1. Chapter 31 Chapter 31 Clinical and Epidemiological Studies: Skeletal Changes across Menopause Copyright © 2013 Elsevier Inc. All rights reserved.

2. FIGURE 31.1 Working model of changes and potential time course of these changes in osteoclast/osteoblast apoptosis (A), in proresorptive cytokines (B), and in osteoblastogenesis, increases in T cells, and osteoclastogenesis (C) after the induction of estrogen deficiency (see text). IL: Interleukin; RANKL: Receptor activator of nuclear factor kappaB ligand; TNFα: Tumor necrosis factor α. Source: Khosla (2010) [8]. 2

3. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 31.2 Annual rate of change in bone mineral density (BMD) of the lumbar spine and total hip in premenopausal (red bars), early perimenopausal (blue bars), late perimenopausal (yellow bars), and postmenopausal (green bars) women (n = 1902). Rates of change were estimated from multivariable linear mixed models and adjusted for multiple covariates. Error bars represent 95% confidence intervals (CI). Comparisons were made across status categories: Early peri- vs. premenopausal, p < 0.001 (spine) and p = 0.002 (hip); late peri- vs. early perimenopausal, p < 0.001 (spine) and p < 0.001 (hip); and post- vs. late perimenopausal, p = 0.002 (spine) and p < 0.001 (hip). Source: Finkelstein et al. (2008) [21]. 3

4. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 31.3 Annual rate of change in bone mineral density (BMD) of the lumbar spine in premenopausal (red bars), early perimenopausal (blue bars), late perimenopausal (yellow bars), and postmenopausal (green bars) women from the full cohort. Source: Finkelstein et al. (2008) [20]. 4

5. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 31.4 Annual rate of change in bone mineral density (BMD) of the lumbar spine (top panel) and total hip (bottom panel) in premenopausal (red bars), early perimenopausal (blue bars), late perimenopausal (yellow bars), and postmenopausal (green bars) women divided by tertiles of baseline body weight (tertile 1, 77.3 kg) in the entire cohort. Rates of change were estimated from multivariable linear mixed models and adjusted for multiple covariates. Error bars represent 95% confidence intervals. Comparisons were made between tertile groups, with p values for lumbar spine in pre-, early peri-, late peri-, and postmenopausal women, respectively, as follows: tertile 1 vs. 3, <0.001, <0.001, <0.001, and <0.001; tertile 2 vs. 3, = 0.033, <0.001, <0.001, and <0.001; tertile 1 vs. = 2, 0.13, = 0.002, = 0.39, and = 0.044; and with P values for total hip in pre-, early peri-, late peri-, and postmenopausal women, respectively: tertile 1 vs. 3, = 0.15, <0.001, = 0.027, and <0.001; tertile 2 vs. 3, = 0.51, = 0.08, = 0.09, and <0.001; tertile 1 vs. 2, = 0.032, = 0.017, = 0.68, and = 0.17. Source: Finkelstein et al. (2008) [20]. 5

6. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 31.5 Mean urine cross-linked N-telopeptide of type I collagen (NTx), serum estradiol (E2), and serum follicle-stimulating hormone (FSH) levels of the entire study population (n = 918) in relations to years from the final menstrual period. The dashed lines or the shaded areas denote the 95% confidence intervals. Source: Sowers et al. (2013) [37]. 6

7. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 31.6 Multivariable-adjusted hazard ratio (HR) and 95% confidence interval (CI) of fracture by baseline cross-linked N-telopeptide of type I collagen (NTx) and lumbar spine bone mineral density (BMD; p interaction = 0.32). fx, fracture. Source: Cauley et al. (2003) [6]. 7