Current Issues in Osteoporosis

Current Issues in Osteoporosis California AACE 18TH Annual Meeting & Symposium Marina del Rey, CA September 15, 2018 Michael R. McClung, MD, FACP,FACE 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: Alexion, Amgen, Radius Health Michael McClung, MD 2018

Learning Objectives At the end of this presentation attendees will be familiar with the updated AACE Guidelines for osteoporosis understand when "drug holidays" are appropriate appreciate the effects of different sequences of osteoporosis drugs

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 Images Courtesy of Drs. David Dempster & Roger Zebazi It is important to develop a strategy for long-term management Black DM and Rosen CJ. N Engl J Med 2016; 374:254-62 Qaseem A et al. Ann Intern Med 2017;166:818-39

AACE Osteoporosis Treatment Guidelines - 2016 Who Needs Pharmacologic Therapy? Patients with osteopenia or low bone mass and a history of fragility fracture of the hip or spine BMD T-score of 2.5 or lower in the spine, femoral neck, total hip or 33% radius patients with a T-score between 1.0 and 2.5 if the FRAX 10-year probability for major osteoporotic fracture is 20% or the 10-year probability of hip frac-ture is 3% in the U.S. or above the country-specific threshold in other countries or regions Camacho PM et al. Endocr Pract. 2016;22(Suppl 4):1-42

AACE Osteoporosis Treatment Guidelines - 2016 No prior fragility fractures or moderate fracture risk Alendronate, denosumab, risedronate, zoledronic acid Alternative: raloxifene Prior fragility fractures or indicators of higher fracture risk Denosumab, teriparatide, zoledronic acid Alternatives: alendronate, risedronate Camacho PM et al. Endocr Pract. 2016;22(Suppl 4):1-42

Osteoporosis: Long-term Treatment Plan Raloxifene Bisphosphonate When concerned about hip fracture Teriparatide Abaloparatide Denosumab After 18-24 months patients at high risk for vertebral fracture After 18-24 months

Osteoporosis: Long-term Treatment Plan Raloxifene Bisphosphonate When concerned about hip fracture Teriparatide Abaloparatide After 18-24 months patients at high risk for vertebral fracture After 18-24 months Bisphosphonates and denosumab are the drugs considered for long-term treatment Denosumab

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

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

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

Age-adjusted incidence of AFF per 100,000 pt-years Long-term Bisphosphonate Therapy Fracture risk reduction begins within 12-24 months of beginning treatment Fracture protection persists - but does not improve with long-term therapy (Patients do not become resistant to bisphosphonates) In untreated patients: 0.3/100,000 patient-years Risk of atypical fracture increases with long-term use, especially after 5 years. Risk after 10 years is about 1:1000 patients 2 5 8-9.9 Years of bisphosphonate therapy McClung MR et al. Am J Med 2013;126:13-20 Dell RM et al. J Bone Miner Res 2012;27:2544-50

Cumulative Incidence of Fractures (%) Bisphosphonate Drug Holiday Justification Protection from fragility fracture persists 1-2 years upon stopping therapy Risk of atypical fracture may decrease when treatment stopped 6 5 4 3 2 ALN 5 years Placebo 5 years Alendronate 10 years RR 55% P = 0.013 5.4% 2.5% 1 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 Schilcher J et al. N Engl J Med 2014;371:974-6

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

AACE Osteoporosis Treatment Guidelines - 2016 Bisphosphonate Holiday R34a. For oral bisphosphonates, consider a bisphosphonate holiday after 5 years of stability in moderate-risk patients (Grade B; BEL 1, downgraded due to limitations of data). R34b. For oral bisphosphonates, consider a bisphosphonate holiday after 6 to 10 years of stability in higher-risk patients (Grade B; BEL 1, downgraded due to limitations of data). R34c. For intravenous (IV) zoledronic acid, consider a drug holiday after 3 annual doses in moderate-risk patients and after 6 annual doses in higher-risk patients. (Grade B, BEL 1, downgraded due to limitations of data). Camacho PM et al. Endocr Pract. 2016;22(Suppl 4):1-42

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

Osteoporosis: Long-term Treatment Plan Raloxifene Re-treat Bisphosphonate Teriparatide Abaloparatide Denosumab When concerned about hip fracture 3-5 years After 18-24 months patients at high risk for vertebral fracture After 18-24 months Low risk High risk Denosumab Consider drug holiday Continue therapy

Percentage Change From Baseline Longterm Bisphosphonate Therapy Hip BMD values plateau after 3-5 years of therapy with bisphosphonates Fracture risk reduction persists but does not improve with longterm bisphosphonate therapy 8 6 4 Long-term Total Hip Denosumab BMD 6.8% Alendronate 10 mg/d 1 4.6% Zoledronic acid 5 mg/y 2 2 0 0 1 2 3 4 5 6 7 8 9 10 Study Year 1. Bone HG et al. New Engl J Med 2004; 350:1189-99 2. Black DM et al. J Bone Miner Res 2015;30:934-44

Percentage Change From Baseline Yearly Incidence of Nonvertebral Fractures (%) Denosumab: Hip BMD and Nonvertebral Fractures Through 10 Years 10 9 8 7 6 5 4 3 2 1 0 FREEDOM a a a a a a a a Total Hip b b b b Extension b b b b 9.2% c b 7.4% c b 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 3.1 FREEDOM 2.6 Placebo 2.9 2.5 2.1 2.2 1.5 Long-term Denosumab 1.2 Extension 1.8 1.6 0.8 1.1 1.9-1 a 0.0-2 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Years of Denosumab Treatment Study Year Bone HG et al. Lancet Diabetes Endocrinol 2017;5:513-23

Total Hip Percent Change From Baseline Switching From Bisphosphonates to Denosumab 4.0% 3.0% Patients who had previously been treated with bisphosphonates randomly assigned to a bisphosphonate or denosumab. 1.6%* 1.4%** 0.9%*** 1.3%* 2.0% 1.0% RIS IBN ALN ZOL 0.0% 0.5% 2.0% 0.9% 2.2% 1.1% 1.9% 0.6% 1.9% vs RIS (1) vs IBN (2) vs ALN (3) vs ZOL (4) 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.

Denosumab: How Long to Treat Efficacy persists or improves over 10 years of therapy No major safety concerns with longterm therapy 2 cases met criteria for AFF in FREEDOM Extension study with >100,000 patient-years of follow-up Bone remodeling quickly returns to or above baseline and rapid loss of BMD occurs when therapy is stopped Protection from vertebral fractures is lost within a few months of discontinuing denosumab and multiple vertebral fractures have been reported within 3-18 months of stopping therapy McClung M. Personal opinion, 2018

Vertebral Fractures After Discontinuing Denosumab or Placebo in FREEDOM Study Vertebral fracture risk was assessed in patients who discontinued either placebo or denosumab in the FREEDOM study or who stopped denosumab in the FREEDOM Extension study and who had a follow-up at least 7 months after their last dose Fracture risk increased upon stopping denosumab but not to levels greater than seen in those who stopped placebo Vertebral fractures Multiple vertebral fractures Cummings SR et al. J Bone Miner Res 2018;33:190-8

Fracture Risk after Stopping Denosumab Protection from vertebral fractures is quickly lost upon stopping denosumab BUT There is no apparent excess or rebound in vertebral fracture risk upon stopping therapy McClung M. Personal opinion, 2018

There are very few reasons to consider stopping denosumab therapy If therapy is stopped after a year or more, consider options to prevent rapid bone loss and fracture risk McClung MR. Osteoporos Int. 2016;27:1677-82

Percent Change From Baseline Denosumab and Alendronate (DAPS Trial) Cross-over Treatment after 12 Months Switching from denosumab to alendronate, bone loss did not occur Denosumab Alendronate Lumbar spine Optimal timing of IV zoledronic acid after denosumab is not known. Total hip Giving IV zoledronic acid 6 months after last dose of denosumab does not prevent the rapid bone loss;. Months Freemantle N et al. Osteoporos Int. 2012;23:317-26

Osteoporosis: Long-term Treatment Plan Raloxifene Re-treat Bisphosphonate Teriparatide Abaloparatide When concerned about hip fracture 3-5 years After 18-24 months patients at high risk for vertebral fracture After 18-24 months Low risk High risk Consider drug holiday Continue therapy Denosumab Denosumab If target is met Bisphosphonate 2 years ALN 1 dose ZOL?

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 Abaloparatide FRAME - romosozumab Placebo Romosozumab ARCH - romosozumab Alendronate Romosozumab 18 36 Months Denosumab Denosumab 12 24 Months Alendronate Alendronate 12 24 Months Alendronate Alendronate Miller PD et al. JAMA. 2016;316:722-33 Cosman F et al. Mayo Clin Proc. 2017;92:200-10 Cosman F et al. N Engl J Med. 2016;375:1532-43 Saag K et al. N Engl J Med. 2017;377:1417-27

Abaloparatide Phase 3 Extension Study (ACTIVExtend) Fracture protection sustained during 6 months of alendronate therapy Placebo Abaloparatide Alendronate Alendronate 18 Months 36 Miller PD et al. JAMA. 2016;316:722-33 Cosman F et al. Mayo Clin Proc. 2017;92:200-10

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

Sclerostin Inhibitor: Romosozumab Phase 3: ARCH: Vertebral Fracture Risk Reduction Romosozumab is more effective than alendronate Treatment advantage of romosozumab is amplified by switching to alendronate Number of vertebral fractures in Year 2 115 45 61% Saag K et al. N Engl J Med. 2017;377:1417-27

Sclerostin Inhibitor: Romosozumab Phase 3: ARCH: Fracture Risk Reduction Unexpected small risk in stroke noted vs alendronate but not vs placebo. This drug is currently under regulatory review at FDA and in Europe. Saag K et al. N Engl J Med. 2017;377:1417-27

VERO Study: Teriparatide vs Risedronate 1366 women with postmenopausal osteoporosis randomly assigned to receive risedronate 35 mg po weekly or teriparatide 20 ugm daily SQ Vertebral and clinical fractures were prevented to a greater extent and earlier (evident by 12 months) with teriparatide vs risedronate Kendler D et al. N Engl J Med 2017;377:1417-27

Osteoporosis: Treatment Plan Re-treat Bisphosphonate Anabolic agent for high risk patient After 12-24 months After 12-24 months 3-5 years Low risk High risk Consider drug holiday Continue therapy? Denosumab Denosumab If treatment is stopped, consider a bisphosphonate McClung M. Personal opinion, 2018

Issues 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 10 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

Issues in Osteoporosis Summary 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 We now have evidence to support beginning therapy with an anabolic agent in patients at high or imminent risk of fracture

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