2017 Santa Fe Bone Symposium McClung

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1 217 Santa Fe Bone Symposium Insights into the Use of Anti-remodeling and Anabolic Agents for Osteoporosis Developing a Long-term Management Plan Michael R., MD, FACP Oregon Osteoporosis Center Portland, Oregon Institute of Health and Ageing, Australian Catholic University, Melbourne mmcclung.ooc@gmail.com Disclosures I am disclosing financial relationships as follows: Scientific Advisory Boards: Amgen, Radius Honorarium for speaking: Amgen, Radius Michael, MD 217 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 longterm management Images Courtesy of Drs. David Dempster & Roger Zebazi Black DM and Rosen CJ. N Engl J Med 21; 374:24-2 1

2 217 Santa Fe Bone Symposium Objectives To review evidence of the benefits and risks of long-term therapy effects of discontinuing bisphosphonate and nonbisphosphonate therapies new information about efficacy of sequential therapy To consider a strategy for long-term management of patients with osteoporosis Osteoporosis Therapies OBJECTIVES 1,2 1. improve bone strength 2. reduce risk of fracture 3. prevent rapid bone loss (less commonly) BENEFITS 2 1. effective protection from fractures vertebral fracture by -7% hip fracture by 4-% non-vertebral fracture by 2-3% 2. in general are well tolerated 3. in clinical trials, have a favorable safety profile 1. Seeman E et al. Bone 24;17 Suppl 2:23S-29S 2. M et al. Amer J Med. 213;12:13-2 Osteoporosis Therapies 1. Fracture protection begins within months of starting therapy continues with long-term therapy wanes when treatment is stopped 2

3 Incidence at Month 3 (%) 217 Santa Fe Bone Symposium Zoledronic Acid and Denosumab Incidence of Vertebral Fracture Vertebral fracture protection happens within first year of treatment HORIZON Study 1 FREEDOM Study Denosumab RRR 1% P <.1 2.2%.9% -12 Months RRR 8% P <.1 RRR 71% P <.1.% 1.4% 7.2% 2.3% -24 Months -3 Months 1. Black DM et al. N Engl J Med. 27;3: Cummings SR et al. New Engl J Med. 29;31:7- Zoledronic Acid and Denosumab Cumulative Incidence of Hip Fracture Cumulative incidence of hip fracture HORIZON Study 1 FREEDOM Study 2 1. Black DM et al. N Engl J Med. 27;3: Cummings SR et al. New Engl J Med. 29;31:7- Osteoporosis Therapies 1. Fracture protection begins within months of starting therapy persists with long-term therapy wanes when treatment is stopped 3

4 Incidence per Year (%) % Patients 217 Santa Fe Bone Symposium Long Term Alendronate Therapy Stable fracture incidence MORPHOMETRIC VERTEBRAL FRACTURE NON-VERTEBRAL FRACTURE Years 1-3: group.2%; pooled alendronate group 3.2% (1.7%/year) Years -1: N=228.% in the alendronate 1 mg/day group (1.% per year) Bone HG et al, New Engl J Med 24;3: Long-term Risedronate Therapy: Vertebral Fracture Vertebral fracture protection persists but does not improve with long term therapy VERT-MN: Radiographic Vertebral Fracture 49% P <.1 9% P =.1 Subjects switched to risedronate mg at end of year 7.% 4.7% 12.3%.2% 3.8% 3.8% Years 1 3 Ris = risedronate. Years 4 Years 7 Mellstrom DD et al. Calcif Tissue Int 24;7:42 8 Vertebral Fractures with Zoledronic Acid Years PBO 1.9% (31/283) ZOL P = <.1 7% (2, 7) Fracture protection persists with long term therapy 1 3.3% (92/2822) Years 4-3.% (14/49) Years % (3/8) Core study Extension study Morphometric Vertebral Fractures Black DM et al. N Engl J Med 27;3: Black DM et al. J Bone Miner Res 212;27:243-4 Black DM et al. J Bone Miner Res 21;3:

5 % Patients Percentage Change From Baseline 217 Santa Fe Bone Symposium Clinical Fractures with Zoledronic Acid Years PBO 12.8% ZOL P = <.1 33% (23, 42) 8.4% Years 4-8.2% Years % Core study Extension study Black DM et al. N Engl J Med 27;3: Black DM et al. J Bone Miner Res 212;27:243-4 Black DM et al. J Bone Miner Res 21;3: Long-term Denosumab Therapy Vertebral and Non-vertebral Fractures Persistent reduction in fracture risk Bone HG et al. Lancet Diabetes Endocrinol 217 Published Online May 22, Effects of Therapy on Total Hip BMD Through 1 Years Total Hip BMD 1 FREEDOM Extension 9.2% 9 Long-term Denosumab Denosumab Study Year.8% Alendronate 1 mg/d 2 4.% Zoledronic acid mg/y Bone HG et al. Lancet Diabetes Endocrinol 217 Published Online May 22, Bone HG et al. New Engl J Med.24;3: Black DM et al. New Engl J Med 212;27:243-4

6 Total Hip Percent Change From Baseline Incidence of non-vertebral fracture at 1 year (%) 217 Santa Fe Bone Symposium Switching From Bisphosphonates to Denosumab 4.% Patients who had previously been treated with bisphosphonates randomly assigned to a bisphosphonate or denosumab. 3.% 1.%* 1.4%*.9%* 1.3%* 2.% 1.% RIS IBN ALN ZOL.%.%.9% 1.1%.% 2.% 2.2% 1.9% 1.9% vs RIS (1) vs IBN (2) vs ALN (3) vs ZOL (4) Data are least-squares means and 9% confidence intervals. *p <.1 denosumab vs BP. (1) Roux C et al. Bone. 214;8:48-4. (2) Recknor C et al. Obstet Gynec 213;121: (3) Kendler DL et al. J Bone Miner Res. 21;2: (4) Miller PD et al. J Clin Endo Metab. 21;11: FNIH Meta-regression Change in Total Hip BMD vs Reduction in Hip Fracture MORE (RAL) Clodronate R 2 =.2 HIP(RIS) FIT II(ALN) FREEDOM (DMAB) WHI HORIZON(ZOL) FIT I(ALN) *Bubble size ~ to n fractures in study Courtesy of Dr D Black et al, ASBMR 21 Relationship Between On-Treatment Total Hip BMD T-score and Non-vertebral Fracture Risk.. Treating to a BMD target may now be feasible Total Hip T-score Ferrari S et al. ASBMR; Seattle, WA; October 21

7 Cumulative Incidence of Fractures (%) 217 Santa Fe Bone Symposium Treat to Target: An Evolving Concept Osteoporosis Therapies 1. Fracture protection begins within months of starting therapy persists with long-term therapy wanes when treatment is stopped even with bisphosphonates Clinical Vertebral Fractures in FLEX Study ALN years years Alendronate 1 years RR % P =.13.4% 2.% Years Since FIT ALN/PLB ALN/ALN Black DM, et al. JAMA. 2;29:

8 Median ng/ml (Q1, Q3) Percent Change (LS Mean ± SE) % Patients Median mcg/l (Q1, Q3) 217 Santa Fe Bone Symposium Vertebral Fractures with Zoledronic Acid 1 1 PBO 1.9% (31/283) ZOL P = <.1 7% (2, 7) Absolute risk of new vertebral fracture if therapy is stopped = 1%/year Z3P3.2% (3/48) Z 2%* (1, 74) P = % (92/2822) 3.% (14/49) Core study 1 Extension study Morphometric Vertebral Fractures Black DM, et al. N Engl J Med. 27;3: Discontinuing Denosumab: BMD Phase 2 Study in Women With Low BMD 21 mg QM Open-label alendronate Lumbar Spine Months Discontinued Treatment Total Hip Discontinued Treatment Months Adapted from Miller PD, M et al. Bone 28;43: Discontinuing Denosumab: BMD Phase 2 Study in Women With Low BMD 21 mg QM Open-label alendronate Serum CTx Months Discontinued Treatment * * BSAP Months Discontinued Treatment *P <.1 at month 3 and =. at month 48 vs placebo. P =.8 at month 3 vs placebo. Adapted from Miller PD, M et al. Bone 28;43:

9 Percentage Change From Baseline Age-adjusted incidence of AFF per 1, pt-years 217 Santa Fe Bone Symposium Discontinuing Denosumab After 8 Years Lumbar Spine BMD Denosumab 21 mg QM Off-treatment Parent Study Extension Study All on DMAb Treatment 1.8% N = 2 N = 2 N = 1 8.1% Observation N = Study Month M et al. Osteoporos Int. 217;28: %.1% Osteoporosis Therapies: Safety of Long-term Therapy Atypical Femoral Fracture and Long-term Bisphosphonate Therapy 11,4 patients with femoral fracture 743 typical hip fracture 142 atypical stress-type fractures 1% occur in untreated patients Duration-dependent risk of AFF: 1.78/1, patient-years in first 2 yr 113/1, patient-years in years May be a decrease in risk if treatment is stopped R Dell: personal communication SchilcherJ et al. N Engl J Med. 214;371: In untreated patients:.3/1, patient-years Years of bisphosphonate therapy Dell RM et al. J Bone Miner Res. 212;27:244-9

10 217 Santa Fe Bone Symposium Denosumab: Long-term Safety Exposure-adjusted Subject Incidence of Adverse Events (Rates per 1 Subject-years) FREEDOM Years 1 3 Extension Years 1 7 (N = 3883) Cross-over Denosumab (N = 22) Long-term Denosumab (N = 2343) All AEs Infections Malignancies Eczema..9.9 Hypocalcemia <.1 <.1 <.1 Pancreatitis <.1 <.1 <.1 Serious AEs Infections Cellulitis or erysipelas <.1 <.1 <.1 Fatal AEs Osteonecrosis of the jaw <.1 <.1 Atypical femoral fracture <.1 <.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.. Cumulative osteonecrosis of the jaw cases: cross-over, 7 long-term. Cumulative atypical femoral fracture cases: 1 cross-over, 1 long-term. Adler R et al. J Bone Miner Res 21; 31:1 3 Bisphosphonate Drug Holiday An opportunity not a necessity Protection from fragility fracture persists 1-2 years upon stopping therapy Risk of atypical fracture may decrease when treatment stopped After 3- 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 1 years Whitaker et al. N Engl J Med 212;3:248-1 NOTE: No evidence that a drug holiday reduces risk of any complication of therapy 1

11 217 Santa Fe Bone Symposium Denosumab Drug Holiday? Vertebral Fractures After Discontinuing Denosumab Therapy At least 24 patients have been reported who experienced vertebral fractures within 3-18 months after discontinuing denosumab therapy. (1) Many or most have had multiple and/or severe fractures Raised concern about rebound risk of fracture Similar to rapid loss of fracture protection when estrogen therapy is discontinued (2,3) 1. Anastasilakis AD et al. J Bone Miner Res. 217 Feb Heiss G et al. JAMA 299: MR. Osteoporos Int. 21;27: Fracture Risk after Stopping Denosumab Subgroup of 797 subjects (47 placebo, 327 denosumab), who discontinued study drug in FREEDOM after 2- doses. During the off-treatment period (median.8 years per subject), 42% versus 28% of placebo- and denosumab-treated subjects, respectively, initiated other therapy. Following discontinuation, similar percentages of subjects in both groups sustained a new fracture (9% placebo, 7% denosumab) Fracture rate per 1 subject-years of 13. for placebo and 9.7 for denosumab Hazard ratio [HR].82; 9% confidence interval [CI], , adjusted for age and total hip BMD T-score at baseline. There was no apparent difference in fracture occurrence pattern between the groups during the off-treatment period. Brown J.P et al. J Bone Miner Res 213;28:74-2 Vertebral Fractures After Discontinuing Denosumab or 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 Brown JP et al. ASBMR Abstract #11, 21 11

12 Percent Change From Baseline 217 Santa Fe Bone Symposium 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 M. Personal opinion, 217 Discontinuing Denosumab Other Information Bone loss and rise in serum CTX is attenuated in patients who stop denosumab but who took bisphosphonates before denosumab therapy. Ferrari S et al. ECTS 21 Bone loss after stopping denosumab is attenuated in patients who then receive anti-remodeling agents M et al. Osteoporos Int. 217;28: Denosumab and Alendronate (DAPS Trial) Cross-over Treatment after 12 Months Switching from denosumab to alendronate, bone loss did not occur 8 Denosumab Alendronate Lumbar spine 4 2 Total hip Months Freemantle N et al. Osteoporos Int. 212;23:

13 217 Santa Fe Bone Symposium Discontinuing Denosumab Change in Prescribing Information A new caution has been added to denosumab label: Multiple vertebral fractures have been reported following Prolia discontinuation. Consider transitioning to another antiresorptive agent if Prolia is discontinued. Long-term Denosumab Therapy Summary There are very few reasons to consider stopping denosumab therapy intolerance or side effect reaching a treatment target If therapy is stopped after a year or more, consider options to prevent rapid bone loss and fracture risk At present, the most appealing strategy would be to treat with weekly alendronate for 2 years and to then re-evaluate the patient. (1) IV zoledronic acid may not be effective (2) 1. MR. Cancel the denosumab holiday. Osteoporos Int. 21;27: Reid IR et al. Calcif Tissue Int. 217May y 13. doi: 1.17/s x. [Epub ahead of print] Zoledronic Acid after Denosumab patients had received denosumab for 7 years. One IV dose of zoledronic acid administered months after the last dose of denosumab. BMD repeated months later. Reid IR et al. Calcif Tiss Int 217;E-pub May 13 13

14 % Change from Baseline Lumbar spine BMD % Change from Baseline Mean (SE) % Change from Baseline 217 Santa Fe Bone Symposium New Insights Into Sequential Therapy Anabolic therapy followed by a potent anti-remodeling agent Alendronate Therapy after PTH 1-84 Alendronate increases BMD after stopping teriparatide PTH 1-84 Alendronate About subjects in each treatment group % 8% Year 1 Year 2 PTH Alendronate Alendronate Alendronate 4 2 4% PTH Baseline Year 1 Year 2 Black, D. M. et al. N Engl J Med 2;33:- Teriparatide after Denosumab DATA Switch Trial Teriparatide followed by denosumab results in progressive gain in BMD 12 9 Total Hip 24 Mo 48 Mo Lumbar Spine BMD DMab 18.3% T to D 1 TPTD 3 1/3 Radius Months -3 T to D Leder BZ et al. Lancet 21;38(9999):

15 217 Santa Fe Bone Symposium New Anabolic Therapies: Phase 3 Study Designs Beginning anabolic therapy followed by an anti-remodeling agent will become standard practice ACTIVE - abaloparatide Abaloparatide Alendronate 18 3 Months Cosman F et al. Mayo Clin Proc 217;92:2-1 FRAME - romosozumab Romosozumab Denosumab Months Cosman F et al. N Engl J Med 21;37: Abaloparatide Phase 3 Extension Study (ACTIVExtend) Fracture protection sustained during months of alendronate therapy Cosman F et al. Mayo Clin Proc 217;92:2-1 Sclerostin Inhibitor: Romosozumab Phase 3: FRAME: Vertebral Fracture Risk Reduction Year 1 Year 2 ClinicalTrials.gov Identifier: NCT17834 Romosozumab All patients on denosumab mg QM Fracture protection sustained during 12 months of denosumab therapy Year 2: N=2 Year 2: N= Romosozumab Romosozumab Cosman F et al. N Engl J Med 21;37:

16 217 Santa Fe Bone Symposium Total Hip BMD Responses to Osteoporosis Therapies 1 T-score = 12% of young normal values Drug Trial 18 MO 24 MO 3 MO 48 MO 8-9 YR Zoledronic acid HORIZON ~3%* - 4% - 4.% Denosumab FREEDOM ~4%* -.% - 8.3% Teriparatide PFT (Neer) 2.% Teriparatide + denosumab DATA -.3% Teriparatide to denosumab DATA - -.% - Teriparatide + denosumab to denosumab DATA % - Abaloparatide ACTIVE 4.2% Abaloparatide to alendronate ACTIVE -.% - - Romosozumab 12 months FRAME.9%** Romosozumab to denosumab FRAME - 8.8% ** data at 12 months Osteoporosis: Long-term Treatment Plan Raloxifene Bisphosphonate Teriparatide When concerned about hip fracture 3- years After months Low risk Higher risk High risk Re-treat Consider drug holiday Continue therapy? After months Denosumab Denosumab If target is met Bisphosphonate for 1-2 years Osteoporosis: Long-term Treatment Plan Re-treat Low risk Consider drug holiday Bisphosphonate 3- years After months High risk ANABOLIC AGENT After months Denosumab Denosumab If target is met Bisphosphonate for 1-2 years 1

17 217 Santa Fe Bone Symposium Osteoporosis Therapy: Long-term Management Plan Photo courtesy of Betsy Love, RN, MN Decisions about therapy must be individualized For high risk patients, anabolic therapy, followed by an anti-remodeling agent should be first line therapy After 3- years of bisphosphonates Consider drug holiday for patients at modest risk switching to denosumab if hip BMD still low Denosumab very rarely a reason to stop therapy if denosumab therapy is to be stopped, consider an alternative anti-resorptive (e.g. bisphosphonate) to prevent rapid bone loss M. Personal opinion, 217 Thank you Michael R., MD, FACP Oregon Osteoporosis Center Portland, Oregon, USA mmcclung.ooc@gmail.com 17