Glucocorticoids and osteoporosis

Czech version

Authors: doc. MUDr. Vít Zikán, Ph.D.
Authors‘ workplace: III. interní klinika 1. lékařské fakulty UK a VFN Praha, přednosta prof. MUDr. Štěpán Svačina, DrSc., MBA
Published in: Vnitř Lék 2007; 53(7-8): 831-840
Category:

Overview

Treatment with glucocorticoids (GC) has no alternative in many medical disciplines for their anti-inflammatory and immunosuppressive effect. However, osteoporosis and the related fractures are a serious complication brought about by longterm GC therapy. The risk of fractures, especially of the vertebras and the ribs, becomes higher as early as in the first months of oral GC therapy. It grows in proportion to the daily dose of GC, and is present even if low doses are administered (2.5–7.5 mg of prednisone per day). Decreasing bone density (BMD) is not accountable for the higher risk of fractures in GC therapy and fractures occur with higher values of BMD than in primary osteoporosis. There is still no tool that we could use to quantify the changes in the bone quality and the increased risk of fracture in clinical practice. The principal mechanism by which GC induces osteoporosis is inhibition of bone formation caused by the suppression of osteoblastogenesis as well as the activity of functional osteoblasts, with accelerated osteocyte and osteoblast apoptosis. There are significant differences between individuals in terms of GC sensitivity, the reasons of which have not yet been explained. Prior to planned long-term GC therapy (> 3 months) with daily doses higher than 2.5 mg of prednisone p.o. (or higher doses of inhaled GC), it is recommended to perform a densitometry exam using dual-energy X-ray absorptiometry (DXA) in the lumbar region of the spine and femoral collum to evaluate additional risk factors of osteoporosis and fractures for a more precise estimate of the risk of fracture in the specific patient. Sufficient intake of calcium (1,000–1,500 mg of elementary calcium per day) and of the vitamin D (800 IU per day) should be assured in all patients treated by GC. Endogenous production of sexagens should be evaluated and possible substitution therapy should be considered in premenopausal women and younger men. Today, bisphosphonates can be given to patients with a high risk of fracture, the effects of which in preventing the decrease of BMD and vertebral fractures have been documented in randomised clinical studies, even though the evaluation of the risk of fractures was not the primary endpoint of those studies. However, in view of the antiremodelling effect of bisphosphonates, it is clear that this therapy does not eliminate the cause of GC induced osteoporosis and drugs with stimulating effect on osteoblasts will certainly be preferred in the future. Very promising are the first clinical studies of injection parathormone (PTH 1-34) which stimulated bone formation in a continuing GC treatment.

Key words:
glucocorticoids – osteoporosis – bone metabolism – bone formation – bone resorption – individual sensitivity to glucocorticoids – calcium – D vitamin – estrogens – testosterone – bisphosphonates – osteoanabolic treatment

Sources

1. Kanis JA, Johansson H, Oden A et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 2004; 19: 893-899.

2. van Staa TP, Leufkens HG, Abenhaim L et al. Use of oral corticosteroids in the United Kingdom. QJM 2000; 93: 105-111.

3. Reid IR Glucocorticoid-induced osteoporosis: assessment and treatment. J Clin Densitom 1998; 1: 65-73.

4. van Staa TP, Leufkens HG, Abenhaim L et al. Use of oral corticosteroids and risk of fractures. J Bone Miner Res 2000; 15: 993-1000.

5. Israel E, Banerjee TR, Fitzmaurice GM et al. Effects of inhaled glucocorticoids on bone density in premenopausal women. N Engl J Med 2001; 345: 941-947.

6. Steinbuch M, Youket TE, Cohen S. Oral glucocorticoid use is associated with an increased risk of fracture. Osteoporos Int 2004; 15: 323-328.

7. Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with systemic and topical corticosteroids. J Intern Med 2005; 257: 374-384.

8. 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: 253-259.

9. Dalle Carbonare L, Arlot ME, Chavassieux PM et al. Comparison of trabecular bone microarchitecture and remodeling in glucocorticoid-induced and postmenopausal osteoporosis. J Bone Miner Res 2001; 16: 97-103.

10. Francucci CM, Pantanetti P, Garrapa GG et al. Bone metabolism and mass in women with Cushing's syndrome and adrenal incidentaloma. Clin Endocrinol (Oxf) 2002; 57: 587-593.

11. Cortet B, Cortet C, Blanckaert F et al. Quantitative ultrasound of bone and markers of bone turnover in Cushing's syndrome. Osteoporos Int 2001; 12: 117-123.

12. Ton FN, Gunawardene SC, Lee H et al. Effects of low-dose prednisone on bone metabolism. J Bone Miner Res 2005; 20: 464-470.

13. Pearce G, Ryan PF, Delmas PD et al. The deleterious effects of low-dose corticosteroids on bone density in patients with polymyalgia rheumatica. Br J Rheumatol 1998; 37: 292-299.

14. LoCascio V, Bonucci E, Imbimbo B et al. Bone loss in response to long-term glucocorticoid therapy. Bone Miner 1990; 8: 39-51.

15. Weinstein RS, Jilka RL, Parfitt AM et al. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids: potential mechanisms of the deleterious effects on bone. J Clin Invest 1998; 102: 274-282.

16. Manning PJ, Evans MC, Reid IR Normal bone mineral density following cure of Cushing's syndrome. Clin Endocrinol (Oxf) 1992; 36: 229-234.

17. van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 2002; 13: 777-787.

18. van Staa TP, Leufkens HG, Abenhaim L et al. Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. Rheumatology (Oxf) 2000; 39: 1383-1389.

19. 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: 191-198.

20. Weinstein RS, Chen JR, Powers CC et al. Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Invest 2002; 109: 1041-1048.

21. Nuttall ME, Gimble JM Is there a therapeutic opportunity to either prevent or treat osteopenic disorders by inhibiting marrow adipogenesis? Bone 2000; 27: 177-184.

22. Nuttall ME, Patton AJ, Olivera DL et al. Human trabecular bone cells are able to express both osteoblastic and adipocytic phenotype: implications for osteopenic disorders. J Bone Miner Res 1998; 13: 371-382.

23. Chang DJ, Ji C, Kim KK et al. Reduction in transforming growth factor beta receptor I expression and transcription factor CBFa1 on bone cells by glucocorticoid. J Biol Chem 1998; 273: 4892-4896.

24. Li X, Jin L, Cui Q et al. Steroid effects on osteogenesis through mesenchymal cell gene expression. Osteoporos Int 2005; 16: 101-108.

25. Sciaudone M, Gazzerro E, Priest L et al. Notch 1 impairs osteoblastic cell differentiation. Endocrinology 2003; 144: 5631-5639.

26. Deregowski V, Gazzerro E, Priest L et al. Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/β-catenin but not bone morphogenetic protein signaling. J Biol Chem 2006; 281: 6203-6210.

27. Smith E, Frenkel B. Glucocorticoids inhibit the transcriptional activity of LEF/TCF in differentiating osteoblasts in a glycogen synthase kinase-3β-dependent and -independent manner. J Biol Chem 2005; 280: 2388-2394.

28. Ohnaka K, Taniguchi H, Kawate H et al. Glucocorticoid enhances the expression of dickkopf-1 in human osteoblasts: novel mechanism of glucocorticoid-induced osteoporosis. Biochem Biophys Res Commun 2004; 318: 259-264.

29. Delany AM, Canalis E. Transcriptional repression of insulin-like growth factor I by glucocorticoids in rat bone cells. Endocrinology 1995; 136: 4776-4781.

30. Cui Q, Wang GJ, Balian G. Steroid-induced adipogenesis in a pluripotential cell line from bone marrow. J Bone Joint Surg Am 1997; 79: 1054-1063.

31. O’Brien CA, Jia D, Plotkin LI et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 2004; 145: 1835-1841.

32. Weinstein RS Manolagas SC. Apoptosis and osteoporosis. Am J Med 2000; 108: 153-164.

33. Weinstein RS, Nicholas RW, Manolagas SC. Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab 2000; 85: 2907-2912.

34. Jia D, O’Brien CA, Stewart SA et al. Glucocorticoids act directly on osteoclasts to increase their life span and reduce bone density. Endocrinology 2006; 147: 5592-5599.

35. 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: 4033-4041.

36. Hofbauer LC, Gori F, Riggs BL 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 1999; 140: 4382-4389.

37. Rubin J, Biskobing DM, Jadhav L et al. Dexamethasone promotes expression of membrane-bound macrophage colony-stimulating factor in murine osteoblast-like cells. Endocrinology 1998; 139: 1006-1012.

38. Dovio A, Perazzolo L, Osella G et al. Immediate fall of bone formation and transient increase of bone resorption in the course of high-dose, short-term glucocorticoid therapy in young patients with multiple sclerosis. J Clin Endocrinol Metab 2004; 89: 4923-4928.

39. Dempster DW, Moonga BS, Stein LS et al. Glucocorticoids inhibit bone resorption by isolated rat osteoclasts by enhancing apoptosis. J Endocrinol 1997; 154: 397-406.

40. Gennari C. Differential effect of glucocorticoids on calcium absorption and bone mass.Br J Rheumatol 1993; 32(Suppl 2): 11-14.

41. 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;152:199-205

42. Doga M, Bonadonna S, Giustina A. Glucocorticoids and bone: cellular, metabolic and endocrine effects. Hormones (Athens) 2004; 3: 184-190.

43. Manelli F, Giustina A. Glucocorticoid-induced osteoporosis. Trends Endocrinol Metab 2000; 11: 79-85.

44. Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 1998; 19: 717-797.

45. Giustina A, Bussi AR, Jacobello C et al. Effects of recombinant human growth hormone (GH) on bone and intermediary metabolism in patients receiving chronic glucocorticoid treatment with suppressed endogenous GH response to GH-releasing hormone. J Clin Endocrinol Metab 1995; 80: 122-129.

46. Delany AM, Durant D, Canalis E. Glucocorticoid suppression of IGF I transcription in osteoblasts. Mol Endocrinol 2001; 15: 1781-1789.

47. Gabbitas B, Pash JM, Delany AM et al. Cortisol inhibits the synthesis of insulin-like growth factor-binding protein-5 in bone cell cultures by transcriptional mechanisms. J Biol Chem 1996; 271: 9033-9038.

48. van Rossum EF, Lamberts SW Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition. Recent Prog Horm Res 2004; 59: 333-357.

49. Cooper MS, Walker EA, Bland R et al. Expression and functional consequences of 11β-hydroxysteroid dehydrogenase activity in human bone. Bone 2000; 27: 375-381.

50. Draper N, Stewart PM 11β-hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action. J Endocrinol 2005; 186: 251-271.

51. Tomlinson JW, Draper N, Mackie J et al. Absence of Cushingoid phenotype in a patient with Cushing's disease due to defective cortisone to cortisol conversion. J Clin Endocrinol Metab 2002; 87: 57-62.

52. Cooper MS, Rabbitt EH, Goddard PE et al. Osteoblastic 11β-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure. J Bone Miner Res 2002; 17: 979-986.

53. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum 2001; 44: 1496-1503.

54. Royal College of Physicians. Glucocorticoid-Induced Osteoporosis: guidelines for prevention and treatment. London: Royal College of Physicians 2002.

55. Růžičková O, Bayer M, Pavelka K et al. Doporučení pro prevenci a léčbu glukokortikoidy indukované osteoporózy u pacientů s revmatickým onemocněním (Společné stanovisko České revmatologické společnosti a Společnosti pro metabolická onemocnění skeletu). Čes Revmatol 2004; 12: 163-174.

56. Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet 2002; 359: 1929-1936.

57. Ichikawa F, Sato K, Nanjo M et al. Mouse primary osteoblasts express vitamin D3 25-hydroxylase mRNA and convert 1-α-hydroxyvitamin D3 into 1-α, 25 dihydroxyvitamin D3. Bone 1995; 16: 129-135.

58. Bouillon R, Van Cromphaut S, Carmeliet G. Intestinal calcium absorption: Molecular vitamin D mediated mechanisms. J Cell Biochem 2003; 88: 332-339.

59. Hoenderop JG, Muller D, Van Der Kemp AW et al. Calcitriol controls the epithelial calcium channel in kidney. J Am Soc Nephrol 2001; 12: 1342-1349.

60. Russell JD, Lettieri D, Sherwood LM Suppression by 1,25-(OH)2D of transcription of the parathyroid hormone gene. Endocrinology 1985; 119: 2864-2866.

61. Schacht E, Richy F, Reginster JY. The therapeutic effects of alfacalcidol on bone strength, muscle metabolism and prevention of falls and fractures. J Musculoskelet Neuronal Interact 2005; 5: 273-284.

62. Mathieu C, Adorini L. The coming of age of 1,25-dihydroxyvitamin D(3) analogs as immunomodulatory agents. Trends Mol Med 2002; 8: 174-179.

63. Li M, Healy DR, Simmons HA et al. Alfacalcidol restores cancellous bone in ovariectomized rats. J Musculoskelet Neuronal Interact 2003; 3: 39-46.

64. Shiraishi A, Takeda S, Masaki T et al. Alfacalcidol inhibits bone resorption and stimulates formation in an ovariectomized rat model of osteoporosis: distinct actions from estrogen. J Bone Miner Res 2000; 15: 770-779.

65. Ohnaka K, Tanabe M, Kawate H et al. Glucocorticoid suppresses the canonical Wnt signal in cultured human osteoblasts. Biochem Biophys Res Commun 2005; 329: 177-181.

66. Scharla SH, Strong DD, Mohan S et al. 1,25-Dihydroxyvitamin D3 differentially regulates the production of insulin-like growth factor I (IGF-I) and IGF-binding protein-4 in mouse osteoblasts. Endocrinology 1991; 129: 3139-3146.

67. Hofbauer LC, Dunstan CR, Spelsberg TC et al. Osteoprotegerin production by human osteoblast lineage cells is stimulated by vitamin D, bone morphogenetic protein-2, and cytokines. Biochem Biophys Res Commun 1998; 250: 776-781.

68. van Driel M, Koedam M, Buurman CJ et al. Evidence for auto/paracrine actions of vitamin D in bone: 1α-hydroxylase expression and activity in human bone cells. FASEB J 2006; 20: 2417-2419.

69. de Nijs RN, Jacobs JW, Lems WF et al. Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis. N Engl J Med 2006; 355: 675-684.

70. Scharla SH, Schacht E, Lempert UG. Alfacalcidol versus plain vitamin D in inflammation induced bone loss. J Rheumatol Suppl 2005; 76: 26-32.

71. Weinstein RS, Jia D, Powers CC et al. The skeletal effects of glucocorticoid excess override those of orchidectomy in mice. Endocrinology 2004; 145: 1980-1987.

72. Pearce G, Tabensky DA, Delmas PD et al. Corticosteroid-induced bone loss in men. J Clin Endocrinol Metab 2005; 83: 801-806.

73. Kousteni S, Chen JR, Bellido TM et al. Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science 2002; 298: 843-846.

74. Gu G, Hentunen TA, Nars M et al. Estrogen protects primary osteocytes against glucocorticoid-induced apoptosis. Apoptosis 2005; 10: 583-595.

75. Plotkin LI, Aguirre JI, Kousteni S et al. Bisphosphonates and estrogens inhibit osteocyte apoptosis via distinct molecular mechanisms downstream of extracellular signal-regulated kinase activation. J Biol Chem 2005; 280: 7317-7325.

76. Mann V, Huber C, Kogianni G et al. The antioxidant effect of estrogen and Selective Estrogen Receptor Modulators in the inhibition of osteocyte apoptosis in vitro. Bone 2007; 40: 674-684.

77. Lukert BP, Johnson BE, Robinson RG. Estrogen and progesterone replacement therapy reduces glucocorticoid-induced bone loss. J Bone Miner Res 1992; 7: 1063-1069.

78. Crawford BA, Liu PY, Kean MT et al. Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment. J Clin Endocrinol Metab 2003; 88: 3167-3176.

79. Saag KG, Emkey R, Schnitzer TJ et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med 1998; 339: 292-299.

80. Cummings SR. How drugs decrease fracture risk: lessons from trials. J Musculoskelet Neuronal Interact 2002; 2: 198-200.

81. Plotkin LI, Manolagas SC, Bellido T. Dissociation of the pro-apoptotic effects of bisphosphonates on osteoclasts from their anti-apoptotic effects on osteoblasts/osteocytes with novel analogs. Bone 2006; 39: 443-452.

82. Patlas N, Golomb G, Yaffe P et al. Transplacental effects of bisphosphonates on fetal skeletal ossification and mineralization in rats. Teratology 1999; 60: 68-73.

83. Franchimont N, Canalis E. Management of glucocorticoid induced osteoporosis in premenopausal women with autoimmune disease. Autoimmun Rev 2003; 2: 224-228.

84. Nishida S, Yamaguchi A, Tanizawa T et al. Increased bone formation by intermittent parathyroid hormone administration is due to the stimulation of proliferation and differentiation of osteoprogenitor cells in bone marrow. Bone 1994; 15: 717-723.

85. Jilka RL, Weinstein RS, Bellido T et al. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 1999; 104: 439-446.

86. Pfeilschifter J, Laukhuf F, Muller-Beckmann B et al. Parathyroid hormone increases the concentration of insulin-like growth factor-I and transforming growth factor β 1 in rat bone. J Clin Invest 1995; 96: 767-774.

87. Tobimatsu T, Kaji H, Sowa H et al. Parathyroid hormone increases β-catenin levels through Smad3 in mouse osteoblastic cells. Endocrinology 2006; 147: 2583-2590.

88. Lane NE, Sanchez S, Modin GW et al. Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J Clin Invest 1998; 102: 1627-1633.