Background/Purpose

Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by joint and bone destruction. Loss of bone in RA is not only localized in joints but is also generalized. Tumor necrosis factor (TNF) alpha is involved in the pathogenesis of joint erosion and loss of bone. TNF alpha is also known to be an inhibitor of bone formation through Wnt pathway and RANKL/osteoprotegerin balance. The use of TNF alpha inhibitors (TNFi) has effect on focal bone erosions. This has led to the hypothesis that TNFi has a positive effect on bone mineral density. The aim of this study is to summarize the published data on the effect of TNFi on bone mineral density (BMD) and bone markers in RA by a systemic review of the literature and meta-analysis.

Methods

We searched Medline via PubMed, COCHRANE and EMBASE database for articles published up to April 2014 using Mesh terms  (“Bone mineral density” (MeSH) OR “bone” (MeSH) OR “bone remodeling” (MeSH) AND “rheumatoid arthritis” AND (“infliximab” OR “adalimumab” OR “etanercept” OR “certolizumab” OR “golimumab” OR “anti-TNF”). To be selected a study need to be a controlled trial with a group treated by TNFi and a control group without treatment of interest or to have values before and after treatment by TNFi or value of variation under treatment of at least one variable among BMD at hip or lumbar spine, CTX-1, Bone Alkaline bone Phosphatase (BAP), osteocalcin (OC) and type 1 collagen amino-terminal propeptide (P1NP). Statistical analysis of pre and post-data was performed using Comprehensive meta-analysis software. The percentage heterogeneity in the study results was determined by the Cochran’s Q-test and the I² values. A significant statistical threshold of 0.05 was used.

Results

The search retrieved 49 articles. 15 articles complied with inclusion criteria. Although heterogeneity was high, BMD at hip and lumbar spine stay unchanged after TNFi (6 studies for hip BMD including 386 patients and 7 studies for lumbar spine BMD including 443 patients ) with a mean difference of  0.058 (-0.220 to 0.337, IC95%) for BMD at hip and of 0.154 (-0.110 to 0.418,IC95%) for BMD at lumbar spine. In controlled trials, no difference was found for BMD at hip or at lumbar spine (6 studies; 558 patients). Concerning bone remodeling markers, CTX level was statistically decreased in 2 studies and showed a trend of decrease in 4 other studies. OC level increased statistically in 4 studies and decreased no significally in a fifth one ; P1NP level was increased significally in 1 study of 3 available whereas BAP level did not significally change in studies available ( 2 studies).  BMD change were influenced by therapeutic response to TNFi in 2 studies, with a trend in a third one whereas no association was found in 3 other studies.

Conclusion

TNFi in RA seem to decrease bone resorption and to increase bone remodeling at biologic levels but do not have an effect on BMD. However, only few data with mid-term assessment are available with an important heterogeneity in terms of patients included, disease duration, comedications and follow up. Several long term trials are required to evaluate the exact effect of TNFi on bone mineral density in rheumatoid arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/can-tumor-necrosis-factor-inhibitors-protect-rheumatoid-arthritis-patients-from-osteoporosis-impact-of-tumor-necrosis-factor-inhibitors-on-bone-mineral-density-and-bone-remodeling-markers/