Effect of Tumor Necrosis Factor Alpha Inhibition on Bone Density and Turnover Markers in Patients with Rheumatoid Arthritis and Spondyloarthropathy

doi:10.1016/j.semarthrit.2008.04.004

Seminars in Arthritis and Rheumatism

Volume 39, Issue 2, October 2009, Pages 116-122

https://doi.org/10.1016/j.semarthrit.2008.04.004 Get rights and content

Objectives

Anti-tumor necrosis factor-α (TNFα) therapy has proven efficacious in improving both disease activity and focal bone erosions in patients with rheumatoid arthritis (RA) and spondyloarthopathies. We review the current literature reporting on the effect of anti-TNFα on bone density as measured by dual energy radiograph absorptiometry at the lumbar spine and hip, as well as markers of bone turnover and resorption, in patients using anti-TNFα for rheumatic disease indications.

Methods

A PubMed search, as well as manual search of related articles and references of articles retrieved, was performed to identify all studies pertaining to the effect of anti-TNFα therapy on bone mineral density (BMD) and bone turnover markers.

Results

In RA, 4 studies (238 patients) showed a stabilization or increase of BMD at the spine (up to 2.8%) or hip (up to 13.1%), with only 1 negative study in 48 patients (decline of 3.2% at the spine and 2.7% at the hip). In spondyloarthopathies, 3 studies (75 patients) all demonstrated an increase in BMD at the lumbar spine (3.2-3.6%) and at the hip (1.8-2.2%). Changes in markers of bone formation and bone resorption were heterogeneous but in general represented a modest increase in formation and decline in resorption.

Conclusions

In general, anti-TNFα therapy has a beneficial effect on bone density and bone turnover markers. Retrieved studies were heterogeneous with regards to patients studied, underlying risks for osteoporosis, and supplemental therapy, which may limit the findings of the true effect of anti-TNFα therapy on bone.

Section snippets

Methods

A PubMed search was completed in December 2007 for all published reports using the following search terms: bone AND anti-TNFα; rheumatoid arthritis AND osteoporosis; anti-TNFα therapy AND osteoporosis; bone mineral density (BMD) AND rheumatoid arthritis; bone turnover markers AND infliximab; osteoporosis AND infliximab AND spondyloarthropathy; along with a search of all related articles and a manual search of retrieved articles' references.

Information abstracted from the articles included the

Effect on Bone Density (Table 4)

In RA patients, only 1 study has demonstrated a decline of BMD of 3.2% at the lumbar region and 2.7% at the hip region during anti-TNFα therapy (10). The remaining identified studies have demonstrated either stable BMD (11, 12, 13) (within a 0.2% decrease or increase range) or a significant increase of 2.8% at the lumbar region and 13.1% at the hip (14). These studies differ widely with respect to a number of variables, including the patients' demographics, prior or current bisphosphonate

Discussion

Anti-TNFα treatment in RA and SpA patients has not only had significant effects on overall disease activity but available evidence would suggest this treatment also has a positive effect on bone. For the most part, the studies indicate a modest improvement in bone density, although most are of short follow-up duration. This effect may be independent of the actual clinical response to anti-TNFα therapy, with nonresponders demonstrating an improvement in BMD (11). However, most studies were of

References (28)

L. Sinigaglia et al.
Epidemiology of osteoporosis in rheumatic diseases
Rheum Dis Clin North Am
(2006)
E. Romas et al.
Inflammation-induced bone loss: can it be prevented?
Rheum Dis Clin North Am
(2006)
N. Saidenberg-Kermanac'h et al.
TNF-α antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis
Bone
(2004)
N.K. Henderson et al.
Relationship between osteoporosis and arthritis and effect of corticosteroids and other drugs on bone
Curr Opin Rheumatol
(1996)
C.J. Rosen
Postmenopausal osteoporosis
New Engl J Med
(2005)
A.D. Woolf
An update on glucocorticoid-induced osteoporosis
Curr Opin Rheumatol
(2007)
K.G. Saag et al.
Teriparatide or alendronate in glucocorticoid-induced osteoporosis
N Engl J Med
(2007)
M. Maricic
New and emerging treatments for osteoporosis
Curr Opin Rheumatol
(2007)
G. Gartlehner et al.
The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and metaanalysis
J Rheumatol
(2006)
W.P. Maksymowych et al.
Canadian Rheumatology Association Consensus on the use of anti-tumor necrosis factor-α directed therapies in the treatment of spondyloarthritis
J Rheumatol
(2003)

F. Chopin et al.

Long term effects of Infliximab on bone and cartilage turnover markers in patients with rheumatoid arthritis

Ann Rheum Dis

(2007)

H. Marotte et al.

A 1-year case-control study in patients with rheumatoid arthritis indicates prevention of loss of bone mineral density in both responders and nonresponders to infliximab

Arthritis Res Ther

(2007)

B. Seriolo et al.

Bone metabolism changes during anti-TNF-α therapy in patients with active rheumatoid arthritis

Ann NY Acad Sci

(2006)

M. Vis et al.

Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFκB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis

Ann Rheum Dis

(2006)

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: Cheryl Barnabe has no conflicts of interest to disclose.

: David Hanley claims Amgen as support, clinical trials of Denosumab; and serves on the Canadian advisory board.

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Rheumatoid arthritisEffect of Tumor Necrosis Factor Alpha Inhibition on Bone Density and Turnover Markers in Patients with Rheumatoid Arthritis and Spondyloarthropathy

Objectives

Methods

Results

Conclusions

Section snippets

Methods

Effect on Bone Density (Table 4)

Discussion

Rheum Dis Clin North Am

Rheum Dis Clin North Am

Bone

Relationship between osteoporosis and arthritis and effect of corticosteroids and other drugs on bone

Curr Opin Rheumatol

Postmenopausal osteoporosis

New Engl J Med

An update on glucocorticoid-induced osteoporosis

Curr Opin Rheumatol

Teriparatide or alendronate in glucocorticoid-induced osteoporosis

N Engl J Med

New and emerging treatments for osteoporosis

Curr Opin Rheumatol

The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and metaanalysis

J Rheumatol

Canadian Rheumatology Association Consensus on the use of anti-tumor necrosis factor-α directed therapies in the treatment of spondyloarthritis

J Rheumatol

Long term effects of Infliximab on bone and cartilage turnover markers in patients with rheumatoid arthritis

Ann Rheum Dis

A 1-year case-control study in patients with rheumatoid arthritis indicates prevention of loss of bone mineral density in both responders and nonresponders to infliximab

Arthritis Res Ther

Bone metabolism changes during anti-TNF-α therapy in patients with active rheumatoid arthritis

Ann NY Acad Sci

Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFκB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis

Ann Rheum Dis

Rheumatoid arthritis
Effect of Tumor Necrosis Factor Alpha Inhibition on Bone Density and Turnover Markers in Patients with Rheumatoid Arthritis and Spondyloarthropathy