1. Chapter 83 Chapter 83 Denosumab for the Treatment of Osteoporosis Copyright © 2013 Elsevier Inc. All rights reserved.

2. FIGURE 83.1 Pharmacokinetic and pharmacodynamic responses to denosumab 60 mg subcutaneous injections. Serum denosumab levels …; serum CTX with denosumab __; serum CTX with alendronate 70 mg weekly - - -. CTX: C-terminal telopeptide of type I collagen; SE: standard error of the mean. Source: adapted from Becker etal. (2004) [13] and McClung etal. (2006) [15]. 2

3. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 83.2 Effect of denosumab on fracture risk at 36 months in the FREEDOM trial. Incidence of fractures in placebo group (open bars) or denosumab group (shaded bars); incidence values in the bars. Relative risk and 95% confidence intervals shown above the bars. Source: adapted from Cummings etal. (2009) [18]. 3

4. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 83.3 Effect of denosumab on fracture risk in high risk subgroups in the FREEDOM trial. Incidence values in the bars represent Kaplan-Meier estimates at month 36. Incidence of fractures in placebo group (open bars) or denosumab group (shaded bars). Relative risk and 95% confidence intervals shown above the bars. BMD: bone mineral density. Source: adapted from Boonen etal. (2011) [20]. 4

5. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 83.4 Y early incidence of nonvertebral fractures in FREEDOM and FREEDOM Extension in placebo group (open bars) or denosumab group (shaded bars). Source: adapted from Papapoulos et al. (2011) [23]. 5

6. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 83.5 Bone mineral density (BMD) changes in the lumbar spine and total hip with prolonged denosumab therapy. Denosumab 60 mg every 6 months (shaded line); placebo (white line). CI: confidence interval; LSM: least-squared means. Source: adapted from McClung etal. (2012) [25]. 6

7. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 83.6 Effects of discontinuing denosumab therapy on bone mineral density and bone turnover markers. A = lumbar spine; B = total hip; C = serum C-terminal telopeptide of type I collagen (sCTX); D = procollagen type I N-propeptide (PINP). Open circles: denosumab 60 mg every 6 months for 2 years followed by placebo for 2 years; closed triangles: placebo for 4 years. Source: adapted from Bone etal. (2011) [37]. 7

8. Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 83.7 Mean magnetic resonance imaging (MRI) erosion score in hands of patients with rheumatoid arthritis treated with placebo (open circles), denosumab 60 mg every 6 months (closed squares), or denosumab 180 mg every 6 months (closed triangles). Source: adapted from Deodhar etal. (2010) [54]. 8