1. New Dimensions and Landmark Advances in Osteoporosis Management Felicia Cosman, MD Professor of Clinical Medicine Columbia University New York, NY Osteoporosis Specialist/Endocrinologist Helen Hayes Hospital, West Haverstraw, NY Clinical Director National Osteoporosis Foundation Washington, DC The Internal Medicine Perspective

2. Universal Management Measures Risk factor reduction Risk factor reduction Bone mass Bone mass Medications- stop or reduce dose if possible Medications- stop or reduce dose if possible Smoking cessation programs Smoking cessation programs Fall Prevention Fall Prevention Medications Medications Environment Environment Balance training Balance training Physical Activity/ Exercise Physical Activity/ Exercise Optimal Nutrition Optimal Nutrition Calcium Calcium Vitamin D Vitamin D BMD Testing When Appropriate BMD Testing When Appropriate

3. FDA Approved Osteoporosis Treatments Antiresorptive Agents Bisphosphonates Bisphosphonates Alendronate (Fosamax®)Alendronate (Fosamax®) Risedronate (Actonel®)Risedronate (Actonel®) Ibandronate (Boniva®: Oral and IV)Ibandronate (Boniva®: Oral and IV) Zoledronic Acid (Reclast® IV)Zoledronic Acid (Reclast® IV) Estrogen Agonist/Antagonists Estrogen Agonist/Antagonists Raloxifene (Evista®)Raloxifene (Evista®) Estrogen/Estrogen-Progestin Combinations Estrogen/Estrogen-Progestin Combinations Calcitonins (Miacalcin, Fortical) Calcitonins (Miacalcin, Fortical) Anabolic Therapies Teriparatide (Forteo) Teriparatide (Forteo)

4. Treating Patients Across the Lifespan Try to take advantage of greatest potential Try to take advantage of greatest potential benefits of specific medications and avoid risks: benefits of specific medications and avoid risks: Age is a key determinantAge is a key determinant HT greatest benefit and least risk early after menopauseHT greatest benefit and least risk early after menopause and for <5 years and for <5 years ET alone: Perhaps can use for longerET alone: Perhaps can use for longer Raloxifene during 50s to mid to late 60sRaloxifene during 50s to mid to late 60s Bisphosphonates: 60s and beyondBisphosphonates: 60s and beyond Teriparatide can be used at any point along this continuumTeriparatide can be used at any point along this continuum for more severe patients, but needs to be followed by an for more severe patients, but needs to be followed by an antiresorptive treatment to maximize and maintain gains antiresorptive treatment to maximize and maintain gains

5. Major Problem with all Current Osteoporosis Therapies: Adherence and Persistence Fewer than 50% of people remain on any of these therapies beyond one year Fewer than 50% of people remain on any of these therapies beyond one year Patients who are not adherent and persistent do not have fracture benefits Patients who are not adherent and persistent do not have fracture benefits Once yearly zoledronic acid has the potential to dramatically improve adherence and persistence to therapy and thus translate clinical trial benefits into real clinical benefits for patients Once yearly zoledronic acid has the potential to dramatically improve adherence and persistence to therapy and thus translate clinical trial benefits into real clinical benefits for patients Denosumab (twice yearly subcutaneously) offers potential improvement in persistence and real clinical benefits Denosumab (twice yearly subcutaneously) offers potential improvement in persistence and real clinical benefits

6. Objectives of Presentation Review Zoledronic Acid Pivotal Trials Review Zoledronic Acid Pivotal Trials Initial study: Pivotal Fracture Trial (PFT) Initial study: Pivotal Fracture Trial (PFT) Most recent study: Recurrent Fracture Trial (RFT) Most recent study: Recurrent Fracture Trial (RFT) Denosumab Overview Denosumab Overview

7. HORIZON Pivotal Fracture Trial (PFT) Overview Objective: To evaluate the potential of once yearly zoledronic acid 5 mg to decrease fracture risk in postmenopausal women with osteoporosis Objective: To evaluate the potential of once yearly zoledronic acid 5 mg to decrease fracture risk in postmenopausal women with osteoporosis 3-year, randomized, double-blind, placebo-controlled clinical trial 3-year, randomized, double-blind, placebo-controlled clinical trial 7736 women from 240 clinical centers in 27 countries 7736 women from 240 clinical centers in 27 countries Treatment Treatment Annual infusion of either zoledronic acid 5 mg or placebo Annual infusion of either zoledronic acid 5 mg or placebo Calcium 1000–1500 mg/d; vitamin D 400– 1200 IU/d Calcium 1000–1500 mg/d; vitamin D 400– 1200 IU/d Follow-up visits at 6, 12, 24 and 36 months Follow-up visits at 6, 12, 24 and 36 months Telephone interviews every 3 months Telephone interviews every 3 months Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. N Eng J Med 2007; 356:1809

8. Study Population: HORIZON Inclusion Inclusion Women 65 to 89 years of age Women 65 to 89 years of age Femoral neck T-score –2.5 or –1.5 with two mild or one moderate prevalent vertebral fracture Femoral neck T-score –2.5 or –1.5 with two mild or one moderate prevalent vertebral fracture Exclusion Exclusion Current use of bisphosphonates, PTH, or strontium ranelate Current use of bisphosphonates, PTH, or strontium ranelate Failure to meet specified washout periods for previous BP use Failure to meet specified washout periods for previous BP use Two strata Two strata Stratum I: No current osteoporosis therapy (80% of total population) Stratum I: No current osteoporosis therapy (80% of total population) Stratum II: SERMs, calcitonin, HT/ET, or tibolone at baseline (20% of total population) Stratum II: SERMs, calcitonin, HT/ET, or tibolone at baseline (20% of total population) Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. N Eng J Med 2007; 356:1809

9. Baseline Characteristics ZOL 5 mg (n = 3875) Placebo (n = 3861) Stratum I, n (%) 3045 (79) 3039 (79) Stratum II, n (%) 830 (21) 822 (21) Mean (SD) age, years 73.1 (5) 73.0 (5) Region, n (%) Western/Eastern Europe 1934 (50) North/South America/Oceania 1391 (36) 1387 (36) Asia 550 (14) 540 (14) Femoral neck T-score, n (%) –2.5 2814 (73) 2734 (71) Prevalent vertebral fracture, n (%) 1 2416 (62) 2477 (64) Prior bisphosphonate use, n (%) 565 (15) 557 (14) Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. N Eng J Med 2007; 356:1809

10. Morphometric Vertebral Fracture Results (Stratum I) Relative risk reductions (95% confidence intervals) vs placebo *P <.0001, based on logistic regression with treatment and baseline fracture status in the model using log-likelihood type approach Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. N Eng J Med 2007; 356:1809 Zoledronic acid 5 mg Placebo % Patients With New Vertebral Fracture 60%* (43%, 72%) 71%* (62%, 78%) 0 10 0–10–20–3 Years 5 15 1.5% 3.7% 2.2% 7.7% 3.3% 10.9% 70%* (62%, 76%)

11. Cumulative Risk of Hip Fracture (Strata I + II) Relative risk reduction ( 95% confidence interval) vs placebo Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. N Eng J Med 2007; 356:1809 P =.0024 1 230 Placebo (n = 3861) ZOL 5 mg (n = 3875) Cumulative Incidence (%) Time to First Hip Fracture (months) 0369121518212427303336 41%* (17%, 58%)

12. Cumulative Risk of Clinical Vertebral Fracture (Strata I & II) Relative risk reduction (95% confidence interval) vs placebo Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. N Eng J Med 2007; 356:1809 P <.0001 Cumulative Incidence (%) Time to First Clinical Vertebral Fracture (months) 0369121518212427303336 77% (63%, 86%) Placebo (n = 3861) ZOL 5 mg (n = 3875) 1 230

13. Cumulative Risk of Clinical Non-vertebral Fracture (Strata I & II) Relative risk reduction (95% confidence interval) vs placebo Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. N Eng J Med 2007; 356:1809 P =.0002 Time to First Clinical Non-vertebral Fracture (months) 2 4 6 8 10120369121518212427303336 25% (13%, 36%) Placebo (n = 3861) ZOL 5 mg (n = 3875) 0 Cumulative Incidence (%)

14. Zoledronic Acid Produced Significant Increases in BMD Over 3 Years Bracketed values are least square mean difference, zoledronic acid vs placebo *P <.0001, P-value computed from 3-way ANOVA with treatment, stratum and region as explanatory variables. Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822. -3 -2 0 1 2 3 4 5 6 7 8 Total Hip Femoral Neck Lumbar Spine Mean % Change From Baseline 6.0%* 5.1%* 6.7%* Zoledronic AcidPlacebo Please see full prescribing information.

15. Placebo (n = 305) Zoledronic acid 5 mg (n = 300) Premenopausal reference range Mean Serum β-CTX (ng/mL) 0.2 0.0 0.6 0.7 0.8 1.0 0.9 0.5 0.1 0.3 0.4 Months 061218243036 Mean Serum CTX Over Time Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. N Eng J Med 2007; 356:1809 = annual dose

16. Mean Serum BSAP Over Time Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. N Eng J Med 2007; 356:1809 Mean Serum BSAP (ng/mL) 4 0 16 18 20 12 2 8 10 6 14 Months 061218243036 Placebo (n = 305) Zoledronic acid 5 mg (n = 300) = annual dose Premenopausal reference range

17. Other Secondary End Points Disability: Significant reductions in limited activity days due to: Disability: Significant reductions in limited activity days due to: Back pain (61 days zoledronic acid vs 72 days placebo, P =.0076) Back pain (61 days zoledronic acid vs 72 days placebo, P =.0076) Fracture (6 days zoledronic acid vs 10 days placebo, P <.001) Fracture (6 days zoledronic acid vs 10 days placebo, P <.001) Height loss Height loss Significantly reduced in zoledronic Significantly reduced in zoledronic acid 5 mg group acid 5 mg group –4 mm zoledronic acid vs 7 mm placebo (P <.0001) placebo (P <.0001) Months ZOL 5 mgPlacebo Height Change (mm) –8 –6 –4 –2 0 0122436 Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. N Eng J Med 2007; 356:1809

18. Common (5% in ZOL) Post-Dose Symptoms Occurring Within 3 Days After Infusion 0 2 4 6 8 10 12 14 16 Annual Infusion Pyrexia Myalgia Flu-like illness Headache Arthralgia 123123123123123 Incidence (%) 15% 2% 1% 2% 1% 2% 1% 2% 1% 8% 7% 6% 5% Placebo values cross-hatched Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. N Eng J Med 2007; 356:1809

19. Systemic Safety Parameters Renal safety Renal safety Short term: 9-11 day post-dose monitoring in >4000 patients Short term: 9-11 day post-dose monitoring in >4000 patients Transient rises in serum creatinine in 1.8% of patients (vs 0.81% placebo) with resolution and all patients redosed Transient rises in serum creatinine in 1.8% of patients (vs 0.81% placebo) with resolution and all patients redosed Overall, no cumulative impact on renal function Overall, no cumulative impact on renal function Hypocalcemia (serum calcium < 2.075 mmol/L) Hypocalcemia (serum calcium < 2.075 mmol/L) 49 cases (2.3%) 9-11 days after 1st ZOL 5 mg infusion, almost none after 2nd (0.1%) or 3rd (0.3%) 49 cases (2.3%) 9-11 days after 1st ZOL 5 mg infusion, almost none after 2nd (0.1%) or 3rd (0.3%) All asymptomatic and transient All asymptomatic and transient Cardiac safety Cardiac safety Atrial fibrillation AEs comparable (2.4% ZOL 5 mg, 1.8% placebo) Atrial fibrillation AEs comparable (2.4% ZOL 5 mg, 1.8% placebo) Atrial fibrillation SAEs more common in ZOL Atrial fibrillation SAEs more common in ZOL n = 50 (1.3%) ZOL 5 mg n = 50 (1.3%) ZOL 5 mg n = 20 (0.5%) placebo n = 20 (0.5%) placebo ECG study (n = 559) 9-11 days after 3rd infusion: No differences observed between ZOL 5 mg and placebo ECG study (n = 559) 9-11 days after 3rd infusion: No differences observed between ZOL 5 mg and placebo Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. N Eng J Med 2007; 356:1809

20. Bone Safety Parameters Histomorphometry evaluable in 93 bone biopsies 1,2 Histomorphometry evaluable in 93 bone biopsies 1,2 Label seen in all specimens Label seen in all specimens Fracture healing 2 Fracture healing 2 Non-union: 1 in ZOL 5 mg, 1 in placebo Non-union: 1 in ZOL 5 mg, 1 in placebo Avascular necrosis (hip or knee) 2 Avascular necrosis (hip or knee) 2 4 in ZOL 5 mg, 3 in placebo 4 in ZOL 5 mg, 3 in placebo Osteonecrosis of the jaw 2 Osteonecrosis of the jaw 2 No spontaneous AE reports No spontaneous AE reports AE database search of 50 MedDRA terms, with adjudication AE database search of 50 MedDRA terms, with adjudication Case definition: exposed bone in the mouth > 6 weeks Case definition: exposed bone in the mouth > 6 weeks 1 in ZOL 5 mg, 1 in placebo 1 in ZOL 5 mg, 1 in placebo Both cases healed with antibiotic therapy and/or debridement Both cases healed with antibiotic therapy and/or debridement 1. Recker RR, et al. JBMR 2007 or 2008 2. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. N Eng J Med 2007; 356:1809

21. The Effect of Once Yearly Zoledronic Acid 5 mg on New Fractures and Mortality After Hip Fracture: The HORIZON-Recurrent Fracture Trial Lyles KW, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809 Landmark Advances in Osteoporosis Therapy

22. HORIZON-Recurrent Fracture Trial (RFT) Primary and Secondary Efficacy End Points Primary Objective Primary Objective Reduce the rate of new clinical fractures after surgical procedure for low-trauma hip fracture Reduce the rate of new clinical fractures after surgical procedure for low-trauma hip fracture Secondary Objectives Secondary Objectives Reduce the risk of clinical vertebral, hip, and non-vertebral fractures Reduce the risk of clinical vertebral, hip, and non-vertebral fractures Increase BMD at the total hip and femoral neck of the non-fractured hip at months 12 and 24 Increase BMD at the total hip and femoral neck of the non-fractured hip at months 12 and 24 Lyles KW, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809

23. HORIZON-Recurrent Fracture Trial Overview Double-blind, placebo-controlled RCT Double-blind, placebo-controlled RCT 2127 men and women, 148 clinical centers, 23 countries 2127 men and women, 148 clinical centers, 23 countries Treatment Treatment Annual infusion of either zoledronic acid 5 mg or placebo Annual infusion of either zoledronic acid 5 mg or placebo Loading dose of vitamin D 50,000–125,000 IU Loading dose of vitamin D 50,000–125,000 IU Calcium 1000–1500 mg/d; vitamin D 800–1200 IU/d Calcium 1000–1500 mg/d; vitamin D 800–1200 IU/d Follow-up visits at 6, 12, 24, and 36 months Follow-up visits at 6, 12, 24, and 36 months Telephone interviews every 3 months starting at month 9 Telephone interviews every 3 months starting at month 9 Lyles KW, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809

24. HORIZON-Recurrent Fracture Trial Study Population Inclusion Inclusion Male or female patients aged 50 years and older Male or female patients aged 50 years and older Randomized up to 90 days following surgical procedure for a low-trauma hip fracture Randomized up to 90 days following surgical procedure for a low-trauma hip fracture Ambulatory prior to hip fracture Ambulatory prior to hip fracture Unwilling or unable to take oral bisphosphonates Unwilling or unable to take oral bisphosphonates Exclusion Exclusion Use of oral bisphosphonates (or any use of IV within 2 years) Use of oral bisphosphonates (or any use of IV within 2 years) Calculated creatinine clearance <30 mL/min Calculated creatinine clearance <30 mL/min Hypercalcemia or hypocalcemia Hypercalcemia or hypocalcemia Other metabolic bone diseases Other metabolic bone diseases Any prior use of parathyroid hormone or its analogs for >1 week, any use of fluoride or strontium Any prior use of parathyroid hormone or its analogs for >1 week, any use of fluoride or strontium Lyles KW, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809

25. Zoledronic acid 5 mg (n = 1065) Placebo (n = 1062) Sex, n (%) Male 248 (23.3) 260 (24.5) Female 817 (76.7) 802 (75.5) Region, n (%) North America 305 (28.6) 318 (29.9) Latin America 132 (12.4) 131 (12.3) Western Europe 359 (33.7) 353 (33.2) Eastern Europe 269 (25.3) 260 (24.5) HORIZON-Recurrent Fracture Trial Baseline Demographics Lyles KW, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809

26. Zoledronic acid 5 mg (n = 1065) Placebo (n = 1062) Age group (year), n (%) <65 <65 172 (16.2) 192 (18.1) 65-74 65-74 307 (28.8) 269 (25.3) 75-84 75-84 446 (41.9) 449 (42.3) 85 85 140 (13.1) 152 (14.3) Age (year) Mean (SD) Mean (SD) 74.4 (9.48) 74.6 (9.86) Min, Median, Max Min, Median, Max 50.0, 76.0, 95.0 50.0, 76.0, 98.0 HORIZON-Recurrent Fracture Trial Baseline Demographics (continued) Lyles KW, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809

27. 0 2 4 6 8 10 10 12 12 14 14 16 16 18 18 20 20 Clinical Fractures Non-Vertebral Fractures Clinical Vertebral Fractures Hip Fractures 10.7% (107/1062) 8.6% (92/1065) 13.9% (139/1062) 7.6% (79/1065) 3.8% (39/1062) 1.7% (21/1065) 3.5% (33/1062) 2.0% (23/1065) 35%* (16%, 50%) 27% (2%, 45%) 46% (8%, 68%) 30% NS (-2%, 59%) *P =.0012; P =.0338; P =.0210, relative risk reduction vs placebo; NS = not significant. Values above bars are cumulative event rates based on Kaplan-Meier estimates at Month 24. Event Rate (%) Zoledronic acid 5 mg Zoledronic acid 5 mgPlacebo Zoledronic Acid 5 mg Reduced Subsequent Fracture Risk Over Time Lyles KW, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809

28. Zoledronic Acid 5 mg Reduced Risk of All-Cause Mortality by 28% Over Time Month 0 2 4 6 8 10 12 14 1618 Hazard Ratio, 0.72 (95% CI, 0.56–0.93) P =.0117 Cumulative Incidence (%) 04812162024283236 No. at Risk ZOL 5 mg 10541029987943806674507348237144 Placebo10571028993945804681511364236149 Zoledronic acid 5 mg (n = 1054) Zoledronic acid 5 mg (n = 1054) Placebo (n = 1057) 28% Absolute Risk Reduction, 3.7% Lyles KW, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809

29. Adjudicated Results for Targeted Events Zoledronic acid 5 mg (n = 1054) n (%) Placebo (n = 1057) n (%) Atrial fibrillation SAEs 11 (1.0) 13 (1.2) Ocular 21 (2.0) 16 (1.5) 16 (1.5) Delayed union/nonunion 3 (0.3) 3 (0.3) Delayed hip fracture healing 34 (3.2) 29 (2.7) 29 (2.7) Avascular necrosis 6 (0.6) 6 (0.6) 3 (0.3) 3 (0.3) Hypocalcemia 0 (0.0) 0 (0.0) Osteonecrosis of the jaw 0 (0.0) 0 (0.0) Renal 87 (8.3) 90 (8.5) 90 (8.5) Lyles KW, et al. Presented at: 29th ASBMR; September 16-19, 2007; Honolulu, Hawaii. Abstract 1055.

30. Where does Zoledronic Acid Fit into the Armamentarium Against Osteoporosis First line for all patients with hip fracture First line for all patients with hip fracture Data show dismal diagnostic and treatment rates for these patients right now Data show dismal diagnostic and treatment rates for these patients right now An easily administered, well tolerated, agent, given only once yearly, has dramatic efficacy in reducing subsequent fracture risk and even reducing mortality An easily administered, well tolerated, agent, given only once yearly, has dramatic efficacy in reducing subsequent fracture risk and even reducing mortality Consider as first line treatment for patients in whom a bisphosphonate is the chosen type of therapy Consider as first line treatment for patients in whom a bisphosphonate is the chosen type of therapy Why not offer all patients a choice? Why not offer all patients a choice? Many prefer this option Many prefer this option Efficacy is unequalled Efficacy is unequalled Certainly offer to all patients who have difficulty taking weekly or monthly bisphosphonates due to upper GI symptoms or difficulty with adherence or persistence to regimen Certainly offer to all patients who have difficulty taking weekly or monthly bisphosphonates due to upper GI symptoms or difficulty with adherence or persistence to regimen

31. Once Yearly Therapy Summary and Conclusions Once Yearly Therapy Summary and Conclusions Infusion Therapy Required: Overcoming barriers and directing patients to IV administration sites Infusion Therapy Required: Overcoming barriers and directing patients to IV administration sites - Infusion centers - Rheumatologists - Endocrinologists - Other specialists skilled in infusion therapy Practical Issues in Placing Patients on an Annual Zoledronic Acid Regimen Practical Issues in Placing Patients on an Annual Zoledronic Acid Regimen

32. Once Yearly Therapy Summary and Conclusions Once Yearly Therapy Summary and Conclusions Most managed care health systems have designated infusion services Most managed care health systems have designated infusion services Initiating therapy in the hospital following hip or osteoporosis-related fracture is an option Initiating therapy in the hospital following hip or osteoporosis-related fracture is an option Practical Issues in Placing Patients on an Annual Zoledronic Acid Regimen Practical Issues in Placing Patients on an Annual Zoledronic Acid Regimen

33. Denosumab: Overview Fully human monoclonal antibody-IgG 2 isotype Fully human monoclonal antibody-IgG 2 isotype High affinity and specificity for human RANK Ligand High affinity and specificity for human RANK Ligand Pharmacokinetics (SC): similar to other fully human IgG 2 monoclonal antibodies Pharmacokinetics (SC): similar to other fully human IgG 2 monoclonal antibodies Absorption is rapid and prolonged (C max 1-4 wks postdose) Absorption is rapid and prolonged (C max 1-4 wks postdose) Long half-life 34 days with max dose Long half-life 34 days with max dose Distribution intravascular volume Distribution intravascular volume Clearance reticuloendothelial system Clearance reticuloendothelial system No kidney filtration or excretion of intact molecule No kidney filtration or excretion of intact molecule Phase 3 should be completed by midyear 2008 Phase 3 should be completed by midyear 2008 NDA should be in by end 2008 NDA should be in by end 2008 Bekker PJ et al. J Bone Miner Res. 2004;19:1059-1066. Boyle WJ et al. Nature. 2003;423:337-342.

34. Mechanism of Action for Denosumab Growth Factors Hormones Cytokines Bone CFU-M = colony forming unit macrophage OsteoblastLineage Osteoclast CFU-M Pre-FusionOsteoclast MultinucleatedOsteoclast RANK RANKL OPG denosumab

35. Denosumab Phase 2 Study 1-year data: N Engl J Med 2006 1-year data: N Engl J Med 2006 McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821-831. 2-year data: J Bone Miner Res 2007 2-year data: J Bone Miner Res 2007 Lewiecki EM, Miller PD, McClung MR, Cohen SB, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low bone mineral density. Lewiecki EM, Miller PD, McClung MR, Cohen SB, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low bone mineral density. J Bone Miner Res. 2007 Dec;22(12):1832-41. 4-year data: ASBMR Oral Presentation 2007 4-year data: ASBMR Oral Presentation 2007 Miller P, Bolognese M, Lewiecki EM, McClung M, et al. Effect of denosumab on bone mineral density and bone turnover markers: 48- month results. ASBMR 2007. Abstract 1205.

36. Denosumab Phase 2 Study Randomized, placebo-controlled, dose-ranging study Randomized, placebo-controlled, dose-ranging study Postmenopausal women (n = 412) with low BMD or OP Postmenopausal women (n = 412) with low BMD or OP Spine T-score -1.8 to -4.0, or TH or FN T-score -1.8 to -3.5) Spine T-score -1.8 to -4.0, or TH or FN T-score -1.8 to -3.5) Mean Spine T-Score -2.1 Mean Spine T-Score -2.1 Treatment Assignments: Treatment Assignments: 7 denosumab dosing groups (6, 14, 30 mg Q3M; 14, 60, 100, or 210 mg Q6M SQ), 7 denosumab dosing groups (6, 14, 30 mg Q3M; 14, 60, 100, or 210 mg Q6M SQ), 1 open label 70 mg weekly alendronate group 1 open label 70 mg weekly alendronate group Placebo group Placebo group All subjects received 1000 mg Ca and 400 IU D daily All subjects received 1000 mg Ca and 400 IU D daily Primary end point: Spine BMD at 12 months Primary end point: Spine BMD at 12 months Prespecified exploratory analysis: BMD, BTMs, safety at 24 and 48 months Prespecified exploratory analysis: BMD, BTMs, safety at 24 and 48 months Lewiecki EM et al. J Bone Miner Res. 2007 Dec;22(12):1832-41.

37. Spine BMD Month -2 B6121824 Lumbar spine BMD percent change (%) a P < 0.001 vs pbo Aln (a) Den 60 (a) Pbo 0 1 2 3 4 5 6 7 8 9 10 Lewiecki EM et al. J Bone Miner Res. 2007 Dec;22(12):1832-41.

38. Total Hip BMD Total hip BMD (percent change (%) Month BL6121824 Aln (a) Den 60 (a, b) Pbo a P < 0.001 vs pbo b P < 0.05 vs aln -3 -2 0 1 2 3 4 5 6 Lewiecki EM et al. J Bone Miner Res. 2007 Dec;22(12):1832-41.

39. 1/3 Radius BMD Month -4 -3 -2 0 1 2 3 BL6121824 Distal 1/3 radius BMD percent change (%) Aln (a) Den 60 (a, b) Pbo a P < 0.05 vs pbo b P < 0.05 vs aln Lewiecki EM et al. J Bone Miner Res. 2007 Dec;22(12):1832-41.

40. Serum CTX Serum CTX percent change (%) (median) Month -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 BL D3 6 D3 121824 Alendronate 60 mg Placebo Lewiecki EM et al. J Bone Miner Res. 2007 Dec;22(12):1832-41.

41. Serum BSAP Month Bone-specific alkaline phosphatase percent change (%) (median) BL 6121824 Alendronate 60 mg Placebo -80 -70 -60 -50 -40 -30 -20 -10 0 1020 Lewiecki EM et al. J Bone Miner Res. 2007 Dec;22(12):1832-41.

42. Medications Under Development Medications Currently Under Development or FDA Review: Medications Currently Under Development or FDA Review: New Estrogen Agonist/Antagonist Agents New Estrogen Agonist/Antagonist Agents Bazedoxifene (Wyeth) and CEE/Bazedoxifene combo Bazedoxifene (Wyeth) and CEE/Bazedoxifene combo Lasofoxifene (Pfizer) Lasofoxifene (Pfizer) Arzoxifene (Lilly) Arzoxifene (Lilly) New PTH Compounds: Cyclic 1- 31PTH (Zelos) New PTH Compounds: Cyclic 1- 31PTH (Zelos) New PTH Delivery Systems (Patch, Oral, Nasal) New PTH Delivery Systems (Patch, Oral, Nasal) Cathepsin K Inhibitor (Merck) Cathepsin K Inhibitor (Merck) PTH Receptor Antagonist (GSK) PTH Receptor Antagonist (GSK) Antisclerostin Antibody (Amgen) Antisclerostin Antibody (Amgen) Glucagon-Like Peptide Glucagon-Like Peptide

43. Summary Landmark Advances and Emerging Therapies New therapies are evolving New therapies are evolving Persistence must be considered Persistence must be considered All approved bisphosphonates are effective if they are taken All approved bisphosphonates are effective if they are taken Two landmark trials demonstrate zoledronic acid reduces vertebral and non-vertebral (including hip) fracture risk; and one study demonstrates mortality reduction Two landmark trials demonstrate zoledronic acid reduces vertebral and non-vertebral (including hip) fracture risk; and one study demonstrates mortality reduction

44. Summary Landmark Advances and Emerging Therapies Mononclonal antibodies are in late stage III development; initial studies promising Mononclonal antibodies are in late stage III development; initial studies promising New Estrogen Agonist/Antagonist Agents might have greater potency than current one (raloxifene) and might provide additional rationale for use New Estrogen Agonist/Antagonist Agents might have greater potency than current one (raloxifene) and might provide additional rationale for use