SAN DIEGO, CA—Significant increases in bone mineral density (BMD) were observed after 12 months of treatment with denosumab vs. placebo in patients with rheumatoid arthritis (RA) regardless of glucocorticoid use, according to a study presented at the 2013 ACR/ARHP Annual Meeting.
Denosumab, a fully human monoclonal IgG2 antibody, is a potent inhibitor of RANKL and osteoclast genesis. “RANKL is an essential factor for osteoclast differentiation and activation,” explained Yoshiya Tanaka, MD, PhD, from the University of Occupational and Environmental Health, Japan. Denosumab inhibits the activation and survival of osteoclasts, which leads to the reduced bone turnover and reduction of bone resorption.
Dr. Tanaka and colleagues investigated the pathological effect of denosumab regarding its efficacy on bone turnover and structural damage in Japanese patients with RA receiving methotrexate. The Phase 2, 12-month, multicenter, randomized, double-blind, placebo-controlled study included the following four treatment arms: denosumab 60mg every 6 months (n=86), every 3 months (n=85), every 2 months (n=87), or placebo (n=88). Bisphosphonate, PTH and PTH derivative use was prohibited; however, us of oral glucocorticoid ≤10 mg/day, prednisolone equivalent) was allowed. Daily vitamin D (≥400 IU) and calcium (≥600mg) supplements were taken concomitantly across all groups.
The primary end point was the change in bone erosion score from baseline to 12 months.
BMD of the lumbar spine (L1–L4) and total hip including the femoral neck were measured by dual energy X-ray absorptiometry at 0, 6, and 12 months. In addition, serum CTX-I and P1NP, and urinary CTX-II were collected at 0, 1, 2, 3, 4, 6, and 12 months.
A total of 350 patients were enrolled, of which 346 patients received treatment. Results showed significant increases in BMD in lumbar spine for the denosumab 60mg every 6 months arm (4.62, 95% CI 3.70, 5.53; P<0.0001), every 3 months arm (5.35, 95% CI 4.41, 6.29; P<0.0001), and every 2 months arm (6.30, 95% CI 5.38, 7.23; P<0.0001), including the patients with concomitant glucocorticoid use.
Similarly, increases in BMD were also seen in and total hip for the denosumab 60mg every 6 months arm (3.32, 95% CI 2.58, 4.06; P<0.0001), every 3 months arm (3.28, 95% CI 2.53, 4.04; P<0.0001), and every 2 months arm (3.51, 95% CI 2.77, 4.26; P<0.0001), including the patients with concomitant glucocorticoid use.
“Denosumab rapidly and strongly decreased bone turnover markers compared with placebo in all dosing regimens,” noted Dr. Tanaka. “The delayed decrease in P1NP compared with sCTX-I suggests that denosumab acts primarily to inhibit bone resorption and then coupling between bone resorption and formation secondarily reduces bone formation. Changes in bone turnover markers caused by denosumab indicate that the increase in BMD, and suppression of erosive progression in joints of the hands and feet is caused by inhibition of bone resorption.”
The investigators noted that the overall number of fractures in this study was low due to the short duration, relatively few patients, and low prevalence of osteoporosis.