Long-term Osteoporosis Therapy What To Do After 5 Years? Developing - PowerPoint PPT Presentation

Long-term Osteoporosis Therapy What To Do After 5 Years? Developing a Long-term Management Plan North American Menopause Society Philadelphia, PA October 11, 2017 Michael R. McClung, MD, FACP Institute for Health and Ageing, Australian Catholic University, Melbourne, Australia Oregon Osteoporosis Center Portland, Oregon, USA OOC OOC mmcclung.ooc@gmail.com

Disclosures I am disclosing financial relationships as follows: Scientific Advisory Boards: Amgen, Radius Honorarium for speaking: Amgen, Radius Michael McClung, MD 2017 OOC OOC

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 Several osteoporosis drugs effectively and Several osteoporosis drugs effectively and Several osteoporosis drugs effectively and • • quickly reduce fracture risk in patients with quickly reduce fracture risk in patients with Images Courtesy of osteoporosis osteoporosis Drs. David Dempster & Roger Zebazi Osteoporosis is a chronic disease requiring Osteoporosis is a chronic disease requiring • prolonged treatment prolonged treatment It is important to develop a strategy for long It is important to develop a strategy for long- • term management term management OOC OOC Black DM and Rosen CJ. N Engl J Med 2016; 374:254-62

Osteoporosis Therapies OBJECTIVES 1,2 1,2 OBJECTIVES improve bone strength improve bone strength 1. 1. reduce risk of reduce risk of fracture fracture 2. 2. prevent rapid bone loss (less commonly) prevent rapid bone loss (less commonly) 3. 3. BENEFITS 2 BENEFITS effective protection from fractures effective protection from fractures 1. 1. vertebral fracture by 60 vertebral fracture by 60-70% 70% hip fracture by 40-50% hip fracture by 40 50% non non-vertebral fracture by 20 vertebral fracture by 20-35% 35% in general are well tolerated in general are well tolerated 2. 2. in clinical trials, have in clinical trials, have a favorable safety profile a favorable safety profile 3. 3. 1. 1. Seeman Seeman E et al. Bone 2004;17 E et al. Bone 2004;17 Suppl Suppl 2:23S 2:23S-29S 29S OOC OOC 2. McClung M et al. 2. McClung M et al. Amer Amer J Med J Med . 2013;126:13 . 2013;126:13-20 20

Long-term Osteoporosis Therapy Bisphosphonates and denosumab are the agents considered Bisphosphonates and denosumab are the agents considered for long for long-term use term use Fracture Fracture protection protection begins within months of starting therapy begins within months of starting therapy • continues with long-term therapy continues with long continues with long continues with long-term therapy term therapy term therapy • wanes when treatment is wanes when treatment is stopped stopped • Long Long-term safety term safety bisphosphonates: atypical femoral fracture bisphosphonates: atypical femoral fracture • incidence: 1/1000 after 8 incidence: 1/1000 after 8-10 years of therapy 10 years of therapy denosumab denosumab • over 10 years, no adverse events increased in frequency with over 10 years, no adverse events increased in frequency with long long-term therapy term therapy 1. 1. Hanley DA, McClung MR, et al. Am J Med Hanley DA, McClung MR, et al. Am J Med 2017;130:862.e1 2017;130:862.e1-862.e7 862.e7 McClung MR et al. McClung MR et al. Am J Med Am J Med 2013;126:13 2013;126:13-20 20 OOC OOC Bone Bone HG et al. HG et al. Lancet Diabetes Lancet Diabetes Endocrinol Endocrinol 2017 2017;5:513 2017 2017;5:513-23 23

Vertebral Fractures with Zoledronic Acid Years 1-3 PBO ZOL 15 P = <0.001 70%† Fracture protection persists with 10.9% (62, 76) (310/2853) long term therapy 10 ients % Patient Years 4-6 Years 7-9 4.4% 5 3.3% (3/68) 3.0% (92/2822) (14/469) 0 Core study Extension study Morphometric Vertebral Fractures Black DM et al. N Engl J Med 2007;356:1809–22 OOC OOC 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 OOC OOC Bone Bone HG et al. HG et al. Lancet Diabetes Lancet Diabetes Endocrinol Endocrinol 2017 2017;5:513 2017 2017;5:513-23 23

Risks and Concerns with Long-term Therapy Bisphosphonates Hypocalcemia • Intolerance • upper GI symptoms: oral drugs • No increase with long-term acute phase reaction: IV drugs therapy • bone and muscle pain bone and muscle pain • • Inflammatory eye problems • Unproven relationship; Atrial fibrillation • minimal evidence of Esophageal cancer: oral drugs • increased risk with long-term Osteonecrosis of the jaw therapy • Concern here of risk of Atypical fractures • long-term therapy 1/1000 patients after 8-10 years • OOC OOC

Atypical Femoral Fracture and Long-term Bisphosphonate Therapy 120 11,466 patients with femoral fracture d incidence of In untreated patients: ,000 pt-years 100 7430 typical hip fracture 0.3/100,000 patient-years 142 atypical stress-type fractures 80 10%occurres in untreated patients Age-adjusted i AFF per 100,0 60 60 Duration-dependent risk of AFF: 40 1.78/100,000 patient-years in first 2 yr 113/100,000 patient-years in years 8-9.9 20 0 2 5 8-9.9 Rapid decrease in risk when treatment is stopped Years of Schilcher J et al.N Engl J Med. 2014;371:974-6 bisphosphonate therapy R Dell: personal communication Dell RM et al. J Bone Miner Res . 2012;27:2544-50 OOC OOC

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 Cross-over Denosumab Long-term Denosumab (N = 3883) (N = 2206) (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 OOC OOC atypical femoral fracture cases: 1 cross-over, 1 long-term. Bone Bone HG et al. HG et al. Lancet Diabetes Lancet Diabetes Endocrinol Endocrinol 2017 2017;5:513 2017 2017;5:513-23 23

Osteoporosis Therapies Fracture protection Fracture protection begins within months of starting therapy begins within months of starting therapy • persists with long-term therapy persists with long term therapy • wanes when treatment is stopped wanes when treatment is stopped • – even with bisphosphonates – even with bisphosphonates even with bisphosphonates even with bisphosphonates OOC OOC

Vertebral Fractures with Zoledronic Acid Absolute risk of new vertebral fracture if PBO ZOL therapy is stopped = 1%/year 15 P = <0.001 No difference in incidence of non- 70%† 10.9% vertebral fractures (62, 76) (310/2853) Z3P3 Z6 10 ients P = 0.0348 52%* 52%* % Patient (10, 74) (10, 74) 6.2% (30/486) 5 3.3% 3.0% (92/2822) (14/469) 0 Core study 1 Extension study Morphometric Vertebral Fractures OOC OOC Black DM, et al. N Engl J Med . 2007;356:1809–22

Clinical Vertebral Fractures in FLEX Study 6 ative Incidence 5.4% ALN 5 years � � Placebo 5 years � � 5 ractures (%) Alendronate 10 years 4 RR � � � � 55% P = 0.013 3 2.5% 2.5% of Fra Cumulat 2 1 0 0 1 2 3 4 5 Years Since FIT ALN/PLB 437 436 425 412 398 387 ALN/ALN 662 660 646 631 615 597 OOC OOC Black DM et al. JAMA. 2006;296:2927-38

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 OOC OOC

High risk Low risk OOC OOC 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 OOC OOC McClung M. Personal opinion, 2017

Denosumab Drug Holiday? OOC OOC