Can metformin relieve tibiofemoral cartilage volume loss and knee symptoms in overweight knee osteoarthritis patients? Study protocol for a randomized, double-blind, and placebo-controlled trial

Abstract

Background Osteoarthritis (OA) is the most common joint disease, and is most frequently seen in the knees. However, there is no effective therapy to relieve the progression of knee OA. Metformin is a safe, well-tolerated oral medication that is extensively used as first-line therapy for type 2 diabetes. Previous observational studies and basic researches suggested that metformin may have protective effects on knee OA, which needs to be verified by clinical trials. This study, therefore, aims to examine the effects of metformin versus placebo on knee cartilage volume loss and knee symptoms in overweight knee OA patients by a randomized controlled trial over 24 months. Methods This protocol describes a multicenter, randomized, double-blind, and placebo-controlled clinical trial aiming to recruit 262 overweight knee OA patients. Participants will be randomly allocated to the two arms of the study, receiving metformin hydrochloride sustained-release tablets or identical inert placebo for 24 months (start from 0.5 g/day for the first 2 weeks, and increase to 1 g/day for the second 2 weeks, and further increase to 2 g/day for the remaining period if tolerated). Primary outcomes will be changes in tibiofemoral cartilage volume and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score over 24 months. Secondary outcomes will be changes in visual analogue scale (VAS) knee pain, tibiofemoral cartilage defects, effusion-synovitis volume, and tibiofemoral bone marrow lesions maximum size over 24 months. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per-protocol analyses will be performed as the secondary analyses. Discussion If metformin is proved to slow knee cartilage volume loss and to relieve knee symptoms among overweight knee OA patients, it will have the potential to become a disease modifying drug for knee OA. Metformin is a convenient intervention with low cost, and its potential effects on slowing down the structural progression and relieving the symptoms of knee OA would effectively reduce the disease burden worldwide. Trial registration ClinicalTrials. gov NCT05034029. Registered on 30 Sept 2021.

Metformin attenuates symptoms of osteoarthritis: role of genetic diversity of Bcl2 and CXCL16 in OA

“…The results of another clinical trial in OA patients confirm the beneficial effects of metformin such as changes in western Ontario and McMaster universities osteoarthritis index (WOMAC) score and visual analog scale (VAS) knee pain with a maximum dose of 2 g/day for 24 months [ 71 ]. In another study, the results showed that metformin (1000 mg/day for 12 weeks) in combination with meloxicam (15 mg/day) significantly improved KOOS components compared to the setting that meloxicam was used alone in OA patients [ 72 ].…”

Evaluating the causal effect of circulating proteome on the risk of osteoarthritis-related traits

“…Moreover, several pathways potentially relevant to OA were enriched in our pathway enrichment analysis, implying the biological interpretability of our findings. As no disease-modifying OA drugs (DMOADs) have been approved currently, the demand for developing DMOADs is urgent 65. MR is increasingly becoming a standard tool for triaging new drug targets 66.…”

Latest insights in disease-modifying osteoarthritis drugs development

“…Currently, at least two clinical trials (NCT04767841 and NCT05034029) are ongoing to explore the effect of metformin on OA patients. 101 Human platelet-rich plasma Human platelet-rich plasma (hPRP) injections are used increasingly to manage OA. 102,103 hPRP is made by centrifugation of autologous blood so that growth factors and cytokines are released from the α-granules found in the platelets.…”

“…Currently, at least two clinical trials (NCT04767841 and NCT05034029) are ongoing to explore the effect of metformin on OA patients. 101 …”