A One Year Case Control Study in Rheumatoid Arthritis Patients Indicates a Prevention of Bone Mineral Density Loss in Both Responders and Non Responders to Infliximab

Hubert Marotte; Beatrice Pallot-Prades; Laurent Grange; Philippe Gaudin; Christian Alexandre; Pierre Miossec


Arthritis Res Ther. 2007;9(3) 

In This Article

Abstract and Introduction

The goal of the present study was to record changes in bone mineral density (BMD) and markers of bone turnover in patients with rheumatoid arthritis (RA) who were treated with methotrexate combined (or not combined) with infliximab. Included were 90 patients with RA who required anti-TNF-α therapy with infliximab because of persistent active disease despite treatment with methotrexate. The historical control group included 99 patients with RA who were treated with methotrexate at a time when anti-TNF-α treatment was not yet available. Lumbar and femoral neck BMD was measured using dual energy X-ray absorptiometry at baseline and 1 year later. Osteocalcin, C-terminal cross-linked telopeptide of type I collagen, parathyroid hormone and 25-hydroxycholecalciferol were measured in plasma at baseline and 1 year later. At 1 year BMD had decreased in the control group at spine (P < 0.01) and femoral neck (P < 0.001). In contrast, BMD at spine and femoral neck did not change after 1 year of infliximab treatment. At the same time point, no change in bone remodelling markers was observed. No association was observed between clinical response and changes in BMD, indicating that even those who did not respond clinically did not lose bone over a 1-year period. These data confirm the BMD decrease observed in RA patients treated with methotrexate alone. This bone loss was prevented by infliximab therapy. Importantly, this beneficial effect was also observed in apparent nonresponders.

Rheumatoid arthritis (RA) is a chronic disease that is characterized by joint inflammation and local bone erosion. In addition, generalized bone loss has been demonstrated in RA patients.[1,2] This could be due to the disease itself, to reduced exercise activity, or to treatment with steroids,[3] but it could also result from common postmenopausal osteoporosis.

Among the factors that can influence bone resorption and osteoclast activity, tumour necrosis factor (TNF)-α plays a central role in the destructive process of RA and has been shown to increase bone resorption in systemic osteoporosis related to oestrogen deficiency[4]. In transgenic mice expressing soluble TNF receptor to neutralize TNF-α, animals were protected from oestrogen deficiency-related bone loss.[5] TNF-α is also a powerful inhibitor of bone formation.[6]

Infliximab is a neutralizing chimeric monoclonal anti-TNF-α antibody that has been successfully used in RA treatment,[7] and has an effect on joint destruction.[8] However, its systemic effect on bone remains to be elucidated. In this study, we compared bone mineral density (BMD) values between RA patients treated with infliximab and those not receiving infliximab. Previous open studies have demonstrated either an increase in BMD or no change. A major limitation of these studies is that they did not include a control group.[9,10] The optimal design for this type of study would be a double-blind randomized comparison with placebo. However, because TNF-α blockers are now on the market, ethical issues would prevent such a randomized, placebo-controlled trial. Another option is to perform a historical control study, with controls being active RA patients followed before the advent of TNF-α blocker therapy and who were treated with methotrexate alone. Such a historical control group is of great interest because it is not influenced by use of TNF inhibitors in patients with the most active disease.

This case-control study was conducted to compare changes in BMD between RA patients treated with infliximab and those not receiving this agent over 1 year. Moreover, we investigated bone turnover using biochemical markers of bone formation and resorption, and we studied the relationship between changes in BMD and clinical response to therapy.


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