The rate of decline of joint space width in patients with osteoarthritis of the knee: a systematic review and meta-analysis of randomized placebo-controlled trials of chondroitin sulfate

ABSTRACT

Background: Chondroitin sulfate has been shown to relieve pain and improve functional limitation in patients with osteoarthritis (OA) of the knee in numerous clinical trials and meta-analyses. Its role as a potential structure-modifying drug for knee OA, however, remains controversial.

Objective: To perform a meta-analysis of randomized double-blind placebo-controlled clinical trials to assess the efficacy of chondroitin sulfate as a structure-modifying drug for knee OA.

Research design and methods: A Medline search was conducted from 1996 through 2007 and five articles that reported results from three trials were identified; one additional trial was identified through review of presentations at annual rheumatology meetings. There was no evidence of heterogeneity across the trials and results were pooled using a fixed effects meta-analysis.

Results: Pooled results demonstrated a small significant effect of chondroitin sulfate on the reduction in rate of decline in minimum joint space width of 0.07?mm/year (95% CI 0.03, 0.10) that corresponded to an effect size of 0.26 (95% CI 0.14, 0.38) (p?<?0.0001). This result was robust in sensitivity analyses.

Limitations: The individual studies included in the meta-analysis varied in the number of patients enrolled and the techniques used to acquire knee radiographs and to measure joint space width.

Conclusion: These results demonstrate that chondroitin sulfate is effective for reducing the rate of decline in minimum joint space width in patients with OA of the knee. Chondroitin sulfate may have a role as a structure-modifying agent in the management of patients with knee OA.     

Advances in chondroitin sulfate analysis: application in physiological and pathological States of connective tissue and during pharmacological treatment of osteoarthritis

Recent glycobiology studies have suggested fundamental biological functions for chondroitin sulfate (CS) and dermatan sulfate (DS), which are widely distributed as glycosaminoglycans (GAGs) sidechains of proteoglycans (PGs) in the extracellular matrix and at cellular level. Several biological functions are closely associated with the structure and in particular with the sulfation patterns of these polysaccharides. CS is also used as a structure-modifying osteoarthritis (OA) drug that reverses, retards, or stabilizes the pathology of OA, thereby providing symptomatic relief in the long-term treatment. Advances in analytical separational techniques, including agarose-gel electrophoresis, high-performance liquid chromatography (HPLC), capillary electrophoresis (HPCE), fluorophore-assisted carbohydrate electrophoresis (FACE) and electrospray ionization mass (ESI-MS) enable us to examine alterations of CS/DS with respect to their quantities and fine structural features in various pathological conditions, thus becoming applicable for diagnosis. Furthermore, sensitive analytical procedures enable us to follow the pharmacological application of CS in the treatment of OA and to monitor the progression of the disorder. In this review, the chromatographic and electromigration procedures developed to analyse and characterise CS/DS are presented. Moreover, a critical evaluation of the biological relevance of the results obtained by the developed methodology is discussed.     

复方盐酸氨基葡萄糖治疗骨关节炎的多中心随机双盲试验

目的:观察并验证复方盐酸氨基葡萄糖胶囊和片剂治疗骨关节炎的疗效及安全性。方法:360例骨关节炎病人采用多中心、随机、双盲的研究方法,分为胶囊剂、片剂及安慰剂3组,按照1:1:1的对照原则,每组120例。分别口服复方盐酸氨基葡萄糖胶囊、片剂和安慰剂,每次3粒,每日3次,连续服用3 mo,随访并观察其临床疗效及不良反应。结果:胶囊剂组与片剂组治疗骨关节炎总有效率为92．5％及93．3％,病人生活质量明显提高,临床上2组间疗效比较无显著差异(P>0．05)。安慰剂组有效率为20．8％,与试验组比较有显著差异(P<0．05)。胶囊剂组和片剂组的不良反应发生率分别为0．8％和3．3％,差异无显著意义(P>0．05)。结论:复方盐酸氨基葡萄糖胶囊和片剂治疗骨关节炎疗效好,安全性高。     

Classification of chondroitin sulfate A, chondroitin sulfate C, glucosamine hydrochloride and glucosamine 6 sulfate using chemometric techniques

Chondroitin sulfate A, chondroitin sulfate C, glucosamine hydrochloride and glucosamine sulfate are natural products that are becoming increasingly popular in the treatment of arthritis. They belong to a class of compounds known as glycosaminoglycans (GAGs). They are available over the counter as nutritional supplements. However, increasing use has led to increasing scrutiny of the quality of products on the market. There is also interest in the pharmacological properties of these compounds. To facilitate this, there is a need for better qualitative and quantitative methods of analysis. This paper describes methods for achieving the qualitative identification of chondroitin sulfate A, chondroitin sulfate C, glucosamine hydrochloride or glucosamine sulfate. Fourier transform infrared spectroscopy coupled with a variety of chemometric methods successfully classified these compounds. Using soft independent modeling of class analogies (SIMCA), hierarchical cluster analysis (HCA) and principal components analysis (PCA) samples were classified as either chondroitin sulfate A, chondroitin sulfate C, glucosamine hydrochloride or glucosamine sulfate. This work also examined the discriminating ability of different sections of the spectrum. It was found that for the classification of these compounds that using the finger print region of the spectrum (below 2000 cm(-1)) gave the best discrimination.     

Therapy of osteoarthritis crystalline glucosamine sulphate/a review of the clinical effcacy

The pharmacological treatment of osteoarthritis is traditionally accomplished with nonspecific symptomatic agents, which are generally effective only for acute symptom relief. Compounds are under investigation that might exert specific effects on osteoarthritis pathogenesis and thus induce at least a similar short-term symptomatic effect, but also control disease progression in the long term. Glucosamine sulphate (CAS 29031-19-4) reverses the proinflammatory and joint-degenerating effects of interleukin-1 by inhibiting the cytokine intracellular pathway. Clinical trials with the crystalline glucosamine sulphate formulation (CGS; dona) approved as a medicinal drug, predominantly used at the oral dose of 1,500 mg once daily, demonstrated a specific symptom-modifying effect on knee osteoarthritis over short- and long-term treatment courses. Two 3-year trials suggested that the drug also has joint structure-modifying properties and, therefore, might be useful as a disease-modifying agent in osteoarthritis.     

'Natural remedies' in the treatment of osteoarthritis

Osteoarthritis (OA) is a common, chronic and painful condition. It is the most common of all rheumatic disorders and is destined to become one of the most prevalent and costly diseases in our society. The conventional therapeutic options employed in the management of OA are simple analgesics and NSAIDs, but these options frequently produce sub-optimal benefit and are associated with an adverse-safety profile. Unsurprisingly patients are looking to alternative and complementary medicine. The aim of this article was to review the available literature on the effectiveness and safety of 'natural remedies' for the treatment of OA. Computerised literature searches were carried out for systematic reviews and randomised controlled trials examining the role of 'natural remedies' in the treatment of OA. There have been few randomised controlled trials of 'natural remedies' that have satisfied the internationally agreed standards. There was, however, evidence of efficacy for glucosamine, chondroitin sulfate and possibly avocado/soybean unsaponifiables for the symptomatic relief of OA. To date, it is not established whether any of the 'natural remedies' are capable of chondroprotection. Even if 'natural remedies' are only modestly effective, they are widely available and well tolerated, suggesting that they may play a significant role in the management of OA in the elderly.     

Pharmaceutical-grade chondroitin sulfate in the management of knee osteoarthritis

Introduction: Chondroitin Sulfate (CS) is a drug which is available as pharmaceutical-grade and nutriceutical-grade products, with important variations in preparation, composition, purity and therapeutic effects. Previous studies using pharmaceutical-grade CS suggested that the compound improves pain and function and delays structural progression in knee osteoarthritis (OA), whereas discrepant results were observed when lower grade preparations were investigated.

Areas covered: The recently published chondroitin versus celecoxib versus Placebo Trial (CONCEPT) assessed the symptomatic effect of pharmaceutical-grade CS 800 mg/day in symptomatic knee OA.

Expert opinion: This prospective, randomized, 6-month, 3-arm, double-blind, double-dummy, placebo and celecoxib (200 mg/day) – controlled trial involved 604 patients aged above 50 years with primary knee OA. This study showed that CS is superior to placebo and similar to celecoxib in reducing pain and improving function in Kellgren-Lawrence grade 1–3 patients supporting the role of pharmaceutical-grade CS as a potential first-line treatment for the management of patients with mild to moderate knee OA.     

氨基葡萄糖治疗骨关节炎的现状

骨关节炎 (OA)是临床上最常见的一种关节炎 ,目前尚无根治疗法 ,治疗主要是通过各种措施减轻疼痛和改善关节功能 ,尚不能延缓或阻断病情进展。新近临床试验结果显示硫酸氨基葡萄糖对OA不仅具有肯定的症状改善作用 ,而且能延缓OA的关节结构改变 ,可望成为第一个治疗OA的病情改善药。其总体安全性较好 ,主要是胃肠道及皮肤的不良反应 ,对血糖和动脉粥样硬化的影响尚待进一步观察。     

复方夏天无片联合盐酸氨基葡萄糖治疗早中期膝关节骨性关节炎的初步探讨

目的 研究复方夏天无片在早中期膝关节骨性关节炎中的临床疗效和安全性。方法 本研究将2010年8月至2011年2月间120例患者分为2组。实验组用复方夏天无片联合盐酸氨基葡萄糖,对照组单纯用盐酸氨基葡萄糖,治疗半年后采用Lequensne指数作为疗效评分标准,观察治疗前后膝关节症状,比较2组之间膝关节症状及不良反应。结果 随访3个月,实验组和对照组的疗效相比较,差异无统计学意义(P>0.05);但随访半年后,2组相比疗效差异有统计学意义(P<0.05)。2组的不良反应相比无统计学意义(P>0.05)。结论 本研究表明复方夏天无片联合盐酸氨基葡萄糖在治疗早中期膝关节骨性关节炎症状改善优于单纯使用盐酸氨基葡萄糖。复方夏天无片不良反应小、安全性高,对于膝关节骨关节炎具有较好的疗效。     

The reverse glucosamine sulfate pathway: application in knee osteoarthritis

Glucosamine is a natural amino sugar and a normal constituent of glycosaminoglycans in the cartilage matrix and synovial fluid of joints. Crystalline glucosamine sulfate salt has been approved as a medicinal product for the treatment of osteoarthritis in several European countries. Nevertheless, although it has been prescribed for more than 10 years, it is only due to the research in the last 5 years that the scientific basis underlying its beneficial effects are starting to be clarified. In randomised, double-blind, placebo-controlled trials, this compound clinically controls pain and produces beneficial effects in patients with knee osteoarthritis, possibly delaying the appearance of long-term structural changes in the joint (i.e., it has a structure-modifying effect). Furthermore, it has an excellent toxicity profile. Despite the different lines of investigation that have been followed, the mechanism of action of glucosamine sulfate still remains to be clearly defined. However, the activity of glucosamine sulfate has recently been related to its capacity to downregulate the catabolic effects of pro-inflammatory molecules, such as IL-1, which are present in osteoarthritic cartilage.     

Quality of different chondroitin sulfate preparations in relation to their therapeutic activity

Objectives Chondroitin sulfate is currently recommended by the European League Against Rheumatism (EULAR) as a SYSADOA (symptomatic slow acting drug for osteoarthritis) in Europe in the treatment of knee and hand osteoarthritis based on research evidence and meta‐analysis of numerous clinical studies. Furthermore, recent clinical trials demonstrated its possible structure‐modifying effects. Chondroitin sulfate, alone or in combination with glucosamine or other ingredients, is also utilized as a nutraceutical in dietary supplements in Europe and the USA. However, it is derived from animal sources by extraction and purification processes. As a consequence, source material, manufacturing processes, the presence of contaminants and many other factors contribute to the overall biological and pharmacological actions of these agents. We aim to review the quality control of chondroitin sulfate in pharmaceutical‐grade preparations and nutraceuticals. Key findings Pharmaceutical‐grade formulations of chondroitin sulfate are of high and standardized quality, purity and properties, due to the stricter regulations to which this drug is subjected by local national health institutes as regards production and characteristics. On the contrary, as several published studies available in literature indicate, the chondroitin sulfate quality of several nutraceuticals is poor. Additionally, there are no definite regulations governing the origin of the ingredients in these nutraceuticals and the origin of the ingredients in natural products is the most important factor ensuring quality, and thus safety and efficacy, in particular for chondroitin sulfate, due to its extraction from different sources. Conclusions Due to the poor chondroitin sulfate quality of some nutraceuticals, we conclude that stricter regulations regarding their quality control should be introduced to guarantee the manufacture of high quality products for nutraceutical utilization and to protect customers from low‐quality, ineffective and potentially dangerous products. There is a need for specific and accurate analytical procedures, which should be enforced to confirm purity and label claims both for raw materials and finished chondroitin sulfate products, and also to govern the origin of ingredients. Until these stricter regulations are in place, then it is strongly recommended that pharmaceutical‐grade chondroitin sulfate is used rather than food supplements.     

Glucosamine therapy for knee osteoarthritis: pharmacokinetic considerations

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.     

高效液相色谱法测定复方盐酸氨基葡糖硫酸软骨素片中硫酸软骨素的含量

目的 建立高效液相色谱法测定复方盐酸氨基葡萄糖硫酸软骨素片中硫酸软骨素的含量.方法 采用nucleosil 100-5SB（强阴离子交换硅胶,（5 μm 4.6 mm×250 mm）柱分离,以pH 3.5的水为流动相A,以pH 3.5的2 mol·L-1氯化钠溶液为流动相B,进行梯度洗脱.检测波长232 nm流速为1.0 mL·min-1,进样量为20 mL.结果 硫酸软骨素B、硫酸软骨素C和硫酸软骨素A的相邻之间分离度分别为24.32和2.37,线性范围为2.5125～20.1 g·L-1 （r=0.999 5,A=712.59C＋137.64）;平均回收率为103.06%,RSD为2.71%.结论 该方法简便,重复性好,结果可靠,可做为复方盐酸氨基硫酸软骨素片质量控制方法之一.     

Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: case report and review of the literature and MedWatch database

We describe a 71-year-old man who had received warfarin 7.5 mg/day for 5 years for atrial fibrillation, which had maintained his international normalized ratio (INR) within a narrow range of 2.5-3.2. During this 5-year period, he had also been treating himself with the supplement glucosamine hydrochloride 500 mg-chondroitin sulfate 400 mg twice/day for arthritis. The patient then increased his dosage of glucosamine to 1500 mg and chondroitin to 1200 mg twice/day; his INR previous to this change was 2.3. Approximately 3 weeks later, his INR increased to 3.9. His supplement dosage was reduced to glucosamine 750 mg-chondroitin 600 mg/day; a repeat INR done 16 days later was 4.7. The supplement was then stopped, and his warfarin schedule was changed to 7.5 mg every other day alternating with 3.75 mg every other day. Sixteen days later, his INR was 2.6. This case report suggests that a potential interaction exists between warfarin and glucosamine that is associated with an increase in the INR. We therefore performed a pharmacovigilance survey of spontaneously reported adverse events in warfarin-treated patients concomitantly exposed to glucosamine, glucosamine-chondroitin sulfate, or chondroitin sulfate and present a literature review of this apparent drug-drug interaction. Using the United States Food and Drug Administration (FDA) MedWatch database, 20 reports of glucosamine or glucosamine-chondroitin sulfate use with warfarin associated with altered coagulation (manifested by increased INR, or increased bleeding or bruising) were identified. In some cases, a decrease in the supplement dosage was followed by a return of the INR to the previous therapeutic range. Similarly, a decrease in warfarin dosage was followed by a decrease in INR in one patient who received long-term warfarin therapy. One report described an intraventricular bleed and subdural hematoma, which resulted in a persistent vegetative state. The World Health Organization (WHO) adverse drug reactions database documented 21 spontaneous reports of increased INR associated with glucosamine use, 17 of which resolved when glucosamine was stopped. We located one published case report of concomitant use of glucosamine-chondroitin sulfate potentiating the effect of warfarin. In aggregate, the reports from the FDA and WHO, the published case report, and our case report suggest that the use of warfarin and glucosamine may lead to an increased INR. Patients should be advised that the use of the two products may cause an increase in INR, and they should inform their health care provider if they consume glucosamine. More information is necessary to define this interaction.     

Osteoarthritis of the knee and hip. Part II: therapy with ibuprofen and a review of clinical trials

Objectives We review the pharmacological properties and clinical evidence pertaining to the efficacy of ibuprofen as a first‐line treatment in hip and knee osteoarthritis (OA). In the context of our previous paper's exploration of the aetiology and pathogenesis of OA as a basis for pharmacotherapy, we discuss the pharmacokinetics (PK) and clinical pharmacodynamics (PD) of ibuprofen relevant to OA. Key findings Although widely used, the benefits and risks of ibuprofen, especially compared with other non‐steroidal anti‐inflammatory drugs (NSAIDs) and placebo, have only recently been evaluated in OA of the hip and knee in randomized‐controlled clinical trials (RCT). The efficacy and occurrence of adverse reactions from ibuprofen was compared with placebo in a structural review of the literature and systematic review of RCTs in large‐scale clinical trials. Ibuprofen has been found to result in approximately 50–60% improvement over placebo in WOMAC scores, including those reflecting inflammatory joint pain in knee and hip OA or other indices of pain, disability and impaired function. Mega‐trials performed in comparison with the newer NSAIDs, the coxibs, have shown that ibuprofen has comparable therapeutic benefits and although serious gastrointestinal conditions are sometimes more frequent after short‐term treatment, longer‐term (several months) therapy in OA reduces the advantages of the coxibs over other NSAIDs including ibuprofen. Cardiovascular risk, though present with coxibs and some NSAIDs in OA, is lower or slightly so with ibuprofen compared with coxibs. Summary Ibuprofen is effective and relatively safe (especially at low over‐the‐counter doses and in the short term) for mild‐to‐moderate OA of the knee and hip. The PK properties of ibuprofen in OA (short plasma t½) confer advantages of this drug for OA, while evidence for clinically relevant PD benefits in joints of patients with OA, though limited, is suggestive of local anti‐inflammatory activity.     

Glucosamine therapy for knee osteoarthritis: pharmacokinetic considerations

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.     

响应面法优化硫酸软骨素提取的酶解工艺

目的以猪喉软骨为原料,提取硫酸软骨素,优化酶解工艺条件。方法采用碱提-酶解-醇沉的方法提取硫酸软骨素,在单因素试验的基础上,通过响应面分析优化酶解工艺。结果酶解最佳工艺组合为:胰酶浓度1.0%、pH值8.6、酶解温度46℃、酶解时间2.8 h。结论采用上述组合,以氨基葡萄糖含量为指标,氨基葡萄糖含量达25.94%。研究结果具有工业应用价值。     

Preformulation studies and characterization of proposed chondroprotective agents: glucosamine HCl and chondroitin sulfate

PURPOSE: Glucosamine HCl and chondroitin sulfate are proposed chondroprotective agents commonly used as dietary supplements. This study examined the physicochemical and mechanical properties of chondroitin sulfate, glucosamine HCl powder, and glucosamine HCl granulation obtained from various sources. METHODS: The particle size distributions of the materials were determined using sieve analysis and time-of-flight techniques. Polarized light microscopy was used to examine particle morphology. Powder x-ray diffraction studies, moisture sorption isotherms, deformation behavior, powder flow, and compaction characteristics were also investigated. The polarized light microscopy and x-ray diffraction patterns showed that chondroitin sulfate is amorphous while glucosamine HCl is crystalline. Particle sizes of chondroitin sulfate and glucosamine HCl varied widely, depending on their source or manufacturing technique (e.g., granulation). The studied samples of shark-derived chondroitin sulfate had a small median particle size (4 microns) compared to that derived from bovine cartilage (17 microns). Different moisture sorption profiles were obtained for the glucosamine HCl granulations studied. Glucosamine HCl granulation from Supplier I showed no observable moisture sorption, while the granulation from Supplier II showed an approximately 5% weight gain. Conversely, chondroitin sulfate was extremely hygroscopic and deliquescent. The Carr's indices for glucosamine HCl samples ranged from 12.5 to 31.5; for chondroitin sulfate the values were 25.2 and 53.6. The compression analysis showed that all chondroitin sulfate samples exhibited plastic deformation behavior, with the shark-derived chondroitin sulfate forming superior compacts when compared to the bovine. The dominant mechanism of compression of glucosamine HCl powder was brittle fracture, whereas wet granulated glucosamine HCl exhibited plastic deformation with enhanced mechanical strength. CONCLUSIONS: The physicochemical and mechanical characteristics between the various dietary supplements studied varied greatly. Data obtained from this study provide an understanding of the physicomechanical behavior of chondroitin sulfate and glucosamine HCl. Application of this knowledge would facilitate development of stable solid dosage forms containing these materials.     

Preformulation Studies and Characterization of Proposed Chondroprotective Agents: Glucosamine HCl and Chondroitin Sulfate

Purpose: Glucosamine HCl and chondroitin sulfate are proposed chondroprotective agents commonly used as dietary supplements. This study examined the physicochemical and mechanical properties of chondroitin sulfate, glucosamine HCl powder, and glucosamine HCl granulation obtained from various sources. Methods: The particle size distributions of the materials were determined using sieve analysis and time-of-flight techniques. Polarized light microscopy was used to examine particle morphology. Powder x-ray diffraction studies, moisture sorption isotherms, deformation behavior, powder flow, and compaction characteristics were also investigated. The polarized light microscopy and x-ray diffraction patterns showed that chondroitin sulfate is amorphous while glucosamine HCl is crystalline. Particle sizes of chondroitin sulfate and glucosamine HCl varied widely, depending on their source or manufacturing technique (e.g., granulation). The studied samples of shark-derived chondroitin sulfate had a small median particle size (4 μm) compared to that derived from bovine cartilage (17 μm). Different moisture sorption profiles were obtained for the glucosamine HCl granulations studied. Glucosamine HCl granulation from Supplier I showed no observable moisture sorption, while the granulation from Supplier II showed an approximately 5% weight gain. Conversely, chondroitin sulfate was extremely hygroscopic and deliquescent. The Carr's indices for glucosamine HCl samples ranged from 12.5 to 31.5; for chondroitin sulfate the values were 25.2 and 53.6. The compression analysis showed that all chondroitin sulfate samples exhibited plastic deformation behavior, with the shark-derived chondroitin sulfate forming superior compacts when compared to the bovine. The dominant mechanism of compression of glucosamine HCl powder was brittle fracture, whereas wet granulated glucosamine HCl exhibited plastic deformation with enhanced mechanical strength. Conclusions: The physicochemical and mechanical characteristics between the various dietary supplements studied varied greatly. Data obtained from this study provide an understanding of the physicomechanical behavior of chondroitin sulfate and glucosamine HCl. Application of this knowledge would facilitate development of stable solid dosage forms containing these materials.