Copyright © 2013 Elsevier Inc. All rights reserved. Chapter 46 Estrogen Deficiency, Postmenopausal Osteoporosis, and Age-Related Bone Loss Copyright © 2013 Elsevier Inc. All rights reserved.

Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 46.1 Cortical porosity index in girls (A) and boys (B). Shaded regions represent the approximate chronological age ranges when the incidence of adolescent forearm fractures peaks based on previous data from Rochester, MN [219] and elsewhere [220–222]. ***P < 0.001 vs. Group I; ††p < 0.01, and ††† p < 0.001 for comparison with the respective group of girls. I, 6–8 yr; II, 9–11 yr; III, 12–14 yr; IV, 15–17 yr; V, 18–21 yr. Source: reproduced from Kirmani et al. [8], with permission. Copyright © 2013 Elsevier Inc. All rights reserved.

Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 46.2 Cross-sectional volumetric bone mineral density (vBMD) data of an age- and sex-stratified population sample from Rochester, MN, assessed by quantitative computerized tomography (QCT) (n = 696) showing patterns of loss of trabecular bone from centrum of vertebrae and cortical bone loss from the distal radius. The age regression in men is shown by the solid line and in women by the broken line. Note that trabecular bone loss is continuous over life in both sexes, with an apparent acceleration at menopause in women. Note also that cortical bone loss does not begin until mid-life in either sex, but the rate of loss is more rapid in women than in men. Source: data are from Riggs et al. [4], with permission. 3 Copyright © 2013 Elsevier Inc. All rights reserved.

Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 46.3 Schematic representation of the role of T cells in the mechanism by which ovariectomy (OVX) promotes osteoclastogenesis, osteoblastogenesis, and hemopoiesis. Estrogen deficiency promotes T-cell activation by increasing the interaction of antigen (Ag) loaded major histocompatibility complex (MHC) molecules with bone marrow macrophages (BMM) and dendritic cells (DC) with the T-cell receptor (TCR). The Ags are likely to be nonself peptides derived from the intestinal macrobiota. T-cell activation also requires at least two costimulatory signals provided by the binding of BMM and DC expressed CD40 and CD80 to the T-cell surface molecules CD40L and CD28, respectively. A critical upstream event is the increased production of reactive oxygen species (ROS), which activate DCs by increasing their expression of CD80. The expansion of T cells in the bone marrow is partially driven by an OVX-induced increase in the thymic output of naïve T cells. Activated T cells secrete tumor necrosis factor (TNF) that stimulates osteoclasts formation primarily by potentiating the response to RANKL. In addition, T cell-expressed CD40L and DLK1/FA-1 increase the osteoclastogenic activity of SC by blunting their secretion of osteoprotegerin (OPG) and augmenting their production of receptor activator of nuclear factor kappa-B ligand (RANKL), macrophage colony-stimulating factor (M-CSF), and other pro-inflammatory factors. Source: reproduced from Pacifici [223], with permission. 4 Copyright © 2013 Elsevier Inc. All rights reserved.

Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 46.4 Schematic representation of the cells and the cytokines by which ovariectomy (OVX) leads to T-cell production of tumor necrosis factor (TNF) and bone loss. The production of transforming growth factor (TGF)β and interleukin (IL)-7 are directly regulated by estrogen. The production of interferon (IFN)γ is a consequence of CD4+ T-cell activation. BMM: bone marrow macrophage; DC: dendritic cell; MHC: major histocompatibility complex; OC: osteoclast; RANKL: receptor activator of nuclear factor kappa-B ligand. Source: from Pacifici [224], with permission . 5 Copyright © 2013 Elsevier Inc. All rights reserved.

Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 46.5 Ovariectomy causes a two-fold lower bone loss in thymectomized (THX) mice than in euthymic controls (SHAM). Bone mineral density (BMD) (mean ± standard error of the mean (SEM)) as measured by dual energy X-ray absorptiometry (DXA). * = p < 0.05 and ** = p < 0.01 as compared to baseline. Source: from Ryan et al. [98], with permission. 6 Copyright © 2013 Elsevier Inc. All rights reserved.

Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 46.6 Changes in serum ionized calcium (Ca) and intact parathyroid hormone (PTH) and urinary free deoxypyridinoline cross-links (fDPD), a bone resorption marker, in 18 early postmenopausal women studied at baseline (BSL) and after 6 months of treatment with physiologic doses of estrogen (EST). At BSL during estrogen deficiency, serum ionized calcium was maintained at a constant level in the presence of increased bone resorption by a reduction in the level of PTH. During estrogen sufficiency, these conditions are reversed. NS: not significant. Source: reproduced from Riggs et al. [225], with permission. 7 Copyright © 2013 Elsevier Inc. All rights reserved.

Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 46.7 Serum parathyroid hormone (PTH) concentrations and bone resorption (assessed by urinary excretion of deoxypyridinoline (DPD)) are increased (p < 0.001 for both variables) in elderly postmenopausal women as compared with premenopausal women. Either a high calcium (Ca) intake of 2400 mg/day over 3 years or chronic estrogen therapy (ERT) reduced values to those that were similar or lower than in premenopausal women. Source: reproduced from Riggs et al. [1], with permission. 8 Copyright © 2013 Elsevier Inc. All rights reserved.

Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 46.8 Experimental testing of the relative importance of estrogen (E) and testosterone (T) in suppressing bone turnover in 59 elderly men. After 3 weeks of suppression of sex steroid production by gonadotropin-releasing hormone (GnRH) agonist treatment and blocking conversion of androgens to estrogen with an aromatase inhibition, the GnRH agonist, but not the aromatase inhibitor, was discontinued. The subjects were then randomly assigned to groups treated with testosterone, estrogen, both, or neither and treated for 3 weeks before reevaluation. Panel A shows the effects of treatment on the resorption markers, urinary deoxypyridinoline (DPD) and N-telopeptide (NTx). By two-factor ANOVA, estrogen, but not testosterone, prevented increases in bone resorption markers. However, the possibility of a small effect on testosterone on opposing this increase cannot be excluded. Panel B shows the effects on bone formation markers, serum osteocalcin and the N-terminal extension of type I procollagen (PINP). Levels of serum bone alkaline phosphatase did not change (data not shown). Withdrawal of estrogen and testosterone leads to a decrease in markers (indicating that bone formation was being stimulated by their presence). For serum osteocalcin, a marker of late osteoblast function decreases, whereas for serum PINP, a marker of all stages of osteoblast function, estrogen, but not testosterone, was effective. For significance of change from baseline: *p < 0.05; ** p < 0.01; *** p < 0.001. Source: reproduced from Falahati et al. [34], with permission. 9 Copyright © 2013 Elsevier Inc. All rights reserved.

Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 46.9 Yearly incidence of fractures as a function of serum estradiol levels in subjects from MrOS Sweden. Poisson regression models were used to determine the relation between serum estradiol levels and fracture risk. Source: reproduced from Mellström et al. [202], with permission 10 Copyright © 2013 Elsevier Inc. All rights reserved.