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. 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. Supplements theorized to support joint health, such as glucosamine sulfate formulations, have maintained popularity as adjunct therapies in osteoarthritis management. 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.
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 overall 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.
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.
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.
Researchers have not identified the mechanisms of action for glucosamine sulfate in vivo, despite being the focus of various studies. What does seem certain, however, is that glucosamine sulfate shows notable bioavailability following oral administration as well as decreased clearance compared to alternative formulations of glucosamine supplements such as glucosamine hydrochloride. 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.
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 as well as 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).
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. Due to these postulated effects on cartilage turnover processes, the hypothesis is that glucosamine sulfate may serve a role in the management of osteoarthritis.
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.
Glucosamine has no serious adverse effects, but possible complications include :
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.
There was also a report of one case study that glucosamine sulfate appeared to have some effect on the efficacy of warfarin when taken in combination, however further studies are needed to validate this finding.
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.
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.
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.
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 its 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 individual 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, a physician must stay educated on various supplements a patient may seek out for his or her condition. Communication between the health-care team and pharmacists is crucial in these situations. A pharmacist will know how different drugs and supplements could interact with a patient's current medications.
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