Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Clinical features and evaluation of glucocorticoid-induced osteoporosis

Harold N Rosen, MD
Section Editor
Clifford J Rosen, MD
Deputy Editor
Jean E Mulder, MD


Glucocorticoid therapy is associated with an appreciable risk of bone loss, which is most pronounced in the first few months of use. In addition, glucocorticoids increase fracture risk, and fractures occur at higher bone mineral density (BMD) values than occur in postmenopausal osteoporosis. The increased risk of fracture has been reported with doses of prednisone or its equivalent as low as 2.5 to 7.5 mg daily [1]. The pathogenesis, clinical features, and evaluation of glucocorticoid-induced osteoporosis will be reviewed here. The prevention and treatment of glucocorticoid-induced osteoporosis are presented separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)


The deleterious effects of glucocorticoid excess on bone result from direct effects on osteoblasts, osteocytes, and osteoclasts. Glucocorticoids increase bone resorption and reduce bone formation (algorithm 1) [2,3]. The risk of bone loss is most pronounced in the first few months of use, followed by slower but steady loss of bone with continued use [3]. Most agents that increase bone loss, such as thyroxine or sustained elevation of parathyroid hormone (PTH), accelerate not only bone resorption but also formation, albeit to a lesser extent [4]. Because glucocorticoids accelerate resorption while inhibiting formation, their use is associated with early rapid bone loss [5,6]. With chronic use, osteoclast-mediated bone resorption slows, and suppression of bone formation becomes the predominant skeletal effect [7-9].

Increase in bone resorption – As in other target tissues, glucocorticoids exert their effects on gene expression via cytoplasmic glucocorticoid type 2 receptors [10]. In adult bone, functional glucocorticoid receptors are found in preosteoblast/stromal cells, osteoblasts (the cells that produce bone matrix), but not in osteoclasts [11,12]. Glucocorticoids stimulate osteoclast proliferation by suppressing synthesis of osteoprotegerin, an inhibitor of osteoclast differentiation from hematopoietic cells of the macrophage lineage, and by stimulating production of the receptor activator of nuclear factor kappa-B (RANK), which is required for osteoclastogenesis. High glucocorticoid levels also stimulate RANK ligand (RANKL) synthesis by preosteoblast/stromal cells, supporting osteoclast differentiation and net bone resorption [12]. In addition, glucocorticoids increase bone resorption by decreasing secretion of androgens and estrogens, mediated primarily by inhibition of gonadotropin secretion [13-16]. (See "Normal skeletal development and regulation of bone formation and resorption", section on 'Osteoclasts'.)

Glucocorticoids also decrease intestinal calcium absorption, in part by opposing the action of vitamin D and by decreasing the expression of calcium channels in the duodenum [3,17-19]. Glucocorticoids increase renal calcium excretion by decreasing calcium reabsorption [18,20,21]. Both of these actions result in an increase in serum PTH and, subsequently, increased bone resorption.

Suppression of bone formation – With long-term use, the predominant effect of glucocorticoids on the skeleton is reduced bone formation. The decline in bone formation is mediated by direct inhibition of osteoblast proliferation and differentiation and by an increase in the apoptosis rates of mature osteoblasts and osteocytes [2,3,22-24]. This apoptosis may also explain the tendency of glucocorticoids to cause osteonecrosis [25]. In addition, glucocorticoids alter PTH secretory dynamics (reduce tonic secretion and increase the amount released as pulses) [26], antagonize the anabolic action of PTH [22,27], and inhibit production of insulin-like growth factor-1 (IGF-1) [3,24,28] and testosterone [13-15]. The reduction in bone formation is associated with a decrease in the mineral apposition rate [29] and in serum and urine biochemical markers of bone formation [20,30]. (See "Normal skeletal development and regulation of bone formation and resorption", section on 'Osteoblasts'.)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Oct 2017. | This topic last updated: Oct 30, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 2002; 13:777.
  2. Manolagas SC, Weinstein RS. New developments in the pathogenesis and treatment of steroid-induced osteoporosis. J Bone Miner Res 1999; 14:1061.
  3. Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 2007; 18:1319.
  4. Mosekilde L, Melsen F. A tetracycline-based histomorphometric evaluation of bone resorption and bone turnover in hyperthyroidism and hyperparathyroidism. Acta Med Scand 1978; 204:97.
  5. Reid IR, Heap SW. Determinants of vertebral mineral density in patients receiving long-term glucocorticoid therapy. Arch Intern Med 1990; 150:2545.
  6. Gennari C, Imbimbo B. Effects of prednisone and deflazacort on vertebral bone mass. Calcif Tissue Int 1985; 37:592.
  7. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med 1990; 112:352.
  8. Cohen S, Levy RM, Keller M, et al. Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 1999; 42:2309.
  9. Reid DM, Hughes RA, Laan RF, et al. 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 2000; 15:1006.
  10. Feldman D, Dziak R, Koehler R, Stern P. Cytoplasmic glucocorticoid binding proteins in bone cells. Endocrinology 1975; 96:29.
  11. Abu EO, Horner A, Kusec V, et al. The localization of the functional glucocorticoid receptor alpha in human bone. J Clin Endocrinol Metab 2000; 85:883.
  12. Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology 2001; 142:5050.
  13. MacAdams MR, White RH, Chipps BE. Reduction of serum testosterone levels during chronic glucocorticoid therapy. Ann Intern Med 1986; 104:648.
  14. Crilly R, Cawood M, Marshall DH, Nordin BE. Hormonal status in normal, osteoporotic and corticosteroid-treated postmenopausal women. J R Soc Med 1978; 71:733.
  15. Pearce G, Tabensky DA, Delmas PD, et al. Corticosteroid-induced bone loss in men. J Clin Endocrinol Metab 1998; 83:801.
  16. Odell WD. Testosterone treatment of men treated with glucocorticoids. Arch Intern Med 1996; 156:1133.
  17. Hahn TJ, Halstead LR, Baran DT. Effects off short term glucocorticoid administration on intestinal calcium absorption and circulating vitamin D metabolite concentrations in man. J Clin Endocrinol Metab 1981; 52:111.
  18. Wajchenberg BL, Pereira VG, Kieffer J, Ursic S. Effect of dexamethasone on calcium metabolism and 47Ca kinetics in normal subjects. Acta Endocrinol (Copenh) 1969; 61:173.
  19. Huybers S, Naber TH, Bindels RJ, Hoenderop JG. Prednisolone-induced Ca2+ malabsorption is caused by diminished expression of the epithelial Ca2+ channel TRPV6. Am J Physiol Gastrointest Liver Physiol 2007; 292:G92.
  20. Nielsen HK, Thomsen K, Eriksen EF, et al. The effects of high-dose glucocorticoid administration on serum bone gamma carboxyglutamic acid-containing protein, serum alkaline phosphatase and vitamin D metabolites in normal subjects. Bone Miner 1988; 4:105.
  21. Suzuki Y, Ichikawa Y, Saito E, Homma M. Importance of increased urinary calcium excretion in the development of secondary hyperparathyroidism of patients under glucocorticoid therapy. Metabolism 1983; 32:151.
  22. Rubin MR, Bilezikian JP. Clinical review 151: The role of parathyroid hormone in the pathogenesis of glucocorticoid-induced osteoporosis: a re-examination of the evidence. J Clin Endocrinol Metab 2002; 87:4033.
  23. Pereira RM, Delany AM, Canalis E. Cortisol inhibits the differentiation and apoptosis of osteoblasts in culture. Bone 2001; 28:484.
  24. Pereira RM, Carvalho JF, Canalis E. Glucocorticoid-induced osteoporosis in rheumatic diseases. Clinics (Sao Paulo) 2010; 65:1197.
  25. Weinstein RS, Nicholas RW, Manolagas SC. Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab 2000; 85:2907.
  26. Bonadonna S, Burattin A, Nuzzo M, et al. Chronic glucocorticoid treatment alters spontaneous pulsatile parathyroid hormone secretory dynamics in human subjects. Eur J Endocrinol 2005; 152:199.
  27. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 1998; 102:274.
  28. Canalis E, Avioli L. Effects of deflazacort on aspects of bone formation in cultures of intact calvariae and osteoblast-enriched cells. J Bone Miner Res 1992; 7:1085.
  29. Bressot C, Meunier PJ, Lejeune E, et al. Histomorphometric profile, pathophysiology and reversibility of corticosteroid-induced osteoporosis. Metab Bone Dis Rel Res 1979; 1:303.
  30. Mitchell DR, Jackson TW, Lyles KW. Effects of short-term administration of glucocorticoids on bone metabolism in healthy elderly men. J Am Geriatr Soc 1991; 39:1179.
  31. Van Staa TP, Leufkens HG, Abenhaim L, et al. Use of oral corticosteroids and risk of fractures. J Bone Miner Res 2000; 15:993.
  32. Angeli A, Guglielmi G, Dovio A, et al. High prevalence of asymptomatic vertebral fractures in post-menopausal women receiving chronic glucocorticoid therapy: a cross-sectional outpatient study. Bone 2006; 39:253.
  33. Kanis JA, Johansson H, Oden A, et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 2004; 19:893.
  34. Rossini M, Viapiana O, Vitiello M, et al. Prevalence and incidence of osteoporotic fractures in patients on long-term glucocorticoid treatment for rheumatic diseases: the Glucocorticoid Induced OsTeoporosis TOol (GIOTTO) study. Reumatismo 2017; 69:30.
  35. Curtis JR, Westfall AO, Allison J, et al. Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Rheum 2006; 55:420.
  36. van Staa TP, Geusens P, Pols HA, et al. A simple score for estimating the long-term risk of fracture in patients using oral glucocorticoids. QJM 2005; 98:191.
  37. Tatsuno I, Sugiyama T, Suzuki S, et al. Age dependence of early symptomatic vertebral fracture with high-dose glucocorticoid treatment for collagen vascular diseases. J Clin Endocrinol Metab 2009; 94:1671.
  38. Sugiyama T, Suzuki S, Yoshida T, et al. Age, initial dose and dose increase are independent risk factors for symptomatic vertebral fractures in glucocorticoid-treated male patients. Intern Med 2011; 50:817.
  39. Waljee AK, Rogers MA, Lin P, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ 2017; 357:j1415.
  40. Rüegsegger P, Medici TC, Anliker M. Corticosteroid-induced bone loss. A longitudinal study of alternate day therapy in patients with bronchial asthma using quantitative computed tomography. Eur J Clin Pharmacol 1983; 25:615.
  41. Gluck OS, Murphy WA, Hahn TJ, Hahn B. Bone loss in adults receiving alternate day glucocorticoid therapy. A comparison with daily therapy. Arthritis Rheum 1981; 24:892.
  42. Dore RK. How to prevent glucocorticoid-induced osteoporosis. Cleve Clin J Med 2010; 77:529.
  43. McDougall R, Sibley J, Haga M, Russell A. Outcome in patients with rheumatoid arthritis receiving prednisone compared to matched controls. J Rheumatol 1994; 21:1207.
  44. Michel BA, Bloch DA, Fries JF. Predictors of fractures in early rheumatoid arthritis. J Rheumatol 1991; 18:804.
  45. Lems WF, Jahangier ZN, Jacobs JW, Bijlsma JW. Vertebral fractures in patients with rheumatoid arthritis treated with corticosteroids. Clin Exp Rheumatol 1995; 13:293.
  46. Suliman AM, Freaney R, Smith TP, et al. The impact of different glucocorticoid replacement schedules on bone turnover and insulin sensitivity in patients with adrenal insufficiency. Clin Endocrinol (Oxf) 2003; 59:380.
  47. Peacey SR, Guo CY, Robinson AM, et al. Glucocorticoid replacement therapy: are patients over treated and does it matter? Clin Endocrinol (Oxf) 1997; 46:255.
  48. Florkowski CM, Holmes SJ, Elliot JR, et al. Bone mineral density is reduced in female but not male subjects with Addison's disease. N Z Med J 1994; 107:52.
  49. Zelissen PM, Croughs RJ, van Rijk PP, Raymakers JA. Effect of glucocorticoid replacement therapy on bone mineral density in patients with Addison disease. Ann Intern Med 1994; 120:207.
  50. Jääskeläinen J, Voutilainen R. Bone mineral density in relation to glucocorticoid substitution therapy in adult patients with 21-hydroxylase deficiency. Clin Endocrinol (Oxf) 1996; 45:707.
  51. Buckley L, Guyatt G, Fink HA, et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol 2017; 69:1521.
  52. Kanis JA, Johansson H, Oden A, McCloskey EV. Guidance for the adjustment of FRAX according to the dose of glucocorticoids. Osteoporos Int 2011; 22:809.
  53. Cauley JA, Hochberg MC, Lui LY, et al. Long-term risk of incident vertebral fractures. JAMA 2007; 298:2761.
  54. Kanis JA, Johnell O, De Laet C, et al. A meta-analysis of previous fracture and subsequent fracture risk. Bone 2004; 35:375.
  55. Kalpakcioglu BB, Engelke K, Genant HK. Advanced imaging assessment of bone fragility in glucocorticoid-induced osteoporosis. Bone 2011; 48:1221.