Хондропротекторы

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Müller and colleagues19 evaluated the short-term 4-week effects of 1,200 mg of GS using Lequesne's severity index and looked at the relative risks of side effects in the GS group versus the ibuprofen group. In this short 1-month study, GS was as effective as ibuprofen and significantly better tolerated (P < .001). Only 6% of patients taking GS reported adverse events, whereas 35% of ibuprofen users had an adverse event (mainly gastrointestinal in origin).
Noack et al.20 published a 4-week study comparing GS with placebo rather than ibuprofen. This short study of 252 patients showed that GS was more effective than placebo in improving OA symptomatology. Patients in the GS arm of the trial enjoyed a 3.3-point drop in Lequesne's severity index, whereas those taking the placebo improved by 2.0 points. A 6-week study by Reichelt et al.21 showed GS to decrease Lequesne's index over placebo in 155 patients. Unfortunately, these studies are too short to make significant long-term conclusions.
In 2001 Reginster et al.22 published the results of a trial in which 212 patients were randomized to receive placebo or GS daily for 3 years. Glucosamine was shown to protect the joint space from the narrowing effects of OA. A trend toward improving Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores was seen without any statistically significant change.
A similar study by Pavelká et al.23 supported the findings of Reginster et al.,22 proving statistically significant effects of glucosamine on both radiographic progression and WOMAC scores.
Bruyere et al.24 used the same outcome measures of joint space narrowing and WOMAC scores to prove that the disease-modifying effects seen in the study of Pavelká et al.23 were also found in the older postmenopausal female population. Bruyere et al.25 investigated joint space narrowing in 212 knee OA patients at 3 years. Patients with less severe radiographic knee OA had the most dramatic disease progression as seen by joint space narrowing. The GS group, compared with the placebo group, showed a nonstatistical trend in significant reduction of joint space narrowing.
Cibere et al.26 tested GS in a 4-center 6-month randomized, double-blind, placebo-controlled study. No differences were found in the severity of disease pain episodes (flare-ups) or other secondary outcomes between placebo- and glucosamine-treated patients. They concluded that there was no evidence of symptomatic benefits from continued GS use from this 6-month study.
Herrero-Beaumont et al.27 evaluated 318 patients with knee OA in an RCT comparing GS, acetaminophen (Tylenol; McNeil Consumer Healthcare, a division of Johnson & Johnson, Guelph, Ontario, Canada), and placebo. After 6 months, 1,500 mg of GS was found to be better than placebo and acetaminophen by use of Lequesne's index and the WOMAC.
Hughes and Carr28 performed a randomized clinical trial with GS in 80 OA patients for 24 weeks. They found a 33% placebo response rate and no statistical improvement over placebo as a symptom modifier.
Collectively, these GS studies showed that GS as an individual agent may have some effect on the progression of the disease and was as safe as placebo at a dose of 1,200 to 1,500 mg/d for up to 3 years. Many studies had a short-term follow-up, and the evidence inconsistently supported the use of glucosamine as an effective alternative to higher-risk medications such as NSAIDs and cyclooxygenase II inhibitors for knee OA

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Glucosamine Hydrochloride
The hydrochloride salt of glucosamine is a common glucosamine product, yet it has received relatively little attention from researchers (Table 3). Houpt et al.29 were unable to show statistically significant changes in the WOMAC pain score subset versus placebo after a short period of therapy with GH (8 weeks). All tested parameters tended to show improvement, and GH did significantly reduce the daily pain reported by patients (P = .018) and improved findings on clinical knee examination (P = .026). GH was shown to be as safe as placebo. Though failing to prove its primary outcome measure, this study suggested that GH benefited some patients with OA without the side effects of other treatment modalities. McAlindon et al.30 performed a 12-week GH study on 205 patients, recruited over the Internet. By use of the WOMAC as the primary outcome, GH was safe but no more effective than placebo in treating symptoms of knee arthritis

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Glucosamine and CS
The highly publicized Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) was published in the New England Journal of Medicine early in 2006 (Table 4).31 The multicenter trial assigned 1,583 patients to randomly receive 1,500 mg glucosamine; 1,200 mg CS; both GH and CS; 200 mg of celecoxib (Celebrex; Pfizer, New York, NY); or placebo for 24 weeks. Patients were allowed to take up to 4,000 mg of acetaminophen for rescue analgesia daily (no pain medications were taken within 24 hours of clinical examination). All patients in the study were aged at least 40 years, had both clinical evidence (knee pain for most days of the month for ≥6 months) and radiographic evidence of OA (osteophytes ≥1 mm), and WOMAC scores from 125 to 400. The primary outcome measure was a 20% decrease in the summed score for the WOMAC pain subscale from baseline to week 24. Over 40 secondary outcome measures were included in the study
In the subgroup of 79 patients with moderate to severe pain (determined by a score of 300-400 on the WOMAC pain scale), GH and CS significantly reduced knee pain. In this subgroup of patients receiving GH and CS, 79% showed a 20% reduction in knee pain, whereas only 54.3% of the placebo group showed this improvement. However, GH and CS were not found to be significantly better than placebo in reducing knee pain by 20% from baseline in the pooled analysis of patients. Adverse effects were mild, infrequent, and evenly distributed across all groups tested, supporting the safety of these nutritional supplements.
Celecoxib was found to yield a statistically significant decrease in pain scores in the combined mild pain and moderate/severe pain subgroups but failed to have a significant effect on the pain scores in the moderate/severe pain subgroup. Celecoxib was also found to yield a faster decrease in pain scores, showing substantial decreases in pain scores at 4 weeks of treatment. Overall, celecoxib was found to have a significant effect on 6 of the 42 outcome measures followed in the study, whereas glucosamine and CS were found to have a significant effect on 14 of the 42 outcome measures.
This study, the largest and most rigorous of its kind, showed that GH and CS had a significant effect on patients with more severe OA. Questions remain about the usefulness of glucosamine and CS in mild OA and their effect on other parameters such as joint function, stiffness, and joint space narrowing. Limitations of the study noted by the authors were the high rate of response to placebo (60%) and the relatively mild degree of OA pain among the participants. Concomitant treatments, such as physical therapy, were not clarified. These limitations decreased the ability of the study to detect the benefits of treatment. Studies with alternative medical therapies have shown a higher placebo response rate.32 Celecoxib at 200 mg/d had noticeably smaller effects in the GAIT study compared with earlier studies.

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The GAIT study was designed to include 1,588 patients to provide the study with statistical power to detect 1 or more clinically meaningful differences based on an assumed placebo response rate of 35%. When this placebo response rate nearly doubled, the number of participants needed to obtain a similar statistical power increased substantially. With far too few patients given its placebo response rate, the data were barely able to prove its control (celecoxib) in the primary outcome measure (P = .04) and was unable to do so in the moderate/severe pain subgroup. Furthermore, the choice of the product tested (GH) has been called into question given the fact that GS has been more rigorously studied in the literature. The GAIT authors also chose less sophisticated methods for dealing with missing data, using the last observation–carried forward method rather than the multiple imputation method.
Alekseeva et al.33 examined 90 women aged between 40 and 75 years with Kellgren-Lawrence stage II or III knee OA who had pain after 40 minutes of walking and regularly took NSAIDs for pain relief. The patients were randomly selected either to receive 500 mg of the glucosamine and CS supplements with optional diclofenac (50 mg) or to receive a placebo and optional diclofenac for a total of 3 months. The results were measured by the WOMAC, daily need for NSAIDs, and evaluation of efficacy by the patient and the physician after 1 and 3 months of treatment and again 3 months after the oral supplementation had been stopped. The true WOMAC score decreased after 3 months of therapy and 3 months after the supplementation had been stopped (P < .03). At the end of the 3 months of therapy, the study group exhibited decreases in pain scores (P = .008) and increases in subjective functional ability. The patients taking the glucosamine and CS supplementation required less diclofenac. After 1 month of therapy, 4.5% stopped taking diclofenac and nearly 40% stopped taking it by the end of the study. Although limited by its size and the small subgroup that was studied (older women), this study showed that combined medications offer significant safety and effective pain relief in the short term with long-lasting effects.
Messier et al.,34 in a double-blind 12-month GH/CS study with 80 patients, incorporated 6 months of exercise after 6 months of a non-exercising treatment. The primary end-point was the WOMAC and functional measures such as the 6-minute walk. At 12 months, there was no difference between groups for the 6-minute walk, knee strength, mobility, and function over the placebo treatment.
Meta-Analyses of Glucosamine and CS Studies
Several important meta-analyses have been published in recent years about the efficacy of glucosamine and CS therapy. By performing exhaustive searches in the literature and applying systematic quality assessment of these studies, these meta-analyses provided pooled information from the many pre-existing small studies.
McAlindon et al.35 examined 15 double-blind, randomized, placebo-controlled trials of 4 weeks' duration or longer for their impact on the symptoms of hip and/or knee OA. They included studies of glucosamine and CS with various routes of administration, including oral, intramuscular, intravenous, and intra-articular. Very few of the examined studies described adequate allocation concealment or use of an intention-to-treat analysis. They also found evidence of significant publication bias, likely because of manufacturer's sponsorship of trials and the financial interests of the authors. When only the larger high-quality studies were evaluated, the effects of glucosamine and CS persisted, although they were noticeably diminished. This study also suggested that the full therapeutic benefit of these supplements likely did not occur in the first 4 weeks and that longer studies would be of significant value.
Richy et al.36 examined both structural and symptomatic efficacy of CS and glucosamine. By examining structural changes via radiographic progression of joint space narrowing, this analysis was the first to evaluate the disease-modifying effects of these supplements. Evaluating the results of 15 studies that included data from 1,775 patients, the authors showed a statistically significant improvement in symptom scores with both glucosamine and CS therapy. They also were able to show a significant effect of glucosamine on the progression of joint space narrowing over a 3-year period, suggesting a disease-modifying effect of the compound (no such studies existed for CS). Importantly, the tolerance for these supplements was again shown to be equal to that of placebo.
Bjoral et al.37 reviewed 63 RCTs using opioids, NSAIDs, glucosamine, CS, and acetaminophen (Tylenol; McNeil Consumer Healthcare) for knee OA including some 14,060 total patients. Acetaminophen, GS, and CS had maximum efficacies at 1 to 4 weeks with mild pain improvements. Overall clinical effects from these knee pharmacologic arthritic interventions were found to be small and limited to the first 2 to 3 weeks after the start of treatment.
Distler and Angueloouch38 reviewed clinical evidence for glucosamine and CS studies analyzing RCTs. Their results were inconclusive regarding the continuous use of these nutraceuticals because of weak research design

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Reichenbach et al.39 performed a meta-analysis of CS for OA of the knee or hip in 20 trials involving 3,846 patients. After analyzing the small and large studies, they found the trial quality to generally be low. They concluded that with the large-scale, methodologically sound trials, CS had minimal to nonexistent symptomatic benefit. They discouraged CS use by itself in routine clinical practice.
Leeb et al.40 performed a meta-analysis of 7 trials of CS including 372 patients. They cited the difficulties in design with co-mixing of medications in several studies using the visual analog scale and Lequesne's index. The findings in the CS groups were significantly superior to those in the placebo groups. They called for better and longer time periods for symptom-modifying evaluations.
The Cochrane Review is perhaps the most thorough of the meta-analyses performed on glucosamine's effect on OA.41 Updated in January 2005, this meta-analysis followed 3 selection criteria: they were RCTs, they were either placebo controlled or comparative, and they were blinded (single or double were both accepted). Twenty articles were found to meet the selection criteria, representing 2,570 patients. Cumulatively, these articles showed that glucosamine induced a 28% improvement from baseline in pain and a 21% improvement in function by use of Lequesne's index. In 8 articles that showed adequate allocation concealment, glucosamine failed to show a benefit for either pain or function. The Cochrane Review confirmed the safety findings of the incorporated studies, finding glucosamine to have adverse events equal to the placebo. Although these conclusions were significant for the number of studies they incorporate, they did have their limitations. This review was designed to include a broad selection of clinical trials, accepting short-term studies, comparative control studies, and single-blind studies. In accepting these lower-quality articles, the power of the pooled results was negatively impacted.
Other Sulfur-Containing Compounds
S-adenosylmethionine (SAMe) and methylsulfonylmethane (MSM) are market leaders among the sulfur-containing compounds advertised for joint health. Despite the public interest in these compounds, few well-designed studies have been completed. An open-label study in 1987 showed that SAMe increased joint mobility with no evaluation of pain or function.42 Subsequent double-blind placebo-controlled studies have supported the use of SAMe and shown it was effective as many anti-inflammatory and pain-relieving drugs.[43], [44] and [45]
In 2004 Najm et al.46 compared the efficacy of SAMe with Celebrex (Pfizer) for the symptoms of OA. In the first month of their 4-month study, celecoxib showed significantly more reduction in subjective pain reports by the participants (P = .024). By the second month, both study arms were equally effective in reducing pain (P < .01). This study noted increased functional health measures and increasing joint mobility in both treatment groups, without significant differences in side effects. These trends were not shown to be statistically significant.
Despite the presence of several studies suggesting the efficacy of MSM in reducing joint pain and enhancing mobility,[47] and [48] the literature on MSM is deficient. With a paucity of research, as well as the short length of follow-up, it is difficult to recommend MSM at this time as an efficacious therapy for OA. Kim et al.49 showed significant decreases in WOMAC pain (decrease of 25% from baseline) and physical function subcategories with MSM versus placebo. Improved performance of MSM users was seen in activities of daily life as measured by the Short Form 36 score (P = .05), but this study found no significant improvement in the total aggregate WOMAC score at 3 months.

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Discussion
This review looked at the current research on the sulfur-containing nutraceuticals and their effects on proven outcome measures. In the literature satisfying our inclusion criteria, GS and CS have shown an inconsistent yet overall positive efficacy in decreasing OA pain and improving joint function. Most trials found the safety of these compounds to be equal to that of placebo. The literature on GH, GS, or CS as an individual supplement suggests a therapeutic value but falls short of proving a role for its independent use.
Although the study by Clegg et al.31 called into question the efficacy of GH and CS in mild OA, it showed the effectiveness of these supplements in the moderate/severe pain subgroup. Their study lacked the size to make up for a placebo response rate of over 60% and the relatively mild disease state of the study participants. When considered within the context of the other studies reviewed, it serves as another study to confirm the safety profile of glucosamine and CS and shows a reduction in pain scores with consistent use.
The scant literature on the sulfur-containing compounds SAM-e and MSM shows trends toward decreased pain and increased function with consistent use but fall short of proving any therapeutic benefit. However, they have a documented 3-month safety profile; there is a need for more randomized clinical trials.
Perhaps the most important trend seen in the current literature on nutraceutical use for OA is the importance of length of therapy. Although some studies have shown significant improvement in OA symptoms during a short time period, these studies involved the use of concomitant pain relievers, were poorly concealed for allocation, or were monetarily supported by manufacturers. In the more rigorous and lengthy studies comparing these compounds, effectiveness was not seen until several months into therapy. For example, in studies on CS significant effects were not seen until 3 to 6 months of treatment. In other studies the effectiveness of CS was not shown until month 9 of the treatment phase or month 4 of the post-treatment phase. In glucosamine studies a similar trend can be noted because treatment effects can be delayed until post-treatment follow-up. These findings support the need for more long-term trials and the importance of consistent use in patients who select these compounds as treatment for OA pain and disability.50
It is important to understand that many of these glucosamine and CS studies have been financed and sponsored by industry and specific manufacturers. Not all studies document this well, and financial relationships with industry, scientific investigators, and academic institutions are widespread. These potential conflicts influence research and have been well studied.51
When considering the use of vitamin or nutrient supplementation, it is important to realize that the supplements tested in trials are not necessarily the same as the supplements sold in stores.52 To reduce any potential complicating factors, clinical trials must use products that have been rigorously tested with regard to the purity and quantity of the supplements. Products available in stores are not adhered to these same specifications by the Food and Drug Administration (FDA) because they do not undergo federal testing for actual content. According to the Dietary Supplement Health and Education Act of 1994, the manufacturer is responsible for determining that the supplement is present in the advertised purity and amount and that any claims made about it are adequately substantiated.53
The FDA allows dietary supplement labels to include information describing the supplement's effect on the body and its biologic functions. These types of claims are referred to as structure/function claims. To make such claims, manufacturers must have some scientific data to substantiate them and not overstate the science. The FDA has the authority to declare a product mislabeled if its labeling is false or misleading. In the future the FDA intends to issue regulations on good manufacturing practices that will focus on ensuring the identity, purity, quality, strength, and composition of dietary supplements.54 In the interim the industry has instituted its own good manufacturing practices to ensure quality products for the consumer.55 Reputable companies provide consumers with carefully formulated supplements that are accurately labeled. These manufacturers ensure that each batch of raw materials is laboratory tested for purity and potency.
For the consumer, it is important to purchase glucosamine and CS supplements that provide the efficacious amount of each ingredient as declared by the label. Several reputable companies, both national and store brands, have been shown to sell products that contain the labeled amount of glucosamine and CS at affordable prices. As a physician, it is important to recommend a brand name that has consistently shown itself to meet or exceed its claims on content quality and quantity in the literature

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Conclusions
In the literature satisfying our inclusion criteria, GS, GH, and CS have individually shown inconsistent efficacy in decreasing OA pain and improving joint function. Many studies confirmed OA pain relief with glucosamine and CS use. The excellent safety profile of glucosamine and CS therapy should be discussed with patients, and these supplements may serve a role as an initial treatment modality for many OA patients.
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[docvad]

OARSI recommendations for the management of hip and knee OA

18. Treatment with glucosamine and/or chondroitin
sulphate may provide symptomatic benefit in
patients with knee OA. If no response is apparent
within 6 months treatment should be discontinued.
SOR: 63% (95% CI 44e82)

[disdas]

Don’t use glucosamine and chondroitin to treat patients with symptomatic osteoarthritis of the knee.


Both glucosamine and chondroitin sulfate do not provide relief for patients with symptomatic osteoarthritis of the knee.
[Ссылки доступны только зарегистрированным пользователям ]