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Denosumab Inhibits Bone Loss in RA
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MedPage Today
Published: May 12, 2010
Treatment with the investigational agent denosumab (Prolia) protected against bone erosions and also increased bone mineral density (BMD) in patients with rheumatoid arthritis, a substudy of a phase II randomized trial found.
Among patients who received low-dose or high-dose denosumab, mean changes in hand BMD were +1% and +2.5% at 12 months, respectively, while the mean change in those who received placebo was -2%, according to Atul Deodhar, MD, of Oregon Health and Science University in Portland, and colleagues.
Mean modified Sharp erosion scores in the hands remained near baseline in the low- and high-dose groups, at +0.15% and +0.02, respectively at 12 months, compared with a change of +1.4% in those receiving placebo, the investigators reported in the May issue of Arthritis Care & Research.
Action Points
* Explain to interested patients that an investigational osteoporosis drug prevented the development of bone erosions and increased bone mineral density in patients with rheumatoid arthritis.
Rheumatoid arthritis is characterized by focal and systemic bone resorption, with increased osteoclast activity leading to abnormalities of bone remodeling.
The bone erosions and juxta-articular osteoporosis that result from this activation of osteoclasts are mediated via the RANKL (Receptor Activator for Nuclear Factor κ B Ligand) pathway.
Denosumab is a fully human monoclonal antibody that binds to RANKL, inhibiting the differentiation and activation of osteoclasts. It is being studied in a range of conditions associated with bone loss, including postmenopausal osteoporosis and cancer.
In addition, the safety and efficacy of the drug was evaluated in a double-blind study that included 227 patients with rheumatoid arthritis.
All patients had erosive disease and were on stable doses of methotrexate and less than 15 mg/day of prednisone.
Denosumab was administered in subcutaneous doses of 60 mg or 180 mg at baseline and again at six months.
In the original trial, BMD was measured at the lumbar spine, hip, femoral neck, and trochanter, and a subset of 56 patients also had hand BMD measured by dual x-ray absorptiometry at baseline and at months one, six, and 12.
To analyze the effects of denosumab on hand BMD and the potential correlation of BMD with hand erosion scores, Deodhar and colleagues analyzed data from this subset of patients.
At six months, mean changes in BMD from baseline were:
* Placebo, -1.2%
* 60 mg denosumab, +0.8%
* 180 mg denosumab, +2%
Mean radiographic Sharp erosion scores at six months were +0.07% for both active treatment groups and +1.2% for placebo.
Erosion scores were also assessed using MRI, and at six months were +0.4% and +0.1% for the low- and high-dose groups, and +3.8% for the placebo group.
Analysis using Spearman's rank correlation determined that scores for hand BMD and the changes from baseline in hand BMD were negatively correlated with the erosion scores and changes from baseline in erosion scores at all time points, with the exception of the change in hand BMD and change in MRI erosion score at six months.
"Bone loss in the hands and feet of patients with RA is one of the first indications of impending bone erosions, and has been shown to be predictive of long-term RA damage," the investigators wrote.
In addition, loss of bone mineral density in the hands is predictive of loss of hand function, so denosumab treatment may help prevent functional deterioration, they said.
Previous studies of biologic (anti-TNF) drugs have found effective prevention of bone erosions, but no agent thus far has shown inhibition of periarticular bone loss.
"Although both types of bone loss are a consequence of RANKL-mediated osteoclast activity, the failure of anti-TNF agents to prevent periarticular bone loss may indicate two different pathologic mechanisms for these two types of bone damage," they wrote.
Periarticular osteoporosis in rheumatoid arthritis may have a TNF-independent mechanism, such as patients' inactivity.
The success of denosumab in preventing the two types of bone loss may in part relate to the drug's final downstream inhibition of osteoclasts, they concluded.
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