Effect of TNF-alpha inhibitor treatment on bone mineral density in patients with ankylosing spondylitis: A systematic review and meta-analysis

https://doi.org/10.1016/j.semarthrit.2014.05.008Get rights and content

Abstract

Objectives

Ankylosing spondylitis (AS) is a chronic inflammatory disease associated with an increased risk of osteoporosis and fractures. TNF inhibitors have been used to treat AS, but their effect on bone is unclear. Thus, we conducted a meta-analysis to study the effect of TNF inhibitors on spine and hip BMD in patients with AS.

Methods

Two authors independently searched MEDLINE and PubMed for longitudinal studies that had assessed the effect of TNF inhibitors on BMD in patients with AS. Studies with a minimum follow-up period of 1 year were included.

Results

Seven longitudinal studies and one randomized control trial were included, with a total of 568 AS patients (mean age range of 36–48 years and disease duration of 9–17 years). Lumbar spine BMD increased by 5.1% (95% CI: 4.0–6.1%, p = 0.00000) after 1 year of treatment with TNF inhibitors and by 8.6% (95% CI: 6.8–10.3%, p < 0.00001) after 2 years. Significant improvements in total hip BMD were also noted after 1 [1.8% (1.0–2.5%)] and 2 years [2.5% (1.9–3.0%)]. Compared to baseline, femoral neck BMD remained stable after 1 year [0.7% (−0.8% to 2.2%), p = 0.34]. No significant heterogeneity was noted amongst the included studies.

Conclusions

TNF inhibitors can increase lumbar spine and total hip BMD and maintain femoral neck BMD for up to 2 years in patients with AS. More research is needed to assess the effect of TNF inhibitors on bone quality and fracture risk.

Introduction

It is established that patients with ankylosing spondylitis (AS) are prone to develop osteoporosis [1], [2]. The prevalence of osteoporosis in AS varies from 19% to 62% [3], [4], [5].

The etiology of osteoporosis in patients with AS is multifactorial, with systemic inflammation mediated by TNF-alpha being the most important etiogenic factor. TNF-alpha is known to adversely affect bone turnover by activating osteoclasts to cause bone resorption. It also increases the osteoblast apoptosis and decreases osteoblast proliferation, thereby inhibiting bone formation. Bone loss occurring from systemic inflammation is likely to be worse in the presence of other confounding factors. These include inflammatory bowel disease, malabsorption, low body weight, hypogonadism, decrease in skeletal loading, genetic factors, and low physical activity [3].

Osteoporosis has serious consequences, such as fractures. Patients with AS who develop osteoporosis are at a high risk of developing vertebral [6], [7], [8], [9], [10], [11], non-vertebral, and hip [7] fractures. Fractures can cause severe pain, physical deformity, disability, need for long-term care assistance, and poor quality of life. Fractures can be a huge financial burden to patients and the health care system [12]. Moreover, they are associated with increased mortality. Thus, it is crucial to identify effective strategies to treat osteoporosis and thereby prevent fractures in patients with AS.

Osteoporosis in patients with AS is generally treated with conservative measures and bisphosphonates. But the use of bisphosphonates in AS raises certain challenges and concerns. Firstly, patients with AS are relatively young, and if diagnosed with bone loss, they may require prolonged use of bisphosphonates. However, the long-term use of bisphosphonates may be associated with atypical femoral fractures (AFFs). The absolute risk of AFFs in patients using bisphosphonates is 3.2–50 cases per 100,000 person-years, but, with long-term use, the relative risk is higher at 100 per 100,000 person-years [13]. Secondly, it is unknown how effective bisphosphonates are in decreasing fracture risk in patients with AS. Thirdly, many patients with AS are in their reproductive years, so the use of bisphosphonates is of concern due to potential adverse effects on the growing embryo. Fourthly, both subclinical bowel inflammation and inflammatory bowel disease occur in patients with AS, resulting in malabsorption [14]. Oral bisphosphonates are poorly absorbed in the setting of malabsorption, limiting their therapeutic efficacy. Finally, prescribing bisphosphonates adds to the financial burden of patients who are already receiving expensive medications like TNF-alpha inhibitors. The new therapeutic agent, denosumab, available for management of osteoporosis, looks promising as an anti-osteoporosis medication in patients with AS. However, the potential adverse effects of adding another biological agent like denosumab to a treatment regimen involving biological drugs such as TNF-alpha inhibitors are still unclear.

TNF-alpha inhibitors have now revolutionized the treatment of AS [15], [16]; and all the above-mentioned issues warrant more focus on how various TNF-alpha inhibitor agents affect bone metabolism. Prior studies have shown that blockade of TNF-alpha reduces bone resorption [17]. This can result in improvement of bone mineral density (BMD). If TNF-alpha inhibitors are shown to be beneficial for preventing bone loss, use of additional osteoporosis medications such as bisphosphonates and denosumab can be avoided. In the past, some studies have attempted to examine how TNF-alpha inhibitors affect BMD. However, most of these studies had small sample sizes, and the effects on total hip and femoral neck BMD were inconsistent. Thus, we performed a systematic review and meta-analysis to critically evaluate the effect of TNF-alpha inhibitors on lumbar spine, total hip, and femoral neck BMD in patients with AS. We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement to guide the reporting of this systematic review and meta-analysis [18].

Section snippets

Selection criteria

We included studies that assessed the effect of TNF-alpha inhibitors on BMD with a minimum follow-up period of 1 year [19], [20], [21], [22], [23], [24], [25], [26]. Studies had to have more than 70% of subjects with AS and had to be published as a full-text original article. We restricted our search to human studies. We also excluded review articles [5], [27], [28], [29], [30], [31], [32], [33], studies with no longitudinal follow-up [34], editorials [35], and studies with follow-up less than

Studies selected

Figure 1 shows the flow diagram of the different phases of this review. We identified eight longitudinal studies for the final analysis [19], [20], [21], [22], [23], [24], [25], [26]. All the eligible studies were conducted at single centers and published in English. The study populations were from UK, USA, France, Germany, Netherlands, Brazil, and South Korea. Most subjects were men, and the proportion of male subjects varied from 56% to 92%. There were a total of 568 AS patients (mean age

Discussion

To our knowledge, this systematic review and meta-analysis is the first to assess the BMD changes occurring with TNF-alpha inhibitors in patients with AS. We found that TNF-alpha inhibitors improved lumbar spine and total hip BMD and maintained femoral neck BMD in patients with AS for up to 2 years. Prolonged exposure of anti-inflammatory agents may be needed for hip (both total hip and femoral neck) BMD to improve, as the hip has more cortical than the trabecular bone compared to the spine [21]

Conclusions

Our meta-analysis suggests that treatment with TNF-alpha inhibitors improves lumbar spine and total hip BMD and maintains femoral neck BMD in patients with AS for up to 2 years. Future research should assess if any difference in BMD gain exists between different TNF-alpha inhibitors. The effect of TNF-alpha inhibitors on bone quality and fracture prevention also needs to be studied. In addition, the potential role of non-TNF-mediated pathways on bone loss needs to be addressed to achieve

Author contributions

Nisha Nigil Haroon was actively involved in formulating the research question, designing the study, extracting data, doing statistical analysis, and writing the article. This study was performed as partial fulfillment for a Master׳s of Science degree at the Institute of Medical Sciences at the University of Toronto. Jeevitha Sriganthan was actively involved in designing the study, extracting data, doing statistical analysis, and writing the article. Nayef AlGhanim was actively involved in

References (47)

  • D. Vosse et al.

    Ankylosing spondylitis and the risk of fracture: results from a large primary care-based nested case–control study

    Ann Rheum Dis

    (2009)
  • R.J. Weiss et al.

    Increased fracture risk in patients with rheumatic disorders and other inflammatory diseases—a case–control study with 53,108 patients with fracture

    J Rheumatol

    (2010)
  • E. Klingberg et al.

    Vertebral fractures in ankylosing spondylitis are associated with lower bone mineral density in both central and peripheral skeleton

    J Rheumatol

    (2012)
  • D. Mitra et al.

    The prevalence of vertebral fractures in mild ankylosing spondylitis and their relationship to bone mineral density

    Rheumatology (Oxford)

    (2000)
  • N. Montala et al.

    Prevalence of vertebral fractures by semi automated morphometry in patients with ankylosing spondylitis

    J Rheumatol

    (2011)
  • S.H. Ralston et al.

    Prevalence of vertebral compression fractures due to osteoporosis in ankylosing spondylitis

    Br Med J

    (1990)
  • S. Budhia et al.

    Osteoporotic fractures: a systematic review of U.S. healthcare costs and resource utilization

    Pharmacoeconomics

    (2012)
  • E. Shane et al.

    Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research

    J Bone Miner Res

    (2014)
  • F. Ciccia et al.

    Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis

    Arthritis Rheum

    (2009)
  • B. Asli et al.

    Inhibition of tumor necrosis factor alpha and ankylosing spondylitis

    N Engl J Med

    (2003)
  • J. Brandt et al.

    Six-month results of a double-blind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitis

    Arthritis Rheum

    (2003)
  • M. Gengenbacher et al.

    Infliximab inhibits bone resorption by circulating osteoclast precursor cells in patients with rheumatoid arthritis and ankylosing spondylitis

    Ann Rheum Dis

    (2008)
  • D. Moher et al.

    Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

    Br Med J

    (2009)
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    Jeevitha Sriganthan and Nayef Al Ghanim have no conflicts of interest related to the preparation of this article. Nisha Nigil Haroon has received fellowship support from an unrestricted research grant supported by Amgen. Angela Cheung has received honoraria from AMGEN, Eli Lilly, and MERCK. Robert Inman has received consulting fees from Abbott, Janssen, and AMGEN.

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