Administration

Glucosamine sulfate may be taken in tablet or capsule form. Due to a lack of FDA approval, there is no validated effective dose.  However, glucosamine sulfate is typically taken as a 500 mg dose three times a day for those taking it as a desired osteoarthritis intervention.[14]

Adverse Effects

Glucosamine has no serious adverse effects, but possible complications include [14]:

• Epigastric pain
• Heartburn
• Diarrhea
• Nausea

There have been no proven drug interactions. There was previously a theory that glucosamine sulfate might interfere with the effectiveness of diabetes medications; however, research has since refuted this concept.[10]

There was also a report of one case study that glucosamine sulfate appeared to exert some effect on the efficacy of warfarin when taken in combination; however, further studies are needed to validate this finding.

Contraindications

The American Academy of Family Physicians lists patients with shellfish allergy, diagnosis of asthma, or use of diabetes medications or warfarin as “C” evidence contraindications (supported by consensus, disease-oriented evidence, usual practice, expert opinion, or case series). Although not prohibitive to glucosamine sulfate use, patients with one or more of these criteria should be monitored cautiously for potential adverse effects.[14][15][16]

Monitoring

Prescribers should initially start patients on a closely monitored 60-day trial to ensure tolerability and screen for adverse side effects. For pharmacologically treated diabetic patients wishing to start glucosamine sulfate supplementation, the Arthritis Foundation recommends an increase in the frequency of blood glucose monitoring due to the theoretical risk of hyperglycemia.[14]

Toxicity

Through various studies, Glucosamine sulfate has consistently been concluded to be a relatively safe oral supplement. A few isolated case studies have reported on the incidence of hepatotoxicity following >3 weeks of glucosamine sulfate use. However, all patients cited had severe preexisting liver disease, with one of the eight patients mentioned developing hepatic failure.[17]

Enhancing Healthcare Team Outcomes

The evidence available on the effectiveness of glucosamine sulfate as a beneficial therapy in the management of osteoarthritis is, to date, inconclusive. Interestingly, studies have shown that patients are not deterred from supplement use when presented with data concluding lack of efficacy, with the only evidence of significant toxicity showing to be capable of causing changes in supplement consumption. Physicians should be mindful of this when discussing the benefits and risks of various treatment modalities with OA patients, particularly those of no validated benefit. The physician must personalize the risk and benefits of taking glucosamine sulfate to each patient. Typically, a 60-day trial of glucosamine sulfate will determine if there are beneficial effects, after which it should be discontinued if the patient has not observed any beneficial effect by that time.

As patients search online for alternatives to medication, clinicians must stay educated on various supplements a patient may seek out for their condition. Communication between all interprofessional healthcare team members, including pharmacists, is crucial in these situations. A pharmacist will know how different drugs and supplements could interact with a patient's current medications. Through collaborative effort and open communication between clinicians, nurses, and pharmacists, patients can integrate glucosamine supplements into their OA treatment regimen more safely and avoid adverse effects. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Nelson AE. Osteoarthritis year in review 2017: clinical. Osteoarthritis Cartilage. 2018 Mar;26(3):319-325. [PMC free article: PMC5835411] [PubMed: 29229563]

2.

Smith SR, Deshpande BR, Collins JE, Katz JN, Losina E. Comparative pain reduction of oral non-steroidal anti-inflammatory drugs and opioids for knee osteoarthritis: systematic analytic review. Osteoarthritis Cartilage. 2016 Jun;24(6):962-72. [PMC free article: PMC4996269] [PubMed: 26844640]

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Henroitin Y, Reginster JY. In-vitro differences among nonsteroidal antiinflammatory drugs in their activities related to osteoarthritis pathophysiology. Osteoarthritis Cartilage. 1999 May;7(3):355-7. [PubMed: 10329331]

4.

Reichenbach S, Sterchi R, Scherer M, Trelle S, Bürgi E, Bürgi U, Dieppe PA, Jüni P. Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med. 2007 Apr 17;146(8):580-90. [PubMed: 17438317]

5.

Vlad SC, LaValley MP, McAlindon TE, Felson DT. Glucosamine for pain in osteoarthritis: why do trial results differ? Arthritis Rheum. 2007 Jul;56(7):2267-77. [PubMed: 17599746]

6.

Zhu X, Sang L, Wu D, Rong J, Jiang L. Effectiveness and safety of glucosamine and chondroitin for the treatment of osteoarthritis: a meta-analysis of randomized controlled trials. J Orthop Surg Res. 2018 Jul 06;13(1):170. [PMC free article: PMC6035477] [PubMed: 29980200]

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Richmond J, Hunter D, Irrgang J, Jones MH, Levy B, Marx R, Snyder-Mackler L, Watters WC, Haralson RH, Turkelson CM, Wies JL, Boyer KM, Anderson S, St Andre J, Sluka P, McGowan R., American Academy of Orthopaedic Surgeons. Treatment of osteoarthritis of the knee (nonarthroplasty). J Am Acad Orthop Surg. 2009 Sep;17(9):591-600. [PMC free article: PMC3170838] [PubMed: 19726743]

8.

Kantor ED, Lampe JW, Navarro SL, Song X, Milne GL, White E. Associations between glucosamine and chondroitin supplement use and biomarkers of systemic inflammation. J Altern Complement Med. 2014 Jun;20(6):479-85. [PMC free article: PMC4048982] [PubMed: 24738579]

9.

Meulyzer M, Vachon P, Beaudry F, Vinardell T, Richard H, Beauchamp G, Laverty S. Comparison of pharmacokinetics of glucosamine and synovial fluid levels following administration of glucosamine sulphate or glucosamine hydrochloride. Osteoarthritis Cartilage. 2008 Sep;16(9):973-9. [PubMed: 18295513]

10.

Henrotin Y, Mobasheri A, Marty M. Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis? Arthritis Res Ther. 2012 Jan 30;14(1):201. [PMC free article: PMC3392795] [PubMed: 22293240]

11.

Yoshimura M, Sakamoto K, Tsuruta A, Yamamoto T, Ishida K, Yamaguchi H, Nagaoka I. Evaluation of the effect of glucosamine administration on biomarkers for cartilage and bone metabolism in soccer players. Int J Mol Med. 2009 Oct;24(4):487-94. [PubMed: 19724889]

12.

Henrotin Y, Chevalier X, Herrero-Beaumont G, McAlindon T, Mobasheri A, Pavelka K, Schön C, Weinans H, Biesalski H., Participants at the Hohenheim Consensus Conference in August 29th 2011. Physiological effects of oral glucosamine on joint health: current status and consensus on future research priorities. BMC Res Notes. 2013 Mar 26;6:115. [PMC free article: PMC3629992] [PubMed: 23531101]

13.

Goldring MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol. 2011 Sep;23(5):471-8. [PMC free article: PMC3937875] [PubMed: 21788902]

14.

Dahmer S, Schiller RM. Glucosamine. Am Fam Physician. 2008 Aug 15;78(4):471-6. [PubMed: 18756654]

15.

Knudsen JF, Sokol GH. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: case report and review of the literature and MedWatch database. Pharmacotherapy. 2008 Apr;28(4):540-8. [PubMed: 18363538]

16.

Gray HC, Hutcheson PS, Slavin RG. Is glucosamine safe in patients with seafood allergy? J Allergy Clin Immunol. 2004 Aug;114(2):459-60. [PubMed: 15341031]

17.

Cerda C, Bruguera M, Parés A. Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease. World J Gastroenterol. 2013 Aug 28;19(32):5381-4. [PMC free article: PMC3752575] [PubMed: 23983444]

Disclosure: Caroline Williams declares no relevant financial relationships with ineligible companies.

Disclosure: George Ampat declares no relevant financial relationships with ineligible companies.