 Exercise and glucosamine with or without chondroitin on osteoarthritis pain and physical functions Eur J Transl Myol 33 (4) 12013, 2023 doi: 10.4081/ejtm.2023.12013 - 1 - Effects of adding glucosamine or glucosamine combined with chondroitin to exercise on pain and physical function in adults with knee osteoarthritis: a systematic review and meta-analysis Tina Čeh (1,2), Nejc Šarabon (1,3,4) (1) University of Primorska, Faculty of Health Sciences, Izola, Slovenia; (2) Community Healthcare Centre Dr. Adolf Drolc, Maribor, Slovenia; (3) S2P, Science to practice, Ltd., Laboratory for Motor Control and Motor Behavior, Ljubljana, Slovenia; (4) InnoRennew Center of excellence, Izola, Slovenia. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (CC BY-NC 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. Abstract It is well known that different types of exercise significantly improve physical function and relieve pain in knee osteoarthritis (KOA) patients. The aim of this study was to investigate the added effects of glucosamine or glucosamine and chondroitin supplementation in combination with an exercise program in the management of KOA. The randomized controlled trials on adding glucosamine (G) or G combined with chondroitin (C) to an exercise program in the treatment of KOA were searched in the PubMed, Cochrane Central Register of Controlled Trials, PEDro, and Web of Science online databases. The Pedro scale tool was used to assess quality of literature. A meta-analysis was performed using the Review Manager 5.4 software. In total, 6 studies (including 297 participants) were included for the final meta-analysis. According to the PEDro scale, the average quality of the studies was rated as good (mean = 8.2 (2)). The results showed that the effect of G, or G and C, in combination with exercise is not significant, as indicated by the assessed knee pain (WOMAC pain: SMD -0.18, 95% CI -0.47 to 0.11, p = 0.23; and VAS pain: SMD -0.34, 95% CI -0.85 to 0.17, p = 0.20) and physical function (SMD -0.13, 95% CI -0.95 to 0.69, p = 0.76). Adding glucosamine alone or a combination of glucosamine and chondroitin to exercise, has no effect on knee pain and physical function compared with exercise alone in KOA patients.. Key Words: treatment; dietary supplement; physical activity; older adults. Eur J Transl Myol 33 (4) 12013, 2023 doi: 10.4081/ejtm.2023.12013 Osteoarthritis is one of the most common joint disorders1 affecting especially adults aged > 50 years.2 According to the Osteoarthritis Research Society International (OARSI) it is defined as a degenerative joint disease characterized by cartilage degradation, bone remodeling, osteophyte formation, joint inflammation and loss of normal joint function causing pain and functional disability.1 It mainly affects large weight- bearing joints such as hips and knees.2 The prevalence of knee osteoarthritis (KOA) increases with age, and millions of people worldwide are suffering from it.3,4 With longer lifetime, the burden of this joint disease will increase globally1 and management of KOA needs to be researched. The most widely used KOA treatment is non-steroidal anti-inflammatory drugs (NSAIDs) therapy.5 Although NSAIDs are effective for alleviation of symptoms, there is evidence for serious adverse effects.6,7 By contrast, the advantage of commonly used symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) such as glucosamine (G) and chondroitin (C) is that they are not associated with any side effects.8 G and C have gained wide popularity as alternative treatments for KOA, although clinical benefits have not been established.9 They were reported to be ineffective or showed arguably clinically unimportant treatment effects. Conversely, some studies have reported that G or C relieve KOA symptoms10,11 to the same extent as exercise.12–14 Exercise is a widely researched non-pharmacological treatment for KOA. In older people with KOA, different types of land-based exercise improve balance and fall risk15, as well as walking function and postural control;16 physical activity provides pain reduction and improves physical function.12,13 Additionally, as regards dietary supplements in the treatment of KOA, there are clinical advantages to using C combined with G. The Exercise and glucosamine with or without chondroitin on osteoarthritis pain and physical functions Eur J Transl Myol 33 (4) 12013, 2023 doi: 10.4081/ejtm.2023.12013 - 2 - combination of both is suggested to be more effective than G or C alone in the treatment of KOA.8,17 The evidence on the comparative effectiveness of the combination of exercise and dietary supplements in alleviating pain and improving physical function is poor and has not yet been identified. The aim of this systematic review and meta-analysis was to investigate the impact of G alone, or the combination of G and C, both with exercise, on pain and physical function in patients with KOA. Materials and Methods Study inclusion and exclusion criteria were structured and organized according to the PICOS tool:18 • population (P): adults aged > 50 years with KOA; • intervention (I): any type of home- or institution- based exercise intervention in duration of at least 4 weeks in combination with G alone or G combined with C; • comparison (C): control or placebo group (exercise intervention only); • outcome (O): any tests assessing physical function and pain (instrumented and non-instrumented measures and questionnaires); • study design (S): interventional clinical trials with at least two groups (exercise + G and/or C and exercise (control/placebo) group). Search strategy Multiple databases of scientific literature (PubMed, Cochrane Central Register of Controlled Trials, PEDro, and Web of Science) were searched in February 2023 with no date restrictions. In the databases that enable using Boolean search operators, we used the following combination of search key words: (osteoarthritis of the knee OR knee osteoarthritis OR knee OA) AND (exercise OR strength training OR resistance training OR physical activity) AND (glucosamine OR glucosamine sulfate OR glucosamine hydrochloride OR chondroitin OR chondroitin sulfate) AND (elderly OR older adults OR ageing). Additionally, reference lists of the relevant published systematic reviews and included studies were reviewed. The authors performed a database search in three stages: 1) assessing the eligibility of the papers based on the title, 2) assessing the eligibility of the papers based on the abstract, and 3) assessing the eligibility of the papers based on the full text. Study quality assessment Study quality was assessed using the PEDro Scale,19 which assesses study quality based on a ten level scale. A higher score indicates a higher quality of the study. Studies scoring 9–10 were considered as excellent, 6–8 as good, 4–5 as fair, and less than 4 as poor quality. The PEDro Scale was chosen because it was developed specifically to assess the quality of randomized controlled trial studies evaluating physical therapist interventions. According to the PEDro Scale, study quality was assessed for the following domains: 1) random allocation; 2) concealed allocation; 3) groups similar baseline; 4) subjects blinding; 5) therapists blinding; 6) assessors blinding; 7) adequate follow-up; 8) intention-to-treat analysis; 9) between-group comparisons; 10) point estimates and variability. Data extraction Data extraction included: a) baseline and post- intervention means and standard deviations (SD) for all outcome measures for the intervention and control groups; b) patients’ demographics (age, sex, body mass index, radiographic classification (Kellgren and Lawrence score); c) intervention characteristics (duration of intervention, weekly frequency, duration of sessions, supervision during intervention, type of exercise program, and dietary supplements); d) exercise characteristics (number of exercises, sets, and repetitions, breaks between exercises and sets, intensity of exercise (a percentage of one-repetition maximum or heart rate, type of used load (machines, bodyweight, free weights); e) outcomes, and f) main conclusions of studies. In cases where the data were reported in mean (SEM) or median and interquartile ranges (IQR), means and standard deviations were accurately estimated using the methods of Luo et al.20 and Wan et al.21 Data were carefully inserted into Microsoft Excel 2013 (Microsoft Corporation). Data synthesis and analysis The main data analyses were carried out in Review Manager (RevMan, Version 5.4, The Cochrane Collaboration, 2020). Before the results were entered into the meta-analytical model, the pre-post differences and pooled standard deviations were calculated according to the following formula SD = √ [(SDpre2 + SDpost2) − (2 × r × SDpre × SDpost). The correction value (r), which represents the pre-test–post-test correlation of outcome measures, was conservatively set at 0.75. It should be noted that a change in the correction value in the range between 0.5 and 0.9 had little effect on the pooled SD and would not change the outcomes of the meta-analysis. For the meta-analysis, the inverse variance method for continuous outcomes with a random-effects model was used. The effect sizes were expressed as standardized mean difference (SMD). For SMD, the respective 95% confidence intervals were also calculated and reported. Statistical heterogeneity among studies was assessed by calculating I2 statistics. According to Cochrane guidelines, the I2 statistics of 0% to 40% might not be important, 30% to 60% may represent moderate heterogeneity, 50% to 90% may represent substantial heterogeneity, and 75% to 100% indicates considerable heterogeneity.22 Statistical significance threshold was set at p ≤ 0.05 for all analyses. Results Search results The search process is presented in a flowchart in Figure 1. 118 articles were identified in the initial database search. After removing the duplicates, 90 titles were identified as potentially relevant for our meta-analysis. Exercise and glucosamine with or without chondroitin on osteoarthritis pain and physical functions Eur J Transl Myol 33 (4) 12013, 2023 doi: 10.4081/ejtm.2023.12013 - 3 - Based on the screening of the title, 18 papers were included for abstract examination, after which 12 papers remained as potential candidates for the meta-analysis. After full-text examinations, 5 studies were included for the final meta-analysis. In addition, 1 study was found through screening the reference lists of existing systematic reviews. Therefore, our meta-analysis included 6 studies.23–28 Study quality assessment According to the PEDro scale, the average quality of the studies was rated as good (mean = 8.2 (2); median = 9.0; range = 5–10). One study was rated as being of fair quality, satisfying 5 items. One study scored 7 and was rated as being of good quality, whereas the remaining four studies with excellent quality scored 9–10. Results from the PEDro scale are summarized in Table 1. Participant data and intervention characteristics The total number of participants finally included in the review was 297 (150 in intervention groups and 147 in control groups), with samples ranging in size from 12 to 45 patients. Four studies included participants of both sexes, and two studies included females only. The total number of women participants was 226. The severity of KOA was assessed using the American College of Rheumatology clinical29 and radiographic classification criteria and the Kellgren-Lawrence grading system;30 the severity score was assessed to be 2–3 (mild to moderate) in three studies, 1–3 (mild to moderate) in two studies, and 1–4 (mild to severe) in one study. The studies were conducted in Japan,24 Turkey,23 Italy,28 United States,25 Denmark,27 and Pakistan.26 In three studies, the duration of the interventions was 12 weeks, one intervention was shorter (4 weeks) and two interventions were longer (12 months and 18 months). Most interventions included 3 sessions per week, while two studies included daily sessions (in one of them, the sessions were held twice daily); the duration of intervention sessions varied. In 5 studies, the exercises were conducted under supervision, while in one study they were home-based and participants were provided with instructions in the form of a brochure. All interventions focused on the lower limb muscles in various types of exercise, such as strength training, aerobic training, active and active-assisted range of motion (ROM) exercises, and mixed training approaches (combined aerobic and strength exercise, or strength training and stretching). In three studies, the intervention group used only G (1500 mg daily), while in two studies G and C were used (1500 mg and 1200 mg daily, respectively), and in one study the intervention group received a combination of G, C and Bio-Curcumin. In two of the studies, the participants in the experimental group were given G tablets of 500 mg 3 times daily,26,27 while in one study they were given a choice of either once-daily or thrice-daily regimens.25 In a study by Sterzi et al.28 patients received two tablets of agent daily, while the remaining two studies did not provide details on the daily supplement regimen. The control group received the same exercise program as the intervention group, while participants were also given placebo tablets in three of the included studies. The interventions included a combination of single-joint and multi-joint exercises. The volume of exercise varied between studies, with the number of exercises ranging from 3 to 8, the number of sets ranging from 1 to 4, and the number of repetitions in sets ranging from 10 to 20. Most of the studies did not report the intensity of exercise; one study assessed intensity through heart rate (between 50% and 70% of heart rate reserve) and two as percentage of repetition maximum. Breaks between sets were only determined in one study. Two exercise programs included machines and cuff weights. Outcomes In total, 4 studies measured quadriceps muscle strength and power (maximal isokinetic and isometric strength, isometric muscle force of knee extension, knee concentric extension and flexion strength, modified sphygmomanometer test for isometric muscle strength in knee flexion and extension). Visual analogue scale (VAS) for pain was reported in four studies (pain scoring during the strength measurements, actual pain level, pain during normal daily living and pain during rest). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used in four studies, while the WOMAC total score was reported only in two studies. Two studies included the performance of the 6-min walk test (6MWT), knee ROM in flexion and extension, blood markers using C-reactive protein (CRP), the Knee Injury and Osteoarthritis Outcome Score (KOOS Fig 1. Summary of search results. Exercise and glucosamine with or without chondroitin on osteoarthritis pain and physical functions Eur J Transl Myol 33 (4) 12013, 2023 doi: 10.4081/ejtm.2023.12013 - 4 - questionnaire), and MRI. Due to substantial discrepancy in outcome measures among the studies, only meta- analysis was performed. Supplementary Materials Table 1 presents all the details regarding the participants, interventions and outcomes of individual studies. Effects of intervention Pain was assessed using WOMAC pain and VAS pain. The meta-analysis showed no significant pain decrease through WOMAC (SMD -0.18, 95% CI -0.47 to 0.11, p = 0.23) and no heterogeneity (I2 = 0%) when comparing the glucosamine and exercise group and the exercise- only group (Figure 2). Similarly, compared to controls for pain reduction on the VAS pain score, the group who received the glucosamine supplement in combination with exercise did not present any significant differences (SMD -0.34, 95% CI -0.85 to 0.17, p = 0.20) while showing moderate heterogeneity (I2 = 60%) (Figure 2). Three included studies assessed physical function through WOMAC. The meta-analysis showed no significant physical function improvements (SMD -0.13, 95% CI -0.95 to 0.69, p = 0.76) with considerable heterogeneity (I2 = 86%) between groups (Figure 3). Stiffness was evaluated using WOMAC stiffness. Compared to the control group, there was no statistically significant reduction of stiffness in intervention groups across the studies (SMD -0.13, 95% CI -0.95 to 0.69, p = Table 1. Assessment of the methodological quality of the included studies by the PEDro scale. Reference 1 2 3 4 5 6 7 8 9 10 total Durmus et al., 201223 yes yes yes no no no yes yes yes yes 7 Kawasaki et al., 200824 yes no yes no no no no yes yes yes 5 Messier et al., 200725 yes yes yes yes yes yes no yes yes yes 9 Osama et al., 202226 yes yes yes yes no yes yes yes yes yes 9 Petersen et al., 201127 yes yes yes yes yes yes yes yes yes yes 10 Sterzi et al., 201628 yes yes yes yes yes yes no yes yes yes 9 Fig 2. The effect of G or G and C in combination with exercise vs. exercise-only group on pain. Exercise and glucosamine with or without chondroitin on osteoarthritis pain and physical functions Eur J Transl Myol 33 (4) 12013, 2023 doi: 10.4081/ejtm.2023.12013 - 5 - 0.97), while a very high heterogeneity was observed (I2 = 86%) (Figure 3). The WOMAC total score was reported in two studies. The meta-analysis demonstrated no significant differences between groups (SMD -0.04, 95% CI -0.44 to 0.36, p = 0.86) and no important heterogeneity (I2 = 25%) (Figure 3). 6MWT was performed in two studies; results are summarized in Figure 3. There were no significant differences between intervention and control group (SMD 0.26, 95% CI -0.11 to 0.64, p = 0.17) without heterogeneity (I2 = 0%). Discussion The aim of this systematic review with meta-analysis was to investigate the effects of G or G and C in combination with exercise on pain and physical function in patients with KOA. The main findings are: 1) knee pain was assessed through the WOMAC pain score in three studies and through the VAS pain score in four studies. The effect of G, or G and C, in combination with exercise was in both cases small and not significant (effects on VAS pain were unclear due to the heterogeneity and assessment during different daily activities); 2) physical function was assessed through the WOMAC score only in three studies and G has been shown to have no effect on it; 3) G, or G and C, in combination with exercise have been shown to have no effect on stiffness, the WOMAC total score, and 6MWT. It is possible that some of the other variables, such as duration of treatment, frequency, type of exercise program, age of participants, sex, BMI and type of dietary supplements, have influenced the results. Exercise program is recommended as first-line treatment for KOA patients.31 Different types of physical activity alone have been considered very beneficial as a conservative therapy for OA patients, showing significant improvements especially in pain and physical function.32–36 Our meta-analysis does not show Fig 3. The effect of G or G and C in combination with exercise vs. exercise-only group on WOMAC score and 6MWT. Exercise and glucosamine with or without chondroitin on osteoarthritis pain and physical functions Eur J Transl Myol 33 (4) 12013, 2023 doi: 10.4081/ejtm.2023.12013 - 6 - significant additional effects of G or G/C, compared to exercise only. Some studies that have compared G intake to the control group in KOA patients have shown no clear effects in terms of reducing pain and improving physical function,37,38 which is in accordance with our findings. On the other hand, a meta-analysis including 54 studies showed that glucosamine alone or G with C were effective in terms of reduced pain, compared to placebo, while only G with C showed significant improvement in function in KOA patients.39 Based on these findings, a combination of G and C seems a better choice in the treatment of knee OA than G only. Due to lack of studies or similar outcomes, it was not possible to perform subgroup analyses to confirm this in our study. It is important to emphasize that there are multiple formulations of SYSADOAs available. Known are prescription-grade products and among patients high popular an over-the-counter agents.40 G and C are natural products, various glucosamine-containing product is usually derived from shells of shellfish. Exogenous glucosamine is administered as a salt, glucosamine hydrochloride (GH) is obtained by extraction, while glucosamine sulfate (GS) is complex molecule and is found only in the prescription drug product as prescription crystalline glucosamine sulfate (pCGS).41 pCGS is the only pharmaceutical product that has demonstrated consistently that it is effective against the symptoms and the progression of the KOA.42 In addition to pCGS the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases strongly support the use of chondroitin sulfate (CS) as background pharmacological treatment in the first step of the knee OA management algorithm and also paracetamol as needed.41 It is a common practice to add sodium sulfate to GH for the misleading use of the term sulfate. The meta-analysis by Runhaar and colleagues confirm that GH and non- characterised GS products are ineffective in osteoarthritis.43 Our review included a mix of different supplements and none of the studies is it explained sources, process for extraction or purity of molecules. In two studies, the intervention group received GS23,27 and GH combined with CS,25,28 while Kawasaki et al.24 and Osama et al.26 decided to include GH and G combined with CS, respectively. The therapeutic regimens and the dosage administered were similar. The dose of G was 1500 mg daily in 5 studies and the dose of C was 1200 mg daily in two studies. With the exception of the study by Sterzi et al.,28 where patients received 2 tablets of agent (doses of GH and CS are unknown), the administered doses were equivalent to those reported by Hochberg et al.44 There were no notable differences in the frequency of glucosamine intake. Three studies did not report the administration frequency; participants in the studies by Osama et al.26 and Petersen et al.27 received glucosamine 3 times daily, while patients in the study by Messier et al.25 were given a choice of either once-daily or thrice-daily regimen. Significant and clinically important reduction in the VAS pain intensity in the affected knee was identified in all the three groups and without differences among them (500 mg GS/400 mg CS as capsules three times daily vs. sachet once daily vs. 500 mg GH/400 mg CS three times daily).45 Persiani et al. confirmed that the bioavailability after once-daily therapeutic dose of 1500 mg was effective.46 It remains questionable if the difference in daily regimen (smaller and more frequent doses) effects in lower bioavailability. Conversely, Messier et al. report that multiple doses may make C more bioavailable.25 Short term exercise therapy alone improved clinical symptoms in the KOA patients,47–50 while for dietary supplements it seems long term interventions are needed. Systematic review of randomized controlled trials of glucosamine long-term treatment limited to studies that lasted at least one year showed moderate effect in improving symptoms of KOA.51 Pavelka et al.52 showed significant improvement in the WOMAC total index and pain, function, and stiffness subscales after 3-year treatment with GS compared to placebo. There is good safety profile of dietary supplement (G and C) without differences in adverse effects compared to placebo after two or three years.38,52 Symptom changes as previously mentioned were evident in the patients with mild to moderate disease according to Kellgren and Lawrence scoring system for classification of knee OA. Most of our studies involved patients with mild to moderate KOA and one study involved patients with mild to severe conditions. The benefits in KOA symptoms in those with severe KOA are questionable, surgery is only suitable for patients with end-stage KOA.14 There are numerous risk factors for the development and progression of the KOA such as age, gender, and obesity.53 It is interesting to note that in the present review there was only one study which included obese people.28 Participants of Kawasaki et al.24 were normal weight, and in other studies subjects were overweight. To our knowledge, an association between weight loss and knee OA exist and weight loss is considered a treatment strategy in KOA patients. Obese KOA patients with muscle weakness experience more pain compared with KOA patients who are non-obese.54 Despite regular exercise intervention in different duration none of the studies confirmed a reduced BMI in any of groups and there is no possible pain relieve. Although not explained in the studies, there is a possibility that the high prevalence of overweight participants encompasses sarcopenic individuals with poor exercise capacity who may not benefit from 4 weeks of training. Additionally, from the standpoint of resistance training, benefits in muscular strength cannot be expected in just 4 weeks. In the included studies a sex misbalance was noted, 24% of analyzed subjects were male and 76% were female. Women have higher KOA prevalence with higher VAS pain score and more impaired function compared to men.55 Based on these findings, the results cannot be generalized to both sexes. Our review found no significant effects of G or G with CS on WOMAC pain Exercise and glucosamine with or without chondroitin on osteoarthritis pain and physical functions Eur J Transl Myol 33 (4) 12013, 2023 doi: 10.4081/ejtm.2023.12013 - 7 - or other WOMAC’s subscales. To relief knee pain, it can be expected that functional performance should increase. Our findings suggest that patients have not been able to show greater exertion in everyday life without reduction in pain. In the intervention group, no effects exist compared to the control group, which suggests that the knee exercise program included in the studies in this review was well designed, and changes from baseline can be attributed to exercise only. On the other hand, a long- term study without supervised training session and without progression in 3 studies has been conducted. One study treatment duration was only 4 weeks, which is less than the shortest duration of the study included in systematic review and meta-analysis of randomized placebo controlled trials to investigate the efficacy of G and CS on KOA symptoms.56 In accordance with this study, there is no additional effect using both oral supplements on KOA symptoms using WOMAC pain or VAS pain. Runge et al.57 reported very low to moderate certainty of evidence that adding manual therapy to an exercise program may benefit pain and the WOMAC global scale in patients with KOA in the short term. We have thus included a study of Osama et al.,26 where a four-week manual therapy was used as an adjunct to resistance exercise and glucosamine. We do not believe that a manual therapy effect could have changed our results. Some limitations to the present study need to be noted. There were 2 studies,25,28 in which the exclusion criterion was the use of glucosamine and/or chondroitin, while in one study,27 a one-month washout period was conducted. In three other studies,23,24,26 there is no report about exclusion criteria or specific monitoring of participants who were using dietary supplements prior to their inclusion in the research. We cannot exclude that some of these subjects might not have been totally clear of dietary supplements or even of NSAIDs. This could be the reason why there were no differences between the groups. The review includes studies with varying intervention durations and a relatively small sample size. Further studies on a larger population for a longer period would be necessary. The sample size might not be sufficient, affecting the reliability of our study. Moreover, due to choosing literature only in aforementioned databases and only in English, selection bias exists. Due to the smaller number of included studies, the subgroup analyses were not possible, and further comparisons were not possible for all outcome measures. 29 different tests and outcomes were used across the studies. The major limitation of the present review is an unbalanced representation of different outcomes and a smaller number of included studies. From the methodological viewpoint, the study protocol is not registered on PROSPERO platform. Regardless the results we have to be cautious in clinical practice giving instruct to patients not to take G and/or C. This may lead to resistance to therapy. Considering the results and current understanding of the benefits of taking G and/or C it is important to be aware that additional benefits of combining exercise with the consumption of G and/or C cannot be achieved. This raises the question of whether there is limited benefit of different therapy combination in KOA management. In conclusion, overall, we observed a high variability among study designs, which made it difficult to assess with certainty the effect that glucosamine and chondroitin may have on KOA symptoms. Conclusions should be viewed with caution, since there are a few questions that remain open. More high-quality studies are needed to explore the role of G and/or C combining with exercise in the treatment of KOA. However, the inclusion of glucosamine alone or in combination with chondroitin in a KOA exercise program did not seem to make exercise therapy more effective. List of acronyms BMI – body mass index C – chondroitin CRP – C-reactive protein CS – chondroitin sulfate G – glucosamine GH – glucosamine hydrochloride GS – glucosamine sulfate KOA – knee osteoarthritis KOOS – Knee injury and Osteoarthritis Outcome Score NSAIDs – non-steroidal anti-inflammatory drugs pCGS – prescription crystalline glucosamine sulfate ROM – range of motion SD – standard deviation SMD – standard mean difference SYSADOAs – symptomatic slow-action drugs for osteoarthritis VAS – visual analogue scale WOMAC – Western Ontario and McMaster Universities Osteoarthritis Index 6MWT – six minute walk test Contributions of Authors TC and NS conceived the original idea of the manuscript. TC and NS participated to the writing of the text. TC and NS reviewed the manuscript and have approved the final edited typescript. Acknowledgments None. Funding The study received no external funding. Conflict of Interest The authors declare no conflicts of interest. Ethical Publication Statement We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Exercise and glucosamine with or without chondroitin on osteoarthritis pain and physical functions Eur J Transl Myol 33 (4) 12013, 2023 doi: 10.4081/ejtm.2023.12013 - 8 - Corresponding Author Prof. dr. Nejc Šarabon, University of Primorska, Faculty of Health Sciences. Polje 42, SI-6310 Izola, Slovenia Phone number: +386 5 662 64 66; Fax number: +386 5 662 64 80 ORCID iD: 0000-0003-0747-3735 E-mail: nejc.sarabon@fvz.upr.si E-mails and ORCID iD of co-author Tina Čeh: 97220490@student.upr.si ORCID ID: 0009-0009-9172-3186 References 1. Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, Bridgett L, Williams S, Guillemin F, Hill CL, Laslett LL, Jones G, Cicuttini F, Osborne R, Vos T, Buchbinder R, Woolf A, March L. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Annals of the Rheumatic Diseases. BMJ Publishing Group Ltd; 2014 Jul 1;73(7):1323–30. doi: 10.1136/annrheumdis-2013-204763. Epub 2014 Feb 19. PMID: 24553908. 2. Abbassy AA, Trebinjac S, Kotb N. The use of cellular matrix in symptomatic knee osteoarthritis. Bosn J Basic Med Sci. 2020 May;20(2):271–4. doi: 10.17305/bjbms.2019.4205. PMCID: PMC7202193. 3. Ashkavand Z, Malekinejad H, Vishwanath BS. The pathophysiology of osteoarthritis. Journal of Pharmacy Research. 2013 Jan 1;7(1):132–8. doi: 10.1016/j.jopr.2013.01.008. 4. Saito T, Tanaka S. Molecular mechanisms underlying osteoarthritis development: notch and NF-κB. Arthritis Res Ther. 2017 May 15;19(1):94. doi: 10.1186/s13075-017-1296-y. Epub 2017 May 15. PMID: 28506315; PMCID: PMC5433029. 5. Fernández-Martín S, González-Cantalapiedra A, Muñoz F, García-González M, Permuy M, López- Peña M. Glucosamine and chondroitin sulfate: is there any scientific evidence for their effectiveness as disease-modifying drugs in knee osteoarthritis preclinical studies?-a systematic review from 2000 to 2021. Animals (Basel). 2021 May 29;11(6):1608. doi: 10.3390/ani11061608. PMID: 34072407; PMCID: PMC8228516. 6. Hanypsiak BT, Shaffer BS. Nonoperative treatment of unicompartmental arthritis of the knee. Orthop Clin North Am. 2005 Oct;36(4):401–11. doi: 10.1016/j.ocl.2005.05.005. Epub: 2005 Sep 13. PMID: 16164945. 7. McAlindon TE, Biggee BA. Nutritional factors and osteoarthritis: recent developments. Curr Opin Rheumatol. 2005 Sep;17(5):647–52. doi: 10.1016/j.joca.2014.01.003. Epub 2014 Jan 24. PMID: 16093847. 8. Meng Z, Liu J, Zhou N. Efficacy and safety of the combination of glucosamine and chondroitin for knee osteoarthritis: a systematic review and meta- analysis. Arch Orthop Trauma Surg. 2023 Jan 1;143(1):409–21. doi: 10.1007/s00402-021-04326- 9. Epub 2022 Jan 13. 9. Liu X, Machado GC, Eyles JP, Ravi V, Hunter DJ. Dietary supplements for treating osteoarthritis: a systematic review and meta-analysis. Br J Sports Med. 2018 Feb;52(3):167–75. doi: 10.1136/bjsports-2016-097333. Epub 2017 Oct 10. PMID: 29018060. 10. Singh JA, Noorbaloochi S, MacDonald R, Maxwell LJ. Chondroitin for osteoarthritis. Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd; 2015;(1). doi: 10.1002/14651858. CD005614.pub2. Epub 2015 Jan 28. PMID: 25629804. 11. Bruyère O, Altman RD, Reginster JY. Efficacy and safety of glucosamine sulfate in the management of osteoarthritis: evidence from real-life setting trials and surveys. Seminars in Arthritis and Rheumatism. 2016 Feb 1;45(4, Supplement):S12–7. doi: 10.1016/j.semarthrit.2015.11.011. Epub 2015 Dec 2. 12. Goh SL, Persson MSM, Stocks J, Hou Y, Lin J, Hall MC, Doherty M, Zhang W. Efficacy and potential determinants of exercise therapy in knee and hip osteoarthritis: a systematic review and meta- analysis. Ann Phys Rehabil Med. 2019 Sep;62(5):356–65. doi: 10.1016/j.rehab.2019.04.006. Epub 2019 May 21. PMID: 31121333; PMCID: PMC6880792. 13. Kus G, Yeldan I. Strengthening the quadriceps femoris muscle versus other knee training programs for the treatment of knee osteoarthritis. Rheumatol Int. 2019 Feb;39(2):203–18. doi: 10.1007/s00296- 018-4199-6. Epub 2018 Nov 15. PMID: 30430202. 14. Zeng CY, Zhang ZR, Tang ZM, Hua FZ. Benefits and mechanisms of exercise training for knee osteoarthritis. Front Physiol. 2021;12:794062. doi: 10.3389/fphys.2021.794062. Epub 2021 Dec 16. PMID: 34975542. 15. Mat S, Tan MP, Kamaruzzaman SB, Ng CT. Physical therapies for improving balance and reducing falls risk in osteoarthritis of the knee: a systematic review. Age Ageing. 2015 Jan;44(1):16– 24. doi: 10.1093/ageing/afu112. Epub 2014 Aug 22. PMID: 25149678. 16. You Y, Liu J, Tang M, Wang D, Ma X. Effects of tai chi exercise on improving walking function and posture control in elderly patients with knee osteoarthritis: a systematic review and meta- analysis. Medicine (Baltimore). 2021 Apr 23;100(16):e25655. doi: 10.1097/MD.0000000000025655. Epub 2021 Apr 23. PMID: 33879749; PMCID: PMC8078456. 17. Wang Z, Wang R, Yao H, Yang J, Chen Y, Zhu Y, Lu C. Clinical efficacy and safety of chondroitin combined with glucosamine in the treatment of mailto:nejc.sarabon@fvz.upr.si mailto:97220490@student.upr.si Exercise and glucosamine with or without chondroitin on osteoarthritis pain and physical functions Eur J Transl Myol 33 (4) 12013, 2023 doi: 10.4081/ejtm.2023.12013 - 9 - knee osteoarthritis: a systematic review and meta- analysis. Comput Math Methods Med. 2022;2022:5285244. doi: 10.1155/2022/5285244. Epub 2022 Jul 25. PMID: 35924114; PMCID: PMC9343191. 18. Methley AM, Campbell S, Chew-Graham C, McNally R, Cheraghi-Sohi S. PICO, PICOS and SPIDER: a comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews. BMC Health Serv Res. 2014 Nov 21;14:579. doi: 10.1186/s12913-014-0579-0. PMID: 25413154; PMCID: PMC4310146. 19. Maher CG, Sherrington C, Herbert RD, Moseley AM, Elkins M. Reliability of the PEDro scale for rating quality of randomized controlled trials. Phys Ther. 2003 Aug;83(8):713–21. PMID: 12882612. 20. Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2018 Jun;27(6):1785–805. doi: 10.1177/0962280216669183. Epub 2016 Sep 27. PMID: 27683581. 21. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014 Dec 19;14:135. doi: 10.1186/1471-2288-14-135. PMID: 25524443; PMCID: PMC4383202. 22. Higgins J, Thomas J. Cochrane handbook for systematic reviews of interventions. Available online: https://training.cochrane.org/handbook/current (accessed on 21 March 2023). 23. Durmus D, Alayli G, Bayrak IK, Canturk F. Assessment of the effect of glucosamine sulfate and exercise on knee cartilage using magnetic resonance imaging in patients with knee osteoarthritis: a randomized controlled clinical trial. J Back Musculoskelet Rehabil. Netherlands; 2012;25(4):275–84. doi: 10.3233/BMR-2012- 0336. PMID: 23220811. 24. Kawasaki T, Kurosawa H, Ikeda H, Kim SG, Osawa A, Takazawa Y, Kubota M, Ishijima M. Additive effects of glucosamine or risedronate for the treatment of osteoarthritis of the knee combined with home exercise: a prospective randomized 18- month trial. J Bone Miner Metab. Japan; 2008;26(3):279–87. doi: 10.1007/s00774-007- 0813-5. PMID: 18470670. 25. Messier SP, Mihalko S, Loeser RF, Legault C, Jolla J, Pfruender J, Prosser B, Adrian A, Williamson JD. Glucosamine/chondroitin combined with exercise for the treatment of knee osteoarthritis: a preliminary study. Osteoarthritis Cartilage. England; 2007 Nov;15(11):1256–66. doi: 10.1016/j.joca.2007.04.016. Epub 2007 Jun 11. PMID: 17561418. 26. Osama M, Babur MN, Siddiqi FA, Tassadaq N, Arshad Tareen MA. Effects of glucosamine and chondroitin sulfate supplementation in addition to resistance exercise training and manual therapy in patients with knee osteoarthritis: A randomized controlled trial. J Pak Med Assoc. 2022 Jul;72(7):1272–77. doi: 10.47391/JPMA.2444. PMID: 36156542. 27. Petersen SG, Beyer N, Hansen M, Holm L, Aagaard P, Mackey AL, Kjaer M. Nonsteroidal anti- inflammatory drug or glucosamine reduced pain and improved muscle strength with resistance training in a randomized controlled trial of knee osteoarthritis patients. Arch Phys Med Rehabil. United States; 2011 Aug;92(8):1185–93. doi: 10.1016/j.apmr.2011.03.009. PMID: 21807137. 28. Sterzi S, Giordani L, Morrone M, Lena E, Magrone G, Scarpini C, Milighetti S, Pellicciari L, Bravi M, Panni I, Ljoka C, Bressi F, Foti C. The efficacy and safety of a combination of glucosamine hydrochloride, chondroitin sulfate and bio- curcumin with exercise in the treatment of knee osteoarthritis: a randomized, double-blind, placebo- controlled study. Eur J Phys Rehabil Med. Italy; 2016 Jun;52(3):321–30. PMID: 26937646. 29. Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, Christy W, Cooke TD, Greenwald R, Hochberg M. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and therapeutic criteria committee of the American rheumatism association. Arthritis Rheum. 1986 Aug;29(8):1039–49. doi: 10.1002/art.1780290816. PMID: 3741515. 30. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957 Dec;16(4):494–502. Available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10 06995/ (accessed on 21 March 2023). PMID: 13498604; PMCID: PMC1006995. 31. McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, Hawker GA, Henrotin Y, Hunter DJ, Kawaguchi H, Kwoh K, Lohmander S, Rannou F, Roos EM, Underwood M. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis and Cartilage. 2014 Mar 1;22(3):363–88. doi: 10.1016/j.joca.2014.01.003. Epub 2014 Jan 14. 32. Xu Z, Wang Y, Zhang Y, Lu Y, Wen Y. Efficacy and safety of aquatic exercise in knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Clin Rehabil. 2023 Mar;37(3):330–47. doi: 10.1177/0269215522113 4240. Epub 2022 Nov 1. 33. Al-Mhanna SB, Mohamed M, Mohd Noor N, Aldhahi MI, Afolabi HA, Mutalub YB, Irekeola AA, Bello KE, Wan Ghazali WS. Effects of circuit training on patients with knee osteoarthritis: a Exercise and glucosamine with or without chondroitin on osteoarthritis pain and physical functions Eur J Transl Myol 33 (4) 12013, 2023 doi: 10.4081/ejtm.2023.12013 - 10 - systematic review and meta-analysis. Healthcare (Basel). 2022 Oct 15;10(10):2041. doi: 10.3390/healthcare10102041. PMID: 36292488; PMCID: PMC9601599. 34. Guo X, Zhao P, Zhou X, Wang J, Wang R. A recommended exercise program appropriate for patients with knee osteoarthritis: A systematic review and meta-analysis. Front Physiol. 2022;13:934511. doi: 10.3389/fphys.2022.934511. Epub 2022 Oct 3. PMID: 36262252; PMCID: PMC9574341. 35. Hua J, Sun L, Teng Y. Effects of high-intensity strength training in adults with knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Am J Phys Med Rehabil. 2023 Apr 1;102(4):292–99. doi: 10.1097/PHM.0000000000002088. Epub 2022 Sep 12. 36. Jurado-Castro JM, Muñoz-López M, Ledesma AST, Ranchal-Sanchez A. Effectiveness of exercise in patients with overweight or obesity suffering from knee osteoarthritis: a systematic review and meta-analysis. Int J Environ Res Public Health. 2022 Aug 24;19(17):10510. doi: 10.3390/ijerph 191710510. PMID: 36078226; PMCID: PMC9518463. 37. Roman-Blas J, Castañeda S, Sánchez-Pernaute O, Largo R, Herrero-Beaumont G. Combined treatment with chondroitin sulfate and glucosamine sulfate shows no superiority over placebo for reduction of joint pain and functional impairment in patients with knee osteoarthritis: a six-month multicenter, randomized, double-blind, placebo- controlled clinical trial. Arthritis Rheumatol; 2017 Jan;69(1). doi: 10.1002/art.39819. PMID: 27477804. 38. Fransen M, Agaliotis M, Nairn L, Votrubec M, Bridgett L, Su S, Jan S, March L, Edmonds J, Norton R, Woodward M, Day R, LEGS study collaborative group. Glucosamine and chondroitin for knee osteoarthritis: a double-blind randomised placebo-controlled clinical trial evaluating single and combination regimens. Ann Rheum Dis. 2015 May;74(5):851–8. doi: 10.1136/annrheumdis- 2013-203954. Epub 2014 Jan 6. PMID: 24395557. 39. Zeng C, Wei J, Li H, Wang Y lun, Xie D xing, Yang T, Gao S guang, Li Y sheng, Luo W, Lei G hua. Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee. Sci Rep. 2015 Nov 18;5:16827. doi: 10.1038/srep16827. PMID: 26576862; PMCID: PMC4649492. 40. Hungerford DS, Jones LC. Glucosamine and chondroitin sulfate are effective in the management of osteoarthritis. J Arthroplasty. 2003 Apr;18(3 Suppl 1):5–9. doi: 10.1054/arth.2003.50067. PMID: 12730919. 41. Bruyère O, Honvo G, Veronese N, Arden NK, Branco J, Curtis EM, Al-Daghri NM, Herrero- Beaumont G, Martel-Pelletier J, Pelletier JP, Rannou F, Rizzoli R, Roth R, Uebelhart D, Cooper C, Reginster JY. An updated algorithm recommendation for the management of knee osteoarthritis from the European society for clinical and economic aspects of osteoporosis, osteoarthritis and musculoskeletal diseases (ESCEO). Semin Arthritis Rheum. 2019 Dec;49(3):337–50. doi: 10.1016/j.semarthrit.2019.04.008. Epub 2019 Apr 30. PMID: 31126594. 42. Altman RD. Glucosamine therapy for knee osteoarthritis: pharmacokinetic considerations. Expert Rev Clin Pharmacol. 2009 Jul;2(4):359–71. doi: 10.1586/ecp.09.17. PMID: 22112180. 43. Runhaar J, Rozendaal RM, van Middelkoop M, Bijlsma HJW, Doherty M, Dziedzic KS, Lohmander LS, McAlindon T, Zhang W, Bierma Zeinstra S. Subgroup analyses of the effectiveness of oral glucosamine for knee and hip osteoarthritis: a systematic review and individual patient data meta-analysis from the OA trial bank. Ann Rheum Dis. 2017 Nov;76(11):1862–9. doi: 10.1136/ annrheumdis-2017-211149. Epub 2017 Jul 28. PMID: 28754801. 44. Hochberg MC, Martel-Pelletier J, Monfort J, Möller I, Castillo JR, Arden N, Berenbaum F, Blanco FJ, Conaghan PG, Doménech G, Henrotin Y, Pap T, Richette P, Sawitzke A, du Souich P, Pelletier JP. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann Rheum Dis. England; 2016 Jan;75(1):37–44. doi: 10.1136/annrheumdis-2014- 206792. Epub 2015 Jan 14. PMID: 25589511; PMCID: PMC4717399. 45. Provenza JR, Shinjo SK, Silva JM, Peron CRGS, Rocha FAC. Combined glucosamine and chondroitin sulfate, once or three times daily, provides clinically relevant analgesia in knee osteoarthritis. Clin Rheumatol. 2015 Aug;34(8):1455–62. doi: 10.1007/s10067-014- 2757-1. PMID: 25085275. 46. Persiani S, Roda E, Rovati LC, Locatelli M, Giacovelli G, Roda A. Glucosamine oral bioavailability and plasma pharmacokinetics after increasing doses of crystalline glucosamine sulfate in man. Osteoarthritis and Cartilage. 2005 Dec 1;13(12):1041–9. doi: 10.1016/j.joca.2005.07.009. Epub 2005 Sep 13. 47. Pazit L, Jeremy D, Nancy B, Michael B, George E, Hill KD. Safety and feasibility of high speed resistance training with and without balance exercises for knee osteoarthritis: a pilot randomised controlled trial. Physical Therapy in Sport. 2018 Nov 1;34:154–63. doi: 10.1016/j.ptsp.2018.10.001. Epub 2018 Oct 3. Exercise and glucosamine with or without chondroitin on osteoarthritis pain and physical functions Eur J Transl Myol 33 (4) 12013, 2023 doi: 10.4081/ejtm.2023.12013 - 11 - 48. Cheung C, Wyman JF, Resnick B, Savik K. Yoga for managing knee osteoarthritis in older women: a pilot randomized controlled trial. BMC Complementary and Alternative Medicine. 2014 May 18;14(1):160. doi: 10.1186/1472-6882-14- 160. Epub 2014 May 18. 49. Chang TF, Liou TH, Chen CH, Huang YC, Chang KH. Effects of elastic-band exercise on lower- extremity function among female patients with osteoarthritis of the knee. Disability and Rehabilitation. Taylor & Francis. 2012 Oct 1;34(20):1727–35. doi: 10.3109/09638288.2012. 660598. Epub 2012 Mar 8. 50. Samut G, Dinçer F, Özdemir O. The effect of isokinetic and aerobic exercises on serum interleukin-6 and tumor necrosis factor alpha levels, pain, and functional activity in patients with knee osteoarthritis. Modern Rheumatology. 2015 Sep 8;25(6):919–24. doi: 10.3109/14397595.2015. 1038425. Epub 2015 May 27. 51. Poolsup N, Suthisisang C, Channark P, Kittikulsuth W. Glucosamine long-term treatment and the progression of knee osteoarthritis: systematic review of randomized controlled trials. Ann Pharmacother. 2005 Jun;39(6):1080–7. doi: 10.1345/aph.1E576. Epub 2005 Apr 26. PMID: 15855241. 52. Pavelká K, Gatterová J, Olejarová M, Machacek S, Giacovelli G, Rovati LC. Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3- year, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2002 Oct 14;162(18):2113–23. doi: 10.1001/archinte.162.18.2113. PMID: 12374520. 53. Palazzo C, Nguyen C, Lefevre-Colau MM, Rannou F, Poiraudeau S. Risk factors and burden of osteoarthritis. Annals of Physical and Rehabilitation Medicine. 2016 Jun 1;59(3):134–8. doi: 10.1016/j.rehab.2016.01.006. Epub 2016 Feb 9. 54. Knoop J, van der Leeden M, Thorstensson CA, Roorda LD, Lems WF, Knol DL, Steultjens MPM, Dekker J. Identification of phenotypes with different clinical outcomes in knee osteoarthritis: data from the Osteoarthritis Initiative. Arthritis Care Res (Hoboken). 2011 Nov;63(11):1535–42. doi: 10.1002/acr.20571. PMID: 21954070. 55. Tschon M, Contartese D, Pagani S, Borsari V, Fini M. Gender and Sex Are Key determinants in osteoarthritis not only confounding variables. A systematic review of clinical data. J Clin Med. 2021 Jul 19;10(14):3178. doi: 10.3390/jcm10143178. Epub 2021 Jul 19. PMID: 34300344; PMCID: PMC8303951. 56. Simental-Mendía M, Sánchez-García A, Vilchez- Cavazos F, Acosta-Olivo CA, Peña-Martínez VM, Simental-Mendía LE. Effect of glucosamine and chondroitin sulfate in symptomatic knee osteoarthritis: a systematic review and meta- analysis of randomized placebo-controlled trials. Rheumatol Int. 2018 Aug;38(8):1413–28. doi: 10.1007/s00296-018-4077-2. Epub 2018 Jun 11. PMID: 29947998. 57. Runge N, Aina A, May S. The benefits of adding manual therapy to exercise therapy for improving pain and function in patients with knee or hip osteoarthritis: a systematic review with meta- analysis. J Orthop Sports Phys Ther. 2022 Oct;52(10):675-A13. doi: 10.2519/jospt.2022. 11062. Epub 2022 Jul 26. PMID: 35881705. Disclaimer All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Submission: October 10, 2023 Revision received: November 5, 2023 Accepted for publication: November 5, 2023 Exercise and glucosamine with or without chondroitin on osteoarthritis pain and physical functions Eur J Transl Myol 33 (4) 12013, 2023 doi: 10.4081/ejtm.2023.12013 12 Supplimentary Materials Table 1. Overview of the studies included into the meta-analysis. Reference Intervention characteristics Participant data (EG; CG) Exercise characteristics Outcome measures Main conclusion Petersen et al., 201127 12 weeks 3 times/week 45 min/session supervised: yes strength training + GS 1500 mg daily vs. strength exercise + placebo n = 24 (12; 12) n female = 14 (7/12; 7/12) age = 62.2 ± 11.8; 63.1 ± 16.3 BMI = 27.3 ± 11.4; 28.3 ± 11.1 K/L grade = 1–4 3 exercises, from 4 sets of 15 RM to 4 sets of 8 RM quadriceps muscle strength and power, habitual walking speed on a 10-m track, stair-climbing time (13 steps), chair stands (30 s), pain during the strength measurements (VAS), KOOS questionnaire, muscle biopsy, CRP, total cholesterol, creatinine, and alkaline phosphatase, MR Similar gains in functional performances were obtained in both groups. Beneficial effects were not convincing enough to recommend treatment with GS. Durmus et al., 201223 12 weeks 3 times/week 45 min/session supervised: yes aerobic exercise + GS 1500 mg daily vs. aerobic exercise n = 39 (19; 20) n female = 39 (19/19; 20/20) age = 57.,7 ± 1,4; 57.1 ± 1,3 BMI = 27.7 ± 1.0; 28.6 ± 0.8 K/L grade = 1–3 4 exercises (active ROM, strength, stretching, flexibility) WOMAC, 6MWT, quadriceps muscle strength, quality of life (SF- 36), depression, MR No statistically significant between- group differences were found in any outcome measures. Exercise alone is effective in improvement of clinical symptoms in a short period in KOA. Kawasaki et al., 200824 18 moths twice a day supervised: no home-based training + GH 1500 mg daily vs. home-based training n = 71 (39; 32) n female = 71 (39/39; 32/32) age = 68.5 ± 7.3; 69.5 ± 7.1 BMI = 23.9 ± 2.5; 24.0 ± 3.0 K/L grade = 2–3 4 exercises (isometric muscle strength + active ROM) 1 set, 20 repetitions JOA score, actual pain level (VAS), WOMAC, tibiofemoral joint space width No statistically significant difference between groups was observed in any outcome measures. Messier et al., 200725 6 months 3 times/week (twice facility-based, once home-based) supervised: yes aerobic and strength exercise program + GH/CS 1500/1200 mg daily vs. aerobic and strength exercise + placebo n = 89 (45; 44) n female = 63 (34/45; 29/44) age = 70.0 ± 8.6; 74.1 ± 8.8 BMI = 30.7 ± 6.2; 27.3 ± 4.8 K/L grade = 2–3 2x15 min walking (50–70% HR reserve), 4 strength exercises 2 sets, 10–12 repetitions cuff weights and machines progression WOMAC, 6MWT, mental status, knee concentric extension and flexion strength, balance No statistically significant between- group differences were found in function, pain, or mobility. Exercise and glucosamine with or without chondroitin on osteoarthritis pain and physical functions Eur J Transl Myol 33 (4) 12013, 2023 doi: 10.4081/ejtm.2023.12013 13 Supplimentary Materials Table 1. Overview of the studies included into the meta-analysis. CONTINUE. Reference Intervention characteristics Participant data (EG; CG) Exercise characteristics Outcome measures Main conclusion Sterzi et al., 201628 12 weeks 3 times/week supervised: yes mixed exercise program + CartiJoint daily (GH, CS, Curcumin) vs. mixed exercise program + placebo n = 50 (23, 27) female = 33 (14/23; 19/27) age = 71.3 ± 8.8; 71.0 ± 8.1 BMI = 34.8 ± 6.4; 34.3 ± 7.5 K/L grade = 2–3 active and active- assisted ROM, stretching and strength exercises pain (VAS 0-100) during normal daily living and during rest, WOMAC, Lequesne Index, flexion and extension ROM, inflammation assessment using CRP and ESR measurements Treatment with Curcumin, GH and CS, accompanied by physical therapy, may improve pain symptoms during the activities of daily living and reduce the Lequesne Algofunctional Index values in KOA. Osama et al., 202226 4 weeks 3 times/week with manual therapy + 4 times/week home-based exercise supervised: yes resistance exercise training + G/CS 1500/1200 mg daily vs. resistance exercise training n = 24 (12, 12) n female = 6 (3/12; 3/12) age = 57 ± 9.2; 57 ± 7.6 BMI = 27.4 ± 3.4; 27.4 ± 1.6 K/L grade = 1–3 8 exercises 3 sets of 8 repetitions 1–2-minute rest between the sets 80% of 8 RM was used as training intensity (reassessed every week) Pain (VAS), KOOS, isometric muscle strength in knee flexion and extension, 5XRSS, knee ROM in flexion and extension, fall risk score, body composition analysis Physical therapy and resistance exercise training are effective in KOA management; short-term supplementation of G and CS showed no additional benefits after 4 weeks of treatment. __________________________________________________________________________________________________________________________________________________ EG: experimental group; CG: control group; BMI: body mass index; K/L: Kellgren/Lawrence; KOOS: Knee Injury and Osteoarthritis Outcome Score; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; ROM: range of motion; MR: magnetic resonance; 6MWT: 6-minute walk test; JOA: Japan Orthopaedic Association; 5XRSS: 5-repetition sit-to-stand test; HR: heart rate; G: glucosamine; GS: glucosamine sulfate; CS: chondroitin sulfate; GH: glucosamine hydrochloride. Results