Controversies in Osteoporosis Management

Controversies in Osteoporosis Management 2018 Northwest Rheumatism Society Meeting Portland, OR April 28, 2018 Michael R. McClung, MD, FACP Director, Oregon Osteoporosis Center Portland, Oregon, USA Institute of Health and Ageing Australian Catholic University, Melbourne, Australia Conflict of Interest I am disclosing financial relationships as follows: Global Advisory Boards: Amgen, Radius Health Honorarium for speaking: Amgen, Radius Health Michael McClung, MD 2018 Learning Objectives Attendees at this lecture will a. appreciate the benefit:risk profile of long-term osteoporosis treatments b. understand when an osteoporosis drug holiday is appropriate c. review the circumstances where combination therapy is indicated 1

Osteoporosis Definition: A disorder due to bone loss that damages skeletal architecture, weakens the skeleton and predisposes a patient to fracture Several osteoporosis drugs effectively and quickly reduce fracture risk in patients with osteoporosis Osteoporosis is a chronic disease requiring prolonged treatment It is important to develop a strategy for long-term management ACP Guidelines 2017: Treat for only 5 years Images Courtesy of Drs. David Dempster & Roger Zebazi Black DM and Rosen CJ. N Engl J Med 2016; 374:254-62 Qaseem A et al. Ann Intern Med 2017;166:818-39 Osteoporosis Therapy ACP recommends that patients with osteoporosis be treated for 5 years without monitoring Recommendation 2: ACP recommends that clinicians treat osteoporotic women with pharmacologic therapy for 5 years. (Grade: weak recommendation; low-quality evidence) Recommendation 4: ACP recommends against bone density monitoring during the 5-year pharmacologic treatment period for osteoporosis in women. (Grade: weak recommendation; low quality evidence) Qaseem A et al. A Clinical Practice Guideline Update From the American College of Physicians. Ann Intern Med 2017;166:818-39 Case 70 year old woman was diagnosed with osteoporosis 1 year earlier, she had experienced a Colles fracture when she fell while hiking BMD T-score: lumbar spine -2.0; total hip -3.0; femoral neck -2.8 FRAX 2

Osteoporosis: Long-term Treatment Plan Raloxifene Bisphosphonate When concerned about hip fracture Teriparatide After 12-24 months Bisphosphonates and denosumab are the drugs considered for long-term treatment After 12-24 months Denosumab McClung M. Personal opinion, 2018 Osteoporosis Therapies OBJECTIVES 1,2 1. improve bone strength 2. reduce risk of fracture 3. prevent rapid bone loss (less commonly) BENEFITS 2,3 Bisphosphonates and denosumab 1. effective protection from fractures vertebral fracture by 50-70% hip fracture by 40-50% non-vertebral fracture by 20-25% 2. in general are well tolerated 3. in clinical trials, have a favorable safety profile 1. Seeman E et al. Bone 2004;17 Suppl 2:23S-29S 2. McClung M et al. Amer J Med 2013;126:13-20 3. Cummings SR, McClung MR et al. N Engl J Med 2009;361:756-65 Long-term Osteoporosis Therapy Bisphosphonates and denosumab Fracture protection begins within months of starting therapy continues with long-term therapy wanes when treatment is stopped Hanley DA, McClung MR, et al. Am J Med 2017;130:862.e1-862.e7 McClung MR et al. Am J Med 2013;126:13-20 Black DM et al. J Bone Miner Res 2015;30:934-44 Bone HG et al. Lancet Diabetes Endocrinol 2017 2017;5:513-23 3

Zoledronic Acid Onset of Fracture Protection Vertebral and hip fracture protection occurs within first year of therapy Radiographic vertebral fracture Hip fracture Zoledronic acid 1 Denosumab 2 1. Black DM et al. N Engl J Med. 2007;356:1809-22 2. Cummings SR, McClung MR et al. N Engl J Med 2009;361:756-65 Vertebral Fractures with Zoledronic Acid 15 Years 1-3 PBO ZOL P = <0.001 10.9% (310/2853) 70% (62, 76) Fracture protection persists with long term therapy % Patients 10 5 3.3% (92/2822) Years 4-6 3.0% (14/469) Years 7-9 4.4% (3/68) 0 Core study Extension study Morphometric Vertebral Fractures Black DM et al. N Engl J Med 2007;356:1809 22 Black DM et al. J Bone Miner Res 2012;27:243-54 Black DM et al. J Bone Miner Res 2015;30:934-44 Long-term Denosumab Therapy Vertebral and Non-vertebral Fractures Persistent reduction in fracture risk Bone HG et al. Lancet Diabetes Endocrinol 2017 2017;5:513-23 4

Osteoporosis Therapies Fracture protection begins within months of starting therapy persists with long-term therapy wanes when treatment is stopped even with bisphosphonates Cumulative Incidence of Fractures (%) 6 5 4 3 2 1 ALN 5 years Placebo 5 years Alendronate 10 years RR 55% P = 0.013 0 0 1 2 3 4 5 Years Since FIT Black DM et al. JAMA 2006;296:2927-38 Black DM, et al. N Engl J Med 2007;356:1809 22 5.4% 2.5% Long-term Osteoporosis Therapy Bisphosphonates and denosumab Fracture protection begins within months of starting therapy continues with long-term therapy wanes when treatment is stopped Long-term safety bisphosphonates: atypical femoral fracture incidence: ~1/1000 after 8-10 years of therapy denosumab over 10 years, no adverse events increased in frequency with long-term therapy Age-adjusted incidence of AFF per 100,000 pt-years In untreated patients: 0.3/100,000 patient-years 2 5 8-9.9 Years of bisphosphonate therapy Bone HG et al. Lancet Diabetes Endocrinol 2017 2017;5:513-23 Dell RM et al. J Bone Miner Res 2012;27:2544-50 Benefits vs Risks of Long-term Bisphosphonate Therapy Events per 1000 patients Clinical fractures prevented Hip fractures prevented Death prevented Atypical femoral fractures 2 5 8-10 Years of bisphosphonate therapy Modeled after data from Cummings SR et al. JAMA.998;280:2077 82 Dell RM et al. J Bone Miner Res 2012;27:2544-50 5

No adverse events increased in frequency with long-term therapy Denosumab: Long-term Safety Exposure-adjusted Subject Incidence of Adverse Events (Rates per 100 Subject-years) FREEDOM Years 1 3 Extension Years 1 7 Placebo (N = 3883) Cross-over Denosumab (N = 2206) Long-term Denosumab (N = 2343) All AEs 156.1 96.8 97.0 Infections 30.7 20.7 19.9 Malignancies 1.6 2.0 2.0 Eczema 0.6 0.9 0.9 Hypocalcemia < 0.1 < 0.1 < 0.1 Pancreatitis < 0.1 < 0.1 < 0.1 Serious AEs 10.4 10.1 10.3 Infections 1.3 1.4 1.5 Cellulitis or erysipelas < 0.1 < 0.1 < 0.1 Fatal AEs 0.8 0.8 0.8 Osteonecrosis of the jaw 0 < 0.1 < 0.1 Atypical femoral fracture 0 < 0.1 < 0.1 N = number of subjects who received 1 dose of investigational product. Treatment groups are based on the original randomized treatments received in FREEDOM. AEs coded using MedDRA v13.0. Cumulative osteonecrosis of the jaw cases: 6 cross-over, 7 long-term. Cumulative atypical femoral fracture cases: 1 cross-over, 1 long-term. Bone HG et al. Lancet Diabetes Endocrinol 2017 2017;5:513-23 Case 70 year old woman was diagnosed with osteoporosis 1 year earlier, she had experienced a Colles fracture when she fell while hiking BMD T-score: lumbar spine -2.0; total hip -3.0; femoral neck -2.8 Began alendronate weekly which she tolerated well and took regularly After 5 years of therapy, she had not experienced additional fractures. Repeat BMD T-scores: lumbar spine -1.5; total hip -2.6; femoral neck -2.5 Adherence is good, No secondary causes identified OPTIONS bisphosphonate holiday continue alendronate switch to zoledronic acid switch to denosumab switch to teriparatide Bisphosphonate Drug Holiday Justification Protection from fragility fracture persists 1-2 years upon stopping therapy Risk of atypical fracture may decrease when treatment stopped After 3-5 years of therapy: Patients at moderate fracture risk: consider a holiday Patients at high risk (low BMD, prior vertebral fracture, elderly): continue to treat and follow to 10 years Whitaker et al. N Engl J Med 2012;366:2048-51 NOTE: No justification for drug holiday with any other osteoporosis drug 6

High risk History of spine or hip fracture or multiple other fragility fractures Hip BMD T-score -2.5 Low risk Adler R et al. J Bone Miner Res 2016; 31:16 35 Bisphosphonate Drug Holiday An opportunity not a necessity and not mandatory There is no rule that therapy must be stopped after any interval of time That decision has to be made on a case-by-case basis In my opinion, she would not be a candidate for a Bisphosphonate Holiday McClung M. Personal opinion, 2018 7

Switching From Bisphosphonates to Denosumab Total Hip Percent Change From Baseline 4.0% 3.0% 2.0% 1.0% 0.0% Patients who had previously been treated with bisphosphonates randomly assigned to a bisphosphonate or denosumab. 1.4%** 1.6%* 0.9%*** 1.3%* RIS IBN Data are least-squares means and 95% confidence intervals. p values, denosumab vs BP. *< 0.0001; **<0.01; ***<0.01. (1) Roux C et al. Bone 2014;58:48-54. (2) Recknor C et al. Obstet Gynec 2013;121:1291-9. (3) Kendler DL et al. J Bone Miner Res. 2010;25:72-81. (4) Miller PD et al. J Clin Endo Metab. 2016;101:3163-70. ALN ZOL 0.5% 0.9% 1.1% 0.6% 2.0% 2.2% 1.9% 1.9% vs RIS (1) vs IBN (2) vs ALN (3) vs ZOL (4) Relationship Between On-Treatment Total Hip BMD T-score and Non-vertebral Fracture Risk Incidence of non-vertebral fracture at 1 year (%) 6.0 5.0 4.0 3.0 2.0 Treating to a BMD target may now be feasible Current non-vertebral fracture risk was strongly correlated with on target hip BMD 1.0-3.0-2.5-2.0-1.5-1.0-0.5 Total Hip T-score Ferrari S et al. ASBMR; Seattle, WA; October 2015 Osteoporosis: Long-term Treatment Plan Raloxifene Bisphosphonate When concerned about hip fracture 3-5 years After 12-24 months Teriparatide Low risk High risk Re-treat Consider drug holiday Continue therapy? After 12-24 months Denosumab Denosumab McClung M. Personal opinion, 2018 Lewiecki EM, McClung MR, et al. J Clin Densitom 2018;21:3-22 8

Combining Osteoporosis Drugs There in no role for combining anti-remodeling agents Combining teriparatide with bisphosphonates: no benefit on BMD denosumab: faster, greater increases in BMD; no fracture data Denosumab fully inhibits the increased resorptive response to teriparatide and substantially blunts the anabolic response Tsai JN et al. Lancet 2013;382:50-6 New Anabolic Therapies: Phase 3 Study Designs ACTIVE - abaloparatide Placebo Alendronate Abaloparatide Alendronate 18 36 Months Miller PD et al. JAMA. 2016;316:722-33 Cosman F et al. Mayo Clin Proc. 2017;92:200-10 FRAME - romosozumab Placebo Denosumab Romosozumab Denosumab 12 24 Months Cosman F et al. N Engl J Med. 2016;375:1532-43 ARCH - romosozumab Alendronate Alendronate Romosozumab Alendronate 12 24 Months Saag K et al. N Engl J Med. 2017;377:1417-27 Sclerostin Inhibitor: Romosozumab Phase 3: FRAME: Vertebral Fracture Risk Reduction Year 1 Year 2 ClinicalTrials.gov Identifier: NCT01575834 Romosozumab Placebo All patients on denosumab 60 mg Q6M Fracture protection sustained during 12 months of denosumab therapy Year 2: N=25 Year 2: N=5 Placebo Romosozumab Placebo Romosozumab Cosman F et al. N Engl J Med 2016;375:1532-43 9

Sclerostin Inhibitor: Romosozumab Phase 3: ARCH: Vertebral Fracture Risk Reduction Saag K et al. N Engl J Med. 2017;377:1417-27 Sclerostin Inhibitor: Romosozumab Phase 3: ARCH: Fracture Risk Reduction Saag K et al. N Engl J Med. 2017;377:1417-27 Controversies in Osteoporosis Summary Osteoporosis is a chronic, incurable medical problem deserving long-term management Even with bisphosphonates, the benefit:risk profile is favorable for at least 1- years in patients at high fracture risk A bisphosphonate holiday may be considered after 3-5 years for patients at low risk of fracture For continuing therapy after 3-5 years of bisphosphonates, switching to denosumab rather than continuing bisphosphonate should be considered If denosumab therapy is discontinued, switching to another antiremodeling agent needs to be considered There is currently no role for the use of more than one osteoporosis drug at a time 10

Thank You Michael R. McClung, MD, FACP Director, Oregon Osteoporosis Center Portland, Oregon, USA Institute of Health and Ageing Australian Catholic University, Melbourne, Australia mmcclung,ooc@gmail.com 11