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

Disclosures

Arthritis Res Ther. 2007;9(3) 

In This Article

Discussion

To our knowledge, this appears to be the first study to examine the effect of infliximab on BMD in RA patients and to compare the findings with those in a control group. The major finding of our study is that bone loss was prevented in RA patients treated with infliximab. This protective effect was also observed in patients who did not exhibit a clinical response.

Bone loss in RA patients depends on a number of factors. This patient population is already at high risk for osteoporosis because of advanced age, female sex and menopause. In addition, active disease and extended duration of disease also have indirect adverse effects on bone, combined with the use of steroids and even methotrexate. Selecting an appropriate control group for such a study is difficult. Even a planned placebo-controlled trial is imperfect, because the application of exclusion criteria represents a difference from the real world situation. Accordingly, we opted to use historical controls because infliximab is now on the market, and it would be unethical not to use and even to withhold infliximab treatment from RA patients with active disease. We regarded the optimal situation to be one in which the only major difference between groups would be receipt/nonreceipt of infliximab. Outside the setting of a formal clinical trial, the best available option was to select a population of RA patients followed at the same institution at a time before the advent of anti-TNF-α treatment.

We first verified that our populations at baseline were representative. We were able to confirm the presence of the typical correlations of age and disease duration with lower BMD. Similarly, patients receiving steroids exhibited lower levels of markers of bone formation markers. Our findings of these usual correlations provide validation of the data at baseline.

In the study, we were unable to demonstrate an increase in BMD with infliximab, as was recently observed in smaller studies conducted without a control group in RA patients (n = 26)[9] and in patients with spondylarthropathy (n = 29)[14] and Crohn's disease (n = 46).[15] Recently, however, infliximab was found to prevent deterioration in BMD at spine and hip, but not in hands in RA patients.[10] Once again, however, no control group was employed.

Regarding markers of bone turnover, no significant changes were observed over the 1 year of follow up. However, negative correlations between BMD and osteocalcin in this population contrast with the physiological association between osteocalcin and bone formation. The findings suggest a defect in bone formation that may be explained, in part, by systemic inflammation. Indeed, in one of our previous studies,[16] uncoupling between bone destruction and formation was observed in destructive RA. Such uncoupling was not observed in benign RA. It now appears that TNF-a inhibition may restore this coupling of destruction with formation.

Early changes in bone markers were previously observed in a study conducted in 68 RA patients who were treated with infliximab.[17] Bone formation markers (osteocalcin and N-propeptide of type I procollagen) increased quickly at weeks 2 and 6 after initiation of infliximab treatment. The long-term effect of infliximab at 1 year was recently described in a small population of patients with RA (n = 26),[9] manifesting as a persistent increase in osteocalcin (reflecting bone formation) and a persistent decrease in CTX-I (reflecting bone resorption). However, in 70 patients with RA who were treated with infliximab plus methotrexate, a decrease was observed only in bone resorption markers (urinary excretion of N-telopeptide of type I collagen and deoxypyridinoline).[18] No effect on serum bone alkaline phosphatase, a marker of bone formation, was observed. In patients with spondylarthropathy treated with infliximab, an early decrease in CTX-I was observed at 3 months (-50%; P = 0.005). However, CTX-I levels further increased at 1 year as compared with baseline.[19] In another study, infliximab therapy had a lesser effect on serum osteoprotegerin and soluble receptor activator of nuclear factor-kB ligand (sRANKL) in RA patients.[20] Recently, decreases in CTX-I and sRANKL were observed over 1 year of infliximab treatment.[10] However, in none of these studies was a control group included, preventing a true estimation of the effect of anti-TNF-a treatment on bone. In this study, an early and transient effect on markers of bone turnover (increased bone formation and decreased bone resorption) was found to be associated with the effect on BMD at 1 year, as was demonstrated in a previous study for CTX-I.[10]

It appears that blocking TNF-a is protective with respect to bone mass, and this effect of infliximab on BMD was independent of use of biphosphonates and other putative covariates. That this protective effect was also observed in clinical nonresponders to infliximab is in accordance with the findings of a recent study[8] that demonstrated protective effects on joint destruction in the absence of clinical response. Similarly, studies conducted in postmenopausal women[4] identified an association between activated status in blood mononuclear cells/monocytes and increased production of proinflammatory cytokines. This increase was sensitive to oestrogen replacement.

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