Henrotin et al. BMC Musculoskeletal Disorders
(2022) 23:650
Page 2 of 11
Rubus Ideaus was not significantly more efficient than the placebo on WOMAC global score, stiffness, and physical function subscores, IPAQ, SF-36, walking distance in treadmill test, SPPB, and evaluation of associated treatments needed to manage OA. Conclusion: Rubus idaeus leaf extract was well tolerated and effective to relieve pain in a patient with knee osteoarthritis. Trial registration: NCT03703024 (11/10/2018). Keywords: Osteoarthritis, Knee, Rubus idaeus, Pain, Clinical trial
Introduction Osteoarthritis (OA) is the major cause of disability in older adults. In the USA, Federal Drug Administration (FDA) has recognized that OA can be a serious disease for which no pharmacological treatment can modify the underlying pathophysiology of the disease and change its natural course [1]. Currently, patient management aims to reduce symptoms and improve quality of life using therapeutic modalities with low side effects. Recently, the Osteoarthritis Research Society International (OARSI) recommended patient education, physical activities including exercise programs, and weight control with diet intervention as the core treatment for all patients what- ever their health status and OA severity [2]. Pharmaco- logical modalities can be associated with core treatment if the core treatment alone is not satisfying or to facilitate patients’ adhesion to exercise programs. Among these pharmacological modalities, the use of Nonsteroidal Anti-Inflammatory Drugs (NSAIDS) was recommended in well-defined conditions while opioids and paraceta- mol were no more recommended. Therefore, there is a need for safe treatments with an efficacy supported by well-conducted clinical trials. One safe approach could be nutraceuticals for which the most used to manage joint discomfort are glucosamine, chondroitin, collagen, Boswellia, and turmeric extracts [3]. Another potential candidate is Rubus idaeus (Raspberry) leaf extract (RIE) rich in flavonoids and phenols that are known to inhibit inflammatory responses [4] by preventing the activa- tion of MAPK or NFkB signaling pathways [5]. Moreo- ver, polyphenolic-enriched red raspberry Rubus fruit extract reduces collagen breakdown in bovine chondro- cytes as well as the severity of arthritis in an antigen- induced arthritis rat model [6]. In cartilage explants, RIE prevented the loss of proteoglycan and MMP-3 and MMP-13 protein expressions. RIE reduced the expres- sion of interleukin (IL)-1 and -6 in macrophages, without change in Tumor Necrosis Factor (TNF) and cyclooxyge- nase (Cox)-2 expression. The secretome of macrophages pre-treated with RIE and transferred in chondrocytes decreased the gene expression and protein synthesis of MMP-3, -13, and Cox-2. Globally, these in vitro stud- ies suggested that RIE could limit synovitis and prevent
cartilage degradation without inducing toxicity [4]. Pat- ented data (US20200222486A1) demonstrated that RIE increased the secretion of 5-HETE and 12-HETE, two intermediaries of the lipoxygenase pathway involved in the resolution of inflammation-induced in mice by injec- tion of methylated bovine serum albumin (mBSA). In this model, Rubus Idaeus extract decreased the level of circu- lating IL-6 plasma but increased the level of 12-HETE, as well as reduced joint swelling in paws [7]. No toxic effects of the investigational product have been reported. In this paper, we report the effect of RIE, on symp- toms impairing the quality of life in people suffering from OA. Thus, we conducted a randomized, double-blinded, placebo-controlled trial to assess whether supplemen- tation with RIE improved OA knee pain and function. This study was the first trial applied to the human body. Further, this phase II study has been conducted in full accordance with the International Council for Harmo- nisation of Technical Requirements for Pharmaceuticals for Human use (ICHE6) that examined the impact of ingesting a food supplement composed of RIE on allevi- ating pain, function, and physical performance in elderly participants who reported having mild to moderate knee pain. Population and design Study design This study was a phase II randomized, double-blind, pla- cebo-controlled with three parallel groups and a mono- centric trial including 195 patients with a primary knee OA. Participants were recruited from June 1, 2017, to December 31, 2018. The main inclusion criteria were an age of 30 to 75 years, a Body Mass Index (BMI) between 18.5 and 35 kg/m 2 , a documented diagnosis of primary OA of the target knee made at least 12 months before screening, radiographic evidence of OA in the tibiofemoral com- partment of the target knee with at least one osteophyte and a measurable joint space narrowing, as diagnosed by standard X-rays taken no longer than 18 months, and a mild to moderate pain not adequately or completely controlled with NSAIDs. The most painful knee was considered the target knee. The main exclusion criteria
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