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Aging Clinical and Experimental Research

, Volume 28, Issue 1, pp 1–16 | Cite as

Balancing benefits and risks of glucocorticoids in rheumatic diseases and other inflammatory joint disorders: new insights from emerging data. An expert consensus paper from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO)

  • Cyrus CooperEmail author
  • Thomas Bardin
  • Maria-Luisa Brandi
  • Patrice Cacoub
  • John Caminis
  • Roberto Civitelli
  • Maurizio Cutolo
  • Willard Dere
  • Jean-Pierre Devogelaer
  • Adolfo Diez-Perez
  • Thomas A. Einhorn
  • Patrick Emonts
  • Olivier Ethgen
  • John A. Kanis
  • Jean-Marc Kaufman
  • Tore K. Kvien
  • Willem F. Lems
  • Eugene McCloskey
  • Pierre Miossec
  • Susanne Reiter
  • Johann Ringe
  • René Rizzoli
  • Kenneth Saag
  • Jean-Yves Reginster
Review

Abstract

Purpose

This consensus review article considers the question of whether glucocorticoid (GC) therapy is still relevant in the treatment of rheumatic diseases, with a particular focus on rheumatoid arthritis (RA), and whether its side effects can be adequately managed. Recent basic and clinical research on the molecular, cellular and clinical effects of GCs have considerably advanced our knowledge in this field. An overview of the subject seems appropriate.

Methods

This review is the result of a multidisciplinary expert working group, organised by European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. The recent literature was surveyed and the salient evidence synthetized.

Results

The pathophysiological basis of RA (and other inflammatory rheumatic diseases) now strongly implicates the adaptive immune system in addition to innate mechanisms. The molecular effect of GCs and differential GC sensitivity is better understood, although exploiting this knowledge is still in its infancy. The newer treatment strategies of early and aggressive control of RA have gr eatly improved clinical outcomes, but improvements are still possible. Newer targeted anti-inflammatory drugs have made an important impact, yet they too are associated with numerous side effects.

Discussion

Short durations of moderate doses of GCs are generally well tolerated and have a positive benefit/risk ratio. Patients should be assessed for fracture risk and bone preserving agents and be prescribed calcium and vitamin D supplementation.

Conclusions

Within a strategy of a disease modifying approach to inflammatory disease, combination therapy including a GC is effective approach.

Keywords

Rheumatoid arthritis Rheumatic diseases Osteoporosis Cohort studies Glucocorticoids Inflammation 

Notes

Acknowledgments

ESCEO is a non-profit Belgian organization (receiving funding from government and industry) dedicated to providing clinical scientists and practitioners with the latest information in evidence-based medicine and health economics. Professor Cooper wishes to acknowledge the Medical Research Council of UK for funding. Professor Miossec acknowledges funding from the IHU prometteur OPERA (Grant ANR-10-IBHU-004) and the EU Marie Curie Network EUTRAIN. The authors would like to thank Jeremy Grierson, PhD, medical writer, for his assistance in preparing the drafts of the manuscript from the presentations and discussions of the working group participants, as well as graphic and bibliographic support.

Compliance with ethical standards

Conflict of interest

The author declares that they have no conflict of interest.

Statement of human and animal rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and /or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Studies performed using animal tissues were done in accordance with accepted ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Baltimore D (2001) Our genome unveiled. Nature 409(6822):814–816PubMedCrossRefGoogle Scholar
  2. 2.
    Boers M (2003) Understanding the window of opportunity concept in early rheumatoid arthritis. Arthritis Rheum 48(7):1771–1774PubMedCrossRefGoogle Scholar
  3. 3.
    Grigor C, Capell H, Stirling A et al (2004) Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 364(9430):263–269PubMedCrossRefGoogle Scholar
  4. 4.
    Bakker MF, Jacobs JW, Verstappen SM et al (2007) Tight control in the treatment of rheumatoid arthritis: efficacy and feasibility. Ann Rheum Dis. doi: 10.1136/ard.2007.078360 PubMedCentralPubMedGoogle Scholar
  5. 5.
    Klareskog L, Catrina AI, Paget S (2009) Rheumatoid arthritis. Lancet. doi: 10.1016/S0140-6736(09)60008-8 PubMedGoogle Scholar
  6. 6.
    Saffar AS, Ashdown H, Gounni AS (2011) The molecular mechanisms of glucocorticoids-mediated neutrophil survival. Curr Drug Targets 12(4):556–562PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Ytterberg AJ, Joshua V, Reynisdottir G et al (2014) Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis: identification and validation. Ann Rheum Dis. doi: 10.1136/annrheumdis-2013-204912 Google Scholar
  8. 8.
    McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med. doi: 10.1056/NEJMra1004965 PubMedGoogle Scholar
  9. 9.
    Miossec P, Korn T, Kuchroo VK (2009) Interleukin-17 and type 17 helper T cells. N Engl J Med. doi: 10.1056/NEJMra0707449 PubMedGoogle Scholar
  10. 10.
    Jonsson H, Allen P, Peng SL (2005) Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis. Nat Med 11(6):666–671PubMedCrossRefGoogle Scholar
  11. 11.
    Turrel-Davin F, Tournadre A, Pachot A et al (2010) FoxO3a involved in neutrophil and T cell survival is overexpressed in rheumatoid blood and synovial tissue. Ann Rheum Dis. doi: 10.1136/ard.2009 PubMedGoogle Scholar
  12. 12.
    Westwood OM, Nelson PN, Hay FC (2006) Rheumatoid factors: what’s new? Rheumatology (Oxford) 45(4):379–385CrossRefGoogle Scholar
  13. 13.
    Zendman AJ, van Venrooij WJ, Pruijn GJ (2006) Use and significance of anti-CCP autoantibodies in rheumatoid arthritis. Rheumatology (Oxford) 45(1):20–25CrossRefGoogle Scholar
  14. 14.
    Lopez-Longo FJ, Oliver-Minarro D, de la Torre I et al (2009) Association between anti-cyclic citrullinated peptide antibodies and ischemic heart disease in patients with rheumatoid arthritis. Arthritis Rheum. doi: 10.1002/art.24390 PubMedGoogle Scholar
  15. 15.
    Kleyer A, Finzel S, Rech J et al (2013) Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann Rheum Dis. doi: 10.1136/annrheumdis-2012-202958 PubMedGoogle Scholar
  16. 16.
    Crowson CS, Rahman MU, Matteson EL (2009) Which measure of inflammation to use? A comparison of erythrocyte sedimentation rate and C-reactive protein measurements from randomized clinical trials of golimumab in rheumatoid arthritis. J Rheumatol. doi: 10.3899/jrheum.081188 Google Scholar
  17. 17.
    Hensvold AH, Magnusson PK, Joshua V et al (2015) Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins. Ann Rheum Dis. doi: 10.1136/annrheumdis-2013-203947 Google Scholar
  18. 18.
    Wolfe F, Mitchell DM, Sibley JT et al (1994) The mortality of rheumatoid arthritis. Arthritis Rheum 37(4):481–494PubMedCrossRefGoogle Scholar
  19. 19.
    Boyer JF, Gourraud PA, Cantagrel A et al (2011) Traditional cardiovascular risk factors in rheumatoid arthritis: a meta-analysis. Joint Bone Spine. 78(2):179–183PubMedCrossRefGoogle Scholar
  20. 20.
    Wolfe F (2000) The effect of smoking on clinical, laboratory, and radiographic status in rheumatoid arthritis. J Rheumatol 27(3):630–637PubMedGoogle Scholar
  21. 21.
    Dessein PH, Joffe BI (2006) Insulin resistance and impaired beta cell function in rheumatoid arthritis. Arthritis Rheum 54(9):2765–2775PubMedCrossRefGoogle Scholar
  22. 22.
    Liao KP, Solomon DH (2013) Traditional cardiovascular risk factors, inflammation and cardiovascular risk in rheumatoid arthritis. Rheumatology (Oxford). doi: 10.1093/rheumatology/kes243 Google Scholar
  23. 23.
    Stavropoulos-Kalinoglou A, Metsios GS, Koutedakis Y et al (2011) Obesity in rheumatoid arthritis. Rheumatology (Oxford) 50(3):450–462CrossRefGoogle Scholar
  24. 24.
    Dougados M, Soubrier M, Antunez A et al (2014) Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis 73(1):62–68PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Wallberg-Jonsson S, Ohman ML, Dahlqvist SR (1997) Cardiovascular morbidity and mortality in patients with seropositive rheumatoid arthritis in Northern Sweden. J Rheumatol 24(3):445–451PubMedGoogle Scholar
  26. 26.
    Watson DJ, Rhodes T, Guess HA (2003) All-cause mortality and vascular events among patients with rheumatoid arthritis, osteoarthritis, or no arthritis in the UK General Practice Research Database. J Rheumatol 30(6):1196–1202PubMedGoogle Scholar
  27. 27.
    Sihvonen S, Korpela M, Laippala P et al (2004) Death rates and causes of death in patients with rheumatoid arthritis: a population-based study. Scand J Rheumatol 33(4):221–227PubMedCrossRefGoogle Scholar
  28. 28.
    Peters MJ, van Halm VP, Voskuyl AE et al (2009) Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study. Arthritis Rheum. doi: 10.1002/art.24836 PubMedCentralGoogle Scholar
  29. 29.
    Avina-Zubieta JA, Thomas J, Sadatsafavi M et al (2012) Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. doi: 10.1136/annrheumdis-2011-20072 Google Scholar
  30. 30.
    Krishnan E, Lingala VB, Singh G (2004) Declines in mortality from acute myocardial infarction in successive incidence and birth cohorts of patients with rheumatoid arthritis. Circulation 110(13):1774–1779PubMedCrossRefGoogle Scholar
  31. 31.
    Meune C, Touze E, Trinquart L et al (2009) Trends in cardiovascular mortality in patients with rheumatoid arthritis over 50 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). doi: 10.1093/rheumatology/kep252 Google Scholar
  32. 32.
    Juni P, Nartey L, Reichenbach S et al (2004) Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 364(9450):2021–2029PubMedCrossRefGoogle Scholar
  33. 33.
    Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356(24):2457–2471PubMedCrossRefGoogle Scholar
  34. 34.
    Trelle S, Reichenbach S, Wandel S et al (2011) Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. doi: 10.1136/bmj.c7086 PubMedCentralPubMedGoogle Scholar
  35. 35.
    Wellen KE, Hotamisligil GS (2005) Inflammation, stress, and diabetes. J Clin Invest 115(5):1111–1119PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Bensinger SJ, Tontonoz P (2008) Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature. doi: 10.1038/nature07202 PubMedGoogle Scholar
  37. 37.
    Toms TE, Panoulas VF, Douglas KM et al (2010) Statin use in rheumatoid arthritis in relation to actual cardiovascular risk: evidence for substantial undertreatment of lipid-associated cardiovascular risk? Ann Rheum Dis. doi: 10.1136/ard.2009.115717 Google Scholar
  38. 38.
    Curtis JR, John A, Baser O (2012) Dyslipidemia and changes in lipid profiles associated with rheumatoid arthritis and initiation of anti-tumor necrosis factor therapy. Arthritis Care Res (Hoboken). doi: 10.1002/acr.21693 Google Scholar
  39. 39.
    Toms TE, Panoulas VF, Smith JP et al (2011) Rheumatoid arthritis susceptibility genes associate with lipid levels in patients with rheumatoid arthritis. Ann Rheum Dis. doi: 10.1136/ard.2010.144634 PubMedGoogle Scholar
  40. 40.
    del Rincon ID, Williams K, Stern MP et al (2001) High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 44(12):2737–2745PubMedCrossRefGoogle Scholar
  41. 41.
    Turesson C, McClelland RL, Christianson TJ et al (2007) Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis. Ann Rheum Dis 66(1):70–75PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Hot A, Lenief V, Miossec P (2012) Combination of IL-17 and TNFalpha induces a pro-inflammatory, pro-coagulant and pro-thrombotic phenotype in human endothelial cells. Ann Rheum Dis. doi: 10.1136/annrheumdis-2011-200468 Google Scholar
  43. 43.
    Hot A, Lavocat F, Lenief V et al (2013) Simvastatin inhibits the pro-inflammatory and pro-thrombotic effects of IL-17 and TNF-alpha on endothelial cells. Ann Rheum Dis. doi: 10.1136/annrheumdis-2012-201887 PubMedGoogle Scholar
  44. 44.
    McCarey DW, McInnes IB, Madhok R et al (2004) Trial of atorvastatin in rheumatoid arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 363(9426):2015–2021PubMedCrossRefGoogle Scholar
  45. 45.
    Young SP, Kapoor SR, Viant MR et al (2013) The impact of inflammation on metabolomic profiles in patients with arthritis. Arthritis Rheum. doi: 10.1002/art.38021 Google Scholar
  46. 46.
    Park YB, Choi HK, Kim MY et al (2002) Effects of antirheumatic therapy on serum lipid levels in patients with rheumatoid arthritis: a prospective study. Am J Med 113(3):188–193PubMedCrossRefGoogle Scholar
  47. 47.
    Nadareishvili Z, Michaud K, Hallenbeck JM et al (2008) Cardiovascular, rheumatologic, and pharmacologic predictors of stroke in patients with rheumatoid arthritis: a nested, case–control study. Arthritis Rheum. doi: 10.1002/art.23935 PubMedCentralPubMedGoogle Scholar
  48. 48.
    Doran MF, Crowson CS, Pond GR et al (2002) Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum 46(9):2287–2293PubMedCrossRefGoogle Scholar
  49. 49.
    Toh ML, Kawashima M, Hot A et al (2010) Role of IL-17 in the Th1 systemic defects in rheumatoid arthritis through selective IL-12Rbeta2 inhibition. Ann Rheum Dis. doi: 10.1136/ard.2009.111757 Google Scholar
  50. 50.
    Felson DT, Anderson JJ, Meenan RF (1990) The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two meta analyses. Arthritis Rheum. 33(10):1449–1461PubMedCrossRefGoogle Scholar
  51. 51.
    O’Dell JR, Haire CE, Erikson N et al (1996) Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 334(20):1287–1291PubMedCrossRefGoogle Scholar
  52. 52.
    Boers M, Verhoeven AC, Markusse HM et al (1997) Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 350(9074):309–318PubMedCrossRefGoogle Scholar
  53. 53.
    Mottonen T, Hannonen P, Leirisalo-Repo M et al (1999) Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet 353(9164):1568–1573PubMedCrossRefGoogle Scholar
  54. 54.
    Svensson B, Boonen A, Albertsson K et al (2005) Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a 2-year randomized trial. Arthritis Rheum 52(11):3360–3370PubMedCrossRefGoogle Scholar
  55. 55.
    Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF et al (2005) Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 52(11):3381–3390PubMedCrossRefGoogle Scholar
  56. 56.
    Bakker MF, Jacobs JW, Welsing PM et al (2012) Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis: a randomized trial. Ann Intern Med 156(5):329–339PubMedCrossRefGoogle Scholar
  57. 57.
    Vermeer M, Kuper HH, Hoekstra M et al (2011) Implementation of a treat-to-target strategy in very early rheumatoid arthritis: results of the Dutch Rheumatoid Arthritis Monitoring remission induction cohort study. Arthritis Rheum. doi: 10.1002/art.30494 PubMedGoogle Scholar
  58. 58.
    Heimans L, Wevers-de Boer KV, Visser K et al (2013) A two-step treatment strategy trial in patients with early arthritis aimed at achieving remission: the IMPROVED study. Ann Rheum Dis. doi: 10.1136/annrheumdis-2013-203243 Google Scholar
  59. 59.
    den Uyl D, Ter Wee M, Boers M et al (2013) A non-inferiority trial of an attenuated combination strategy (‘COBRA-light’) compared to the original COBRA strategy: clinical results after 26 weeks. Ann Rheum Dis. doi: 10.1136/annrheumdis-2012-202818 Google Scholar
  60. 60.
    Kirwan JR, Bijlsma JW, Boers M et al (2007) Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Database Syst Rev 1:CD006356PubMedGoogle Scholar
  61. 61.
    Gorter SL, Bijlsma JW, Cutolo M et al (2010) Current evidence for the management of rheumatoid arthritis with glucocorticoids: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. doi: 10.1136/ard.2009.127332 PubMedCentralGoogle Scholar
  62. 62.
    Knevel R, Schoels M, Huizinga TW et al (2010) Current evidence for a strategic approach to the management of rheumatoid arthritis with disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. doi: 10.1136/ard.2009.126748 Google Scholar
  63. 63.
    Smolen JS, Aletaha D, Bijlsma JW et al (2010) Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. doi: 10.1136/ard.2009.123919 Google Scholar
  64. 64.
    Smolen JS, Landewe R, Breedveld FC et al (2013) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. doi: 10.1136/annrheumdis-2013-204573 Google Scholar
  65. 65.
    Gaujoux-Viala C, Nam J, Ramiro S et al (2014) Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. doi: 10.1136/annrheumdis-2013-204588 Google Scholar
  66. 66.
    Singh JA, Furst DE, Bharat A et al (2012) 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). doi: 10.1002/acr.21641 Google Scholar
  67. 67.
    Curtis JR, Westfall AO, Allison J et al (2006) Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Rheum 55(3):420–426PubMedCrossRefGoogle Scholar
  68. 68.
    van der Goes MC, Jacobs JW, Boers M et al (2010) Patient and rheumatologist perspectives on glucocorticoids: an exercise to improve the implementation of the European League Against Rheumatism (EULAR) recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis. doi: 10.1136/ard.2009.114579 Google Scholar
  69. 69.
    Saag KG (2012) Short-term and long-term safety of glucocorticoids in rheumatoid arthritis. Bull NYU Hosp Jt Dis 70(Suppl 1):21–25PubMedGoogle Scholar
  70. 70.
    Santiago T, da Silva JA (2014) Safety of low- to medium-dose glucocorticoid treatment in rheumatoid arthritis: myths and reality over the years. Ann N Y Acad Sci. doi: 10.1111/nyas.12428 PubMedGoogle Scholar
  71. 71.
    Saag KG (1997) Low-dose corticosteroid therapy in rheumatoid arthritis: balancing the evidence. Am J Med 103(6A):31S–39SPubMedCrossRefGoogle Scholar
  72. 72.
    van Staa TP, Leufkens HG, Abenhaim L et al (2000) Use of oral corticosteroids and risk of fractures. J Bone Miner Res 15(6):993–1000PubMedCrossRefGoogle Scholar
  73. 73.
    van Staa TP, Leufkens HG, Abenhaim L et al (2000) Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. Rheumatology (Oxford) 39(12):1383–1389CrossRefGoogle Scholar
  74. 74.
    da Silva JA, Jacobs JW, Kirwan JR et al (2006) Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann Rheum Dis 65(3):285–293PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Vestergaard P, Olsen ML, Paaske JS et al (2003) Corticosteroid use and risk of hip fracture: a population-based case-control study in Denmark. J Intern Med 254(5):486–493PubMedCrossRefGoogle Scholar
  76. 76.
    van Staa TP, Laan RF, Barton IP et al (2003) Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy. Arthritis Rheum 48(11):3224–3229PubMedCrossRefGoogle Scholar
  77. 77.
    Kanis JA, Johansson H, Oden A et al (2004) A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 19(6):893–899PubMedCrossRefGoogle Scholar
  78. 78.
    Manning LI, Briggs AM, van Doornum DS et al (2013) Glucocorticoid-induced bone loss is associated with abnormal intravertebral areal bone mineral density distribution. Int J Endocrinol. doi: 10.1155/2013/768579 PubMedCentralPubMedGoogle Scholar
  79. 79.
    Dalle Carbonare L, Arlot ME, Chavassieux PM et al (2001) Comparison of trabecular bone microarchitecture and remodeling in glucocorticoid-induced and postmenopausal osteoporosis. J Bone Miner Res 16(1):97–103PubMedCrossRefGoogle Scholar
  80. 80.
    Sambrook PN, Hughes DR, Nelson AE et al (2003) Osteocyte viability with glucocorticoid treatment: relation to histomorphometry. Ann Rheum Dis 62(12):1215–1217PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Aeberli D, Schett G (2013) Cortical remodeling during menopause, rheumatoid arthritis, glucocorticoid and bisphosphonate therapy. Arthritis Res Ther. doi: 10.1186/ar4180 PubMedCentralPubMedGoogle Scholar
  82. 82.
    Harvey NC, Gluer CC, Binkley N et al (2015) Trabecular bone score (TBS) as a new complementary approach for osteoporosis evaluation in clinical practice. Bone. doi: 10.1016/j.bone.2015.05.016 PubMedCentralGoogle Scholar
  83. 83.
    Lems WF, Jacobs JW, Van Rijn HJ et al (1995) Changes in calcium and bone metabolism during treatment with low dose prednisone in young, healthy, male volunteers. Clin Rheumatol 14(4):420–424PubMedCrossRefGoogle Scholar
  84. 84.
    Ton FN, Gunawardene SC, Lee H et al (2005) Effects of low-dose prednisone on bone metabolism. J Bone Miner Res 20(3):464–470PubMedCrossRefGoogle Scholar
  85. 85.
    Chan M, Chan PK, Griffith JF et al (2006) Steroid-induced osteonecrosis in severe acute respiratory syndrome: a retrospective analysis of biochemical markers of bone metabolism and corticosteroid therapy. Pathology. 38(3):229–235PubMedCrossRefGoogle Scholar
  86. 86.
    Kusumbe AP, Ramasamy SK, Adams RH (2014) Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. doi: 10.1038/nature13145 Google Scholar
  87. 87.
    Ramasamy SK, Kusumbe AP, Wang L et al (2014) Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature. doi: 10.1038/nature13146 Google Scholar
  88. 88.
    van Staa TP, Leufkens HG, Abenhaim L et al (2000) Use of oral corticosteroids in the UK. QJM 93(2):105–111PubMedCrossRefGoogle Scholar
  89. 89.
    van Staa TP, Abenhaim L, Cooper C et al (2001) Public health impact of adverse bone effects of oral corticosteroids. Br J Clin Pharmacol 51(6):601–607PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Saag KG, Emkey R, Schnitzer TJ et al (1998) Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med 339(5):292–299PubMedCrossRefGoogle Scholar
  91. 91.
    Cohen S, Levy RM, Keller M et al (1999) Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 42(11):2309–2318PubMedCrossRefGoogle Scholar
  92. 92.
    Devogelaer JP (2006) Glucocorticoid-induced osteoporosis: mechanisms and therapeutic approach. Rheum Dis Clin North Am 32(4):733–757PubMedCrossRefGoogle Scholar
  93. 93.
    van der Goes MC, Jacobs JW, Jurgens MS et al (2013) Are changes in bone mineral density different between groups of early rheumatoid arthritis patients treated according to a tight control strategy with or without prednisone if osteoporosis prophylaxis is applied? Osteoporos Int. doi: 10.1007/s00198-012-2073-z PubMedCentralPubMedGoogle Scholar
  94. 94.
    Homik J, Cranney A, Shea B et al (2000) Bisphosphonates for steroid induced osteoporosis. Cochrane Database Syst Rev 2:D001347Google Scholar
  95. 95.
    Lems WF, Saag K (2015) Bisphosphonates and glucocorticoid-induced osteoporosis: cons. Endocrine. doi: 10.1007/s12020-015-0639-1 PubMedCentralPubMedGoogle Scholar
  96. 96.
    Silverman S, Curtis J, Saag K et al (2015) International management of bone health in glucocorticoid-exposed individuals in the observational GLOW study. Osteoporos Int. doi: 10.1007/s00198-014-2883-2 Google Scholar
  97. 97.
    Souverein PC, Berard A, van Staa TP et al (2004) Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case–control study. Heart 90(8):859–865PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Ruyssen-Witrand A, Fautrel B, Saraux A et al (2011) Cardiovascular risk induced by low-dose corticosteroids in rheumatoid arthritis: a systematic literature review. Joint Bone Spine. doi: 10.1016/j.jbspin.2010.02.040 PubMedGoogle Scholar
  99. 99.
    el-Shaboury AH, Hayes TM (1973) Hyperlipidaemia in asthmatic patients receiving long-term steroid therapy. Br Med J 2(5858):85–86PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Panthakalam S, Bhatnagar D, Klimiuk P (2004) The prevalence and management of hyperglycaemia in patients with rheumatoid arthritis on corticosteroid therapy. Scott Med J 49(4):139–141PubMedGoogle Scholar
  101. 101.
    Fraser R, Ingram MC, Anderson NH et al (1999) Cortisol effects on body mass, blood pressure, and cholesterol in the general population. Hypertension 33(6):1364–1368PubMedCrossRefGoogle Scholar
  102. 102.
    Wolfe F, Michaud K (2008) The risk of myocardial infarction and pharmacologic and nonpharmacologic myocardial infarction predictors in rheumatoid arthritis: a cohort and nested case–control analysis. Arthritis Rheum. doi: 10.1002/art.23811 Google Scholar
  103. 103.
    Davis JM III, Maradit KH, Crowson CS et al (2007) Glucocorticoids and cardiovascular events in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum 56(3):820–830PubMedCrossRefGoogle Scholar
  104. 104.
    Panoulas VF, Douglas KM, Stavropoulos-Kalinoglou A et al (2008) Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis. Rheumatology (Oxford) 47(1):72–75CrossRefGoogle Scholar
  105. 105.
    Johannesdottir SA, Horvath-Puho E, Dekkers OM et al (2013) Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case–control study. JAMA Intern Med. doi: 10.1001/jamainternmed.2013.122 PubMedGoogle Scholar
  106. 106.
    Cutolo M, Seriolo B, Pizzorni C et al (2008) Use of glucocorticoids and risk of infections. Autoimmun Rev. doi: 10.1016/j.autrev.2008.07.010 Google Scholar
  107. 107.
    Dixon WG, Kezouh A, Bernatsky S et al (2011) The influence of systemic glucocorticoid therapy upon the risk of non-serious infection in older patients with rheumatoid arthritis: a nested case–control study. Ann Rheum Dis. doi: 10.1136/ard.2010.144741 Google Scholar
  108. 108.
    Dixon WG, Abrahamowicz M, Beauchamp ME et al (2012) Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid arthritis: a nested case–control analysis. Ann Rheum Dis. doi: 10.1136/annrheumdis-2011-200702 Google Scholar
  109. 109.
    Sihvonen S, Korpela M, Mustonen J et al (2006) Mortality in patients with rheumatoid arthritis treated with low-dose oral glucocorticoids. A population-based cohort study. J Rheumatol 33(9):1740–1746PubMedGoogle Scholar
  110. 110.
    Dixon WG, Suissa S, Hudson M (2011) The association between systemic glucocorticoid therapy and the risk of infection in patients with rheumatoid arthritis: systematic review and meta-analyses. Arthritis Res Ther. doi: 10.1186/ar3453 PubMedCentralPubMedGoogle Scholar
  111. 111.
    Singh JA, Cameron C, Noorbaloochi S et al (2015) Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet. doi: 10.1016/S0140-6736(14)61704-9 Google Scholar
  112. 112.
    Silverman MN, Sternberg EM (2008) Neuroendocrine-immune interactions in rheumatoid arthritis: mechanisms of glucocorticoid resistance. Neuroimmunomodulation. doi: 10.1159/000135620 PubMedCentralPubMedGoogle Scholar
  113. 113.
    Kadmiel M, Cidlowski JA (2013) Glucocorticoid receptor signaling in health and disease. Trends Pharmacol Sci. doi: 10.1016/j.tips.2013.07.003 PubMedCentralPubMedGoogle Scholar
  114. 114.
    Clore JN, Thurby-Hay L (2009) Glucocorticoid-induced hyperglycemia. Endocr Pract. doi: 10.4158/EP08331.RAR PubMedGoogle Scholar
  115. 115.
    Angelopoulos TP, Tentolouris NK, Bertsias GK et al (2014) Steroid-induced diabetes in rheumatologic patients. Clin Exp Rheumatol 32(1):126–130PubMedGoogle Scholar
  116. 116.
    Iwamoto T, Kagawa Y, Naito Y et al (2004) Steroid-induced diabetes mellitus and related risk factors in patients with neurologic diseases. Pharmacotherapy. 24(4):508–514PubMedCrossRefGoogle Scholar
  117. 117.
    Hoes JN, van der Goes MC, van Raalte DH et al (2011) Glucose tolerance, insulin sensitivity and beta-cell function in patients with rheumatoid arthritis treated with or without low-to-medium dose glucocorticoids. Ann Rheum Dis. doi: 10.1136/ard.2011.151464 PubMedGoogle Scholar
  118. 118.
    den Uyl D, van Raalte DH, Nurmohamed MT et al (2012) Metabolic effects of high-dose prednisolone treatment in early rheumatoid arthritis: balance between diabetogenic effects and inflammation reduction. Arthritis Rheum. doi: 10.1002/art.3337 Google Scholar
  119. 119.
    Simard JF, Mittleman MA (2007) Prevalent rheumatoid arthritis and diabetes among NHANES III participants aged 60 and older. J Rheumatol 34(3):469–473PubMedGoogle Scholar
  120. 120.
    Jurgens MS, Jacobs JW, Geenen R et al (2013) Increase of body mass index in a tight controlled methotrexate-based strategy with prednisone in early rheumatoid arthritis: side effect of the prednisone or better control of disease activity? Arthritis Care Res (Hoboken). doi: 10.1002/acr.21797 Google Scholar
  121. 121.
    Toms TE, Panoulas VF, Douglas KM et al (2008) Lack of association between glucocorticoid use and presence of the metabolic syndrome in patients with rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther. doi: 10.1186/ar2578 PubMedCentralPubMedGoogle Scholar
  122. 122.
    Babadjanova G, Allolio B, Vollmer M et al (1996) Comparison of the pharmacodynamic effects of deflazacort and prednisolone in healthy subjects. Eur J Clin Pharmacol 51(1):53–57PubMedCrossRefGoogle Scholar
  123. 123.
    Saez Barcelona JA, Carmona MM, Navarro LV et al (1999) An open comparison of the diabetogenic effect of deflazacort and prednisone at a dosage ratio of 1.5 mg:1 mg. Eur J Clin Pharmacol 55(2):105–109PubMedCrossRefGoogle Scholar
  124. 124.
    Fardet L, Feve B (2014) Systemic glucocorticoid therapy: a review of its metabolic and cardiovascular adverse events. Drugs. doi: 10.1007/s40265-014-0282-9 PubMedGoogle Scholar
  125. 125.
    James ER (2007) The etiology of steroid cataract. J Ocul Pharmacol Ther 23(5):403–420PubMedCrossRefGoogle Scholar
  126. 126.
    Celojevic D, Carlsson T, Johansson B et al (2012) Cell adhesion molecule expression in human lens epithelial cells after corticosteroid exposure. Open Ophthalmol J. doi: 10.2174/1874364101206010042 PubMedCentralPubMedGoogle Scholar
  127. 127.
    Chang JR, Koo E, Agron E et al (2011) Risk factors associated with incident cataracts and cataract surgery in the Age-related Eye Disease Study (AREDS): AREDS report number 32. Ophthalmology. doi: 10.1016/j.ophtha.2011.03.032 Google Scholar
  128. 128.
    Herbert J (2013) Cortisol and depression: three questions for psychiatry. Psychol Med. doi: 10.1017/S0033291712000955 Google Scholar
  129. 129.
    Matcham F, Rayner LF, Steer S et al (2013) The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology (Oxford). doi: 10.1093/rheumatology/ket169 Google Scholar
  130. 130.
    Matcham F, Norton S, Scott DL et al (2015) Symptoms of depression and anxiety predict treatment response and long-term physical health outcomes in rheumatoid arthritis: secondary analysis of a randomized controlled trial. Rheumatology (Oxford). doi: 10.1093/rheumatology/kev306 Google Scholar
  131. 131.
    Dinsen S, Baslund B, Klose M et al (2013) Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself. Eur J Intern Med. doi: 10.1016/j.ejim.2013.05.014 PubMedGoogle Scholar
  132. 132.
    Fardet L, Nazareth I, Whitaker HJ et al (2013) Severe neuropsychiatric outcomes following discontinuation of long-term glucocorticoid therapy: a cohort study. J Clin Psychiatry. doi: 10.4088/JCP.12m08034 PubMedGoogle Scholar
  133. 133.
    Debono M, Ross RJ (2011) Optimal glucocorticoid therapy. Endocr Dev. doi: 10.1159/000321241 PubMedGoogle Scholar
  134. 134.
    Cutolo M, Iaccarino L, Doria A et al (2013) Efficacy of the switch to modified-release prednisone in rheumatoid arthritis patients treated with standard glucocorticoids. Clin Exp Rheumatol 31(4):498–505PubMedGoogle Scholar
  135. 135.
    Buttgereit F, Mehta D, Kirwan J et al (2013) Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann Rheum Dis. doi: 10.1136/annrheumdis-2011-201067 Google Scholar
  136. 136.
    Emkey RD, Lindsay R, Lyssy J et al (1996) The systemic effect of intraarticular administration of corticosteroid on markers of bone formation and bone resorption in patients with rheumatoid arthritis. Arthritis Rheum 39(2):277–282PubMedCrossRefGoogle Scholar
  137. 137.
    Axelsen MB, Eshed I, Horslev-Petersen K et al (2015) A treat-to-target strategy with methotrexate and intra-articular triamcinolone with or without adalimumab effectively reduces MRI synovitis, osteitis and tenosynovitis and halts structural damage progression in early rheumatoid arthritis: results from the OPERA randomised controlled trial. Ann Rheum Dis. doi: 10.1136/annrheumdis-2013-204537 PubMedGoogle Scholar
  138. 138.
    Osamura H (1982) Penetration of topical corticosteroids through human epidermis. J Dermatol 9(1):45–58PubMedCrossRefGoogle Scholar
  139. 139.
    Vestergaard P, Rejnmark L, Mosekilde L (2005) Fracture risk associated with systemic and topical corticosteroids. J Intern Med 257(4):374–384PubMedCrossRefGoogle Scholar
  140. 140.
    Derendorf H, Mollmann H, Gruner A et al (1986) Pharmacokinetics and pharmacodynamics of glucocorticoid suspensions after intra-articular administration. Clin Pharmacol Ther 39(3):313–317PubMedCrossRefGoogle Scholar
  141. 141.
    Derendorf H, Möllmann H, Barth J (1990) Pharmakokinetik von intraartikulär applizierten Glukokortikoiden. Akt Rheumatol 15:145–153CrossRefGoogle Scholar
  142. 142.
    Dernis E, Ruyssen-Witrand A, Mouterde G et al (2010) Use of glucocorticoids in rheumatoid arthritis—pratical modalities of glucocorticoid therapy: recommendations for clinical practice based on data from the literature and expert opinion. Joint Bone Spine. doi: 10.1016/j.jbspin.2009.12.010 Google Scholar
  143. 143.
    Yoon SH, Lee HY, Lee HJ et al (2013) Optimal dose of intra-articular corticosteroids for adhesive capsulitis: a randomized, triple-blind, placebo-controlled trial. Am J Sports Med. doi: 10.1177/0363546513480475 Google Scholar
  144. 144.
    Pereira RM, Freire de Carvalho CJ (2011) Glucocorticoid-induced myopathy. Joint Bone Spine. doi: 10.1016/j.jbspin.2010.02.025 Google Scholar
  145. 145.
    Buttgereit F, Burmester GR, Lipworth BJ (2005) Optimised glucocorticoid therapy: the sharpening of an old spear. Lancet 365(9461):801–803PubMedCrossRefGoogle Scholar
  146. 146.
    van der Laan S, Meijer OC (2008) Pharmacology of glucocorticoids: beyond receptors. Eur J Pharmacol. doi: 10.1016/j.ejphar.2008.01.060 PubMedGoogle Scholar
  147. 147.
    De Bosscher K, Haegeman G, Elewaut D (2010) Targeting inflammation using selective glucocorticoid receptor modulators. Curr Opin Pharmacol. doi: 10.1016/j.coph.2010.04.007 PubMedGoogle Scholar
  148. 148.
    Barnes PJ, Adcock IM (2009) Glucocorticoid resistance in inflammatory diseases. Lancet. doi: 10.1016/S0140-6736(09)60326-3 Google Scholar
  149. 149.
    Biddie SC, Conway-Campbell BL, Lightman SL (2012) Dynamic regulation of glucocorticoid signalling in health and disease. Rheumatology (Oxford). doi: 10.1093/rheumatology/ker215 Google Scholar
  150. 150.
    Quax RA, Koper JW, de Jong PH et al (2012) In vitro glucocorticoid sensitivity is associated with clinical glucocorticoid therapy outcome in rheumatoid arthritis. Arthritis Res Ther. doi: 10.1186/ar4029 Google Scholar
  151. 151.
    Barnes PJ (2011) Glucocorticosteroids: current and future directions. Br J Pharmacol. doi: 10.1111/j.1476-5381.2010.01199.x PubMedCentralPubMedGoogle Scholar
  152. 152.
    van Oosten MJ, Dolhain RJ, Koper JW et al (2010) Polymorphisms in the glucocorticoid receptor gene that modulate glucocorticoid sensitivity are associated with rheumatoid arthritis. Arthritis Res Ther. doi: 10.1186/ar3118 PubMedCentralPubMedGoogle Scholar
  153. 153.
    Quax RA, Koper JW, Huisman AM et al (2015) Polymorphisms in the glucocorticoid receptor gene and in the glucocorticoid-induced transcript 1 gene are associated with disease activity and response to glucocorticoid bridging therapy in rheumatoid arthritis. Rheumatol Int. doi: 10.1007/s00296-015-3235-z PubMedCentralPubMedGoogle Scholar
  154. 154.
    Sorrells SF, Sapolsky RM (2007) An inflammatory review of glucocorticoid actions in the CNS. Brain Behav Immun 21(3):259–272PubMedCentralPubMedCrossRefGoogle Scholar
  155. 155.
    Harbuz MS, Jessop DS (1999) Is there a defect in cortisol production in rheumatoid arthritis? Rheumatology (Oxford) 38(4):298–302CrossRefGoogle Scholar
  156. 156.
    Cutolo M, Foppiani L, Minuto F (2002) Hypothalamic-pituitary-adrenal axis impairment in the pathogenesis of rheumatoid arthritis and polymyalgia rheumatica. J Endocrinol Invest 25(10 Suppl):19–23PubMedGoogle Scholar
  157. 157.
    Straub RH, Bijlsma JW, Masi A et al (2013) Role of neuroendocrine and neuroimmune mechanisms in chronic inflammatory rheumatic diseases–the 10-year update. Semin Arthritis Rheum. doi: 10.1016/j.semarthrit.2013.04.008 PubMedGoogle Scholar
  158. 158.
    Devogelaer JP, Goemaere S, Boonen S et al (2006) Evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis: a consensus document of the Belgian Bone Club. Osteoporos Int 17(1):8–19PubMedCrossRefGoogle Scholar
  159. 159.
    Grossman JM, Gordon R, Ranganath VK et al (2010) American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken). doi: 10.1002/acr.20295 Google Scholar
  160. 160.
    Weinstein RS (2011) Clinical practice. Glucocorticoid-induced bone disease. N Engl J Med. doi: 10.1056/NEJMcp1012926 PubMedCentralGoogle Scholar
  161. 161.
    Lekamwasam S, Adachi JD, Agnusdei D et al (2012) A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporos Int. doi: 10.1007/s00198-012-1958-1 PubMedGoogle Scholar
  162. 162.
    Hoes JN, Jacobs JW, Boers M et al (2007) EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 66(12):1560–1567PubMedCentralPubMedCrossRefGoogle Scholar
  163. 163.
    Duru N, van der Goes MC, Jacobs JW et al (2013) EULAR evidence-based and consensus-based recommendations on the management of medium to high-dose glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis. doi: 10.1136/annrheumdis-2013-203249 PubMedGoogle Scholar
  164. 164.
    Kanis JA, McCloskey EV, Johansson H et al (2013) European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. doi: 10.1007/s00198-012-2074-y PubMedCentralGoogle Scholar
  165. 165.
    Eastell R, Krege JH, Chen P et al (2006) Development of an algorithm for using PINP to monitor treatment of patients with teriparatide. Curr Med Res Opin 22(1):61–66PubMedCrossRefGoogle Scholar
  166. 166.
    Arnson Y, Amital H, Shoenfeld Y (2007) Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis 66(9):1137–1142PubMedCentralPubMedCrossRefGoogle Scholar
  167. 167.
    Sans S, Kesteloot H, Kromhout D (1997) The burden of cardiovascular diseases mortality in Europe. Task Force of the European Society of Cardiology on Cardiovascular Mortality and Morbidity Statistics in Europe. Eur Heart J 18(12):1231–1248CrossRefGoogle Scholar
  168. 168.
    Solomon DH, Greenberg J, Curtis JR et al (2015) Derivation and Internal Validation of an Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis: a Consortium of Rheumatology Researchers of North America Registry Study. Arthritis Rheumatol. doi: 10.1002/art.39195 PubMedCentralGoogle Scholar
  169. 169.
    van der Goes MC, Jacobs JW, Boers M et al (2010) Monitoring adverse events of low-dose glucocorticoid therapy: EULAR recommendations for clinical trials and daily practice. Ann Rheum Dis. doi: 10.1136/ard.2009.124958 Google Scholar
  170. 170.
    Fardet L (2013) Long term glucocorticoid therapy: so much remains to be done…. Rev Med Intern. doi: 10.1016/j.revmed.2013.02.017 Google Scholar
  171. 171.
    Clark AR (2007) Anti-inflammatory functions of glucocorticoid-induced genes. Mol Cell Endocrinol 275:79–97. doi: 10.1016/j.mce.2007.04.013 PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Cyrus Cooper
    • 1
    • 2
    Email author
  • Thomas Bardin
    • 3
  • Maria-Luisa Brandi
    • 4
  • Patrice Cacoub
    • 5
    • 6
  • John Caminis
    • 7
  • Roberto Civitelli
    • 8
  • Maurizio Cutolo
    • 9
  • Willard Dere
    • 10
  • Jean-Pierre Devogelaer
    • 11
  • Adolfo Diez-Perez
    • 12
  • Thomas A. Einhorn
    • 13
  • Patrick Emonts
    • 14
  • Olivier Ethgen
    • 15
  • John A. Kanis
    • 16
  • Jean-Marc Kaufman
    • 17
  • Tore K. Kvien
    • 18
  • Willem F. Lems
    • 19
  • Eugene McCloskey
    • 16
  • Pierre Miossec
    • 20
  • Susanne Reiter
    • 21
  • Johann Ringe
    • 22
  • René Rizzoli
    • 23
  • Kenneth Saag
    • 24
  • Jean-Yves Reginster
    • 25
  1. 1.MRC Lifecourse Epidemiology UnitUniversity of SouthamptonSouthamptonUK
  2. 2.NIHR Musculoskeletal Biomedical Research UnitUniversity of OxfordOxfordUK
  3. 3.Department of Rhumatologie, Hôpital Lariboisière Assistance Publique Hôpitaux de ParisUniversity Paris VIIParisFrance
  4. 4.Department of Internal MedicineUniversity of FlorenceFlorenceItaly
  5. 5.Department Hospitalo-Universitaire I2B, INSERM, UMR S 959, CNRS 7211UPMC University of Paris 06ParisFrance
  6. 6.Group Hospitalier Pitié-Salpêtrière, Department of Internal MedicineParisFrance
  7. 7.UCB BiosciencesRaleighUSA
  8. 8.Division of Bone and Mineral DiseasesWashington UniversitySt. LouisUSA
  9. 9.Research Laboratories and Clinical Academic Division of RheumatologyUniversity Medical School of GenoaGenoaItaly
  10. 10.Internal MedicineUniversity of UtahSalt Lake CityUSA
  11. 11.Rheumatology Department, Saint-Luc University HospitalLouvain University in BrusselsBrusselsBelgium
  12. 12.Servicio de Medicina Interna y Enfermedades InfecciosasHospital del Mar-IMIM and RETICEFBarcelonaSpain
  13. 13.Department of Orthopaedic SurgeryBoston University Medical CenterBostonUSA
  14. 14.Bone and Cartilage Metabolism Unit, Department of Public Health SciencesUniversity of LiegeLiègeBelgium
  15. 15.Department of Public Health, Epidemiology and Health EconomicsUniversity of LiègeLiègeBelgium
  16. 16.Centre for Metabolic Bone Diseases, Centre for Integrated Research in Musculoskeletal AgeingUniversity of SheffieldSheffieldUK
  17. 17.Department of EndocrinologyGhent University HospitalGhentBelgium
  18. 18.Department of RheumatologyDiakonhjemmet HospitalOsloNorway
  19. 19.Department of RheumatologyVU University Medical HospitalAmsterdamThe Netherlands
  20. 20.Immunogenomics and Inflammation Research Unit, Department of Immunology and RheumatologyUniversity of Lyon 1LyonFrance
  21. 21.BonnGermany
  22. 22.West German Osteoporosis Center (WOC)University of CologneLeverkusenGermany
  23. 23.Service of Bone Diseases, Faculty of MedicineGeneva University HospitalsGenevaSwitzerland
  24. 24.Division of Clinical Immunology and RheumatologyUniversity of AlabamaBirminghamUSA
  25. 25.Department of Public Health, Epidemiology and Health EconomicsUniversity of LiegeLiègeBelgium

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