Henrotin et al. BMC Musculoskeletal Disorders
(2022) 23:650
Page 10 of 11
Conclusions This randomized controlled clinical trial demonstrated that RIE, a rubus ideaus extract, is a safe and efficient treatment to manage symptoms of patients with knee OA. Of course, this result needs to be confirmed in a larger phase III clinical trial including not only clinical parameters but also biochemical markers of inflamma- tion and cartilage degradation and imaging structural analysis of joint tissues. This trial provides useful infor- mation for the design of a larger phase III clinical trial including the sample size estimate, the choice of the dose, and the selection of primary outcomes. Abbreviations AE: Adverse effect; BMI: Body Mass Index; COX: Cyclooxygenase; ES: Effect Size; HETE: Hydroxyeicosatetraenoic acids; IPAQ: International Physical Activ‑ ity Questionnaire; ITT: Intention-To-Treat; MAPK: Mitogen-activated protein kinases; MET: Metabolic Equivalent of Task; MMP: Matrix MetalloProteinase; NFKB: Nuclear Factor-Kappa B; NSAIDs: Nonsteroidal Anti-inflammatory Drugs; OA: Osteoarthritis; OARSI: Osteoarthritis Research Society International; OMERACT: Outcome Measures in Rheumatology; RIE: Rubaeus Ideaus Extract; SEM: Standard Error of Mean; SF-36: Short Form (36); SPPB: Short Physical Performance Battery; VAS: Visual Analog Scale; WOMAC: Western Ontario McMaster osteoarthritis index. Supplementary Information The online version contains supplementary material available at https://doi. org/10.1186/s12891-022-05612-2. Additional file 1. Listing 1. By Participant Listing Of Analysis Sets. Additional file 2. Comparison of demographic and clinical outcomes atbaseline between normal BMI and overweight/obese BMI group in the ITTpopulation ( N = 198). Additional file 3. Absolute change from baselinein normal BMI group. Additional file 4. Absolute change from baseline in BMI ≥ 25group.
0.33), RIE was even more efficient [10]. Considering the excellent safety of RIE, this extract could be a good alternative to NSAIDs and paracetamol that show severe adverse effects after long-term administration. Further, our study demonstrated that RIE treatment was associated with a greater reduction of rescue med- ications including paracetamol and NSAIDS than pla- cebo. This data again indicates that RIE has an antalgic effect superior to that of paracetamol and NSAIDs. A feature of this study was that it included participants with mild to moderate pain not adequately or com- pletely controlled with NSAIDs. This finding indicates that RIE is efficient where NSAIDS are not. This could be explained by the difference in the mechanisms of action. NSAIDs act on inflammation mainly by inhibit- ing cyclooxygenases while RIE acts by preventing the activation of MAPK or NFkB signaling pathways that lead to the secretion of a large panel of pro-inflam- matory cytokines and metalloproteases [3] as well as on the resolution of the inflammation. We can spec- ulate that in some participants RIE mechanisms of action are more appropriate to relieve symptoms in chronic inflammatory conditions than NSAIDs. This was already observed with other polyphenols like cur- cumin [11]. Interestingly, a subgroup analysis showed that RIE effect on VAS pain was significant only in overweight/obese participants. Our study fails to bring an explanation to that finding. Both populations were similar in terms of pain or physical activity level at baseline. The only difference was the sex ratio. There were proportionally more men in the overweight/ obese group. One hypothesis would be that men are better responders than women to RIE treatment. This needs to be confirmed as we have not observed a dif- ference in RIE efficacy between men and women in the overall population. Another possible explanation would be that RIE through its anti-inflammatory prop- erties acts on systemic inflammation which is associ- ated with obesity. Inflammatory biomarkers should be explored to verify this hypothesis. Globally, this study also showed that 400 mg per day of RIE is the adequate posology to relieve VAS pain. It is at this dose that we recorded the most responders according to the OMERACT-OARSI criterion. We can also conclude that three months of treatment are nec- essary to obtain significant analgesia. This study showed promising effects of RIE on symp- toms of knee OA but should also be interpreted with caution because our study suffers from some limita- tions. First, RIE was not efficient on the primary out- come. The second main limitation was the small sample size as larger groups will be required to confirm the positive findings observed in this study [12].
Acknowledgements Not applicable.
Authors’ contributions YH participated in the analysis and interpretation of data, drafted and participated in the finalization of the manuscript. RLC conceived the study design, interpreted the results, participated in manuscript drafting, and was responsible for the final approval of the manuscript version to be submitted. PFB took part in the conception and design of the study, participated in the interpretation of data and final approval of the submitted version. RT per‑ formed the statistical analysis and reviewed the final version of the paper. MCS participated in the analysis and interpretation of data, drafted and revised the manuscript. GDG drafted the protocol, organized the study, and reviewed the final version of the paper. JMG performed the statistical analysis and reviewed the final version of the paper. AD drafted the protocol, organized the study, and reviewed the final version of the paper. The author(s) read and approved the final manuscript. Funding All the operational phase of this study (patient recruitment, data collection, and statistical analysis) was funded by Naturex and run by Atlantia. Availability of data and materials All data are available and can be obtained by sending a request by mail to Naturex SA, Avignon, France, or by e-mail to romain.le_cozannet@givaudan. com.
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