ArticleLiterature Review

A review of glucosamine for knee osteoarthritis: Why patented crystalline glucosamine sulfate should be differentiated from other glucosamines to maximize clinical outcomes

Current Medical Research and Opinion

February 2016
32(6):1-33

DOI:10.1185/03007995.2016.1154521

Authors:

Eugene Joseph Kucharz

Medical University of Silesia

Volodymyr Kovalenko

Shupyk National Healthcare University of Ukraine

Sandor Szanto

University of Debrecen

Olivier Bruyère

University of Liège

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The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm for knee osteoarthritis (OA) recommends symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) first line for the medium to long term management of OA, due to their ability to control pain, improve function, and delay joint structural changes. Among SYSADOAs, glucosamine is probably the most widely used intervention. In the present review of glucosamine for knee OA, we have investigated whether the evidence is greater for the patented crystalline glucosamine sulfate (pCGS) preparation (Rottapharm/Meda) than for other glucosamine formulations. Glucosamine is actually widely available in many forms, as the prescription-grade pCGS preparation, generic and over-the-counter formulations of glucosamine sulfate (GS) and food supplements containing glucosamine hydrochloride (GH), which vary substantially in molecular form, pharmaceutical formulation and dose regimens. Only pCGS is given as a highly bioavailable once-daily dose (1500 mg) with a proven pharmacological effect. pCGS consistently reaches the plasma levels of around 10 μM required to inhibit interleukin-1 induced expression of genes involved in the pathophysiology of joint inflammation and tissue destruction, compared with sub-therapeutic levels achieved with GH. It is evident from careful consideration of the evidence base, that only the pCGS formulation of glucosamine reliably provides an effect size on pain that is higher than that of paracetamol and equivalent to that provided by non-steroidal anti-inflammatory drugs. In comparison, the effect size on pain of non-crystalline GS preparations and GH from randomized controlled trials is repeatedly demonstrated to be zero. In addition, there is evidence that chronic administration of pCGS has disease-modifying effects, with a reduction in the need for total joint replacement surgery lasting for at least 5 years after treatment cessation. Consequently, the pCGS preparation (Rottapharm/Meda) is the logical choice, with demonstrated medium-term control of pain and lasting impact on disease progression.

MicroRNA as Possible Mediators of the Synergistic Effect of Celecoxib and Glucosamine Sulfate in Human Osteoarthritic Chondrocyte Exposed to IL-1β

Preprint

Full-text available

Sep 2023

This study investigated the role of a pattern of microRNA (miRNA) as possible mediators of celecoxib and prescription-grade glucosamine sulfate (GS) effects in human osteoarthritis (OA) chondrocytes. Chondrocytes were treated with celecoxib (1.85 µM) and GS (9 µM), alone or in combination, for 24 hrs, with or without interleukin (IL)-1β (10 ng/mL). Viability was detected by MTT assay, apoptosis and reactive oxygen species (ROS) by cytometry, nitric oxide (NO) by Griess method. Gene levels of miRNA, antioxidant enzymes, nuclear factor erythroid (NRF)2, and B-cell lym-phoma (BCL)2 expressions were analyzed by quantitative real time PCR. Protein expression of NRF2 and BCL2 was also detected at immunofluorescence and western blot. Celecoxib and GS, alone or in combination, significantly increased viability, reduced apoptosis, ROS and NO production and the gene expression of miR-34a, -146a, -181a, -210, in comparison to baseline and to IL-1β. The transfection with miRNA specific inhibitors significantly counteracted the IL-1β activity and potentiated the properties of celecoxib and GS on viability, apoptosis and oxidant system, through NF-κB regulation. The observed effects were enhanced when the drugs were tested in combination. Our data confirmed the synergistic anti-inﬂammatory and chondroprotective properties of celecoxib and GS, suggesting miRNA as possible mediators.

A Malaysian Delphi consensus on managing knee osteoarthritis

Article

Full-text available

Jun 2021
BMC MUSCULOSKEL DIS

Background The 2013 Malaysian Clinical Practice Guidelines on the Management of Osteoarthritis (OA) recommend a linear step-up approach to manage knee OA. However, patients with knee OA often require a multimodal approach to address OA-related pain symptoms and functional limitations. This consensus aimed to provide doctors with an updated set of evidence-based, clinical experience-guided recommendations to manage knee OA. Methods A multi-speciality expert panel consisting of nine Malaysian physicians from different healthcare settings who manage a diverse OA patient population was convened. Using a combination of the ADAPTE process and modified Delphi method, the panel reviewed current evidence on the management of knee OA and synthesised a set of nine recommendations on the management of knee OA, supported by an algorithm that summarises the consensus’ core messages. Results A multimodal intervention strategy is the mainstay of OA management and the choice of any single or multimodal intervention may vary over the course of the disease. Overall, a non-pharmacological core treatment set of patient education, weight loss and exercise is recommended for all patients. When pharmacotherapy is indicated, symptomatic slow-acting drugs for osteoarthritis are recommended at the early stage of disease, and they can be paired with physical therapy as background treatment. Concurrent advanced pharmacotherapy that includes non-steroidal anti-inflammatory drugs, intraarticular injections and short-term weak opioids can be considered if patients do not respond sufficiently to background treatment. Patients with severe symptomatic knee OA should be considered for knee replacement surgery. Management should begin with specific treatments with the least systemic exposure or toxicity, and the choice of treatment should be determined as a shared decision between patients and their team of healthcare providers. Conclusions This consensus presents nine recommendations that advocate an algorithmic approach in the management of patients living with knee OA. They are applicable to patients receiving treatment from primary to tertiary care providers in Malaysia as well as other countries.

The clinical significance of and prospects for the use of biopolymer-based microheterogeneous collagen-containing injectable hydrogel in the therapy of osteoarthritis

Article

Full-text available

Nov 2020

The paper gives the current definition of osteoarthritis (OA), which reflects the pathogenetic and clinical characteristics of this disease, as well as general principles for choosing an OA treatment. It describes the effect of glucosamine and chondroitin on the key pathogenetic mechanisms of OA. It is noted that one of the promising areas of therapy for OA is the intra-articular administration of biopolymer-based hydrogels that provide not only an anti-inflammatory, but also regenerative effect that has been experimentally confirmed during their injection into the tendon sheaths. There are data on the efficacy and safety of the Russian drug Sphero®gel, a biopolymer-based microheterogeneous collagen-containing hydrogel that belongs to a class of multicomponent biopolymer-based extracellular matrix mimetics. It consists of the cross-linked farm animal tissue-derived collagen microparticles placed in the gel base. The gel is not only a structural base for collagen microparticles; it also has its own therapeutic potential, since it is structurally similar to the natural extracellular matrix. The drug contains collagen, biologically active components of the extracellular matrix, such as proteoglycans, glycoproteins, uronic acids, growth factors, monosaccharides, and chondroitin sulfate. Extended-release symptomatic agents, Sphero®gel among them, are currently recommended for the treatment of OA. Application of Sphero®gel contributes to increased joint mobility and reduced pain, which allows the limited use of nonsteroidal anti-inflammatory drugs that cause adverse reactions, especially in the presence of comorbid diseases.

Expert Opinion on the Extensive Use of Prescription Crystalline Glucosamine Sulfate in the Multimodal Treatment of Osteoarthritis in Ukraine, Kazakhstan, Uzbekistan, and Armenia

Article

Full-text available

Aug 2020

Objective The present work was led by a multidisciplinary panel of experts and proposes an extensive review on the use of prescription crystalline glucosamine sulfate (pCGS) in the multimodal treatment of osteoarthritis (OA) applicable in Ukraine and other Commonwealth of Independent States (CIS) countries. Methods A panel of rheumatologists, orthopedic surgeons, and field experts from Ukraine and CIS regions discussed the management of OA. Literature was systematically searched using Medline, EMBASE, CIHNAL, and Cochrane Library databases. The 2-day meeting critically reviewed the available literature, treatment algorithms, pharmacoeconomic aspects, and real-world instances to form a multimodal approach based both on real-life clinical practice and systematic literature research for the management of OA in Ukraine and CIS countries. Expert Opinion pCGS plays a pivotal role in the stepwise approach to OA treatment. If it is necessary (step 1), the combined use of pCGS with paracetamol and topical nonsteroidal anti-inflammatory drugs (NSAIDs) has been recommended. If symptoms persist, oral NSAIDs and intra-articular (IA) hyaluronic acid or corticosteroids are added to the therapy (step 2) of pCGS in the patients. In case of insufficient relief and severe OA (step 3), pCGS along with oral NSAIDs, IA corticosteroids, and duloxetine have been recommended. Patient stratification with regular monitoring and careful alterations in treatment were advocated. Conclusions This expert opinion article recommends a modified approach to the existing guidelines incorporating pCGS in treatment modality of OA in Ukraine and CIS countries. Extensive use of pCGS targets early symptomatic relief in OA while limiting the adverse effects due to long-term use of analgesics and NSAIDs.

Comparison of functional performance outcomes between oral patented crystalline glucosamine sulfate and platelet-rich plasma among knee osteoarthritis patients: a propensity score matching analysis

Article

Full-text available

Aug 2024
AGING CLIN EXP RES

Background Among the medications used to treat knee osteoarthritis (OA), oral patented crystalline glucosamine sulfate (pCGS) and platelet-rich plasma (PRP) have become popular alternatives to painkillers or nonsteroidal anti-inflammatory drugs (NSAIDs). Although studies have shown that pCGS and PRP improve clinical outcomes, no study has compared outcomes between these optional treatments. We compared functional performance outcomes from baseline to the 1-year follow-up (FU) between oral pCGS and PRP in patients with knee OA. Materials and methods Three hundred eighty-two patients receiving oral pCGS and 122 patients receiving PRP injections were enrolled for a review of functional performance outcomes, including a five-time sit-to-stand test (5xSST), time up-and-go test (TUGT), and 3-minute walk distance test (3MWDT). The patients were followed up for one year. The pCGS group received 1500 mg daily, whereas the PRP group received 2 cycles of intra-articular injections at week 0 and week 6. Using propensity score matching based on age, sex, height, weight, BMI, and Kellgren and Lawrence (KL) classification, all three functional performance outcomes were compared between the baseline (pretreatment), 6-week, 12-week, 24-week, and 1-year FUs. Results With a ratio of 2:1 (pCGS: PRP), 204 patients in the pCGS group were matched with 102 patients in the PRP group. Compared with the baseline levels, the PRP group showed significant improvements in 5xSST and TUGT outcomes from 6 weeks and significant improvements in 3MWDT outcomes from 12 weeks, whereas the pCGS group showed significant improvements in TUGT outcomes from 6 weeks and significant improvements in 5xSST and 3MWDT outcomes from 12 weeks. At the 24-week and 1-year FU, both groups showed significant improvements in all three functional performance tests without adverse events. Conclusions Although the PRP group showed faster improvements in 5xSST outcomes at six weeks, from the 12-week to 1-year FU, both the pCGS and PRP groups showed significant improvements in 5xSST, TUGT, and 3MWDT outcomes. As the use of PRP is more complicated and invasive than the use of oral pCGS, the benefits and drawbacks of selecting PRP over pCGS in knee OA treatment should be examined.

2016-07-1245

Article

Full-text available

Jan 2024

Potential of Icariin–Glucosamine Combination in the Treatment of Osteoarthritis by Topical Application: Development of Topical Formulation and In Vitro Permeation Study

Article

Full-text available

Feb 2023

The aim of this study was to develop a topically applied formulation with the potential to alleviate arthritis ailments. A combination of two active ingredients, icariin from Epimedium L. (Species: Epimedium Koreanum) extract as a potential promoter of chondrogenesis and glucosamine sulfate as a precursor of cartilage tissues, was tested. In permeation studies, the potential for skin permeation of both substances was confirmed; however, the in vitro release test did not accurately reflect the degree of skin permeation. The in vitro release of icariin was at a level of 15.0–19.0% for the plant-extract-derived icariin and 29.0–35.0% for the pure substance. The level of glucosamine sulfate release was 38.4% (on average). For icariin of both origins, the release results were higher than those obtained via oral administration (about 12.0%), which shows the potential superiority of topical application. In addition, the physicochemical parameters that affect the in vitro release and performance of topical formulations were addressed. This preliminary research and permeation analysis of the formulation produced a promising picture of its prospects regarding arthritis treatment, although further investigation is needed.

The optimal way to fill the deficiency of essential substances for the well-being of the joints

Article

Full-text available

Jul 2022

The article presents basic information about the role and structure of cartilage tissue and its components, the impact of an imbalance in the structure of nutrition on the well-being of the joints, evidence of the symptomatic and structural-modifying effect of chondroitin and glucosamine in the composition of original drugs and dietary supplements in the treatment of osteoarthritis. Particular attention is paid to the structure and synthesis of collagen, its biological role in the body in the formation of the cell structure of various tissues, especially cartilage. Found 28 types of collagen, differing in amino acid sequence and degree of modification, which are encoded by more than 40 genes. It was noted that the activity of enzymes involved in the synthesis of collagen depends on sufficient intake of products containing ascorbic acid (vitamin C), and the degradation and decrease in the amount of collagen is associated with the development and progression of osteoarthritis and other diseases of the musculoskeletal system. The use of type 2 collagen, including in combination with chondroitin and glucosamine, is considered as a promising method for preventing joint problems. It is emphasized that the main substances necessary for the syn thesis of cartilage components come from food. An imbalance in the structure of nutrition (reducing the consumption of proteins, microelements and vitamins, excessive consumption of fats and carbohydrates) negatively affects the state of the connective tissue and causes problems for all structures that form the joint. One way to correct eating behavior and replenish essential deficiencies is through the use of vitamin-mineral complexes and dietary supplements, which are gaining interest in the medical community as evidence accumulates for their effectiveness in supporting joint well-being.

Heterologous Expression of a Thermostable Chitinase from Myxococcus xanthus and Its Application for High Yield Production of Glucosamine from Shrimp Shell

Article

Full-text available

Nov 2021

Glucosamine (GlcN) is a widely used food supplement. Hence, enormous attention has been concerned with enzymatic production of GlcN owing to its advantage over a chemical approach. In this study, a previously unstudied chitinase gene (MxChi) in the genome of Myxococcus xanthus was cloned, expressed in recombinant soluble form and purified to homogeneity. TLC-, UPLC-, and microplate-reader- based activity tests confirmed MxChi hydrolyzes colloidal chitin to chitobiose as sole product. The optimal catalytic pH and temperature of MxChi was identified as 7.0 and 55 °C, respectively. MxChi exhibited 80% activity after 72 h incubation at 37 °C. The site-directed mutagenesis revealed that the amino acids D323A, D325A, and E327A of MxChi were in the DXDXE catalytic motif of GH18. When coupled with β-N-acetylhexosaminidase (SnHex) and deacetylase (CmCBDA), the enzyme allowed one-pot extraction of GlcN from colloidal chitin and shrimp shell. The optimal condition was 37 °C, pH 8.0, and 1/3/16.5 (MxChi/SnHex/CmCBDA), conducted by orthogonal design for the enzymatic cascades. Under this condition, the yield of GlcN was 26.33 mg from 400 mg shrimp shell. Facile recombinant in E. coli, robust thermostability and pure product herein makes newly discovered chitinase a valuable candidate for the green recycling of chitin rich waste.

A Combination of Celecoxib and Glucosamine Sulfate Has Anti-Inflammatory and Chondroprotective Effects: Results from an In Vitro Study on Human Osteoarthritic Chondrocytes

Article

Full-text available

Aug 2021
INT J MOL SCI

This study investigated the possible anti-inflammatory and chondroprotective effects of a combination of celecoxib and prescription-grade glucosamine sulfate (GS) in human osteoarthritic (OA) chondrocytes and their possible mechanism of action. Chondrocytes were treated with celecoxib (1.85 µM) and GS (9 µM), alone or in combination with IL-1β (10 ng/mL) and a specific nuclear factor (NF)-κB inhibitor (BAY-11-7082, 1 µM). Gene expression and release of some pro-inflammatory mediators, metalloproteinases (MMPs), and type II collagen (Col2a1) were evaluated by qRT-PCR and ELISA; apoptosis and mitochondrial superoxide anion production were assessed by cytometry; B-cell lymphoma (BCL)2, antioxidant enzymes, and p50 and p65 NF-κB subunits were analyzed by qRT-PCR. Celecoxib and GS alone or co-incubated with IL-1β significantly reduced expression and release of cyclooxygenase (COX)-2, prostaglandin (PG)E2, IL-1β, IL-6, tumor necrosis factor (TNF)-α, and MMPs, while it increased Col2a1, compared to baseline or IL-1β. Both drugs reduced apoptosis and superoxide production; reduced the expression of superoxide dismutase, catalase, and nuclear factor erythroid; increased BCL2; and limited p50 and p65. Celecoxib and GS combination demonstrated an increased inhibitory effect on IL-1β than that observed by each single treatment. Drugs effects were potentiated by pre-incubation with BAY-11-7082. Our results demonstrated the synergistic effect of celecoxib and GS on OA chondrocyte metabolism, apoptosis, and oxidative stress through the modulation of the NF-κB pathway, supporting their combined use for the treatment of OA.

Attenuation of IL-1ß on the use of glucosamine as an adjuvant in meloxicam treatment in rat models with osteoarthritis

Article

Jan 2020
J Basic Clin Physiol Pharmacol

Background Osteoarthritis (OA) is the most prevalent joint disease and a common cause of joint pain, functional loss, and disability. The severity of this disease is always associated with increased levels of proinflammatory cytokines, which play an important role in cartilage damage, synovitis, and other damage to joint tissues. The discovery that many soluble mediators such as cytokines or prostaglandins can increase the production of matrix metalloproteinases by chondrocytes led to the first steps of an inflammatory state. Several studies show that cytokines, such as interleukin 1ß, have a major role in the development of inflammation that occurs in these joints. The use of glucosamine as an adjuvant to meloxicam therapy is expected to inhibit the development of inflammatory OA. Methods The OA model in rat was induced by single injection of intraarticular monosodium iodoacetate (MIA). The development of OA was observed for 21 days. Furthermore, the evaluation of glucosamine potency as an adjuvant of meloxicam therapy for reducing IL-1ß was done by combined treatment at a low dose of meloxicam 1 mg/kg BW with glucosamine at a dose of 125, 250, or 500 mg/kg BW orally for 28 days. Response to hyperalgesia and knee joint diameter was measured on days 0, 7, 14, 21, 28, 35, 42, and 49. IL-1ß levels were measured on day 21 and day 49 after MIA injection. Results MIA injection successfully induced OA as marked by a significant difference in the time of latency to heat stimulus (p < 0.01) and a significant increase in joint diameter (p < 0.01). On day 21, IL-1ß levels showed a significant decrease in MIA injection (p = 0.05). The administration of meloxicam and glucosamine did not induce significant decrease in knee joint diameter (p > 0.10), but was able to significantly increase the latency time to heat stimulus (p < 0.01). IL-1ß levels also showed a significant decrease after administering a combination of glucosamine and meloxicam (p < 0.01). Conclusions Taken together, the use of glucosamine as an adjuvant in meloxicam therapy may be caused by the synergistic mechanism of meloxicam for the attenuation of OA development through systemically reducing IL-1ß.

Hit two birds with one stone: why crystalline glucosamine sulphate used for osteoarthritis medication is beneficial for patients with risk of cardiovascular disorders

Article

Full-text available

Oct 2019

Eugeniusz Kucharz

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Effect of glucosamine sulfate on intraocular pressure in patients with knee osteoarthritis: A prospective randomized controlled trial

Article

May 2019

Purpose: Glucosamine sulfate is one of the treatment options for patients with osteoarthritis of the knee. It has been postulated that glucosamine sulfate affects intraocular pressure (IOP). This study aimed to evaluate the effect of crystalline glucosamine sulfate on IOP in patients with osteoarthritis of the knee. Methods: Forty-two patients with osteoarthritis of the knee were randomized into two groups. The first group of patients received 1500mg of crystalline glucosamine sulfate once daily for 6 months and the conventional treatment protocol. The second group of patients received only the conventional treatment protocol. IOP was recorded at the start of the study and at 6 weeks, 3 months, 6 months, and 9 months. Results: The patient demographic data were not different between the two groups. There were no differences in the IOPs between the groups (P>0.05) nor differences in baseline IOPs within each group compared with each follow-up visit (P>0.05). Conclusions: Glucosamine sulfate is still an option without significant concern over elevated IOP in patients with osteoarthritis of the knee and normal ocular pressure.

Recent Advances in Osteoarthritis: Pathophysiology, Diagnosis, and Therapeutic Strategies

Article

Full-text available

Jan 2025

Zulekha Ali, Shalini Sharma, Shabnam Ain, Qurratul Ain

Osteoarthritis (OA) is a chronic, degenerative joint disease that affects millions of people worldwide, representing a major cause of disability, particularly in aging populations. Characterized by progressive cartilage breakdown, subchondral bone changes, and synovial inflammation, OA severely impacts joint function and quality of life. Despite significant research efforts, effective disease-modifying treatments remain elusive, and current therapies primarily focus on symptomatic relief rather than halting or reversing disease progression. Recent advances in understanding the molecular and cellular mechanisms underlying OA have provided new insights into its pathophysiology, which includes altered chondrocyte function, extracellular matrix degradation, and inflammatory cytokine signaling.

Red Algae Alters Expression of Inflammatory Pathways in an Osteoarthritis In Vitro Co-Culture

Article

Full-text available

Feb 2025

Background/Objectives: Osteoarthritis (OA) is one of the most prevalent chronic conditions and significantly contributes to local and global disease burden. Common pharmaceuticals that are used to treat OA cause significant side effects, thus non-pharmaceutical bioactive alternatives have been developed that can impact OA symptoms without severe side-effects. One such alternative is the Red Algae Lithothamnion species (Litho). However, there is little mechanistic knowledge of its potential to effect OA gene expression, and a human in vitro model using commercially available cell lines to test its effectiveness has yet to be developed. Methods: Human osteoblast (hFOB 1.19. CRL-11372) and chondrocyte (C28/I2) cell lines were co-cultured indirectly using transwells. IL1-β was used to induce an inflammatory state and gene expression profiles following treatment were the primary outcome. Conclusions: Results indicated that the model was physiologically relevant, remained viable over at least seven days, untreated or following induction of an inflammatory state while maintaining hFOB 1.19. and C28/I2 cell phenotypic characteristics. Following treatment, Litho reduced the expression of inflammatory and pain associated genes, most notably IL-1β, IL-6, PTGS2 (COX-2) and C1qTNF2 (CTRP2). Confirmatory analysis with droplet digital PCR (ddPCR) revealed that Il-1β induced a significant reduction in C1qTNF2 at 7 days which was ameliorated with Litho treatment. These data present a novel and replicable co-culture model of inflammatory OA that can be used to investigate bioactive nutraceuticals. For the first time, this model demonstrated a reduction in C1qTNF2 expression that was mitigated by Red Algae Lithothamnion species.

MicroRNA as Possible Mediators of the Synergistic Effect of Celecoxib and Glucosamine Sulfate in Human Osteoarthritic Chondrocyte Exposed to IL-1β

Article

Full-text available

Oct 2023
INT J MOL SCI

This study investigated the role of a pattern of microRNA (miRNA) as possible mediators of celecoxib and prescription-grade glucosamine sulfate (GS) effects in human osteoarthritis (OA) chondrocytes. Chondrocytes were treated with celecoxib (1.85 µM) and GS (9 µM), alone or in combination, for 24 h, with or without interleukin (IL)-1β (10 ng/mL). Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, apoptosis and reactive oxygen species (ROS) by cytometry, nitric oxide (NO) by Griess method. Gene levels of miRNA, antioxidant enzymes, nuclear factor erythroid (NRF)2, and B-cell lymphoma (BCL)2 expressions were analyzed by quantitative real time polymerase chain reaction (real time PCR). Protein expression of NRF2 and BCL2 was also detected at immunofluorescence and western blot. Celecoxib and GS, alone or in combination, significantly increased viability, reduced apoptosis, ROS and NO production and the gene expression of miR-34a, -146a, -181a, -210, in comparison to baseline and to IL-1β. The transfection with miRNA specific inhibitors significantly counteracted the IL-1β activity and potentiated the properties of celecoxib and GS on viability, apoptosis and oxidant system, through nuclear factor (NF)-κB regulation. The observed effects were enhanced when the drugs were tested in combination. Our data confirmed the synergistic anti-inflammatory and chondroprotective properties of celecoxib and GS, suggesting microRNA as possible mediators.

The Pro-Inflammatory Cytokine IL-Iβ Alteration by Deer (Rusa unicolor) Antler Extract on Osteoarthritis Rat Model

Article

Full-text available

Apr 2023

Osteoarthritis is a disease associated with articular cartilage degradation, intra-articular area inflammation, and subchondral bone replacement. Cytokine IL-1β has a prominent function in the inflammations process that passes in the joints. The 70% ethanol extracts of deer antler (250 and 500 mg/kg BW) and glucosamine sulfate (250 kg/BW) were evaluated for four weeks in reducing cytokine IL-1β to rat model OA-induced Monosodium iodoacetate. Measurements of joint diameter in rat’s knee and hyperalgesia were performed on weeks 0, 1, 2, 3, 4, 5, 6, and 7. The presence of a significant difference in the stimulation thermal latency (p = 0.00) and the resulting increase in swelling of joint diameter (p = 0.00) are evidence that MIA has successfully induced the rat modeling of OA. A significant decrease in cytokine IL-Iβ levels was shown on week 3 after MIA injection (p = 0.00). Both concentrations of deer extracts significantly reduced knee joint diameter (p = 0.00), latency thermal stimulation (p = 0.00), and cytokine IL-1β levels (p = 0.00). Based on the results, it can be concluded that the 70% ethanol extract of deer antler is a potential medicine for OA therapy.

Evaluation of the effects of glucosamine sulfate on poly(3- hydroxybutyrate) -chitosan/carbon nanotubes electrospun scaffold for cartilage tissue engineering applications

Article

Mar 2022

Blend nanofibres composed of synthetic polymers with biological macromolecules, such as natural biopolymers, and 3D structures created via electrospinning technique, have a high potential for modification to promote cell growth and function. In this study, 5 and 7 wt% of glucosamine sulfate (GAS), as one of the key components in the extracellular matrix (ECM) of natural cartilage tissue, were added to poly (3-hydroxybutyrate)-chitosan (PHB-CS)/functionalized multiwalled carbon nanotubes (f-MWCNTs) solution (100:20:1) for production of electrospun scaffolds. Prepared fibrous scaffolds are characterized by SEM, FTIR, XRD, TGA, and DSC. Tensile tests are used to study their mechanical properties and their hydrophilicity is also assessed. subsequently, the drug release profile of the scaffolds, adipose stem cell proliferation, cell viability, and the differentiation of adipose stem cells to chondrocyte cells were evaluated for further cartilage tissue engineering application. Our results showed that the addition GAS has a positive effect on the hydrophilicity of the fibers and the initiation of chondrogenic differentiation. Without, effects on tensile strength of the scaffolds by adding 5%. So, that PHB-CS/f-MWCNTs scaffold containing GAS has more acceptable properties than the PHB or PHB-CS for cartilage tissue engineering.

Possible synergic action of non-steroidal anti-inflammatory drugs and glucosamine sulfate for the treatment of knee osteoarthritis: a scoping review

Article

Full-text available

Dec 2022
BMC MUSCULOSKEL DIS

Background Several studies have reported that glucosamine sulfate (GS) can improve knee osteoarthritis (OA) symptomatology. In parallel, the disease-modifying effects of non-steroidal anti-inflammatory drugs (NSAIDs) in knee OA have also been investigated. However, limited literature has reported the combined effect of GS and NSAIDs. The aim of this scoping review is to describe the scope and volume of the literature investigating the potential benefits and synergistic effect of a combination of GS and NSAIDs in patients with knee OA. Methods PubMed and Embase were searched for studies published from inception through April 2022, evaluating the effects of the combination of GS and NSAIDs in OA patients, versus either treatment alone. Data are reported narratively. Results Five studies were included in this review; 4 were randomized control trials and one was a prospective observational study. The duration of combination treatment was 6 to 12 weeks. The combination was compared to celecoxib in 2 studies, meloxicam in 1, etoricoxib in 1, and a conventional NSAID in 1 (ibuprofen or piroxicam). All 5 studies reported that in patients with knee OA, the combination of GS plus NSAID yielded a significantly greater benefit than single-agent therapy, in terms of outcomes including pain reduction, function, joint stiffness, and markers of inflammatory activity and cartilage degradation. Conclusion The 5 studies included in this scoping review all report a significantly greater clinical benefit with a combination of GS plus NSAID compared to either treatment alone. The evidence supports efficacy in reducing pain, improving function, and possibly regulating joint damage. However, further randomized trials with larger sample sizes are warranted to confirm these findings.

The management of knee osteoarthritis in elderly: results from a national survey compared to ESCEO guidelines

Article

Full-text available

Nov 2022

Objective: Knee osteoarthritis (KOA) is a degenerative and inflammatory disease with a rising incidence and prevalence worldwide. Various therapeutic strategies have been proposed over time, depending on the degrees of severity and usually based on individual clinical practice. However, several European and international scientific societies published guidelines, to provide practical clinical stepwise guidance and to facilitate individualized therapeutic decisions regarding the management of KOA. The aim of this prospective multicentre observational study was to describe the real outpatient territorial management of patients with knee osteoarthritis and to compare it with the ESCEO guidelines, in order to identify operational strategies for delivering patient-centric care. Materials and methods: The educational project was divided in three modules: the first and the last through webinar; the second held in daily practice. The participants had to register structured observations. Results: The project has been joined by 155 discussants, and the 2,656 observations collected allowed the understanding of the most common therapeutic approaches for knee osteoarthritis on the Italian territory. Conclusions: The educational project proved to be useful for updating on the state of the art of therapeutic management of knee osteoarthritis, and to increase expertise in detecting prevention and treatment strategies according to ESCEO guidelines to apply in the Real-Life context.

GLUCOSAMINE: EVIDENCE IN THE TREATMENT OF OSTEOARTHRITIS

Article

Full-text available

Mar 2022

Osteoarthritis is a chronic multifactorial degenerative disease of the articular cartilage, characterized by joint pain and loss of function. Glucosamine consists of an amino-monosaccharide and an essential component of articular cartilage. It is produced endogenously, but it can also be administered as a slow-acting drug in osteoarthritis to reduce symptoms. This literature review aims to understand the effects of glucosamine on osteoarthritis, specifically its metabolism, mechanism of action, efficacy, and safety. A literature search was carried out, based on articles published in the last ten years, in “Pubmed” and “Sciencedirect” databases, using the descriptors “glucosamine” in association with “osteoarthritis” and “pharmacokinetics”. Official recommendations from health organizations were also considered. Orally administered glucosamine is absorbed in the duodenum and transported by GLUT-2 into cells. This compound participates in the hexosamine pathway, contributing to the biosynthesis of proteoglycans and glycoproteins, which are significant components of the extracellular matrix of the cartilage. In osteoarthritis, glucosamine has an anti-inflammatory and protective effect against cartilage degradation. According to the literature, the therapeutic dose of glucosamine capable of decreasing joint pain and improving function is 1500 mg/ day. The brand and formulation are essential factors for its effectiveness. This substance was considered safe, and no serious adverse effects or cases of overdose were observed. Glucosamine may have a positive effect on alleviating the symptoms of osteoarthritis. However, there is still no consensus on its efficacy, nutrient-drug interactions and impacts on glucose metabolism. Therefore, further studies are needed.

THE USE OF GLUCOSAMINE AND THE INCREASE OF IOP: A LITERATURE REVIEW

Article

Full-text available

Jul 2022

Highlights: 1. There are differences in the result of the use of glucosamine and the increase of intraocular pressure.2. There are many other factors that may contribute to the increase in the intraocular pressure other than the use of glucosamine such as races, genetics, different dose, and duration of glucosamine use. Abstract: Background: Glucosamine is an amino monosaccharide that can directly stimulate the synthesis of glycosaminoglycans in the cartilage. It has been widely used as an osteoarthritis treatment. However, several literatures show the possible side effects of glucosamine, such as increased intraocular pressure (IOP). Objective: The objective of this study was to determine if there was any correlation between the use of glucosamine and the increase in IOP. Material and Method: This was a descriptive qualitative study that implied a systematic review design. The study sample consisted of patients with osteoarthritis (OA) and glaucoma in Iran, Indonesia, Thailand, the USA, and India between 2013 and 2018. The literature search was conducted on a database (PubMed and Google Scholar) and selected using inclusion and exclusion criteria. Discussion: The research identified 5 studies on the use of glucosamine and the increase of IOP. Two articles provide significant results on the correlation between the use of glucosamine and the increase of IOP (P < 0.05). In addition, two studies showed significant IOP reduction outcomes after discontinuation of glucosamine (P < 0.05). A case series indicated an increase in IOP during the 6th month of glucosamine use but still at normal value. Conclusion: Many other factors contribute to IOP growth, other than the use of glucosamine. Therefore, a large-scale randomized clinical trial or a multicentre cohort study using the same parameters is still needed to improve the quality of the subsequent systematic review

Prescription-grade crystalline glucosamine sulfate as an add-on therapy to conventional treatments in erosive osteoarthritis of the hand: results from a 6-month observational retrospective study

Article

Full-text available

Jul 2022
AGING CLIN EXP RES

Objective To evaluate the efficacy of prescription-grade Crystalline Glucosamine Sulfate (pCGS) as an add-on treatment to conventional therapy, compared to usual therapy alone, in patients with erosive osteoarthritis of the hand (EHOA). Methods This 6-month retrospective case–control study included patients with concomitant knee osteoarthritis and symptomatic EHOA. Participants were stratified into two groups based on whether or not pCGS (1500 mg/day) was added to the conventional therapy (education and training in ergonomic principles, exercise and use on-demand of symptomatic drugs) for hand osteoarthritis. Patients were evaluated at baseline, after 3 and 6 months. Primary outcomes were the change from baseline to month 6 in Visual Analogue Scale (VAS) hand pain and in Functional Index for Hand Osteoarthritis (FIHOA) score. A set of secondary parameters was also evaluated. Results 123 patients were included as follows: 67 treated with pCGS in addition to conventional therapy (pCGS Group) and 56 with conventional therapy alone (Control Group). After 6 months a significant difference in VAS and in FIHOA score (p < 0.01 and p < 0.001, respectively) was observed in favor of pCGS Group. Similar results were found for morning stiffness duration (p < 0.05), health assessment questionnaire (p < 0.01) and physical and mental component score of 36-item short form (p < 0.05 and p < 0.001, respectively). A significant reduction of symptomatic drug consumption at 3 and 6 months was reported in the pCGS Group (p < 0.001). No serious adverse event was recorded in both groups. Conclusions Despite all the limitations inherent to an observational study, our results suggest the potential effectiveness of pCGS, when used in combination with conventional therapy in EHOA. Further randomized placebo-controlled trials are needed to confirm these positive findings. Trial Registration ClinicalTrials.gov, http://www.clinicaltrials.gov, date of registration: February 2, 2022, NCT05237596. The present trial was retrospectively registered.

Evaluation of the effects of glucosamine sulfate on poly (3-hydroxybutyrate)-chitosan/carbon nanotubes electrospun scaffold for cartilage tissue engineering applications

Article

Apr 2022

Osteoarthritis of the knee - biochemical aspect of applied therapies (review)

Article

Full-text available

Feb 2022

The most prevalent form of arthritis is osteoarthritis (OA) of the knee, which is characterized by a degeneration of articular cartilage resulting in the development of osteophytes, or bone spurs. Main goals of OA treatment are to reduce pain, slow the disease progression, and improve joint function and the quality of life. The purpose of this study was to verify all the therapies recommended by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) from the biochemical point of view. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesis of eicosanoids, whereas paracetamol prevents the production of prostaglandin (PG) by interacting with peroxidase (POX) site of the prostaglandin H2 synthase complex. Tramadol is an opioid that has a dual mechanism of action: it binds to the μ-opioid receptor and it inhibits serotonin and adrenaline. Corticosteroids, which are also prescribed for OA pain, inhibit the activity of phospholipase A2 and block the synthesis of arachidonate-derived eicosanoids. Symptomatic slow-acting drugs for osteoarthritis (SYSADOA) are drugs that are well tolerated by patients and help to restore proteoglycan matrix of the cartilage. These drugs include compounds that naturally build articular cartilage. The articular cartilage, as well as the bone located around the cartilage, are destroyed as osteoarthritis progresses. Thus, bisphosphonates, commonly used in the treatment of osteoporosis, were evaluated as potential therapy. However, there is no official recommendation for their use in therapy. The aim of the study was to analyze the biochemical mechanisms of principal drugs used for the treatment of knee OA. Therefore, a narrative review summarizing the current knowledge regarding the applied therapies was prepared.

Efficient production of D-glucosamine by diacetylchitobiose deacetylase catalyzed deacetylation of N-acetyl-D-glucosamine

Article

Full-text available

Mar 2022
BIOTECHNOL LETT

Objective d-Glucosamine (GlcN) is an important amino sugar with various applications in medicine, food & beverages, nutritional supplements, and dairy products. This study aimed to produce GlcN from N-acetyl-d-glucosamine (GlcNAc) with an efficient deacetylase, and apply different strategies to enhance GlcN production. Results We screened a series of deacetylases that involved in the deacetylation of GlcNAc to form GlcN. A diacetylchitobiose deacetylase (TKDac) from Thermococcus kodakarensis exhibited high-efficient deacetylation activity for GlcNAc, yet mostly in the form of inclusion bodies. The soluble expression of TKDac was improved by a co-expressing molecular chaperone (groEL) and TKDac, and insertion of rare codon ATA encoding isoleucine. As such, the recombinant strain TKEL4 was constructed to express TKDac, and 48 g/L GlcN was achieved by TKDac-catalyzed deacetylation. To overcome the inhibition of byproduct (acetate), immobilized TKDac was carried out to produce GlcN from GlcNAc. The immobilized TKDac was conveniently re-used for several batches (above 8) with a 90% conversion rate. Conclusions TKDac from T. kodakarensis was found to be an efficient deacetylase to produce GlcN. Co-expression of molecular chaperone and target protein, and insertion of rare codons were effective to improve the soluble expression of TKDac. The immobilized TKDac represents a promising method for future GlcN production.

Health Technology Assessment (HTA) evidence, regulatory classification and reimbursement of medicine: the case of glucosamine

Article

Nov 2021

Objectives To examine the relationship among Health Technology Assessment (HTA) evidence, regulatory classification and reimbursement of health products using glucosamine as a case study. Data of HTA evidence, regulatory classification and reimbursement of glucosamine from 13 countries were extracted from official government websites and peer-reviewed journal articles. Role and responsibility of HTA in each country along as well as the regulatory approval process and reimbursement status of health products were reviewed. The case of glucosamine was then analysed to explore the regulatory classification, reimbursement and its HTA evidence from past to present. Key findings For regulatory classification, we found that glucosamine is classified as either medicine (9 from 13 countries) or a dietary supplement (4 from 13 countries) depends on where glucosamine is seeking its market approval. Reimbursement also differs among the countries. We summarized the key factors that could be the cause of these variations. First, the clinical evidence of glucosamine is still in question especially its efficacy and as a results its cost-effectiveness. This evidence is important for policy consideration. Secondly, different level of HTA approach in each healthcare system and country context effect on how HTA evidence is utilized and synthesized. Lastly, company’s strategic positioning is the first key stakeholder to decide whether their product would be registered as medicine or dietary supplement. Summary The variation of HTA evidence in a diverse healthcare system affects regulatory classifications and reimbursement. This can result in different levels of patient access to health products.

The Implication of Reactive Oxygen Species and Antioxidants in Knee Osteoarthritis

Article

Full-text available

Jun 2021

Knee osteoarthritis (KOA) is a chronic multifactorial pathology and a current and essential challenge for public health, with a negative impact on the geriatric patient’s quality of life. The pathophysiology is not fully known; therefore, no specific treatment has been found to date. The increase in the number of newly diagnosed cases of KOA is worrying, and it is essential to reduce the risk factors and detect those with a protective role in this context. The destructive effects of free radicals consist of the acceleration of chondrosenescence and apoptosis. Among other risk factors, the influence of redox imbalance on the homeostasis of the osteoarticular system is highlighted. The evolution of KOA can be correlated with oxidative stress markers or antioxidant status. These factors reveal the importance of maintaining a redox balance for the joints and the whole body’s health, emphasizing the importance of an individualized therapeutic approach based on antioxidant effects. This paper aims to present an updated picture of the implications of reactive oxygen species (ROS) in KOA from pathophysiological and biochemical perspectives, focusing on antioxidant systems that could establish the premises for appropriate treatment to restore the redox balance and improve the condition of patients with KOA.

Glucosamine sulphate: an umbrella review of health outcomes

Article

Full-text available

Dec 2020
Ther Adv Musculoskelet Dis

Background and Aims: Glucosamine sulphate (GS) can be used as background therapy in people affected by knee osteoarthritis (OA). Knowledge regarding the efficacy and safety of GS is of importance since its use worldwide is increasing. Therefore, the present study aimed to map and grade the diverse health outcomes associated with GS using an umbrella review approach. Methods: Medline, Cinahl and Embase databases were searched until 1 April 2020. An umbrella review of systematic reviews and meta-analyses of randomized controlled trials (RCTs) was carried out. The evidence from the RCTs was graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. Results: From 140 articles returned, 11 systematic reviews, for a total of 21 outcomes (37 RCTs; 3949 participants; almost all using 1500 mg/day), were included. No systematic reviews/meta-analyses of observational studies were included. Regarding the findings of the meta-analyses, 9/17 outcomes were statistically significant, indicating that GS is more effective than placebo. A high certainty of evidence, as assessed by GRADE, supported the use of GS (versus placebo) in improving the Lequesne Index, joint space width change, joint space width change after 3 years of follow up, joint space narrowing and OA progression. No difference in terms of adverse effects was found between GS and placebo. In systematic reviews, GS was associated with a better glucose profile and a better physical function performance than placebo. Conclusion: GS, when used as a prescription drug (i.e. crystalline glucosamine sulphate) at 1500 mg daily dosage, can positively affect the cartilage structure, reduce pain, improve function and glucose metabolism in people with knee OA, without having a greater incidence of adverse effects than placebo.

Evaluation Factors Affecting on Falling of Elderly Women With Knee Arthritis Following Tai Chi ‎Exercises and Glucosamine

Article

Full-text available

Nov 2019

Elham Attari

Background Knee osteoarthritis is one of the most common musculoskeletal problems in older women. Objective The purpose of study is to evaluate certain physical fitness factors affecting on falling of elderly women with knee osteoarthritis following Tai Chi exercise and glucosamine supplementation. Methods In this semi-experimental study, 90 elderly women with knee osteoarthritis were chosen randomly with pre-test,post-test design from Qazvin city in 2016, whose arthritis were homogeneous with the Kellgren and Lawrence scale. Participants were randomly assigned into three groups. The 1st experimental group performed three times a week Tai Chi for three months, the 2nd experimental group consumed glucosamine supplement three times a week. The control group received no special intervention. To compare the differences between groups used paired t-test and analysis of variance. Findings T-test showed only Tai Chi exercise significantly improved the dynamic balance, lower limb strength, and flexibility, before and after intervention (P=0.001). The differences between three groups, by using Multivariate analysis of variance and Tukey post hoc test, the only difference between exercise and control groups was statistically significant in dynamic balance (P=0.001; F=12.19), lower limb strength (P=0.006; F=5.65) and flexibility (P=0.04; F=3.45). Conclusion Tai Chi exercise significantly decreased postural sway and improved physical fitness in elderly woman with knee osteoarthritis.

A retrospective observational study of glucosamine sulfate in addition to conventional therapy in hand osteoarthritis patients compared to conventional treatment alone

Article

Full-text available

Jun 2020
AGING CLIN EXP RES

Background The optimal management of hand osteoarthritis (HOA) is still challenging. Aim To evaluate the effects of glucosamine sulfate (GS) in addition to conventional therapy compared to conventional therapy alone in HOA. Methods This 6-month retrospective study included 108 patients with concomitant knee and hand OA. Fifty-five patients (GS Group) were treated for six consecutive months with crystalline GS (1500 mg once/day) in addition to conventional therapy for HOA [exercise combined with acetaminophen and/or non-steroidal anti-inflammatory drugs (NSAIDs)] and 53 patients (Control Group) with the conventional therapy alone. Primary outcomes were the difference between groups in the change of hand pain on a Visual Analogue Scale (VAS) and in the Functional Index for Hand Osteoarthritis (FIHOA) from baseline to 6 months. Secondary outcomes were Health Assessment Questionnaire (HAQ), medical outcomes study 36-item short form (SF-36) and symptomatic drug consumption. Results The patients who received GS presented a significant decrease (p < 0.001) in VAS pain and FIHOA scores compared with the Control Group at 3 and 6 months. Furthermore, GS therapy was associated to a significant improvement of HAQ score and to a significant reduction of acetaminophen and NSAID consumption during the follow-up. No differences in the number of side effects were observed between the groups. Discussion GS could represent a potential successful therapy for HOA and should be tried in large randomized placebo and active controlled trials. Conclusions The combination of GS with conventional treatment seems to be more effective in improving pain and function than conventional HOA treatment alone. Trial registration ClinicalTrials.gov, http://www.clinicaltrials.gov date of registration: April 9, 2019, NCT03911570. The present trial was retrospectively registered.

Correction to: Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis

Article

Full-text available

Sep 2019
RHEUMATOL INT

In the Original Publication, the e-mail address of the author Milan Petronijević is incorrect. The correct e-mail address is milanpetronijevic@yahoo.com.

Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis

Article

Full-text available

May 2019

Osteoarthritis (OA) is characterized by deterioration of the joints and associated with considerable pain and disability. OA is a chronic disease that requires intervention with both non-pharmacological and pharmacological treatment modalities and, inevitably, disease progression may necessitate successive treatments throughout the course of the disease. There is increasing data on the shortfalls of current pharmacological treatment of OA, and safety concerns associated with analgesic therapy use in OA arising from increasing evidence of gastrointestinal, cardiovascular, hepatic and renal adverse events with paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs). Consequently, symptomatic slow-acting drugs for OA (SYSADOAs) may now be considered as a first-line treatment for knee OA, with a particular emphasis placed on the outstanding benefit: risk ratio of pharmaceutical-grade glucosamine and chondroitin sulfate formulations. In this short communication we review recent publications concerned with the safety of paracetamol, NSAIDs and SYSADOAs. Greater understanding of the benefits and limitations of current medications will lead to better disease management in OA. Furthermore, adherence to guideline recommendations across Europe and internationally, such as those from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), will promote evidence-based medicine and patient-centric care, ultimately leading to greater physician and patient satisfaction.

Nutraceuticals in therapy of knee osteoarthritis: Orthopaedic view

Article

Apr 2018

Jiri Gallo

Knee osteoarthritis is one of the most frequent diagnoses of load-carrying joints encountered in orthopaedic surgeons offices. Depending on the clinical stage, the therapy starts with conservative treatment. Corrective osteotomy is indicated in younger patients without an extensive and serious impairment. Implantation of TKR (total knee replacement) is usually indicated in more advanced stages. One of the pillars of conservative therapy is analgesics and non-steroidal antirheumatic drugs. A specific group consists of perorally administered drugs for suppression of symptoms or even deceleration of knee osteoarthrosis. These products are popular mainly thanks to their good tolerance and minimal side effects. The clinical effect ranges between minimal and medium depending on the degree of osteoarthrosis, type of drug and study. Similar to rheumatologists, orthopaedic surgeons also find it difficult to identify candidates suitable for a particular type of therapy, except indication for TKR. By all means, nutraceuticals are still considered part of clinical practice.Key words: chondroitin sulphate - glucosamine sulphate - knee osteoarthrosis - methylsulfonylmethane - nutraceuticals - pharmaceutical intervention.

Nutrition supplementation combined with exercise versus exercise alone in treating knee osteoarthritis: a double-blinded, randomised, placebo-controlled trial

Article

Feb 2025
AGE AGEING

Objective To investigate the effectiveness of formula nutrition supplementation (mainly containing glucosamine sulphate, chondroitin sulphate and rhizoma drynariae) plus supervised exercise versus exercise alone for the treatment of knee osteoarthritis (OA). Methods This was a double-blinded, single-centre, randomised, placebo-controlled trial. The study recruited 65 participants (40–75 years) with knee OA. Participants were randomly allocated to nutrition supplementation plus exercise (N + E) group or placebo plus exercise (P + E) group. The intervention lasted for 6 months. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. Secondary outcomes included physical function and performance scores, lower extremity strength and serum biomarkers. Results Among the 65 randomised patients, 56 (86%) completed the trial. At 3 months, more participants in the N + E group than in the P + E group achieved minimum clinically important difference (MCID) in WOMAC total score (19/30 [63.3%] vs 8/26 [30.8%]; P < .01). At 6 months, more participants in the N + E group than in the P + E group achieved MCID in WOMAC stiffness score (19/30 [63.3%] vs 10/26 [38.5%]; P < .05). Meanwhile, at 6 months the decreased percentages of WOMAC stiffness score in the N + E group was greater than in the P + E group (P < .05). The flexor peak torque at 120°/s and 180°/s in the N + E group were significantly higher than those in the P + E group at 3 months (P < .05). Moreover, compared with baseline, improvements in the WOMAC overall and pain score, visual analogue scale pain and 30-second chair stand test were observed in both groups at 6 months. However, these indicators in the N + E group were improved as early as 3 months (P < .05). Conclusions The improvement effects of nutrition supplementation plus exercise were superior to those of exercise alone, and the improvement occurred earlier. Nutrition supplementation plus exercise would be a more efficient strategy for knee OA.

Using a discrete choice experiment to elicit patients’ preferences and willingness-to-pay for knee osteoarthritis treatments in Thailand

Article

Full-text available

Jul 2023

Osteoarthritis is the most common type of joint disease among elderly patients around the world. In response to the need for patient-centered care, patients’ and physicians’ preferences for knee osteoarthritis treatments have been studied in multiple countries, but not in Thailand. The objective of this study was to investigate Thai patients’ preferences and their willingness to pay (WTP) for knee osteoarthritis treatments by using a discrete choice experiment (DCE). Six knee osteoarthritis treatment attributes, including pain relief, delayed disease progression, gastrointestinal side effects, kidney side effects, cardiovascular side effects, and cost, were used to develop a paper-based, DCE questionnaire survey. Patients with knee osteoarthritis, who were at least 18 years old and who provided written informed consent, were recruited from the orthopedic department in a tertiary care hospital in Thailand via convenience sampling. The conditional logit model was used to determine patients’ preferences and WTP. The Institutional Review Board at Chulalongkorn University approved this study before it started. A total of 232 patients were collected and analyzed in this study. Patients preferred treatments with a higher efficacy (pain relief and delayed disease progression), a lower probability of side effects (gastrointestinal, kidney, and cardiovascular side effects), and a lower cost. Regarding efficacy and side effects, the patients weighted the importance of a 1% change in cardiovascular side effects (− 0.08) more heavily than 1% changes in kidney (− 0.07) and gastrointestinal (− 0.02) side effects, delayed disease progression (0.02), and pain relief (0.01). Patients were willing to pay 29.56 Thai Baht (THB) and 41.84 THB per month for every 1% increase in pain relief and delayed disease progression, respectively. Conversely, patients were willing to pay 52.04 THB, 145.18 THB and 164.23 THB per month for every 1% decrease in gastrointestinal, kidney, and cardiovascular side effects, respectively. In conclusion, pain relief, delayed disease progression, gastrointestinal side effects, kidney side effects, cardiovascular side effects, and the cost of treatment were significant factors among patients undergoing knee osteoarthritis treatment. Additionally, patients had a higher WTP for delayed disease progression than pain relief and a higher WTP for a reduced probability of cardiovascular side effects than gastrointestinal and kidney side effects. These findings could be used to support treatment decisions for knee osteoarthritis patients in Thailand.

Evidence-based therapy for knee osteoarthritis: expected short-, medium-, and long-term outcomes of prescription crystalline glucosamine sulfate administration

Article

Full-text available

Aug 2022

The need for effective drugs for the treatment of knee osteoarthritis (OA) is constantly growing. Current guidelines recommend the use of symptomatic slow acting drugs for osteoarthritis (SYSADOA) such as glucosamine (GCA) in this disease. Among various drugs containing GCA, high bioavailability and clinical efficacy have been shown only for prescription crystalline GCA sulfate (pGCAS) administration. Several meta-analyses and network meta-analyses have shown that efficacy of pGCAS 1500 mg once daily is superior to other GCA-based products (such as GCA hydrochloride with or without sodium sulfate) and the combination of GCA with chondroitin sulfate (CS) in terms of reducing the intensity of pain and improving the functional state. These studies confirmed the favorable safety profile of pGCAS, which was comparable to placebo in the incidence of adverse events. Pharmacoeconomic studies have also demonstrated greater cost-effectiveness of pGCAS compared to other GCA drugs.A group of Russian experts at a meeting of the advisory committee reviewed the evidence in favor of the use of pGCAS and evidence of its effectiveness in the treatment of knee OA in comparison with other products that include GCA, and the fixed combination of GCA with CS. Taking into account the results obtained, the use of pGCAS at a dose of 1500 mg once a day is recommended as a rational choice for the treatment of knee OA.

2021 revised algorithm for the management of knee osteoarthritis—the Chinese viewpoint

Article

Full-text available

Aug 2021
AGING CLIN EXP RES

Aim The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) algorithm for the management of knee osteoarthritis (OA) is available worldwide from 2014, but in 2019 an update was published. Based on this algorithm, a Working Group (WG), including ESCEO members and Chinese experts, wished to see how the new ESCEO algorithm was perceived by Chinese experts in knee OA and how it was integrated into their clinical practice. Methods A WG was held between members of the international ESCEO task force and a group of Chinese experts. Results Non-pharmacological approach should be combined with pharmacological interventions. In step 1, symptomatic slow-acting drugs for osteoarthritis (SYSADOA) are the most important background drugs. Evidence, supported by high-quality research, is available only for crystalline glucosamine sulfate (pCGS) and chondroitin sulfate. Topical NSAIDs could be used as an additional option. In step 2, oral NSAIDs could be useful, but cardiovascular/renal/gastrointestinal profiles of the patients should be considered. Intra-articular hyaluronic acid and corticosteroids are alternative to oral NSAIDs, but the evidence is still limited. If steps 1 and 2 are not sufficient, weak opioids could be used. Overall, the conclusions of the ESCEO algorithm are accepted in China for products available in this country. The WG suggests the importance of economic studies, specifically made in China. Conclusion This work provides evidence-based advice to establish a treatment algorithm in knee OA, for practical implementation in clinical practice in China.

2019 revised algorithm for the management of knee osteoarthritis: the Southeast Asian viewpoint

Article

Full-text available

Mar 2021
AGING CLIN EXP RES

Background Since 2014, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) algorithm for the management of knee osteoarthritis (OA) is available worldwide. Aim Based on this document, a Southeast Asia Working Group (SEAWG) wished to see how the new ESCEO algorithm developed in 2019 was perceived by Southeast Asian experts and how it was integrated into their clinical practice. Methods A SEAWG was set up between members of the international ESCEO task force and a group of Southeast Asian experts. Results Non-pharmacological management should always be combined with pharmacological management. In step 1, symptomatic slow-acting drugs for osteoarthritis are the main background therapy, for which high-quality evidence is available only for the formulations of patented crystalline glucosamine sulfate and chondroitin sulfate. In step 2, oral NSAIDs are a useful option, considering the cardiovascular/renal/gastrointestinal profiles of the individual patient. Intra-articular hyaluronic acid and corticosteroids are a possible alternative to oral NSAIDs, but limited evidence is available. If steps 1 and 2 do not give adequate relief of symptoms, tramadol can be used, but its safety is debated. In general, the indications of the ESCEO algorithm are important in Southeast Asian countries, but the reimbursement criteria of local health systems are an important aspect for adherence to the ESCEO algorithm. Conclusion This guidance provides evidence-based and easy-to-follow advice on how to establish a treatment algorithm in knee OA, for practical implementation in clinical practice in Southeast Asian countries.

Nutraceutical Alternatives to Pharmaceutical Analgesics in Osteoarthritis

Chapter

Full-text available

Mar 2021

Chronic pain is a considerable health concern worldwide, effecting almost 30% of all European adults. Osteoarthritis (OA), a progressive pro-inflammatory condition, is one of the leading causes of chronic pain (effecting 13% of all those over 50 years, globally) and is the most common cause of joint pain. The prevalence of non-steroidal anti-inflammatory drug (NSAIDs) and analgesic use has been well studied and is abundant throughout the western world, with women being the greatest users and ibuprofen generally being the most reported NSAID. In the US, 65% of all OA patients are prescribed NSAIDs for pain management and form part of the current recommended strategy for OA clinical management. While some NSAIDs and analgesics are effective at improving pain and physical function, they come with significant and harmful side effects such as gastrointestinal complications, renal disturbances and severe cardiovascular events. Given these side-effects, any reduction in NSAID and analgesia use (and the resulting potentially harmful side effects) is of particular importance to OA public health. As such, a number of non-pharmaceutical alternatives (bioactive nutraceuticals) have been developed that may reduce NSAID and analgesia use while maintaining pain reduction and improvements in physical function. This chapter will discuss select nutraceuticals that are not currently in mainstream use but may have the potential to aid in the treatment of OA.

Subchronic toxicity evaluation of glucosamine and glucosamine in combination with chondroitin sulfate in obese Zucker rats

Article

Dec 2020

D-Glucosamine is a widely consumed dietary supplement used to promote joint health and treat osteoarthritis. It also stimulates intracellular hexosamine flux and increases transforming growth factor β1 (TGFβ1) mRNA expression and insulin resistance in animal studies. The effects of D-glucosamine exposure were investigated in obese Zucker rats. Male (leprfa/leprfa) Zucker rats were exposed to 30, 120, 300 and 600 mg D-glucosamine HCl per kg/day either alone or with chondroitin sulfate (24, 96, 240 and 480 mg/kg/day respectively) for 90 days. After 4 weeks exposure, these doses produced Cmax D-glucosamine concentrations of up to 24 μM in tail vein serum concurrent with a transient 30% increase in blood glucose concentration in the 600 mg/kg/day dose group. D-Glucosamine did not significantly alter body weight, blood glucose or serum insulin levels at any dose tested after 13 weeks exposure, but did increase urinary TGFβ1 concentrations. The Zucker rats developed nephropathy and scrotal sores that were related to their hyperglycemia and obesity, and D-glucosamine exposure exacerbated these conditions to a small extent. The incidence of pulmonary osseous metaplasia was increased in rats exposed to D-glucosamine and a single incidence of adrenal osseous metaplasia was noted in one animal exposed to 600/480 mg D-glucosamine HCl/chondroitin sulfate. These lesions may have been treatment related. These studies suggest that the risk of adverse effects of oral D-glucosamine is small compared to that of hyperglycemia in these animals, but the potential for TGFβ1-mediated pathologies, such as osseous metaplasia and renal nephropathy may be increased.

Many years of experience in using a combination of glucosamine and chondroitin in clinical practice

Article

Full-text available

Jul 2020

The article presents the main approaches to choosing the treatment of osteoarthritis and the main links in the pathogenesis of this disease. The effects of glucosamine and chondroitin on the main pathogenetic mechanisms of osteoarthritis that prevent its progression are described. There are discussed an effectiveness and safety of treatment of the disease with a focus on the use of a combination of glucosamine hydrochloride and chondroitin sulfate (Arthra), as well as their combination with methylsulfonylmethane and sodium hyaluronic acid (Arthra MSM). Methylsulfonylmethane reduces pain, it is involved in the processes of maintaining and regeneration of connective tissue, in the synthesis of sulfated glycosaminoglycans and collagen. It is suggested that this compound may have analgesic and anti-inflammatory properties due to the inhibition of the nuclear factor kB signaling pathway, which allows to reduce the local and systemic inflammatory response, as well as suppressing the expression of proinflammatory cytokines and much more. This article also presents experimental and clinical evidence of the effectiveness and safety of these compounds. It has been convincingly demonstrated the possibility with these drugs to reduce joint pain and the need for analgesics and non-steroidal anti-inflammatory drugs, to improve the quality of life. Currently, symptomatic slow-acting drugs, which include the discussed ones, are recommended to be prescribed as first-line drugs for the treatment of osteoarthritis. Timely administration of symptomatic slow-acting drugs, their long-term use contributes not only to reducing the progression of the disease, but also makes it possible to avoid or delay endoprosthetics. In this article there is indicated the contribution of Russian scientists to obtaining evidence of the effectiveness and safety of Arthra and Arthra MSM in the application of various treatment modes in osteoarthritis of the knee joints and lower back pain.

Mineral rich algae with pine bark improved pain, physical function and analgesic use in mild-knee joint osteoarthritis, compared to Glucosamine: A randomized controlled pilot trial

Article

Feb 2020
COMPLEMENT THER MED

Introduction Osteoarthritis (OA) is characterised by synovial joint pain, functional disability and affects ∼13% of people worldwide, of which ∼16-27% report Knee-OA (KOA). Glucosamine (Glu) is the most widely used nutraceutical treatment for OA despite a lack of scientific consensus, therefore alternative nutraceutical treatments are required. The aim of this study was to investigate the effect of Lithothamnion species, seawater-derived magnesium and pine bark (Aq⁺) on pain, symptoms and improve physical function in symptomatic (sKOA), compared to Glu. Methods 358 participants were screened. In a double-blinded crossover pilot-trial, sKOA participant (n = 30) were randomly assigned to either the Glu group (2000 mg day⁻¹) or Aq⁺ (3056 mg day⁻¹) for 12 weeks (clinicaltrials.gov:NCT03106584). The Knee Injury and Osteoarthritis Outcome Score was used to assess subjective pain and symptoms. Timed-up-and-Go (TuG) and Six minute walking distance were used to assess functional change and analgesic use was recorded. Results Aq⁺ improved pain, with a large effect (P < 0.01, d’ = 0.73, 95%CI 0.201-1.265) and no change for Glu (d’ = 0.38, P = 0.06). Only Aq⁺ improved pain (P < 0.05) for males (d’ = 0.91, 95%CI 0.162-1.667) and females (d’ = 0.55, 95%CI 0.210-1.299). In females, Aq⁺ improved TuG by -7.02% (d’ = 0.92, 95%CI 1.699-0.141) while Glu worsened performance by 4.18% (P = 0.04). Aq⁺ reduced analgesia by 71.6%, compared to Glu (P = 0.02; d’ = 0.82, 95%CI 1.524-0.123). Aq⁺ was superior to Glu at improving pain, KOOS subscales, physical function and analgesia use in mild-sKOA. Given these data, Aq⁺ should be considered as a supplementary treatment for early-stage-KOA and may have the potential to reduce use of pain medication, although larger replication studies are required.

Algorithm for the management of patients at low, high and very high risk of osteoporotic fractures

Article

Full-text available

Nov 2019

Guidance is provided in an international setting on the assessment and specific treatment of postmenopausal women at low, high and very high risk of fragility fractures. Introduction The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2019. This manuscript seeks to apply this in an international setting, taking additional account of further categorisation of increased risk of fracture, which may inform choice of therapeutic approach. Methods Clinical perspective and updated literature search. Results The following areas are reviewed: categorisation of fracture risk and general pharmacological management of osteoporosis. Conclusions A platform is provided on which specific guidelines can be developed for national use to characterise fracture risk and direct interventions.

An updated algorithm recommendation for the management of knee osteoarthritis from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO)

Article

Full-text available

Apr 2019
SEMIN ARTHRITIS RHEU

Objectives: The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) sought to revisit the 2014 algorithm recommendations for knee osteoarthritis (OA), in light of recent efficacy and safety evidence, in order to develop an updated stepwise algorithm that provides practical guidance for the prescribing physician that is applicable in Europe and internationally. Methods: Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process, a summary of evidence document for each intervention in OA was provided to all members of an ESCEO working group, who were required to evaluate and vote on the strength of recommendation for each intervention. Based on the evidence collected, and on the strength of recommendations afforded by consensus of the working group, the final algorithm was constructed. Results: An algorithm for management of knee OA comprising a stepwise approach and incorporating consensus on 15 treatment recommendations was prepared by the ESCEO working group. Both "strong" and "weak" recommendations were afforded to different interventions. The algorithm highlights the continued importance of non-pharmacological interventions throughout the management of OA. Benefits and limitations of different pharmacological treatments are explored in this article, with particular emphasis on safety issues highlighted by recent literature analyses. Conclusions: The updated ESCEO stepwise algorithm, developed by consensus from clinical experts in OA and informed by available evidence for the benefits and harms of various treatments, provides practical, current guidance that will enable clinicians to deliver patient-centric care in OA practice.

The Comparison of Effects between Tai Chi Exercise and Glucosamine Supplementation on Balance in Older Woman with Knee Osteoarthritis

Article

Full-text available

Oct 2017

Introduction: Knee osteoarthritis is one of the most common musculoskeletal problems in older women which affects their daily life. It causes balance impairment, and increases the rate of falling in these patients. Therefore, the aim of this study was to compare the effects between tai chi exercise and glucosamine supplementation on the balance of older women with knee osteoarthritis. Materials and Methods: This was a clinical trial study, in which 75 women with knee osteoarthritis (according to the Kellgren and Lawrence scale) were chosen, and randomly assigned into 3 groups of tai chi exercise (performed 3 times a week for 3 month), glucosamine supplementation (3 times a week), and control (no intervention). Before and after interventions, static balance (measured by stabilometer in both open and closed eye) and dynamic balance [measured by timed up and go (TUG) test] were examined. Paired sample t and ANOVA tests were implemented for data analyzing at a significant level of less than 0.050. Results: Tai chi exercise had a significant effect on static [open (t = 9.57, P = 0.001) and closed (t = 5.30, P = 0.001) eye] and dynamic balance (t = 8.54, P = 0.001); supplementation variable had a significant effect only on dynamic balance (t = 2.21, P = 0.040); in control group, there was not any significant difference between before and after intervention. Comparing three groups, the ANOVA test showed a significant difference between the exercise and control group in static [open (P = 0.001) and closed (P = 0.001) eye] and dynamic balance (P = 0.040). Conclusion: It seems that tai chi exercises enhance the balance in older women with knee osteoarthritis. It also could be concluded from the results that only the exercise variable has the significant effect on subject’s balance compared to glucosamine supplementation. Keywords: Osteoarthritis of knee, Exercise therapy, Glucosamine, Accidental falls, Elderly, Women

Improvement of Visual and Spatial Memory as a Result of Neurofeedback with an Emphasis on Decreasing Beta Wave and Increasing SMR Wave

Article

Oct 2018

Introduction: Neurofeedback training is known as a useful and inexpensive tool for enhancing and improving in memory types, however, its effect on the visual and spatial memory has no been investigated yet. Therefore, the aim of this study was to improve visual and spatial memory because of neurofeedback training with an emphasis on decreasing beta wave and increasing SMR wave. Method: The present study’s design was a within group with a pre-test post-test method. The research method was semi-experimental and in terms of purpose was applied. To did this research, 11 students (mean age: 27.63 ± 2.76) participated voluntarily in this study. By obtaining informed consent, the visual memory pre-test was first taken from the subjects through short-term visual test of the Vienna and spatial memory through the LM-01 spatial memory device. Then subjects perform for 5 sessions of neurofeedback training protocol with an emphasis on decreasing beta wave and increasing SMR wave. After training completion, the post-test was done. The data were analyzed by paired t-test at a significant level of p≤0.05. Results: The results showed that neurofeedback training significantly improved visual memory (P≤0.020) and spatial memory (P≤0.013). Conclusion: Therefore, neurofeedback training can be considered as useful tools for improving cognitive abilities such as memory.

Lifestyle Intervention to Improve Mobility in Apparently Healthy Chinese Elders: A Hypothesis Generating Study: 10th International Symposium

Chapter

Jan 2019

Population aging has emerged as a major demographic trend worldwide due to improved health and longevity. This has a major impact on healthcare systems. In order to have a healthy life in old age, the maintenance of good physical function or mobility is fundamental because it allows older people to perform basic activities of daily living necessary for independence, to avoid falls causing injuries, and hence to have the quality of life they desire.

General Protocol to Obtain D‐Glucosamine from Biomass Residues: Shrimp Shells, Cicada Sloughs and Cockroaches

Article

Full-text available

Aug 2018

A general protocol is developed to obtain D‐glucosamine from three widely available biomass residues: shrimp shells, cicada sloughs, and cockroaches. The protocol includes three steps: (1) demineralization, (2) deproteinization, and (3) chitin hydrolysis. This simple, general protocol opens the door to obtain an invaluable nitrogen‐containing compound from three biomass residues, and it can potentially be applied to other chitin sources. White needle‐like crystals of pure D‐glucosamine are obtained in all cases upon purification by crystallization. Characterization data (NMR, IR, and mass spectrometry) of D‐glucosamine obtained from the three chitin sources are similar and confirm its high purity. NMR investigation demonstrates that D‐glucosamine is obtained mainly as the α‐anomer, which undergoes mutarotation in aqueous solution achieving equilibrium after 440 min, in which the anomeric glucosamine distribution is 60% α‐anomer and 40% β‐anomer. The valuable nitrogen‐containing compound D‐glucosamine is easily obtained from biomass residues such as shrimp shells, cicada sloughs, and cockroaches, utilizing a simple, general protocol. The mutarotation process of D‐glucosamine obtained is investigated by 1H NMR, showing that the anomeric equilibrium in aqueous solution is achieved after 440 min.

Chondroitin, glucosamine, diacerein, piascledine, and methylsulphonylmethane in the prevention and treatment of joint diseases

Article

Full-text available

Jan 2017

Metabolic disorders and inflammatory processes in cartilage tissue have a pivotal role in the course of degenerative and other joint diseases. These processes are aimed at by orally administered medication for treatment of osteoarthritis and joint symptoms. Some of these substances stimulate recovery of the extracellular matrix in the cartilage, take part in its metabolic regulation and supress inflammatory changes to a certain extent. These drugs have a slow onset of effect, alleviate symptoms and are thought to have a disease-modifying effect. Chondroitin sulfate and glucosamine sulfate are most commonly used and best studied; less information is available for diacerein, piascledine and methylsulfonylmethane. An agreement on their clinical usefulness is yet to be found. Most of the clinical societies involved in osteoarthritis treatment recommend administering these substances. However, significance of this intervention can differ in various guidelines.

Assessing the quality of reports of RCT: is blinding necessary?

Article

Full-text available

Jan 1996

Efficacy and Safety of Glucosamine Sulfate in the Management of Osteoarthritis: Evidence from Real-Life Setting Trials and Surveys

Article

Full-text available

Dec 2015
SEMIN ARTHRITIS RHEU

The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm recommends chronic symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) including glucosamine sulfate (GS) and chondroitin sulfate (CS) as first-line therapy for knee osteoarthritis (OA). Numerous studies are published on the use of SYSADOAs in OA; however, the efficacy of this class is still called into question largely due to the regulatory status, labeling and availability of these medications differ substantially across the world. Examination of the evidence for the prescription patented crystalline GS (pCGS) formulation at a dose of 1500mg once-daily demonstrates superiority over other GS and glucosamine hydrochloride (GH) formulations and dosage regimens. Thus, the ESCEO task force advocates differentiation of prescription pCGS over other glucosamine preparations. Long-term clinical trials and real-life studies show that pCGS may delay joint structural changes, suggesting potential benefit beyond symptom control when used early in the management of knee OA. Real-life pharmacoeconomic studies demonstrate a long-term reduction in the need for additional pain analgesia and non-steroidal anti-inflammatory drugs (NSAIDs) with pCGS, with a significant reduction of over 50% in costs associated with medications, healthcare consultations and examinations over 12 months. Furthermore, treatment with pCGS for at least 12 months leads to a reduction in the need for total joint replacement for at least 5 years following treatment cessation. Thus, pCGS (1500mg od) is a logical choice to maximize clinical benefit in OA patients, with demonstrated medium-term control of pain and lasting impact on disease progression.

Effects of Glucosamine Sulfate on the use of Rescue Non-Steroidal Anti-Inflammatory Drugs in Knee Osteoarthritis: Results From The Pharmaco-Epidemiology Of Gonarthrosis (PEGAsus) Study

Article

Full-text available

Oct 2015
SEMIN ARTHRITIS RHEU

Background and objective: The use of Symptomatic Slow-Acting Drugs in Osteoarthritis (SYSADOAs) may be expected to decrease the use of concomitant medications for rescue analgesia, including non-steroidal anti-inflammatory drugs (NSAIDs). The Pharmaco-Epidemiology of GonArthroSis (PEGASus) study was designed to assess this possibility. Methods: PEGASus was a cohort study of continuous recruitment of patients with "dynamic" exposure to the investigated SYSADOA (crystalline glucosamine sulfate, glucosamine hydrochloride, chondroitin sulfate, diacerein, and avocado-soybean unsaponifiables, all at approved dosages). Investigators were rheumatologists or general practitioners randomly selected from French telephone lists. Patients diagnosed with knee osteoarthritis (OA) were recruited when consulting an investigator for a symptom flare and were prescribed, or not, one of the SYSADOAs as per clinical judgment. Follow-up visits were as per routine medical practice in the 12 months following enrollment, with telephone interviews after 1 month and at 4-month intervals thereafter up to 24 months. Use of NSAIDs was recorded, as well as the dynamism of treatment exposure consisting of continuing the prescribed SYSADOA, switching, discontinuation or initiation of a SYSADOA. Patient exposure was expressed in 2-month time units, with any NSAID use as Yes/No binary outcome during each unit. Odds ratios [OR and 95% confidence interval (CI)] of NSAID use were calculated for periods of exposure to each SYSADOA, by multivariate logistic regression for an 80% power and 95% confidence to see a decrease of at least 15%. Results: This report consists of the full data pertaining to crystalline glucosamine sulfate, while results of other SYSADOAs were summarized as available from the French Health Authority (HAS) website (www.has-sante.fr). Of 6451 patients in the PEGASus cohort, 315 patients received crystalline glucosamine sulfate, they were exposed for 481 2-month time units and had an incident use of NSAIDs of 18.7%. In the control cohort (9237 time units) NSAID incident use was 23.8%. Crystalline glucosamine sulfate significantly decreased the risk of NSAID consumption by up to 36% (OR = 0.64; 95% CI: 0.45-0.92) in the primary analysis foreseen by the protocol; OR was 0.74 95% CI: 0.54-1.01), i.e. at the very limit of significance, in a sensitivity analysis accounting for an extension of the study and of the control cohort. None of the other SYSADOAs showed any hint of a decrease in the use of NSAIDs. Conclusion: Crystalline glucosamine sulfate was the only SYSADOA that decreased the use of NSAIDs in this pharmaco-epidemiology study in patients with knee OA.

Comments on the discordant recommendations for the use of symptomatic slow acting drugs in knee osteoarthritis

Article

Full-text available

Mar 2015

Abstract Despite the near concurrent publication by influential scientific organizations, there are important differences in interpretation of the evidence base and the conclusions derived from the recent Osteoarthritis Research Society International (OARSI) guidelines for the management of knee osteoarthritis, the American College of Rheumatology (ACR) (concerning also hip and hand osteoarthritis) and the algorithm recommendations by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). This is particularly evident for the drug class of Symptomatic Slow-Acting Drugs in OsteoArthritis. In this paper, we highlight these differences and try to understand where they derive from, proposing an evidence-based interpretation.

An Algorithm Recommendation for the Management of Knee Osteoarthritis in Europe and Internationally: A Report From a Task Force of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO)

Article

Full-text available

Dec 2014
SEMIN ARTHRITIS RHEU

Objectives Existing practice guidelines for osteoarthritis (OA) analyze the evidence behind each proposed treatment but do not prioritize the interventions in a given sequence. The objective was to develop a treatment algorithm recommendation that is easier to interpret for the prescribing physician, based on the available evidence and applicable in Europe and internationally. The knee was used as the model OA joint. Methods ESCEO assembled a task force of 13 international experts (rheumatologists, clinical epidemiologists, clinical scientists). Existing guidelines were reviewed, all interventions listed and recent evidence retrieved using established databases. A first schematic flow chart with treatment prioritization was discussed in a one-day meeting and shaped to the treatment algorithm. Fine tuning occurred by electronic communication and three consultation rounds until consensus. Results Basic principles consist of the need of combined pharmacological and non-pharmacological treatment, with a core set of initial measures including information access/education, weight loss if overweight and an appropriate exercise program. Four multimodal steps are then established. Step 1 consists of background therapy, either non-pharmacological (referral to a physical therapist for re-alignment treatment if needed and sequential introduction of further physical interventions initially and at any time thereafter) and pharmacological. The latter consists of chronic Symptomatic Slow Acting Drugs for OA (e.g. prescription glucosamine sulfate and/or chondroitin sulfate) with paracetamol at-need; topical NSAIDs are added in the still symptomatic patient. Step 2 consists of the advanced pharmacological management in the persistent symptomatic patient and is centered on the use of oral COX-2 selective or non-selective NSAIDs, chosen based on concomitant risk factors, with intra-articular corticosteroids or hyaluronate for further symptom relief if insufficient. In Step 3, the last pharmacological attempts before surgery are represented by weak opioids and other central analgesics. Finally, Step 4 consists of end-stage disease management and surgery, with classical opioids as a difficult to manage alternative when surgery is contraindicated. Conclusions The proposed treatment algorithm may represent a new framework for the development of future guidelines for the management of OA, more easily accessible to physicians.

How to define responders in osteoarthritis

Article

Full-text available

Apr 2013
CURR MED RES OPIN

Background: Osteoarthritis is a clinical syndrome of failure of the joint accompanied by varying degrees of joint pain, functional limitation, and reduced quality of life due to deterioration of articular cartilage and involvement of other joint structures. Scope: Regulatory agencies require relevant clinical benefit on symptoms and structure modification for registration of a new therapy as a disease-modifying osteoarthritis drug (DMOAD). An international Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and International Osteoporosis Foundation was convened to explore the current burden of osteoarthritis, review current regulatory guidelines for the conduct of clinical trials, and examine the concept of responder analyses for improving drug evaluation in osteoarthritis. Findings: The ESCEO considers that the major challenges in DMOAD development are the absence of a precise definition of the disease, particularly in the early stages, and the lack of consensus on how to detect structural changes and link them to clinically meaningful endpoints. Responder criteria should help identify progression of disease and be clinically meaningful. The ideal criterion should be sensitive to change over time and should predict disease progression and outcomes such as joint replacement. Conclusion: The ESCEO considers that, for knee osteoarthritis, clinical trial data indicate that radiographic joint space narrowing >0.5 mm over 2 or 3 years might be a reliable surrogate measure for total joint replacement. On-going research using techniques such as magnetic resonance imaging and biochemical markers may allow the identification of these patients earlier in the disease process.

Crystalline glucosamine sulfate in the management of knee osteoarthritis: Efficacy, safety, and pharmacokinetic properties

Article

Full-text available

Jun 2012
Ther Adv Musculoskelet Dis

Glucosamine is an amino monosaccharide and a natural constituent of glycosaminoglycans in articular cartilage. When administered exogenously, it is used for the treatment of osteoarthritis as a prescription drug or a dietary supplement. The latter use is mainly supported by its perception as a cartilage building block, but it actually exerts specific pharmacologic effects, mainly decreasing interleukin 1-induced gene expression by inhibiting the cytokine intracellular signaling cascade in general and nuclear factor-kappa B (NF-kB) activation in particular. As a whole, the use of glucosamine in the management of osteoarthritis is supported by the clinical trials performed with the original prescription product, that is, crystalline glucosamine sulfate. This is the stabilized form of glucosamine sulfate, while other formulations or different glucosamine salts (e.g. hydrochloride) have never been shown to be effective. In particular, long-term pivotal trials of crystalline glucosamine sulfate 1500 mg once daily have shown significant and clinically relevant improvement of pain and function limitation (symptom-modifying effect) in knee osteoarthritis. Continuous administration for up to 3 years resulted in significant reduction in the progression of joint structure changes compared with placebo as assessed by measuring radiologic joint space narrowing (structure-modifying effect). The two effects combined may suggest a disease-modifying effect that was postulated based on an observed decrease in the risk of undergoing total joint replacement in the follow up of patients receiving the product for at least 12 months in the pivotal trials. The safety of the drug was good in clinical trials and in the postmarketing surveillance. Crystalline glucosamine sulfate 1500 mg once daily is therefore recommended in the majority of clinical practice guidelines and was found to be cost effective in pharmacoeconomic analyses. Compared with other glucosamine formulations, salts, or dosage forms, the prescription product achieves higher plasma and synovial fluid concentrations that are above the threshold for a pharmacologically relevant effect, and may therefore justify its distinct therapeutic characteristics.

Role of glucosamine in the treatment for osteoarthritis

Article

Full-text available

Mar 2012
RHEUMATOL INT

Over the last 20 years, several studies have investigated the ability of glucosamine sulfate to improve the symptoms (pain and function) and to delay the structural progression of osteoarthritis. There is now a large, convergent body of evidence that glucosamine sulfate, given at a daily oral dose of 1,500 mg, is able to significantly reduce the symptoms of osteoarthritis in the lower limbs. This dose of glucosamine sulfate has also been shown, in two independent studies, to prevent the joint space narrowing observed at the femorotibial compartment in patients with mild-to-moderate knee osteoarthritis. This effect also translated into a 50 % reduction in the incidence of osteoarthritis-related surgery of the lower limbs during a 5-year period following the withdrawal of the treatment. Some discrepancies have been described between the results of studies performed with a patent-protected formulation of glucosamine sulfate distributed as a drug and those having used glucosamine preparations purchased from global suppliers, packaged, and sold over-the-counter as nutritional supplements.

Experimental Pharmacology of Glucosamine Sulfate

Article

Full-text available

Jan 2011

Several clinical studies demonstrated that glucosamine sulfate (GS) is effective in controlling osteoarthritis (OA), showing a structure-modifying action. However, little is known about the molecular mechanism(s) by which GS exerts such action and about the effects of GS at a tissue level on osteoarthritic cartilage and other joint structures. Here we provide mechanistic evidence suggesting that in vitro GS attenuates NF-κB activation at concentrations in the range of those observed after GS administration to volunteers and patients, thus strengthening previous findings. Furthermore, we describe the effects of GS at a tissue level on the progression of the disease in a relevant model of spontaneous OA, the STR/ort mouse. In this model, the administration of GS at human corresponding doses was associated with a significant decrease of OA scores. Histomorphometry showed that the lesion surface was also significantly decreased, while the number of viable chondrocytes within the matrix was significantly increased. GS improved the course of OA in the STR/Ort mouse, by delaying cartilage breakdown as assessed histologically and histomorphometrically.

Current role of glucosamine in the treatment of osteoarthritis

Article

Full-text available

May 2007

To evaluate the interest of using the various preparations of glucosamine for symptomatic and structural management of osteoarthritis (OA). A critical analysis of the literature based on an exhaustive search (Medline, PubMed and manual search within the bibliography of retrieved manuscripts) from 1980 to 2005. Despite multiple controlled clinical trials of the use of glucosamine in OA (mainly of the knee), controversy on efficacy related to symptomatic improvement continues. Differences in results originate from the differences in products, study design and study populations. Symptomatic efficacy described in multiple studies performed with glucosamine sulphate (GS) support continued consideration in the OA therapeutic armamentarium. The most compelling evidence of a potential for inhibiting the progression of OA is also obtain with GS. GS has shown positive effects on symptomatic and structural outcomes of knee OA. These results should not be extrapolated to other glucosamine salts [hydrochloride or preparations (over-the-counter or food supplements)] in which no warranty exists about content, pharmacokinetics and pharmacodynamics of the tablets.

Assessing the quality of reports of randomized clinical trials: Is blinding necessary?

Article

Full-text available

Feb 1996
Contr Clin Trials

It has been suggested that the quality of clinical trials should be assessed by blinded raters to limit the risk of introducing bias into meta-analyses and systematic reviews, and into the peer-review process. There is very little evidence in the literature to substantiate this. This study describes the development of an instrument to assess the quality of reports of randomized clinical trials (RCTs) in pain research and its use to determine the effect of rater blinding on the assessments of quality. A multidisciplinary panel of six judges produced an initial version of the instrument. Fourteen raters from three different backgrounds assessed the quality of 36 research reports in pain research, selected from three different samples. Seven were allocated randomly to perform the assessments under blind conditions. The final version of the instrument included three items. These items were scored consistently by all the raters regardless of background and could discriminate between reports from the different samples. Blind assessments produced significantly lower and more consistent scores than open assessments. The implications of this finding for systematic reviews, meta-analytic research and the peer-review process are discussed.

Long-term effects of glucosamine sulphate on osteoarthritis progression: A randomised, placebo-controlled clinical trial

Article

Full-text available

Feb 2001

Treatment of osteoarthritis is usually limited to short-term symptom control. We assessed the effects of the specific drug glucosamine sulphate on the long-term progression of osteoarthritis joint structure changes and symptoms. We did a randomised, double-blind placebo controlled trial, in which 212 patients with knee osteoarthritis were randomly assigned 1500 mg sulphate oral glucosamine or placebo once daily for 3 years. Weightbearing, anteroposterior radiographs of each knee in full extension were taken at enrolment and after 1 and 3 years. Mean joint-space width of the medial compartment of the tibiofemoral joint was assessed by digital image analysis, whereas minimum joint-space width--ie, at the narrowest point--was measured by visual inspection with a magnifying lens. Symptoms were scored by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index. The 106 patients on placebo had a progressive joint-space narrowing, with a mean joint-space loss after 3 years of -0.31 mm (95% CI -0.48 to -0.13). There was no significant joint-space loss in the 106 patients on glucosamine sulphate: -0.06 mm (-0.22 to 0.09). Similar results were reported with minimum joint-space narrowing. As assessed by WOMAC scores, symptoms worsened slightly in patients on placebo compared with the improvement observed after treatment with glucosamine sulphate. There were no differences in safety or reasons for early withdrawal between the treatment and placebo groups. The long-term combined structure-modifying and symptom-modifying effects of gluosamine sulphate suggest that it could be a disease modifying agent in osteoarthritis.

Glucosamine Sulfate Use and Delay of Progression of Knee Osteoarthritis: A 3-Year, Randomized, Placebo-Controlled, Double-blind Study

Article

Full-text available

Oct 2002
ARCH INTERN MED

Conventional symptomatic treatments for osteoarthritis do not favorably affect disease progression. The aim of this randomized, placebo-controlled trial was to determine whether long-term (3-year) treatment with glucosamine sulfate can modify the progression of joint structure and symptom changes in knee osteoarthritis, as previously suggested. Two hundred two patients with knee osteoarthritis (using American College of Rheumatology criteria) were randomized to receive oral glucosamine sulfate, 1500 mg once a day, or placebo. Changes in radiographic minimum joint space width were measured in the medial compartment of the tibiofemoral joint, and symptoms were assessed using the algo-functional indexes of Lequesne and WOMAC (Western Ontario and McMaster Universities). Osteoarthritis was of mild to moderate severity at enrollment, with average joint space widths of slightly less than 4 mm and a Lequesne index score of less than 9 points. Progressive joint space narrowing with placebo use was -0.19 mm (95% confidence interval, -0.29 to -0.09 mm) after 3 years. Conversely, there was no average change with glucosamine sulfate use (0.04 mm; 95% confidence interval, -0.06 to 0.14 mm), with a significant difference between groups (P =.001). Fewer patients treated with glucosamine sulfate experienced predefined severe narrowings (>0.5 mm): 5% vs 14% (P =.05). Symptoms improved modestly with placebo use but as much as 20% to 25% with glucosamine sulfate use, with significant final differences on the Lequesne index and the WOMAC total index and pain, function, and stiffness subscales. Safety was good and without differences between groups. Long-term treatment with glucosamine sulfate retarded the progression of knee osteoarthritis, possibly determining disease modification.

Active ingredient consistency of commercially available glucosamine sulfate products

Article

Full-text available

Dec 2002

To assess the content of active ingredient in over-the-counter (OTC) glucosamine sulfate (GLS) preparations. We analyzed in a coded, blind manner 14 commercially available capsules or tablets of GLS, plus one herbal mixture as a control. We used a high performance liquid chromatography system as described. The amount of free base varied from 41 to 108% of the mg content stated on the label; the amount of glucosamine varied from 59 to 138% even when expressed as sulfate. If GLS is used as a therapeutic agent, it is important that the products conform to a standard in their description. The content is probably best expressed in terms of free base.

EULAR Recommendations 2003: An evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT)

Article

Full-text available

Jan 2004

To update the EULAR recommendations for management of knee osteoarthritis (OA) by an evidence based medicine and expert opinion approach. The literature search and guidelines were restricted to treatments for knee OA pertaining to clinical and/or radiological OA of any compartment of the knee. Papers for combined treatment of knee and other types of OA were excluded. Medline and Embase were searched using a combination of subject headings and key words. Searches for those treatments previously investigated were conducted for January 1999 to February 2002 and for those treatments not previously investigated for 1966 to February 2002. The level of evidence found for each treatment was documented. Quality scores were determined for each paper, an effect size comparing the treatment with placebo was calculated, where possible, and a toxicity profile was determined for each treatment modality. 497 new publications were identified by the search. Of these, 103 were intervention trials and included in the overall analysis, and 33 treatment modalities were identified. Previously identified publications which were not exclusively knee OA in the initial analysis were rejected. In total, 545 publications were included. Based on the results of the literature search and expert opinion, 10 recommendations for the treatment of knee OA were devised using a five stage Delphi technique. Based on expert opinion, a further set of 10 items was identified by a five stage Delphi technique as important for future research. The updated recommendations support some of the previous propositions published in 2000 but also include modified statements and new propositions. Although a large number of treatment options for knee OA exist, the evidence based format of the EULAR Recommendations continues to identify key clinical questions that currently are unanswered.

Glucosamine therapy for treating osteoarthritis

Article

Full-text available

Feb 2005

Osteoarthritis (OA) is the most common form of arthritis, and it is often associated with significant disability and an impaired quality of life. To review all randomized controlled trials (RCTs) evaluating the effectiveness and toxicity of glucosamine in OA. We searched MEDLINE, PREMEDLINE, EMBASE, AMED, ACP Journal Club, DARE, CDSR, and the CCTR. We also wrote letters to content experts, and hand searched reference lists of identified RCTs and pertinent review articles. All searches were updated in January 2005. Relevant studies met the following criteria: 1) RCTs evaluating the effectiveness and safety of glucosamine in OA, 2) Both placebo controlled and comparative studies were eligible, 3) Both single blinded and double blinded studies were eligible. Data abstraction was performed independently by two investigators and the results were compared for degree of agreement. Gotzsche's method and a validated tool (Jadad 1996) were used to score the quality of the RCTs. Continuous outcome measures were pooled using standardized mean differences (SMD) as the measure of effect size. Dichotomous outcome measures were pooled using relative risk ratios (RR). Analysis restricted to eight studies with adequate allocation concealment failed to show benefit of glucosamine for pain and WOMAC function. Collectively, the 20 analyzed RCTs found glucosamine favoured placebo with a 28% (change from baseline) improvement in pain (SMD -0.61, 95% CI -0.95, -0.28) and a 21% (change from baseline) improvement in function using the Lequesne index (SMD -0.51 95% CI -0.96, -0.05). However, the results are not uniformly positive, and the reasons for this remain unexplained. WOMAC pain, function and stiffness outcomes did not reach statistical significance. In the 10 RCTs in which the Rotta preparation of glucosamine was compared to placebo, glucosamine was found to be superior for pain (SMD -1.31, 95% CI -1.99, -0.64) and function using the Lequesne index (SMD -0.51, 95% CI -0.96, -0.05). Pooled results for pain (SMD -0.15, 95% CI -0.35, 0.05) and function using the WOMAC index (SMD 0.03, 95% CI -0.18, 0.25) in those RCTs in which a non-Rotta preparation of glucosamine was compared to placebo did not reach statistical significance. In the four RCTs in which the Rotta preparation of glucosamine was compared to an NSAID, glucosamine was superior in two, and equivalent in two. Two RCTs using the Rotta preparation showed that glucosamine was able to slow radiological progression of OA of the knee over a three year period (SMD 0.24, 95% CI 0.04, 0.43). Glucosamine was as safe as placebo in terms of the number of subjects reporting adverse reactions (RR=0.97, 95% CI, 0.88, 1.08). This update includes 20 studies with 2570 patients. Pooled results from studies using a non-Rotta preparation or adequate allocation concealment failed to show benefit in pain and WOMAC function while those studies evaluating the Rotta preparation show that glucosamine was superior to placebo in the treatment of pain and functional impairment resulting from symptomatic OA. WOMAC outcomes of pain, stiffness and function did not show a superiority of glucosamine over placebo for both Rotta and non-Rotta preparations of glucosamine. Glucosamine was as safe as placebo.

Glucosamine, Chondroitin Sulfate, and the Two in Combination for Painful Knee Osteoarthritis

Article

Full-text available

Mar 2006
NEW ENGL J MED

Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis. We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24. The mean age of the patients was 59 years, and 64 percent were women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent. As compared with the rate of response to placebo (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups. Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. (ClinicalTrials.gov number, NCT00032890.).

OARSI recommendations for the management of hip and knee osteoarthritis Part III: Changes in evidence following systematic cumulative update of research published through

Article

Jan 2010

Glucosamine and chondroitin sulfate for knee osteoarthritis - Reply

Article

May 2006

Glucosamine oral bioavailability and plasma pharmacokinetics after increasing doses of cristalline glucosamine sulfate in man

Article

Jan 2005
OSTEOARTHR CARTILAGE

Objective: Pharmacokinetic data on glucosamine are scant, limiting the understanding of glucosamine sulfate mechanism of action in support of its treatment effects in osteoarthritis. This study investigated the oral pharmacokinetics and dose-proportionality of glucosamine after administration of the patented crystalline glucosamine sulfate in man. Methods: Twelve healthy volunteers received three consecutive once-daily oral administrations of glucosamine sulfate soluble powder at the doses of 750, 1500, and 3000 mg, in an open, randomised, cross-over fashion. Glucosamine was determined in plasma collected up to 48 h after the last dose by a validated Liquid Chromatography method with Mass Spectrometry detection. Pharmacokinetic parameters were calculated at steady state. Results: Endogenous plasma levels of glucosamine were detected (10.4e204 ng/ml, with low intra-subject variability). Glucosamine was rapidly absorbed after oral administration and its pharmacokinetics were linear in the dose range 750e1500 mg, but not at 3000 mg, where the plasma concentrationetime profiles were less than expected based on dose-proportionality. Plasma levels increased over 30-folds from baseline and peaked at about 10 mM with the standard 1500 mg once-daily dosage. Glucosamine distributed to extravascular compartments and its plasma concentrations were still above baseline up to the last collection time. Glucosamine elimination half-life was only tentatively estimated to average 15 h. Conclusions: Glucosamine is bioavailable after oral administration of crystalline glucosamine sulfate, persists in circulation, and its pharmacokinetics support once-daily dosage. Steady state peak concentrations at the therapeutic dose of 1500 mg were in line with those found to be effective in selected in vitro mechanistic studies. This is the only glucosamine formulation for which pharmacokinetic, efficacy and safety data are now available.

Synovial and plasma glucosamine concentrations in osteoarthritic patients following oral crystalline glucosamine sulphate at therapeutic dose

Article

Jan 2007
OSTEOARTHR CARTILAGE

Risk of bias and brand explain the observed inconsistency in trials on glucosamine for osteoarthritis:a meta-analysis of placebo-controlled trials

Article

Apr 2014

P.R. Eriksen

Commentary on recent therapeutic guidelines for osteoarthritis

Article

Dec 2014
SEMIN ARTHRITIS RHEU

Background: Despite availability of international evidence-based guidelines for osteoarthritis (OA) management, agreement on the different treatment modalities is lacking. Method: A symposium of European and US OA experts was held within the framework of the Annual European Congress of Rheumatology to discuss and compare guidelines and recommendations for the treatment of knee OA and to reach a consensus for management, particularly for areas in which there is no clear consensus: non-pharmacological therapy; efficacy and safety of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs); intra-articular (i.a.) hyaluronates (HA); and the role of chondroitin sulfate (CS) and/or glucosamine sulfate (GS). Results: All guidelines reviewed agree that knee OA is a progressive disease of the joint whose management requires non-pharmacological and pharmacological approaches. Discrepancies between guidelines are few and mostly reflect heterogeneity of expert panels involved, geographical differences in the availability of pharmacotherapies, and heterogeneity of the studies included. Panels chosen for guideline development should include experts with real clinical experience in drug use and patient management. Implementation of agreed guidelines can be thwarted by drug availability and reimbursement plans, resulting in optimal OA treatment being jeopardized, HA and symptomatic slow-acting drugs for osteoarthritis (SySADOAs) being clear examples of drugs whose availability and prescription can greatly vary geographically. In addition, primary care providers, often responsible for OA management (at least in early disease), may not adhere to clinical care guidelines, particularly for non-pharmacological OA treatment. Conclusion: Harmonization of the recommendations for knee OA treatment is challenging but feasible, as shown by the step-by-step therapeutic algorithm developed by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). More easily disseminated and implemented guidance for OA treatment in the primary care setting is key to improved management of OA.

Gaucher Disease and Bone Manifestations

Article

Nov 2014
CALCIFIED TISSUE INT

Gaucher disease is a relatively rare metabolic disease caused by the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Gaucher disease affects multiple organs, among which is the skeleton. Bone involvement occurs frequently in Gaucher disease, and is one of its most debilitating features, reducing the quality of life of patients. Bone status is an important consideration for treatment to ameliorate symptoms and reduce the risk of irreversible complications. We have conducted a systematic review of all the various aspects of Gaucher disease, focusing on different skeletal manifestations, pathophysiology of bone alterations, clinical symptoms, and current diagnostic and therapeutic approaches.

Risk of Bias and Brand Explain the Observed: Inconsistency in Trials on Glucosamine Symptomatic Relief of Osteoarthritis: A Meta-Analysis of Placebeo-Controlled Trials

Article

Dec 2014

Objective: To determine whether study sponsor, chemical formulation, brand of glucosamine, and/or risk of bias explain observed inconsistencies in trials of glucosamine's efficacy for treating pain in osteoarthritis (OA). Methods: A systematic review and stratified meta-analysis of randomized placebo-controlled trials was performed, and random-effects models were applied with inconsistency (I(2) ) and heterogeneity (tau(2) ) estimated using Review Manager and SAS, respectively. The major outcome was reduction of pain; the standardized mean difference (SMD [95% confidence interval (95% CI)]) served as effect size. Results: The inclusion criteria yielded 25 trials (3,458 patients). Glucosamine moderately reduced pain (SMD -0.51 [95% CI -0.72, -0.30]), although a high level of between-trial inconsistency was observed (I(2) = 88%). The single most important explanation (i.e., covariate) was brand, reducing heterogeneity by 41% (P = 0.00032). Twelve trials (1,437 patients) using the Rottapharm/Madaus product resulted in significant pain reduction (SMD -1.07 [95% CI -1.47, -0.67]), although a sensitivity analysis of 3 low risk of bias trials using the Rottapharm/Madaus product showed less promising results (SMD -0.27 [95% CI -0.43, -0.12]), which is only a small effect size. Thirteen trials (1,963 patients) using non-Rottapharm/Madaus products consistently failed to show a reduction in pain (SMD -0.11 [95% CI -0.46, 0.24]). The second most important explanation was overall risk of bias (reducing heterogeneity by 32%). Conclusion: Most of the observed heterogeneity in glucosamine trials is explained by brand. Trials using the Rottapharm/Madaus glucosamine product had a superior outcome on pain in OA compared to other preparations of glucosamine. Large inconsistency was found, however. Low risk of bias trials, using the Rottapharm/Madaus product, revealed a small effect size.

Challenges for the Development of Bone-Forming Agents in Europe

Article

Apr 2014
CALCIFIED TISSUE INT

OARSI Guidelines for the Non-Surgical Management of Knee Osteoarthritis.

Article

Jan 2014
OSTEOARTHR CARTILAGE

To develop concise, up-to-date, patient-focused, evidence-based, expert consensus guidelines for the management of knee osteoarthritis, intended to inform patients, physicians, and allied health care professionals worldwide. Thirteen experts from relevant medical disciplines (primary care, rheumatology, orthopedics, physical therapy, physical medicine and rehabilitation, and evidence-based medicine), three continents and ten countries (USA, UK, France, Netherlands, Belgium, Sweden, Denmark, Australia, Japan, and Canada) and a patient representative comprised the Osteoarthritis Guidelines Development Group (OAGDG). Based on previous OA guidelines and a systematic review of the osteoarthritis (OA) literature, twenty-nine treatment modalities were considered for recommendation. Evidence published subsequent to the 2010 OARSI guidelines was based on a systematic review conducted by the OARSI evidence team at Tufts Medical Center, Boston, USA. Medline, EMBASE, Google Scholar, Web of Science, and the Cochrane Central Register of Controlled Trials were initially searched in first quarter 2012 and last searched in March 2013. Included evidence was assessed for quality using AMSTAR criteria, and published criticism of included evidence was also considered. To provide recommendations for individuals with a range of health profiles and OA burden, treatment recommendations were stratified into four clinical subphenotypes. Consensus recommendations were produced using the Rand/UCLA Appropriateness method and Delphi voting process. Treatments were recommended as Appropriate, Uncertain, or Not Appropriate, for each of four clinical subphenotypes and accompanied by 1-10 risk and benefit scores. Appropriate treatment modalities for all individuals with knee OA included biomechanical interventions, intra-articular corticosteroids, exercise (land-based and water-based), self-management and education, strength training, and weight management. Treatments appropriate for specific clinical subphenotypes included acetaminophen (paracetamol), balneotherapy, capsaicin, cane (walking stick), duloxetine, oral NSAIDs (COX-2 selective and non-selective), and topical NSAIDs. Treatments of uncertain appropriateness for specific clinical subphenotypes included acupuncture, avocado soybean unsaponfiables, chondroitin, crutches, diacerein, glucosamine, intra-articular hyaluronic acid, opioids (oral and transdermal), rosehip, transcutaneous electrical nerve stimulation, and ultrasound. Treatments voted not appropriate included risedronate and electrotherapy (neuromuscular electrical stimulation). These evidence-based consensus recommendations provide guidance to patients and practitioners on treatments applicable to all individuals with knee OA, as well as therapies that can be considered according to individualized patient needs and preferences.

Treatment of Osteoarthritis of the Knee: Evidence-Based Guideline, 2nd Edition

Article

Sep 2013

David S Jevsevar

Treatment of Osteoarthritis of the Knee: Evidence-Based Guideline, 2nd Edition, is based on a systematic review of the current scientific and clinical research. This guideline contains 15 recommendations, replaces the 2008 AAOS clinical practice guideline, and was reevaluated earlier than the 5-year recommendation of the National Guideline Clearinghouse because of methodologic concerns regarding the evidence used in the first guideline. The current guideline does not support the use of viscosupplementation for the treatment of osteoarthritis of the knee. In addition, the work group highlighted the need for better research in the treatment of knee osteoarthritis.

Glucosamine modulates IL1-induced activation of rat chondrocytes at a receptor level, and by inhibiting the NF-κB pathway

Article

Jan 2002

We recently reported that glucosamine reversed the decrease in proteoglycan synthesis and in UDP-glucuronosyltransferase I mRNA expression induced by interleukin-1β (IL-1β) [Arthritis Rheum. 44 (2001) 351–360]. In the present work, we show that glucosamine does not exert the same effects when chondrocytes were stimulated with reactive oxygen species (ROS). In order to better understand its mechanism of action, we determined if glucosamine could prevent the binding of IL-1β to its cellular receptors or could interfere with its signaling pathway at a post-receptor level. Addition of glucosamine to rat chondrocytes treated with IL-1β or with ROS decreased the activation of the nuclear factor κB, but not the activator protein-1. After treatment with IL-1β, glucosamine increased the expression of mRNA encoding the type II IL-1β receptor. These results emphasize the potential role of two regulating proteins of the IL-1β signaling pathway that could account for the beneficial effect of glucosamine in osteoarthritis.

Glucosamine inhibits IL1??-induced NF??B activation in human osteoarthritic chondrocytes

Article

Apr 2003
OSTEOARTHR CARTILAGE

Objective: Glucosamine sulfate (GS) is a commonly used drug for the treatment of osteoarthritis. The mechanism of the action of this drug does, however, remain to be elucidated. In human osteoarthritic chondrocytes (HOC) stimulated with a proinflammatory cytokine, we studied whether GS could modify the NFκB activity and the expression of COX-2, a NFκB-dependent gene.Methods: Using HOC in culture stimulated with interleukin-1 β (IL-1β), the effects of GS on NFκB activation, nuclear translocation of NFκB/Rel family members, COX-1 and COX-2 expressions and syntheses and prostaglandin E2 (PGE2) concentration were studied.Results: GS significantly inhibited NFκB activity in a dose-dependent manner, as well as the nuclear translocation of p50 and p65 proteins. Furthermore, GS-preincubated IL-1β-stimulated HOC showed an increase in IκBα in the cell cytoplasm in comparison with HOC incubated with IL-1β alone. GS also inhibited the gene expression and the protein synthesis of COX-2 induced by IL-1β, while no effect on COX-1 synthesis was seen. GS also inhibited the release of PGE2 to conditioned media of HOC stimulated with IL-1β.Conclusions: GS inhibits the synthesis of proinflammatory mediators in HOC stimulated with IL-1β through a NFκB-dependent mechanism. Our study further supports the role of GS as a symptom- and structure-modifying drug in the treatment of OA.

American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee

Article

Apr 2012

To update the American College of Rheumatology (ACR) 2000 recommendations for hip and knee osteoarthritis (OA) and develop new recommendations for hand OA. A list of pharmacologic and nonpharmacologic modalities commonly used to manage knee, hip, and hand OA as well as clinical scenarios representing patients with symptomatic hand, hip, and knee OA were generated. Systematic evidence-based literature reviews were conducted by a working group at the Institute of Population Health, University of Ottawa, and updated by ACR staff to include additions to bibliographic databases through December 31, 2010. The Grading of Recommendations Assessment, Development and Evaluation approach, a formal process to rate scientific evidence and to develop recommendations that are as evidence based as possible, was used by a Technical Expert Panel comprised of various stakeholders to formulate the recommendations for the use of nonpharmacologic and pharmacologic modalities for OA of the hand, hip, and knee. Both “strong” and “conditional” recommendations were made for OA management. Modalities conditionally recommended for the management of hand OA include instruction in joint protection techniques, provision of assistive devices, use of thermal modalities and trapeziometacarpal joint splints, and use of oral and topical nonsteroidal antiinflammatory drugs (NSAIDs), tramadol, and topical capsaicin. Nonpharmacologic modalities strongly recommended for the management of knee OA were aerobic, aquatic, and/or resistance exercises as well as weight loss for overweight patients. Nonpharmacologic modalities conditionally recommended for knee OA included medial wedge insoles for valgus knee OA, subtalar strapped lateral insoles for varus knee OA, medially directed patellar taping, manual therapy, walking aids, thermal agents, tai chi, self management programs, and psychosocial interventions. Pharmacologic modalities conditionally recommended for the initial management of patients with knee OA included acetaminophen, oral and topical NSAIDs, tramadol, and intraarticular corticosteroid injections; intraarticular hyaluronate injections, duloxetine, and opioids were conditionally recommended in patients who had an inadequate response to initial therapy. Opioid analgesics were strongly recommended in patients who were either not willing to undergo or had contraindications for total joint arthroplasty after having failed medical therapy. Recommendations for hip OA were similar to those for the management of knee OA. These recommendations are based on the consensus judgment of clinical experts from a wide range of disciplines, informed by available evidence, balancing the benefits and harms of both nonpharmacologic and pharmacologic modalities, and incorporating their preferences and values. It is hoped that these recommendations will be utilized by health care providers involved in the management of patients with OA.

Glucosamine therapy for knee osteoarthritis: Pharmacokinetic considerations

Article

Jul 2009

Roy D. Altman

Knee osteoarthritis is the most common form of arthritis. Given the aging of the world's population, the burden of this disease is expected to increase significantly over the next few decades. As a pharmacological agent, glucosamine has been investigated for the treatment of symptoms and progression of knee osteoarthritis, demonstrating symptomatic and disease-modifying effects. However, among the glucosamine studies conducted to date in knee osteoarthritis, there have been conflicting results due to differences and/or weaknesses in study design and sample size, in addition to product formulation, salt and quality. This review describes the current knowledge regarding the pharmacokinetics of glucosamine to provide a means for the interpretation of the pharmacodynamic and clinical efficacy results obtained in the different clinical trials.

Long-term oral administration of glucosamine or chondroitin sulfate reduces destruction of cartilage and up-regulation of MMP-3 mRNA in a model of spontaneous osteoarthritis in Hartley guinea pigs

Article

May 2012
J ORTHOP RES

Histological and molecular changes were examined to investigate the effects of long-term administration of glucosamine (GlcN) and chondroitin sulfate (CS) in a model of spontaneous osteoarthritis (OA) in Hartley guinea pigs. Three groups of female 3-week-old Hartley guinea pigs received GlcN, CS, and neither agent, respectively. Five animals in each group were sacrificed at 8, 12, and 18 months of age. At 8 months of age, Hartley guinea pigs had severe degeneration of knee joint cartilage, chondrocyte apoptosis, marked reduction of tissue total RNA, decreases of aggrecan and collagen type 2 mRNAs, and increases in MMP-3 and MMP-8 mRNAs. Long-term administration of GlcN and CS reduced cartilage degeneration at 8 months of age. The marked loss of total RNA and the increase in MMP-3 mRNA were also inhibited by GlcN and CS. Thus, long-term oral administration of GlcN or CS inhibits OA progression, maintains total RNA and down-regulates MMP-3 mRNA in a spontaneous OA model in Hartley guinea pigs.

Glucosamine sulphate in the treatment of knee osteoarthritis: Cost-effectiveness comparison with paracetamol

Article

May 2010
INT J CLIN PRACT

The aim of this study was to explore the cost-effectiveness of glucosamine sulphate (GS) compared with paracetamol and placebo (PBO) in the treatment of knee osteoarthritis. For this purpose, a 6-month time horizon and a health care perspective was used. The cost and effectiveness data were derived from Western Ontario and McMaster Universities Osteoarthritis Index data of the Glucosamine Unum In Die (once-a-day) Efficacy trial study by Herrero-Beaumont et al. Clinical effectiveness was converted into utility scores to allow for the computation of cost per quality-adjusted life year (QALY) For the three treatment arms Incremental Cost-Effectiveness Ratio were calculated and statistical uncertainty was explored using a bootstrap simulation. In terms of mean utility score at baseline, 3 and 6 months, no statistically significant difference was observed between the three groups. When considering the mean utility score changes from baseline to 3 and 6 months, no difference was observed in the first case but there was a statistically significant difference from baseline to 6 months with a p-value of 0.047. When comparing GS with paracetamol, the mean baseline incremental cost-effectiveness ratio (ICER) was dominant and the mean ICER after bootstrapping was -1376 euro/QALY indicating dominance (with 79% probability). When comparing GS with PBO, the mean baseline and after bootstrapping ICER were 3617.47 and 4285 euro/QALY, respectively. The results of the present cost-effectiveness analysis suggested that GS is a highly cost-effective therapy alternative compared with paracetamol and PBO to treat patients diagnosed with primary knee OA.

Glucosamine sulfate reduces experimental osteoarthritis and nociception in rats: Association with changes of mitogen-activated protein kinase in chondrocytes

Article

Sep 2010
OSTEOARTHR CARTILAGE

To study the effects of oral glucosamine sulfate on the development of osteoarthritis (OA) and to examine concomitant changes in the nociceptive behavior of rats. OA was induced in Wistar rats by anterior cruciate ligament transection (ACLT) of the right knee; the left knee was untreated. The OA+glucosamine group received oral glucosamine sulfate (250 mg/kg/day) in a 2-g wafer once a day for 10 consecutive weeks starting at week 5 after ACLT. The OA group was treated as above with 2-g wafers (placebo). The control group of naïve rats received 2-g wafers only. The glucosamine alone group comprised naïve rats receiving glucosamine sulfate only. Nociceptive behavior (mechanical allodynia and weight-bearing distribution of hind paws) during OA development was analyzed pre- and 3, 6, 9, 12, 15, and 18 weeks post-ACLT. Macroscopic and histologic studies were then performed on the cartilage and synovia. Immunohistochemical analysis was performed to examine the effect of glucosamine on expression of mitogen-activated protein kinases (MAPKs) in the articular cartilage chondrocytes. OA rats receiving glucosamine showed a significantly lower degree of cartilage degeneration than the rats receiving placebo. Glucosamine treatment also suppressed synovitis. Mechanical allodynia and weight-bearing distribution studies showed significant improvement in the OA+glucosamine group as compared to the OA group. Moreover, glucosamine attenuated p38 and c-Jun N-terminal kinase (JNK) but increased extracellular signal-regulated kinase 1/2 (ERK) expression in OA-affected cartilage. Our results indicate that treatment with oral glucosamine sulfate in a rat OA model (1) attenuates the development of OA, (2) concomitantly reduces nociception, and (3) modulates chondrocyte metabolism, possibly through inhibition of cell p38 and JNK and increase of ERK expression.

OARSI recommendations for the management of hip and knee osteoarthritis, Part III: Changes in evidence following systematic cumulative update of research published through January 2009

Article

Feb 2010
OSTEOARTHR CARTILAGE

To update evidence for available therapies in the treatment of hip and knee osteoarthritis (OA) and to examine whether research evidence has changed from 31 January 2006 to 31 January 2009. A systematic literature search was undertaken using MEDLINE, EMBASE, CINAHL, AMED, Science Citation Index and the Cochrane Library. The quality of studies was assessed. Effect sizes (ESs) and numbers needed to treat were calculated for efficacy. Relative risks, hazard ratios (HRs) or odds ratios were estimated for side effects. Publication bias and heterogeneity were examined. Sensitivity analysis was undertaken to compare the evidence pooled in different years and different qualities. Cumulative meta-analysis was used to examine the stability of evidence. Sixty-four systematic reviews, 266 randomised controlled trials (RCTs) and 21 new economic evaluations (EEs) were published between 2006 and 2009. Of 51 treatment modalities, new data on efficacy have been published for more than half (26/39, 67%) of those for which research evidence was available in 2006. Among non-pharmacological therapies, ES for pain relief was unchanged for self-management, education, exercise and acupuncture. However, with new evidence the ES for pain relief for weight reduction reached statistical significance, increasing from 0.13 [95% confidence interval (CI) -0.12, 0.36] in 2006 to 0.20 (95% CI 0.00, 0.39) in 2009. By contrast, the ES for electromagnetic therapy which was large in 2006 (ES=0.77, 95% CI 0.36, 1.17) was no longer significant (ES=0.16, 95% CI -0.08, 0.39). Among pharmacological therapies, the cumulative evidence for the benefits and harms of oral and topical non-steroidal anti-inflammatory drugs, diacerhein and intra-articular (IA) corticosteroid was not greatly changed. The ES for pain relief with acetaminophen diminished numerically, but not significantly, from 0.21 (0.02, 0.41) to 0.14 (0.05, 0.22) and was no longer significant when analysis was restricted to high quality trials (ES=0.10, 95% CI -0.0, 0.23). New evidence for increased risks of hospitalisation due to perforation, peptic ulceration and bleeding with acetaminophen >3g/day have been published (HR=1.20, 95% CI 1.03, 1.40). ES for pain relief from IA hyaluronic acid, glucosamine sulphate, chondroitin sulphate and avocado soybean unsponifiables also diminished and there was greater heterogeneity of outcomes and more evidence of publication bias. Among surgical treatments further negative RCTs of lavage/debridement were published and the pooled results demonstrated that benefits from this modality of therapy were no greater than those obtained from placebo. Publication of a large amount of new research evidence has resulted in changes in the calculated risk-benefit ratio for some treatments for OA. Regular updating of research evidence can help to guide best clinical practice.

The human pharmacokinetics of oral ingestion of glucosamine and chondroitin sulfate taken separately or in combination

Article

Nov 2009
OSTEOARTHR CARTILAGE

As part of the National Institutes of Health (NIH)-sponsored Glucosamine/Chondroitin sulfate Arthritis Intervention Trial (GAIT) our objective here was to examine (1) the pharmacokinetics (PK) of glucosamine (GlcN) and chondroitin sulfate (CS) when taken separately or in combination as a single dose in normal individuals (n=29) and (2) the PK of GlcN and CS when taken as a single dose after 3 months daily dosing with GlcN, CS or GlcN+CS, in patients with symptomatic knee pain (n=28). The concentration of GlcN in the circulation was determined by established fluorophore-assisted carbohydrate electrophoresis (FACE) methods. The hydrodynamic size and disaccharide composition of CS chains in the circulation and dosage samples was determined by Superose 6 chromatography and FACE. We show that circulating levels of CS in human plasma are about 20 microg/ml. Most significantly, the endogenous concentration and CS disaccharide composition were not detectably altered by ingestion of CS, when the CS was taken alone or in combination with GlcN. On the other hand, the Cmax (single-dose study) and AUC values (multiple-dose study) for ingested GlcN were significantly reduced by combination dosing with CS, relative to GlcN dosing alone. We conclude that pain relief perceived following ingestion of CS probably does not depend on simultaneous or prior intake of GlcN. Further, such effects on joint pain, if present, probably do not result from ingested CS reaching the joint space but may result from changes in cellular activities in the gut lining or in the liver, where concentrations of ingested CS, or its breakdown products, could be substantially elevated following oral ingestion. Moreover, since combined dosing of GlcN with CS was found to reduce the plasma levels seen with GlcN dosing alone, any improved pain relief by combination dosing cannot be explained by higher circulating concentrations of GlcN.

The clinical effectiveness of glucosamine and chondroitin supplements in slowing or arresting progression of osteoarthritis of the knee: A systematic review and economic evaluation

Article

Nov 2009
HEALTH TECHNOL ASSES

To assess the clinical effectiveness and cost-effectiveness of glucosamine sulphate/hydrochloride and chondroitin sulphate in modifying the progression of osteoarthritis (OA) of the knee. Electronic databases were searched from 1950 to 2008 and included: MEDLINE and PubMed; EMBASE; Cochrane Library (including Cochrane Systematic Reviews Database, CENTRAL, DARE, NHS EED and HTA databases); Allied and Complementary Medicine (AMED); National Research Register (NRR); Web of Science Proceedings; Current Controlled Trials; and Clinical Trials.gov. Other sources included bibliographies of retrieved papers, registered but unpublished trials, internet searches and the Food Standards Agency website. A search was conducted for systematic reviews of randomised controlled trials (RCTs), which were used to identify RCTs of at least 12 months' duration and updated with searches for primary studies. A cost-effectiveness model was constructed using cohort simulation and drawing on available evidence. Sensitivity analysis was undertaken and value of information analysis conducted. A review of studies of mechanism of action was carried out to explore the biological plausibility of the preparations. Five systematic reviews and one clinical guideline met the inclusion criteria. They reported inconsistent conclusions with only modest effects on reported pain and function. A reduction in joint space narrowing was more consistently observed, but the effect size was small and the clinical significance uncertain. A separate review of eight primary trials of > 12 months' duration showed evidence of statistically significant improvements in joint space loss, pain and function for glucosamine sulphate, but the clinical importance of these differences was not clear. In two studies of glucosamine sulphate, the need for knee arthroplasty was reduced from 14.5% to 6.3% at 8 years' follow-up. For other preparations of glucosamine, chondroitin and combination therapy, there was less evidence to support a clinical effect. Cost-effectiveness modelling was restricted to glucosamine sulphate. Over a lifetime horizon the incremental cost per quality-adjusted life-year (QALY) gain for adding glucosamine sulphate to current care was estimated to be 21,335 pounds. Deterministic sensitivity analysis suggested that the cost-effectiveness of glucosamine sulphate therapy was particularly dependent on the magnitude of the quality of life (QoL) gain, the change in knee arthroplasty probability with therapy and the discount rate. At a cost per QALY gained threshold of 20,000 pounds, the likelihood that glucosamine sulphate is more cost-effective than current care is 0.43, while at a threshold of 30,000 pounds, the probability rises to 0.73. Probabilistic sensitivity analysis showed that estimates were imprecise and subject to a degree of decision uncertainty. Value of information analysis demonstrated the need for further research. Several biologically plausible mechanisms of action for glucosamine sulphate and chondroitin were proposed. There was evidence that glucosamine sulphate shows some clinical effectiveness in the treatment of OA of the knee. No trial data came from the UK and caution should be exercised in generalising the findings to the UK health-care setting. Cost-effectiveness was not conclusively demonstrated. There was evidence to support the potential clinical impact of glucosamine sulphate. The value of information analysis identified three research priorities: QoL, structural outcomes and knee arthroplasty. The biological mechanism of glucosamine sulphate and chondroitin remains uncertain and, in particular, the proposal that the active substance may be sulphate should be explored further.

The American College of Rheumatology criteria for the classfication and reporting of osteoarthritis of the hip

Article

Jun 1991

Clinical criteria for the classification of patients with hip pain associated with osteoarthritis (OA) were developed through a multicenter study. Data from 201 patients who had experienced hip pain for most days of the prior month were analyzed. The comparison group of patients had other causes of hip pain, such as rheumatoid arthritis or spondylarthropathy. Variables from the medical history, physical examination, laboratory tests, and radiographs were used to develop different sets of criteria to serve different investigative purposes. Multivariate methods included the traditional "number of criteria present" format and "classification tree" techniques. Clinical criteria: A classification tree was developed, without radiographs, for clinical and laboratory criteria or for clinical criteria alone. A patient was classified as having hip OA if pain was present in combination with either 1) hip internal rotation greater than or equal to 15 degrees, pain present on internal rotation of the hip, morning stiffness of the hip for less than or equal to 60 minutes, and age greater than 50 years, or 2) hip internal rotation less than 15 degrees and an erythrocyte sedimentation rate (ESR) less than or equal to 45 mm/hour; if no ESR was obtained, hip flexion less than or equal to 115 degrees was substituted (sensitivity 86%; specificity 75%). Clinical plus radiographic criteria: The traditional format combined pain with at least 2 of the following 3 criteria: osteophytes (femoral or acetabular), joint space narrowing (superior, axial, and/or medial), and ESR less than 20 mm/hour (sensitivity 89%; specificity 91%). The radiographic presence of osteophytes best separated OA patients and controls by the classification tree method (sensitivity 89%; specificity 91%). The "number of criteria present" format yielded criteria and levels of sensitivity and specificity similar to those of the classification tree for the combined clinical and radiographic criteria set. For the clinical criteria set, the classification tree provided much greater specificity. The value of the radiographic presence of an osteophyte in separating patients with OA of the hip from those with hip pain of other causes is emphasized.

The Biology of Osteoarthritis

Article

Jun 1989

David Hamerman

OSTEOARTHRITIS, "an almost inevitable consequence of aging,"1 is second only to cardiovascular diseases in producing severe chronic disability, and it affects nearly 10 percent of the population over the age of 60.2 This prevalence and its costs — billions of dollars in medications, surgery, and days lost from work3 — account for the growing interest in uncovering the basic mechanisms by which this disease affects human joints.4 5 6 7 8 9 Osteoarthritis can involve axial, or spinal, as well as peripheral joints — those that bear weight (such as the hips and knees) as well as those that do not (such as the distal . . .

The STR/Ort mouse and its use as a model of osteoarthritis

Article

Mar 2001

Sulfate could mediate the therapeutic effect of glucosamine sulfate

Article

Jul 2001
METABOLISM

Glucosamine sulfate is a controversial osteoarthritis remedy that is presumed to stimulate articular cartilage glycosaminoglycan synthesis by increasing glucosamine concentrations in the joint space. However, this is not plausible because even large oral doses of the product have no effect on serum glucosamine concentrations. We propose instead that sulfate could mediate the clinical benefit attributed to this treatment. Sulfate is required for glycosaminoglycan synthesis, and unlike glucosamine, its serum level can be modified by dietary and other factors. In this study, we tested whether oral glucosamine sulfate increases serum sulfate concentrations and whether the sulfate concentration in the synovial fluid reflects that in the serum. The serum sulfate concentration of 7 normal subjects was 331 +/- 21 micromol/L before ingestion of 1.0 g glucosamine sulfate and 375 +/- 17 micromol/L 3 hours after (P <.05). Serum sulfate concentrations decreased from 325 +/- 19 to 290 +/- 19 micromol/L when the same dose of glucosamine sulfate was ingested with 1.0 g of the analgesic drug acetaminophen, which is largely metabolized by sulfation (P <.05). Unlike glucosamine sulfate, oral sodium sulfate did not significantly increase the serum sulfate concentration. Synovial fluid and serum sulfate concentrations were closely similar when measured in 15 patients undergoing diagnostic needle aspiration of a knee effusion (r =.99, slope =.97, P <.0001). These results do not prove that glucosamine sulfate improves osteoarthritis, but considered with other data, they do provide a plausible biochemical mechanism for its reported beneficial effects. This hypothesis is clinically relevant because it predicts that nonsulfate salts of glucosamine will be ineffective and that renal function, diet, and concurrent acetaminophen therapy could confound clinical trials of this therapy.

Chondroitin sulfate and other sulfate containing chondroprotective agents may exhibit their effects by overcoming a deficiency of sulfur amino acids

Article

Apr 2003

Dietary supplements derived from cartilage and medications containing sulfated amino sugars, are used with increasing frequency by individuals affected with osteoarthritis (OA). Our lack of knowledge regarding their mode of action is further complicated by the fact that many of these compounds have to be degraded by the intestinal flora for absorption. The metabolic studies performed in this work suggest that the sulfate moiety present in these molecules may be overcoming a dietary deficiency of sulfur amino acids (SAA; cysteine and methionine), our primary sources of sulfate. The compounds tested are rapidly converted into free sulfate before or after absorption, depending on their chemical nature, and excreted quantitatively when the intake of protein seems to exceed the dietary requirement for the SAA. At lower levels of protein intake, sulfur is retained and excretion considerably reduced. Cartilage is a unique tissue that after acquiring its full complement of cells during early development expands in size by deposition of collagen type II, and tissue specific glycosaminoglycans (GAG) that require a source of inorganic sulfate for their synthesis. After maturity, the turnover of these molecules is very limited. Classical studies by Mankin and Maroundas estimated a T1/2 of 3.5 years for some proteoglycan fractions and 25 years for most others 1–3 . Sub-optimal amounts of SAA, our major sources of inorganic sulfate used for the de novo synthesis of GAG, may not cause any significant problem to healthy cartilage, but when OA begins to progress could lead to serious consequences. During the onset of disease GAG turnover is greatly enhanced, as evidenced by the rapid loss of

Glucosamine inhibits IL-1β-induced NFκB activation in human osteoarthritic chondrocytes

Article

May 2003

Glucosamine sulfate (GS) is a commonly used drug for the treatment of osteoarthritis. The mechanism of the action of this drug does, however, remain to be elucidated. In human osteoarthritic chondrocytes (HOC) stimulated with a proinflammatory cytokine, we studied whether GS could modify the NFkappaB activity and the expression of COX-2, a NFkappaB-dependent gene. Using HOC in culture stimulated with interleukin-1 beta (IL-1beta), the effects of GS on NFkappaB activation, nuclear translocation of NFkappaB/Rel family members, COX-1 and COX-2 expressions and syntheses and prostaglandin E2 (PGE2) concentration were studied. GS significantly inhibited NFkappaB activity in a dose-dependent manner, as well as the nuclear translocation of p50 and p65 proteins. Furthermore, GS-preincubated IL-1beta-stimulated HOC showed an increase in IkappaBalpha in the cell cytoplasm in comparison with HOC incubated with IL-1beta alone. GS also inhibited the gene expression and the protein synthesis of COX-2 induced by IL-1beta, while no effect on COX-1 synthesis was seen. GS also inhibited the release of PGE2 to conditioned media of HOC stimulated with IL-1beta. GS inhibits the synthesis of proinflammatory mediators in HOC stimulated with IL-1beta through a NFkappaB-dependent mechanism. Our study further supports the role of GS as a symptom- and structure-modifying drug in the treatment of OA.

Relief in mild-to-moderate pain is not a confounder in joint space narrowing assessment of full extension knee radiographs in recent osteoarthritis structure-modifying drug trials

Article

Nov 2003

To assess whether improvement in knee pain biased the determination of the structure-modifying effect reported for glucosamine sulfate in two recent 3-year, randomised, placebo-controlled clinical trials, in which conventional standing antero-posterior full extension knee radiographs were used for the measurement of joint space narrowing, and in which pain relief might have improved knee full extension. Patients completing the 3-year treatment course were selected based on a WOMAC pain decrease at least equal to the mean improvement in the glucosamine sulfate arms in either of the original studies, irrespective of treatment with glucosamine sulfate or placebo (drug responders or placebo responders). In a second approach, 3-year completers were selected if their baseline standing knee pain (item #5 of the WOMAC pain scale) was 'severe' or 'extreme' and improved by any degree at the end of the trials. In both cases, changes in minimum joint space width were compared between treatment groups. Global knee pain was mild-to-moderate in the two study populations and in all patient subsets identified. There were obviously more pain improvers in the glucosamine sulfate subsets (N=76 in the two studies combined) than in the placebo subsets (N=57), but WOMAC pain scores improved to the same extent, which was as large as over 50% relative to baseline. Nevertheless, the placebo subsets in both studies underwent an evident mean (SD) joint space narrowing, which in the pooled analysis of both studies was -0.22 (0.80) mm, and was not observed with glucosamine sulfate: +0.15 (0.60) mm (P=0.003 vs placebo). Similar results were found in the smaller subsets with > or = severe baseline standing knee pain that improved after 3 years, with a joint space narrowing nevertheless of -0.28 (0.76) mm with placebo (N=26), not observed with glucosamine sulfate: +0.21 (0.68) mm (N=31; P=0.014 vs placebo). Knee pain relief did not bias the report of a structure-modifying effect of glucosamine sulfate in two recent long-term trials using conventional standing antero-posterior radiographs, possibly due to the mild-to-moderate patient characteristics.

Total joint replacement of hip or knee as an outcome measure for structure modifying trials in osteoarthritis

Article

Jan 2005

The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working group to assess the value of time to joint surgery as a potential therapeutic failure outcome criterion for osteoarthritis (OA) of the hip or knee in the assessment of potential structure modifying agents. PubMed was searched for manuscripts from 1976 to 2004. Relevant studies were discussed at a 1-day meeting. There are no accepted guidelines for 'time to' and 'indications for' joint replacement surgery. A limited number of trials have examined joint replacement surgery within the study population. Several parameters, particularly joint space narrowing (interbone distance), correlate with surgical intervention. However, at the level of the knee, none of the parameters have positive predictive value for joint replacement surgery better than 30%. In contrast, lack of significant joint space narrowing has a strong negative predictive value for joint replacement surgery (>90%), that remains after controlling for OA pain severity. At this time, GREES cannot recommend time to joint surgery as a primary endpoint of failure for structure modifying trials of hip or knee OA-as the parameter has sensitivity but lacks specificity. In contrast, in existing trials, a lack of progression of joint space narrowing has predictive value of >90% for not having surgery. GREES suggests utilizing joint space narrowing (e.g., >0.3-0.7 mm) combined with a lack of clinically relevant improvement in symptoms (e.g., >/=20-25%) for 'failure' of a secondary outcome in structure modifying trials of the hip and knee.

Glucosamine and chondroitin sulfate regulate gene expression and synthesis of nitric oxide and prostaglandin E

Article

Jun 2005

Glucosamine (GLN) and chondroitin sulfate (CS) are widely used to alleviate symptoms of osteoarthritis (OA). However, the mechanism(s) of action of these nutraceuticals remains unresolved. In the present study, we determined the effect of physiologically relevant concentrations of GLN and CS on gene expression and synthesis of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in cytokine-stimulated articular cartilage explants. Using bovine articular cartilage explants in culture stimulated with IL-1, the effects of physiologically relevant concentrations of GLN and CS on gene expression of inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGEs1) were assessed with quantitative real-time polymerase chain reaction (Q-RT-PCR). The production of NO and PGE(2) was also quantified. CS and the GLN and CS combination at concentrations attainable in the blood down-regulated IL-1 induced mRNA expression of iNOS at 24 and 48 h post-culture. Up-regulated iNOS expression at 24h by IL-1 was also suppressed by GLN. GLN and CS transiently repressed the cytokine-stimulated mPGEs1 transcript. Synthesis of NO was reduced with CS alone and the combination after 24h of culture. Repression of COX-2 transcripts by GLN and CS was accompanied by concomitant reduction in PGE(2). Our results indicate that physiologically relevant concentrations of GLN and CS can regulate gene expression and synthesis of NO and PGE(2), providing a plausible explanation for their purported anti-inflammatory properties.

Glucosamine oral bioavailability after increasing doses of crystalline glucosamine sulfate in man

Article

Jan 2006

Pharmacokinetic data on glucosamine are scant, limiting the understanding of glucosamine sulfate mechanism of action in support of its treatment effects in osteoarthritis. This study investigated the oral pharmacokinetics and dose-proportionality of glucosamine after administration of the patented crystalline glucosamine sulfate in man. Twelve healthy volunteers received three consecutive once-daily oral administrations of glucosamine sulfate soluble powder at the doses of 750, 1,500, and 3,000 mg, in an open, randomised, cross-over fashion. Glucosamine was determined in plasma collected up to 48 h after the last dose by a validated Liquid Chromatography method with Mass Spectrometry detection. Pharmacokinetic parameters were calculated at steady state. Endogenous plasma levels of glucosamine were detected (10.4-204 ng/ml, with low intra-subject variability). Glucosamine was rapidly absorbed after oral administration and its pharmacokinetics were linear in the dose range 750-1,500 mg, but not at 3,000 mg, where the plasma concentration-time profiles were less than expected based on dose-proportionality. Plasma levels increased over 30-folds from baseline and peaked at about 10 microM with the standard 1,500 mg once-daily dosage. Glucosamine distributed to extravascular compartments and its plasma concentrations were still above baseline up to the last collection time. Glucosamine elimination half-life was only tentatively estimated to average 15 h. Glucosamine is bioavailable after oral administration of crystalline glucosamine sulfate, persists in circulation, and its pharmacokinetics support once-daily dosage. Steady state peak concentrations at the therapeutic dose of 1,500 mg were in line with those found to be effective in selected in vitro mechanistic studies. This is the only glucosamine formulation for which pharmacokinetic, efficacy and safety data are now available.

Glucosamine decreases expression of anabolic and catabolic genes in human osteoarthritic cartilage explants

Article

Apr 2006

To investigate the effect of glucosamine (GlcN) in a human osteoarthritic explant model on expression of genes involved in anabolic and catabolic activities of chondrocytes. Human osteoarthritic explants, obtained during knee arthroplasty surgery, were pre-cultured (3 days) and treated with glucosamine-hydrochloride (GlcN-HCl) or glucosamine-3-sulphate (GlcN-S) at 0.5mM and 5mM (4 days). RNA was isolated from the explants and real time RT-PCR was performed. Additionally, total matrix metalloproteinase (MMP) activity was measured in culture medium. Addition of 5mM GlcN led to significant down-regulation of aggrecan (2.65-7.73-fold) and collagen type II (7.75-22.17-fold) gene expression, indicating inhibited anabolic activity. Considering catabolic activities, 5mM GlcN significantly down-regulated aggrecanase-1 and MMP3 and 5mM GlcN-S additionally down-regulated aggrecanase-2 and tissue inhibitor of MMP gene expression significantly. Gene expression was not significantly altered by 0.5mM GlcN. Total MMP activity in culture medium was only significantly reduced after addition of 5mM GlcN-HCl. The effects of GlcN on gene expression in a human osteoarthritic explant model suggest that enzymatic breakdown of the extra-cellular matrix might be reduced by the addition of 5mM GlcN. Additionally, restoration of already damaged cartilage is not to be expected, because gene expression of anabolic genes is also down-regulated. We suggest that chondroprotective properties of GlcN in vivo may be based on inhibiting further degradation due to catabolic activities, rather than on the ability to rebuild cartilage.

Short-term efficacy of pharmacotherapeutic interventions in osteoarthritic knee pain: A meta-analysis of randomised placebo-controlled trials

Article

Mar 2007

Pain is the most debilitating symptom in osteoarthritis of the knee (OAK). To determine the short-term pain-relieving effects of seven commonly used pharmacological agents for OAK pain by performing a systematic review of randomised placebo-controlled trials. In total, 14,060 patients in 63 trials were evaluated. Opioids and oral NSAIDs therapy in patients with moderate to severe pain (mean baseline 64.3 and 72.8 mm on VAS respectively) had maximum efficacies compared to placebo at 2-4 weeks of 10.5 mm [95% CI: 7.4-13.7] and 10.2 mm [95% CI: 8.8-11.2] respectively. The efficacy of opioids may be inflated by high withdrawal rates (24-50%) and "best-case" scenarios reported in intention-to-treat analyses. In patients with moderate pain scores on VAS (mean range from 51 to 57 mm), intra-articular steroid injections and topical NSAIDs had maximum efficacies at 1-3 weeks of 14.5mm [95% CI: 9.7-19.2] and 11.6 mm [95% CI: 7.4-15.7], respectively. Paracetamol, glucosamin sulphate and chondroitin sulphate had maximum mean efficacies at 1-4 weeks of only 4.7 mm or lower. Heterogeneity tests revealed that best efficacy values of topical NSAIDs may be slightly deflated, while data for oral NSAIDs may be slightly inflated due to probable patient selection bias. Clinical effects from pharmacological interventions in OAK are small and limited to the first 2-3 weeks after start of treatment. The pain-relieving effects over placebo in OAK are smaller than the patient-reported thresholds for relevant improvement.

A review of glucosamine for knee osteoarthritis: Why patented crystalline glucosamine sulfate should be differentiated from other glucosamines to maximize clinical outcomes

Abstract

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