Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Pathogenesis of glucocorticoid-induced osteoporosis and options for treatment

Nature Reviews Endocrinology volume 16, pages 437–447 (2020)Cite this article

Subjects

Abstract

Glucocorticoids are widely used to suppress inflammation or the immune system. High doses and long-term use of glucocorticoids lead to an important and common iatrogenic complication, glucocorticoid-induced osteoporosis, in a substantial proportion of patients. Glucocorticoids mainly increase bone resorption during the initial phase (the first year of treatment) by enhancing the differentiation and maturation of osteoclasts. Glucocorticoids also inhibit osteoblastogenesis and promote apoptosis of osteoblasts and osteocytes, resulting in decreased bone formation during long-term use. Several indirect effects of glucocorticoids on bone metabolism, such as suppression of production of insulin-like growth factor 1 or growth hormone, are involved in the pathogenesis of glucocorticoid-induced osteoporosis. Fracture risk assessment for all patients with long-term use of oral glucocorticoids is required. Non-pharmacological interventions to manage the risk of fracture should be prescribed to all patients, while pharmacological management is reserved for patients who have increased fracture risk. Various treatment options can be used, ranging from bisphosphonates to denosumab, as well as teriparatide. Finally, appropriate monitoring during treatment is also important.

Key points

  • Glucocorticoid-induced osteoporosis is the most common cause of secondary osteoporosis and is an iatrogenic disease; the main pathogenesis in the long term is a reduction in bone formation.

  • Fracture risk is correlated with the dose and duration of glucocorticoid administration, and seems to decrease rapidly on discontinuation; the underlying disease requiring glucocorticoid therapy often contributes to bone loss.

  • Evaluation of fracture risk, using tools such as FRAX, is recommended in all patients treated with glucocorticoids, preferably around the time of treatment initiation.

  • Non-pharmacological management (such as nutrition and exercise) should be advocated in all patients receiving long-term glucocorticoid treatment.

  • Using the minimally effective dose and duration of glucocorticoids with steroid-sparing drugs should be considered where possible.

  • Pharmacological anti-osteoporotic treatment is recommended in patients at high risk of fracture; anti-resorptives are the primary option but anabolic therapy might also be considered.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Bone cell activity and regulation in health and during glucocorticoid exposure.
Fig. 2: Management pathway for postmenopausal women and men aged ≥50 years undergoing treatment with glucocorticoids.

Similar content being viewed by others

References

  1. Caplan, A., Fett, N., Rosenbach, M., Werth, V. P. & Micheletti, R. G. Prevention and management of glucocorticoid-induced side effects: a comprehensive review: a review of glucocorticoid pharmacology and bone health. J. Am. Acad. Dermatol. 76, 1–9 (2017).

    PubMed  Google Scholar 

  2. Kaltsas, G. & Makras, P. Skeletal diseases in Cushing’s syndrome: osteoporosis versus arthropathy. Neuroendocrinology 92 (Suppl. 1), 60–64 (2010).

    CAS  PubMed  Google Scholar 

  3. Devogelaer, J. P., Crabbe, J. & Nagant de Deuxchaisnes, C. Bone mineral density in Addison’s disease: evidence for an effect of adrenal androgens on bone mass. Br. Med. J. 294, 798–800 (1987).

    CAS  Google Scholar 

  4. Bjornsdottir, S. et al. Risk of hip fracture in Addison’s disease: a population-based cohort study. J. Intern. Med. 270, 187–195 (2011).

    CAS  PubMed  Google Scholar 

  5. Vandewalle, J., Luypaert, A., De Bosscher, K. & Libert, C. Therapeutic mechanisms of glucocorticoids. Trends Endocrinol. Metab. 29, 42–54 (2018).

    CAS  PubMed  Google Scholar 

  6. van Staa, T. P. et al. Use of oral corticosteroids in the United Kingdom. QJM 93, 105–111 (2000).

    PubMed  Google Scholar 

  7. Overman, R. A., Yeh, J. Y. & Deal, C. L. Prevalence of oral glucocorticoid usage in the United States: a general population perspective. Arthritis Care Res. 65, 294–298 (2013).

    Google Scholar 

  8. Fardet, L., Petersen, I. & Nazareth, I. Prevalence of long-term oral glucocorticoid prescriptions in the UK over the past 20 years. Rheumatology 50, 1982–1990 (2011).

    PubMed  Google Scholar 

  9. Compston, J. Glucocorticoid-induced osteoporosis: an update. Endocrine 61, 7–16 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Mazziotti, G., Angeli, A., Bilezikian, J. P., Canalis, E. & Giustina, A. Glucocorticoid-induced osteoporosis: an update. Trends Endocrinol. Metab. 17, 144–149 (2006).

    CAS  PubMed  Google Scholar 

  11. Briot, K. & Roux, C. Glucocorticoid-induced osteoporosis. RMD Open 1, e000014 (2015).

    PubMed  PubMed Central  Google Scholar 

  12. LoCascio, V. et al. Bone loss in response to long-term glucocorticoid therapy. Bone Miner. 8, 39–51 (1990).

    CAS  PubMed  Google Scholar 

  13. De Vries, F. et al. Fracture risk with intermittent high-dose oral glucocorticoid therapy. Arthritis Rheum. 56, 208–214 (2007).

    PubMed  Google Scholar 

  14. Oshagbemi, O. A. et al. Use of high-dose intermittent systemic glucocorticoids and the risk of fracture in patients with chronic obstructive pulmonary disease. Bone 110, 238–243 (2018).

    CAS  PubMed  Google Scholar 

  15. van Staa, T. P., Leufkens, H. G., Abenhaim, L., Zhang, B. & Cooper, C. Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. Rheumatology 39, 1383–1389 (2000).

    PubMed  Google Scholar 

  16. Seckl, J. R. 11beta-hydroxysteroid dehydrogenases: changing glucocorticoid action. Curr. Opin. Pharmacol. 4, 597–602 (2004).

    CAS  PubMed  Google Scholar 

  17. Hardy, R. S., Seibel, M. J. & Cooper, M. S. Targeting 11beta-hydroxysteroid dehydrogenases: a novel approach to manipulating local glucocorticoid levels with implications for rheumatic disease. Curr. Opin. Pharmacol. 13, 440–444 (2013).

    CAS  PubMed  Google Scholar 

  18. Kanis, J. A. et al. A meta-analysis of prior corticosteroid use and fracture risk. J. Bone Miner. Res. 19, 893–899 (2004).

    PubMed  Google Scholar 

  19. Weinstein, R. S. Clinical practice. Glucocorticoid-induced bone disease. N. Engl. J. Med. 365, 62–70 (2011).

    CAS  PubMed  Google Scholar 

  20. van Staa, T. P., Leufkens, H. G. & Cooper, C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos. Int. 13, 777–787 (2002).

    PubMed  Google Scholar 

  21. Amiche, M. A. et al. Fracture risk in oral glucocorticoid users: a Bayesian meta-regression leveraging control arms of osteoporosis clinical trials. Osteoporos. Int. 27, 1709–1718 (2016).

    CAS  PubMed  Google Scholar 

  22. Balasubramanian, A. et al. Glucocorticoid exposure and fracture risk in patients with new-onset rheumatoid arthritis. Osteoporos. Int. 27, 3239–3249 (2016).

    CAS  PubMed  Google Scholar 

  23. Adler, R. A. & Hochberg, M. C. Glucocorticoid-induced osteoporosis in men. J. Endocrinol. Invest. 34, 481–484 (2011).

    CAS  PubMed  Google Scholar 

  24. Ebeling, P. R. Clinical practice. Osteoporosis in men. N. Engl. J. Med. 358, 1474–1482 (2008).

    CAS  PubMed  Google Scholar 

  25. Hoff, M. et al. Anti-osteoporosis drug use: too little, too much, or just right? The HUNT study, Norway. Osteoporos. Int. 29, 1875–1885 (2018).

    CAS  PubMed  Google Scholar 

  26. Frediani, B. et al. Effects of high dose methylprednisolone pulse therapy on bone mass and biochemical markers of bone metabolism in patients with active rheumatoid arthritis: a 12-month randomized prospective controlled study. J. Rheumatol. 31, 1083–1087 (2004).

    CAS  PubMed  Google Scholar 

  27. Goncalves, P. A. et al. Inhaled glucocorticoids are associated with vertebral fractures in COPD patients. J. Bone Miner. Metab. 36, 454–461 (2018).

    CAS  PubMed  Google Scholar 

  28. Sosa, M. et al. Inhaled steroids do not decrease bone mineral density but increase risk of fractures: data from the GIUMO study group. J. Clin. Densitom. 9, 154–158 (2006).

    CAS  PubMed  Google Scholar 

  29. Wheelock, C., Glass, J. & St Anna, L. Clinical inquiry. Do inhaled steroids reduce bone mineral density and increase fracture risk? J. Fam. Pract. 61, 493–508 (2012).

    PubMed  Google Scholar 

  30. Vestergaard, P., Rejnmark, L. & Mosekilde, L. Fracture risk associated with systemic and topical corticosteroids. J. Intern. Med. 257, 374–384 (2005).

    CAS  PubMed  Google Scholar 

  31. Loke, Y. K., Cavallazzi, R. & Singh, S. Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. Thorax 66, 699–708 (2011).

    PubMed  Google Scholar 

  32. Vestergaard, P. Skeletal effects of systemic and topical corticosteroids. Curr. Drug Saf. 3, 190–193 (2008).

    CAS  PubMed  Google Scholar 

  33. Loftus, J. et al. Randomized, double-blind trial of deflazacort versus prednisone in juvenile chronic (or rheumatoid) arthritis: a relatively bone-sparing effect of deflazacort. Pediatrics 88, 428–436 (1991).

    CAS  PubMed  Google Scholar 

  34. Ferraris, J. R. et al. Effect of deflazacort versus methylprednisone on growth, body composition, lipid profile, and bone mass after renal transplantation. The Deflazacort Study Group. Pediatr. Nephrol. 14, 682–688 (2000).

    CAS  PubMed  Google Scholar 

  35. Markham, A. & Bryson, H. M. Deflazacort. A review of its pharmacological properties and therapeutic efficacy. Drugs 50, 317–333 (1995).

    CAS  PubMed  Google Scholar 

  36. Parente, L. Deflazacort: therapeutic index, relative potency and equivalent doses versus other corticosteroids. BMC Pharmacol. Toxicol. 18, 1 (2017).

    PubMed  PubMed Central  Google Scholar 

  37. Tatsuno, I. et al. Age dependence of early symptomatic vertebral fracture with high-dose glucocorticoid treatment for collagen vascular diseases. J. Clin. Endocrinol. Metab. 94, 1671–1677 (2009).

    CAS  PubMed  Google Scholar 

  38. Thompson, J. M., Modin, G. W., Arnaud, C. D. & Lane, N. E. Not all postmenopausal women on chronic steroid and estrogen treatment are osteoporotic: predictors of bone mineral density. Calcif. Tissue Int. 61, 377–381 (1997).

    CAS  PubMed  Google Scholar 

  39. Adler, R. A., et al. Osteoporosis (eds Marcus, R. et al.) 1191–1223 (Academic Press, 2013).

  40. Kanis, J. A. Assessment of osteoporosis at the primary health care level. https://www.sheffield.ac.uk/FRAX/pdfs/WHO_Technical_Report.pdf (WHO, 2007).

  41. Russcher, H. et al. Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression. J. Clin. Endocrinol. Metab. 90, 5804–5810 (2005).

    CAS  PubMed  Google Scholar 

  42. Cooper, M. S. et al. Osteoblastic 11beta-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure. J. Bone Miner. Res. 17, 979–986 (2002).

    CAS  PubMed  Google Scholar 

  43. Cooper, M. S. et al. Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation. J. Bone Miner. Res. 16, 1037–1044 (2001).

    CAS  PubMed  Google Scholar 

  44. Weinstein, R. S., Jilka, R. L., Parfitt, A. M. & Manolagas, S. C. 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, 274–282 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Hofbauer, L. C. & Rauner, M. Minireview: live and let die: molecular effects of glucocorticoids on bone cells. Mol. Endocrinol. 23, 1525–1531 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. den Uyl, D., Bultink, I. E. & Lems, W. F. Advances in glucocorticoid-induced osteoporosis. Curr. Rheumatol. Rep. 13, 233–240 (2011).

    CAS  Google Scholar 

  47. Shen, G. et al. Autophagy as a target for glucocorticoid-induced osteoporosis therapy. Cell Mol. Life Sci. 75, 2683–2693 (2018).

    CAS  PubMed  Google Scholar 

  48. Wang, L., Heckmann, B. L., Yang, X. & Long, H. Osteoblast autophagy in glucocorticoid-induced osteoporosis. J. Cell Physiol. 234, 3207–3215 (2019).

    CAS  PubMed  Google Scholar 

  49. Wu, Z., Bucher, N. L. & Farmer, S. R. Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. Mol. Cell Biol. 16, 4128–4136 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Yang, Y. J. et al. Tanshinol alleviates impaired bone formation by inhibiting adipogenesis via KLF15/PPARgamma2 signaling in GIO rats. Acta Pharmacol. Sin. 39, 633–641 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Ohnaka, K., Tanabe, M., Kawate, H., Nawata, H. & Takayanagi, R. Glucocorticoid suppresses the canonical Wnt signal in cultured human osteoblasts. Biochem. Biophys. Res. Commun. 329, 177–181 (2005).

    CAS  PubMed  Google Scholar 

  52. Hildebrandt, S. et al. Glucocorticoids suppress Wnt16 expression in osteoblasts in vitro and in vivo. Sci. Rep. 8, 8711 (2018).

    PubMed  PubMed Central  Google Scholar 

  53. Ohlsson, C. et al. WNT16 overexpression partly protects against glucocorticoid-induced bone loss. Am. J. Physiol. Endocrinol. Metab. 314, E597–E604 (2018).

    CAS  PubMed  Google Scholar 

  54. Delany, A. M., Jeffrey, J. J., Rydziel, S. & Canalis, E. Cortisol increases interstitial collagenase expression in osteoblasts by post-transcriptional mechanisms. J. Biol. Chem. 270, 26607–26612 (1995).

    CAS  PubMed  Google Scholar 

  55. Zhang, S., Liu, Y. & Liang, Q. Low-dose dexamethasone affects osteoblast viability by inducing autophagy via intracellular ROS. Mol. Med. Rep. 17, 4307–4316 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Han, Y. et al. Autophagy relieves the function inhibition and apoptosis-promoting effects on osteoblasts induced by glucocorticoid. Int. J. Mol. Med. 41, 800–808 (2018).

    CAS  PubMed  Google Scholar 

  57. Pereira, R. M., Delany, A. M., Durant, D. & Canalis, E. Cortisol regulates the expression of Notch in osteoblasts. J. Cell Biochem. 85, 252–258 (2002).

    CAS  PubMed  Google Scholar 

  58. Zanotti, S. & Canalis, E. Notch signaling and the skeleton. Endocr. Rev. 37, 223–253 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Zanotti, S., Yu, J., Adhikari, S. & Canalis, E. Glucocorticoids inhibit notch target gene expression in osteoblasts. J. Cell Biochem. 119, 6016–6023 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Tu, X. et al. Physiological notch signaling maintains bone homeostasis via RBPjk and Hey upstream of NFATc1. PLoS Genet. 8, e1002577 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Swanson, C., Lorentzon, M., Conaway, H. H. & Lerner, U. H. Glucocorticoid regulation of osteoclast differentiation and expression of receptor activator of nuclear factor-kappaB (NF-kappaB) ligand, osteoprotegerin, and receptor activator of NF-kappaB in mouse calvarial bones. Endocrinology 147, 3613–3622 (2006).

    CAS  PubMed  Google Scholar 

  62. Hofbauer, L. C. et al. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 140, 4382–4389 (1999).

    CAS  PubMed  Google Scholar 

  63. Piemontese, M., Xiong, J., Fujiwara, Y., Thostenson, J. D. & O’Brien, C. A. Cortical bone loss caused by glucocorticoid excess requires RANKL production by osteocytes and is associated with reduced OPG expression in mice. Am. J. Physiol. Endocrinol. Metab. 311, E587–E593 (2016).

    PubMed  PubMed Central  Google Scholar 

  64. Rubin, J. et al. Dexamethasone promotes expression of membrane-bound macrophage colony-stimulating factor in murine osteoblast-like cells. Endocrinology 139, 1006–1012 (1998).

    CAS  PubMed  Google Scholar 

  65. Dovio, A. et al. High-dose glucocorticoids increase serum levels of soluble IL-6 receptor alpha and its ratio to soluble gp130: an additional mechanism for early increased bone resorption. Eur. J. Endocrinol. 154, 745–751 (2006).

    CAS  PubMed  Google Scholar 

  66. Takuma, A. et al. Dexamethasone enhances osteoclast formation synergistically with transforming growth factor-beta by stimulating the priming of osteoclast progenitors for differentiation into osteoclasts. J. Biol. Chem. 278, 44667–44674 (2003).

    CAS  PubMed  Google Scholar 

  67. Kim, H. J. et al. Glucocorticoids suppress bone formation via the osteoclast. J. Clin. Invest. 116, 2152–2160 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Teitelbaum, S. L. Glucocorticoids and the osteoclast. Clin. Exp. Rheumatol. 33, S37–S39 (2015).

    PubMed  Google Scholar 

  69. Jia, D., O’Brien, C. A., Stewart, S. A., Manolagas, S. C. & Weinstein, R. S. Glucocorticoids act directly on osteoclasts to increase their life span and reduce bone density. Endocrinology 147, 5592–5599 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Dallas, S. L., Prideaux, M. & Bonewald, L. F. The osteocyte: an endocrine cell… and more. Endocr. Rev. 34, 658–690 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Liu, Y. et al. Prevention of glucocorticoid-induced apoptosis in osteocytes and osteoblasts by calbindin-D28k. J. Bone Miner. Res. 19, 479–490 (2004).

    CAS  PubMed  Google Scholar 

  72. Lane, N. E. et al. Glucocorticoid-treated mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice. J. Bone Miner. Res. 21, 466–476 (2006).

    CAS  PubMed  Google Scholar 

  73. Baylink, D. J. & Wergedal, J. E. Bone formation by osteocytes. Am. J. Physiol. 221, 669–678 (1971).

    CAS  PubMed  Google Scholar 

  74. Yao, W. et al. Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis: a longitudinal study of gene expression in bone tissue from glucocorticoid-treated mice. Arthritis Rheum. 58, 1674–1686 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Wang, F. S., Ko, J. Y., Yeh, D. W., Ke, H. C. & Wu, H. L. Modulation of Dickkopf-1 attenuates glucocorticoid induction of osteoblast apoptosis, adipocytic differentiation, and bone mass loss. Endocrinology 149, 1793–1801 (2008).

    CAS  PubMed  Google Scholar 

  76. Weinstein, R. S. et al. Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell 9, 147–161 (2010).

    CAS  PubMed  Google Scholar 

  77. Seeman, E. & Delmas, P. D. Bone quality — the material and structural basis of bone strength and fragility. N. Engl. J. Med. 354, 2250–2261 (2006).

    CAS  PubMed  Google Scholar 

  78. Canalis, E., Centrella, M., Burch, W. & McCarthy, T. L. Insulin-like growth factor 1 mediates selective anabolic effects of parathyroid hormone in bone cultures. J. Clin. Invest. 83, 60–65 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Canalis, E. & Delany, A. M. Mechanisms of glucocorticoid action in bone. Ann. NY Acad. Sci. 966, 73–81 (2002).

    CAS  PubMed  Google Scholar 

  80. Delany, A. M., Durant, D. & Canalis, E. Glucocorticoid suppression of IGF 1 transcription in osteoblasts. Mol. Endocrinol. 15, 1781–1789 (2001).

    CAS  PubMed  Google Scholar 

  81. Lane, N. E. et al. Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J. Clin. Invest. 102, 1627–1633 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Huybers, S., Naber, T. H., Bindels, R. J. & Hoenderop, J. G. Prednisolone-induced Ca2+ malabsorption is caused by diminished expression of the epithelial Ca2+ channel TRPV6. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G92–G97 (2007).

    CAS  PubMed  Google Scholar 

  83. Ritz, E., Kreusser, W. & Rambausek, M. Effects of glucocorticoids on calcium and phosphate excretion. Adv. Exp. Med. Biol. 171, 381–397 (1984).

    CAS  PubMed  Google Scholar 

  84. Bonadonna, S. et al. Chronic glucocorticoid treatment alters spontaneous pulsatile parathyroid hormone secretory dynamics in human subjects. Eur. J. Endocrinol. 152, 199–205 (2005).

    CAS  PubMed  Google Scholar 

  85. Urena, P. et al. Regulation of parathyroid hormone (PTH)/PTH-related peptide receptor messenger ribonucleic acid by glucocorticoids and PTH in ROS 17/2.8 and OK cells. Endocrinology 134, 451–456 (1994).

    CAS  PubMed  Google Scholar 

  86. Canalis, E., Mazziotti, G., Giustina, A. & Bilezikian, J. P. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos. Int. 18, 1319–1328 (2007).

    CAS  PubMed  Google Scholar 

  87. Rubin, M. R. & Bilezikian, J. P. 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. 87, 4033–4041 (2002).

    CAS  PubMed  Google Scholar 

  88. Manelli, F. et al. Growth hormone in glucocorticoid-induced osteoporosis. Front. Horm. Res. 30, 174–183 (2002).

    CAS  PubMed  Google Scholar 

  89. Lombardi, G. et al. The role of growth hormone in glucocorticoid-induced osteoporosis. J. Endocrinol. Invest. 31, 38–42 (2008).

    CAS  PubMed  Google Scholar 

  90. van Staa, T. P. The pathogenesis, epidemiology and management of glucocorticoid-induced osteoporosis. Calcif. Tissue Int. 79, 129–137 (2006).

    CAS  PubMed  Google Scholar 

  91. MacAdams, M. R., White, R. H. & Chipps, B. E. Reduction of serum testosterone levels during chronic glucocorticoid therapy. Ann. Intern. Med. 104, 648–651 (1986).

    CAS  PubMed  Google Scholar 

  92. Morrison, D. et al. Testosterone levels during systemic and inhaled corticosteroid therapy. Respir. Med. 88, 659–663 (1994).

    CAS  PubMed  Google Scholar 

  93. Sato, A. Y. et al. Glucocorticoids induce bone and muscle atrophy by tissue-specific mechanisms upstream of E3 ubiquitin ligases. Endocrinology 158, 664–677 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Riso, E. M. et al. Relationship between extracellular matrix, contractile apparatus, muscle mass and strength in case of glucocorticoid myopathy. J. Steroid Biochem. Mol. Biol. 108, 117–120 (2008).

    CAS  PubMed  Google Scholar 

  95. Black, R. J., Hill, C. L., Lester, S. & Dixon, W. G. The association between systemic glucocorticoid use and the risk of cataract and glaucoma in patients with rheumatoid arthritis: a systematic review and meta-analysis. PLoS One 11, e0166468 (2016).

    PubMed  PubMed Central  Google Scholar 

  96. Judd, L. L. et al. Adverse consequences of glucocorticoid medication: psychological, cognitive, and behavioral effects. Am. J. Psychiatry 171, 1045–1051 (2014).

    PubMed  Google Scholar 

  97. Compston, J. et al. UK clinical guideline for the prevention and treatment of osteoporosis. Arch. Osteoporos. 12, 43 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Buckley, L. et al. 2017 American College of Rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res. 69, 1095–1110 (2017).

    Google Scholar 

  99. Lekamwasam, S. et al. A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporos. Int. 23, 2257–2276 (2012).

    CAS  PubMed  Google Scholar 

  100. Yu, S. F. et al. Beyond bone mineral density, FRAX-based tailor-made intervention thresholds for therapeutic decision in subjects on glucocorticoid: a nationwide osteoporosis survey. Medicine 96, e5959 (2017).

    PubMed  PubMed Central  Google Scholar 

  101. Hill, Q. A. et al. The prevention of glucocorticoid-induced osteoporosis in patients with immune thrombocytopenia receiving steroids: a British Society for Haematology Good Practice Paper. Br. J. Haematol. 185, 410–417 (2019).

    PubMed  Google Scholar 

  102. Albaum, J. M., Youn, S., Levesque, L. E., Gershon, A. S. & Cadarette, S. M. Osteoporosis management among chronic glucocorticoid users: a systematic review. J. Popul. Ther. Clin. Pharmacol. 21, e486–e504 (2014).

    PubMed  Google Scholar 

  103. Kanis, J. A. et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos. Int. 18, 1033–1046 (2007).

    CAS  PubMed  Google Scholar 

  104. Kanis, J. A., Johansson, H., Oden, A. & McCloskey, E. V. Guidance for the adjustment of FRAX according to the dose of glucocorticoids. Osteoporos. Int. 22, 809–816 (2011).

    CAS  PubMed  Google Scholar 

  105. Johansson, H. et al. Impact of femoral neck and lumbar spine BMD discordances on FRAX probabilities in women: a meta-analysis of international cohorts. Calcif. Tissue Int. 95, 428–435 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Majumdar, S. R. et al. The disconnect between better quality of glucocorticoid-induced osteoporosis preventive care and better outcomes: a population-based cohort study. J. Rheumatol. 40, 1736–1741 (2013).

    CAS  PubMed  Google Scholar 

  107. Majumdar, S. R. et al. Population-based trends in osteoporosis management after new initiations of long-term systemic glucocorticoids (1998–2008). J. Clin. Endocrinol. Metab. 97, 1236–1242 (2012).

    CAS  PubMed  Google Scholar 

  108. Hernlund, E. et al. Osteoporosis in the European Union: medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch. Osteoporos. 8, 136 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Rizzoli, R. & Biver, E. Glucocorticoid-induced osteoporosis: who to treat with what agent? Nat. Rev. Rheumatol. 11, 98–109 (2015).

    CAS  PubMed  Google Scholar 

  110. Park, S. Y. et al. Korean guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. J. Bone Metab. 25, 195–211 (2018).

    PubMed  PubMed Central  Google Scholar 

  111. Pereira, R. M. et al. Guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. Rev. Bras. Reumatol. 52, 580–593 (2012).

    PubMed  Google Scholar 

  112. Suzuki, Y. et al. Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese Society for Bone and Mineral Research: 2014 update. J. Bone Miner. Metab. 32, 337–350 (2014).

    PubMed  Google Scholar 

  113. Compston, J. Clinical question: what is the best approach to managing glucocorticoid-induced osteoporosis? Clin. Endocrinol. 74, 547–550 (2011).

    CAS  Google Scholar 

  114. Compston, J. et al. Recommendations for the registration of agents for prevention and treatment of glucocorticoid-induced osteoporosis: an update from the Group for the Respect of Ethics and Excellence in Science. Osteoporos. Int. 19, 1247–1250 (2008).

    CAS  PubMed  Google Scholar 

  115. Cremers, S. C., Pillai, G. & Papapoulos, S. E. Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis. Clin. Pharmacokinet. 44, 551–570 (2005).

    CAS  PubMed  Google Scholar 

  116. Porras, A. G., Holland, S. D. & Gertz, B. J. Pharmacokinetics of alendronate. Clin. Pharmacokinet. 36, 315–328 (1999).

    CAS  PubMed  Google Scholar 

  117. Dunn, C. J. & Goa, K. L. Risedronate: a review of its pharmacological properties and clinical use in resorptive bone disease. Drugs 61, 685–712 (2001).

    CAS  PubMed  Google Scholar 

  118. Cryer, B. & Bauer, D. C. Oral bisphosphonates and upper gastrointestinal tract problems: what is the evidence? Mayo Clin. Proc. 77, 1031–1043 (2002).

    PubMed  Google Scholar 

  119. Ghirardi, A. et al. Risk of severe upper gastrointestinal complications among oral bisphosphonate users. PLoS One 8, e73159 (2013).

    PubMed  PubMed Central  Google Scholar 

  120. Siris, E. S. et al. Association between gastrointestinal events and compliance with osteoporosis therapy. Bone Rep. 4, 5–10 (2016).

    PubMed  Google Scholar 

  121. Miller, P. D., Jamal, S. A., Evenepoel, P., Eastell, R. & Boonen, S. Renal safety in patients treated with bisphosphonates for osteoporosis: a review. J. Bone Miner. Res. 28, 2049–2059 (2013).

    CAS  PubMed  Google Scholar 

  122. Lipton, A. The safety of zoledronic acid. Expert Opin. Drug Saf. 6, 305–313 (2007).

    CAS  PubMed  Google Scholar 

  123. Allen, C. S., Yeung, J. H., Vandermeer, B. & Homik, J. Bisphosphonates for steroid-induced osteoporosis. Cochrane Database Syst. Rev. 10, CD001347 (2016).

    PubMed  Google Scholar 

  124. Kim, D. H. et al. Bisphosphonates and risk of cardiovascular events: a meta-analysis. PLoS One 10, e0122646 (2015).

    PubMed  PubMed Central  Google Scholar 

  125. Sharma, A. et al. Risk of serious atrial fibrillation and stroke with use of bisphosphonates: evidence from a meta-analysis. Chest 144, 1311–1322 (2013).

    CAS  PubMed  Google Scholar 

  126. Cohen, S. et al. Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. 42, 2309–2318 (1999).

    CAS  PubMed  Google Scholar 

  127. Saag, K. G. et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N. Engl. J. Med. 339, 292–299 (1998).

    CAS  PubMed  Google Scholar 

  128. Wallach, S. et al. Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcif. Tissue Int. 67, 277–285 (2000).

    CAS  PubMed  Google Scholar 

  129. Adachi, J. D. et al. Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum. 44, 202–211 (2001).

    CAS  PubMed  Google Scholar 

  130. Reid, D. M. 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. 15, 1006–1013 (2000).

    CAS  PubMed  Google Scholar 

  131. Kishimoto, M., Oishi, A. & Motojima, S. Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis. N. Engl. J. Med. 355, 2156–2157 (2006).

    CAS  PubMed  Google Scholar 

  132. Sambrook, P. N. et al. Bisphosphonates and glucocorticoid osteoporosis in men: results of a randomized controlled trial comparing zoledronic acid with risedronate. Bone 50, 289–295 (2012).

    CAS  PubMed  Google Scholar 

  133. Reid, D. M. et al. Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet 373, 1253–1263 (2009).

    CAS  PubMed  Google Scholar 

  134. Gluer, C. C. et al. Comparative effects of teriparatide and risedronate in glucocorticoid-induced osteoporosis in men: 18-month results of the EuroGIOPs trial. J. Bone Miner. Res. 28, 1355–1368 (2013).

    PubMed  PubMed Central  Google Scholar 

  135. Saag, K. G. et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N. Engl. J. Med. 357, 2028–2039 (2007).

    CAS  PubMed  Google Scholar 

  136. Saag, K. G. et al. Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial. Arthritis Rheum. 60, 3346–3355 (2009).

    CAS  PubMed  Google Scholar 

  137. Axelsson, K. F., Nilsson, A. G., Wedel, H., Lundh, D. & Lorentzon, M. Association between alendronate use and hip fracture risk in older patients using oral prednisolone. JAMA 318, 146–155 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. de Boissieu, P., Gaboriau, L., Morel, A. & Trenque, T. Bisphosphonate-related osteonecrosis of the jaw: data from the French national pharmacovigilance database. Fundam. Clin. Pharmacol. 30, 450–458 (2016).

    PubMed  Google Scholar 

  139. Jadu, F., Lee, L., Pharoah, M., Reece, D. & Wang, L. A retrospective study assessing the incidence, risk factors and comorbidities of pamidronate-related necrosis of the jaws in multiple myeloma patients. Ann. Oncol. 18, 2015–2019 (2007).

    CAS  PubMed  Google Scholar 

  140. Saita, Y. et al. The incidence of and risk factors for developing atypical femoral fractures in Japan. J. Bone Miner. Metab. 33, 311–318 (2015).

    CAS  PubMed  Google Scholar 

  141. Takakubo, Y. et al. The incidence of atypical femoral fractures in patients with rheumatic disease: Yamagata prefectural committee of atypical femoral fractures (YamaCAFe) study. Tohoku J. Exp. Med. 242, 327–334 (2017).

    PubMed  Google Scholar 

  142. Meier, R. P., Perneger, T. V., Stern, R., Rizzoli, R. & Peter, R. E. Increasing occurrence of atypical femoral fractures associated with bisphosphonate use. Arch. Intern. Med. 172, 930–936 (2012).

    PubMed  Google Scholar 

  143. Shane, E. et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J. Bone Miner. Res. 29, 1–23 (2014).

    PubMed  Google Scholar 

  144. Chiu, C. T., Chiang, W. F., Chuang, C. Y. & Chang, S. W. Resolution of oral bisphosphonate and steroid-related osteonecrosis of the jaw — a serial case analysis. J. Oral Maxillofac. Surg. 68, 1055–1063 (2010).

    PubMed  Google Scholar 

  145. Saag, K. G. et al. Denosumab versus risedronate in glucocorticoid-induced osteoporosis: a multicentre, randomised, double-blind, active-controlled, double-dummy, non-inferiority study. Lancet Diabetes Endocrinol. 6, 445–454 (2018).

    CAS  PubMed  Google Scholar 

  146. Saag, K. G. et al. Denosumab versus risedronate in glucocorticoid-induced osteoporosis: final results of a twenty-four-month randomized, double-blind, double-dummy trial. Arthritis Rheumatol. 71, 1174–1184 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Bone, H. G. et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J. Clin. Endocrinol. Metab. 96, 972–980 (2011).

    CAS  PubMed  Google Scholar 

  148. McClung, M. R., Wagman, R. B., Miller, P. D., Wang, A. & Lewiecki, E. M. Observations following discontinuation of long-term denosumab therapy. Osteoporos. Int. 28, 1723–1732 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Cummings, S. R. et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J. Bone Miner. Res. 33, 190–198 (2018).

    CAS  PubMed  Google Scholar 

  150. Anastasilakis, A. D. et al. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J. Bone Miner. Res. 32, 1291–1296 (2017).

    CAS  PubMed  Google Scholar 

  151. Popp, A. W., Zysset, P. K. & Lippuner, K. Rebound-associated vertebral fractures after discontinuation of denosumab — from clinic and biomechanics. Osteoporos. Int. 27, 1917–1921 (2016).

    CAS  PubMed  Google Scholar 

  152. Anastasilakis, A. D. & Makras, P. Multiple clinical vertebral fractures following denosumab discontinuation. Osteoporos. Int. 27, 1929–1930 (2016).

    CAS  PubMed  Google Scholar 

  153. Tsourdi, E. et al. Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS. Bone 105, 11–17 (2017).

    PubMed  Google Scholar 

  154. Reid, I. R. et al. Bone loss after denosumab: only partial protection with zoledronate. Calcif. Tissue Int. 101, 371–374 (2017).

    CAS  PubMed  Google Scholar 

  155. Horne, A. M., Mihov, B. & Reid, I. R. Effect of zoledronate on bone loss after romosozumab/denosumab: 2-year follow-up. Calcif. Tissue Int. 105, 107–108 (2019).

    CAS  PubMed  Google Scholar 

  156. Anastasilakis, A. D. et al. Zoledronate for the prevention of bone loss in women discontinuing denosumab treatment. A prospective 2-year clinical trial. J. Bone Miner. Res. 34, 2220–2228 (2019).

    CAS  PubMed  Google Scholar 

  157. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03396315 (2019).

  158. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03087851 (2019).

  159. Khan, A. A. et al. Case-based review of osteonecrosis of the jaw (ONJ) and application of the international recommendations for management from the international task force on ONJ. J. Clin. Densitom. 20, 8–24 (2017).

    PubMed  Google Scholar 

  160. Devogelaer, J. P. et al. Baseline glucocorticoid dose and bone mineral density response with teriparatide or alendronate therapy in patients with glucocorticoid-induced osteoporosis. J. Rheumatol. 37, 141–148 (2010).

    CAS  PubMed  Google Scholar 

  161. Caggiari, G. et al. Safety and effectiveness of teriparatide vs alendronate in postmenopausal osteoporosis: a prospective non randomized clinical study. Clin. Cases Miner. Bone Metab. 13, 200–203 (2016).

    PubMed  Google Scholar 

  162. Karatoprak, C. et al. Severe hypercalcemia due to teriparatide. Indian J. Pharmacol. 44, 270–271 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Adami, G. & Saag, K. G. Glucocorticoid-induced osteoporosis: 2019 concise clinical review. Osteoporos. Int. 30, 1145–1156 (2019).

    CAS  PubMed  Google Scholar 

  164. Haas, A. V. & LeBoff, M. S. Osteoanabolic agents for osteoporosis. J. Endocr. Soc. 2, 922–932 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Cosman, F. et al. Romosozumab treatment in postmenopausal women with osteoporosis. N. Engl. J. Med. 375, 1532–1543 (2016).

    CAS  PubMed  Google Scholar 

  166. Miller, P. D. et al. Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial. JAMA 316, 722–733 (2016).

    CAS  PubMed  Google Scholar 

  167. Adachi, J. D. et al. Management of corticosteroid-induced osteoporosis. Semin. Arthritis Rheum. 29, 228–251 (2000).

    CAS  PubMed  Google Scholar 

  168. Rizzoli, R. et al. Management of glucocorticoid-induced osteoporosis. Calcif. Tissue Int. 91, 225–243 (2012).

    CAS  PubMed  Google Scholar 

  169. Vasikaran, S. et al. International osteoporosis foundation and international federation of clinical chemistry and laboratory medicine position on bone marker standards in osteoporosis. Clin. Chem. Lab. Med. 49, 1271–1274 (2011).

    CAS  PubMed  Google Scholar 

  170. Devogelaer, J. P. et al. Evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis: a consensus document of the Belgian Bone Club. Osteoporos. Int. 17, 8–19 (2006).

    CAS  PubMed  Google Scholar 

  171. Diez-Perez, A. et al. Treatment failure in osteoporosis. Osteoporos. Int. 23, 2769–2774 (2012).

    CAS  PubMed  Google Scholar 

  172. Briot, K. et al. 2014 update of recommendations on the prevention and treatment of glucocorticoid-induced osteoporosis. Joint Bone Spine 81, 493–501 (2014).

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Pojchong Chotiyarnwong

  2. Academic Unit of Bone Metabolism, Department of Oncology and Metabolism, The Mellanby Centre For Bone Research, University of Sheffield, Sheffield, UK

    Pojchong Chotiyarnwong & Eugene V. McCloskey

  3. Centre for Metabolic Diseases, University of Sheffield Medical School, Beech Hill Road, Sheffield, UK

    Eugene V. McCloskey

  4. Centre for Integrated Research into Musculoskeletal Ageing, University of Sheffield Medical School, Sheffield, UK

    Eugene V. McCloskey

Authors
  1. Pojchong Chotiyarnwong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eugene V. McCloskey
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Eugene V. McCloskey.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Endocrinology thanks N. Lane and J.-P. Devogelaer for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related link

The FRAX tool: https://www.sheffield.ac.uk/FRAX/

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chotiyarnwong, P., McCloskey, E. Pathogenesis of glucocorticoid-induced osteoporosis and options for treatment. Nat Rev Endocrinol 16, 437–447 (2020). https://doi.org/10.1038/s41574-020-0341-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-020-0341-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing