Denosumab in the treatment on structural damage caused by rheumatoid arthritis: a systematic review and meta-analysis

Background: Rheumatoid arthritis (RA) is a chronic inammatory joint disease, which can cause cartilage and bone damage as well as disability. The effects of denosumab in patients with RA have been analyzed in several clinical studies. These results provide strong evidence to suggest that denosumab signicantly inhibited the progression of bone erosion, increased BMD in patients with RA. We undertook a meta-analysis to summarize the ecacy and safety of denosumab in the treatment on structural damage caused by rheumatoid arthritis. Methods: We searched PubMed, Embase, Medline, The Cochrane Library, and collected randomized controlled trials of denosumab in patients with rheumatoid arthritis from the database was established until January 19, 2021.Literature was screened according to inclusion and exclusion criteria, and RevMan 5.3 software was used for Meta-analysis after quality assessment. Results: Five eligible studies were included in the primary meta-analysis. Denosumab signicantly inhibited the increase of the modied Sharp erosion score(MD=-0.62, 95%CI (cid:0) -0.91 (cid:0) -0.33,P (cid:0) 0.0001) (cid:0) modied total Sharp score(MD=-0.78, 95%CI (cid:0) 1.23 (cid:0) -0.33,P=0.0007)compared to placebo groups at 12 months. In addition, denosumab also signicantly increased lumbar spine BMD (3.73, 95% CI 2.00, 5.46, P<0.0001) compared to placebo or bisphosphonates. There was no evidence of an effect of denosumab on joint space narrowing. Adverse events, serious adverse events were similar between denosumab and placebo arms. Conclusion: rheumatoid with group. with (registration no other meta-analysis focusing on denosumab use for structural damage caused by rheumatoid arthritis were found in the PROSPERO The analysis focused on changes in modied Sharp score among 138 participants,rheumatoid arthritis patients received subcutaneous placebo, denosumab 60 or denosumab 180 mg injections every 6 months for 12 months. Herein, we report the results for the placebo and 60 mg denosumab arms, since the 60 mg dose is FDA approved for osteoporosis in postmenopausal women and men. A signicant difference in the modied Sharp erosion score was observed as early as 12 months in the 60mg denosumab group (P = 0.012) as compared with placebo. no evidence of an effect of on joint space narrowing. Rates of adverse events were comparable between the denosumab and placebo groups. multicenter, II analysis on changes in modied Sharp erosion

Conclusion: Results suggest that denosumab inhibits the progression of structural damage caused by rheumatoid arthritis, with no increase in the rates of adverse events as compared with control group.
Preliminary research suggests that denosumab is reasonable and promising options for preventing and treating structural destruction in rheumatoid arthritis.
Trial registration: We registered our study with PROSPERO (registration number CRD42021239783); no other meta-analysis focusing on denosumab use for structural damage caused by rheumatoid arthritis were found in the PROSPERO database.

Background
Rheumatoid arthritis is the most common in ammatory arthritis and is a major cause of disability.(1) In industrialized country, rheumatoid arthritis affects 0.5-1.0% of adults, with 5-50 per 100 000 new cases annually. It seriously affects people's health. (2) Clinical studies have demonstrated Methotrexate as well as targeted synthetic DMARDs (e.g., Janus kinase inhibitors) effectively suppresses disease activity in patients with RA, not only reduce joint in ammation but also ameliorate joint destruction in RA. (3)(4)(5)(6)(7)However, the joint-protective effect of these reagents is not complete and they are frequently accompanied by serious adverse effects such as infection as a result of immune system suppression. (8) Recent studies have demonstrated that osteoclasts are responsible for bone destruction in RA.(9)Bone loss is a hallmark of RA, bone erosions and 'periarticular' bone loss directly affect the joint architecture Page 3/14 and lead to impairment of joint function. Erosions in RA are the consequence of the induction of bone resorbing osteoclasts, while at the same time osteoblasts are suppressed. (10,11)Since osteoclast differentiation and activity are key events in arthritic bone damage, the signals that trigger osteoclastogenesis are potential therapeutic targets. (12) Denosumab is a fully human monoclonal IgG2 antibody that binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors, prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone,(13-15) as a treatment for osteoporosis in men and post-menopausal women at high risk of fractures,(16, 17)as well as for the treatment of bone loss associated with androgen-deprivation therapy for prostate cancer in men at high risk of fractures(18), glucocorticoidinduced osteoporosis (GIOP) (19)and bone destruction due to rheumatoid arthritis (RA) or metastatic cancers. (20) Clinical research reports in recent years, denosumab signi cantly inhibited the progression of bone erosion and no difference in the risk of side effects compared to placebo. (21)(22)(23) Other studies shows that compared with treatment by biological disease-modifying antirheumatic drugs (bDMARDs) alone, concurrent use of denosumab and bDMARDs in RA patients was e cacious in inhibiting structural damage. (24) Combining denosumab with disease modifying anti-rheumatic drugs may be considered for RA patients with progressive bone erosions. (25)The purpose of this systematic review and meta-analysis is to summarize published data describing the e cacy and safety of denosumab in the treatment on structural damage caused by rheumatoid arthritis.

Materials And Methods
We searched PubMed, Embase, Medline, The Cochrane Library from the database was established until January 19, 2021 using the terms "denosumab," "rheumatoid arthritis," "bone erosion," "structural damage" and "safety." Studies in any language were included. Two authors independently reviewed the abstracts of all publications to determine eligibility. We searched PubMed to determine whether relevant abstracts presented at these meetings were subsequently published. If not published, we next contacted authors via email to inquire on the date of anticipated publication. We updated our literature search in January 2021.
Studies were included if they recruited subjects clinically diagnosed patients with rheumatoid arthritis with varying degrees of bone destruction, used denosumab and control arm, and assessed the effect of treatment on modi ed Sharp erosion score and safety. We excluded review articles, case reports and case series. Figure 1 summarizes the total number of articles identi ed and reasons for exclusion.
Both authors independently extracted data from included publications including the year of publication, number of subjects assigned to control and denosumab therapy, and study outcomes including changes in modi ed Sharp erosion score, modi ed total Sharp score, modi ed Sharp joint space narrowing score, bone mineral density(BMD) and side effects.
Both authors independently rated the quality of each included publication, using the Cochrane quality assessment for intervention studies. One author prepared a table summarizing details of the included studies. (Table 2) Statistical analysis We performed using RevMan 5.3 software, and the inspection level was α = 0.05. The χ 2 test analysis was used to test the homogeneity of the relevant literature included in the study. If I ²<50%, the xed effects model should be used for analysis, and if I²≥ 50%, the random effects model should be used for analysis. After treatment, continuous variables such as Sharp scores were studied using standardized mean difference (MD), and non-continuous variables such as adverse reactions were used relative risk ratio (RR). The interval estimates were all based on 95% con dence intervals (95% CI). (26)The funnel chart was used to assess publication bias. If the funnel chart shows that most of the studies are in the upper part of the "inverted funnel chart" and the bottom part is less, and the left and right sides are basically symmetrical, it indicates that the publication bias is not obvious; otherwise, it indicates that there is a signi cant publication bias. Our primary analyses focused on the ve trials comparing denosumab to control group.

Results
From our literature search, we identi ed 226 articles of interest. After screening for eligibility based on the aforementioned inclusion criteria, 214 articles were excluded (Fig. 1). We assessed the remaining 14 fulllength articles for eligibility. Of these, 9 publications were excluded due to lack of a control or no focus on bone erosion caused by rheumatoid arthritis, leaving 5 publications for inclusion in the meta-analysis. (Table 1) and the paragraphs below summarize the main ndings of these studies. Amgen Incorporated (Thousand Oaks, CA, USA). The analysis focused on changes in modi ed Sharp score among 138 participants,rheumatoid arthritis patients received subcutaneous placebo, denosumab 60 mg, or denosumab 180 mg injections every 6 months for 12 months. Herein, we report the results for the placebo and 60 mg denosumab arms, since the 60 mg dose is FDA approved for osteoporosis in postmenopausal women and men. A signi cant difference in the modi ed Sharp erosion score was observed as early as 12 months in the 60mg denosumab group (P = 0.012) as compared with placebo. There was no evidence of an effect of denosumab on joint space narrowing. Rates of adverse events were comparable between the denosumab and placebo groups.
Takeuchi, T. et al (22)reported effect of denosumab on Japanese patients with rheumatoid arthritis: a dose-response study of AMG 162 (Denosumab) in patients with rheumatoid arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)--a 12-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. The analysis focused on changes in modi ed Sharp erosion score among 160 participants,patients with RA between 6 months and < 5 years, strati ed by glucocorticoid use and rheumatoid factor status, were randomly assigned to subcutaneous injections of placebo or denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or every 2 months (Q2M). The primary endpoint was change in the modi ed Sharp erosion score from baseline to 12 months.
Denosumab signi cantly inhibited the progression of bone erosion at 12 months compared with the placebo, and the mean changes of the modi ed Sharp erosion score at 12 months from baseline were 0.99, 0.27 (compared with placebo, p = 0.0082) and also signi cantly inhibited the increase of the modi ed total Sharp score compared with the placebo, with no obvious evidence of an effect on joint space narrowing for denosumab. No apparent difference was observed in the safety pro les of denosumab and placebo.
Takeuchi, T. et al (23) reported effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease modifying antirheumatic drugs (DESIRABLE study): a randomized, double-blind, placebo-controlled phase 3 trial. The analysis focused on changes modi ed total Sharp score. Denosumab groups showed signi cantly less progression of joint destruction. The mean changes in the modi ed total Sharp score at 12 months were 1.49 (95% CI 0.99 to 1.99) in the placebo group, 0.99 (95% CI 0.49 to 1.49) in the Q6M group (p = 0.0235). The mean changes in bone erosion score were 0.98 (95% CI 0.65 to 1.31) in the placebo group, 0.51 (95% CI 0.22 to 0.80) in the Q6M group (p = 0.0104). No signi cant between-group difference was observed in the joint space narrowing score. No major differences were observed among safety pro les.
Hasegawa, T.et al (24) reported e cacy of denosumab combined with bDMARDs on radiographic progression in rheumatoid arthritis. Compared with treatment by bDMARDs alone, concurrent use of denosumab and bDMARDs in RA patients was e cacious in inhibiting structural damage.
In our meta-analysis, we focused on four studies (21)(22)(23)25)comparing changes in bone mineral density(BMD) between participants randomized to experimental or control. In these studies, denosumab prevented a decrease in lumbar spine BMD and signi cantly increased the BMD compared to control (3.73, 95% CI 2.00,5.46 P < 0.0001, Fig. 5) .
Cochrane quality assessment indicated that ve studies were of good quality, and they were of excellent quality( Table 2).

Discussion
Rheumatoid arthritis is a prevalent autoimmune disease characterized by the in ammation of multiple synovial joints followed by joint destruction and deformity,the expression of RANKL in rheumatoid arthritis patients and found that synovial broblasts express RANKL and induce osteoclastogenesis. (27) Anti-RANKL antibodies, the most direct method to suppress bone destruction.Denosumab is currently the most active RANKL inhibitor that can be used in human treatment. It binds with RANKL with high a nity to inhibit the interaction of RANKL and RANK, inhibits the formation and function of osteoclasts, thereby reducing bone resorption, increasing bone mass, and improving bone strength,(28) were approved for rheumatoid arthritis in Japan in 2017, and be added to the indication for the inhibition of rheumatoid arthritis with bone erosion in 2020. Initiating the targeting of osteoclasts in the treatment of rheumatoid arthritis is one of the important fruits of osteoimmunology. (29) We performed a meta-analysis of ve randomized-controlled trials evaluating the e cacy and safety of denosumab in the treatment of rheumatoid arthritis. These results provide strong evidence to suggest that denosumab can prevent the progression of bone erosion in RA patients.(30)Treatment with denosumab signi cantly greater increments in lumbar spine BMD compared to placebo or bisphosphonate therapy. No apparent difference was observed in the safety pro les of denosumab and placebo. Notably, however, denosumab treatment has little or no effect on cartilage deterioration or disease activity.
In addition, patients with RA are at increased risk of osteoporotic fractures. Denosumab has additional bene ts for patients with RA by preventing osteoporosis. (31)(32)(33)(34)Some studies show denosumab treatment increased BMD and reduced bone turnover markers regardless of baseline BMD or marker levels or concomitant bisphosphonate or glucocorticoid use. (35)(36)(37) We acknowledge several limitations of our study. First, there were few randomized-controlled trials that met our criteria for inclusion in the meta-analysis, leading us to include a retrospective cohort study designs. Second, all studies were short in duration (12 months), thus the long-term e cacy and safety of denosumab for rheumatoid arthritis cannot be addressed at this time. Third, the medication and treatment courses of the included studies are not exactly the same. Due to the small number of included studies, it is impossible to conduct subgroup analysis based on the treatment courses.Therefore, whether the clinical e cacy between different courses of treatment is the same, still needs further veri cation.
Finally,among the 5 studies included, only 3 reported adverse reactions. Other literature reported that no adverse reactions were found during the observation period. It is not ruled out that there are some milder adverse reactions that may be eliminated by human factors, or some late-onset adverse reactions. Not counted due to short observation time.
In conclusion,data from this systematic review and meta-analysis indicate that denosumab is a reasonable drug to prescribe, in the treatment of rheumatoid arthritis. Denosumab inhibits the progression of structural damage caused by rheumatoid arthritis and effectively increase BMD with no increase in the rates of adverse events. Based on our literature review and meta-analysis, preliminary research suggests that denosumab is reasonable and promising options for preventing and treating structural destruction in rheumatoid arthritis.

Conclusions
The collective data from ve clinical trials shows that denosumab therapy signi cantly inhibited the increase of structural damage caused by rheumatoid arthritis. The collective data from the completed trials showed no difference in the risk of mild or serious side effects between people who took denosumab compared to placebo.
Abbreviations RA, rheumatoid arthritis; BMD, bone mineral density; FDA, Food and Drug Administration; RANKL, receptor-activator nuclear kappa B ligand; bDMARDs, biological disease-modifying antirheumatic drugs; JSN, joint space narrowing; mTSS, modi ed total Sharp score; GIOP, Glucocorticoid-induced osteoporosis.    Percent change in incidence of adverse event between two groups