Erosive hand osteoarthritis (OA), a prevalent and disabling condition, predominantly affects women and is characterized by significant structural damage to the finger joints. Existing treatments primarily focus on symptom management, lacking the ability to modify disease progression. This study aimed to investigate the structure-modifying potential of denosumab, a fully human monoclonal antibody that inhibits bone resorption by targeting RANKL, a key regulator of osteoclast activity. Previous studies have shown denosumab's efficacy in delaying erosive disease progression in rheumatoid arthritis, suggesting its potential applicability to erosive hand OA. The study hypothesized that denosumab would slow the progression of structural damage and prevent the formation of new erosive joints in patients with erosive hand OA. This proof-of-concept study focused primarily on radiographic endpoints, recognizing the heterogeneity of the disease and the possibility of a delayed clinical impact.

Erosive hand OA, often considered the more inflammatory subtype of hand OA, presents a substantial clinical burden. The disease is characterized by articular cartilage resorption, followed by subchondral bone osteolysis and eventual joint collapse. However, reparative processes like subchondral bone remodeling and the formation of bony nodules also occur. This simultaneous presence of destructive and reparative processes can persist for decades. Recent research indicates a link between bone loss and hand OA progression, suggesting erosive hand OA may be better viewed as a systemic bone disease rather than solely a cartilage disease. Histological studies have confirmed increased osteoclast activity in erosive hand OA, further supporting this concept. Previous studies exploring biological agents like TNF and IL-1 inhibitors for erosive hand OA have shown limited efficacy. However, denosumab, a well-established RANKL inhibitor used for osteoporosis and cancer-associated bone loss, has shown promise in delaying erosive progression in rheumatoid arthritis. This study aimed to build upon these observations by investigating denosumab's potential in erosive hand OA.

This monocentric, randomized, double-blind, placebo-controlled, parallel-group, phase 2a trial enrolled 100 patients with erosive hand OA, defined by radiographic evidence of at least one interphalangeal (IP) joint in the J or E phase of the Verbruggen and Veys anatomical phase scoring system, along with clinical and ultrasound signs of inflammation. Patients were randomized 1:1 to receive subcutaneous denosumab (60 mg) or placebo every 12 weeks for 48 weeks, followed by an open-label extension with denosumab for another 48 weeks. Daily oral calcium (1000 mg) and vitamin D (880 IU) supplementation was provided. The primary endpoint was the change in total GUSS score from baseline to week 24. Secondary endpoints included GUSS change at week 48 and the number of new erosive joints at week 48. Exploratory endpoints encompassed clinical and patient-reported outcome measures (pain, function), ultrasound assessments, and bone mineral density measurements. Two experienced rheumatologists independently assessed radiographic images using the GUSS and Verbruggen and Veys scoring systems. Statistical analyses utilized generalized estimating equations (GEE) for joint-level analyses and appropriate methods for patient-level data. Missing data were handled using predefined imputation models.

At week 24, the denosumab group showed a statistically significant improvement in the primary endpoint (estimated difference in GUSS change of 8.9; 95% CI, 1.0 to 16.9; P=0.024) compared to placebo. This effect was sustained at week 48 (estimated difference of 14.3; 95% CI, 4.6 to 24.0; P=0.003). Significantly fewer new erosive joints developed in the denosumab group at week 48 (odds ratio 0.24; 95% CI, 0.08 to 0.72; P=0.009). While changes in pain and function scores were not statistically significant at week 24 or 48, the open-label extension phase (weeks 48-96) revealed significant improvements in pain (P=0.02) and disability (P=0.04) in the denosumab group compared to the initial placebo group. Bone mineral density increased significantly in the denosumab group at the lumbar spine (P<0.001). The incidence of adverse events was higher in the placebo group compared to denosumab.

This study provides the first evidence that denosumab can effectively modulate structural damage in erosive hand OA. The observed reduction in radiographic progression and prevention of new erosive joints highlight the potential of RANKL inhibition as a disease-modifying treatment strategy. The lack of significant clinical improvement in the first 48 weeks aligns with previous studies demonstrating denosumab's primarily structure-modifying effects in rheumatoid arthritis. The subsequent clinical benefits observed in the long-term extension phase underscore the importance of sustained treatment to achieve comprehensive disease management, highlighting a potential shift in treatment focus from pain relief to structural damage prevention. The safety profile was reassuring, with a similar or lower rate of adverse events compared to the placebo group.

This placebo-controlled trial demonstrates the structure-modifying potential of denosumab in erosive hand OA. Denosumab significantly reduced radiographic progression and prevented the development of new erosive joints. Although initial clinical improvement was not seen within the first year, prolonged treatment led to a reduction in pain and disability. These findings suggest a promising new treatment avenue for a disease with significant unmet needs. Future research should investigate the long-term effects of denosumab, its impact on bone quality in non-osteoporotic patients, and the role of RANKL in disease pathogenesis. A larger, multicenter phase 3 trial is warranted to confirm these findings.

This study's monocentric design and relatively small sample size limit the generalizability of the results. The focus on a specific subset of patients with inflammatory signs may restrict the applicability of findings to other erosive hand OA subtypes. The lack of a validated surrogate marker for disease activity in erosive hand OA makes it difficult to fully assess the relationship between structural changes and clinical symptoms. The use of global questionnaires for pain and function may have masked the effects of treatment on individual joints. Furthermore, the delayed clinical benefits observed may be a limitation for some patients.