Subjects Randomized to Denosumab or Bisphosphonate Therapy Appendix Figure 1: Funnel Plot of Three Studies Comparing Change in Spine Bone Mineral Density Between Subjects Randomized to Denosumab or Bisphosphonate Therapy

Between Subjects Randomized to Denosumab versus Bisphosphonate Appendix Figure 2: Funnel Plot of Studies Comparing the Percent Change in Total Hip Bone Mineral Density Between Subjects Randomized to Denosumab versus Bisphosphonate

Between Subjects Randomized to Denosomab versus Bisphosphonate Appendix Figure 3. Funnel Plot of Studies Comparing the Percent Change in Femoral Neck Bone Mineral Density Between Subjects Randomized to Denosomab versus Bisphosphonate

Randomization to Denosumab or Bisphosphonate Therapy Appendix Figure 4: Funnel Plot of Studies Describing Relative Risk of Fractures by Randomization to Denosumab or Bisphosphonate Therapy

Bisphosphonate in Studies of Glucocorticoid Induced Osteoporosis Appendix Figure 5. Funnel Plot of Studies Comparing Risk of Infections between Denosumab vs. Bisphosphonate in Studies of Glucocorticoid Induced Osteoporosis

Relative Risk of Adverse Events by Treatment Assignment RR Study Random effects Heterogeneity: I 2 = 83% , t = 0.7207 p < 0.01 Mok, 2015 Iseri, 2018 Saag, 2018 Events 18 4 285 Total 429 21 14 394 Denosumab 5 265 419 384 Bisphosphonate 0.01 0.1 1 10 100 Risk Ratio Relative Risk of Adverse Events by Treatment Assignment RR 2.23 3.60 9.00 1.05 95% CI [0.70; 7.08] [1.64; 7.89] [0.53; 152.45] [0.96; 1.15] 100.0% 39.5% 12.4% 48.1% Weight Appendix Figure 6: Relative Risk of Adverse Events by Treatment Assignment

Appendix Figure 7: Funnel Plot of Three Studies Comparing Adverse Events of Denosumab vs. Bisphosphonate Therapy in Studies of Glucocorticoid Induced Osteoporosis

Relative Risk of Serious Adverse Events by Treatment Assignment RR Appendix Figure 8: Relative Risk of Serious Adverse Events by Treatment Assignment Study Random effects Heterogeneity: I 2 = 18% , t = 0.2444 p = 0.27 Mok, 2015 Iseri, 2018 Saag, 2018 Events 63 Total 429 21 14 394 Denosumab 65 419 384 Bisphosphonate 0.1 0.5 1 10 Risk Ratio Relative Risk of Serious Adverse Events by Treatment Assignment RR 1.11 5.00 0.94 95% CI [0.42; 2.93] [0.26; 95.32] [0.69; 1.30] 100.0% 0.0% 9.7% 90.3% Weight

vs Bisphosphonate for Glucocorticoid Induced Osteoporosis Appendix Figure 9: Funnel Plot of Studies Reporting Serious Adverse Events of Denosumab vs Bisphosphonate for Glucocorticoid Induced Osteoporosis

Percent Change in Spine BMD MD 95%-CI Weight Appendix Figure 10: Percent Change in Spine Bone Mineral Density between Subjects Randomized to Denosumab or Control Denosumab Control Study Total Mean SD Total Mean SD Percent Change in Spine BMD MD 95%-CI Weight Mok 2015 20 3.39 4.02 20 1.48 1.79 1.91 [-0.02; 3.84] 8.7% Iseri 2018 14 5.30 3.74 14 2.00 4.49 3.30 [ 0.24; 6.36] 3.4% Saag, 2018 starting GC 118 3.70 4.00 126 0.90 3.90 2.80 [ 1.81; 3.79] 32.8% Saag, 2018 continuing GC 209 4.30 4.00 210 2.30 4.50 2.00 [ 1.18; 2.82] 48.6% Dore* 2010 21 3.50 2.90 15 0.40 3.70 3.10 [ 0.85; 5.35] 6.4% 382 385 Random effects 2.37 [ 1.80; 2.94] 100.0% Heterogeneity: I 2 = 0% , t 2 = 0 , p = 0.65 -6 -4 -2 2 4 6 *The Dore study used a placebo control; all other studies used bisphosphonate as the control ←Favors Bisphosphonate Favors Denosumab→

Bone Mineral Density between Denosumab and Control Appendix Figure 11: Funnel Plot of Four Studies Comparing Percent Change in Spine Bone Mineral Density between Denosumab and Control

Percent Change in Total Hip Bone Mineral Density Study Random effects Heterogeneity: I 2 = 25% , t = 0.0711 p = 0.26 Mok 2015 Saag 2018, GC starting Saag 2018, GC continuing Dore* 2010 Total 364 20 115 208 21 Mean 1.38 1.70 2.20 1.60 SD 2.683 2.700 2.900 1.900 Denosumab 368 125 15 0.8 0.1 0.6 -1.2 2.24 2.60 3.10 Control -4 -2 4 Percent Change in Total Hip Bone Mineral Density Appendix Figure 12: Percent Change in Total Hip Bone Mineral Density in Subjects Randomized to Denosumab versus Control ←Favors Bisphosphonate Favors Denosumab→ MD 1.62 0.58 2.80 95%-CI [ 1.10; 2.13] [-0.95; 2.11] [ 0.93; 2.27] [ 1.02; 2.18] [ 1.25; 4.35] 100.0% 10.1% 36.4% 43.6% 9.9% Weight *The Dore study used a placebo control; all other studies used bisphosphonate as the control

in Subjects Randomized to Denosumab versus Control Appendix Figure 13: Funnel Plot of Studies Comparing the Percent Change in Total Hip Bone Mineral Density in Subjects Randomized to Denosumab versus Control

Relative Risk of Fractures by Treatment Assignment RR Study Random effects Heterogeneity: I 2 = 0% , t ? = 0 , p = 0.54 Mok 2015 Iseri 2018 Saag 2018 Dore* 2010 Events 1 26 Total 504 21 14 398 71 Denosumab 23 507 397 75 Control 0.1 0.5 10 Risk Ratio Relative Risk of Fractures by Treatment Assignment RR 1.16 3.00 1.13 95%-CI [0.68; 1.98] [0.13; 67.72] [0.65; 1.94] 100.0% 0.0% 3.0% 97.0% Weight Appendix Figure 14: Relative Risk of Fractures by Treatment with Bisphosphonate versus Control *The Dore study used a placebo control; all other studies used bisphosphonate as the control

with Bisphosphonate versus Control Appendix Figure 15: Funnel Plots of Studies Reporting the Relative Risk of Fractures by Treatment with Bisphosphonate versus Control

Relative Risk of Infection by Treatment Assignment RR Study Random effects Heterogeneity: I 2 = 35% , t = 0.0802 p = 0.21 Mok 2015 Iseri 2018 Saag^ 2018 Dore* 2010 Events 7 17 29 Total 500 21 14 394 71 Denosumab 1 15 27 494 384 75 Other 0.1 0.5 10 Risk Ratio Relative Risk of Infection by Treatment Assignment RR 1.26 7.00 1.10 1.13 95% CI [0.75; 2.13] [0.94; 52.04] [0.56; 2.18] [0.75; 1.71] 100.0% 6.4% 0.0% 35.8% 57.8% Weight Appendix Figure 16: Relative Risk of Infection by Treatment Assignment *The Dore study used a placebo control; all other studies used bisphosphonate as the control

Bisphosphonate or Placebo in Glucocorticoid Induced Osteoporosis Appendix Figure 17: Funnel Plot of Infections in Studies Comparing Denosumab vs. Bisphosphonate or Placebo in Glucocorticoid Induced Osteoporosis

Relative Risk of Adverse Events by Treatment Assignment RR Study Random effects Heterogeneity: I 2 = 78% , t = 0.0333 p < 0.01 Mok, 2015 Iseri, 2018 Saag, 2018 Dore,* 2010 Events 18 4 285 60 Total 500 21 14 394 71 Denosumab 5 265 67 494 384 75 Other 0.01 0.1 1 10 100 Risk Ratio Relative Risk of Adverse Events by Treatment Assignment RR 1.13 3.60 9.00 1.05 0.95 95% CI [0.88; 1.46] [1.64; 7.89] [0.53; 152.45] [0.96; 1.15] [0.83; 1.07] 100.0% 8.5% 0.8% 46.6% 44.1% Weight Appendix Figure 18: Relative Risk of Adverse Events by Treatment Assignment *The Dore study used a placebo control; all other studies used bisphosphonate as the control

Appendix Figure 19: Funnel Plot of Studies Comparing Adverse Events of Denosumab vs. Bisphosphonate or Placebo in Studies of Glucocorticoid Induced Osteoporosis

Relative Risk of Serious Adverse Events by Treatment Assignment RR Study Random effects Heterogeneity: I 2 = 17% , t = 0.082 p = 0.30 Mok, 2015 Iseri, 2018 Saag, 2018 Dore,* 2010 Events 63 3 Total 500 21 14 394 71 Denosumab 65 7 494 384 75 Other 0.1 0.5 1 10 Risk Ratio Relative Risk of Serious Adverse Events by Treatment Assignment RR 0.89 5.00 0.94 0.45 95% CI [0.50; 1.59] [0.26; 95.32] [0.69; 1.30] [0.12; 1.68] 100.0% 0.0% 3.7% 80.0% 16.3% Weight Appendix Figure 20: Relative Risk of Serious Adverse Events by Treatment Assignment; Denosumab vs Bisphosphonate or Placebo *The Dore study used a placebo control; all other studies used bisphosphonate as the control

Appendix Figure 21: Funnel Plot of Studies Comparing Serious Adverse Events of Denosumab vs. Bisphosphonate or Placebo in Studies of Glucocorticoid Induced Osteoporosis