The Paradox of Bone Formation and Bone Loss in Ankylosing Spondylitis: Evolving New Concepts of Bone Formation and Future Trends in Management
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Purpose of Review
The purpose of the study is to briefly review the molecular mechanisms that leads to structural damage in ankylosing spondylitis (AS), defined as new bone formation resulting in complete or incomplete ankylosis of the spine, and the impact of treatment with biologics to retard this process.
The understanding of molecular mechanisms leading to new bone formation in AS has significantly improved but is still incomplete. Availability of biologics has greatly enhanced the treatment of patients with AS, but its impact on slowing the structural damage is still a matter of debate, although a few observational studies have shown that long term use of TNF-α blockers may slow radiographic progression. The availability of newer biologics targeting IL-17/1L23 has shown some promising results in slowing radiographic progression in AS.
Although the availability of TNF-inhibitors has greatly enhanced the treatment options for patients with AS, their impact on slowing the structural damage is still not clearly established. However, preliminary results using newer biologics targeting IL-17/1L23 axis are more encouraging but longer follow-up is needed.
KeywordsAnkylosing spondylitis Axial spondyloarthritis Osteoproliferation Osteoporosis Bone morphogenetic proteins Wnt signaling pathways MicroRNAs TNF-α inhibitors Il-17 inhibitors Syndesmophytes New bone formation
We would like to thank Dr. Irving Kushner, Dr. Stanley Ballou, and Dr. Maria Antonelli for reviewing the paper and making necessary edits.
Compliance With Ethical Standards
Conflict of Interest
Dr. Magrey reports personal fees from UCB PHARMA and personal fees from Jansenn, outside the submitted work.
Dr. Khan declares no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
- 1.•• Taurog JD, Chhabra A, Colbert RA. Ankylosing spondylitis and axial spondyloarthritis. N Engl J Med. 2016;374:2563–74. This review article highlights recent advances in our understanding of relationship between spondyloarthritis and ankylosing spondylitis and treatments available.CrossRefPubMedGoogle Scholar
- 14.•• Xie Z, Wang P, Li Y, Deng W, Zhang X, et al. Imbalance between bone morphogenetic protein 2 and noggin induces abnormal osteogenic differentiation of mesenchymal stem cells in ankylosing spondylitis. Arthritis Rheum. 2016;68:430–40. The study revealed a mechanism of pathologic osteogenesis in AS by demonstrating an imbalance between BMP-2 and Noggin secretion in AS patients that possibly leads to abnormal osteogenic differentiation of AS MSCs.CrossRefGoogle Scholar
- 15.•• Magrey MN, Haqqi T, Haseeb A. Identification of plasma microRNA expression profile in radiographic axial spondyloarthritis—a pilot study. Clin Rheumatol. 2016;35:1323–7. Brief report about microRNA expression in AS and microRNA 34a is differentially expressed in SpA and has been shown to inhibit bone loss.CrossRefPubMedGoogle Scholar
- 29.Pedersen SJ, Sorensen IJ, Lambert RG, Hermann KG, Garnero P, Johansen JS, et al. Radiographic progression is associated with resolution of systemic inflammation in patients with axial spondylarthritis treated with tumor necrosis factor a inhibitors: a study of radiographic progression, inflammation on magnetic resonance imaging, and circulating biomarkers of inflammation, angiogenesis, and cartilage and bone turnover. Arthritis Rheum. 2011;63:3789–800.CrossRefPubMedGoogle Scholar
- 35.•• Haroon N, Inman RD, Learch TJ, et al. The impact of tumor necrosis factor alpha inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum. 2013;65:2645–54. This observational study shows that long term use of TNF inhibitors decreases the odds of radiographic progression in AS.PubMedPubMedCentralGoogle Scholar
- 40.van Duivenvoorde LM, Dorris ML, Satumtira N, van Tok MN, Redlich K, Tak PP, et al. Relationship between inflammation, bone destruction, and osteoproliferation in the HLA-B27/human β2-microglobulin-transgenic rat model of spondylarthritis. Arthritis Rheum. 2012;64:3210–9.CrossRefPubMedPubMedCentralGoogle Scholar
- 41.Poddubnyy D, Haibel H, Listing J, Märker-Hermann E, Zeidler H, Braun J, et al. Baseline radiographic damage, elevated acute-phase reactant levels, and cigarette smoking status predict spinal radiographic progression in early axial spondylarthritis. Arthritis Rheum. 2012;64:1388–98.CrossRefPubMedGoogle Scholar
- 42.•• Baraliakos X, Heldmann F, Callhoff J, Listing J, Appelboom T, Brandt J, et al. Which spinal lesions are associated with new bone formation in patients with ankylosing spondylitis treated with anti-TNF agents? A long-term observational study using MRI and conventional radiography. Ann Rheum Dis. 2014;73:1819–25. The study revealed that combination of acute inflammation on STIR sequence (fat-suppressed sequence) and fatty lesions are most predictive of syndesmophyte formation in AS.CrossRefPubMedGoogle Scholar
- 43.Maksymowych WP, Chiowchanwisawakit P, Clare T, et al. Inflammatory lesions of the spine on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis: evidence of a relationship between inflammation and new bone formation. Arthritis Rheum. 2009;60:93–102.CrossRefPubMedGoogle Scholar
- 44.Rudwaleit M, Jurik AG, Hermann KG, Landewe R, van der Heijde D, Baraliakos X, et al. Defining active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial spondyloarthritis:a consensual approach by the ASAS/OMERACT MRI group. Ann Rheum Dis. 2009;68:1520–7.CrossRefPubMedGoogle Scholar
- 45.•• Bleil J, Maier R, Hempfing A, Sieper J, Appel H, Syrbe U. Granulation tissue eroding the subchondral bone also promotes new bone formation in ankylosing spondylitis. Arthritis Rheum. 2016;68:2456–65. Granulation tissue and not fatty metaplasia may be promoting new bone formation in AS.CrossRefGoogle Scholar
- 47.•• Ward MM, Deodhar A, Akl EA, Lui A, Ermann J, Gensler LS, et al. American college of rheumatology/spondylitis association of america/spondyloarthritis research and treatment network 2015 recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Care Res (Hoboken). 2016;68:151–66. ACR/SPARTAN recommendation for treatment of AS.CrossRefGoogle Scholar
- 48.Rohekar S, Chan J, Tse SM, Haroon N, Chandran V, Bessette L, et al. 2014 update of the Canadian rheumatology association/spondyloarthritis research consortium of Canada treatment recommendations for the management of spondyloarthritis. Part II: specific management recommendations. J Rheumatol. 2015;42:665–81.CrossRefPubMedGoogle Scholar
- 51.Maas F, Spoorenberg A, Brouwer E, Bos R, Efde M, Chaudhry RN, et al. Spinal radiographic progression in patients with ankylosing spondylitis treated with TNF-α blocking therapy: a prospective longitudinal observational cohort study. PLoS One. 2015;10(4):e0122693.CrossRefPubMedPubMedCentralGoogle Scholar
- 52.•• Maas F, Arends S, Brouwer E, Essers I, van der Veer E, Efde M, et al. Reduction in spinal radiographic progression in ankylosing spondylitis patients receiving prolonged treatment with TNF-α inhibitors. Arthritis Care Res (Hoboken). 2016. doi: 10.1002/acr.23097. A longitudinal observational cohort study in daily clinical practice showed an overall slow and linear spinal radiographic progression in AS patients with long-term TNF-α blocking therapy.Google Scholar
- 53.van der Heijde D, Baraliakos X, Hermann KG, Landewé R, Machado P, Maksymowych W, Davies O, de Peyrecave N, Hoepken B, Bauer L, Nurminen T, Braun J. Four year imaging outcomes in patients with axial spondyloarthritis treated with certolizumab pegol, including patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10).Google Scholar
- 56.Appel H, Maier R, Wu P, Scheer R, Hempfing A, Kayser R, et al. Analysis of IL- 17(+) cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response. Arthritis Res Ther. 2011;13:R95.CrossRefPubMedPubMedCentralGoogle Scholar
- 59.van Tok M, van Duivenvoorde L, et al. Anti-IL17A treatment blocks new bone formation in experimental spondyloarthritis in HLA-B27 transgenic rats. Arthritis Rheumatol. 2015; 67 (suppl 10) [abstract].Google Scholar
- 60.•• Braun J, Baraliakos X, Deodhar A, Baeten D, Sieper J, Emery P, Readie A, Martin R, Mpofu S, Richards HB. Effect of secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2-year results from the randomised phase III MEASURE 1 study. Ann Rheum Dis. 2016 Dec 13. The paper describes the results from the international phase III MEASURE 1 study which showed low mean progression rates in spinal radiographic change with the anti-interleukin 17A antibody, secukinumab in patients with AS.Google Scholar
- 65.•• Sieper J, Listing J, Poddubnyy D, et al. Effect of continuous versus on-demand treatment of ankylosing spondylitis with diclofenac over 2 years on radiographic progression of the spine: results from a randomized multicenter trial (ENRADAS). Ann Rheum Dis. 2016;75:1438–43. The study could not confirm the disease modifying effect of NSAIDs in AS.CrossRefPubMedGoogle Scholar