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Chapter 49 Chapter 49 Glucocorticoid-Induced Osteoporosis Copyright © 2013 Elsevier Inc. All rights reserved.

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Presentation on theme: "Chapter 49 Chapter 49 Glucocorticoid-Induced Osteoporosis Copyright © 2013 Elsevier Inc. All rights reserved."— Presentation transcript:

1 Chapter 49 Chapter 49 Glucocorticoid-Induced Osteoporosis Copyright © 2013 Elsevier Inc. All rights reserved.

2 FIGURE 49.1 Bone mineral density (BMD)–fracture threshold relations comparing the placebo arms of two risedronate glucocorticoid trials (containing 306 total patients with 30 incident fractures) with three risedronate trials of postmenopausal osteoporosis at both the lumbar spine (A) and the femoral neck (B). Rate of fractures was approximately six-fold higher among the glucocorticoid users compared to nonusers after adjustment for covariates. Source: reproduced from T. P. van Staa, R. F. Laan, I. P. Barton, S. Cohen, D. M. Reid, and C. Cooper, Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy. Arthritis Rheum 48, 3224–3229 (2003), with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. 2

3 Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 49.2 Effects of low-dose prednisolone on bone. The relative risk of both hip and spine fracture increases in a dosage-dependent fashion, with a trend toward increased risk seen even below the physiologic replacement range of 2.5–7.5 mg/day of prednisolone. Source: reproduced from T. P. Van Staa, H. G. M. Leufkens, L. Abenhaim, et al., Use of oral corticosteroids and risk of fractures. J Bone Miner Res 15, 993–1000 (2000), with permission. 3

4 Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 49.3 Effects of daily prednisolone dose on nonvertebral fractures. Dashed lines represent 95% confidence intervals (CI). Source: adapted from T. P. van Staa, H. G. M. Leukens, L. Abenhaim, B. Zhang, and C. Cooper, Oral corticosteroids and fracture risk: Relationship to daily and cumulative doses. Rheumatology (Oxford) 39, 1383–1389 (2000), with permission of Oxford University Press. 4

5 Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 49.4 New paradigm of glucocorticoid-induced osteoporosis (GIOP). Excess glucocorticoids decrease gastrointestinal calcium absorption and increase renal calcium excretion, at least in the short term, but these events do not cause secondary hyperparathyroidism or increase bone remodeling units. As many as half of women with Cushing syndrome may be amenorrheic, but this also fails to increase bone remodeling. Decreased bone formation, the most characteristic feature of GIOP, is due to direct effects on osteoblasts rather than indirect effects through other tissues or hormones. FSH: follicle-timuating hormone; GH: growth hormone; IGFBP: insulin-like growth factor-binding protein; LH: luteinizing hormone; PTH: parathyroid hormone. 5

6 Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 49.5 Apoptosis of osteoblasts and osteocytes in glucocorticoid-induced osteoporosis (GIOP). Transiliac bone biopsy specimen from a patient with GIOP exhibits apoptosis of osteoblasts and osteocytes. Apoptotic bone cells were absent in control bone biopsy specimens. Morphological changes typical of apoptosis accompanied the TUNEL-positive osteoblasts and osteocytes, including sharply defined, condensed chromatin plastered against the nuclear membrane, nuclear fragmentation, and cell shrinkage. Approximately 5% of the osteocytes and 30% of the osteoblasts were apoptotic. Methyl green counterstain viewed with Nomarski differential interference microscopy; original magnification, ×630. 6

7 Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 49.6 Chronic glucocorticoid therapy caused the accumulation of markedly pyknotic, apoptotic osteocytes, and lining cells (dark brown). TUNEL with toluidine blue counterstain; original magnification, ×250. Source: reproduced from R. S. Weinstein, R. W. Nicholas, and S. C. Manolagas, Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab 85, 2907–2912 (2000). Copyright 2000, The Endocrine Society. 7

8 Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 49.7 Evidence of osteocyte apoptosis in glucocorticoid-induced osteonecrosis (GIOP). Sections are from a whole femoral head obtained during total hip replacement. A and B are stained with hematoxylin and eosin: A, ×1; B, ×2.5. C and the insert are stained by TUNEL: C, ×100; insert, ×630. Apoptotic osteocytes had condensed nuclei and fragmented chromatin (C and insert). The apoptotic cells were more frequent adjacent to the subchondral fracture crescent (A), whereas empty osteocytic lacunae, the cardinal sign of bone necrosis, were infrequent. Furthermore, the presence of apoptotic cells was associated with reduced cancellous bone area, increased marrow adipocytes, and decreased hematopoietic marrow in patients with GIOP (B). Signs of inflammation and necrosis, such as hyperemia, round cell infiltration, or lipid cyst formation, were absent (B). Reproduced from R. S. Weinstein, R. W. Nicholas, and S. C. Manolagas, Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab 85, 2907–2912 (2000). Copyright 2000, The Endocrine Society. 8

9 Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 49.8 Efficacy of alphacalcidol and calcitrol in reducing bone loss. Source: reproduced from F. Richy, O. Ethgen, O. Bruyere, and J. Y. Reginster, Efficacy of alphacalcidol and calcitriol in primary and corticosteroid- induced osteoporosis: a meta-analysis of their effects on bone mineral density and fracture rate. Osteoporos Int 15, 301–310 (2004), with permission of Springer Science and Business Media. 9

10 Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 49.9 Guidelines for the treatment of postmenopausal women and men aged 50 and over from the Joint International Osteoporosis Foundation (IOF)–European Calcified Tissue Society (ECTS) glucocorticoid-induced osteoporosis (GIO) Guidelines Working Group [202]. 10

11 Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 49.10 Guidelines for the treatment of premenopausal women and men aged less than 50 from the Joint International Osteoporosis Foundation (IOF)–European Calcified Tissue Society (ECTS) glucocorticoid-induced osteoporosis (GIO) Guidelines Working Group [202]. 11

12 Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 49.11 Efficacy of oral bisphosphonates in reducing fracture risk in glucocorticoid-induced osteoporosis (GIOP) taken from a trend seen in the following oral bisphosphonate studies: Adachi et al. [236], Wallach et al. [211], Saag et al. [41], and Adachi et al. [209]. 12

13 Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 49.12 Improvements in BMD with teriparatide (TER) and estrogen compared to estrogen alone in glucocorticoid-treated women as indicated in previous trials. Source: data from Lane et al. [169,314]. 13


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