Jenei-Lanzl Zsuzsa, Maurer Svenja, Brenner Rolf E, Zaucke Frank, Fuchs Michael, Riegger Jana
Dr Rolf M. Schwiete Research Unit for Osteoarthritis, Department of Trauma Surgery and Orthopedics, Goethe University Frankfurt, University Hospital, 60528, Frankfurt/Main, Germany.
Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopaedics, University of Ulm, 89081, Ulm, Germany.
Arch Pharm Res. 2025 Jun 28. doi: 10.1007/s12272-025-01551-3.
Osteoarthritis (OA) is the most common joint disease worldwide. Despite significant efforts byresearchers, no disease-modifying osteoarthritis drugs (DMOADs) have been approved yet. This review compares preclinical and clinical studies of promising therapeutic approaches to gain insights into the potential reasons for their failure in clinical trials. For this purpose, prime examples of different therapeutic groups, including the antioxidant NAC, senotherapeutic UBX0101, anti-inflammatory drug Anakinra®, Wnt inhibitor Lorecevivint®, chondroanabolic growth factor Sprifermin™, and various protease inhibitors, are discussed in detail. The limitations of commonly used OA animal models are elaborated to understand this failure better. Moreover, this review addresses the challenges of patient stratification into different endotypes and phenotypes, the consideration of subgrouping in clinical trials, and the lack of suitable clinical outcome parameters. In summary, this review highlights potential reasons for the high failure rate of DMOADs in clinical trials and outlines key points for future improvement.
骨关节炎（OA）是全球最常见的关节疾病。尽管研究人员付出了巨大努力，但目前尚无疾病修饰性骨关节炎药物（DMOADs）获批。本综述比较了有前景的治疗方法的临床前和临床研究，以深入了解它们在临床试验中失败的潜在原因。为此，详细讨论了不同治疗组的典型例子，包括抗氧化剂NAC、衰老治疗药物UBX0101、抗炎药阿那白滞素®、Wnt抑制剂洛雷西维文特®、软骨合成生长因子司普明™以及各种蛋白酶抑制剂。阐述了常用OA动物模型的局限性，以便更好地理解这种失败。此外，本综述还探讨了将患者分层为不同终末型和表型的挑战、临床试验中考虑亚组划分的问题以及缺乏合适的临床结局参数。总之，本综述强调了DMOADs在临床试验中高失败率的潜在原因，并概述了未来改进的关键点。
