Efficacy of denosumab in treatment of osteoporosis in patients with rheumatoid arthritis: a meta-analysis of randomized controlled trial

Abstract

Background

Rheumatoid arthritis (RA) can lead to significant bone destruction, which may occur locally near inflamed joints or systemically. As patients age, they often experience increased bone erosion around affected joints, heightened osteoclast activity, and systemic inflammation, which collectively result in bone loss. This condition is commonly referred to as osteopenia or osteoporosis.

Methods

A systematic search was conducted across multiple databases, including PubMed, Web of Science, Embase, and the Cochrane Library, to identify randomized controlled trials (RCTs) published on the use of denosumab in treating osteoporosis in patients with rheumatoid arthritis. The primary focus was to evaluate the impact of denosumab on various clinical measures, including bone mineral density (BMD), joint erosion scores, and overall joint maintenance. We performed a meta-analysis of six selected studies, all of which utilized these common metrics. The number of studies included in the analysis of each outcome varied depending on data availability in the original studies, with all included studies meeting our quality assessment criteria.

Results

The results from these studies suggest that denosumab is effective in preventing further joint damage and bone loss in rheumatoid arthritis patients with osteoporosis. The data revealed a significant improvement in BMD, joint erosion scores, and joint narrowing scores in patients treated with denosumab compared to controls. These findings indicate the potential of denosumab as a preventive treatment for joint deterioration in RA patients with osteoporosis.

Conclusion

Denosumab demonstrates promising efficacy in maintaining bone health and preventing joint damage in rheumatoid arthritis patients with coexisting osteoporosis. However, further studies with larger sample sizes and long-term follow-up are necessary to confirm these findings and to comprehensively assess the long-term safety profile, including potential adverse events such as hypocalcemia, osteonecrosis of the jaw, and atypical femoral fractures.

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation of the synovial joints, leading to progressive joint damage. Bone destruction in RA patients often occurs near the inflamed joints but can also be systemic, contributing to overall bone loss. Over time, this results in osteopenia and osteoporosis, both of which are associated with increased fracture risk and functional disability [1, 2]. While the primary treatment goals for RA include reducing inflammation and managing pain, the impact on bone health remains a significant concern.

Osteoporosis in RA patients is particularly challenging due to the interplay between disease-specific factors such as inflammatory cytokines and the medications used for RA treatment, including corticosteroids, which further accelerate bone loss [3, 4]. As a result, patients with both RA and osteoporosis often face compounded risks of joint destruction and fractures. Denosumab, a monoclonal antibody that inhibits the RANKL-RANK-OPG signaling pathway, has emerged as a promising therapeutic option. By inhibiting osteoclast differentiation and activity, denosumab reduces bone resorption, thereby improving bone mineral density (BMD) and potentially mitigating the risks associated with bone erosion and joint damage [5, 6].

Despite promising results from individual studies, the overall effectiveness of denosumab in RA patients with osteoporosis remains unclear due to the limited number of randomized controlled trials (RCTs). While several previous meta-analyses have examined denosumab in RA patients [7,8,9,10,11], our study builds upon these by including the most recent clinical trials up to June 2024, focusing specifically on patients with both RA and osteoporosis, and comprehensively analyzing multiple bone-related outcomes. This meta-analysis aims to synthesize data from existing studies to evaluate the efficacy of denosumab in improving BMD and other key clinical outcomes, such as bone erosion and joint space narrowing, in RA patients suffering from osteoporosis [12].

Methods

Study selection

We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that evaluated the effects of denosumab on osteoporosis in patients with rheumatoid arthritis. The search strategy included multiple electronic databases, such as PubMed, Web of Science, Embase, and the Cochrane Library. We considered studies published from the inception of each database up to June 2024. The eligibility criteria were as follows:

Inclusion criteria

• 1. RCTs investigating the effects of denosumab on patients diagnosed with both rheumatoid arthritis and osteoporosis.

• 2. Studies that measured bone mineral density (BMD), bone erosion scores, joint space narrowing, or the modified total Sharp score (mTSS) as primary or secondary outcomes.

• 3. Studies published in English or with English translations available.

Exclusion criteria

• 1. Studies that included patients with other significant bone disorders apart from osteoporosis.

• 2. Non-randomized studies, observational studies, or studies without relevant outcome measures.

• 3. Studies with insufficient data or incomplete reporting of outcomes.

Two independent reviewers screened the titles and abstracts of the retrieved studies for eligibility. Any discrepancies between the reviewers were resolved through consensus or consultation with a third reviewer.

Data extraction and quality assessment

Data from the included studies were extracted by two reviewers using a pre-designed data extraction form. Extracted data included the following:

• 1. Study characteristics (author, year of publication, sample size, study design, and duration of treatment)

• 2. Participant characteristics (age, sex, race/ethnicity, and baseline clinical status)

• 3. Intervention details (denosumab dosage, treatment duration, and control group treatments)

• 4. Outcome measures (BMD, bone erosion score, joint space narrowing score, and mTSS)

The methodological quality of each study was assessed using the Cochrane risk-of-bias tool, which evaluates domains such as random sequence generation, allocation concealment, blinding, and incomplete outcome data. Studies were rated as having low, high, or unclear risk of bias in each domain.

Statistical analysis

We performed a meta-analysis using the Review Manager (RevMan) software (version 5.4). The results were expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Statistical heterogeneity across studies was assessed using the I² statistic, where I² values of 25%, 50%, and 75% were considered low, moderate, and high heterogeneity, respectively. A random-effects model was used in cases of high heterogeneity. If sufficient data were available, subgroup analyses were performed based on participant characteristics (e.g., age, gender, baseline BMD) and treatment specifics (e.g., denosumab dosage). Sensitivity analyses were also conducted to assess the robustness of the results.

For publication bias assessment, we used Begg's and Egger's tests when sufficient studies were available (≥ 5 studies for an outcome). However, we acknowledge that these tests have limited power when the number of included studies is small, and therefore, results should be interpreted with caution.

PRISMA guidelines

This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PRISMA checklist was used to ensure transparency and completeness of the review process.

Results

Literature search results

A total of 651 potentially relevant articles were identified through the search process, which resulted in 458 unique records after the removal of duplicates. Following the review of titles and abstracts, 12 articles was selected for further assessment. Subsequent to the exclusion of articles that did not meet the outcome criteria and those that were retrospective studies, a final total of 7 articles were included in the analysis [13,14,15,16,17,18,19]. The basic characteristics of the included studies are summarized in Table 1, and the PRISMA flow diagram, illustrating the study selection process, is presented in Fig. 1. The literature incorporated in this study is of relatively high quality (Figs. 2 and 3).

Table 1 The basic characteristics of the included studies. Treat: treatment; Con: control. ①BMD; ②Bone erosion score; ③Joint space narrowing score; ④Modified total sharp score; ⑤DAS28.28-joint count Disease Activity Scores

Fig. 1

Flow chart of denosumab in treatment of osteoporosis in patients with rheumatoid arthritis

Fig. 2

Risk of bias summary

Fig. 3

Risk of bias graph

BMD

A cumulative total of 2 studies have reported on the impact of denosumab on BMD in rheumatoid arthritis patients undergoing osteoporosis treatment. This limited number of studies for BMD analysis reflects the fact that not all RCTs investigating denosumab in RA patients measured BMD as an outcome, rather than indicating poor study quality or data exclusion. The findings indicated a statistically significant improvement (P < 0.01, SMD: 3.08; 95% CI: 1.73 to 4.42; Fig. 4). This suggests that the BMD outcomes for individuals with rheumatoid arthritis who received denosumab were superior to those in the placebo group. Due to the limited number of studies, site-specific BMD analyses (e.g., lumbar spine versus femoral neck) could not be performed, which represents a limitation of this analysis.

Fig. 4

Forest plot of BMD of denosumab in treatment of osteoporosis in patients with rheumatoid arthritis

Bone erosion score

A cumulative total of 6 studies have reported on the impact of denosumab on bone erosion score in rheumatoid arthritis patients undergoing osteoporosis treatment. The findings indicated a statistically significant improvement (P < 0.01, SMD: −0.62; 95% CI: −1.09 to −0.16; Fig. 5). In this analysis, Begg's and Egger's tests were utilized to assess the potential for publication bias concerning the reported outcome measures. The results of the Begg's test were non-significant with P = 0.452, exceeding the 0.05 threshold, and similarly, the Egger's test also yielded non-significant results with P = 0.302. These findings suggest that there is no evidence of publication bias in the study. This suggests that the bone erosion score outcomes for individuals with rheumatoid arthritis who received denosumab were superior to those in the placebo group.

Fig. 5

Forest plot of bone erosion score of denosumab in treatment of osteoporosis in patients with rheumatoid arthritis

Joint space narrowing score

A cumulative total of 5 studies have reported on the impact of denosumab on joint space narrowing score in rheumatoid arthritis patients undergoing osteoporosis treatment. The findings indicated a statistically significant improvement (P < 0.01, SMD: −0.11; 95% CI: −0.16 to −0.05; Fig. 6). The results of the Begg's test were non-significant with P = 0.806 and the Egger's test also yielded non-significant results with P = 0.619. These findings suggest that there is no evidence of publication bias in the study. This suggests that the joint space narrowing score outcomes for individuals with rheumatoid arthritis who received denosumab were superior to those in the placebo group.

Fig. 6

Forest plot of joint space narrowing score of denosumab in treatment of osteoporosis in patients with rheumatoid arthritis

The mechanism by which denosumab improves joint space narrowing scores is particularly interesting, as RANKL inhibition primarily affects osteoclast differentiation and bone resorption, while joint space narrowing predominantly results from cartilage loss. This suggests possible cross-talk between bone and cartilage metabolism pathways that warrant further investigation.

Modified total sharp score

A cumulative total of 5 studies have reported on the impact of denosumab on modified total sharp score in rheumatoid arthritis patients undergoing osteoporosis treatment. The findings indicated a statistically significant improvement (P < 0.01, SMD: −0.50; 95% CI: −0.80 to −0.21; Fig. 7). The results of the Begg's test were non-significant with P = 0.806 and the Egger's test also yielded non-significant results with P = 0.831. These findings suggest that there is no evidence of publication bias in the study. This suggests that the modified total sharp score outcomes for individuals with rheumatoid arthritis who received denosumab were superior to those in the placebo group.

Fig. 7

Forest plot of modified total sharp score of denosumab in treatment of osteoporosis in patients with rheumatoid arthritis

DAS28

A cumulative total of 2 studies have reported on the impact of denosumab on DAS28 in rheumatoid arthritis patients undergoing osteoporosis treatment. The research results show that there is no statistically significant difference (P = 0.574, SMD: 0.09; 95% CI: −0.23 to 0.42; Fig. 8). This suggests that the DAS28 outcomes for individuals with rheumatoid arthritis who received denosumab were not superior to those in the placebo group.

Fig. 8

Forest plot of DAS28 of denosumab in treatment of osteoporosis in patients with rheumatoid arthritis

Discussion

The results of this meta-analysis provide compelling evidence that denosumab significantly improves bone mineral density (BMD) and reduces bone erosion, joint space narrowing, and joint damage in patients with rheumatoid arthritis (RA) and osteoporosis. Our findings support the growing body of literature suggesting that denosumab is an effective treatment for osteoporosis in RA patients, where joint destruction and bone loss are major concerns.

Bone mineral density (BMD) improvement

Our analysis demonstrated a significant increase in BMD in the denosumab-treated group compared to the control group (P < 0.01). This is consistent with previous studies that have shown the effectiveness of denosumab in increasing BMD in osteoporotic patients, including those with RA. Denosumab inhibits osteoclast activity by binding to receptor activator of nuclear factor-kappa B ligand (RANKL), a critical mediator in osteoclast formation and function. By reducing osteoclast-mediated bone resorption, denosumab helps restore bone density and reduce fracture risk, which is particularly important in RA patients who are at an elevated risk of fractures due to both the inflammatory disease process and the use of corticosteroids [13, 14].

Bone erosion and joint space narrowing

The reduction in bone erosion and joint space narrowing observed in this study is an important finding. RA patients often experience progressive joint damage due to chronic inflammation, which results in the loss of bone and cartilage in the joints. Previous studies have shown that denosumab can effectively reduce bone erosion in RA patients [15]. Our meta-analysis extends these findings by showing a clear benefit of denosumab in preventing further bone damage in the presence of both RA and osteoporosis. These outcomes are clinically significant, as they suggest that denosumab not only improves bone mass but may also help to maintain joint function and prevent further deterioration, which is critical for improving quality of life and reducing disability in these patients [16].

The mechanism by which denosumab affects joint space narrowing deserves special attention, as this effect is less directly explained by RANKL inhibition. While denosumab primarily targets osteoclast differentiation through RANKL inhibition, several potential mechanisms may explain its effects on cartilage preservation:

• 1. Recent studies suggest that fibroblast-like synoviocytes (FLS) in RA also express RANKL. By inhibiting RANKL, denosumab may reduce FLS-mediated production of inflammatory cytokines and matrix metalloproteinases that contribute to cartilage degradation.

• 2. The RANKL/RANK/OPG system may have direct effects on chondrocytes or influence the bone-cartilage cross-talk through paracrine signaling mechanisms.

• 3. Reduction in bone erosion may decrease mechanical stress at the bone-cartilage interface, indirectly contributing to cartilage preservation.

• 4. RANKL inhibition may reduce levels of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) that drive both bone erosion and cartilage destruction.

Further research is needed to fully elucidate these mechanisms and to determine whether denosumab has direct effects on cartilage metabolism in addition to its well-established effects on bone.

Modified total sharp score (mTSS)

The decrease in the modified total Sharp score (mTSS) in the denosumab group indicates that denosumab may help to slow the progression of both joint damage and joint space narrowing in RA patients. mTSS is a widely used outcome measure in RA clinical trials, as it combines both bone erosion and joint space narrowing to assess overall joint damage. By reducing the rate of joint damage, denosumab offers a dual benefit in RA patients: improving bone density while potentially preserving joint integrity [17]. This finding is especially important given the high incidence of disability and joint deformities in patients with long-term RA.

Heterogeneity and sensitivity analysis

While the overall results were robust, we observed high heterogeneity (I² = 85%) in the BMD analysis. This suggests that there are differences in treatment regimens, patient characteristics, and study designs that may have influenced the results. However, the use of a random-effects model accounted for this variability and provided reliable estimates of treatment effects. Sensitivity analyses further confirmed the stability of our findings, indicating that the conclusions drawn from this meta-analysis are not significantly influenced by any single study.

The high heterogeneity observed is not unusual in meta-analyses of RA, as the disease presents differently across individuals, and the choice of denosumab dosage and treatment duration can vary between studies. It is also possible that differences in the populations studied (e.g., age, baseline disease severity, use of other medications) contributed to the variability in results. These factors highlight the importance of conducting subgroup analyses, which we performed, to explore the effects of denosumab across different patient groups [18].

Several important confounding factors should be considered when interpreting these results:

• 1. Disease activity: Baseline RA disease activity (as measured by DAS28) varied across studies and may influence treatment response. While our analysis of DAS28 showed no significant effect of denosumab on disease activity, baseline disease activity might still affect bone and joint outcomes.

• 2. Concurrent treatments: The use of conventional DMARDs, biological DMARDs, and glucocorticoids varied across studies and participants. These medications independently affect bone metabolism and joint damage progression.

• 3. Patient demographics: Age, gender, disease duration, and menopausal status (in women) can influence both osteoporosis severity and treatment response.

• 4. Treatment duration and dosage: Variations in denosumab dosing regimens and treatment duration may contribute to heterogeneity in outcomes.

While randomization in the included RCTs helps mitigate these confounding factors, differences in study designs and populations limit the ability to completely control for these variables in our meta-analysis.

Clinical implications

This meta-analysis provides strong evidence supporting the use of denosumab as an effective treatment for osteoporosis in patients with rheumatoid arthritis. By improving BMD, reducing bone erosion, and slowing joint space narrowing, denosumab addresses several critical aspects of the disease. RA patients with osteoporosis represent a particularly challenging group, as they face both the consequences of systemic inflammation and the negative effects of long-term corticosteroid use. Denosumab's ability to target osteoclasts directly provides a promising therapeutic option for maintaining bone health and reducing the risk of fractures and joint damage in this population.

In clinical practice, denosumab should be considered alongside other established treatments for osteoporosis in RA patients. Alternative treatments include:

• 1. Bisphosphonates (e.g., alendronate, zoledronic acid): These agents also inhibit osteoclast activity and are widely used in osteoporosis management. Compared to denosumab, bisphosphonates have a longer history of use and extensive safety data, but may be associated with gastrointestinal side effects (oral formulations) and have limitations in patients with renal impairment.

• 2. Teriparatide and abaloparatide: As anabolic agents that stimulate bone formation, these PTH analogs work through a different mechanism than denosumab. They may be particularly useful in patients with severe osteoporosis but are limited by their short approved treatment duration.

• 3. Selective estrogen receptor modulators (SERMs): Drugs like raloxifene may be options for postmenopausal women with RA and osteoporosis, though they typically produce smaller BMD gains compared to denosumab.

The choice between these agents should be individualized based on patient characteristics, preferences, contraindications, and cost considerations. In some cases, sequential or combination therapy may be beneficial.

The findings from this study have important clinical implications. Healthcare providers should consider denosumab as a treatment option for RA patients with osteoporosis, particularly those who are at high risk of fractures or who have already experienced significant joint damage. Given the proven efficacy of denosumab in improving bone health and joint outcomes, it may also be beneficial to incorporate denosumab into treatment strategies aimed at preventing further disease progression and disability in RA patients [19, 20].

Safety considerations

The safety profile of denosumab is an important clinical consideration. In our included studies, the most commonly reported adverse events included:

• 1. Infections: Upper respiratory tract infections, urinary tract infections, and pneumonia were reported, though rates were generally similar between denosumab and placebo groups.

• 2. Injection site reactions: These were typically mild and transient.

• 3. Hypocalcemia: Monitoring of calcium levels is recommended, particularly in patients with renal impairment.

More serious but rare adverse events associated with long-term denosumab use include:

• 1. Osteonecrosis of the jaw (ONJ): Risk factors include invasive dental procedures, poor oral hygiene, and concurrent use of glucocorticoids.

• 2. Atypical femoral fractures: These rare fractures have been reported with long-term antiresorptive therapy, including denosumab.

• 3. Serious infections: Given RANKL's role in immune function, theoretical concerns exist regarding infection risk, though clinical trials have not shown consistent significant increases.

• 4. Rebound bone turnover after discontinuation: Rapid bone loss and increased fracture risk have been observed after denosumab discontinuation, necessitating appropriate follow-up therapy.

The current meta-analysis could not comprehensively assess these safety outcomes due to limited reporting in the included studies and relatively short follow-up periods. Long-term safety surveillance remains essential for patients receiving denosumab.

Limitations

Despite the strengths of this meta-analysis, several limitations should be acknowledged. First, the high heterogeneity observed in the studies included in the analysis suggests that variability in study design, patient characteristics, and treatment regimens may have influenced the results. While we addressed this by using a random-effects model, further studies with more consistent methodologies are needed to clarify the optimal dosing and treatment duration of denosumab for RA patients.

Second, the small number of studies for certain outcomes, particularly BMD (only 2 studies), limits the statistical power and generalizability of these findings. This is a notable limitation that affects our ability to draw definitive conclusions about denosumab's effects on BMD in RA patients with osteoporosis, especially regarding site-specific effects (e.g., lumbar spine versus femoral neck BMD).

Third, although Begg's and Egger's tests did not detect significant publication bias, these tests have limited statistical power when the number of included studies is small. Therefore, the absence of detected publication bias should be interpreted cautiously. Additionally, the potential influence of industry funding on study design and reporting cannot be ruled out, as several included trials were sponsored by pharmaceutical companies that manufacture denosumab.

Additionally, the lack of long-term follow-up in the included studies means that the long-term benefits and potential adverse effects of denosumab treatment remain uncertain. Future research should explore the long-term safety and efficacy of denosumab in RA patients, especially in terms of fracture prevention and joint preservation.

Moreover, although this meta-analysis included data from seven RCTs, the total number of studies available for analysis is still limited. More RCTs with larger sample sizes are needed to confirm these findings and explore the effects of denosumab in different RA subgroups, such as patients with varying disease severity or those on different RA medications [21].

Conclusion

In conclusion, our meta-analysis demonstrates that denosumab appears to be a valuable therapeutic option for managing osteoporosis in RA patients, with the potential to improve both bone and joint outcomes. The treatment significantly improves BMD, reduces bone erosion, and slows joint space narrowing, addressing multiple aspects of bone and joint health in this challenging patient population.

When considering treatment options for RA patients with osteoporosis, clinicians should weigh denosumab alongside other available osteoporosis treatments such as bisphosphonates, considering individual patient factors, preferences, and contraindications. While our findings support denosumab's efficacy, longer-term studies with larger sample sizes are needed to better establish its long-term safety profile, optimal treatment duration, and effects on clinically important outcomes such as fracture risk reduction.

Given its ability to enhance bone mineral density and reduce joint damage, denosumab should be considered a key treatment in the management of osteoporosis in RA patients, particularly those who are at an increased risk of fractures and functional decline. However, vigilance regarding potential adverse effects, including hypocalcemia, infections, osteonecrosis of the jaw, and atypical femoral fractures, is essential for safe clinical use.