Effect of Glucosamine on Intraocular Pressure and Risk of Developing Glaucoma.

PRCIS: Glucosamine supplementation is common but can be associated with increased intraocular pressure (IOP) and could contribute to the pathogenesis of glaucoma. It may be prudent for ophthalmologists to elicit any history of glucosamine use from their patients and advise them accordingly. Further studies on the role of glucosamine in glaucoma are warranted. BACKGROUND: The most frequently recommended slow-acting medication for osteoarthritis symptoms is glucosamine, although its effectiveness is questionable. Widely used glucosamine sulfate supplements may increase IOP. METHODS: In the current study, we analyzed online databases such as UK Biobank, MedWatch, and FinnGen to evaluate the relationship between glucosamine and IOP and glaucoma. We included budesonide and fluticasone in the analysis for comparison since these drugs are associated with increased IOP. RESULTS: In UK Biobank subjects, glucosamine use was associated with increased corneal compensated IOP ( P =0.002, 2-tailed t test). This was also true in subjects without glaucoma ( P =0.002, 2-tailed t test). However, no significant association between glucosamine and IOP was detected in subjects with a diagnosis of glaucoma. In MedWatch, 0.21% of subjects taking glucosamine reported glaucoma, 0.29% of subjects using budesonide reported glaucoma, and 0.22% of subjects using fluticasone reported glaucoma. In contrast, 0.08% of subjects using any other drug reported glaucoma. This variability is significant ( P <0.001, 2-tailed Fisher exact test). Data from FinnGen on the risk of primary open angle glaucoma or glaucoma in subjects using glucosamine before the diagnosis of the disease revealed a significantly increased risk for both primary open angle glaucoma (hazard ratio: 2.35) and glaucoma (hazard ratio: 1.95). CONCLUSION: Glucosamine supplementation is common but can be associated with increased IOP and could contribute to the pathogenesis of glaucoma. It may be prudent for ophthalmologists to elicit any history of glucosamine use from their patients and advise them accordingly. Further studies on the role of glucosamine in glaucoma are warranted.

Pre-clinical investigation of protective effect of nutraceutical D-glucosamine on TNBS-induced colitis.

OBJECTIVE: The level of precursors involved in the biosynthesis of glycosaminoglycan (GAG), glucosamine synthase, and N-acetyl glucosamine (NAG), are significantly reduced in inflammatory bowel disease (IBD). This results in deficient GAG content in mucosa, which eventually disrupt the gut wall integrity, provoking abnormal immunological responses. This is characterized by colossal liberation of inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukins (ILs), and reactive oxygen species (ROS) provoking colonic inflammation. D-glucosamine (D-GLU) is reported to suppress oxidative stress, and pro-inflammatory cytokines and acts as a starting material for biosynthesis of NAG. The potential of D-GLU and its combination with mesalamine (5-ASA) was investigated in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-instigated IBD in Wistar rats. MATERIALS AND METHODS: Standard and test drugs were given orally for 5 d to separate groups of rats. Colonic inflammation was evaluated by disease activity score rate (DASR), colon/body weight ratio, colon length, diameter, colon pH, histological injury, and score. Inflammatory biomarkers IL-1ß, TNF-α, along with reduced glutathione (GSH), and malondialdehyde (MDA) were assessed. RESULTS: Combination of D-GLU + 5-ASA significantly ameliorated severity of colonic inflammation by lowering DASR (p < 0.001) and colon/body weight ratio (p < 0.001), restored the colonic architecture and suppressed the histopathological score (p < 0.001), along with the absence of major adverse reactions. The combination suppressed the levels of inflammatory markers (p < 0.001) and MDA (p < 0.001) while enhancing GSH level (p < 0.001). CONCLUSION: In comparison to individual 5-ASA and D-GLU, combination of drugs significantly diminished colitis severity through their combined anti-inflammatory and antioxidant effects by acting on multiple targets simultaneously. The combination holds remarkable potential in the management of IBD.

Glucosamine Use Is Associated with a Higher Risk of Cardiovascular Diseases in Patients with Osteoarthritis: Results from a Large Study in 685,778 Subjects.

Glucosamine is widely used around the world and as a popular dietary supplement and treatment in patients with osteoarthritis in China; however, the real-world cardiovascular risk of glucosamine in long-term use is still unclear. A retrospective, population-based cohort study was performed, based on the Beijing Medical Claim Data for Employees from 1 January 2010 to 31 December 2017. Patients newly diagnosed with osteoarthritis were selected and divided into glucosamine users and non- glucosamine users. The glucosamine users group was further divided into adherent, partially adherent, and non-adherent groups according to the medication adherence. New-onset cardiovascular diseases (CVD) events, coronary heart diseases (CHD), and stroke, were identified during the observational period. COX proportional regression models were used to estimate the risks. Of the 685,778 patients newly diagnosed with osteoarthritis including 240,419 glucosamine users and 445,359 non-users, the mean age was 56.49 (SD: 14.45) years and 59.35% were females. During a median follow-up of 6.13 years, 64,600 new-onset CVD, 26,530 CHD, and 17,832 stroke events occurred. Glucosamine usage was significantly associated with CVD (HR: 1.10; 95% CI: 1.08−1.11) and CHD (HR: 1.12; 95% CI: 1.09−1.15), but not with stroke (HR: 1.03; 95% CI: 0.99−1.06). The highest CVD risk was shown in the adherent group (HR: 1.68; 95% CI: 1.59−1.78), followed by the partially adherent group (HR: 1.26, 95% CI: 1.22−1.30), and the non-adherent group (HR: 1.03; 95% CI: 1.02−1.05), with a significant dose−response relationship (p-trend < 0.001). In this longitudinal study, adherent usage of glucosamine was significantly associated with a higher risk for cardiovascular diseases in patients with osteoarthritis.

Glucosamine and Chondroitin Supplements and Risk of Colorectal Adenoma and Serrated Polyp.

BACKGROUND: Studies have shown an inverse association between use of glucosamine and chondroitin supplements and colorectal cancer risk. However, the association with the precursor lesion, colorectal adenoma and serrated polyp, has not been examined. METHODS: Analyses include 43,163 persons from the Nurses' Health Study (NHS), Health Professionals Follow-up Study (HPFS), and NHS2 who reported on glucosamine/chondroitin use in 2002 and who subsequently underwent ≥1 lower gastrointestinal endoscopy. By 2012, 5,715 conventional (2,016 high-risk) adenomas were detected, as were 4,954 serrated polyps. Multivariable logistic regression for clustered data was used to calculate OR and 95% confidence intervals (CI). RESULTS: Glucosamine/chondroitin use was inversely associated with high risk and any conventional adenoma in NHS and HPFS: in the pooled multivariable-adjusted model, glucosamine + chondroitin use at baseline was associated with a 26% (OR = 0.74; 95% CI, 0.60-0.90; P heterogeneity = 0.23) and a 10% (OR = 0.90; 95% CI, 0.81-0.99; P heterogeneity = 0.36) lower risk of high-risk adenoma and overall conventional adenoma, respectively. However, no association was observed in NHS2, a study of younger women (high-risk adenoma: OR = 1.09; 95% CI, 0.82-1.45; overall conventional adenoma: OR = 1.00; 95% CI, 0.86-1.17), and effect estimates pooled across all three studies were not significant (high-risk: OR = 0.83; 95% CI, 0.63-1.10; P heterogeneity = 0.03; overall conventional adenoma: OR = 0.93; 95% CI, 0.85-1.02; P heterogeneity = 0.31). No associations were observed for serrated polyps. CONCLUSIONS: Glucosamine/chondroitin use was associated with lower risks of high-risk and overall conventional adenoma in older adults; however, this association did not hold in younger women, or for serrated polyps. IMPACT: Our study suggests that glucosamine and chondroitin may act on early colorectal carcinogenesis in older adults.

Effect of glucosamine on intraocular pressure: a randomized clinical trial.

PurposeThe purpose of the study was to investigate ocular hypertensive effect of exogenous glucosamine in comparison with placebo in patients with osteoarthritis.Patients and methodsIn this double-masked randomized clinical trial, 88 patients with osteoarthritis were included. Forty-four patients were randomized into either glucosamine sulfate or the placebo group.Comprehensive ophthalmologic exam including intraocular pressure (IOP) at baseline, month 1, and 3 was performed. Ocular response analyzer parameters were also checked at baseline and month 3.ResultsThe mean IOP at the time of presentation was 12.4±2.7 mm Hg in glucosamine and 13±2.8 mm Hg in the placebo group (P=0.329). At month 1 the corresponding values were 12.6±2.4 and 12.9±2.4 mm Hg (P=0.868), and at 3 months follow-up were 13.5±2.3 and 13±2.7 mm Hg (P=0.002), respectively. About 34.1% in treatment and 12.5% in the placebo group had clinically significant (defined as ≥ 2 mm Hg) rise in IOP at final follow-up (P=0.023). Mean age in those with significant rise in IOP was 66 vs 57.7 years in patients with <2 mm Hg (P=0.034). The ORA parameters remained unchanged in both the groups during the course of study.ConclusionGlucosamine supplement therapy causes statistically significant rise of IOP, which is more pronounced in elderly patients. Clinical implication of this finding needs further evaluation.

The Effect of Prolonged Glucosamine Usage on HbA1c Levels and New-Onset Diabetes Mellitus in Overweight and Obese Middle-Aged Women.

OBJECTIVE: The aim of the present study was to evaluate the effect of a 2.5-year glucosamine sulfate intervention on hemoglobin A1c (HbA1c) levels and the incidence of new-onset diabetes mellitus over 6.5 years in middle-aged women with a body mass index ≥27 kg/m2. METHODS: In total, 407 women were randomized into either oral crystalline glucosamine sulfate or placebo. At baseline, 1 year, 2.5 years, and 6.5 years, a blood sample for the HbA1c level was drawn and questionnaires were taken. After 6.5 years there were missing data for some variables, therefore, multiple imputation was used. With the imputed data, a generalized estimating equation was performed to analyze the effect of glucosamine sulfate usage over 6.5 years. Finally, these analyses were rerun for the 2 subgroups of participants with and without high HbA1c level (≥42 mmol/mol) at baseline. RESULTS: There was no significant effect of a 2.5-year glucosamine sulfate intervention on mean HbA1c level or on obtaining a high HbA1c level or new-onset diabetes mellitus over 6.5 years. The subgroup analyses of participants with and without high HbA1c level at baseline were also not statistically significant. However, participants with a high HbA1c level at baseline had higher odds ratios compared with the participants with a normal HbA1c at baseline. CONCLUSIONS: There was no effect of glucosamine sulfate on mean HbA1c level nor on obtaining a high HbA1c level or new-onset diabetes mellitus over 6.5 years, especially in participants with a normal HbA1c level at baseline.

Your questions about complementary medicines answered: glucosamine.

This is the second article in a series providing evidence-based answers to common questions about complementary medicines from consumers and healthcare professionals.

Multiorgan dysfunction syndrome secondary to joint supplement overdosage in a dog.

A 5-year-old spayed female Bernese mountain dog, with a chief complaint of vomiting and melena ingested approximately 200 nutritional joint supplement tablets. Despite aggressive therapy, the patient developed a coagulopathy, pancreatitis, peritonitis, acute kidney injury, and was euthanized. Postmortem examination revealed myocardial necrosis, pneumonia, centrilobular hemorrhage and necrosis of the liver, vasculitis, and acute tubular necrosis.

Syndrome de défaillance multiviscérale secondaire à un surdosage d'un supplément pour articulation chez un chien. Une chienne Bouvier bernois stérilisée âgée de 5 ans présentée avec une plainte principale de vomissements et de mélæna avait ingéré environ 200 comprimés de suppléments nutritionnels pour les articulations. Malgré une thérapie agressive, la patiente a développé une coagulopathie, une pancréatite, une péritonite et une blessure aiguë aux reins et a été euthanasiée. L'autopsie a révélé une nécrose du myocarde, une pneumonie, une hémorragie centrilobulaire et une nécrose du foie, une vasculite et une nécrose tubulaire.(Traduit par Isabelle Vallières).

Randomized trial of glucosamine and chondroitin supplementation on inflammation and oxidative stress biomarkers and plasma proteomics profiles in healthy humans.

BACKGROUND: Glucosamine and chondroitin are popular non-vitamin dietary supplements used for osteoarthritis. Long-term use is associated with lower incidence of colorectal and lung cancers and with lower mortality; however, the mechanism underlying these observations is unknown. In vitro and animal studies show that glucosamine and chondroitin inhibit NF-kB, a central mediator of inflammation, but no definitive trials have been done in healthy humans. METHODS: We conducted a randomized, double-blind, placebo-controlled, cross-over study to assess the effects of glucosamine hydrochloride (1500 mg/d) plus chondroitin sulfate (1200 mg/d) for 28 days compared to placebo in 18 (9 men, 9 women) healthy, overweight (body mass index 25.0-32.5 kg/m2) adults, aged 20-55 y. We examined 4 serum inflammatory biomarkers: C-reactive protein (CRP), interleukin 6, and soluble tumor necrosis factor receptors I and II; a urinary inflammation biomarker: prostaglandin E2-metabolite; and a urinary oxidative stress biomarker: F2-isoprostane. Plasma proteomics on an antibody array was performed to explore other pathways modulated by glucosamine and chondroitin. RESULTS: Serum CRP concentrations were 23% lower after glucosamine and chondroitin compared to placebo (P = 0.048). There were no significant differences in other biomarkers. In the proteomics analyses, several pathways were significantly different between the interventions after Bonferroni correction, the most significant being a reduction in the "cytokine activity" pathway (P = 2.6 x 10-16), after glucosamine and chondroitin compared to placebo. CONCLUSION: Glucosamine and chondroitin supplementation may lower systemic inflammation and alter other pathways in healthy, overweight individuals. This study adds evidence for potential mechanisms supporting epidemiologic findings that glucosamine and chondroitin are associated with reduced risk of lung and colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT01682694.

Grape seed procyanidin B2 ameliorates mitochondrial dysfunction and inhibits apoptosis via the AMP-activated protein kinase-silent mating type information regulation 2 homologue 1-PPARγ co-activator-1α axis in rat mesangial cells under high-dose glucosamine.

Grape seed procyanidin B2 (GSPB2), an antioxidative and anti-inflammatory polyphenol in grape seed, has been found to have protective effects on diabetic nephropathy. Based on its favourable biological activities, in the present study, we aimed to investigate whether GSPB2 could inhibit apoptosis in rat mesangial cells treated with glucosamine (GlcN) under high-dose conditions. The results showed that the administration of GSPB2 (10 µg/ml) significantly increased the viability of mesangial cells treated with GlcN at a dose of 15 mM. We found that GSPB2 inhibited apoptosis in mesangial cells using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphates (dUTP) nick-end labelling staining and flow cytometry technique (P< 0·05 for both). GSPB2 treatment also suppressed oxidative stress by elevating the activity of glutathione peroxidase (P< 0·05) and superoxide dismutase (P< 0·01), as well as prevented cellular damage. GSPB2 enhanced the mRNA expression of nuclear respiratory factor 1, mitochondrial transcription factor A and mitochondrial DNA copy number in mesangial cells as determined by real-time PCR (P< 0·05 for each). Finally, GSPB2 treatment activated the protein expression of PPARγ co-activator-1α (PGC-1α), silent mating type information regulation 2 homologue 1 (SIRT1) and AMP-activated protein kinase (AMPK) in mesangial cells. These findings suggest that GSPB2 markedly ameliorates mitochondrial dysfunction and inhibits apoptosis in rat mesangial cells treated with high-dose GlcN. This protective effect could be, at least in part, due to the activation of the AMPK-SIRT1-PGC-1α axis.

Oral glucosamine sulfate supplementation does not induce endoplasmic reticulum stress or activate the unfolded protein response in circulating leukocytes of human subjects.

Glucosamine sulfate is a dietary supplement that is marketed as a treatment for osteoarthritis. Recent evidence from animal and cell culture models have suggested that glucosamine treatment can promote the misfolding of proteins and the activation of the unfolded protein response (UPR). We investigated whether glucosamine sulfate supplementation activates the UPR in circulating leukocytes of human subjects. Cultured Thp1 human monocytes were exposed to increasing concentrations of glucosamine (0, 0.25, 1.0, 4.0 mmol · L(-1)) for 18 h. We observed a dose-dependent increase in intracellular glucosamine levels as well as the activation of UPR. To test the effect of glucosamine sulfate supplementation in humans, 14 healthy human subjects took 1500 mg · day(-1) glucosamine sulfate for 14 days. Metabolic parameters and blood samples were collected before and after supplementation. In humans, glucosamine sulfate supplementation did not alter metabolic parameters including lipid levels and glucose tolerance. Further, glucosamine sulfate supplementation did not affect intracellular glucosamine levels or activate the UPR in the leukocytes of human subjects. Our results indicate that in healthy human subjects, the recommended dose of glucosamine sulfate (1500 mg · day(-1)) for 14 days does not significantly alter intracellular glucosamine levels and does not activate the UPR in circulating leukocytes.

Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease.

Glucosamine and chondroitin sulfate are molecules involved in the formation of articular cartilage and are frequently used for symptom relief in patients with arthrosis. These molecules are well tolerated with scarce secondary effects. Very few cases of possible hepatotoxicity due to these substances have been described. The aim of this paper is to report the frequency of presumed glucosamine hepatotoxicity in patients with liver disease. A questionnaire was given to 151 consecutive patients with chronic liver disease of different etiology (mean age 59 years, 56.9% women) attended in an outpatient clinic with the aim of evaluating the frequency of consumption of these drugs and determine whether their use coincided with a worsening in liver function test results. Twenty-three patients (15.2%) recognized having taken products containing glucosamine or chondroitin sulfate previously or at the time of the questionnaire. Review of the clinical records and liver function tests identified 2 patients presenting an elevation in aminotransferase values temporarily associated with glucosamine treatment; one of the cases simultaneously presented a skin rash attributed to the drug. Review of these two patients and the cases described in the literature suggest toxicity of glucosamine and chondroitin sulfate. The clinical spectrum is variable, and the mechanism of toxicity is not clear but may involve reactions of hypersensitivity. The consumption of products containing glucosamine and/or chondroitin sulfate is frequent among patients with chronic liver diseases and should be taken into account on the appearance of alterations in liver function tests not explained by the underlying disease.

An unusual case of peripheral neuropathy possibly due to arsenic toxicity secondary to excessive intake of dietary supplements.

A 74-year-old woman presented to the neurology clinic with worsening of her longstanding peripheral neuropathy of unknown cause. There was below knee loss of spinothalamic sensation, reduced joint position of toes, absent below hips vibration sensation and absent ankle jerks. Neurophysiology studies showed further progression of her axonal sensory neuropathy. Urine and blood analysis previously carried out in Australia suggested elevated levels of arsenic. After abstinence from seafood, a random urine sample was collected and this confirmed the elevation in urine arsenic (622.1 nmol/L, reference range <534 nmol/L). The household water was found to be uncontaminated and the patient had no occupational or environmental exposure to arsenic. On questioning the patient admitted to taking fish oils, omega-3 oils and glucosamine sulphate dietary supplements in excess of the recommended dosage. These supplements were identified as possible sources of arsenic and the patient was asked to stop all supplements. One month later the urine arsenic had reduced to 57.5 nmol/L. There was an improvement in patient wellbeing, she no longer required Gabapentin for pain relief and the neurophysiology studies also showed improvement. Clinicians should consider heavy metal toxicity as a cause of peripheral neuropathy of unknown cause. A detailed patient history including all dietary supplements is essential to help elucidate the source of heavy metal toxicity.

Pharmacologic treatment of hand-, knee- and hip-osteoarthritis.

Osteoarthritis (OA) is a joint disease of high prevalence and affects > 90 % of the population, depending on several risk factors. Symptomatic OA is less frequent, but requires an individually tailored therapeutic regimen consisting of non-pharmacological and pharmacological treatment modalities. Pharmacologic therapy, however, is mainly limited to analgetic and anti-inflammatory agents; structure modifying remedies do not exist. The therapeutic approach to hand-, knee- and hip-OA is basically similar and differs only at some minor points. Generally, topical agents or paracetamol are recommended as first-line agents. If unsuccessful oral non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2-selctive inhibitors should be introduced. Tramadol is an option in the case patients will not respond satisfactorily to NSAIDs. Glucosamine and chondroitine sulphate are no longer recommended in knee and hip OA, but chondroitine might be efficient in treating hand OA. Oral NSAIDs should be prescribed with caution due to potential side effects. Opioids are not recommended as their benefits are outweighed by an increased risk for serious adverse events.

Drug-induced acute liver injury mimicking autoimmune hepatitis after intake of dietary supplements containing glucosamine and chondroitin sulfate.

INTRODUCTION: Herbal and dietary supplements are widely used as measures to improve and preserve health and well-being. Among the bestselling preparations are dietary supplement containing glucosamine and chondroitine sulfate taken to improve symptoms of osteoarthritis. METHODS AND RESULTS: We here present a case of a male patient with biopsy-proven acute and severe autoimmune hepatitis subsequent to intake of a preparation containing glucosamine and chondroitine sulfate. Response to steroids was favorable and resulted in complete remission of the patient. Diagnostic work-up of the case revealed no other possible cause of liver injury, and causality assessment using the Roussel Uclaf Causality Assessment Method (RUCAM) resulted in a possible causal relationship between intake of glucosamine and chondroitine sulfate and the adverse hepatic reaction. CONCLUSION: The present case recalls that products containing glucosamine and chondroitine sulfate can occasionally cause acute liver injury mimicking autoimmune hepatitis, and reminds of the potential dangers of compounds with poor efficacy and ill-defined safety records.

Acute liver injury associated with glucosamine dietary supplement.

A 55-year-old woman taking  over-the-counter (OTC) glucosamine developed symptomatic hepatotoxicity. Several of her liver enzymes were elevated to 10 times the upper limit of normal. One week after discontinuing glucosamine, serum transaminases fell dramatically, with some returning to normal limits. Four weeks after glucosamine was discontinued, all her liver tests were normal. Rechallenge was not attempted. The potential causes of hepatocellular injury were evaluated. Glucosamine is a dietary supplement available in a wide variety of commercial preparations, primarily used for joint relief in osteoarthritis. Despite the extensive use of glucosamine supplements, significant elevations of transaminases are rare. The mechanism of hepatotoxicity in many OTC herbal preparations is unknown. It is vital for physicians to elicit a careful history of OTC medications and educate their patients on their potential adverse effects.

p38 Mitogen-activated protein kinase is required for glucosamine-induced endothelial nitric oxide synthase uncoupling and plasminogen-activator inhibitor expression.

BACKGROUND: Hexosamine biosynthetic pathway (HBP) is implicated in increased plasminogen activator inhibitor-1 (PAI-1), and endothelial nitric oxide synthase (eNOS) dysfunction in diabetes. Glucosamine (GlcN) that directly activates HBP is a dietary supplement and is clinically used to treat osteoarthritis despite uncertain efficacy and adverse cardiovascular effects observed in animal models. p38 mitogen-activated protein kinase (p38mapk) has been shown to be involved in HBP-mediated biological processes. The aim of the present study was to investigate the role of p38mapk in GlcN-induced endothelial PAI-1 expression and eNOS dysfunction. METHODS AND RESULTS: In cultured human endothelial cells, GlcN time- and concentration-dependently increased PAI-1 protein level that was further enhanced by tumor necrosis factor (TNF)-α, which was accompanied by a transient synergistic activation of p38mapk. The stimulation of PAI-1 by GlcN alone or by GlcN and TNF-α in combination was inhibited by the specific inhibitor of p38mapk, but not that of JNK or ERK1/2. Moreover, in isolated mouse aortas, GlcN caused eNOS uncoupling resulting in enhanced superoxide and decreased NO production, as well as impaired endothelium-dependent relaxations, which were also fully prevented by the p38mapk inhibitor. CONCLUSIONS: HBP activated by GlcN increases PAI-1 expression and eNOS uncoupling depending on p38mapk, which not only explains hyperglycemic vascular complications, but also may bring into question the clinical use of GlcN. The present results, support currently ongoing clinical application of p38mapk inhibitor in patients with cardiovascular disease.