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Glucosamine sulphate in the treatment of knee osteoarthritis: Cost-effectiveness comparison with paracetamol
International Journal of Clinical Practice
Abstract
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.
... Furthermore, the early use of glucosamine can also help reduce the need for NSAIDs. This is significantly important as the prolonged use of NSAIDs can lead to adverse effects, especially for patients at high risk of gastrointestinal and cardiovascular issues [53]. ...
... The results from this study are consistent with the results from several previous studies on the cost-effectiveness of glucosamine, such as Scholtissen et al. (2010) [53], who demonstrated that flucosamine is cost-effectiveness compared to paracetamol and a placebo. Bruyère et al. (2019Bruyère et al. ( , 2021 [46,54] concluded that crystalline glucosamine sulfate is cost-effective compared to a placebo and other forms of glucosamine at 3-month, 6-month, [58] stated that glucosamine is clinically effective but does not achieve the desired cost-effectiveness. ...
... The results from this study are consistent with the results from several previous studies on the cost-effectiveness of glucosamine, such as Scholtissen et al. (2010) [53], who demonstrated that flucosamine is cost-effectiveness compared to paracetamol and a placebo. Bruyère et al. (2019Bruyère et al. ( , 2021 [46,54] concluded that crystalline glucosamine sulfate is cost-effective compared to a placebo and other forms of glucosamine at 3-month, 6-month, [58] stated that glucosamine is clinically effective but does not achieve the desired cost-effectiveness. ...
Osteoarthritis (OA) is the degeneration of cartilage in joints that results in bones rubbing against each other; it causes uncomfortable symptoms such as pain, swelling, and stiffness and can lead to disability. It usually occurs in the elderly and causes a large medical burden. The aim of this study is to evaluate the cost-effectiveness between the standard treatment for osteoarthritis and standard treatment with added crystalline glucosamine sulfate at various stages. Markov analysis modeling was applied to evaluate the effect of both adding glucosamine compared to standard treatment from a societal perspective during whole patients’ lifetimes. Data input was collected from reviews in previous studies. The outcome was measured in quality-adjusted life years (QALYs), and the Incremental Cost-Effectiveness Ratio (ICER) from a societal perspective was applied with 3% and discounted for all costs and outcomes. One-way analysis via the Tornado diagram was performed to investigate the change in factors in the model. In general, adding glucosamine into the standard treatment proved to be more cost-effective compared to the standard treatment. Particularly, the early-stage addition of glucosamine in the treatment was cost-effective compared to the post-stage addition of glucosamine. The addition of supplementing crystalline glucosamine sulfate to the whole regimen at any stage was cost-effective at the willingness-to-pay (WTP) threshold.
... The assessment of glucosamine's cost-effectiveness based on scientific studies has mainly concentrated on comparing cost-effectiveness among various formulations or with other therapies, whereas, overall, reviews exploring the financial efficacy of glucosamine are very limited. In addition, state management agencies relied on pharmacoeconomic-related data to determine the type of resource allocation that would produce the greatest efficacy; hence, these evaluations are crucial for setting price limits and reimbursement [41]. Furthermore, since we cannot access patients' personal data due to technical and legal issues, as well as patient consent, we conducted our assessment based on scientific data. ...
... While Scholtissen et al. [41] reported a 6-month time horizon, Luksameesate et al. [15] and Black et al. [49] both documented lifetime horizons. ...
... Adding pCGS increased efficiency and thus saved money. In Scholtissen's study [41], the ICERs for glucosamine compared with paracetamol and placebo were 1376 EUR/QALY and 3617.47 EUR/QALY, respectively. ...
Osteoarthritis (OA) is a chronic condition that most frequently affects older adults. It is currently the most common disability. The cost of treating an aging population places pressure on the healthcare budget. As a result, it is imperative to evaluate medicines’ cost-effectiveness and, accordingly, their influence on health resource allocation. Our study aims to summarize the cost and outcome of utilizing glucosamine in OA treatment. Databases like Medline, Cochrane, and Scopus were searched as part of the identification process up until April 2023. Our primary inclusion criteria centered on the economic evaluation of glucosamine in OA treatments, providing an incremental cost-effectiveness ratio (ICER). The Quality of Health Economic Studies (QHES) instrument was applied to grade the quality of the studies. Seven qualified studies that discussed the cost-effectiveness of glucosamine with or without other formulations were selected. All of them demonstrated that glucosamine was cost-effective. There was an increase in quality-adjusted life years (QALYs) when incorporating glucosamine in conventional care. Moreover, patented crystalline glucosamine sulfate (pCGS) was more cost-effective than the other formulations of glucosamine (OFG). Overall, utilizing pCGS was more beneficial than using OFG in terms both of cost and quality of life.
... The assessment of glucosamine's cost-effectiveness from scientific studies mainly concentrated on comparing cost-effectiveness among various formulations or with other therapies, whereas overall reviews about financial efficacy of glucosamine were very limited. In addition, the management agencies relied on pharmacoeconomic-related data to determine the type of resources allocation that would produce the greatest efficacy, hence these evaluations are crucial for setting price limits and reimbursement [41]. Furthermore, since we cannot access the personal data of each patient due to technical, legal issues as well as patient consent, we conduct our assessment based on scientific data. ...
... It should be noted that only 3/7 studies presented information about the time horizon. While Scholtissen et al. [41] reported a 6-month time horizon, Luksameesate et al. [15] and Black et al. [48] both documented life time horizons. ...
... Adding pCGS increased efficiency and thus saved money. In Scholtissen's study [41], ICER of Glucosamine compared with paracetamol and placebo was 1376€/QALY, 3617.47€/QALY, respectively. ...
The osteoarthritis (OA), the main cause of disability, is a chronic condition that most frequently affects older adults. As the population ages, the cost of treatment is placing pressure on the healthcare budget. As a result, it is imperative to evaluate the medicines' cost-effectiveness and the influence they have on health resource allocation. Hence, our study aims to summarize the cost and outcome of utilizing glucosamine in OA treatment. Authentic databases like Medline, Cochrane, and Scopus were adopted for the identification process up until July 2023. Our primary inclusion criteria centered on the economic evaluation of Glucosamine in OA treatments with provided the incremental cost-effectiveness ratio (ICER) at least. The Quality of Health Economic Studies (QHES) instrument was applied to grade the quality of the studies. A total of 7 qualified studies were selected and discussed the cost-effectiveness of glucosamine with or without other formulations. All of them demonstrated that glucosamine was cost-effective. There was an in-creasement of QALY when incorporating Glucosamine into conventional care. Moreover, Crystalline Glucosamine Sulfate (pCGS) was more cost-effective than the Other Formulations of Glucosamine (OFG). In overall, utilizing pCGS was more beneficial than OFG in terms both of cost and quality of life.
... Most studies used NSAIDs and/or coxibs as interventions, which were often combined with a proton pump inhibitor (PPI). A total of 13 studies used IA injection as the intervention [36,39,45,59,68,71,72], while three studies used opioids only [34,49,61]. Economic evaluation typically compares an intervention with current best practice or usual care, which may vary by clinical setting. ...
... To estimate health utilities for a QALY calculation, the Western Ontario McMaster University Osteoarthritis Index (WOMAC) [77] or another instrument (Sleep Problems Index [SPI]) were often translated into a utilitybased instrument (e.g. the EQ-5D or Health Utility Index [HUI]). Four studies [34,49,61,68] translate WOMAC into the HUI and three [50,53,66] into EQ-5D, while five studies [52,56,[62][63][64] directly used the EQ-5D and three [45,51,59] use the HUI3. Table 3 identifies seven articles evaluating economic outcomes in Asia [35,44,62,66,73,74,76]. ...
... Of the seven studies included, one reported a threshold range, three reported a single threshold, and the remaining three studies did not report a threshold. Table 4 presents a total of 15 studies conducted in nine European countries, with one study involving two countries [61]. The UK and Sweden were the only countries in which more than one study was conducted. ...
Background and objective:
Osteoarthritis (OA) is a highly prevalent, disabling disease requiring chronic management that is associated with an enormous individual and societal burden. This systematic review provides a global cost-effectiveness evaluation of pharmacological therapy for the management of OA.
Methods:
Following Center for Reviews and Dissemination (CRD) guidance, a literature search strategy was undertaken using PubMed, EMBASE, Cochrane Library, Health Technology Assessment (HTA) database, and National Health Service Economic Evaluation database (NHS EED) to identify original articles containing cost-effectiveness evaluation of OA pharmacological treatment published before 4 November 2021. Risk of bias was assessed by two independent reviewers using the Joanna Briggs Institute (JBI) critical appraisal checklist for economic evaluations. The Quality of Health Economic Studies (QHES) instrument was used to assess the reporting quality of included articles.
Results:
Database searches identified 43 cost-effectiveness analysis studies (CEAs) on pharmacological management of OA that were conducted in 18 countries and four continents, with one study containing multiple continents. A total of four classes of drugs were assessed, including non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, symptomatic slow-acting drugs for osteoarthritis (SYSADOAs), and intra-articular (IA) injections. The methodological approaches of these studies showed substantial heterogeneity. The incremental cost-effectiveness ratios (ICERs) per quality-adjusted life-year (QALY) were (in 2021 US dollars) US307,013.56 for NSAIDS, US128,028.74 for opioids, US27,799.73 for SYSADOAs, and US58,447.97 for IA injections in different continents. The key drivers of cost effectiveness included medical resources, productivity, relative risks, and selected comparators.
Conclusion:
This review showed substantial heterogeneity among studies, ranging from a finding of dominance to very high ICERs, but most studies found interventions to be cost effective based on specific ICER thresholds. Important challenges in the analysis were related to the standardization and methodological quality of studies, as well as the presentation of results.
... The first key characteristic is the different glucosamine formulations. Three studies used glucosamine sulfate as an intervention [54][55][56] , one study used glucosamine hydrochloride, [57] while another used crystalline glucosamine sulfate. [58] These evaluations of economic viability of glucosamine sulfate concluded mixed results. ...
... [58] These evaluations of economic viability of glucosamine sulfate concluded mixed results. Scholtissen et al. [54] found that it was cost-effective over paracetamol and a placebo. Inconsistency with the two other studies by Black et al. [55] and Chaiyakunapruk et al. [56] showed that it might not be cost-effective at the willingness-to-pay threshold of their countries, the UK and Thailand, respectively. ...
... Interestingly, both the Black et al. and Chaiyakunapruk et al.'s studies showed that glucosamine lacked cost-effectiveness when compared with current care, but the other three studies found glucosamine to be more cost-effective when compared with a placebo. [54][55][56][57][58] Only Scholtissen et al.'s study compared paracetamol and glucosamine and showed that glucosamine sulfate was more cost-effective than paracetamol. [54] The last key characteristic involves the variety of Downloaded from https://academic.oup.com/jphsr/advance-article/doi/10.1093/jphsr/rmab058/6423235 by Chulalongkorn University, Parnnaphat.luk@gmail.com on 09 November 2021 the treatment duration, including 6 months, 3 years and a lifetime horizontal. ...
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.
... These evaluations play a growing role in pricing and reimbursement decisions as regulatory agencies rely more and more on pharmacoeconomic data to make decisions about limited resources [10]. To the best of our knowledge, only one clinical trial has explored the cost-effectiveness of glucosamine (and in this particular case the pCGS formulation) compared with that of paracetamol and placebo in the treatment of knee OA [11]. The authors concluded that compared with paracetamol and placebo, pCGS was a highly cost-effective therapy to treat patients diagnosed with knee OA. ...
... To validate the procedure, we tested it on data from the only study on glucosamine in which individual health utility values were published [11] and for which we have access to the individual values for WOMAC scores, age and years since OA diagnosis, at baseline and after 3 months of treatment. We computed means and standard deviations for and between these values with the CORR procedure of SAS at baseline, after 3 months and for subjects in the placebo and pCGS groups. ...
... When available, means and SD were extracted from published articles, after correction for the scales (to be on the scale for WOMAC indexes as the one used in the equation of Grootendorst). We replaced missing data in the summary statistic of published studies (i.e., sometimes data, such as the standard deviation or a specific variable such as years since OA, were unavailable) with data from the study used to develop and validate the procedure [11]. We simulated a total of 20,000 patients in each study (10,000 glucosamine and 10,000 placebo), and data were examined by two independent experts. ...
Background
The economic evaluation of treatments usually requires access to individual patient data, which is difficult to obtain. Moreover, in osteoarthritis, health utility scores are unavailable and can be assessed only using a validated equation model based on various clinical data. We aimed to develop and validate a methodology to simulate individual health utility scores from aggregated clinical data available in published studies to calculate the cost-effectiveness of different glucosamine preparations (i.e., crystalline glucosamine sulfate, glucosamine sulfate, and glucosamine hydrochloride) used for osteoarthritis.
Methods
We developed a method to simulate individual utility values and validated the model by comparing the results obtained with the simulation and the results of one trial where the utility scores are available. Then, we simulated the utility scores of 10 published trials that used different glucosamine preparations. The utility estimates were used to calculate the quality-adjusted life year (QALY) using the area-under-the-curve method. Costs were for the glucosamine product only. The incremental cost/effectiveness ratio (ICER) was then calculated.
Results
The values of utility scores calculated from data sources and those simulated with the model were similar. From 10 studies where utility was simulated, four used crystalline glucosamine sulfate, and six used other formulations. The ICER revealed that compared to placebo, crystalline glucosamine sulfate only was cost-effective at all time points and up to 3 years with a median ICER of 5347.2 €/QALY at month 3, 4807.2 €/QALY at month 6 and 11535.5 €/QALY at year 3. The use of other formulations was not cost-effective.
Conclusion
Using a new model to simulate individual health utility scores of patients included in ten published trials, ICER analysis showed that the use of crystalline glucosamine sulfate is cost-effective, while other formulations were not. The results confirm the importance of the formulation of glucosamine products.
... We obtained 95 article titles with abstracts through the meta-search, and 20 abstracts were selected. The assessment of full texts resulted in 13 articles selected for the review (Figure 1): four concerned DMOADs and nine IAHA [23][24][25][26][27][28][29][30][31][32][33][34][35]. Two articles were excluded because of their design : that was observational multicentre non controlled before-after studies [36,37]. ...
... The 13 articles were heterogeneous (Table 1). Study design were model simulation of knee OA (n=4) [26,28,30,31], randomized clinical trial (n=8) [23][24][25]27,29,[32][33][34] or case control study (n=1) [35]. Sample sizes varied from 37 to 1,000. ...
... Sample sizes varied from 37 to 1,000. Control group were usual care (n=8) [23,26,27,[30][31][32][33][34] or imposed care (n=5) [24,25,28,29,35]. Different perspectives have been used to evaluate costs: perspective was societal (n=6) [23,[27][28][29]31,33] or payer (n=7) [24][25][26]30,32,34,35]. ...
Background:
The place of disease-modifying osteoarthritis drugs (DMOADs) and intra-articular hyaluronic acid (IAHA) in the therapeutic arsenal for knee osteoarthritis (OA) remains uncertain. Indeed, these treatments have demonstrated symptomatic efficacy but no efficacy for disease modification.
Objective:
This report reviews the cost effectiveness of IAHA and DMOADs used in the treatment of knee OA.
Methods:
A systematic literature search of the MEDLINE, Scopus, EMBASE and Cochrane databases was performed independently by two rheumatologists who used the same predefined eligibility criteria to identify relevant articles. Papers without abstracts and in languages other than English or French were excluded. Extracted costs were annualised and converted to 2015 euros (€) using the Consumer Price Index of the relevant countries and the 2013 Purchasing Power Parities between these countries and the European Union average.
Results:
A total of 95 abstracts were selected, and 13 articles were considered for the review: nine articles on IAHA and four on DMOADs. Only one article directly compared different IAHA compounds. Articles showed substantial heterogeneity in methodological approaches. The incremental cost-effectiveness ratios (ICERs) ranged from €4000 to €57,550 and from €240 to €53,225 per quality-adjusted life-year (QALY) gained for DMOADs and IAHA, respectively.
Conclusions:
This review highlights substantial heterogeneity between studies, ranging from a cost saving (or dominating) position to very high ICERs, far above the acceptability threshold of €50,000/QALY. Additional research is needed to determine reliable and robust ICER estimates for knee OA therapies.
... Furthermore, the early use of Glucosamine can also help reduce the need for NSAIDs. This is significant importance as prolonged use of NSAIDs can lead to adverse effects, especially for patients at high risk of gastrointestinal and cardiovascular issues 49 . ...
... The results from this study are consistent with the results from several previous studies on the cost-effectiveness of Glucosamine such as: Scholtissen et al. (2010) 49 54 stated that Glucosamine is clinically effective but does not achieve the desired cost-effectiveness. The observed difference could be attributed to varying state management policies and the differences in the structure of the research model. ...
Osteoarthritis (OA) is the degeneration of cartilage in joints that results in bones rubbing against each other, it causes uncomfortable symptoms such as pain, swelling, stiffness, and can lead to disability. It usually occurs in the elderly and causes a large medical burden. The aim of this study is to evaluate cost-effectiveness between the standard treatment for osteoarthritis and the standard treatment with added crystalline glucosamine sulfate at various stages. The Markov analysis modelling was applied to evaluate the effect of both adding glucosamine compared to standard treatment from a societal perspective during whole patients’ lifetimes. Data input was collected by review in previous studies. The outcome was measured in quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) from a societal perspective was ap-plied with 3%-discounted for all cost and outcome. One-way analysis via Tornado diagram was performed to investigate the change of factors in model. In general, the adding glucosamine into the standard treatment proved to be more cost-effectiveness compared to the standard treatment. Particularly, early stage adding glucosamine in the treatment was cost-effectiveness then post-stage adding glucosamine. The addition of supplementing crystalline glucosamine sulfate to whole regimen at any stage was cost-effectiveness at willingness-to-pay (WTP) threshold
... Several economic evaluation studies of knee OA treatment were conducted to compare NSAIDs either selective COX-2 NSAIDs or non-selective NSAIDs (Yen et al., 2004;Contreras-Hernández et al., 2008) as well as glucosamine sulfate (Black et al., 2009;Chaiyakunapruk et al., 2010;Scholtissen et al., 2010;Bruyère et al., 2019). However, most of these studies compared between two knee OA treatments and focused only on efficacy or adverse events but not on both aspects of knee OA treatment together. ...
... For glucosamine sulfate, our findings were consistent with two previous studies which concluded that glucosamine sulfate was a cost-effective therapy. Scholtissen et al. (Scholtissen et al., 2010) reported that crystalline glucosamine sulfate was a highly cost-effective dominant over paracetamol and placebo. Bruyere et al. (Bruyère et al., 2019) showed that crystalline glucosamine sulfate was cost-effective compared to placebo. ...
Objective: The objective of this study is to evaluate the cost-effectiveness of different knee OA care sequences compared to standard treatment reimbursed by the major health insurance payer in Thailand.
Method: We used decision analytical modeling to evaluate the effect of either adding etoricoxib or crystalline glucosamine sulfate compared to standard treatment from a societal perspective over patients’ lifetimes. Data were analyzed based on efficacy, whereas adverse events were considered as a substate. Model input data were retrieved from relevant published literature and the Standard Cost Lists for Health Technology Assessment, Thailand. All health outcomes were measured in a unit of quality-adjusted life-year (QALY). An incremental cost-effectiveness ratio (ICER) was applied to examine the costs and QALYs. Sensitivity analysis was performed to investigate the robustness of the model.
Result: The results demonstrated that adding crystalline glucosamine sulfate (before diclofenac plus proton pump inhibitors, PPI) into the standard care sequence was a dominant strategy compared to the standard care sequence. Adding etoricoxib alone or including crystalline glucosamine sulfate (after diclofenac plus PPI) was dominated by adding crystalline glucosamine sulfate (before diclofenac plus PPI), whereas in a willingness-to-pay (WTP) threshold in Thailand, adding of both crystalline glucosamine sulfate (before diclofenac plus PPI) and etoricoxib were cost-effective when compared to adding crystalline glucosamine sulfate alone with ICER of 125,547 Thai baht/QALY (3,472 US dollars/QALY).
Conclusion: The addition of crystalline glucosamine sulfate and etoricoxib into standard knee OA treatment were cost-effective at the WTP threshold in Thailand. In addition, early initiation of crystalline glucosamine sulfate would be less costly and more effective than delayed treatment or the use of standard treatment alone.
... To identify the key attributes of knee OA treatments, literature reviews were conducted to derive an initial list of attributes and the focus group was performed to prioritize and determine the key attributes as recommended by Helter and Boehler 26 . From the literature, there were 35 attributes divided into three main groups of knee OA treatments including efficacy (e.g., pain relief, stiffness, physical function, delayed disease progression, onset of action), side effects (e.g., GI, CV, hepatic, kidney, skin ulceration, anemia) and costs 9,11,13,15,[27][28][29][30][31][32] . These attributes were then used as a guide for focus group discussion to elicit the important treatment attributes. ...
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.
... Finally, we were not able to analyse the economic aspects of GS, since no systematic review has been published, which is indeed of great clinical importance. 9,71,72 In conclusion, the present umbrella review suggests that prescription GS, when used at 1500 mg/ daily dosage, can positively affect the cartilage structure and improve the pain and function in people with knee OA, without having a greater incidence of adverse effects than placebo, indicating a possible role in older people. Moreover, some promising results indicated that GS is associated with a better glucose profile than placebo. ...
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.
... Cost-effectiveness of GS makes it a drug of interest compared with paracetamol. 58 pCGS provides an improved affordable treatment, for an extensive time range of 3 months to 3 years. 59 Moreover, early administration of pCGS assists in better pharmaco-economical outcome by controlling the usage of analgesics, NSAIDs, and other health resources. ...
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.
... These estimations are not very precise [2]. In 2010 an economic analysis has showed an increase of the cost efficacy of €10.491 versus placebo and €13.835 against paracetamol, suggesting that SG is an effective therapeutic alternative compared to placebo and paracetamol primary OA knees [94]. ...
... Фармакокинетические параметры пКГС (1500 мг 1 раз в день) и ГГ (1500 мг 1 раз в день или 500 мг 3 раза в день). По материалам S. Persiani и соавт., 2005 [31] и C.G. Jackson и соавт., 2010 [32] лом и ПЛ [35,43]. Более того, пКГС является безопасным при применении в течение длительного периода, со сравнимой с ПЛ частотой НР [19,22,23,35]. ...
The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm for the management of knee osteoarthritis (OA), published in December 2014, provides practical guidance for the prioritization of interventions. This current paper represents an assessment and endorsement of the algorithm by Russian experts in OA for use in Russian clinical practice, with the aim of providing easy-to-follow advice on how to establish a treatment flow in patients with knee OA, in support of the clinicians’ individualized assessment of the patient. Medications recommended by the ESCEO algorithm are available in Russia. In step 1, background maintenance therapy with symptomatic slow-acting drugs for osteoarthritis (SYSADOA) is advised, for which high-quality evidence is provided only for the formulations of patented crystalline glucosamine sulphate (pCGS) (Rottapharm/Meda) and prescription chondroitin sulfate. Paracetamol may be added for rescue analgesia only, due to limited efficacy and increasing safety signals. Topical non-steroidal anti-inflammatory drugs (NSAIDs) may provide additional symptomatic treatment with the same degree of efficacy as oral NSAIDs but without the systemic safety concerns. To be effective, topical NSAIDs must have high bioavailability, and among NSAIDs molecules like etofenamate have high absorption and bioavailability alongside evidence for accumulation in synovial tissues. Oral NSAIDs maintain a central role in step 2 advanced management of persistent symptoms. However, oral NSAIDs are highly heterogeneous in terms of gastrointestinal and cardiovascular safety profile, and patient stratification with careful treatment selection is advocated to maximize the risk: benefit ratio. Intra-articular hyaluronic acid as a next step provides sustained clinical benefit with effects lasting up to 6 months after a short-course of weekly injections. As a last step before surgery, the slow titration of sustained-release tramadol, a weak opioid, affords sustained analgesia with improved tolerability.
... 46 Six months treatment with pCGS is shown to be a highly cost-effective therapy compared with paracetamol and placebo in the treatment of knee OA, in terms of incremental cost-effectiveness ratio (ICER). 33,47 The incremental cost per QALY gain for adding pCGS to current care over a lifetime horizon is estimated at around US$30,000. 48 The cost-effectiveness of pCGS therapy is dependent on the magnitude of the quality of life gain, the change in knee TJR probability and the discount rate. ...
Symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) are recommended for the medium- to long-term management of knee osteoarthritis (OA) due to their abilities to control pain, improve function and delay joint structural changes. Among SYSADOAs, evidence is greatest for the patented crystalline glucosamine sulfate (pCGS) formulation (Mylan). Glucosamine is widely available as glucosamine sulfate (GS) and glucosamine hydrochloride (GH) preparations that vary substantially in molecular form, pharmaceutical formulation and dose regimen. Only pCGS is given as a highly bioavailable once-daily dose (1500 mg), which consistently delivers the plasma levels of around 10 μmol/L required to inhibit interleukin-1-induced expression of genes involved in the pathophysiology of joint inflammation and tissue destruction. Careful consideration of the evidence base reveals that only pCGS reliably provides a moderate effect size on pain that is higher than paracetamol and equivalent to non-steroidal anti-inflammatory drugs (NSAIDs), while non-crystalline GS and GH fail to reach statistical significance for pain reduction. Chronic administration of pCGS has disease-modifying effects, with a reduction in need for total joint replacement lasting for 5 years after treatment cessation. Pharmacoeconomic studies of pCGS demonstrate long-term reduction in additional pain analgesia and NSAIDs, with a 50% reduction in costs of other OA medication and healthcare consultations. Consequently, pCGS is the logical choice, with demonstrated medium-term control of pain and lasting impact on disease progression. Physician and patient education on the differentiation of pCGS from other glucosamine formulations will help to improve treatment selection, increase treatment adherence, and optimize clinical benefit in OA.
... quality-adjusted life years (QALYs). Six months' treatment with pCGS is shown to be a highly cost-effective therapy compared with paracetamol and placebo in the treatment of knee OA, in terms of incremental cost-effectiveness ratio (ICER) 35,44 . Further, a systematic review and economic evaluation has determined the incremental cost per QALY gain for adding GS to current care over a lifetime horizon to be around £21,335 45 . ...
... quality-adjusted life years (QALYs). Six months' treatment with pCGS is shown to be a highly cost-effective therapy compared with paracetamol and placebo in the treatment of knee OA, in terms of incremental cost-effectiveness ratio (ICER) 35,44 . Further, a systematic review and economic evaluation has determined the incremental cost per QALY gain for adding GS to current care over a lifetime horizon to be around £21,335 45 . ...
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.
... General utility scores were available for knee osteoarthritis [31][32][33] , primary total knee arthroplasty 31,33 , revision total knee arthroplasty 34,35 , and chronically failed total knee arthroplasty 36 (Table II). However, utilities explicitly differentiating health-related quality-of-life differences between morbidly obese patients and those who had achieved weight loss for these states were not available. ...
Background
Obesity is associated with adverse outcomes and increased costs after total knee arthroplasty. Bariatric surgery is an effective treatment for morbid obesity, but its cost-effectiveness for weight loss prior to total knee arthroplasty is unknown. The purpose of this study was to evaluate the cost-effectiveness of bariatric surgery prior to total knee arthroplasty for patients in whom medical treatment of obesity and knee osteoarthritis had failed.
Methods
A state-transition Markov model was constructed to compare the cost-utility of two treatment protocols for patients with morbid obesity and end-stage knee osteoarthritis: (1) immediate total knee arthroplasty and (2) bariatric surgery two years prior to the total knee arthroplasty. The probability of transition for each health state and its utility were derived from the literature. Costs, expressed in 2012 United States dollars, were estimated with use of administrative and claims data. Costs and utilities were discounted at 3% annually, and effectiveness was expressed in quality-adjusted life-years (QALYs). The principal outcome measure was the incremental cost-effectiveness ratio (ICER). One-way, two-way, and probabilistic sensitivity analyses were performed, using 13,910 per QALY, well below the threshold willingness to pay. Results were stable across broad value ranges for independent variables. Probabilistic sensitivity analysis found that the median ICER was 4875 to $51,210 per QALY).
Conclusions
This model supports bariatric surgery prior to total knee arthroplasty as a cost-effective option for improving outcomes in morbidly obese patients with end-stage knee osteoarthritis who are indicated for total knee arthroplasty.
Level of Evidence
Economic and Decision Analysis Level II . See Instructions for Authors for a complete description of levels of evidence.
... Economic evaluation allows comparison of different treatment strategies in terms of cost (intervention costs and disease costs) and consequences, e.g., quality-adjusted life years (QALYs). Cost-effectiveness analysis of a 6-month treatment trial has shown pCGS to be a highly costeffective therapy compared with paracetamol and placebo in the treatment of knee OA, in terms of incremental cost-effectiveness ratio (ICER) [23,44]. Further, a systematic review and economic evaluation has determined the incremental cost per QALY gain for adding GS to current care over a lifetime horizon to be around £21,335 (approx. ...
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.
... Finally, a recent pharmacoeconomic study demonstrated that prescription crystalline glucosamine sulfate formulation is a cost-effective therapy compared with acetaminophen or placebo for use in patients with OA of the knee [14,63]. Thus, the prescribed glucosamine sulfate formulation represents an attractive alternative for the management of OA, which has a high socioeconomical and personal cost. ...
The pharmacological treatment of osteoarthritis is traditionally accomplished with nonspecific symptomatic agents that are generally effective only for acute symptom relief. Compounds are currently being searched for that might exert specific effects on osteoarthritis pathogenesis and thus induce at least a similar short-term symptomatic effect, but also control the progression of the disease in the long-term. Glucosamine sulfate is, so far, the only drug that has demonstrated a combined symptom-modifying and potential structure-modifying effect in knee osteoarthritis when used as the prescription crystalline glucosamine sulfate formulation at the dose of 1500 mg once daily. These effects may be explained by reversal of the proinflammatory and joint-degenerating effects of IL-1 through the inhibition of the cytokine intracellular signaling pathway. However, efficacy data obtained with this prescription glucosamine sulfate formulation may not be applicable to all glucosamine products available as generics or dietary supplements, owing to pharmacodynamic and pharmacokinetic reasons.
... However, accumulating data show that many of these pharmaceutical drugs frequently produce insufficient benefits, with an associated risk of untoward side effects [36][37][38]. Glucosamine appears to be an attractive alternative, as it is a naturally occurring compound in the articular cartilage, while DGL is a symptom modifying drug with good evidence for favorable long-term effects on disease progression [39,40]. DGL exerts a significant pain relief effect in treating osteoarthritis. ...
It is well known that D-glucosamine hydrochloride (DGL) has a variety of biological activities and is regarded as a nutritional supplement effective in improving various disorders, including osteoarthritis and atherosclerosis. Although it has been reported that DGL has a significant pain relief effect in treating osteoarthritis, little is known about the characteristics of the effects of this compound on dental pain. The present study was undertaken to evaluate the applicability of DGL as a medicament to control pulpalgia. Using an in vitro rat mandible-inferior alveolar nerve preparation (jaw-nerve preparation), we evaluated the effects of DGL on 5-hydroxytryptamine (5-HT) sensitive nociceptive responses in the tooth pulpal nerve. 5-HT-induced nociceptive responses were fairly suppressed by direct application of DGL, suggesting that DGL have a pain relief effect on patients with dental pain.
... The data indeed suggest that administration of crystalline glucosamine sulfate for at least 12 months might affect the progression of knee OA since there were significantly fewer patients undergoing total joint replacement in the average 5-year follow up after drug withdrawal, with a risk reduction equal to 57% compared with placebo [Bruyere et al. 2008]. Finally, at least three reports described the costeffectiveness of crystalline glucosamine sulfate 1500 mg once daily in knee OA [Black et al. 2009; Scholtissen et al. 2010; National Collaborating Centre for Chronic Conditions, 2008]. Their results are summarized inTable 1. ...
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.
... A study was designed to explore the cost-effectiveness of GS compared with paracetamol and placebo (PBO) in the treatment for knee osteoarthritis, and a 6-month time horizon and a health care perspective were 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) [58] 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). ...
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.
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.
Aims
Though glucosamine and chondroitin have become common practices for treating knee osteoarthritis, the clinical value of these two drugs in combination are still questionable. To evaluate the efficacy and safety of the combination of glucosamine (GS) and chondroitin (CS) in knee osteoarthritis (KOA) treatment.
Methods
We searched electronic databases, including PubMed, Embase, Web of Science, SCOPUS, The Cochrane Central Register of Controlled Trials (CENTRAL), OVID, Chinese Clinical Trial Registry (ChiCTR), CBM, CNKI, WanFang and VIP from their inception to August 20, 2020, for literature concerning the combination of glucosamine and chondroitin in knee osteoarthritis treatment. The Cochrane Collaboration’s tool for assessing risk of bias and Jadad scale were used to evaluate the risk of bias and quality of literature. The meta-analysis was performed using Review Manager 5.3 software.
Results
Eight randomized controlled trials (RCTs) were included, including 7 studies in English and 1 study in Chinese. While the number of included papers was quite limited, the number of participants was decent, and quality appraisal result is acceptable. The total number of patients was 3793, with 1067 patients receiving a combination of glucosamine and chondroitin and 2726 patients receiving other treatments. The meta-analysis results revealed the following: (1) Regarding the total Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, compared with the placebo group, the combination group showed a statistically significant advantage [MD = − 12.04 (− 22.33 ~ − 1.75); P = 0.02], while the other groups showed no significance. (2) Regarding the VAS score, none of the comparisons showed significance. (3) In the secondary outcomes, except the comparison of JSN between the combination and placebo groups (MD = − 0.09 (− 0.18 ~ − 0.00); P = 0.04) and the comparison of the WOMAC stiffness score between the combination and CS groups [MD = − 4.70 (− 8.57 ~ − 0.83); P = 0.02], none of the comparisons showed a significant difference. (4)Safety analysis results show that none of the comparisons have significant differences.
Conclusion
Our study confirmed that the combination of glucosamine and chondroitin is effective and superior to other treatments in knee osteoarthritis to a certain extent. It is worthwhile to popularize and apply the combination in KOA treatment considering the point of effect, tolerability and economic costs. Additionally, regarding the limited number of studies and uneven trial quality, more high-quality trials are required to investigate the accurate clinical advantages of the combination.
PROSPERO registration ID
CRD42020202093.
Introduction
Chronic knee pain is a common musculoskeletal condition, which usually leads to decreased quality of life and a substantial financial burden. Various non-surgical treatments have been developed to relieve pain, restore function and delay surgical intervention. Research on the benefits of medical cannabis (MC) is emerging supporting its use for chronic pain conditions. The purpose of this study was to evaluate the cost-effectiveness of MC compared to current non-surgical therapies for chronic knee pain conditions.
Methods
We conducted a cost-utility analysis from a Canadian, single payer perspective and compared various MC therapies (oils, soft gels and dried flowers at different daily doses) to bracing, glucosamine, pharmaceutical-grade chondroitin oral non-steroidal anti-inflammatory drugs (NSAIDs), and opioids. We estimated the quality-adjusted life years (QALYs) gained with each treatment over 1 year and calculated incremental cost-utility ratios (ICURs) using both the mean and median estimates for costs and utilities gained across the range of reported values. The final ICURs were compared to willingness-to-pay (WTP) thresholds of 133 428 and 133 428/QALY gained.
Conclusion
Our study showed that MC may be a cost-effective strategy in the management of chronic knee pain; however, the evidence on the medical use of cannabis is limited and predominantly low-quality. Additional trials on MC are definitely needed, specifically in patients with chronic knee pain.
Background
The economic burden of musculoskeletal diseases is substantial and growing. Economic evaluations compare costs and health benefits of interventions simultaneously to help inform value-based care; thus, it is crucial to ensure that studies are using appropriate methodology to provide valid evidence on the cost-effectiveness of interventions. This is particularly the case in orthopaedic sports medicine, where several interventions of varying costs are available to treat common hip and knee conditions.
Purpose
To summarize and evaluate the quality of economic evaluations in orthopaedic sports medicine for knee and hip interventions and identify areas for quality improvement.
Study Design
Systematic review; Level of evidence, 3.
Methods
The Medline, AMED, OVID Health Star, and EMBASE databases were searched from inception to March 1, 2020, to identify economic evaluations that compared ≥2 interventions for hip and/or knee conditions in orthopaedic sports medicine. We assessed the quality of full economic evaluations using the Quality of Health Economic Studies (QHES) tool, which consists of 16 questions for a total score of 100. We classified studies into quartiles based on QHES score ( extremely poor quality to high quality) and we evaluated the frequency of studies that addressed each of the 16 QHES questions.
Results
A total of 93 studies were included in the systematic review. There were 41 (44%) cost analyses, of which 21 (51%) inappropriately concluded interventions were cost-effective. Only 52 (56%) of the included studies were full economic evaluations, although 40 of these (77%) fell in the high-quality quartile. The mean QHES score was 83.2 ± 19. Authors consistently addressed 12 of the QHES questions; questions that were missed or unclear were related to statistical uncertainty, appropriateness of costing methodology, and discussion of potential biases. The most frequently missed question was whether the cost perspective of the analysis was stated and justified.
Conclusion
The number of studies in orthopaedic sports medicine is small, despite their overall good quality. Yet, there are still many highly cited studies based on low-quality or partial economic evaluations that are being used to influence clinical decision-making. Investigators should follow international health economic guidelines for study design and critical appraisal of studies to further improve quality.
Background:
This article describes an updated stepwise algorithm for the pharmacological management of osteoarthritis (OA) to establish a treatment method for patients with OA.
Summary:
In step 1, background maintenance therapy includes symptomatic slow-acting drugs for OA, especially prescription crystalline glucosamine sulfate product, for which the high-quality evidence base of efficacy is unequivocal, or prescription chondroitin sulfate. Oral nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol only as rescue analgesia is given on top of the background therapy. Step 2: For patients with persistent OA symptoms, the use of oral NSAIDs is mandatory for maintaining supportive therapy with symptomatic slow-acting drugs for OA. It is recommended to properly stratify patients and carefully select oral NSAID therapy to maximize the benefit-to-risk ratio. Intra-articular hyaluronic acid and intra-articular corticosteroids are recommended as well in step 2 of the algorithm, especially for patients who do not respond to the previous therapies. Step 3: Duloxetine is considered along with the previous procedures, especially in patients with pain from central sensitization. Step 4: Total joint replacement is recommended for patients with severe symptoms and poor quality of life.
Major conclusions:
The current guidelines and literature review provide evidence-based recommendations supported by clinical experience on how to organize the treatment process in patients with knee OA applicable in the Russian clinical practice.
Future research directions:
International evidence-based guidelines lack consensus on different treatments, including the use of prescription crystalline glucosamine sulfate, NSAIDs, and intra-articular hyaluronic acid. The content of this article needs a further discussion about the clinical evidence and harmonization of recommendations for knee OA management.
d-glucosamine contributes to cell membrane stability. d-Glucosamine controls biological responses and protect both cells and tissues. This review focuses the mechanisms of stability in biomedical situations. Positively charged amino groups of d-glucosamine can bind the cell membrane electrically to protect against tissue damage. Wound healing can be accelerated by the application of a d-glucosamine dressing, which promotes cell proliferation and differentiation. d-Glucosamine has superoxide/hydroxyl radical scavenging activities, a strong chelating effect on ferrous ions, and enhances the reduced glutathione level to promote activity against intracellular oxidative stress. The prompt repair of microleakage through electropores on the cell membrane occurs after electroporation using d-glucosamine. The effects of this stability can also explain the pain relief as d-glucosamine binds to sodium channel to result in a longer open time. Furthermore, specific applications of d-glucosamine are proposed for the regenerative medicine.
Chitosan is a well-known biomaterial. D-glucosamine, which consists of a natural amino monosaccharide, is the smallest molecular weight of chitosan. D-glucosamine is widely used for relieving the pain associated with osteoarthritis. It has recently been confirmed that D-glucosamine contributes to cell membrane stability in the biomedical field. D-glucosamine may control biological responses and protect both cells and tissues. This chapter briefly focuses the mechanisms of this stability in several important biomedical situations. Positive charged amino groups of D-glucosamine can bind the cell membrane electrically to protect against tissue damage. Wound healing can be accelerated by the application of a D-glucosamine dressing, which promotes cell proliferation and differentiation. D-glucosamine has superoxide/hydroxyl radical scavenging activities and a strong chelating effect on ferrous ions, and enhances the reduced glutathione level to promote activity against intracellular oxidative stress. The early and prompt repair of microleakage through electropores on the cell membrane occurs after electroporation using D-glucosamine. The effects of this stability can also explain the pain relief as D-glucosamine binds to sodium channel to result in a longer open time. Furthermore, specific applications of D-glucosamine are proposed for the regenerative medicine.
The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) published a treatment algorithm for the management of knee osteoarthritis (OA) in 2014, which provides practical guidance for the prioritization of interventions. Further analysis of real world data for OA provides additional evidence in support of pharmacological interventions, in terms of management of OA pain and function, avoidance of adverse events, disease-modifying effects and long-term outcomes, e.g. delay of total joint replacement surgery, and pharmacoeconomic factors such as reduction in healthcare resource utilization. This paper provides an updated assessment of the literature for selected interventions in OA, focusing on real-life data, with the aim of providing easy-to-follow advice on how to establish a treatment flow in patients with knee OA in primary care clinical practice, in support of the clinicians’ individualized assessment of the patient. In step 1, background maintenance therapy with symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) is recommended, for which high-quality evidence is provided only for the prescription formulations of crystalline glucosamine sulfate and chondroitin sulfate. Paracetamol may be added for rescue analgesia only, due to limited efficacy and increasing safety signals. Topical non-steroidal anti-inflammatory drugs (NSAIDs) may provide additional symptomatic treatment with the same degree of efficacy as oral NSAIDs without the systemic safety concerns. Oral NSAIDs maintain a central role in step 2 advanced management of persistent symptoms. However, oral NSAIDs are highly heterogeneous in terms of gastrointestinal and cardiovascular safety profile, and patient stratification with careful treatment selection is advocated to maximize the risk:benefit ratio. Intra-articular hyaluronic acid as a next step provides sustained clinical benefit with effects lasting up to 6 months after a short-course of weekly injections. As a last step before surgery, the slow titration of sustained-release tramadol, a weak opioid, affords sustained analgesia with improved tolerability.
There is an important need to evaluate therapeutic approaches for osteoarthritis (OA) in terms of cost-effectiveness as well as efficacy.
The ESCEO expert working group met to discuss the epidemiological and economic evidence that justifies the increasing concern of the impact of this disease and reviewed the current state-of-the-art in health economic studies in this field.
OA is a debilitating disease; it is increasing in frequency and is associated with a substantial and growing burden on society, in terms of both burden of illness and cost of illness. Economic evaluations in this field are relatively rare, and those that do exist, show considerable heterogeneity of methodological approach (such as indicated population, comparator, decision context and perspective, time horizon, modeling and outcome measures used). This heterogeneity makes comparisons between studies problematic.
Better adherence to guidelines for economic evaluations is needed. There was strong support for the definition of a reference case and for what might constitute "standard optimal care" in terms of best clinical practice, for the control arms of interventional studies.
Objective:
To establish the pharmacological cost incurred by an urban Primary Health Care centre for treating osteoarthritis (OA) of the knee, including the main drugs used in its treatment and its contribution to the total cost of each group studied.
Patients and methods:
A cross-sectional, descriptive study of 188 patients diagnosed with OA of the knee. After counting the total number of pre-packaged pharmaceutical products assigned to each patient over one year, the average cost of each product was calculated. The ratio between the total cost and the total number of patients was then calculated, which gave the cost per patient per year.
Results:
NSAIDs (non-steroids anti-inflammatory drugs) were the most frequently prescribed. SYSADOAs (symptomatic slow-acting drugs for osteoarthritis) rated second in both frequency and cost. Acetaminophen rated third. Topical treatments, "other analgesics" and proton pump inhibitors (PPIs), cost much less. The total pharmacological cost per patient per year thus amounted to 151.6 € (SD:±101,9).
Conclusions:
The pharmacological cost for treatment of osteoarthritis of the knee incurs an increase in cost of health resources in Primary Care. The total pharmacological cost per patient per year was 151.60 €. In our centre, NSAIDs account for most of the pharmacological costs in the treatment of osteoarthritis of the knee.
To determine the efficacies of different preparations of glucosamine for the treatment of osteoarthritis (OA).
Systematic searches of the bibliographic databases Medline, Embase, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews for randomised, double-blind, placebo-controlled trials (RCTs) concerning glucosamine treatment of OA. Effect size (ES) was estimated using Cohen's standardised mean difference. Consistency was evaluated via the I(2) index.
Nineteen trials (3159 patients) contributed to the meta-analysis, revealing a large degree of inconsistency among the trials in terms of pain-reduction outcome: the combined ES in glucosamine sulphate (GS) trials was -0.22 [95% confidence intervals (CI) -0.48, 0.04], I(2) was 82.3%. The combined ES in glucosamine hydrochloride (GH) trials was -0.03 (95% CI -0.14, 0.08), with an absence of heterogeneity. No treatment ES was observed [-0.38 (95% CI -0.99, 0.23)] favouring GS in trials of less than 24 weeks duration and the I(2) remained high (I(2) = 88.5%). No significant treatment ES -0.09 (95% CI -0.21, 0.03) was observed in trials of more than 24 weeks duration compared with placebo, with a heterogeneity of zero. In terms of function-modifying outcomes, GS showed no significant effect on Lequesne Index reduction vs. placebo in trials of less than 24 weeks duration (ES -0.55 (95% CI -1.22, 0.11)) with a high degree of heterogeneity (I(2) = 92.9%). Pooling data from studies with durations of more than 24 weeks presented a significant combined ES of -0.36 (95% CI: -0.56, -0.17) with an absence of heterogeneity. No risk of publication bias could be detected using Egger test.
GH is ineffective for pain reduction in patients with knee OA. GS may have function-modifying effects in patients with knee OA when administered for more than 6 months. However, it showed no pain-reduction benefits after 6 months of therapy.
Background and objective:
Osteoarthritis (OA) is a highly prevalent and chronic condition characterized by pain and physical disability. Currently, many treatments are available, and they primarily target pain relief. The objectives of this study were to systematically review economic evaluations for pharmaceutical management of OA pain and to provide methodological recommendations for future economic evaluation.
Methods:
Published literature was identified by searching the following bibliographic databases: MEDLINE (1948-16 November 2011) with In-Process records and EMBASE (1980-2011 Week 47) via Ovid; The Cochrane Library (Issue 4 of 4, 2011) and the Health Economic Evaluations Database (HEED) via Wiley; and PubMed (for non-MEDLINE records). The main search terms were OA and economic evaluations. Two reviewers independently screened all identified articles and extracted the data from those included in the final review.
Results:
Twelve articles reporting the cost-effectiveness of various pharmaceuticals were included, with five being trial-based and seven being model-based economic evaluations. The mean health economics quality score of the included articles was 84 (minimum-maximum: 63-99). These evaluations varied in study design, treatments compared, and outcomes measured.
Conclusion:
The existing economic evaluations on pharmaceutical management of OA pain were of acceptable quality. Comparability of economic evaluations could be improved by selecting standard comparators, adopting a longer time horizon, and directly measuring health utilities.
Osteoarthritis is one of the most common chronic inflammatory conditions seen in the general population. Current pharmacological treatments focus on reduction of pain and increased mobility to improve overall quality of life. However, the relief afforded by current standard care is often insufficient and can be associated with significant side effects. Many patients, therefore, seek the option of non-standard therapies, such as nutritional and herbal supplements, acupuncture, and exercise regimens. Glucosamine, Harpagophytum procumbens, and acupuncture are among the most commonly used complementary and alternative medicine approaches utilized by patients suffering from osteoarthritis. Their clinical relevance, safety, and potential mechanisms of action are discussed in this review.
This highly successful textbook is now available in its third edition. Over the years it has become the standard textbook in the field world-wide. It mirrors the huge expansion of the field of economic evaluation in health care, since the last edition was published in 1997. This new edition builds on the strengths of previous editions, being clearly written in a style accessible to a wide readership. Key methodological principles are outlined using a critical appraisal checklist that can be applied to any published study. The methodological features of the basic forms of analysis are then explained in more detail with special emphasis of the latest views on productivity costs, the characterisation of uncertainty and the concept of net benefit. The book has been greatly revised and expanded especially concerning analysing patient-level data and decision-analytic modelling. There is discussion of new methodological approaches, including cost effectiveness acceptability curves, net benefit regression, probalistic sensitivity analysis and value of information analysis. There is an expanded chapter on the use of economic evaluation, including discussion of the use of cost-effectiveness thresholds, equity considerations and the transferability of economic data. This new edition is required reading for anyone commissioning, undertaking or using economic evaluations in health care, and will be popular with health service professionals, health economists, pharmacand health care decision makers. It is especially relevant for those taking pharmacoeconomics courses.
The number of economic evaluations that have been carried out of pharmaceuticals and medical technologies has grown exponentially in recent years. Guidelines have been published in many countries to ensure the quality of economic evaluations. This contribution reviews guidelines from six European countries and from Australia and Canada. In addition, we present European guidelines in the form of a consensus report of the EUROMET group, which may serve as an umbrella for national guidelines and be useful for the development of guidelines for economic evaluation studies in medical care in other countries.
Symptomatic slow-acting drugs (SYSADOA) have been largely studied over the last decade. The objective of this study is to prepare a document providing recommendations for the use of SYSADOA in osteoarthritis (OA).
The following interventions were taken into consideration: avocado/soybean unsaponifiables, chondroitin sulfate, diacereine, glucosamine sulfate, hyaluronic acid, oral calcitonin, risedronate, strontium ranelate. Recommendations were based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The GRADE system is based on a sequential assessment of the quality of evidence, followed by assessment of the balance between benefits versus downsides and subsequent judgment about the strength of recommendations.
Chondroitin sulfate, diacereine, glucosamine sulfate, avocado/soybean unsaponifiables and hyaluronic acid have demonstrated pain reduction and physical function improvement with very low toxicity, with moderate to high quality evidence. Even if pre-clinical data and some preliminary in vivo studies have suggested that oral calcitonin and strontium ranelate could be of potential interest in OA, additional well-designed studies are needed.
In the benefit/risk ratio, the use of chondroitin sulfate, diacereine, glucosamine sulfate, avocado/soybean unsaponifiables and hyaluronic acid could be of potential interest for the symptomatic management of OA.
Glucosamine and chondroitin preparations are widely touted in the lay press as remedies for osteoarthritis (OA), but uncertainty about their efficacy exists among the medical community.
To evaluate benefit of glucosamine and chondroitin preparations for OA symptoms using meta-analysis combined with systematic quality assessment of clinical trials of these preparations in knee and/or hip OA.
We searched for human clinical trials in MEDLINE (1966 to June 1999) and the Cochrane Controlled Trials Register using the terms osteoarthritis, osteoarthrosis, degenerative arthritis, glucosamine, chondroitin, and glycosaminoglycans. We also manually searched review articles, manuscripts, and supplements from rheumatology and OA journals and sought unpublished data by contacting content experts, study authors, and manufacturers of glucosamine or chondroitin.
Studies were included if they were published or unpublished double-blind, randomized, placebo-controlled trials of 4 or more weeks' duration that tested glucosamine or chondroitin for knee or hip OA and reported extractable data on the effect of treatment on symptoms. Fifteen of 37 studies were included in the analysis.
Reviewers performed data extraction and scored each trial using a quality assessment instrument. We computed an effect size from the intergroup difference in mean outcome values at trial end, divided by the SD of the outcome value in the placebo group (0.2, small effect; 0.5, moderate; 0.8, large), and applied a correction factor to reduce bias. We tested for trial heterogeneity and publication bias and stratified for trial quality and size. We pooled effect sizes using a random effects model.
Quality scores ranged from 12.3% to 55.4% of the maximum, with a mean (SD) of 35.5% (12%). Only 1 study described adequate allocation concealment and 2 reported an intent-to-treat analysis. Most were supported or performed by a manufacturer. Funnel plots showed significant asymmetry (P< or =.01) compatible with publication bias. Tests for heterogeneity were nonsignificant after removing 1 outlier trial. The aggregated effect sizes were 0.44 (95% confidence interval [CI], 0.24-0.64) for glucosamine and 0.78 (95% CI, 0.60-0.95) for chondroitin, but they were diminished when only high-quality or large trials were considered. The effect sizes were relatively consistent for pain and functional outcomes.
Trials of glucosamine and chondroitin preparations for OA symptoms demonstrate moderate to large effects, but quality issues and likely publication bias suggest that these effects are exaggerated. Nevertheless, some degree of efficacy appears probable for these preparations.
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.
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.
To assess the structural and symptomatic efficacy of oral glucosamine sulfate and chondroitin sulfate in knee osteoarthritis through independent meta-analyses of their effects on joint space narrowing, Lequesne Index, Western Ontario MacMaster University Osteoarthritis Index (WOMAC), visual analog scale for pain, mobility, safety, and response to treatment.
An exhaustive systematic research of randomized, placebo-controlled clinical trials published or performed between January 1980 and March 2002 that assessed the efficacy of oral glucosamine or chondroitin on gonarthrosis was performed using MEDLINE, PREMEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Current Contents, BIOSIS Previews, HealthSTAR, EBM Reviews, manual review of the literature and congressional abstracts, and direct contact with the authors and manufacturers of glucosamine and chondroitin. Inclusion, quality scoring, and data abstraction were performed systematically by 2 independent reviewers who were blinded to sources and authors. Conservative approaches were used for clear assessment of potential efficacy.
Our results demonstrated a highly significant efficacy of glucosamine on all outcomes, including joint space narrowing and WOMAC. Chondroitin was found to be effective on Lequesne Index, visual analog scale pain, mobility, and responding status. Safety was excellent for both compounds.
Our study demonstrates the structural efficacy of glucosamine and indistinguishable symptomatic efficacies for both compounds. Regarding the relatively sparse data on glucosamine and joint space narrowing and the absence of data on structural effects of chondroitin, further studies are needed to investigate the relationship among time, dose, patient baseline characteristics, and structural efficacy for an accurate, disease-modifying characterization of these 2 compounds.
This is a review of the Health Utilities Index (HUI) multi-attribute health-status classification systems, and single- and multi-attribute utility scoring systems. HUI refers to both HUI Mark 2 (HUI2) and HUI Mark 3 (HUI3) instruments. The classification systems provide compact but comprehensive frameworks within which to describe health status. The multi-attribute utility functions provide all the information required to calculate single-summary scores of health-related quality of life (HRQL) for each health state defined by the classification systems. The use of HUI in clinical studies for a wide variety of conditions in a large number of countries is illustrated. HUI provides comprehensive, reliable, responsive and valid measures of health status and HRQL for subjects in clinical studies. Utility scores of overall HRQL for patients are also used in cost-utility and cost-effectiveness analyses. Population norm data are available from numerous large general population surveys. The widespread use of HUI facilitates the interpretation of results and permits comparisons of disease and treatment outcomes, and comparisons of long-term sequelae at the local, national and international levels.
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.
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.
Adherence to anti-osteoporosis medications is currently low and is associated with poor anti-fracture efficacy. This manuscript reviews the potential design of clinical studies that aim to demonstrate improved adherence, with new chemical entities to be used in the management of osteoporosis.
Several medications have been unequivocally shown to decrease fracture rates in clinical trials. However, in real life settings, long-term persistence and compliance to anti-osteoporosis medication is poor, hence decreasing the clinical benefits for patients.
An extensive search of Medline from 1985 to 2006 retrieved all trials including the keywords osteoporosis, compliance, persistence or adherence followed by a critical appraisal of the data obtained through a consensus expert meeting.
The impact of non-adherence on the clinical development of interventions is reviewed, so that clinicians, regulatory agencies and reimbursement agencies might be better informed of the problem, in order to stimulate the necessary research to document adherence.
Adherence to therapy is a major problem in the treatment of osteoporosis. Both patients and medication factors are involved. Adherence studies are an important aspect of outcomes studies, but study methodologies are not well developed at the moment and should be improved. Performing adherence studies will be stimulated when registration authorities accept the result of these studies and include the relevant information in Sect. 5.1 of the summary of product characteristics. Reimbursement authorities might also consider such studies as important information for decisions on reimbursement.
Mapping has been used to convert scores from condition-specific measures into utility scores, and to produce estimates of cost-effectiveness. We sought to compare the QALY gains, and incremental cost per QALY estimates, predicted on the basis of mapping to those based on actual EQ-5D scores.
In order to compare 4 different interventions 389 individuals were asked to complete both the EQ-5D and the Western Ontartio and McMaster Universities Osteoarthritis Index (WOMAC) at baseline, 6, 12, and 24 months post-intervention. Using baseline data various mapping models were developed, where WOMAC scores were used to predict the EQ-5D scores. The performance of these models was tested by predicting the EQ-5D post-intervention scores. The preferred model (that with the lowest mean absolute error (MAE)) was used to predict the EQ-5D scores, at all time points, for individuals who had complete WOMAC and EQ-5D data. The mean QALY gain associated with each intervention was calculated, using both actual and predicted EQ-5D scores. These QALY gains, along with previously estimated changes in cost, were also used to estimate the actual and predicted incremental cost per QALY associated with each of the four interventions.
The EQ-5D and the WOMAC were completed at baseline by 348 individuals, and at all time points by 259 individuals. The MAE in the preferred model was 0.129, and the mean QALY gains for each of the four interventions was predicted to be 0.006, 0.058, 0.058, and 0.136 respectively, compared to the actual mean QALY gains of 0.087, 0.081, 0.120, and 0.149. The most effective intervention was estimated to be associated with an incremental cost per QALY of pound6,068, according to our preferred model, compared to pound13,154 when actual data was used.
We found that actual QALY gains, and incremental cost per QALY estimates, differed from those predicted on the basis of mapping. This suggests that though mapping may be of value in predicting the cost-effectiveness of interventions which have not been evaluated using a utility measure, future studies should be encouraged to include a method of actual utility measurement.
Current Controlled Trials ISRCTN93206785.
BACKGROUND: Symptomatic slow-acting drugs (SYSADOA) have been largely studied over the last decade. The objective of this study is to prepare a document providing recommendations for the use of SYSADOA in osteoarthritis (OA). METHODS: The following interventions were taken into consideration: avocado/soybean unsaponifiables, chondroitin sulfate, diacereine, glucosamine sulfate, hyaluronic acid, oral calcitonin, risedronate, strontium ranelate. Recommendations were based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The GRADE system is based on a sequential assessment of the quality of evidence, followed by assessment of the balance between benefits versus downsides and subsequent judgment about the strength of recommendations. RESULTS: Chondroitin sulfate, diacereine, glucosamine sulfate, avocado/soybean unsaponifiables and hyaluronic acid have demonstrated pain reduction and physical function improvement with very low toxicity, with moderate to high quality evidence. Even if pre-clinical data and some preliminary in vivo studies have suggested that oral calcitonin and strontium ranelate could be of potential interest in OA, additional well-designed studies are needed. CONCLUSION: In the benefit/risk ratio, the use of chondroitin sulfate, diacereine, glucosamine sulfate, avocado/soybean unsaponifiables and hyaluronic acid could be of potential interest for the symptomatic management of OA
Objective:
To examine the validity of a newly developed prediction model translating osteoarthritis (OA)-specific health-related quality of life (HRQL) scores measured using the Western Ontario and McMaster Osteoarthritis Index (WOMAC) into generic utility-based HRQL scores measured using the Health Utilities Index Mark 3 (HUI3).
Methods:
Preintervention data from 145 patients with hip OA and complete WOMAC and HUI3 baseline assessments from the Alberta Hip Improvement Project study were used to validate three utility prediction models. These models were estimated using data from a previous study of knee OA patients. Predictive performance was assessed using the mean absolute prediction error (MAE) criterion and several other criteria.
Results:
The validation sample appeared healthier (on the basis of the HUI3 and WOMAC) than the subjects used toestimate the prediction models. Nevertheless, the validation sample outperformed the predictive performance of the model sample. The results from the validation sample support the conclusions from the original study in that the primary model identified during model development (a model using WOMAC subscales, their interactions, their square terms, age, OA duration, their square terms, and gender) performed better on the MAE criterion than competing models.
Conclusion:
These results support the external validity of the prediction model for the retrospective estimation of HUI3 utility scores for use in economic evaluation.
It is becoming increasingly important to examine the relationship between the outcomes of a clinical trial and the costs of the medical therapy under study. The results of such analysis can affect reimbursement decisions for new medical technologies, for example drugs, devices or diagnostics; aid companies seeking to make claims about the cost-effectiveness of their product; allow early consideration of the economic value of therapies, which may be important to improving initial adoption decisions; or address the requirements of regulatory bodies. Economic evaluation in clinical trials uses a consistent set of data collected within the trial, or by projection from this data, and avoids having to incorporate unrelated (and potentially inconsistent) data from many different sources. This book provides a practical guide to conducting economic evaluation in ongoing clinical trials. It covers issues and techniques related to the collection of both cost and outcome data, as well as a framework for reporting and interpreting economic reports from clinical trials. This is illustrated by detailed supporting examples and exercises, designed to teach the reader how to apply this model. These exercises are supported with datasets, programmes and solutions made available online. ABOUT THE SERIES - series editors Alastair Gray and Andrew Briggs Economic evaluation of health intervention is a growing specialist field, and this series of practical handbooks tackles, in depth, topics superficially addressed in more geinconsistent economics books. Each volume includes illustrative material, case histories and worked examples to encourage the reader to apply the methods discussed, with supporting material provided online. This series is aimed at health economists in academia, the pharmaceutical industry and the health sector, those on advanced health economics courses, and health researchers in associated fields.
Statistics is a subject of many uses and surprisingly few effective practitioners. The traditional road to statistical knowledge is blocked, for most, by a formidable wall of mathematics. The approach in An Introduction to the Bootstrap avoids that wall. It arms scientists and engineers, as well as statisticians, with the computational techniques they need to analyze and understand complicated data sets.
The concept of cost-effectiveness is illustrated graphically on the CE plane. Strategies are represented according to their effectiveness (e) and cost (c) relative to those of some reference standard. A straight line with slope K passes through the origin, where K is the maximum acceptable cost-effectiveness ratio. Strategies plotted to the right of line K are cost-effective, while those plotted to the left are not. Furthermore, the most cost-effective of two or more mutually exclusive alternatives is that plotted the greatest distance to the right of K. The CE plane can be used to resolve ambiguities about the meaning of cost-effectiveness and to illustrate its relevance to medical decision making.
Within the context of a double blind randomized controlled parallel trial of 2 nonsteroidal antiinflammatory drugs, we validated WOMAC, a new multidimensional, self-administered health status instrument for patients with osteoarthritis of the hip or knee. The pain, stiffness and physical function subscales fulfil conventional criteria for face, content and construct validity, reliability, responsiveness and relative efficiency. WOMAC is a disease-specific purpose built high performance instrument for evaluative research in osteoarthritis clinical trials.
Cost-effectiveness acceptability curves (CEACs) have been widely adopted as a method to quantify and graphically represent uncertainty in economic evaluation studies of health-care technologies. However, there remain some common fallacies regarding the nature and shape of CEACs that largely result from the 'textbook' illustration of the CEAC. This 'textbook' CEAC shows a smooth curve starting at probability 0, with an asymptote to 1 for higher money values of the health outcome (lambda). But this familiar 'ogive' shape which makes the 'textbook' CEAC look like a cumulative distribution function is just one special case of the CEAC. The reality is that the CEAC can take many shapes and turns because it is a graphic transformation from the cost-effectiveness plane, where the joint density of incremental costs and effects may 'straddle' quadrants with attendant discontinuities and asymptotes. In fact CEACs: (i) do not have to cut the y-axis at 0; (ii) do not have to asymptote to 1; (iii) are not always monotonically increasing in lambda; and (iv) do not represent cumulative distribution functions (cdfs). Within this paper we present a 'gallery' of CEACs in order to identify the fallacies and illustrate the facts surrounding the CEAC. The aim of the paper is to serve as a reference tool to accompany the increased use of CEACs within major medical journals.
Cost-effectiveness acceptability curves (CEACs) are a method used to present uncertainty surrounding incremental cost-effectiveness ratios (ICERs). Construction of the curves relies on the assumption that the willingness to pay (WTP) for health gain is identical to the willingness to accept (WTA) health loss. The objective of this paper is to explore the impact that differences between WTP and WTA health changes have on CEACs.
Previous empirical evidence has shown that the relationship between WTP and WTA is not 1: 1. The discrepancy between WTP and WTA for health changes can be expressed as a ratio: the accept/reject ratio (which can vary between 1 and infinity). Depending on this ratio, the area within the southwest quadrant of the cost-effectiveness plane in which any bootstrap cost-effect pairs will be considered to be cost effective will be smaller, resulting in a lower CEAC. We used data from two clinical trials to illustrate that relaxing the 1: 1 WTP/WTA assumption has an impact on the CEACs. Given the difficulty in assessing the accept/reject ratio for every evaluation, we suggest presenting a series of CEACs for a range of values for the accept/reject ratio, including 1 and infinite.
Although it is not possible to explain this phenomenon within the extra-welfarist framework, it has been shown empirically that individuals give a higher valuation to the removal of effective therapies than to the introduction of new therapies that are more costly and effective. In cost-effectiveness analyses where uncertainty of the ICER covers the southwest quadrant of the cost-effectiveness plane, the discrepancy between societies’ WTP and WTA should be indicated by drawing multiple CEACs.
To assess the effects of the prescription formulation of glucosamine sulfate (1,500 mg administered once daily) on the symptoms of knee osteoarthritis (OA) during a 6-month treatment course.
Three hundred eighteen patients were enrolled in this randomized, placebo-controlled, double-blind trial in which acetaminophen, the currently preferred medication for symptomatic treatment of OA, was used as a side comparator. Patients were randomly assigned to receive oral glucosamine sulfate 1,500 mg once daily (n = 106), acetaminophen 3 gm/day (n = 108), or placebo (n = 104). The primary efficacy outcome measure was the change in the Lequesne index after 6 months. Secondary parameters included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and response according to the Osteoarthritis Research Society International criteria. These outcome measures were assessed using an intent-to-treat analysis.
At baseline, the study patients had moderately severe OA symptoms (mean Lequesne index approximately 11 points). Glucosamine sulfate was more effective than placebo in improving the Lequesne score, with a final decrease of 3.1 points, versus 1.9 with placebo (difference between glucosamine sulfate and placebo -1.2 [95% confidence interval -2.3, -0.8]) (P = 0.032). The 2.7-point decrease with acetaminophen was not significantly different from that with placebo (difference -0.8 [95% confidence interval -1.9, 0.3]) (P = 0.18). Similar results were observed for the WOMAC. There were more responders to glucosamine sulfate (39.6%) and acetaminophen (33.3%) than to placebo (21.2%) (P = 0.004 and P = 0.047, respectively, versus placebo). Safety was good, and was comparable among groups.
The findings of this study indicate that glucosamine sulfate at the oral once-daily dosage of 1,500 mg is more effective than placebo in treating knee OA symptoms. Although acetaminophen also had a higher responder rate compared with placebo, it failed to show significant effects on the algofunctional indexes.
To develop a formula to translate Western Ontario and McMaster University Osteoarthritis Index (WOMAC) scores collected in clinical trials of patients with osteoarthritis (OA) into Health Utilities Index Mark 3 (HUI3) utility scores for application in economic evaluation.
Data from a previously published open-label randomized controlled trial of appropriate care with hylan G-F 20 versus appropriate care without hylan G-F 20 in 255 outpatients with knee OA. We estimated linear regression models of HUI3 scores using various functions of WOMAC, demographics, and clinical variables. Out-of-sample predictive performance of the models was assessed using the mean absolute error and several other criteria.
The preferred formula included WOMAC pain, stiffness, function subscales, demographic variables; it accounted for almost 40% of the variation in the HUI3 utility scores. At the group level, absolute differences between predicted and actual overall HUI3 utility scores were < 0.001 and not statistically significantly different from zero.
A formula was derived from the WOMAC index to estimate overall utility scores based on the HUI3 for studies of patients with OA for whom utility has not been recorded. Researchers can estimate overall utility scores, compute quality-adjusted life-years, and perform cost-utility analyses within a defined range of certainty.
Osteoarthritis (OA) is one of the most common forms of musculoskeletal disorders and incurs significant economic, social and psychological costs. OA increases in prevalence and also progresses with aging. Clinically OA is characterised by joint pain, crepitus, stiffness after immobility and limitation of movement. Many cases are 'idiopathic' (disease or condition of unknown course or which arises spontaneously), but OA can also be the end result of several other conditions or due to the combination of several other factors. There are various lifestyle factors that increase the risk of developing OA. Preventable or modifiable risk factors include obesity, occupational factors, sports participation, muscle weakness, nutritional factors and hormonal influence. Pharmacological therapies reduce pain and may reduce joint damage. Surgical interventions correct altered biomechanics to prevent OA. For severely damaged joints, partial or total replacement of the joint is possible for all of the large joints that are commonly affected by OA. OA is commonly associated with a limited function that can be improved with a wide variety of rehabilitative interventions: joint specific exercises, physical fitness, physical modalities. Education and self-management are very important to prevent overuse and to use the joints in the most adequate way.
Investigators in trials of glucosamine report a range of estimates for efficacy, making conclusions difficult. We undertook this study to identify factors that explain heterogeneity in trials of glucosamine.
We searched for reports of trial results in Ovid Medline, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and proceedings of scientific conferences. We selected reports of randomized, double-blind, placebo-controlled trials of glucosamine for pain from osteoarthritis of the knee or hip. We extracted data regarding features of design, subjects, and markers of industry involvement, including industry funding, whether a drug was supplied by industry, industry participation, and industry-affiliated authorship. We examined which factors best accounted for differences in the effect sizes of studies grouped by these characteristics, and we examined changes in I(2), a measure of heterogeneity.
Fifteen trials met our inclusion criteria. The summary effect size was 0.35 (95% confidence interval 0.14, 0.56). I(2) was 0.80. Except for allocation concealment, no feature of study design explained this substantial heterogeneity. Summary effect sizes ranged from 0.05 to 0.16 in trials without industry involvement, but the range was 0.47-0.55 in trials with industry involvement. The effect size was 0.06 for trials using glucosamine hydrochloride and 0.44 for trials using glucosamine sulfate. Trials using Rottapharm products had an effect size of 0.55, compared with 0.11 for the rest.
Heterogeneity among trials of glucosamine is larger than would be expected by chance. Glucosamine hydrochloride is not effective. Among trials with industry involvement, effect sizes were consistently higher. Potential explanations include different glucosamine preparations, inadequate allocation concealment, and industry bias.
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