DMARDs Effect on Bone Loss in Rheumatoid Arthritis

August 9, 2019

Modern pharmacologic therapies for rheumatoid arthritisare effective in controlling inflammation and preventing bone erosions however, a multitude of factors are likely to blame for ongoing bone loss in rheumatoid arthritis.

Modern pharmacologic therapies for rheumatoid arthritisare effective in controlling inflammation and preventing bone erosions however, a multitude of factors are likely to blame for ongoing bone loss in rheumatoid arthritis.

“The overall framework seems to point towards a favorable effect on bone health exerted by these drugs, even though for some of them the clinical benefit appears small or still hypothetical. It is arguable that some of the observed benefits may be simply a consequence of the inhibition of inflammation, while for some drugs it might be also dependent by the drug-specific mechanism of action, ” according to the authors a review published in Pharmacological Research last month.

Local and systemic bone loss leading to osteopenia and osteoporosis are common consequences of rheumatoid arthritis. Bone loss leading to fragility fractures can lead to greater disability in rheumatoid arthritis patients and in turn increase erosive progression of the disease. While inflammation and immune dysregulation are clear culprits in joint erosion, there are other risk factors tied to bone loss such as smoking, alcohol, decreased physical exercise, and reduced intake of calcium and vitamin D.

Multiple pathways including osteo-immunologic inflammation lead to increased bone absorption and blunted bone formation in rheumatoid arthritis. Cytokines and other modulators mediate this imbalance in removal and replacement of bone by osteoclasts and osteoblasts with nutritional vitamin D and calcium homeostasis having a more direct effect on bone mass. The authors sought to determine the effects current disease modifying anti-rheumatic drugs have on bone mass in patients with rheumatoid arthritis. To this end the authors performed a meta-analysis of current literature on the subject.

TNF INHIBITORS

Studies most consistently show that patients treated with adalimumab and infliximab for rheumatoid arthritis had stable bone mineral density in the hips and slight increases at the spine. Patients treated with tumor necrosis factor inhibitors showed better outcomes with regards to bone density when compared to those on conventional synthetic disease modifying anti-rheumatic drugs. With regards to fracture risk, rheumatoid arthritis patients on tumor necrosis factor inhibitors either saw no change or reduced risk.

INTERLEUKIN-6 INHIBITORS

Studies are limited looking at interleukin inhibitors and bone density in rheumatoid arthritis. In one study looking at tocilizumab, a small increase in femoral and lumbar bone mineral density was observed while in a more recent one density remained stable over two years. Across studies the effect of interleukin inhibitors on bone mass is limited to stabilization or a small gain.

CO-STIMULATION INHIBITION

Abatacept is a fusion protein inhibitor of the second signal co-stimulatory pathway activation of T cells. While studies are limited abatacept appears to reduce the activity of osteoclast cells, which may reduce bone resorption. All in all the limited evidence appears promising.

B-CELLS DEPLETION

Rituximab is a monoclonal antibody licensed for the treatment of rheumatoid arthritis that acts by impairing B cells’ function. Although evidence is sparse, significant positive effects on bone metabolism have been reported with rituximab. However, the use of steroids and bisphosphonates may attenuate any benefit to bone mass with rituximab.

JAK STAT BLOCKADE

Tofacitinib, a small molecule traditional synthetic disease modifying anti-rheumatic drug, inhibits Janus kinase and in turn the transcription of inflammatory cytokines. While almost no data exist looking at JAK drugs and bone density the JAK STAT pathway has been implicated in low mineral density found in some patients as well as in mouse models.

TAKE-HOME POINTS FOR CLINICIANS AND FINAL THOUGHTS

DMARDs are effective in reducing inflammation and bone erosions in rheumatoid arthritis. Although inflammation is the key feature of rheumatoid arthritis, it is clear that bone metabolism plays an important role in the loss of bone mass over time.

Clinicians should strive to control disease activity in rheumatoid arthritis and promote bone-sparing modifications related to comorbidities through exercise, limiting glucocorticoid treatment and maintaining good nutrition.

Ultimately clinicians should see inflammatory erosions in rheumatoid arthritis as both a cause and result of osteoporosis with one worsening the other in a circular fashion.

Modern disease modifying anti-rheumatic drugs appear to have a net positive effect on bone mineral density in patients with rheumatoid arthritis and should be a part of a holistic treatment plan aimed at lower disease activity and reduced bone loss in patients with rheumatoid arthritis.

REFERENCE:  Orsolini G, Fassio A, Rossini M, et al. “Effects of biological and targeted synthetic dmards on bone loss in rheumatoid arthritis.” Pharmacological Research (2019), https://doi.org/10.1016/j.phrs.2019.104354