Technetium [99Tc] methylene diphosphonate injection (99Tc-MDP) is widely used for the treatment of rheumatoid arthritis (RA), but there is still insufficient evidence for its application. Through the utilization of meta-analysis and systematic reviews, this study aimed to evaluate the effectiveness and safety of 99 TC-MDP in combination with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) for RA.This study was registered on PROSPERO in advance (CRD42021220780). A systematic search was conducted in PubMed, Embase, the Cochrane Library, and multiple international public databases from their inception to April 2023 to identify clinical randomized controlled trials exploring the use of 99Tc-MDP combined with csDMARDs in the treatment of RA. Each outcome was subjected to meta-analysis, and the quality of evidence was assessed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The American College of Rheumatology's 50 %/70 % response criteria scores (ACR50/70) scores were utilized as the primary effectiveness outcomes, and risks were measured by assessing the rates of AEs. Moreover, secondary efficacy outcomes were evaluated, including the Disease Activity Score 28 (DAS28) and bone mineral density (BMD) as joint function indicators and the erythrocyte sedimentation rate (ESR) and interleukin-17 (IL-17) as inflammatory indicators.In this meta-analysis, a total of 34 studies (2296 patients) were included out of 1149 retrieved studies. The summarized results showed that the treatment group treated with the combination of 99Tc-MDP and csDMARDs had significantly higher ACR50 (RR = 1.32, 95 % CI: 1.13-1.55, P = 0.0004) and ACR70 (RR = 1.40, 95 % CI: 1.07-1.82, P = 0.01) scores than the control group receiving csDMARDs alone. In addition, the overall incidence of AEs was lower with the combination of 99Tc-MDP and csDMARDs than with csDMARDs alone (RR = 0.75, 95 % CI: 0.60-0.93, P = 0.009), but the possibility of phlebitis was higher in the treatment group (RR = 4.15, 95 % CI: 1.04-16.50, P = 0.04). In addition, the combination of 99Tc-MDP and csDMARDs had advantages over csDMARDs alone in improving DAS28 (WMD = 1.56, 95 % CI: 0.86-2.25, P < 0.0001), BMD (SMD = 1.12, 95 % CI 0.46-1.78, P = 0.0008), ESR (SMD = 0.71, 95 % CI 0.45-0.97, P < 0.00001), and IL-17 (WMD = 5.82, 95 % CI 3.86-7.77, P < 0.00001). However, the above results might have been influenced by the 99Tc-MDP dosage, csDMARD category, and treatment duration. Combining methotrexate and leflunomide, administering continuous treatment for 24 weeks, or using 3 sets of 99Tc-MDP doses (16.5 mg) may be the optimal 99Tc-MDP treatment plan for RA.Compared with csDMARD therapy alone, the combination therapy with 99Tc-MDP is more effective for RA patients and is associated with a lower overall incidence of adverse events, although the possibility of phlebitis was higher. However, due to the inherent limitations of the included RCTs, high-quality clinical trials are still needed to further assess the effectiveness and safety of this combination therapy.© 2023 The Authors.