Calcified Tissue International

, Volume 98, Issue 5, pp 438–445 | Cite as

Higher Level of Dickkopf-1 is Associated with Low Bone Mineral Density and Higher Prevalence of Vertebral Fractures in Patients with Ankylosing Spondylitis

  • Maurizio RossiniEmail author
  • Ombretta Viapiana
  • Luca Idolazzi
  • Francesco Ghellere
  • Elena Fracassi
  • Sonila Troplini
  • Maria Rosaria Povino
  • Vidya Kunnathully
  • Silvano Adami
  • Davide Gatti
Original Research


Patients with ankylosing spondylitis (AS) have an increased risk of bone loss and vertebral fractures. In this study, we explored the hypothesis that the excess bone loss and vertebral fractures might be related with the activity of the Wingless signaling pathway, and in particular with the serum levels of its circulating inhibitors, Sclerostin and Dickkopf-1 (DKK1). We recruited 71 patients diagnosed with AS. Lateral radiographs of the total spine were analyzed to detect the presence of vertebral fractures, and bone mineral density (BMD) was assessed in all patients using dual X-ray absorptiometry at lumbar spine and proximal femoral site. Blood samples were obtained and levels of C-reactive protein (CRP), DKK1, and Sclerostin were measured. Blood samples from 71 healthy sex- and age-matched volunteers were collected to be used as controls. Vertebral fractures were detected more commonly among men than in women (29 vs 8 %, respectively). DKK1, but not Sclerostin serum levels, were inversely correlated to lumbar spine Z-score BMD. Patients with one or more prevalent vertebral fractures had significantly higher DKK1 levels, without significant difference in Sclerostin serum levels. A significant positive correlation was found between DKK1 serum levels and CRP (r = 0.240, p = 0.043). The association we found between serum DKK1 levels and BMD values and vertebral fracture prevalence suggests that DKK1 might contribute to the severity of osteoporosis in AS.


Ankylosing spondylitis DKK1 Bone mineral density Osteoporosis Sclerostin 



The authors would like to thank the laboratory teams, especially Caterina Fraccarollo and Cristina Bosco for performing the biochemical analyses. The authors thank Sara Rossini who provided editorial assistance.


No funding sources to disclose.

Compliance with Ethical Standards

Conflict of Interest

Maurizio Rossini, Ombretta Viapiana, Luca Idolazzi, Francesco Ghellere, Elena Fracassi, Sonila Troplini, Maria Rosaria Povino, Vidya Kunnathully, Silvano Adami, and Davide Gatti declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

The clinical study was conducted in accordance with the ethics principles of the Declaration of Helsinki and was approved by the local ethics committee. Each enrolled patient signed the informed consent to participate in the study.


  1. 1.
    Carette S, Graham D, Little H, Rubenstein J, Rosen P (1983) The natural disease course of ankylosing spondylitis. Arthritis Rheum 26:186–190CrossRefPubMedGoogle Scholar
  2. 2.
    Klingberg E, Lorentzon M, Gothlin J, Mellstrom D, Geijer M, Ohlsson C et al (2013) Bone microarchitecture in ankylosing spondylitis and the association with bone mineral density, fractures, and syndesmophytes. Arthritis Res Ther 15:R179CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Robinson Y, Sanden B, Olerud C (2013) Increased occurrence of spinal fractures related to ankylosing spondylitis: a prospective 22-year cohort study in 17,764 patients from a national registry in Sweden. Patient Saf Surg 7:2CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Munoz-Ortego J, Vestergaard P, Rubio JB, Wordsworth P, Judge A, Javaid MK et al (2014) Ankylosing spondylitis is associated with an increased risk of vertebral and non-vertebral clinical fractures: a population-based cohort study. J Bone Miner Res 29:1770–1776CrossRefPubMedGoogle Scholar
  5. 5.
    Roux C (2011) Osteoporosis in inflammatory joint diseases. Osteoporos Int 22:421–433CrossRefPubMedGoogle Scholar
  6. 6.
    Geusens P, Vosse D, van der Linden S (2007) Osteoporosis and vertebral fractures in ankylosing spondylitis. Curr Opin Rheumatol 19:335–339CrossRefPubMedGoogle Scholar
  7. 7.
    Bessant R, Keat A (2002) How should clinicians manage osteoporosis in ankylosing spondylitis? J Rheumatol 29:1511–1519PubMedGoogle Scholar
  8. 8.
    Bronson WD, Walker SE, Hillman LS, Keisler D, Hoyt T, Allen SH (1998) Bone mineral density and biochemical markers of bone metabolism in ankylosing spondylitis. J Rheumatol 25:929–935PubMedGoogle Scholar
  9. 9.
    El Maghraoui A, Tellal S, Chaouir S, Lebbar K, Bezza A, Nouijai A et al (2005) Bone turnover markers, anterior pituitary and gonadal hormones, and bone mass evaluation using quantitative computed tomography in ankylosing spondylitis. Clin Rheumatol 24:346–351CrossRefPubMedGoogle Scholar
  10. 10.
    Toussirot E, Michel F, Wendling D (2001) Bone density, ultrasound measurements and body composition in early ankylosing spondylitis. Rheumatology (Oxford) 40:882–888CrossRefGoogle Scholar
  11. 11.
    Baek HJ, Kang SW, Lee YJ, Shin KC, Lee EB, Yoo CD et al (2005) Osteopenia in men with mild and severe ankylosing spondylitis. Rheumatol Int 26:30–34CrossRefPubMedGoogle Scholar
  12. 12.
    Cooper C, Carbone L, Michet CJ, Atkinson EJ, O’Fallon WM, Melton LJ 3rd (1994) Fracture risk in patients with ankylosing spondylitis: a population based study. J Rheumatol 21:1877–1882PubMedGoogle Scholar
  13. 13.
    Feldtkeller E, Vosse D, Geusens P, van der Linden S (2006) Prevalence and annual incidence of vertebral fractures in patients with ankylosing spondylitis. Rheumatol Int 26:234–239CrossRefPubMedGoogle Scholar
  14. 14.
    Geusens P, Lems WF (2011) Osteoimmunology and osteoporosis. Arthritis Res Ther 13:242CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Jun JB, Joo KB, Her MY, Kim TH, Bae SC, Yoo DH et al (2006) Femoral bone mineral density is associated with vertebral fractures in patients with ankylosing spondylitis: a cross-sectional study. J Rheumatol 33:1637–1641PubMedGoogle Scholar
  16. 16.
    Karberg K, Zochling J, Sieper J, Felsenberg D, Braun J (2005) Bone loss is detected more frequently in patients with ankylosing spondylitis with syndesmophytes. J Rheumatol 32:1290–1298PubMedGoogle Scholar
  17. 17.
    Lange U, Kluge A, Strunk J, Teichmann J, Bachmann G (2005) Ankylosing spondylitis and bone mineral density—what is the ideal tool for measurement? Rheumatol Int 26:115–120CrossRefPubMedGoogle Scholar
  18. 18.
    Vosse D, Feldtkeller E, Erlendsson J, Geusens P, van der Linden S (2004) Clinical vertebral fractures in patients with ankylosing spondylitis. J Rheumatol 31:1981–1985PubMedGoogle Scholar
  19. 19.
    Vosse D, Landewe R, van der Heijde D, van der Linden S, van Staa TP, Geusens P (2009) Ankylosing spondylitis and the risk of fracture: results from a large primary care-based nested case-control study. Ann Rheum Dis 68:1839–1842CrossRefPubMedGoogle Scholar
  20. 20.
    Ghozlani I, Ghazi M, Nouijai A, Mounach A, Rezqi A, Achemlal L et al (2009) Prevalence and risk factors of osteoporosis and vertebral fractures in patients with ankylosing spondylitis. Bone 44:772–776CrossRefPubMedGoogle Scholar
  21. 21.
    Sambrook PN, Geusens P (2012) The epidemiology of osteoporosis and fractures in ankylosing spondylitis. Ther Adv Musculoskelet Dis 4:287–292CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Klingberg E, Geijer M, Gothlin J, Mellstrom D, Lorentzon M, Hilme E et al (2012) Vertebral fractures in ankylosing spondylitis are associated with lower bone mineral density in both central and peripheral skeleton. J Rheumatol 39:1987–1995CrossRefPubMedGoogle Scholar
  23. 23.
    Klingberg E, Lorentzon M, Mellstrom D, Geijer M, Gothlin J, Hilme E et al (2012) Osteoporosis in ankylosing spondylitis—prevalence, risk factors and methods of assessment. Arthritis Res Ther 14:R108CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D et al (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13:156–163CrossRefPubMedGoogle Scholar
  25. 25.
    Tamamura Y, Otani T, Kanatani N, Koyama E, Kitagaki J, Komori T et al (2005) Developmental regulation of Wnt/beta-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. J Biol Chem 280:19185–19195CrossRefPubMedGoogle Scholar
  26. 26.
    Haynes KR, Pettit AR, Duan R, Tseng HW, Glant TT, Brown MA et al (2012) Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors. Arthritis Res Ther 14:R253CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Daoussis D, Liossis SN, Solomou EE, Tsanaktsi A, Bounia K, Karampetsou M et al (2010) Evidence that Dkk-1 is dysfunctional in ankylosing spondylitis. Arthritis Rheum 62:150–158CrossRefPubMedGoogle Scholar
  28. 28.
    Sapir-Koren R, Livshits G (2014) Osteocyte control of bone remodeling: is sclerostin a key molecular coordinator of the balanced bone resorption-formation cycles? Osteoporos Int 25:2685–2700CrossRefPubMedGoogle Scholar
  29. 29.
    Lewiecki EM (2014) Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases. Ther Adv Musculoskelet Dis 6:48–57CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Li J, Sarosi I, Cattley RC, Pretorius J, Asuncion F, Grisanti M et al (2006) Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 39:754–766CrossRefPubMedGoogle Scholar
  31. 31.
    MacDonald BT, Joiner DM, Oyserman SM, Sharma P, Goldstein SA, He X et al (2007) Bone mass is inversely proportional to Dkk1 levels in mice. Bone 41:331–339CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Senolt L, Hulejova H, Krystufkova O, Forejtova S, Andres Cerezo L, Gatterova J et al (2012) Low circulating Dickkopf-1 and its link with severity of spinal involvement in diffuse idiopathic skeletal hyperostosis. Ann Rheum Dis 71:71–74CrossRefPubMedGoogle Scholar
  33. 33.
    Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B et al (2003) The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 349:2483–2494CrossRefPubMedGoogle Scholar
  34. 34.
    Rossini M, Gatti D, Adami S (2013) Involvement of WNT/beta-catenin signaling in the treatment of osteoporosis. Calcif Tissue Int 93:121–132CrossRefPubMedGoogle Scholar
  35. 35.
    Appel H, Ruiz-Heiland G, Listing J, Zwerina J, Herrmann M, Mueller R et al (2009) Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum 60:3257–3262CrossRefPubMedGoogle Scholar
  36. 36.
    van der Linden S, Valkenburg HA, Cats A (1984) Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 27:361–368CrossRefPubMedGoogle Scholar
  37. 37.
    Creemers MCW, Franssen MJAM, van’t Hof MA, Gribnau FWJ, van de Putte LBA, van Riel PLCM (2005) Assessment of outcome in ankylosing spondylitis: an extended radiographic scoring system. Ann Rheum Dis 64:127–129CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Genant HK, Wu CY, van Kuijk C, Nevitt MC (1993) Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8:1137–1148CrossRefPubMedGoogle Scholar
  39. 39.
    Felsenberg D, Silman AJ, Lunt M, Armbrecht G, Ismail AA, Finn JD et al (2002) Incidence of vertebral fracture in Europe: results from the European Prospective Osteoporosis Study (EPOS). J Bone Miner Res 17:716–724CrossRefPubMedGoogle Scholar
  40. 40.
    Van der Klift M, De Laet CE, McCloskey EV, Hofman A, Pols HA (2002) The incidence of vertebral fractures in men and women: the Rotterdam Study. J Bone Miner Res 17:1051–1056CrossRefPubMedGoogle Scholar
  41. 41.
    Viapiana O, Gatti D, Idolazzi L, Fracassi E, Adami S, Troplini S et al (2014) Bisphosphonates vs infliximab in ankylosing spondylitis treatment. Rheumatology (Oxford) 53:90–94CrossRefGoogle Scholar
  42. 42.
    van der Weijden MA, Claushuis TA, Nazari T, Lems WF, Dijkmans BA, van der Horst-Bruinsma IE (2012) High prevalence of low bone mineral density in patients within 10 years of onset of ankylosing spondylitis: a systematic review. Clin Rheumatol 31:1529–1535CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Mandl P, Navarro-Compan V, Terslev L, Aegerter P, van der Heijde D (2015) EULAR recommendations for the use of imaging in the diagnosis and management of spondyloarthritis in clinical practice. Ann Rheum Dis 74:1327–1339CrossRefPubMedGoogle Scholar
  44. 44.
    Saad CG, Ribeiro AC, Moraes JC, Takayama L, Goncalves CR, Rodrigues MB et al (2012) Low sclerostin levels: a predictive marker of persistent inflammation in ankylosing spondylitis during anti-tumor necrosis factor therapy? Arthritis Res Ther 14:R216CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Kwon SR, Lim MJ, Suh CH, Park SG, Hong YS, Yoon BY et al (2012) Dickkopf-1 level is lower in patients with ankylosing spondylitis than in healthy people and is not influenced by anti-tumor necrosis factor therapy. Rheumatol Int 32:2523–2527CrossRefPubMedGoogle Scholar
  46. 46.
    Klingberg E, Nurkkala M, Carlsten H, Forsblad-d’Elia H (2014) Biomarkers of bone metabolism in ankylosing spondylitis in relation to osteoproliferation and osteoporosis. J Rheumatol 41:1349–1356CrossRefPubMedGoogle Scholar
  47. 47.
    Heiland GR, Appel H, Poddubnyy D, Zwerina J, Hueber A, Haibel H et al (2012) High level of functional Dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann Rheum Dis 71:572–574CrossRefPubMedGoogle Scholar
  48. 48.
    Ahmed SF, Fouda N, Abbas AA (2013) Serum Dickkopf-1 level in postmenopausal females: correlation with bone mineral density and serum biochemical markers. J Osteoporos 2013:460210CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Dovjak P, Dorfer S, Föger-Samwald U, Kudlacek S, Marculescu R, Pietschmann P (2014) Serum levels of Sclerostin and Dickkopf-1: effects of age, gender and fracture status. Gerontology 60:493–501CrossRefPubMedGoogle Scholar
  50. 50.
    Rossini M, Viapiana O, Adami S, Fracassi E, Idolazzi L, Dartizio C et al (2015) In patients with rheumatoid arthritis, Dickkopf-1 serum levels are correlated with parathyroid hormone, bone erosions and bone mineral density. Clin Exp Rheumatol 33:77–83PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Maurizio Rossini
    • 1
    Email author
  • Ombretta Viapiana
    • 1
  • Luca Idolazzi
    • 1
  • Francesco Ghellere
    • 1
  • Elena Fracassi
    • 1
  • Sonila Troplini
    • 1
  • Maria Rosaria Povino
    • 1
  • Vidya Kunnathully
    • 1
  • Silvano Adami
    • 1
  • Davide Gatti
    • 1
  1. 1.Rheumatology Unit, Department of MedicineUniversity of Verona, Policlinico Borgo RomaVeronaItaly

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