1 Effect of Hormone Therapy: Estrogen Discontinuation EPIC study - PDF document

Individualizing Osteoporosis Therapy Disclosures I am disclosing financial relationships as follows: 2019 NAMS Annual Meeting Scientific Advisory Boards: Amgen, Myovant Honorarium for speaking: Amgen Chicago, IL September 26, 2019 Michael McClung, MD 2019 Michael R. McClung, MD, FACP, FASBMR Oregon Osteoporosis Center Portland, Oregon, USA Mary MacKillop Institute for Health Research Australian Catholic University, Melbourne, VIC OOC OOC mmcclung.ooc@gmail.com Osteoporosis Case 1 Definition: • Healthy 65 year old woman Lumbar Total Femoral Age spine hip neck A disorder due to bone loss that damages • menopause at age 51 skeletal architecture, weakens the skeleton 55 -2.1 -1.6 -1.5 • age 55: hot flashes persist and predisposes a patient to fracture 60 -1.4 -1.2 -1.0 • weight 118 # ; BMI 21.6; BMD • 65 -1.5 -1.1 -1.1 Several osteoporosis drugs effectively and • began transdermal estradiol and micronized progesterone quickly reduce fracture risk in patients with Images Courtesy of osteoporosis • hot flashes abated • Management choices: Drs. David Dempster & Roger Zebazi • • age 65: insurance plan and PCP • discontinue estrogen Osteoporosis is a chronic disease requiring recommend stopping estrogen prolonged treatment • continue estrogen • no CV or fracture risk factors • • discontinue estrogen and It is important to develop a strategy for long- begin raloxifene term management • discontinue estrogen and begin alendronate OOC OOC Black DM and Rosen CJ. N Engl J Med 2016; 374:254-62 1

Effect of Hormone Therapy: Estrogen Discontinuation – EPIC study Fractures in WHI EPIC Prevention Trial--women between ages 45-59 Treated for 4 years; followed for 2 more years CEE-MPA Treatment (N=8506) Placebo (N=8102) CEE-MPA Post-treatment (N-8052) PBO Post-treatment (N=7678) Hormone Therapy/Placebo Lumbar spine BMD Total hip BMD Placebo 9 6 Mean Percent Change Mean Percent Change 24% Annualized rates - % 2 6 4 from Baseline from Baseline 2 3 1.5 0 0 1 -3 -2 -4 -6 0 1 2 3 4 5 6 0.5 0 1 2 3 4 5 6 34% 33% Years Years 0 Hip Vertebral Other fracture fracture fractures OOC Wasnich RD, McClung M et al, Menopause 2004;11:622-30 OOC Heiss G et al. JAMA 2008;299:1036-45 Effect of Withdrawing Hormone Therapy: Effect of Withdrawing Hormone Therapy: Fractures in WHI Fractures in WHI Cumulative hazard ratio of total fractures in WHI study participants CEE-MPA Treatment (N=8506) Placebo (N=8102) followed for 5 years after stopping hormone therapy or placebo CEE-MPA Post-treatment (N-8052) PBO Post-treatment (N=7678) Loss of fracture protection during first 2 years off hormone therapy but no excess fracture risk after stopping estrogen CEE-MPA Arm CEE Alone Arm Annualized rates - % 2 1.5 Small (15%) residual benefit to prior therapy observed 1 0.5 N=10,134 N=5053 0 Hip Vertebral Other fracture fracture fractures Watts NB et al, J Clin Endocrinol Metab 2017;102:302–8 OOC OOC Heiss G et al. JAMA 2008;299:1036-45 2

Preventing Bone Loss When Case 1 Estrogen is Stopped Lumbar spine BMD • Healthy 65 year old woman 3 Lumbar Total Femoral % Change from Baseline + SE Age • menopause at age 51 spine hip neck 2.3%* 55 -2.1 -1.6 -1.5 124 PM women who discontinued 2 • age 55: hot flashes persist HT or ET within 6 months Alendronate 70 mg once weekly randomized (1:1) to: 60 -1.4 -1.2 -1.0 • weight 118 # ; BMI 21.6; BMD 1 65 -1.5 -1.1 -1.1 ALN 70 mg once weekly • began transdermal estradiol - or - 0 and micronized progesterone RLX 60 mg once daily • Management choices: Raloxifene 60 mg daily • hot flashes abated -1 • discontinue estrogen Double dummy PBO -1.4%* • age 65: insurance plan and PCP Calcium 1000 mg and vitamin D • continue estrogen 400 IU daily -2 recommend stopping estrogen Baseline 6 months 12 months` • discontinue estrogen and • no CV or fracture risk factors begin raloxifene Between group difference at 12 months • discontinue estrogen and Mean 3.5% (95% CI 2.6, 4.4) p<0.001 begin alendronate McClung MR, Watts NB et al, J Bone Miner Res 2005;20:S397 OOC OOC Case 1 Case 1 – Key Points • Healthy 65 year old woman • Estrogen therapy prevents bone loss in almost all postmenopausal Lumbar Total Femoral Age women spine hip neck • menopause at age 51 55 -2.1 -1.6 -1.5 • In my opinion, estrogen should be considered to prevent bone loss in early • age 55: hot flashes persist postmenopausal women at risk for osteoporosis, even without menopausal 60 -1.4 -1.2 -1.0 symptoms • weight 118 # ; BMI 21.6; BMD 65 -1.5 -1.1 -1.1 • low peak BMD, thin, family history, history of fracture • began transdermal estradiol and micronized progesterone • Discontinuation of estrogen results in loss of skeletal benefit (BMD • Management choices: and fracture protection) very quickly - within one year • hot flashes abated • discontinue estrogen • Bisphosphonates but not raloxifene prevent the loss of BMD upon • age 65: insurance plan and PCP • continue estrogen stopping estrogen recommend stopping estrogen • discontinue estrogen and • no CV or fracture risk factors begin raloxifene • If/when estrogen is stopped, think of skeletal consequences and • discontinue estrogen and consider switching to a bisphosphonate in patients at risk begin alendronate OOC OOC 3

Case 2 Criteria for Bisphosphonate “Holiday” • Healthy 73 year old woman • After 3-5 years of therapy Lumbar Total Femoral Age • menopause at age 52 spine hip neck • Continue a treatment if patient still 68 -2.6 -2.9 -2.5 meets criteria for therapy • age 62: wrist fracture • age 68: humerus fracture; BMD 70 -2.1 -2.7 -2.4 • History of hip or spine fracture or multiple other fragility fractures • begun on alendronate; well tolerated 73 -1.9 -2.6 -2.5 • BMD consistent with osteoporosis • age 73: BMD • Other risk factors resulting in high fracture risk • Management choices: • discontinue alendronate therapy • For patients not meeting these • continue alendronate therapy criteria, consider a bisphosphonate • switch to IV zoledronic acid holiday • switch to denosumab • switch to a bone-building agent OOC OOC Adler R et al. J Bone Miner Res 2016; 31:16–35 Fractures with Long-term Zoledronate Transition from Alendronate to Zoledronate Fracture protection persists but does not improve with long term therapy Postmenopausal women with PBO ZOL P = <0.001 Alendronate 15 15 osteoporosis who received 25% 12.2% Zoledronate P = <0.001 (12, 36) (10/95) alendronate for at least 12 10.9% 10.7% 2 70% (310/2853) months (mean 36 months) (388/3875) (62, 76) % change from baseline 10 8.0% 82% Lumbar spine BMD 10 % Patients Randomly assigned to (292/3861) (45/616) 1 continue alendronate or to zoledronate 5 mg IV 4.4% 0 5 5 3.3% (3/68) 3.0% Baseline Month 12 (92/2822) (14/469) -1 In the absence of non-compliance 0 or malabsorption, there appears to -2 Years 1-3 4-6 7-9 Years 1-3 4-6 7-9 be no BMD advantage to switching Core study Extension study Core study Extension study Morphometric Vertebral Fractures Non-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 McClung M et al. Bone 2007;41:122–28 Black DM et al. J Bone Miner Res 2015;30:934-44 4

Effects of Long-term Therapy on Total Hip BMD Effects of Long-term Therapy on Total Hip BMD Percentage Change From Baseline Percentage Change From Baseline FREEDOM Extension 10 FREEDOM Extension 10 - 9.2% Long-term Denosumab Long-term Denosumab 8 - 8 Denosumab 2 Progressive increase with 6 - 6 denosumab vs plateau 4.6% 4.6% after 5 years with 4 - 4 bisphosphonates Zoledronate 5 mg/y 1 Zoledronate 5 mg/y 1 2 - 2 0 - 0 -2 - -2 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Study Year Study Year 1. Black DM et al. J Bone Miner Res 2015;30:934-44 1. Black DM et al. J Bone Miner Res 2015;30:934-44 OOC OOC 2. Bone HG et al. Lancet Diabetes Endocrinol 2017 2017;5:513-23 Switching From Bisphosphonates to Denosumab Teriparatide After Bisphosphonate Therapy 245 women treatment-naïve or previously treated with antiresorptive Patients who had previously been treated with bisphosphonates drugs began teriparatide therapy for 24 months (EUROFORS) randomly assigned to a bisphosphonate or denosumab. 4.0% Total Hip Percent Change From Baseline 1.4% * Denosumab Substantial increase in spine and hip BMD 1.6% * 0.9% * 1.3% * 3.0% % change in BMD from 10 Lumbar spine 8 2.0% baseline Total hip 6 ALN IBN ZOL 4 1.0% RIS 2 0.5% 2.0% 0.9% 2.2% 1.1% 1.9% 0.6% 1.9% 0.0% 0 1 2 3 Non- vs RIS vs IBN vs ALN vs ZOL Alendronate Risedronate bisphosphonate Data are least-squares means and 95% confidence intervals. * p < 0.0001 denosumab vs BP. OOC 1 Recknor C et al. ASBMR Poster FR0388. 2 Kendler DL et al. J Bone Miner Res . 2010;25:72-81. OOC Boonen S et al. J Clin Endocrinol Metab 2008;93:852–60 3 Miller PD et al. J Clin Endo Metab . 2016;101:3163-70. 5