REVISITING HYALURONIC ACID THERAPY IN ORTHOPEDICS: BETWEEN SCIENCE AND SKEPTICISM
Abstract
Introduction: Hyaluronic acid (HA) is a long, unbranched polysaccharide classified as a glycosaminoglycan. Since its isolation from the vitreous body of an ox in 1934 by Karl Meyer and John Palmer, HA has attracted considerable interest across medical disciplines. Naturally occurring HA possesses several favorable properties, including high water-binding capacity, biocompatibility, viscoelasticity, free radical scavenging, and unique rheological characteristics. It also exhibits anti-inflammatory, antiangiogenic, and immunosuppressive effects, contributing to its increasing popularity—especially in orthopedics. HA is present in high concentrations within synovial fluid, joint capsules, and cartilage, making it highly relevant in conditions involving joint degeneration or injury. Accordingly, HA-based therapies have found widespread application in treating osteoarthritis, rheumatoid arthritis, tendinopathies, and other soft tissue disorders.
Aim: The aim of this work is to evaluate the clinical relevance, efficacy, and safety of hyaluronic acid (HA) in the treatment of orthopedic conditions, particularly osteoarthritis, tendinopathies, and other soft tissue injuries. The objective is to clarify HA's therapeutic value, especially via intra-articular injection, amid ongoing debate regarding its clinical effectiveness compared to placebo and standard non-surgical treatments.
Materials and Methods: This review is based on an analysis of numerous studies, particularly randomized controlled trials (RCTs), that assessed the efficacy of HA in orthopedic applications. Emphasis was placed on comparing HA treatment outcomes—most notably intra-articular injections—with those of placebo and conventional non-operative therapies. Literature was reviewed from relevant medical databases and peer-reviewed sources.
Results: Evidence from multiple studies suggests that intra-articular HA injections can lead to improvements in pain and joint function compared to baseline or non-surgical treatments. However, many randomized controlled trials have shown no statistically significant advantage of HA over placebo. Despite this, patient-reported outcomes often indicate symptom relief and improved function following HA administration.
Conclusion: Due to conflicting data regarding its clinical utility, the use of HA in orthopedics remains a topic of ongoing debate. Nonetheless, HA's favorable safety profile and biological properties support its consideration in selected orthopedic cases. When used appropriately, HA injections may offer a viable non-surgical option for managing joint and soft tissue disorders.
References
Fallacara, A., Baldini, E., Manfredini, S., & Vertuani, S. (2018). Hyaluronic acid in the third millennium. Polymers, 10(7), 701. https://doi.org/10.3390/polym10070701
Boeriu, C. G., Springer, J., Kooy, F. K., van den Broek, L. A. M., & Eggink, G. (2013). Production methods for hyaluronan. International Journal of Carbohydrate Chemistry, 2013, 624967. https://doi.org/10.1155/2013/624967
Meyer, K., & Palmer, J. W. (1934). The polysaccharide of the vitreous humor. Journal of Biological Chemistry, 107(3), 629–634. https://doi.org/10.1016/s0021-9258(18)75338-6
Woo, J. E., Seong, H. J., Lee, S. Y., & Jang, Y. S. (2019). Metabolic engineering of Escherichia coli for the production of hyaluronic acid from glucose and galactose. Frontiers in Bioengineering and Biotechnology, 7, 351. https://doi.org/10.3389/fbioe.2019.00351
de Oliveira, J. D., Carvalho, L. S., Gomes, A. M. V., Queiroz, L. R., Magalhães, B. S., & Parachin, N. S. (2016). Genetic basis for hyper production of hyaluronic acid in natural and engineered microorganisms. Microbial Cell Factories, 15(1), 119. https://doi.org/10.1186/s12934-016-0517-4
Sugahara, K., Schwartz, N. B., & Dorfman, A. (1979). Biosynthesis of hyaluronic ac-id by Streptococcus. Journal of Biological Chemistry, 254(14), 6252–6261. https://doi.org/10.1016/s0021-9258(18)50356-2
Narayanan, R., & Kuppermann, B. D. (2009). Hyaluronidase for pharmacologic vitre-olysis. Developments in Ophthalmology, 44, 20–25. https://doi.org/10.1159/000223941
Itano, N., Sawai, T., Yoshida, M., et al. (1999). Three isoforms of mammalian hyalu-ronan synthases have distinct enzymatic properties. Journal of Biological Chemistry, 274(35), 25085–25092. https://doi.org/10.1074/jbc.274.35.25085
Cyphert, J. M., Trempus, C. S., & Garantziotis, S. (2015). Size matters: Molecular weight specificity of hyaluronan effects in cell biology. International Journal of Cell Biology, 2015, 563818. https://doi.org/10.1155/2015/563818
Khunmanee, S., Jeong, Y., & Park, H. (2017). Crosslinking method of hyaluronic-based hydrogel for biomedical applications. Journal of Tissue Engineering, 8, 204173141772646. https://doi.org/10.1177/2041731417726464
Slevin, M., Krupinski, J., Gaffney, J., et al. (2007). Hyaluronan-mediated angiogenesis in vascular disease: Uncovering RHAMM and CD44 receptor signaling pathways. Matrix Biology, 26(1), 58–68. https://doi.org/10.1016/j.matbio.2006.08.261
Gupta, R. C., Lall, R., Srivastava, A., & Sinha, A. (2019). Hyaluronic acid: Molecular mechanisms and therapeutic trajectory. Frontiers in Veterinary Science, 6, 192. https://doi.org/10.3389/fvets.2019.00192
Khan, M., Shanmugaraj, A., Prada, C., Patel, A., Babins, E., & Bhandari, M. (2022). The role of hyaluronic acid for soft tissue indications: A systematic review and meta-analysis. Sports Health, 15(1), 3–10. https://doi.org/10.1177/19417381211073316
Ferkel, E., Manjoo, A., Martins, D., Bhandari, M., Sethi, P. M., & Nicholls, M. (2023). Intra-articular hyaluronic acid treatments for knee osteoarthritis: A systematic review of product properties. Cartilage, 14(4). https://doi.org/10.1177/19476035231154530
Pereira, T. V., Jüni, P., Saadat, P., et al. (2022). Viscosupplementation for knee osteoar-thritis: Systematic review and meta-analysis. BMJ, 378, e069722. https://doi.org/10.1136/bmj-2022-069722
Brun, P., Panfilo, S., Daga Gordini, D., Cortivo, R., & Abatangelo, G. (2003). The ef-fect of hyaluronan on CD44-mediated survival of normal and hydroxyl radical-damaged chondrocytes. Osteoarthritis and Cartilage, 11(3), 208–216. https://doi.org/10.1016/s1063-4584(02)00352-7
Abatangelo, G., Vindigni, V., Avruscio, G., Pandis, L., & Brun, P. (2020). Hyaluronic acid: Redefining its role. Cells, 9(7), 1743. https://doi.org/10.3390/cells9071743
Forsey, R., Fisher, J., Thompson, J., Stone, M., Bell, C., & Ingham, E. (2006). The ef-fect of hyaluronic acid and phospholipid-based lubricants on friction within a human cartilage damage model. Biomaterials, 27(26), 4581–4590. https://doi.org/10.1016/j.biomaterials.2006.04.018
Balazs, E. A. (2004). Viscosupplementation for treatment of osteoarthritis: From ini-tial discovery to current status and results. Surgical Technology International, 12, 278–289. https://pubmed.ncbi.nlm.nih.gov/15455338/
Glyn-Jones, S., Palmer, A. J. R., Agricola, R., et al. (2015). Osteoarthritis. The Lancet, 386(9991), 376–387. https://doi.org/10.1016/s0140-6736(14)60802-3
Julovi, S. M., Yasuda, T., Shimizu, M., Hiramitsu, T., & Nakamura, T. (2004). Inhibi-tion of interleukin-1β-stimulated production of matrix metalloproteinases by hyalu-ronan via CD44 in human articular cartilage. Arthritis & Rheumatism, 50(2), 516–525. https://doi.org/10.1002/art.20004
Karna, E., Miltyk, W., Surażyński, A., & Pałka, J. A. (2007). Protective effect of hya-luronic acid on interleukin-1-induced deregulation of β1-integrin and insulin-like growth factor-I receptor signaling and collagen biosynthesis in cultured human chon-drocytes. Molecular and Cellular Biochemistry, 308(1–2), 57–64. https://doi.org/10.1007/s11010-007-9612-5
Altman, R. D., Manjoo, A., Fierlinger, A., Niazi, F., & Nicholls, M. (2015). The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: A sys-tematic review. BMC Musculoskeletal Disorders, 16, 321. https://doi.org/10.1186/s12891-015-0775-z
Peng, H., Zhou, J., Liu, S., Hu, Q., Ming, J., & Qiu, B. (2010). Hyaluronic acid inhib-its nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes in vitro. Inflammation Research, 59(7), 519–530. https://doi.org/10.1007/s00011-010-0156-x
Yasui, T., Akatsuka, M., Tobetto, K., Hayaishi, M., & Ando, T. (1992). The effect of hyaluronan on interleukin-1α-induced prostaglandin E2 production in human osteoar-thritic synovial cells. Agents and Actions, 37(1–2), 155–156. https://doi.org/10.1007/bf01987905
Li, J., Gorski, D. J., Anemaet, W., et al. (2012). Hyaluronan injection in murine osteo-arthritis prevents TGFβ1-induced synovial neovascularization and fibrosis and main-tains articular cartilage integrity by a CD44-dependent mechanism. Arthritis Research & Therapy, 14(3), R151. https://doi.org/10.1186/ar3887
Balogh, L., Polyak, A., Mathe, D., et al. (2008). Absorption, uptake and tissue affinity of high-molecular-weight hyaluronan after oral administration in rats and dogs. Jour-nal of Agricultural and Food Chemistry, 56(22), 10582–10593. https://doi.org/10.1021/jf8017029
Tashiro, T., Seino, S., Sato, T., Matsuoka, R., Masuda, Y., & Fukui, N. (2012). Oral administration of polymer hyaluronic acid alleviates symptoms of knee osteoarthritis: A double-blind, placebo-controlled study over a 12-month period. TheScientific-WorldJournal, 2012, 167928. https://doi.org/10.1100/2012/167928
Ricci, M., Micheloni, G. M., Berti, M., et al. (2016). Clinical comparison of oral ad-ministration and viscosupplementation of hyaluronic acid (HA) in early knee osteoar-thritis. Musculoskeletal Surgery, 101(1), 45–49. https://doi.org/10.1007/s12306-016-0428-x
Bijlsma, J. W., Berenbaum, F., & Lafeber, F. P. (2011). Osteoarthritis: An update with relevance for clinical practice. The Lancet, 377(9783), 2115–2126. https://doi.org/10.1016/s0140-6736(11)60243-2
Berenbaum, F. (2013). Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis and Cartilage, 21(1), 16–21. https://doi.org/10.1016/j.joca.2012.11.012
Man, G., & Mologhianu, G. (2014). Osteoarthritis pathogenesis – A complex process that involves the entire joint. Journal of Medicine and Life, 7(1), 37–41. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956093/
Colen, S., Haverkamp, D., Mulier, M., & Mulier, P. J. (2012). Hyaluronic acid for the treatment of osteoarthritis in all joints except the knee. BioDrugs, 26(2), 101–112. https://doi.org/10.2165/11630830-000000000-00000
De Lucia, O., Murgo, A., Pregnolato, F., et al. (2020). Hyaluronic acid injections in the treatment of osteoarthritis secondary to primary inflammatory rheumatic diseases: A systematic review and qualitative synthesis. Advances in Therapy, 37(4), 1347–1359. https://doi.org/10.1007/s12325-020-01256-7
Belk, J. W., Houck, D. A., Littlefield, C. P., et al. (2021). Platelet-rich plasma versus hyaluronic acid for hip osteoarthritis yields similarly beneficial short-term clinical outcomes: A systematic review and meta-analysis of level I and II randomized con-trolled trials. Arthroscopy, 38(6). https://doi.org/10.1016/j.arthro.2021.11.005
Familiari, F., Ammendolia, A., Rupp, M. C., et al. (2023). Efficacy of intra-articular injections of hyaluronic acid in patients with glenohumeral joint osteoarthritis: A sys-tematic review and meta-analysis. Journal of Orthopaedic Research, 41(11), 2345–2358. https://doi.org/10.1002/jor.25648
Bannuru, R. R., Osani, M. C., Vaysbrot, E. E., et al. (2019). OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis and Cartilage, 27(11), 1578–1589. https://doi.org/10.1016/j.joca.2019.06.011
Conrozier, T., Diraçoglù, D., Monfort, J., et al. (2022). EUROVISCO good practice recommendations for a first viscosupplementation in patients with knee osteoarthritis. Cartilage, 14(2), 125–135. https://doi.org/10.1177/19476035221138958
Millar, N. L., Silbernagel, K. G., Thorborg, K., et al. (2021). Tendinopathy. Nature Reviews Disease Primers, 7(1), 1. https://doi.org/10.1038/s41572-020-00234-1
Oliva, F., Marsilio, E., Asparago, G., Frizziero, A., Berardi, A. C., & Maffulli, N. (2021). The impact of hyaluronic acid on tendon physiology and its clinical applica-tion in tendinopathies. Cells, 10(11), 3081. https://doi.org/10.3390/cells10113081
Conrozier, T., Diraçoglù, D., Monfort, J., et al. (2022). EUROVISCO good practice recommendations for a first viscosupplementation in patients with knee osteoarthritis. Cartilage, 14(2), 125–135. https://doi.org/10.1177/19476035221138958
American Academy of Orthopaedic Surgeons (AAOS). (2021). Management of osteo-arthritis of the knee (non-arthroplasty): Evidence-based clinical practice guideline. https://www.aaos.org/oak3cpg
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