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Glucosamine Sulfate

Nutrient Name: Glucosamine sulfate.
Synonyms: Glucosamine sulphate;D-glucosamine sulfate potassium salt; GS.
Related Substances: Glucosamine hydrochloride, N-acetyl-D-glucosamine (NAG, N-A-G).

Summary Table
nutrient description

Chemistry

D-Glucosamine (2-amino-2-deoxy-D-glucose) is a chemically defined, small molecule (molecular weight, 179.17 daltons) with a p Kaof 6.91. It is an amino-monosaccharide molecule, formed of glucose and an amine moiety, and one of the basic constituents of the disaccharidic units of articular cartilage glycosaminoglycans (GAGs). The amine is positively charged at physiologic pH and will hold a counter anion, either two chlorides or one sulfate.

See also Nutrient Preparations section.

Physiology and Function

Glucosamine plays a central role in determining the strength and resiliency of connective tissue. An amino sugar biosynthesized from glucose, glucosamine is one of the principal substrates used in the biosynthesis of macromolecules that comprise articular cartilage and thus a key compound within the ground substance that makes up connective tissue. Glucosamine is the preferred substrate for biosynthesis of mucopolysaccharides and bipolymers of the articulations and bones and has been reported to facilitate the hexosamine pathway of proteoglycan synthesis by the chondrocytes. It modulates interleukin-1 (IL-1)–induced activation of chondrocytes for cartilage rebuilding and stimulates production of proteoglycans (including therefore the proteic moiety) with a normal polymeric structure while simultaneously inhibiting proteoglycan degradation. Glucosamine also stimulates synthesis of GAGs and collagen, as well as synovial production of hyaluronic acid, which is critical to the lubricating and shock-absorbing properties of synovial fluid. Glucosamine sulfate (GS), in particular, can increase serum sulfate concentrations and thereby elevate synovial fluid sulfate concentrations and enable proteoglycan sulfation. 1 In addition to these nutritive and stimulating functions, GS also inhibits some cartilage-destroying enzymes, such as serine proteases collagenase and phospholipase A2(PLA2), and the generation of cell-damaging superoxide radicals. Thus, GS exerts a mild anti-inflammatory effect by a mechanism of action other than the inhibition of the biosynthesis of prostaglandins, most likely inhibition of proinflammatory effects of the nuclear factor kappa B (NF-κB) pathway.

nutrient in clinical practice

Known or Potential Therapeutic Uses

Glucosamine (sulfate) is primarily used to relieve symptoms, stop disease progression, and stimulate joint cartilage growth in the treatment of osteoarthritis (OA). In this role, GS acts as chondroprotective agent by stopping the pathogenic mechanism of OA, relieving its symptoms, and reducing its progression. Surveys show that it is one of the most widely used nutraceuticals in self-medication practices, especially among the elderly population. 2 Most, 3-12but not all, 13 published studies, have shown positive effects on both joint pain and joint structure (e.g., joint space narrowing) in patients with OA, particularly of the knee, compared with nonsteroidal anti-inflammatory drugs (NSAIDs) or placebo. In addition to its beneficial activities on cartilage and chondrocytes, glucosamine has generally demonstrated mild anti-inflammatory properties and a favorable pharmacokinetic profile. Until recently, long-term studies on the effectiveness of GS have been lacking.

Historical/Ethnomedicine Precedent

No historical precedents have been reported.

Possible Uses

Cartilage injuries, gonarthritis, kidney stones, low back pain, minor injuries, osteoarthritis (OA), sprains and strains, temporomandibular joint (TMJ) dysfunction pain and joint noises, wound healing.

Deficiency Symptoms

There are no reports of a glucosamine deficiency, per se, in humans. The issue of sulfate deficiencies may deserve further attention.

Dietary Sources

Tempeh, a fermented soy product, is a food source of glucosamine. 14 However, significant amounts of glucosamine are not a normal constituent of most diets.

Nutrient Preparations Available

Commercially available glucosamine products are available in three forms. Glucosamine sulfate (GS) is the primary form used in clinical settings. However, many products labeled as “glucosamine” contain glucosamine hydrochloride. N-acetyl-D-glucosamine (NAG) is a related substance found in joints and connective tissue.

Glucosamine sulfate is the preferred form because of its very high absorption, ease of utilization, immediacy of incorporation into connective tissue matrix, and history of clinical studies. Sulfur is an essential nutrient for joint tissue, where it functions in the stabilization of the connective tissue matrix of cartilage, tendons, and ligaments. In particular, sulfation is an active metabolic process in cartilage, and the sulfate moiety seems to be essential to sulfation, an active metabolic process in cartilage. The sulfate moiety also seems to be essential to synovial fluid delivery to articular cartilage as well as improving efficacy of the synovial fluid by strengthening cartilage and aiding GAG synthesis. 3,15Further, even though it is often used in clinical trials, evidence supporting efficacy of the hydrochloride (HCl) salt of glucosamine is weak and unclear, and its use is rarely recommended by experienced clinicians. 16

Chitin is a polymer ofD-glucosamine with randomly assignedD-glucosamine monomers having a chemically bonded “acetyl” group, giving rise to NAG units. After extraction from the exoskeletons of shrimp and other shellfish, chitin can be chemically modified with hydrochloric acid digestion and deacetylation to yield quite pureD-glucosamine HCl monomers. Combining glucosamine HCl with sulfuric acid yields glucosamine sulfate. Glucosamine sulfate is produced through a co-crystallization step with sodium chloride (NaCl), resulting in a GS-NaCl complex. Alternatively, potassium chloride (KCl) can be used as the co-crystallization agent. Although most clinical trials have focused on the NaCl-stabilized form, the form using KCl as a stabilizer may be preferable for most individuals, given general dietary tendencies toward excess sodium and inadequate potassium intake. However, this issue has not yet been studied in controlled trials. In either form, these mineral salts stabilize GS by decreasing oxidation and moisture absorption.

In contrast, glucosamine HCl is typically granulated to reduce moisture absorption from the air. Salts are usually not necessary for its crystallization, but polyvinylpyrrolidone and corn syrup are often used as binders for granule formation. 17

Regarding the N-acetyl form of glucosamine, researchers have concluded that “glucosamine is a more efficient precursor of macromolecular hexosamine (glycosaminoglycans) than N-acetylglucosamine. It is possible that N-acetylglucosamine does not penetrate the cell membranes and, as a result, is not available for incorporation into glycoproteins and mucopolysaccharides.” 18 Further, clinical trials using NAG in the treatment of osteoarthritis are lacking.

Dosage Forms Available

Capsule, tablet, liquid, powder.

Source Materials for Nutrient Preparations

Supplemental glucosamine is usually derived from the processed exoskeletons of shellfish, such as shrimp, lobster, and crab. Glucosamine may also be synthesized. A novel source of the HCl form is fermented corn-derived glucose, although this may not be a preferred form.

Dosage Range

Adult

Dietary: Not appreciable.

Supplemental/Maintenance: Generally not considered as recommended on a preventive basis, but glucosamine is widely used by individuals with a history of or susceptibility to joint pain or injury.

Pharmacological/Therapeutic: 500 to 2000 mg daily, most often 500 mg three times daily (of GS) orally. Obese individuals may need to increase dosages by 20 mg/kg body weight daily. 19 Anecdotally, many clinicians experienced in treating pain and injuries with nutritional therapies report that doses at two to three times typical levels (i.e., 3000-4500 mg/day) for 3 to 5 days decreases pain and accelerates tissue repair immediately after injury.

Toxic: Glucosamine sulfate is generally considered nontoxic.

Pediatric (<18 Years)

Dietary: Not appreciable.

Supplemental/Maintenance: Not applicable.

Pharmacological/Therapeutic: Ehler-Danlos syndrome, Marfan syndrome.

Toxic: Glucosamine sulfate is generally considered nontoxic.

safety profile

Overview

In the majority of studies, oral GS at standard dosage levels appears to be safe, nontoxic, and well tolerated, with only minor, transient, and reversible adverse effects. Several studies have reported an incidence of adverse effects no greater than among subject receiving placebo. 4,10,20,21A meta-analysis by the Cochrane Collaboration reported only 16 adverse events requiring withdrawal from investigation, of 1000 patients treated for OA with glucosamine in 16 clinical trials. 22 Injectable and parenteral forms have also generally demonstrated an excellent safety profile. Allergic reactions appear to be rare and when suspected may derive from the shellfish used as source material for most preparations. 23

Nutrient Adverse Effects

General Adverse Effects

Rarely mild and transient gastrointestinal (GI) effects, including flatulence, abdominal bloating, indigestion, heartburn, nausea, and diarrhea. These symptoms are often reduced by taking GS with a meal.

Adverse Effects among Specific Populations

One study noted that the onset of possible adverse effects was significantly related to preexisting GI disorders and related treatments and to concomitant diuretic treatment. 20

One unqualified case report of impaired kidney function in a 79-year-old woman with myasthenia gravis, also undergoing corticosteroid and immunosuppressive therapy, resolved with discontinuation of glucosamine. 24

Pregnancy and Nursing

Although evidence or reports of adverse events associated with glucosamine administration during pregnancy or breastfeeding are lacking, no clinical studies have demonstrated safety in such populations.

Infants and Children

Evidence or reports of adverse events associated with glucosamine intake are lacking, but glucosamine administration is generally inappropriate for most children and should be avoided in those under 2 years of age.

Contraindications

None documented, with the exception of possible (and probably rare) allergic reactivity to shellfish.

Precautions and Warnings

Some individuals with preexisting peptic ulcers or other GI conditions may have increased susceptibility to adverse effects.

interactions review

Strategic Considerations

In general, comprehensive formal drug interaction studies involving glucosamine compounds are lacking. At this time, potential or suspected interactions involving diuretics or oral hypoglycemic agents appear to be discredited, clinically insignificant, or exceptional. A review of the scientific literature indicates that NSAIDs are the drug class most likely to manifest a clinically significant pattern of interaction with GS, and different agents within that class may theoretically produce different outcomes. Although evidence indicates that acetaminophen may obstruct the therapeutic activity of glucosamine, research is warranted to investigate opportunities for possible synergy or additive therapeutic benefit from coadministration with certain NSAIDs, such as ibuprofen.

Over the years, evidence supporting the clinical effectiveness of GS in the treatment of OA has increased in number, depth, and quality. Nevertheless, published clinical guidelines for integrative therapeutics involving glucosamine in the treatment of OA remain nascent and out of step with the clinical practices that have matured based on anecdotes, outcomes, and collective experience. At this point, the position of glucosamine as a potential first-line agent for repair of damaged or degenerating joint cartilage is reaching consensus level, at minimum for patients with knee OA who have mild to moderate pain. Ongoing and future studies of structure-modifying anti-OA drugs such as GS and chondroitin sulfate (CS) present the opportunity for further confirming the efficacy of these agents and clarifying appropriate therapeutic protocols customized to meet the needs of individuals and their variable life stages, personal history, genetic predispositions, diagnoses, and prognoses.

More fundamentally, the challenge of integrative medical care for OA will be to investigate, analyze, and synthesize the therapeutic strengths and opportunities presented by the range of treatment modalities. The therapeutic approach to integrative care of OA cannot rely solely on natural substances such as glucosamine alone or, for that matter, on any exclusively pharmacological approach. Other nutritional and botanical approaches, such as S-adenosylmethionine (SAMe), vitamin E, vitamin B3(niacinamide), bromelain, green-lipped mussel (Perna canaliculus), methylsulfonylmethane (MSM), cetyl myristoleate (CMO), topical capsaicin, turmeric (Curcuma longa), ginger (Zingiber officinale), devil's claw (Harpagophytum procumbens), boswellia (Boswellia serrata), and cat's claw (Uncaria tomentosa), are beginning to be studied in well-designed clinical trials, as are interventions such as aerobic exercise, quadriceps exercises, and footwear modification. Although the role of NSAIDs continues to undergo reformation in light of its limitations and adverse effects, new cyclooxygenase-2 (COX-2) inhibitors may have a role in situational symptom management in patients for whom simple analgesia is inadequate. Intra-articular hyaluronate injections may also have a limited role. Furthermore, the patient population appears receptive to medical and lifestyle interventions, such as weight reduction, yoga, tai qi, massage, acupuncture, and manipulative therapies, which are often beyond the realm of the average physician's training and experience, but which may be able to play an important role in restoring mobility and enhancing vitality within the context of an integrative therapeutic strategy.

Gottlieb 25 calls for a fundamental reevaluation of the medical view of OA and presents a perspective that remains challenging in its comprehensive approach in his 1997 review article, “Conservative management of spinal osteoarthritis with glucosamine sulfate and chiropractic treatment”: The rationales for using NSAIDs in the treatment of osteoarthritis is controversial and openly contested. Given the detrimental effects of NSAIDs on joints and other organs, their use should be discouraged and their classification as a first choice conservative treatment should be abolished. A truly effective and conservative approach to the treatment of osteoarthritis should include chiropractic manipulation [or other forms of joint mobilization and manipulation], essential nutrient supplementation, exogenous administration of glucosamine sulfate and rehabilitative stretches and exercises to maintain joint function. Because there is no correlation between pain levels and the extent of degeneration detected by radiographic or physical examination, conservative treatment should be initiated and sustained based on functional, objective findings and not strictly on how the patient feels. The use of NSAIDs should be limited to the treatment of gross inflammation and analgesics should only be used in the short-term when absolutely necessary for pain palliation. The present conservative approach could lead not only to a better quality of life but also to the saving of health care dollars by reducing the iatrogenic morbidity and mortality associated with NSAID use.

Thus, emerging approaches to treatment of OA may be prime ground for exploring the broad value, in terms of quality of life and meaningful outcomes standards, for multidisciplinary collaboration and integrative therapeutics.

nutrient-drug interactions
Acetaminophen, Ibuprofen, and Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Diuretics
nutrient-drug interactions
Oral Hypoglycemic Agents and Insulin
Buformin (Andromaco Gliporal, Buformina), chlorpropamide (Diabinese), glimepiride (Amaryl), glipizide (Glucotrol; Glucotrol XL), glyburide (glibenclamide; Diabeta, Glynase, Glynase Prestab, Micronase, Pres Tab), insulin (animal-source insulin: Iletin, human analog insulin: Humanlog; human insulin: Humulin, Novolin, NovoRapid, Oralin), metformin (Dianben, Glucophage, Glucophage XR); combination drugs: glipizide and metformin (Metaglip), glyburide and metformin (Glucovance); tolazamide (Tolinase), phenformin (Debeone, Fenformin), tolbutamide (Orinase, Tol-Tab).
Potential or Theoretical Adverse Interaction of Uncertain Severity

Probability: 5. Improbable
Evidence Base: Emerging

Effect and Mechanism of Action

It has been hypothesized that because of the chemical similarity between glucosamine-6-phosphate and glucose-6-phosphate, glucosamine could activate the hexosamine pathway and induce inhibition of liver glucokinase and thereby cause clinically significant changes in glucose metabolism and potentially contribute to the development of insulin resistance. 36-45 If proven in humans, such effects might theoretically mean that glucosamine administration could decrease the effectiveness of insulin or other oral hypoglycemic agents used in the management of diabetes mellitus.

Research

Several preliminary animal studies suggested that glucosamine, often administered in relatively high dosage levels by continuous intravenous (IV) infusion, could accelerate the hexosamine pathway and lead to peripheral insulin resistance and decreased insulin secretion. Giaccari et al. 38 found that high-dose glucosamine infusions significantly (40%-50%) impaired glucose-induced insulin secretion (both first and second phases), greatly reduced muscle glucose 6-phosphate concentration and reduced insulin stimulation of both glycolysis and glycogen synthesis in rats. Rossetti et al. 37 found that in vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic rats. Barzilai et al. 39 observed that glucosamine induced inhibition of liver glucokinase, which in turn impaired the ability of hyperglycemia to suppress endogenous glucose production. Virkamaki et al. 40 reported that activation of the hexosamine pathway by glucosamine in vivo induced insulin resistance and increased risk of glucose toxicity in skeletal muscle and other insulin-sensitive tissues. Collectively, these and other findings from animal studies suggested that exogenous glucosamine might alter glucose metabolism to such an extent as to aggravate insulin resistance and potentially adversely interact with insulin and other medications prescribed for glucose control. However, the speculative nature of these findings was generally acknowledged, especially in light of dosage levels, based on weight, that were beyond the range of normal therapeutic dosages and usually significantly higher than might ever be obtained in humans through oral administration. 46,47

Human trials that have examined the effects of glucosamine intake, in various forms, on glucose metabolism have generally found evidence lacking of adverse effects on glycemic control. Noack et al. 5 found that glucose metabolism is not impaired by short-term GS intake, 500 mg three times daily, in a general population of 252 patients being treated for knee OA. In this multicenter, randomized, placebo-controlled, double-blind, parallel-group study, fasting plasma glucose levels were not modified over a 4-week treatment with GS or placebo, 5 nor were they modified in the small subset of subjects the authors thought could be defined as diabetic, “in whom mean plasma glucose concentrations fell both in the nine patients on glucosamine and the 14 given placebo.” 46 In a large, 3-year, placebo-controlled OA study, researchers observed only a tendency for fasting blood glucose to decrease with glucosamine, compared with subjects receiving placebo for whom it remained stable. Although there were few diabetic patients in this long-term study, those with high baseline glucose concentrations, when analyzed separately, showed a tendency for similar results, with a fall in plasma glucose among those taking glucosamine. 48 In related research, Pouwels et al. 49 determined that short-term glucosamine infusion does not affect insulin sensitivity in healthy human subjects ( n=18); thus, their findings did not support involvement of the hexosamine pathway in the regulation of insulin sensitivity in humans. In a focused and definitive study, the first placebo-controlled, double-blind trial of its kind, Scroggie et al. 47 evaluated the effects of glucosamine hydrochloride (1500 mg/day), together with chondroitin sulfate (1200 mg/day), versus placebo, for 90 days on glycemic control in a group of 34 mostly elderly patients with type 2 diabetes. They reported that mean hemoglobin A 1c levels, a marker for long-term blood-glucose control, remained relatively stable in the glucosamine group and decreased in the placebo group. In a double-blind clinical trial involving 19 healthy adults, Tannis et al. 50 administered 1500 mg GS or placebo daily for 12 weeks to test for glucosamine-induced glucose intolerance. Three-hour oral glucose tolerance tests were performed before the start of administration, at 6 weeks, and at the completion of administration. These researchers found no significant differences between fasted levels of serum insulin or blood glucose. They observed that GS treatment did not alter serum insulin or plasma glucose during the glucose tolerance tests, and that glycosylated hemoglobin (HbA 1c ) measurements at the three time points showed no significant change over time, within or between treatments, ages, or gender. Collectively, these human trials provide significant evidence that oral glucosamine, at recommended dosage levels, does not result in clinically significant alterations in glucose metabolism in patients with type 2 diabetes mellitus and is unlikely to interact adversely with insulin or other oral hypoglycemic agents.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Given its favorable risk/benefit ratio, especially compared with NSAIDs, GS therapy offers an attractive option to both patients and physicians in the treatment of appropriate conditions. Thus, Scroggie et al. 47 concluded: “Since patients with diabetes are at risk for toxic effects from some of the current treatments for osteoarthritis (NSAIDs in particular), glucosamine may provide a safe alternative treatment for these patients.” Nevertheless, introduction of new medications or significant alterations in existing prescriptions can disrupt glycemic control in patients being treated for type 2 diabetes. Thus far, the weight and direction of evidence indicates that GS, or related forms, does not pose a significant risk of disrupting clinical management of such patients. Even so, it would be judicious to monitor short-term and long-term markers of blood glucose control closely in such patients whenever there are significant changes in treatment of glucose-related or other conditions.

nutrient-nutrient interactions
Bromelain

Glucosamine sulfate and bromelain are often used together in clinical practice for the treatment of joint pain and inflammation of traumatic or degenerative origin. The mechanism and efficacy of any additive or synergistic interaction remain to be investigated in well-designed clinical trials. However, the rationale of supportive activity appears reasonable, especially in light of bromelain's more immediate anti-inflammatory effects complementing glucosamine's relatively gradual, long-term, and primarily nutritive action.

Chondroitin Sulfate
Manganese
Methylsulfonylmethane
Oligomeric Proanthocyanidins
Omega-3 Fatty Acids, Especially Fish Oils, Eicosapentaenoic Acid, and Docosahexanoic Acid
Vitamin C
Citations and Reference Literature
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  • 3.Lopes Vaz A. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthrosis of the knee in out-patients. Curr Med Res Opin 1982;8:145-149.View Abstract
  • 4.Muller-Fassbender H, Bach GL, Haase W et al. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage 1994;2:61-69.View Abstract
  • 5.Noack W, Fischer M, Forster KK et al. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage 1994;2:51-59.View Abstract
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  • 36.Balkan B, Dunning BE. Glucosamine inhibits glucokinase in vitro and produces a glucose-specific impairment of in vivo insulin secretion in rats. Diabetes 1994;43:1173-1179.View Abstract
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  • 39.Barzilai N, Hawkins M, Angelov I et al. Glucosamine-induced inhibition of liver glucokinase impairs the ability of hyperglycemia to suppress endogenous glucose production. Diabetes 1996;45:1329-1335.View Abstract
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  • 47.Scroggie DA, Albright A, Harris MD. The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med 2003;163:1587-1590.View Abstract
  • 48.Reginster JY et al. Glucosamine sulfate significantly reduces progression of knee osteoarthritis over 3 years: a large, randomized, double-blind placebo-controlled prospective trial. American College of Rheumatology, Association of Rheumatology Health Professionals, 1999 Annual Scientific Meeting. Boston; 1999.
  • 49.Pouwels MJ, Jacobs JR, Span PN et al. Short-term glucosamine infusion does not affect insulin sensitivity in humans. J Clin Endocrinol Metab 2001;86:2099-2103.
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  • 53.Leffler CT, Philippi AF, Leffler SG et al. Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study. Mil Med 1999;164:85-91.View Abstract
  • 54.Lippiello L, Woodward J, Karpman R, Hammad TA. In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Clin Orthop 2000:229-240.View Abstract
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