Calcified Tissue International

, Volume 99, Issue 4, pp 360–364 | Cite as

Effects of TNF Inhibitors on Parathyroid Hormone and Wnt Signaling Antagonists in Rheumatoid Arthritis

  • Giovanni AdamiEmail author
  • Giovanni Orsolini
  • Silvano Adami
  • Ombretta Viapiana
  • Luca Idolazzi
  • Davide Gatti
  • Maurizio Rossini
Original Research


Tumor necrosis factor α inhibitors (TNFi) are the major class of biologic drug used for the treatment of Rheumatoid arthritis (RA). Their effects on inflammation and disease control are well established, but this is not true also for bone metabolism, especially for key factors as parathyroid hormone and Wnt pathway. Those two pathways are gaining importance in the pathogenesis RA bone damage, both systemic and local, but how the new treatment affects them is still largely unknown. We studied 54 RA patients who were starting an anti-TNFα treatment due to the failure of the conventional synthetic disease-modifying antirheumatic drugs. Serum levels of Wnt/βcatenin pathway inhibitors (Dickkopf-related protein 1, Dkk1, and Sclerostin), Parathyroid hormone (PTH), vitamin D, and bone turnover markers were measured at baseline in the morning after fasting and after 6 months of therapy. We found a significant percentage increase in serum PTH (+32 ± 55 %; p = 0.002) and a decrease in Dkk1 mean serum levels (−2.9 ± 12.1; p = 0.05). PTH percentage changes were positively correlated both with C-terminal telopeptide of type I collagen and Dkk1 percentage changes. Sclerostin serum levels showed no significant difference. TNFi treatment provokes in the short term a rise in PTH levels and a decrease in Dkk1 serum levels. The increase of PTH might promote bone resorption and blunt the normalization of Dkk1 serum levels in RA. Those data give a new insight into TNFi metabolic effects on bone and suggest new strategies to achieve better results in terms of prevention of bone erosions and osteoporosis with TNFi treatment in RA.


TNF-blocking antibody Wnt pathway parathyroid hormone Dkk1 Rheumatoid arthritis 



This study was performed in part in the LURM (Laboratorio Universitario di Ricerca Medica) Research Center, the University of Verona. The authors would like to thank Prof. Silvano Adami who left us the love for research and truth and the laboratory teams, especially Caterina Fraccarollo, for performing the biochemical analyses

Compliance with Ethical Standards

Conflict of Interest

Adami Giovanni, Orsolini Giovanni, Adami Silvano, Viapiana Ombretta, Idolazzi Luca, Gatti Davide, and Rossini Maurizio have no conflict of interest to declare.

Human and Animal Rights and Informed Consent

The study was approved by the institutional review board of the Medical School of Verona and performed according to the Helsinki declaration. All patients provided written informed consent for their participation in the study.


  1. 1.
    Gravallese EM (2002) Bone destruction in arthritis. Ann Rheum Dis 61:84–86CrossRefGoogle Scholar
  2. 2.
    Schett G, Gravallese E (2012) Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol 8:656–664. doi: 10.1038/nrrheum.2012.153 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Scott DL, Wolfe F, Huizinga TWJ (2010) Rheumatoid arthritis. Lancet Lond Engl 376:1094–1108. doi: 10.1016/S0140-6736(10)60826-4 Google Scholar
  4. 4.
    Roux S, Orcel P (2000) Bone loss. Factors that regulate osteoclast differentiation: an update. Arthritis Res 2:451–456. doi: 10.1186/ar127 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Jilani AA, Mackworth-Young CG (2015) The role of citrullinated protein antibodies in predicting erosive disease in rheumatoid arthritis: a systematic literature review and meta-analysis. Int J Rheumatol 2015:728610. doi: 10.1155/2015/728610 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Diarra D, Stolina M, Polzer K et al (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13:156–163. doi: 10.1038/nm1538 CrossRefPubMedGoogle Scholar
  7. 7.
    Rossini M, Gatti D, Adami S (2013) Involvement of WNT/β-catenin signaling in the treatment of osteoporosis. Calcif Tissue Int 93:121–132. doi: 10.1007/s00223-013-9749-z CrossRefPubMedGoogle Scholar
  8. 8.
    Wang S-Y, Liu Y-Y, Ye H et al (2011) Circulating Dickkopf-1 is correlated with bone erosion and inflammation in rheumatoid arthritis. J Rheumatol 38:821–827. doi: 10.3899/jrheum.100089 CrossRefPubMedGoogle Scholar
  9. 9.
    Rossini M, Viapiana O, Adami S 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
  10. 10.
    Heiland GR, Zwerina K, Baum W et al (2010) Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression. Ann Rheum Dis 69:2152–2159. doi: 10.1136/ard.2010.132852 CrossRefPubMedGoogle Scholar
  11. 11.
    Kotake S, Nanke Y (2014) Effect of TNFα on osteoblastogenesis from mesenchymal stem cells. Biochim Biophys Acta 1840:1209–1213. doi: 10.1016/j.bbagen.2013.12.013 CrossRefPubMedGoogle Scholar
  12. 12.
    Adamopoulos IE, Mellins ED (2015) Alternative pathways of osteoclastogenesis in inflammatory arthritis. Nat Rev Rheumatol 11:189–194. doi: 10.1038/nrrheum.2014.198 CrossRefPubMedGoogle Scholar
  13. 13.
    Aletaha D, Neogi T, Silman AJ et al (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69:1580–1588. doi: 10.1136/ard.2010.138461 CrossRefPubMedGoogle Scholar
  14. 14.
    Prevoo ML, van ’t Hof MA, Kuper HH et al (1995) Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38:44–48CrossRefPubMedGoogle Scholar
  15. 15.
    Orsolini G, Adami G, Adami S et al (2016) Short-term effects of TNF inhibitors on bone turnover markers and bone mineral density in rheumatoid arthritis. Calcif Tissue Int. doi: 10.1007/s00223-016-0114-x Google Scholar
  16. 16.
    Szentpetery A, McKenna MJ, Murray BF et al (2013) Periarticular bone gain at proximal interphalangeal joints and changes in bone turnover markers in response to tumor necrosis factor inhibitors in rheumatoid and psoriatic arthritis. J Rheumatol 40:653–662. doi: 10.3899/jrheum.120397 CrossRefPubMedGoogle Scholar
  17. 17.
    Vis M, Havaardsholm EA, Haugeberg G et al (2006) Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFkappaB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis. Ann Rheum Dis 65:1495–1499. doi: 10.1136/ard.2005.044198 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Lim MJ, Kwon SR, Joo K et al (2014) Early effects of tumor necrosis factor inhibition on bone homeostasis after soluble tumor necrosis factor receptor use. Kor J Intern Med 29:807–813. doi: 10.3904/kjim.2014.29.6.807 CrossRefGoogle Scholar
  19. 19.
    Manara M, Sinigaglia L (2015) Bone and TNF in rheumatoid arthritis: clinical implications. RMD Open 1:e000065. doi: 10.1136/rmdopen-2015-000065 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lips P (2001) Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev 22:477–501. doi: 10.1210/edrv.22.4.0437 CrossRefPubMedGoogle Scholar
  21. 21.
    Augustine MV, Leonard MB, Thayu M et al (2014) Changes in vitamin D-related mineral metabolism after induction with anti-tumor necrosis factor-α therapy in Crohn’s disease. J Clin Endocrinol Metab 99:E991–E998. doi: 10.1210/jc.2013-3846 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Pacifici R (2013) Role of T cells in the modulation of PTH action: physiological and clinical significance. Endocrine 44:576–582. doi: 10.1007/s12020-013-9960-8 CrossRefPubMedGoogle Scholar
  23. 23.
    Tawfeek H, Bedi B, Li J-Y et al (2010) Disruption of PTH receptor 1 in T cells protects against PTH-induced bone loss. PloS One 5:e12290. doi: 10.1371/journal.pone.0012290 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Viapiana O, Fracassi E, Troplini S et al (2013) Sclerostin and DKK1 in primary hyperparathyroidism. Calcif Tissue Int 92:324–329. doi: 10.1007/s00223-012-9665-7 CrossRefPubMedGoogle Scholar
  25. 25.
    Gatti D, Viapiana O, Idolazzi L et al (2011) The waning of teriparatide effect on bone formation markers in postmenopausal osteoporosis is associated with increasing serum levels of DKK1. J Clin Endocrinol Metab 96:1555–1559. doi: 10.1210/jc.2010-2552 CrossRefPubMedGoogle Scholar
  26. 26.
    Borggrefe J, Graeff C, Nickelsen TN et al (2010) Quantitative computed tomographic assessment of the effects of 24 months of teriparatide treatment on 3D femoral neck bone distribution, geometry, and bone strength: results from the EUROFORS study. J Bone Miner Res 25:472–481. doi: 10.1359/jbmr.090820 CrossRefGoogle Scholar
  27. 27.
    Garnero P, Tabassi NC-B, Voorzanger-Rousselot N (2008) Circulating dickkopf-1 and radiological progression in patients with early rheumatoid arthritis treated with etanercept. J Rheumatol 35:2313–2315CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Rheumatology Section, Department of MedicineUniversity of VeronaVeronaItaly

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