genortГений ортопедииGenij Ortopedii1028-44272542-131XЦЕНТР ИЛИЗАРОВА10.18019/1028-4427-2026-32-4-479-487genort-3525Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESВлияние глюкозамина-хондроитина, хитозана и фитоэстрогенов на воспалительные процессы, биомаркеры дегенерации хряща и клинические симптомы при остеоартрозе коленного сустава у женщин в постменопаузеEffects of Glucosamine-Chondroitin, Chitosan, and Phytoestrogen on Knee Osteoarthritis Inflammatory and Cartilage Degeneration Biomarkers and Clinical Symptoms in Postmenopausal WomenKermawanP.KermawanP.

Bali

Bali

YasaI.W.P.S.YasaI.W.P.S.

Bali

Bali

KarnaМ. B.KarnaM. B.

Bali

Bali

HerawatiS.HerawatiS.

Bali

Bali

SuyasaI. K.SuyasaI. K.

Bali

Bali

ArsaniN.L.K.A.ArsaniN.L.K.A.

Bali

Bali

CalistoK. E.CalistoK. E.

Yogyakarta

Yogyakarta

YoganandaK.S.S.YoganandaK.S.S.

Yogyakarta

Yogyakarta

WiwekanandaK.S.S.WiwekanandaK.S.S.

Yogyakarta

Yogyakarta

WijayaN.S.N.WijayaN.S.N.

Bali

Bali

JawiI. M.JawiI. M.

Bali

Bali

Universitas Pendidikan GaneshaИндонезияUniversitas Pendidikan GaneshaIndonesiaUdayana UniversityИндонезияUdayana UniversityIndonesiaNgoerah General Hospital, Udayana UniversityРоссияNgoerah General Hospital, Udayana UniversityRussian FederationUniversitas Gadjah MadaИндонезияUniversitas Gadjah MadaIndonesia202618082026324479487Copyright © Kermawan P., Yasa I., Karna М.B., Herawati S., Suyasa I.K., Arsani N., Calisto K.E., Yogananda K., Wiwekananda K., Wijaya N., Jawi I.M., 20262026Kermawan P., Yasa I., Karna М.B., Herawati S., Suyasa I.K., Arsani N., Calisto K.E., Yogananda K., Wiwekananda K., Wijaya N., Jawi I.M.Kermawan P., Yasa I., Karna M.B., Herawati S., Suyasa I.K., Arsani N., Calisto K.E., Yogananda K., Wiwekananda K., Wijaya N., Jawi I.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.ilizarov-journal.com/jour/article/view/3525Введение

Введение. Остеоартроз коленного сустава (ОА) — прогрессирующее заболевание, вызывающее боль и дисфункцию коленного сустава, особенно у женщин в постменопаузе.

Цель работы — оценить терапевтическую эффективность комбинации глюкозамина-хондроитина, хитозана, фитоэстрогена и парацетамола по сравнению с применением только парацетамола у женщин в постменопаузе с остеоартрозом коленного сустава.

Материалы и методы

Материалы и методы. Проведено двойное слепое рандомизированное контролируемое исследование с участием 60 женщин в постменопаузе с остеоартрозом коленного сустава II–III степени по Келлгрену – Лоуренсу, которые случайным образом распределены на две группы: основную (n = 30) — пациентки получали глюкозамин-хондроитин, хитозан и фитоэстроген в сочетании с парацетамолом, и контрольную группу (n = 30) — пациентки получали только парацетамол. Возраст пациенток основной группы — (59,77 ± 2,99) г., контрольной группы — (60,4 ± 3,21) г., статистически значимых различий не выявлено (p = 0,43). Уровни растворимого рецептора интерлейкина-6 (sIL-6R), интерлейкина-10 (IL-10), олигомерного матриксного белка хряща (COMP), а также показатели визуальной аналоговой шкалы (ВАШ) и индекса остеоартрита по системе Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) измеряли до лечения и после двух недель лечения.

Результаты

Результаты. После фармакологического вмешательства в основной группе наблюдали значимое снижение показателей WOMAC, COMP и sIL-6R по сравнению с контрольной группой (p < 0,01). В обеих группах после лечения зарегистрировано повышение уровня IL-10, более выраженное в контрольной группе.

Обсуждение

Обсуждение. Комбинированная терапия продемонстрировала улучшение показателей функции сустава и снижение маркеров воспаления и дегенерации хряща. Эти данные подтверждают противовоспалительный и хондропротективный потенциал природных соединений в лечении пациентов с остеоартрозом коленного сустава.

Заключение

Заключение. Использование комбинации глюкозамин-хондроитина, хитозана, фитоэстрогена и парацетамола у женщин в постменопаузе с остеоартритом коленного сустава II–III степени продемонстрировало лучшие краткосрочные результаты снижения показателей биомаркеров воспаления и дегенерации хряща, а также улучшение клинических симптомов по сравнению с использованием одного парацетамола.

Introduction Knee osteoarthritis (OA) is a progressive disease causing pain and dysfunction in postmenopausal women.

Purpose This study aimed to evaluate the therapeutic efficacy of a combination of glucosamine-chondroitin, chitosan, and phytoestrogen with paracetamol compared to paracetamol alone in postmenopausal women with knee osteoarthritis.

Materials and Methods A double-blind randomized controlled trial was conducted on 60 postmenopausal women with Kellgren – Lawrence grade II–III knee osteoarthritis. A total of 60 patients were included in this study and divided into treatment and control groups with a 1:1 ratio. The mean age of patients was 59.77 years (± 2.99) while the control group had a mean age of 60.4 years (± 3.21), there was no significant difference (p = 0.43). Patients were randomly assigned into two groups: the treatment group (n = 30), which received glucosamine-chondroitin, chitosan, and phytoestrogen in combination with paracetamol, and the control group (n = 30), which received paracetamol alone. The levels of soluble interleukin-6 receptor (sIL-6R), interleukin-10 (IL-10), cartilage oligomeric matrix protein (COMP), as well as Visual Analog Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were measured at baseline and after two weeks of treatment.

Results After the pharmacological intervention, the treatment group showed significant reductions in WOMAC score, COMP, and sIL-6R compared to the control group (p < 0.01). Both groups had increased IL-10 levels following treatment, but the increase was greater in the control group.

Discussion The combination therapy demonstrated improvement in joint function and a reduction in inflammatory and cartilage degeneration markers. These findings support the anti-inflammatory and chondroprotective potential of natural compounds in the management of knee osteoarthritis.

Conclusion The combination of glucosamine-chondroitin, chitosan, phytoestrogen, and paracetamol demonstrated superior short-term effects in reducing inflammatory and cartilage degeneration biomarkers and improving clinical symptoms in postmenopausal women with grade II-III knee osteoarthritis compared with paracetamol alone.

остеоартроз коленного суставапостменопаузаглюкозамин-хондроитинхитозанфитоэстрогенknee osteoarthritispostmenopausaglucosamine-chondroitinchitosanphytoestrogenАвторы выражают искреннюю благодарность всем пациентам, любезно принявшим участие в данном исследовании. Мы также выражаем благодарность Фанди Хендравану за его ценный вклад в анализ данныхThe authors sincerely thank all the patients who participated in this study. We also acknowledge Fandi Hendrawan for his valuable contribution to data analysisReferencesWHO. Osteoarthritis. 2023. Available from: https://www.who.int/news-room/fact-sheets/detail/osteoarthritis. Accessed Sept 19, 2025.WHO. Osteoarthritis. 2023. Available from: https://www.who.int/news-room/fact-sheets/detail/osteoarthritis. Accessed Sept 19, 2025.WHO. Menopause. 2022. Available from: https://www.who.int/news-room/fact-sheets/detail/menopause. Accessed Sept 19, 2025.WHO. Menopause. 2022. Available from: https://www.who.int/news-room/fact-sheets/detail/menopause. Accessed Sept 19, 2025.Primorac D, Molnar V, Matišić V, et al. Comprehensive Review of Knee Osteoarthritis Pharmacological Treatment and the Latest Professional Societies' Guidelines. Pharmaceuticals (Basel). 2021;14(3):205. doi: 10.3390/ph14030205.Primorac D, Molnar V, Matišić V, et al. Comprehensive Review of Knee Osteoarthritis Pharmacological Treatment and the Latest Professional Societies' Guidelines. Pharmaceuticals (Basel). 2021;14(3):205. doi: 10.3390/ph14030205.Hsu H, Siwiec RM. Knee Osteoarthritis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publ.; 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507884/. Accessed Sept 19, 2025.Hsu H, Siwiec RM. Knee Osteoarthritis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publ.; 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507884/. Accessed Sept 19, 2025.Arellano RD, Aguilar LS, Argüello R, et al. Cartilage Oligomeric Matrix Protein Levels in Synovial Fluid in Patients With Primary Knee Osteoarthritis And Healthy Controls: A Preliminary Comparative Analysis With Serum Cartilage Oligomeric Matrix Protein. Arch Rheumatol. 2017;32(3):189-196. doi: 10.5606/ArchRheumatol.2017.6220.Arellano RD, Aguilar LS, Argüello R, et al. Cartilage Oligomeric Matrix Protein Levels in Synovial Fluid in Patients With Primary Knee Osteoarthritis And Healthy Controls: A Preliminary Comparative Analysis With Serum Cartilage Oligomeric Matrix Protein. Arch Rheumatol. 2017;32(3):189-196. doi: 10.5606/ArchRheumatol.2017.6220.Boureau F, Schneid H, Zeghari N, et al. The IPSO study: ibuprofen, paracetamol study in osteoarthritis. A randomised comparative clinical study comparing the efficacy and safety of ibuprofen and paracetamol analgesic treatment of osteoarthritis of the knee or hip. Ann Rheum Dis. 2004;63(9):1028-1034. doi: 10.1136/ard.2003.011403.Boureau F, Schneid H, Zeghari N, et al. The IPSO study: ibuprofen, paracetamol study in osteoarthritis. A randomised comparative clinical study comparing the efficacy and safety of ibuprofen and paracetamol analgesic treatment of osteoarthritis of the knee or hip. Ann Rheum Dis. 2004;63(9):1028-1034. doi: 10.1136/ard.2003.011403.Kermawan P, Karna MB, Jawi IM, et al. Potential use of glucosamine, chondroitine, chitosan and phytoestrogen for patients with osteoarthritis. Int J Res Med Sci. 2022;10(10):2316-2319. doi: 10.18203/2320-6012.ijrms20222543.Kermawan P, Karna MB, Jawi IM, et al. Potential use of glucosamine, chondroitine, chitosan and phytoestrogen for patients with osteoarthritis. Int J Res Med Sci. 2022;10(10):2316-2319. doi: 10.18203/2320-6012.ijrms20222543.Bannwarth B, Péhourcq F. Pharmacologic basis for using paracetamol: pharmacokinetic and pharmacodynamic issues. Drugs. 2003;63 Spec No 2:5-13. (In French)Bannwarth B, Péhourcq F. Pharmacologic basis for using paracetamol: pharmacokinetic and pharmacodynamic issues. Drugs. 2003;63 Spec No 2:5-13. (In French)Kirkham SG, Samarasinghe RK. Review article: Glucosamine. J Orthop Surg (Hong Kong). 2009;17(1):72-76. doi: 10.1177/230949900901700116.Kirkham SG, Samarasinghe RK. Review article: Glucosamine. J Orthop Surg (Hong Kong). 2009;17(1):72-76. doi: 10.1177/230949900901700116.Oprenyeszk F, Chausson M, Maquet V, et al. Protective effect of a new biomaterial against the development of experimental osteoarthritis lesions in rabbit: a pilot study evaluating the intra-articular injection of alginate-chitosan beads dispersed in an hydrogel. Osteoarthritis Cartilage. 2013;21(8):1099-1107. doi: 10.1016/j.joca.2013.04.017.Oprenyeszk F, Chausson M, Maquet V, et al. Protective effect of a new biomaterial against the development of experimental osteoarthritis lesions in rabbit: a pilot study evaluating the intra-articular injection of alginate-chitosan beads dispersed in an hydrogel. Osteoarthritis Cartilage. 2013;21(8):1099-1107. doi: 10.1016/j.joca.2013.04.017.Charan J, Biswas T. How to calculate sample size for different study designs in medical research? Indian J Psychol Med. 2013;35(2):121-126. doi: 10.4103/0253-7176.116232.Charan J, Biswas T. How to calculate sample size for different study designs in medical research? Indian J Psychol Med. 2013;35(2):121-126. doi: 10.4103/0253-7176.116232.Lubis AMT, Siagian C, WonggokusumaE, etal. Comparison of Glucosamine-Chondroitin Sulfatewith and without Methylsulfonylmethane in Grade I-II Knee Osteoarthritis: A Double Blind Randomized Controlled Trial. Acta Med Indones. 2017;49(2):105-111.Lubis AMT, Siagian C, WonggokusumaE, etal. Comparison of Glucosamine-Chondroitin Sulfatewith and without Methylsulfonylmethane in Grade I-II Knee Osteoarthritis: A Double Blind Randomized Controlled Trial. Acta Med Indones. 2017;49(2):105-111.Kantor ED, Lampe JW, Navarro SL, et al. Associations between glucosamine and chondroitin supplement use and biomarkers of systemic inflammation. J Altern Complement Med. 2014;20(6):479-485. doi: 10.1089/acm.2013.0323.Kantor ED, Lampe JW, Navarro SL, et al. Associations between glucosamine and chondroitin supplement use and biomarkers of systemic inflammation. J Altern Complement Med. 2014;20(6):479-485. doi: 10.1089/acm.2013.0323.Lecomte S, Demay F, Ferrière F, Pakdel F. Phytochemicals Targeting Estrogen Receptors: Beneficial Rather Than Adverse Effects? Int J Mol Sci. 2017;18(7):1381. doi: 10.3390/ijms18071381.Lecomte S, Demay F, Ferrière F, Pakdel F. Phytochemicals Targeting Estrogen Receptors: Beneficial Rather Than Adverse Effects? Int J Mol Sci. 2017;18(7):1381. doi: 10.3390/ijms18071381.Tu J, Xu Y, Xu J, Ling Y, Cai Y. Chitosan nanoparticles reduce LPS-induced inflammatory reaction via inhibition of NF-B pathway in Caco-2 cells. Int J Biol Macromol. 2016;86:848-856. doi: 10.1016/j.ijbiomac.2016.02.015.Tu J, Xu Y, Xu J, Ling Y, Cai Y. Chitosan nanoparticles reduce LPS-induced inflammatory reaction via inhibition of NF-B pathway in Caco-2 cells. Int J Biol Macromol. 2016;86:848-856. doi: 10.1016/j.ijbiomac.2016.02.015.Chavda VP, Chaudhari AZ, Balar PC, et al. Phytoestrogens: Chemistry, potential health benefits, and their medicinal importance. Phytother Res. 2024;38(6):3060-3079. doi: 10.1002/ptr.8196.Chavda VP, Chaudhari AZ, Balar PC, et al. Phytoestrogens: Chemistry, potential health benefits, and their medicinal importance. Phytother Res. 2024;38(6):3060-3079. doi: 10.1002/ptr.8196.Christiansen BA, Bhatti S, Goudarzi R, Emami S. Management of Osteoarthritis with Avocado/Soybean Unsaponifiables. Cartilage. 2015;6(1):30-44. doi: 10.1177/1947603514554992.Christiansen BA, Bhatti S, Goudarzi R, Emami S. Management of Osteoarthritis with Avocado/Soybean Unsaponifiables. Cartilage. 2015;6(1):30-44. doi: 10.1177/1947603514554992.Dresler S, Wójciak-Kosior M, Sowa I, et al. Effect of Long-Term Strontium Exposure on the Content of Phytoestrogens and Allantoin in Soybean. Int J Mol Sci. 2018;19(12):3864. doi: 10.3390/ijms19123864.Dresler S, Wójciak-Kosior M, Sowa I, et al. Effect of Long-Term Strontium Exposure on the Content of Phytoestrogens and Allantoin in Soybean. Int J Mol Sci. 2018;19(12):3864. doi: 10.3390/ijms19123864.Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol. 2008;180(9):5771-5777. doi: 10.4049/jimmunol.180.9.5771.Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol. 2008;180(9):5771-5777. doi: 10.4049/jimmunol.180.9.5771.Zhang GX, Yu S, Gran B, Rostami A. Glucosamine abrogates the acute phase of experimental autoimmune encephalomyelitis by induction of Th2 response. J Immunol. 2005;175(11):7202-7208. doi: 10.4049/jimmunol.175.11.7202.Zhang GX, Yu S, Gran B, Rostami A. Glucosamine abrogates the acute phase of experimental autoimmune encephalomyelitis by induction of Th2 response. J Immunol. 2005;175(11):7202-7208. doi: 10.4049/jimmunol.175.11.7202.Kong Y, Zhang Y, Zhao X, et al. Carboxymethyl-chitosan attenuates inducible nitric oxide synthase and promotes interleukin-10 production in rat chondrocytes. Exp Ther Med. 2017;14(6):5641-5646. doi: 10.3892/etm.2017.5258.Kong Y, Zhang Y, Zhao X, et al. Carboxymethyl-chitosan attenuates inducible nitric oxide synthase and promotes interleukin-10 production in rat chondrocytes. Exp Ther Med. 2017;14(6):5641-5646. doi: 10.3892/etm.2017.5258.Minshawi F, Lanvermann S, McKenzie E, et al. The Generation of an Engineered Interleukin-10 Protein With Improved Stability and Biological Function. Front Immunol. 2020;11:1794. doi: 10.3389/fimmu.2020.01794.Minshawi F, Lanvermann S, McKenzie E, et al. The Generation of an Engineered Interleukin-10 Protein With Improved Stability and Biological Function. Front Immunol. 2020;11:1794. doi: 10.3389/fimmu.2020.01794.Bhadricha H, Patel V, Singh AK, et al. Increased frequency of Th17 cells and IL-17 levels are associated with low bone mineral density in postmenopausal women. Sci Rep. 2021;11(1):16155. doi: 10.1038/s41598-021-95640-0.Bhadricha H, Patel V, Singh AK, et al. Increased frequency of Th17 cells and IL-17 levels are associated with low bone mineral density in postmenopausal women. Sci Rep. 2021;11(1):16155. doi: 10.1038/s41598-021-95640-0.Singh B, Kumari S, Kureel AK, et al. In-vitro evidence indicating that IL-10 causes aging-related hypoalbuminemia via JAK1/STAT3 and CEBP-β. Exp Cell Res. 2024;443(1):114327. doi: 10.1016/j.yexcr.2024.114327.Singh B, Kumari S, Kureel AK, et al. In-vitro evidence indicating that IL-10 causes aging-related hypoalbuminemia via JAK1/STAT3 and CEBP-β. Exp Cell Res. 2024;443(1):114327. doi: 10.1016/j.yexcr.2024.114327.Suyasa IK, Kawiyana IK, Bakta IM, Widiana IG. Interleukin-6 and ratio of plasma interleukin-6/interleukin-10 as risk factors of symptomatic lumbar osteoarthritis. World J Orthop. 2017;8(2):149-155. doi: 10.5312/wjo.v8.i2.149.Suyasa IK, Kawiyana IK, Bakta IM, Widiana IG. Interleukin-6 and ratio of plasma interleukin-6/interleukin-10 as risk factors of symptomatic lumbar osteoarthritis. World J Orthop. 2017;8(2):149-155. doi: 10.5312/wjo.v8.i2.149.Hadeel A. Hameed, Hassan AF. The Prophylactic Anti-Inflammatory Effect of Omega-7 Against Paracetamol-Induced Liver Injury in Rats. Iraqi J Vet Med. 2022;46(2):43-47. doi: 0000-0001-8089-4726.Hadeel A. Hameed, Hassan AF. The Prophylactic Anti-Inflammatory Effect of Omega-7 Against Paracetamol-Induced Liver Injury in Rats. Iraqi J Vet Med. 2022;46(2):43-47. doi: 0000-0001-8089-4726.Tseng S, Reddi AH, Di Cesare PE. Cartilage Oligomeric Matrix Protein (COMP): A Biomarker of Arthritis. Biomark Insights. 2009;4:33-44. doi: 10.4137/bmi.s645.Tseng S, Reddi AH, Di Cesare PE. Cartilage Oligomeric Matrix Protein (COMP): A Biomarker of Arthritis. Biomark Insights. 2009;4:33-44. doi: 10.4137/bmi.s645.Fan X, Chen G, Wang S, et al. Applications of Chitosan and its Derivatives in the Treatment of Osteoarthritis. Aging Dis. 2024. doi: 10.14336/AD.2024.1080.Fan X, Chen G, Wang S, et al. Applications of Chitosan and its Derivatives in the Treatment of Osteoarthritis. Aging Dis. 2024. doi: 10.14336/AD.2024.1080.Ge Y, Zhou S, Li Y, et al. Estrogen prevents articular cartilage destruction in a mouse model of AMPK deficiency via ERK-mTOR pathway. Ann Transl Med. 2019;7(14):336. doi: 10.21037/atm.2019.06.77.Ge Y, Zhou S, Li Y, et al. Estrogen prevents articular cartilage destruction in a mouse model of AMPK deficiency via ERK-mTOR pathway. Ann Transl Med. 2019;7(14):336. doi: 10.21037/atm.2019.06.77.Roman-Blas JA, Castañeda S, Largo R, Herrero-Beaumont G. Osteoarthritis associated with estrogen deficiency. Arthritis Res Ther. 2009;11(5):241. doi: 10.1186/ar2791.Roman-Blas JA, Castañeda S, Largo R, Herrero-Beaumont G. Osteoarthritis associated with estrogen deficiency. Arthritis Res Ther. 2009;11(5):241. doi: 10.1186/ar2791.Nguyen C, Coudeyre E, Boutron I, et al. Oral resveratrol in adults with knee osteoarthritis: A randomized placebo-controlled trial (ARTHROL). PLoS Med. 2024;21(8):e1004440. doi: 10.1371/journal.pmed.1004440.Nguyen C, Coudeyre E, Boutron I, et al. Oral resveratrol in adults with knee osteoarthritis: A randomized placebo-controlled trial (ARTHROL). PLoS Med. 2024;21(8):e1004440. doi: 10.1371/journal.pmed.1004440.Vo NX, Le NNH, Chu TDP, et al. Effectiveness and Safety of Glucosamine in Osteoarthritis: A Systematic Review. Pharmacy (Basel). 2023;11(4):117. doi: 10.3390/pharmacy11040117Vo NX, Le NNH, Chu TDP, et al. Effectiveness and Safety of Glucosamine in Osteoarthritis: A Systematic Review. Pharmacy (Basel). 2023;11(4):117. doi: 10.3390/pharmacy11040117Honvo G, Bruyère O, Geerinck A, et al. Efficacy of Chondroitin Sulfate in Patients with Knee Osteoarthritis: A Comprehensive Meta-Analysis Exploring Inconsistencies in Randomized, Placebo-Controlled Trials. Adv Ther. 2019;36(5):1085-1099. doi: 10.1007/s12325019-00921-w.Honvo G, Bruyère O, Geerinck A, et al. Efficacy of Chondroitin Sulfate in Patients with Knee Osteoarthritis: A Comprehensive Meta-Analysis Exploring Inconsistencies in Randomized, Placebo-Controlled Trials. Adv Ther. 2019;36(5):1085-1099. doi: 10.1007/s12325019-00921-w.Manocchio N, Pirri C, Ljoka C, et al. Long-Term Efficacy of Carboxymethyl-Chitosan in Advanced Knee Osteoarthritis: A Twelve-Month Follow-Up Study on Non-Responders to Hyaluronic Acid. Biomedicines. 2025;13(2):270. doi: 10.3390/biomedicines13020270.Manocchio N, Pirri C, Ljoka C, et al. Long-Term Efficacy of Carboxymethyl-Chitosan in Advanced Knee Osteoarthritis: A Twelve-Month Follow-Up Study on Non-Responders to Hyaluronic Acid. Biomedicines. 2025;13(2):270. doi: 10.3390/biomedicines13020270.Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139(2):267-284. doi: 10.1016/j.cell.2009.09.028.Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139(2):267-284. doi: 10.1016/j.cell.2009.09.028.Clegg Daniel O., Reda Domenic J., Harris Crystal L., et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354(8):795-808. doi: 10.1056/NEJMoa052771.Clegg Daniel O., Reda Domenic J., Harris Crystal L., et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354(8):795-808. doi: 10.1056/NEJMoa052771.Emans PJ, Skaliczki G, Haverkamp D, et al. First-in-human Study to Evaluate a Single Injection of KiOmedine®CM-Chitosan for Treating Symptomatic Knee Osteoarthritis. Open Rheumatol J. 2022;16. doi: 10.2174/18743129-v16-e2206100.Emans PJ, Skaliczki G, Haverkamp D, et al. First-in-human Study to Evaluate a Single Injection of KiOmedine®CM-Chitosan for Treating Symptomatic Knee Osteoarthritis. Open Rheumatol J. 2022;16. doi: 10.2174/18743129-v16-e2206100.Marouf BH, Hussain SA, Ali ZS, Ahmmad RS. Clinical efficacy of resveratrol as an adjuvant with meloxican in the treatment of knee osteoarthritis patients: A double-blind, randomised, placebo-controlled trial. Braz J Pharm Sci. 2018;54(4):e17773. doi: 10.1590/s2175-97902018000417773.Marouf BH, Hussain SA, Ali ZS, Ahmmad RS. Clinical efficacy of resveratrol as an adjuvant with meloxican in the treatment of knee osteoarthritis patients: A double-blind, randomised, placebo-controlled trial. Braz J Pharm Sci. 2018;54(4):e17773. doi: 10.1590/s2175-97902018000417773.Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis. 2004;63(8):901-907. doi:10.1136/ard.2003.018531.Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis. 2004;63(8):901-907. doi:10.1136/ard.2003.018531.

The authors declare that there are no conflicts of interest present.