Pain Phenotype in Knee Osteoarthritis: Implications for Mechanism-Based Therapy

Abstract

Pain is the main symptom of knee osteoarthritis (KOA) and the main cause for patients to seek medical treatment. Despite the development of various therapies to address pain, its efficacy often remains uncertain. According to the new classification of the International Association for the Study of Pain, pain is classified as nociceptive pain, neuropathic pain and nociplastic pain. This review sought to outline potential mechanisms and clinical manifestations within this new classification framework and provided tailored treatment recommendations for each type of pain. Moreover, we further divided nociceptive pain into three subgroups including Inflammatory Pain, Mechanical Pain, and BMLs-related Pain. We suggest: (1) For inflammatory pain, the use of anti-inflammatory medications such as NSAIDs and corticosteroids is recommended. (2) For mechanical pain, weight loss, adjustments to mechanical alignment of the lower limb, and rehabilitation training may significantly alleviate symptoms. (3) For BMLs-related pain, patients might benefit from treatment, such as reducing weight-bearing and implementing antiosteoporosis drugs. (4) For neuropathic pain, management may involve tricyclic antidepressants or anticonvulsants. (5) For nociplastic pain, we give priority to nonpharmacological therapies, with an emphasis on the biopsychosocial model, and encourage patients to adopt positive lifestyle changes, including physical activity, weight management, sleep hygiene, and self-management, as well as involvement in psychotherapy and intervention. In clinical practice, it is essential to recognize that many patients may present with a combination of these pain types. Thus, it becomes imperative to identify the primary pain type and craft precise and individual treatment strategies tailored to their specific needs.

Keywords

knee osteoarthritis / neuropathic pain / nociceptive pain / nociplastic pain / pain management

References

[1] GBD 2021 Gout Collaborators, “Global, Regional, and National Burden of Gout, 1990–2020, and Projections to 2050: A Systematic Analysis of the Global Burden of Disease Study 2021,” Lancet the Rheumatologist 6, no. 8 (2024): e507–e517.

[2] R. H. Brophy and Y. A. Fillingham, “AAOS Clinical Practice Guideline Summary: Management of Osteoarthritis of the Knee (Nonarthroplasty), Third Edition,” Journal of the American Academy of Orthopaedic Surgeons 30, no. 9 (2022): e721–e729.

[3] Y. Zhang and J. M. Jordan, “Epidemiology of Osteoarthritis,” Clinics in Geriatric Medicine 26, no. 3 (2010): 355–369.

[4] Q. Liu, S. Wang, J. Lin, and Y. Zhang, “The Burden for Knee Osteoarthritis Among Chinese Elderly: Estimates From a Nationally Representative Study,” Osteoarthritis and Cartilage 26, no. 12 (2018): 1636–1642.

[5] R. J. Cleveland, C. Alvarez, T. A. Schwartz, et al., “The Impact of Painful Knee Osteoarthritis on Mortality: A Community-Based Cohort Study With Over 24 Years of Follow-Up,” Osteoarthritis and Cartilage 27, no. 4 (2019): 593–602.

[6] J. Katz, K. Arant, and R. Loeser, “Diagnosis and Treatment of Hip and Knee Osteoarthritis: A Review,” Journal of the American Medical Association 325, no. 6 (2021): 568–578.

[7] P. H. Finan, L. F. Buenaver, S. C. Bounds, et al., “Discordance Between Pain and Radiographic Severity in Knee Osteoarthritis: Findings From Quantitative Sensory Testing of Central Sensitization,” Arthritis and Rheumatism 65, no. 2 (2013): 363–372.

[8] L. Li, Z. Li, Y. Li, X. Hu, Y. Zhang, and P. Fan, “Profiling of Inflammatory Mediators in the Synovial Fluid Related to Pain in Knee Osteoarthritis,” BMC Musculoskeletal Disorders 21, no. 1 (2020): 99.

[9] R. F. Loeser, S. R. Goldring, C. R. Scanzello, and M. B. Goldring, “Osteoarthritis: A Disease of the Joint as an Organ,” Arthritis and Rheumatism 64, no. 6 (2012): 1697–1707.

[10] E. Kosek, M. Cohen, R. Baron, et al., “Do We Need a Third Mechanistic Descriptor for Chronic Pain States?,” Pain 157, no. 7 (2016): 1382–1386.

[11] L. Gambari, A. Cellamare, F. Grassi, et al., “Overview of Anti-Inflammatory and Anti-Nociceptive Effects of Polyphenols to Halt Osteoarthritis: From Preclinical Studies to New Clinical Insights,” International Journal of Molecular Sciences 23, no. 24 (2022): 15861.

[12] S. Suri, S. E. Gill, S. Massena de Camin, D. Wilson, D. F. McWilliams, and D. A. Walsh, “Neurovascular Invasion at the Osteochondral Junction and in Osteophytes in Osteoarthritis,” Annals of the Rheumatic Diseases 66, no. 11 (2007): 1423–1428.

[13] T. A. Nees, N. Rosshirt, J. A. Zhang, et al., “Synovial Cytokines Significantly Correlate with Osteoarthritis-Related Knee Pain and Disability: Inflammatory Mediators of Potential Clinical Relevance,” Journal of Clinical Medicine 8, no. 9 (2019): 1343.

[14] S. N. Wijesinghe, C. Ditchfield, S. Flynn, et al., “Immunomodulation and Fibroblast Dynamics Driving Nociceptive Joint Pain Within Inflammatory Synovium: Unravelling Mechanisms for Therapeutic Advancements in Osteoarthritis,” Osteoarthritis and Cartilage 32 (2024): 1358–1370.

[15] D. E. Clapham, “TRP Channels as Cellular Sensors,” Nature 426, no. 6966 (2003): 517–524.

[16] Y. Takayama, S. Derouiche, K. Maruyama, and M. Tominaga, “Emerging Perspectives on Pain Management by Modulation of TRP Channels and ANO1,” International Journal of Molecular Sciences 20, no. 14 (2019): 3411.

[17] M. Kapoor, J. Martel-Pelletier, D. Lajeunesse, J.-P. Pelletier, and H. Fahmi, “Role of Proinflammatory Cytokines in the Pathophysiology of Osteoarthritis,” Nature Reviews Rheumatology 7, no. 1 (2011): 33–42.

[18] F. Berenbaum, “Osteoarthritis as an Inflammatory Disease (Osteoarthritis Is Not Osteoarthrosis!),” Osteoarthritis and Cartilage 21, no. 1 (2013): 16–21.

[19] J. Lieberthal, N. Sambamurthy, and C. R. Scanzello, “Inflammation in Joint Injury and Post-Traumatic Osteoarthritis,” Osteoarthritis and Cartilage 23, no. 11 (2015): 1825–1834.

[20] D. J. Hunter and S. Bierma-Zeinstra, “Osteoarthritis,” Osteoarthritis. Lancet 393, no. 10182 (2019): 1745–1759.

[21] R. Suresh and D. M. Mosser, “Pattern Recognition Receptors in Innate Immunity, Host Defense, and Immunopathology,” Advances in Physiology Education 37, no. 4 (2013): 284–291.

[22] M. Attur, S. Krasnokutsky, H. Zhou, et al., “The Combination of an Inflammatory Peripheral Blood Gene Expression and Imaging Biomarkers Enhance Prediction of Radiographic Progression in Knee Osteoarthritis,” Arthritis Research & Therapy 22, no. 1 (2020): 208.

[23] Z. Lv, Y. X. Yang, J. Li, et al., “Molecular Classification of Knee Osteoarthritis,” Frontiers in Cell and Development Biology 9 (2021): 725568.

[24] H. Zhang, D. Cai, and X. Bai, “Macrophages Regulate the Progression of Osteoarthritis,” Osteoarthritis and Cartilage 28, no. 5 (2020): 555–561.

[25] X. Y. Zhao, Z. B. Yang, Z. J. Zhang, et al., “CCL3 Serves as a Potential Plasma Biomarker in Knee Degeneration (Osteoarthritis),” Osteoarthritis and Cartilage 23, no. 8 (2015): 1405–1411.

[26] E. Barboza, J. Hudson, W.-P. Chang, et al., “Profibrotic Infrapatellar Fat Pad Remodeling Without M1 Macrophage Polarization Precedes Knee Osteoarthritis in Mice With Diet-Induced Obesity,” Arthritis & Rheumatology (Hoboken, NJ) 69, no. 6 (2017): 1221–1232.

[27] H. Zhang, C. Lin, C. Zeng, et al., “Synovial Macrophage M1 Polarisation Exacerbates Experimental Osteoarthritis Partially Through R-Spondin-2,” Annals of the Rheumatic Diseases 77, no. 10 (2018): 1524–1534.

[28] A. R. Sun, S. K. Panchal, T. Friis, et al., “Obesity-Associated Metabolic Syndrome Spontaneously Induces Infiltration of Pro-Inflammatory Macrophage in Synovium and Promotes Osteoarthritis,” PLoS One 12, no. 8 (2017): e0183693.

[29] N. Fahy, M. L. de Vries-van Melle, J. Lehmann, et al., “Human Osteoarthritic Synovium Impacts Chondrogenic Differentiation of Mesenchymal Stem Cells Via Macrophage Polarisation State,” Osteoarthritis and Cartilage 22, no. 8 (2014): 1167–1175.

[30] R. R. Bannuru, M. C. Osani, E. E. Vaysbrot, et al., “OARSI Guidelines for the Non-Surgical Management of Knee, Hip, and Polyarticular Osteoarthritis,” Osteoarthritis and Cartilage 27, no. 11 (2019): 1578–1589.

[31] M. Hall, S. Doherty, P. Courtney, K. Latief, W. Zhang, and M. Doherty, “Ultrasound Detected Synovial Change and Pain Response Following Intra-Articular Injection of Corticosteroid and a Placebo in Symptomatic Osteoarthritic Knees: A Pilot Study,” Annals of the Rheumatic Diseases 73, no. 8 (2014): 1590–1591.

[32] O. T. Cheng, D. Souzdalnitski, B. Vrooman, and J. Cheng, “Evidence-Based Knee Injections for the Management of Arthritis,” Pain Medicine 13, no. 6 (2012): 740–753.

[33] C. Scarpignato, A. Lanas, C. Blandizzi, W. F. Lems, M. Hermann, and R. H. Hunt, “Safe Prescribing of Non-Steroidal Anti-Inflammatory Drugs in Patients With Osteoarthritis—An Expert Consensus Addressing Benefits as Well as Gastrointestinal and Cardiovascular Risks,” BMC Medicine 13 (2015): 55.

[34] G. C. Machado, C. G. Maher, P. H. Ferreira, et al., “Efficacy and Safety of Paracetamol for Spinal Pain and Osteoarthritis: Systematic Review and Meta-Analysis of Randomised Placebo Controlled Trials,” BMJ 350 (2015): h1225.

[35] T. Rhen and J. A. Cidlowski, “Antiinflammatory Action of Glucocorticoids—New Mechanisms for Old Drugs,” New England Journal of Medicine 353, no. 16 (2005): 1711–1723.

[36] Osteoarthritis in Over 16 s: Diagnosis and Management (National Institute for Health and Care Excellence (NICE), 2022).

[37] D. N. Graf, A. Thallinger, V. Zubler, and R. Sutter, “Intraarticular Steroid Injection in Hip and Knee With Fluoroscopic Guidance: Reassessing Safety,” Radiology 304, no. 2 (2022): 363–369.

[38] A. Latourte, A.-C. Rat, A. Omorou, et al., “Do Glucocorticoid Injections Increase the Risk of Knee Osteoarthritis Progression Over 5 Years?,” Arthritis & Rheumatology (Hoboken, NJ) 74, no. 8 (2022): 1343–1351.

[39] S. Hawley, A. Prats-Uribe, G. S. Matharu, et al., “Effect of Intra-Articular Corticosteroid Injections for Osteoarthritis on the Subsequent Use of Pain Medications: A UK CPRD Cohort Study,” Rheumatology (Oxford, England) 64 (2025): 3832–3841.

[40] T. L. Vincent, “Mechanoflammation in Osteoarthritis Pathogenesis,” Seminars in Arthritis and Rheumatism 49, no. 3S (2019): S36–S38.

[41] A. Okun, P. Liu, P. Davis, et al., “Afferent Drive Elicits Ongoing Pain in a Model of Advanced Osteoarthritis,” Pain 153, no. 4 (2012): 924–933.

[42] B. H. He, M. Christin, S. Mouchbahani-Constance, A. Davidova, and R. Sharif-Naeini, “Mechanosensitive Ion Channels in Articular Nociceptors Drive Mechanical Allodynia in Osteoarthritis,” Osteoarthritis and Cartilage 25, no. 12 (2017): 2091–2099.

[43] K. Honda, M. Shinoda, M. Kondo, et al., “Sensitization of TRPV1 and TRPA1 via Peripheral mGluR5 Signaling Contributes to Thermal and Mechanical Hypersensitivity,” Pain 158, no. 9 (2017): 1754–1764.

[44] X. Luo, O. Chen, Z. Wang, et al., “IL-23/IL-17A/TRPV1 Axis Produces Mechanical Pain Via Macrophage-Sensory Neuron Crosstalk in Female Mice,” Neuron 109, no. 17 (2021): 2691–2706.e5.

[45] M. Ito, K. Ono, S. Hitomi, et al., “Prostanoid-Dependent Spontaneous Pain and PAR2-Dependent Mechanical Allodynia Following Oral Mucosal Trauma: Involvement of TRPV1, TRPA1 And TRPV4,” Molecular Pain 13 (2017): 1744806917704138.

[46] M. Zhang, Y. Wang, J. Geng, S. Zhou, and B. Xiao, “Mechanically Activated Piezo Channels Mediate Touch and Suppress Acute Mechanical Pain Response in Mice,” Cell Reports 26, no. 6 (2019): 1419–1431.e4.

[47] W. Lee, H. A. Leddy, Y. Chen, et al., “Synergy Between Piezo1 and Piezo2 Channels Confers High-Strain Mechanosensitivity to Articular Cartilage,” Proceedings of the National Academy of Sciences of the United States of America 111, no. 47 (2014): E5114–E5122.

[48] B. Coste, J. Mathur, M. Schmidt, et al., “Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels,” Science 330, no. 6000 (2010): 55–60.

[49] A. W. Visser, R. de Mutsert, S. le Cessie, M. den Heijer, F. R. Rosendaal, and M. Kloppenburg, “The Relative Contribution of Mechanical Stress and Systemic Processes in Different Types of Osteoarthritis: The NEO Study,” Annals of the Rheumatic Diseases 74, no. 10 (2015): 1842–1847.

[50] S. Panunzi, S. Maltese, A. De Gaetano, E. Capristo, S. R. Bornstein, and G. Mingrone, “Comparative Efficacy of Different Weight Loss Treatments on Knee Osteoarthritis: A Network Meta-Analysis,” Obesity Reviews 22, no. 8 (2021): e13230.

[51] S. P. Messier, A. E. Resnik, D. P. Beavers, et al., “Intentional Weight Loss in Overweight and Obese Patients With Knee Osteoarthritis: Is More Better?,” Arthritis Care & Research (Hoboken) 70, no. 11 (2018): 1569–1575.

[52] Z. Salis, B. Gallego, T. V. Nguyen, and A. Sainsbury, “Association of Decrease in Body Mass Index With Reduced Incidence and Progression of the Structural Defects of Knee Osteoarthritis: A Prospective Multi-Cohort Study,” Arthritis & Rheumatology (Hoboken, NJ) 75, no. 4 (2023): 533–543.

[53] D. J. McCormack, D. Puttock, and S. P. Godsiff, “Medial Compartment Osteoarthritis of the Knee: A Review of Surgical Options,” EFORT Open Review 6, no. 2 (2021): 113–117.

[54] O. S. Lee, S. H. Lee, S. J. Mok, and Y. S. Lee, “Comparison of the Regeneration of Cartilage and the Clinical Outcomes After the Open Wedge High Tibial Osteotomy With or Without Microfracture: A Retrospective Case Control Study,” BMC Musculoskeletal Disorders 20, no. 1 (2019): 267.

[55] B. Zhang, H. Qian, H. Wu, and X. Yang, “Unicompartmental Knee Arthroplasty Versus High Tibial Osteotomy for Medial Knee Osteoarthritis: A Systematic Review and Meta-Analysis,” Journal of Orthopaedic Surgery (Hong Kong) 31, no. 1 (2023): 10225536231162829.

[56] M. Stam, J. Verschueren, M. V. Van Outeren, et al., “Unloader Brace or High Tibial Osteotomy in the Treatment of the Young Patient With Medial Knee Osteoarthritis: A Randomized Controlled Trial,” Acta Orthopaedica 96 (2025): 102–109.

[57] H. Kobayashi, S. Saito, Y. Akamatsu, K. Kumagai, S. Nejima, and Y. Inaba, “The Relationship Between the “Fujisawa Point” and Anatomical Femorotibial Angle Following Simulated Open Wedge High Tibial Osteotomy,” BMC Musculoskeletal Disorders 23, no. 1 (2022): 776.

[58] I. Komnik, J. Funken, S. Zachow, R. Schmidt-Wiethoff, A. Ellermann, and W. Potthast, “Surgical Planning in HTO—Alternative Approaches to the Fujisawa Gold-Standard,” Technology and Health Care 33, no. 3 (2025): 1571–1583.

[59] R. W. K. Loke, B. W. L. Tan, E. Y. E. K. Tan, and J. H. P. Hui, “Total Knee Arthroplasty After Prior High Tibial Osteotomy Results in Comparable Survival and Clinical Outcomes but Significantly Higher Complication Rates Compared to Primary Total Knee Arthroplasty: A Systematic Review and Meta-Analysis of 550,000 Patients,” European Journal of Orthopaedic Surgery & Traumatology 35, no. 1 (2025): 119.

[60] F. Ter Heegde, A. P. Luiz, S. Santana-Varela, et al., “Noninvasive Mechanical Joint Loading as an Alternative Model for Osteoarthritic Pain,” Arthritis & Rheumatology (Hoboken, NJ) 71, no. 7 (2019): 1078–1088.

[61] K. T. M. Seah, J. Rammanohar, J. Sutton, To K, and W. S. Khan, “The Effectiveness of Anti-Nerve Growth Factor Monoclonal Antibodies in the Management of Pain in Osteoarthritis of the Hip and Knee: A PRISMA Systematic Review and Meta-Analysis,” Pain Medicine 22, no. 5 (2021): 1185–1204.

[62] S. Yang, Y. Huang, Z. Ye, L. Li, and Y. Zhang, “The Efficacy of Nerve Growth Factor Antibody for the Treatment of Osteoarthritis Pain and Chronic Low-Back Pain: A Meta-Analysis,” Frontiers in Pharmacology 11 (2020): 817.

[63] J. Chen, J. Li, R. Li, et al., “Efficacy and Safety of Tanezumab on Osteoarthritis Knee and Hip Pains: A Meta-Analysis of Randomized Controlled Trials,” Pain Medicine 18, no. 2 (2017): 374–385.

[64] A. E. Wluka, Y. Wang, M. Davies-Tuck, D. R. English, G. G. Giles, and F. M. Cicuttini, “Bone Marrow Lesions Predict Progression of Cartilage Defects and Loss of Cartilage Volume in Healthy Middle-Aged Adults Without Knee Pain Over 2 Yrs,” Rheumatology (Oxford, England) 47, no. 9 (2008): 1392–1396.

[65] D. A. Walsh, N. Sofat, A. Guermazi, and D. J. Hunter, “Osteoarthritis Bone Marrow Lesions,” Osteoarthritis and Cartilage 31, no. 1 (2023): 11–17.

[66] A. Kuttapitiya, L. Assi, K. Laing, et al., “Microarray Analysis of Bone Marrow Lesions in Osteoarthritis Demonstrates Upregulation of Genes Implicated in Osteochondral Turnover, Neurogenesis and Inflammation,” Annals of the Rheumatic Diseases 76, no. 10 (2017): 1764–1773.

[67] Y. Zhang, M. Nevitt, J. Niu, et al., “Fluctuation of Knee Pain and Changes in Bone Marrow Lesions, Effusions, and Synovitis on Magnetic Resonance Imaging,” Arthritis and Rheumatism 63, no. 3 (2011): 691–699.

[68] Y. C. Foong, H. I. Khan, L. Blizzard, et al., “The Clinical Significance, Natural History and Predictors of Bone Marrow Lesion Change Over Eight Years,” Arthritis Research & Therapy 16, no. 4 (2014): R149.

[69] K. Aso, S. M. Shahtaheri, R. Hill, D. Wilson, D. F. McWilliams, and D. A. Walsh, “Associations of Symptomatic Knee Osteoarthritis With Histopathologic Features in Subchondral Bone,” Arthritis & Rheumatology (Hoboken, NJ) 71, no. 6 (2019): 916–924.

[70] S. Zhu, J. Zhu, G. Zhen, et al., “Subchondral Bone Osteoclasts Induce Sensory Innervation and Osteoarthritis Pain,” Journal of Clinical Investigation 129, no. 3 (2019): 1076–1093.

[71] T. Hügle and J. Geurts, “What Drives Osteoarthritis?-Synovial Versus Subchondral Bone Pathology,” Rheumatology (Oxford, England) 56, no. 9 (2017): 1461–1471.

[72] D. A. Walsh, D. F. McWilliams, M. J. Turley, et al., “Angiogenesis and Nerve Growth Factor at the Osteochondral Junction in Rheumatoid Arthritis and Osteoarthritis,” Rheumatology (Oxford, England) 49, no. 10 (2010): 1852–1861.

[73] P. I. Mapp and D. A. Walsh, “Mechanisms and Targets of Angiogenesis and Nerve Growth in Osteoarthritis,” Nature Reviews Rheumatology 8, no. 7 (2012): 390–398.

[74] W. Damman, R. Liu, J. L. Bloem, F. R. Rosendaal, M. Reijnierse, and M. Kloppenburg, “Bone Marrow Lesions and Synovitis on MRI Associate With Radiographic Progression After 2 Years in Hand Osteoarthritis,” Annals of the Rheumatic Diseases 76, no. 1 (2017): 214–217.

[75] P. F. Sharkey, S. B. Cohen, C. F. Leinberry, and J. Parvizi, “Subchondral Bone Marrow Lesions Associated With Knee Osteoarthritis,” American Journal of Orthopedics (Belle Mead, N.J.) 41, no. 9 (2012): 413–417.

[76] D. Muratovic, D. M. Findlay, F. M. Cicuttini, A. E. Wluka, Y.-R. Lee, and J. S. Kuliwaba, “Bone Matrix Microdamage and Vascular Changes Characterize Bone Marrow Lesions in the Subchondral Bone of Knee Osteoarthritis,” Bone 108 (2018): 193–201.

[77] D. J. Hunter and T. D. Spector, “The Role of Bone Metabolism in Osteoarthritis,” Current Rheumatology Reports 5, no. 1 (2003): 15–19.

[78] D. J. Hunter, L. Gerstenfeld, G. Bishop, et al., “Bone Marrow Lesions From Osteoarthritis Knees Are Characterized by Sclerotic Bone That Is Less Well Mineralized,” Arthritis Research & Therapy 11, no. 1 (2009): R11.

[79] S. Koushesh, S. M. Shahtaheri, D. F. McWilliams, et al., “The Osteoarthritis Bone Score (OABS): A New Histological Scoring System for the Characterisation of Bone Marrow Lesions in Osteoarthritis,” Osteoarthritis and Cartilage 30, no. 5 (2022): 746–755.

[80] J. L. Jaremko, D. Jeffery, M. Buller, et al., “Preliminary Validation of the Knee Inflammation MRI Scoring System (KIMRISS) for Grading Bone Marrow Lesions in Osteoarthritis of the Knee: Data From the Osteoarthritis Initiative,” RMD Open 3, no. 1 (2017): e000355.

[81] S. Ota, D. Chiba, E. Sasaki, et al., “Symptomatic Bone Marrow Lesions Induced by Reduced Bone Mineral Density in Middle-Aged Women: A Cross-Sectional Japanese Population Study,” Arthritis Research & Therapy 21, no. 1 (2019): 113.

[82] D. J. Hunter, M. Lavalley, J. Li, et al., “Biochemical Markers of Bone Turnover and Their Association With Bone Marrow Lesions,” Arthritis Research & Therapy 10, no. 4 (2008): R102.

[83] S. R. Jafarzadeh, T. Neogi, J. J. Stefanik, et al., “Mediating Role of Bone Marrow Lesions, Synovitis, Pain Sensitization, and Depressive Symptoms on Knee Pain Improvement Following Substantial Weight Loss,” Arthritis & Rheumatology (Hoboken, NJ) 72, no. 3 (2020): 420–427.

[84] D. Aitken, L. L. Laslett, G. Cai, et al., “A Protocol for a Multicentre, Randomised, Double-Blind, Placebo-Controlled Trial to Compare the Effect of Annual Infusions of Zoledronic Acid to Placebo on Knee Structural Change and Knee Pain Over 24 Months in Knee Osteoarthritis Patients—ZAP2,” BMC Musculoskeletal Disorders 19, no. 1 (2018): 217.

[85] D.-g. Yu, B. Yu, Y.-q. Mao, et al., “Efficacy of Zoledronic Acid in Treatment of Teoarthritis Is Dependent on the Disease Progression Stage in Rat Medial Meniscal Tear Model,” Acta Pharmacologica Sinica 33, no. 7 (2012): 924–934.

[86] L. L. Laslett, D. A. Doré, S. J. Quinn, et al., “Zoledronic Acid Reduces Knee Pain and Bone Marrow Lesions Over 1 Year: A Randomised Controlled Trial,” Annals of the Rheumatic Diseases 71, no. 8 (2012): 1322–1328.

[87] J.-P. Pelletier, C. Roubille, J.-P. Raynauld, et al., “Disease-Modifying Effect of Strontium Ranelate in a Subset of Patients From the Phase III Knee Osteoarthritis Study SEKOIA Using Quantitative MRI: Reduction in Bone Marrow Lesions Protects Against Cartilage Loss,” Annals of the Rheumatic Diseases 74, no. 2 (2015): 422–429.

[88] M. A. Karsdal, K. Henriksen, M. Arnold, and C. Christiansen, “Calcitonin: A Drug of the Past or for the Future? Physiologic Inhibition of Bone Resorption While Sustaining Osteoclast Numbers Improves Bone Quality,” BioDrugs 22, no. 3 (2008): 137–144.

[89] J. Zhou, W. Xiong, P. Gou, et al., “Clinical Effect of Intramuscular Calcitonin Compared With Oral Celecoxib in the Treatment of Knee Bone Marrow Lesions: A Retrospective Study,” Journal of Orthopaedic Surgery and Research 15, no. 1 (2020): 230.

[90] H. G. Choi, J. S. Kim, H. J. Yoo, Y. S. Jung, and Y. S. Lee, “The Fate of Bone Marrow Lesions After Open Wedge High Tibial Osteotomy: A Comparison Between Knees With Primary Osteoarthritis and Subchondral Insufficiency Fractures,” American Journal of Sports Medicine 49, no. 6 (2021): 1551–1560.

[91] S. Akhavan, S. C. Martinkovich, C. Kasik, and P. J. DeMeo, “Bone Marrow Edema, Clinical Significance, and Treatment Options: A Review,” Journal of the American Academy of Orthopaedic Surgeons 28, no. 20 (2020): e888–e899.

[92] H. G. Schaible, G. S. von Banchet, M. K. Boettger, et al., “The Role of Proinflammatory Cytokines in the Generation and Maintenance of Joint Pain,” Annals of the New York Academy of Sciences 1193 (2010): 60–69.

[93] T. T. Pan, F. Pan, W. Gao, S.-S. Hu, and D. Wang, “Involvement of Macrophages and Spinal Microglia in Osteoarthritis Pain,” Current Rheumatology Reports 23, no. 5 (2021): 29.

[94] R.-R. Ji, A. Nackley, Y. Huh, N. Terrando, and W. Maixner, “Neuroinflammation and Central Sensitization in Chronic and Widespread Pain,” Anesthesiology 129, no. 2 (2018): 343–366.

[95] T. Blikman, W. Rienstra, J. J. A. M. van Raay, et al., “Neuropathic-Like Symptoms and the Association With Joint-Specific Function and Quality of Life in Patients With Hip and Knee Osteoarthritis,” PLoS One 13, no. 6 (2018): e0199165.

[96] C. A. von Hehn, R. Baron, and C. J. Woolf, “Deconstructing the Neuropathic Pain Phenotype to Reveal Neural Mechanisms,” Neuron 73, no. 4 (2012): 638–652.

[97] H.-G. Schaible, F. Richter, A. Ebersberger, et al., “Joint Pain,” Experimental Brain Research 196, no. 1 (2009): 153–162.

[98] R. Liu-Bryan and R. Terkeltaub, “Emerging Regulators of the Inflammatory Process in Osteoarthritis,” Nature Reviews Rheumatology 11, no. 1 (2015): 35–44.

[99] A.-M. Malfait and T. J. Schnitzer, “Towards a Mechanism-Based Approach to Pain Management in Osteoarthritis,” Nature Reviews Rheumatology 9, no. 11 (2013): 654–664.

[100] Y. Hu, X. Chen, S. Wang, Y. Jing, and J. Su, “Subchondral Bone Microenvironment in Osteoarthritis and Pain,” Bone Research 9, no. 1 (2021): 20.

[101] C. J. Woolf, “Central Sensitization: Implications for the Diagnosis and Treatment of Pain,” Pain 152, no. 3 Suppl (2011): S2–S15.

[102] K. Phillips and D. J. Clauw, “Central Pain Mechanisms in the Rheumatic Diseases: Future Directions,” Arthritis and Rheumatism 65, no. 2 (2013): 291–302.

[103] Y. C. Lee, N. J. Nassikas, and D. J. Clauw, “The Role of the Central Nervous System in the Generation and Maintenance of Chronic Pain in Rheumatoid Arthritis, Osteoarthritis and Fibromyalgia,” Arthritis Research & Therapy 13, no. 2 (2011): 211.

[104] S. E. Gwilym, J. R. Keltner, C. E. Warnaby, et al., “Psychophysical and Functional Imaging Evidence Supporting the Presence of Central Sensitization in a Cohort of Osteoarthritis Patients,” Arthritis and Rheumatism 61, no. 9 (2009): 1226–1234.

[105] M. Kremer, E. Salvat, A. Muller, I. Yalcin, and M. Barrot, “Antidepressants and Gabapentinoids in Neuropathic Pain: Mechanistic Insights,” Neuroscience 338 (2016): 183–206.

[106] P. Moss, H. A. E. Benson, R. Will, and A. Wright, “Patients With Knee Osteoarthritis Who Score Highly on the PainDETECT Questionnaire Present With Multimodality Hyperalgesia, Increased Pain, and Impaired Physical Function,” Clinical Journal of Pain 34, no. 1 (2018): 15–21.

[107] N. B. Finnerup, S. Haroutounian, P. Kamerman, et al., “Neuropathic Pain: An Updated Grading System for Research and Clinical Practice,” Pain 157, no. 8 (2016): 1599–1606.

[108] G. E. Ferreira, A. J. McLachlan, C.-W. C. Lin, et al., “Efficacy and Safety of Antidepressants for the Treatment of Back Pain and Osteoarthritis: Systematic Review and Meta-Analysis,” BMJ (Clinical Research Ed.) 372 (2021): m4825.

[109] S. Kolasinski, T. Neogi, M. Hochberg, et al., “2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee,” Arthritis and Rheumatology 72, no. 2 (2020): 220–233.

[110] H. M. Bryson and M. I. Wilde, “Amitriptyline. A Review of Its Pharmacological Properties and Therapeutic Use in Chronic Pain States,” Drugs & Aging 8, no. 6 (1996): 459–476.

[111] A. E. Wluka, D. M. Urquhart, A. J. Teichtahl, et al., “Effect of Low-Dose Amitriptyline on Reducing Pain in Clinical Knee Osteoarthritis Compared to Benztropine: Study Protocol of a Randomised, Double Blind, Placebo-Controlled Trial,” BMC Musculoskeletal Disorders 22, no. 1 (2021): 826.

[112] M. Sumitani, T. Sakai, Y. Matsuda, et al., “Executive Summary of the Clinical Guidelines of Pharmacotherapy for Neuropathic Pain: Second Edition by The Japanese Society of Pain Clinicians,” Journal of Anesthesia 32, no. 3 (2018): 463–478.

[113] A. Enteshari-Moghaddam, A. Azami, K. Isazadehfar, H. Mohebbi, A. Habibzadeh, and P. Jahanpanah, “Efficacy of Duloxetine and Gabapentin in Pain Reduction in Patients With Knee Osteoarthritis,” Clinical Rheumatology 38, no. 10 (2019): 2873–2880.

[114] O. G. Illeez, K. N. K. Oktay, I. Aktas, et al., “Comparison of the Effects of Duloxetine and Pregabalin on Pain and Associated Factors in Patients With Knee Osteoarthritis,” Revista da Associação Médica Brasileira 68, no. 3 (1992): 377–383.

[115] M.-A. Fitzcharles, S. P. Cohen, D. J. Clauw, G. Littlejohn, C. Usui, and W. Häuser, “Nociplastic Pain: Towards an Understanding of Prevalent Pain Conditions,” Lancet 397, no. 10289 (2021): 2098–2110.

[116] N. J. Jayathilake, T. T. Phan, J. Kim, K. P. Lee, and J. M. Park, “Modulating Neuroplasticity for Chronic Pain Relief: Noninvasive Neuromodulation as a Promising Approach,” Experimental & Molecular Medicine 57, no. 3 (2025): 501–514.

[117] N. Üçeyler, M. Burgmer, E. Friedel, et al., “Etiology and Pathophysiology of Fibromyalgia Syndrome: Updated Guidelines 2017, Overview of Systematic Review Articles and Overview of Studies on Small Fiber Neuropathy in FMS Subgroups,” Schmerz 31, no. 3 (2017): 239–245.

[118] R.-D. Treede, W. Rief, A. Barke, et al., “Chronic Pain as a Symptom or a Disease: The IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11),” Pain 160, no. 1 (2019): 19–27.

[119] K. K. Petersen, A. E. Olesen, O. Simonsen, and L. Arendt-Nielsen, “Mechanistic Pain Profiling as a Tool to Predict the Efficacy of 3-Week Nonsteroidal Anti-Inflammatory Drugs Plus Paracetamol in Patients With Painful Knee Osteoarthritis,” Pain 160, no. 2 (2019): 486–492.

[120] M. Imamura, S. T. Imamura, H. H. S. Kaziyama, et al., “Impact of Nervous System Hyperalgesia on Pain, Disability, and Quality of Life in Patients With Knee Osteoarthritis: A Controlled Analysis,” Arthritis and Rheumatism 59, no. 10 (2008): 1424–1431.

[121] B. Kulkarni, D. E. Bentley, R. Elliott, et al., “Arthritic Pain Is Processed in Brain Areas Concerned With Emotions and Fear,” Arthritis and Rheumatism 56, no. 4 (2007): 1345–1354.

[122] L. M. Arnold, R. M. Bennett, L. J. Crofford, et al., “AAPT Diagnostic Criteria for Fibromyalgia,” Journal of Pain 20, no. 6 (2019): 611–628.

[123] E. Kosek, D. Clauw, J. Nijs, et al., “Chronic Nociplastic Pain Affecting the Musculoskeletal System: Clinical Criteria and Grading System,” Pain 162, no. 11 (2021): 2629–2634.

[124] D. K. Patten, B. G. Schultz, and D. J. Berlau, “The Safety and Efficacy of Low-Dose Naltrexone in the Management of Chronic Pain and Inflammation in Multiple Sclerosis, Fibromyalgia, Crohn's Disease, and Other Chronic Pain Disorders,” Pharmacotherapy 38, no. 3 (2018): 382–389.

[125] London: National Institute for Health and Care Excellence, “Chronic Pain (Primary and Secondary) in Over 16 s: Assessment of All Chronic Pain and Management of Chronic Primary Pain,” 2021.

[126] M. S. McDonagh, S. S. Selph, D. I. Buckley, et al., AHRQ Comparative Effectiveness Reviews. Nonopioid Pharmacologic Treatments for Chronic Pain (Agency for Healthcare Research and Quality (US), 2020).

[127] J. Neumann, J. B. Guimaraes, U. Heilmeier, et al., “Diabetics Show Accelerated Progression of Knee Cartilage and Meniscal Lesions: Data From the Osteoarthritis Initiative,” Skeletal Radiology 48, no. 6 (2019): 919–930.

[128] A. M. Alenazi, S. M. Obaidat, M. M. Alshehri, et al., “Type 2 Diabetes Affects Joint Pain Severity in People With Localized Osteoarthritis: A Retrospective Study,” Pain Medicine 21, no. 5 (2020): 1025–1031.

[129] J. Neumann, F. C. Hofmann, U. Heilmeier, et al., “Type 2 Diabetes Patients Have Accelerated Cartilage Matrix Degeneration Compared to Diabetes Free Controls: Data From the Osteoarthritis Initiative,” Osteoarthritis and Cartilage 26, no. 6 (2018): 751–761.

[130] S. Khoza and J. C. Barner, “Glucose Dysregulation Associated With Antidepressant Agents: An Analysis of 17 Published Case Reports,” International Journal of Clinical Pharmacy 33, no. 3 (2011): 484–492.

[131] N. Fathallah, R. Slim, S. Larif, H. Hmouda, and S. C. Ben, “Drug-Induced Hyperglycaemia and Diabetes,” Drug Safety 38, no. 12 (2015): 1153–1168.

[132] C.-P. Lin, C.-H. Chung, C.-H. Lu, et al., “Glucagon-Like Peptide-1 Receptor Agonists Therapy to Attenuate the Risk of Knee Osteoarthritis and Total Knee Replacement in Type 2 Diabetes Mellitus: A Nation-Wide Population-Based Cohort Study,” Medicine 104, no. 6 (2025): e41243.

RIGHTS & PERMISSIONS

2025 The Author(s). Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.