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Joint erosions in RA result from a complex process with multiple contributing mechanisms. One of those mechanisms involves RANK receptor activation by RANKL leading to osteoclast differentiation, activation and survival.
Denosumab is a fully human monoclonal antibody that binds specifically to human RANKL. Approved for treatment of osteoporosis, denosumab is now being investigated in RA studies, in view of its potential ability to inhibit the progression of bone erosion and bone loss.
The DRIVE study was a multicenter, randomized, double-blind, placebo-controlled, phase II study in Japan, conducted over 12 months. Japanese patients who had RA were randomized in a 1:1:1:1 ratio to receive one of four treatments: a placebo; denosumab 60 mg every 6 months (Q6M); denosumab 60 mg every 3 months (Q3M); or denosumab 60 mg every 2 months (Q2M). Radiographs at baseline, 6 and 12 months were submitted to the central analyzing center (Synarc, California, USA) for Modified Sharp score evaluation.
Denosumab significantly inhibited the progression of bone erosion at 12 months. The mean changes of the modified Sharp erosion score at 12 months from baseline were as follows:
- 0.27 in denosumab Q6M
- 0.14 in denosumab Q3M (p=0.0082)
- 0.09 in denosumab Q2M (p=0.0036)
- 0.99 in the placebo (p<0.0001).
Meanwhile, modified Sharp JSN (Joint Space Narrowing) score did not differ between denosumab and placebo groups.
Modified TSS was significantly different in all denosumab treatment groups as opposed to placebo at 12 months, but at 6 months only Q2M group appeared to show statistically significant difference. Investigators pointed out that effect of denosumab on BMD was not affected by steroid use in RA patients. Also, the safety profiles of denosumab groups were generally comparable with the placebo group.
The authors concluded that denosumab in combination with methotrexate has potential to be a new therapeutic option for patients with RA with risk factors for joint destruction.