Calcified Tissue International

, Volume 79, Issue 3, pp 129–137 | Cite as

The Pathogenesis, Epidemiology and Management of Glucocorticoid-Induced Osteoporosis



Oral glucocorticoids (GCs) are frequently used in the treatment of inflammatory conditions, such as rheumatoid arthritis or asthma. They have adverse skeletal effects, primarily through reductions in bone formation and osteocyte apoptosis. Several findings indicate that changes in the quality of bone may significantly contribute to the increased risk of fracture and that loss of BMD only partially explains the increased risk of fracture in oral GC users. Epidemiological studies have found that the increases in the risk of fracture in oral GC users are dose dependent and occur within three months of starting GC therapy. Daily doses of >2.5 mg prednisone equivalent have been associated with increases in the risk of fractures and randomised studies reported adverse skeletal effects with daily doses as low as 5 mg. After discontinuation of GC treatment, the risk of fracture may reduce towards baseline levels unless patients previously used high cumulative doses of oral GCs. Users of inhaled GCs have also an increased risk of fracture, especially at higher doses. But it is likely that this excess risk is related to the severity of the underlying respiratory disease, rather than to the inhaled GC therapy. It has been recommended that patients who start on oral GC therapy should receive calcium and vitamin D supplementation. Patients with a higher risk of fracture should also receive a bisphosphonate.


Glucocorticoids Corticosteroids Osteoporosis Fracture Iatrogenic disease 


  1. 1.
    van Staa TP, Cooper C, Abenhaim L, Begaud B, Zhang B, Leufkens HGM (2000) Utilisation of oral corticosteroids in the United Kingdom. Q J Med 93:105–111Google Scholar
  2. 2.
    Cushing H (1932) The basophilic adenomas of the pituitary body and their clinical manifestations (pituirary basophilism). Bull Johns Hopkins Hosp 1:137–192Google Scholar
  3. 3.
    Guyatt GH, Webber CE, Mewa AA, Sackett DL (1984) Determining causation-a case study: adrenocorticosteroids and osteoporosis. J Chron Dis 37:343–352PubMedCrossRefGoogle Scholar
  4. 4.
    Dalle Carbonare L, Bertoldo F, Valenti MT, Zenari S, Zanatta M, Sella S, Giannini S, Cascio VL (2005) Histomorphometric analysis of glucocorticoid-induced osteoporosis: a review. Micron 36:645–652PubMedCrossRefGoogle Scholar
  5. 5.
    Patschan D, Loddenkemper K, Buttgereit F (2001) Molecular mechanisms of glucocorticoid-induced osteoporosis. Bone 29:498–505PubMedCrossRefGoogle Scholar
  6. 6.
    Papaioannou A, Ferko NC, Adachi JD (2002) Corticosteroids and the skeletal system. In: Lin AN, Paget SA. Eds Principles of corticosteroid therapy. Arnold Publishers, New York, 69–86Google Scholar
  7. 7.
    O’Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA, Manolagas SC, Weinstein RS (2004) Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 145:1835–1841PubMedCrossRefGoogle Scholar
  8. 8.
    Canalis E (1996) Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis. J Clin Endocrinol Metab 81:3441–3446PubMedCrossRefGoogle Scholar
  9. 9.
    Weinstein RS, Chen JR, Powers CC, Stewart SA, Landes RD, Bellido T, Jilka RL, Parfitt AM, Manolagas SC (2002) Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Invest 109:1041–1048PubMedCrossRefGoogle Scholar
  10. 10.
    Ton FN, Gunawardene SC, Lee H, Neer RM (2005) Effects of low-dose prednisone on bone metabolism. J Bone Miner Res 20:464–470PubMedCrossRefGoogle Scholar
  11. 11.
    Sivagurunathan S, Muir MM, Brennan TC, Seale JP, Mason RS (2005) Influence of glucocorticoids on human osteoclast generation and activity. J Bone Miner Res 20:390–398PubMedCrossRefGoogle Scholar
  12. 12.
    Manolagas SC (2000) Corticosteroids and fractures: a close encounter of the third cell kind (editorial). J Bone Miner Res 15:1001–1005PubMedCrossRefGoogle Scholar
  13. 13.
    Weinstein RS, Nicholas RW, Manolagas SC (2000) Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab 85:2907–2912PubMedCrossRefGoogle Scholar
  14. 14.
    Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC (1998) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 102:274–282PubMedGoogle Scholar
  15. 15.
    Gu G, Mulari M, Peng Z, Hentunen TA, Vaananen HK (2005) Death of osteocytes turns off the inhibition of osteoclasts and triggers local bone resorption. Biochem Biophys Res Commun 335:1095–1101PubMedGoogle Scholar
  16. 16.
    Paz-Pacheco E, Fuleihan GE, LeBoff MS (1995) Intact parathyroid hormone levels are not elevated in glucocorticoid-treated subjects. J Bone Miner Res 10:1713–1718PubMedCrossRefGoogle Scholar
  17. 17.
    Klein RG, Arnaud SB, Gallagher JC, Deluca HF, Riggs BL (1977) Intestinal calcium absorption in exogenous hypercortisonism. Role of 25-hydroxyvitamin D and corticosteroid dose. J Clin Invest 60:253–259PubMedGoogle Scholar
  18. 18.
    Kagen LJ (2002) Steroid myopathy. In: Lin AN, Paget SA. Eds Principles of corticosteroid therapy. Arnold Publishers, New York, 87–90Google Scholar
  19. 19.
    Walsh LJ, Wong CA, Oborne J, Cooper S, Lewis SA, Pringle M, Hubbard R, Tattersfield AE (2001) Adverse effects of oral corticosteroids in relation to dose in patients with lung disease. Thorax 56:279–284PubMedCrossRefGoogle Scholar
  20. 20.
    Weiner P, Azgad Y, Weiner M (1993) The effect of corticosteroids on inspiratory muscle performance in humans. Chest 104:1788–1791PubMedGoogle Scholar
  21. 21.
    Hopkinson NS, Man WDC, Dayer MJ, Ross ET, Nickol AJ, Hart N, Moxham J, Polkey MI (2004) Acute effect of oral steroids on muscle function in chronic obstructive pulmonary disease. Eur Respir J 24:137–142PubMedCrossRefGoogle Scholar
  22. 22.
    van Staa TP, Leufkens HGM, Abenhaim L, Zhang B, Cooper C (2000) Use of oral corticosteroids and risk of fractures. J Bone Miner Res 15:993–1000PubMedCrossRefGoogle Scholar
  23. 23.
    Clowes JA, Riggs BL, Khosla S (2005) The role of the immune system in the pathophysiology of osteoporosis. Immunol Rev 208:207–227PubMedCrossRefGoogle Scholar
  24. 24.
    van Staa TP, Cooper C, Brusse LS, Leufkens H, Javaid MK, Arden NK (2003) Inflammatory bowel disease and the risk of fracture. Gastroenterology 125:1591–1597PubMedCrossRefGoogle Scholar
  25. 25.
    Cooper C, Coupland C, Mitchell M (1995) Rheumatoid arthritis, corticosteroid therapy and hip fracture. Ann Rheum Dis 54:49–52PubMedGoogle Scholar
  26. 26.
    van Staa TP, Geusens P, Pols HA, de Laet C, Leufkens HG, Cooper C (2005) A simple score for estimating the long-term risk of fracture in patients using oral glucocorticoids. QJM 98:191–198PubMedCrossRefGoogle Scholar
  27. 27.
    Laan RFJM, van Riel PLCM, van de Putte LBA, van Erning LJTO, van’t Hof MA, Lemmens JAM (1993) Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis. Ann Intern Med 119:963–968PubMedGoogle Scholar
  28. 28.
    van Rossum EF, Lamberts SW (2004) Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition. Recent Prog Horm Res 59:333–357PubMedCrossRefGoogle Scholar
  29. 29.
    van Staa TP, Leufkens HGM, Abenhaim L, Zhang B, Cooper C (2000) Fractures and oral corticosteroids: relationship to daily and cumulative dose. Rheumatol 39:1383–1389CrossRefGoogle Scholar
  30. 30.
    Kanis JA, Johansson H, Oden A, Johnell O, de Laet C, Melton III LJ, Tenenhouse A, Reeve J, Silman AJ, Pols HA, Eisman JA, McCloskey EV, Mellstrom D (2004) A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 19:893–899PubMedCrossRefGoogle Scholar
  31. 31.
    Steinbuch M, Youket TE, Cohen S (2004) Oral glucocorticoid use is associated with an increased risk of fracture. Osteoporos Int 15:323–328PubMedCrossRefGoogle Scholar
  32. 32.
    Donnan PT, Libby G, Boyter AC, Thompson P (2005) The population risk of fractures attributable to oral corticosteroids. Pharmacoepidemiol Drug Saf 14:177–186PubMedCrossRefGoogle Scholar
  33. 33.
    Vestergaard P, Rejnmark L, Mosekilde L (2005) Fracture risk associated with systemic and topical corticosteroids. J Intern Med 257:374–384PubMedCrossRefGoogle Scholar
  34. 34.
    van Staa TP, Leufkens HGM, Cooper C (2002) The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 13(10):777–787PubMedCrossRefGoogle Scholar
  35. 35.
    van Staa TP, Laan RF, Barton I, Cohen S, Reid DM, Cooper C (2003) Predictors and bone density threshold for vertebral fracture in patients using oral glucocorticoids. Arth Rheum 48:3224–3229CrossRefGoogle Scholar
  36. 36.
    Luengo M, Picado C, Del Rio L, Guańabens N, Montserrat JM, Setoain J (1991) Vertebral fractures in steroid dependant asthma and involutional osteoporosis: a comparative study. Thorax 46:803–806PubMedGoogle Scholar
  37. 37.
    Selby PL, Halsey JP, Adams KRH, Klimiuk P, Knight SM, Pal B, Stewart IM, Swinson DR (2000) Corticosteroids do not alter the threshold for vertebral fracture. J Bone Miner Res 15:952–956PubMedCrossRefGoogle Scholar
  38. 38.
    Manning PJ, Evans MC, Reid IR (1992) Normal bone mineral density following cure of Cushing’s syndrome. Clin Endocrinol 36:229–234Google Scholar
  39. 39.
    Aaron JE, Francis RM, Peacock M, Makins NB (1989) Contrasting microanatomy of idiopathic and corticosteroid-induced osteoporosis. Clin Orthop 243:294–305PubMedGoogle Scholar
  40. 40.
    Dalle Carbonare L, Arlot ME, Chavassieux PM, Roux JP, Portero NR, Meunier PJ (2001) Comparison of trabecular bone microarchitecture and remodeling in glucocorticoid-induced and postmenopausal osteoporosis. J Bone Miner Res 16:97–103PubMedCrossRefGoogle Scholar
  41. 41.
    Jones A, Fay JK, Burr M, Stone M, Hood K, Roberts G (2003) Inhaled corticosteroid effects on bone metabolism in asthma and mild chronic obstructive pulmonary disease (Cochrane Review). The Cochrane Library, Issue 3, 2003. Oxford: Update SoftwareGoogle Scholar
  42. 42.
    Richy F, Bousquet J, Ehrlich GE (2003) Inhaled corticosteroids effects on bone in asthmatic and COPD patients: a quantitative systematic review. Osteoporos Int 14:179–190PubMedGoogle Scholar
  43. 43.
    van Staa TP, Leufkens HGM, Cooper C (2001) Use of inhaled corticosteroids and risk of fractures. J Bone Miner Res 3:581–588CrossRefGoogle Scholar
  44. 44.
    Hubbard RB, Smith CJP, Smeeth L, Harrison TW, Tattersfield AE (2002) Inhaled corticosteroids and hip fracture: a population-based case-control study. Am J Respir Crit Care Med 166:1563–1566PubMedCrossRefGoogle Scholar
  45. 45.
    van Staa TP, Leufkens B, Cooper C (2002) Bone loss and inhaled glucocorticoids. N Engl J Med 346:533–535PubMedCrossRefGoogle Scholar
  46. 46.
    Israel E, Banerjee TR, Fitzmaurice GM, Kotlov TV, LaHive K, LeBoff MS (2001) Effects of inhaled glucocorticoids on bone density in premenopausal women. N Engl J Med 345(13):941–947PubMedCrossRefGoogle Scholar
  47. 47.
    de Vries F, van Staa TP, Bracke MS, Cooper C, Leufkens HG, Lammers JW (2005) Severity of obstructive airway disease and risk of osteoporotic fracture. Eur Respir J 25:879–884PubMedCrossRefGoogle Scholar
  48. 48.
    Johannes CB, Schneider GA, Dube TJ, Alfredson TD, Davis KJ, Walker AM (2005) The risk of nonvertebral fractures related to inhaled corticosteroid exposure among adults with chronic respiratory disease. Chest 127:1:89–97PubMedCrossRefGoogle Scholar
  49. 49.
    Lekamwasam S, Trivedi DP, Khaw KT (2002) An association between respiratory function and bone mineral density in women from the general community: a cross sectional study. Osteoporos Int 13:710–715PubMedCrossRefGoogle Scholar
  50. 50.
    Sin DD, Man JP, Man SF (2003) The risk of osteoporosis in Caucasian men and women with obstructive airways disease. Am J Med 114:10–14PubMedCrossRefGoogle Scholar
  51. 51.
    Royal College of Physicians (2002) Glucocorticoid-induced osteoporosis: guidelines for prevention and treatment. London: Royal College of PhysiciansGoogle Scholar
  52. 52.
    American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis (2001) Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheum 44:1496–1503CrossRefGoogle Scholar
  53. 53.
    Weiner P, Azgad Y, Weiner M (1995) Inspiratory muscle training during treatment with corticosteroids in humans. Chest 107:1041–1044PubMedGoogle Scholar
  54. 54.
    Mayoux-Benhamou MA, Roux C, Perraud A, Fermanian J, Rahali-Kachlouf H, Revel M (2005) Predictors of compliance with a home-based exercise program added to usual medical care in preventing postmenopausal osteoporosis: an 18-month prospective study. Osteoporos Int 16:325–331PubMedCrossRefGoogle Scholar
  55. 55.
    Amin S, Lavalley MP, Simms RW, Felson DT (2002) The comparative efficacy of drug therapies used for the management of corticosteroid-induced osteoporosis: a meta-regression. J Bone Miner Res 17:1512–1526PubMedCrossRefGoogle Scholar
  56. 56.
    Haguenauer D, Welch V, Shea B, Tugwell P, Adachi JD, Wells G (2000) Fluoride for the treatment of postmenopausal osteoporotic fractures: a meta-analysis. Osteoporos Int 11:727–738PubMedCrossRefGoogle Scholar
  57. 57.
    Watts NB, Cooper C, Lindsay R, Eastell R, Manhart MD, Barton IP, van Staa TP, Adachi JD (2004) Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom 7:255–261PubMedCrossRefGoogle Scholar
  58. 58.
    Sambrook PN, Kotowicz M, Nash P, Styles CB, Naganathan V, Henderson-Briffa KN, Eisman JA, Nicholson GC (2003) Prevention and treatment of glucocorticoid-induced osteoporosis: a comparison of calcitriol, vitamin D plus calcium, and alendronate plus calcium. J Bone Miner Res 18:919–924PubMedCrossRefGoogle Scholar
  59. 59.
    Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere S, Thamsborg G, Liberman UA, Delmas PD, Malice MP, Czachur M, Daifotis AG (1998) Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med 339:292–299PubMedCrossRefGoogle Scholar
  60. 60.
    Frediani B, Falsetti P, Baldi F, Acciai C, Filippou G, Marcolongo R (2003) Effects of 4-year treatment with once-weekly clodronate on prevention of corticosteroid-induced bone loss and fractures in patients with arthritis: evaluation with dual-energy X-ray absorptiometry and quantitative ultrasound. Bone 33:575–581PubMedCrossRefGoogle Scholar
  61. 61.
    Roux C, Oriente P, Laan R, Hughes RA, Ittner J, Goemaere S, Di Munno O, Pouilles JM, Horlait S, Cortet B (1998) Randomized trial of effect of cyclical etidronate in the prevention of corticosteroid-induced bone loss. Ciblos Study Group. J Clin Endocrinol Metab 83:1128–1133PubMedCrossRefGoogle Scholar
  62. 62.
    Adachi JD, Bensen WG, Brown J, Hanley D, Hodsman A, Josse R, Kendler DL, Lentle B, Olszynski W, Ste-Marie LG, Tenenhouse A, Chines AA (1997) Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 337:382–387PubMedCrossRefGoogle Scholar
  63. 63.
    Campbell IA, Douglas JG, Francis RM, Prescott RJ, Reid DM (2004) Research Committee of the British Thoracic Society. Five year study of etidronate and/or calcium as prevention and treatment for osteoporosis and fractures in patients with asthma receiving long term oral and/or inhaled glucocorticoids. Thorax 59:761–768PubMedCrossRefGoogle Scholar
  64. 64.
    Sato S, Ohosone Y, Suwa A, Yasuoka H, Nojima T, Fujii T, Kuwana M, Nakamura K, Mimori T, Hirakata M (2003) Effect of intermittent cyclical etidronate therapy on corticosteroid induced osteoporosis in Japanese patients with connective tissue disease: 3 year followup. J Rheumatol 30:2673–2679PubMedGoogle Scholar
  65. 65.
    Cohen S, Levy RM, Keller M, Boling E, Emkey RD, Greenwald M, Zizic TM, Wallach S, Sewell KL, Lukert BP, Axelrod DW, Chines AA (1992) Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 42:2309–2318CrossRefGoogle Scholar
  66. 66.
    Reid DM, Hughes RA, Laan RF, Sacco-Gibson NA, Wenderoth DH, Adami S, Eusebio RA, Devogelaer JP (2000) Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study. J Bone Miner Res 15:1006–1013PubMedCrossRefGoogle Scholar
  67. 67.
    Weinstein RS, Powers CC, Parfitt AM, Manolagas SC (2002) Preservation of osteocyte viability by bisphosphonates contributes to bone strength in glucocorticoid-treated mice independently of BMD: an unappreciated determinant of bone strength. J Bone Miner Res 17(Suppl 1):S156Google Scholar
  68. 68.
    Plotkin LI, Weinstein RS, Parfitt AM, Roberson PK, Manolagas SC, Bellido T (1999) Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest 104:1363–1374PubMedGoogle Scholar
  69. 69.
    Gu G, Hentunen TA, Nars M, Harkonen PL, Vaananen HK (2005) Estrogen protects primary osteocytes against glucocorticoid-induced apoptosis. Apoptosis 10:583–595PubMedCrossRefGoogle Scholar
  70. 70.
    Homik JJEH, Cranney A, Shea BJ, Suarez-Almazor ME, Tugwell P, Wells G (1998) Calcium and vitamin D for corticosteroid-induced osteoporosis. The Cochrane Database of Systematic Reviews, Issue 2Google Scholar
  71. 71.
    Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD (1998) Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J Clin Invest 102:1627–1633PubMedCrossRefGoogle Scholar
  72. 72.
    Buxton EC, Yao W, Lane NE (2004) Changes in serum receptor activator of nuclear factor-kappaB ligand, osteoprotegerin, and interleukin-6 levels in patients with glucocorticoid-induced osteoporosis treated with human parathyroid hormone (1–34). J Clin Endocrinol Metab 89:3332–3336PubMedCrossRefGoogle Scholar
  73. 73.
    van Staa TP, Geusens P, Leufkens HGM, Boonen A, Cooper C (2006) Individual fracture risk and the cost-effectiveness of bisphosphonates in patients using oral glucorticoids. Rheumatology (in press)Google Scholar
  74. 74.
    Harris J (1991) Unprincipled QALYs: a response to Cubbon. J Med Ethics 17:185–188PubMedCrossRefGoogle Scholar
  75. 75.
    Kanis JA, Johnell O, Oden A, Dawson A, De Laet C, Jonsson B (2001) Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int 12:989–995PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.Utrecht Institute for Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
  2. 2.MRC Resource Centre in EpidemiologyUniversity of SouthamptonSouthamptonUK
  3. 3.General Practice Research DatabaseMedicines and Healthcare Products Regulatory AgencyLondonUK

Personalised recommendations