Osteoporosis Treatment Update

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1 //7 steoporosis Treatment Update What is steoporosis? steoporosis is a skeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fracture. rofessor T.Masud Bone strength ottingham University Hospitals HS Trust University of ottingham University of Derby University of Southern Denmark Bone quality architecture damage accumulation bone turnover Bone density (gm/cm) IH Consensus Development anel on steoporosis. JAMA (): 7-9 Current Therapeutic ptions Bone Remodeling Bone is in a constant cycle of remodeling Central to this process are the balanced activity of the osteoclast and the osteoblast Anti-resorptive (Calcitriol) (Calcitonin)x Estrogens SERMs Bisphosphonates Denosumab Calcium + Vit D Anabolic - stimulators of bone formation arathyroid Hormone - arathyroid Hormone - x Resorption and formation are balanced Resorption exceeds formation Dual action? Strontium ranelate Mundy GR. In: rimer n The Metabolic Bone Diseases And Disorders f Mineral Metabolism, th ed. Lippincott 999. EIC Bone Loss Study Hormone Replacement Therapy Estrogen-rogestin and Lower Alendronte Doses Estrogen+ET Spine Estrogen+MA la/la n=9 mg.mg Mean Change BMD, % mg/placebo.mg/placebo - - reviously used as a treatment for osteoporosis Useful for controlling menopausal symptoms Adverse extra-skeletal effects Is not generally recommended for long-term use Has bone benefits if taking for other reasons Can have a role in early menopause Years Ravn, Annals Int Med 999; : 9-9

2 //7 SERM - Raloxifene Effective in preventing post-menopausal bone loss Effective in preventing vertebral fractures o evidence for hip or non-vertebral fractures Absolute risk of vertebral fracture Significant based on CIs p values not given % % % % % % rimary prevention Control Ettinger B, et al. JAMA 999; : 7-..% Secondary prevention ARR =.% rimary prevention Raloxifene.%.% ARR =.%.% n = n = 77 n = 9 n = 79 Secondary prevention Basic Bisphosphonate Structure C R R Evolution of Bisphosphonate Development First Licensed Bisphosphonate amidronate Etidronate First Generation Aminobisphosphonates H H a HC C - a + a H - a + Second Generation Aminobisphosphonates H C CH - a + - a + - a + Ibandronate Bisphosphonate (B) Cellular and Molecular Mechanisms of Action itrogen bisphosphonates (-B) inhibit here HMG Co-A Mevalonate Farnesyl- Geranylgeranyl- B B B B B Active Inactive Apoptotic steoclast steoclast steoclast Farnesyl pyrophosphate (F) synthase Diez-erez A. Bisphosphonates. Maturitas. ;:9-. : Fracture Intervention Trial Vertebral fractures in women with osteoporosis Incidence (%) per year Reduction = % p<. o prior fracture (T<-.). Black DM, et al. Lancet 99;:-. Cummings SR, et al. JAMA 99;:77- Reduction = 7% p <. rior fracture (T<-.) Vertebral fracture status at baseline Adapted from Black DM et al, & Cummings SR et al, 99 Absolute risk of hip fracture Bisphosphonate - % % % % Black DM, et al. Lancet 99; : -. Effects on hip fracture.% Control ARR =.% =.7.% n = n =

3 //7 Bisphosphonate - Effects on bone loss Effects on preventing fractures of vertebral, hip, and non-vertebral fractures Absolute risk of hip fracture % % % %.%.% McClung MR, et al. Engl J Med ; : -..9%.% Group Group Group Group Control ARR =.% =.9 ARR =.9% = S n = n = n = n = 7 Ibandronate: Vertebral fracture incidence over years Incidence new vertebral fractures at year (%) p=. vs placebo 9.% Adapted from: Chesnut CH, et al. J Bone Miner Res ;9: 9 % fracture risk reduction.7%. mg daily ibandronate Zoledronic Acid annual mg IV (Black et al Eng J M 7) ivotal Fracture Trial 77 women aged -9 years 7% vertebral #s % hip #s % non-vert #s Single Infusion Zoledronic acid in Frail Seniors n=, years ursing H. & Assisted living Mean age. yrs Greenspan SL et al JAMA Zoledronic acid- fractures and mortality after hip fractures (HRIZ) Mortality revious Faller % % p=. Frailty (Fried) 7% % p=. EJM 7 Lyles K et al Recurrent Faller 9% % p=. (prospective) Single Infusion- Zoledronic Acid: ost hoc HRIZ studies Reid IR et al J Clin Endorinol Metab Relative efficacy of old and new bisphosphonates Relative otency 7 Etid Clod am Aln Iba Ris Zol Fleish H. Bisphosphonates in bone disease 99

4 //7 The itrogen Bisphosphonate otency Triangle Binding to Bone amidronate Ibandronate Increasing kinetic binding What Is the ptimal Reduction in Bone Turnover for an Antiresorptive Drug? Insufficient turnover Accumulation of microdamage Increased brittleness due to excessive mineralization Excessive turnover Increase in stress risers (weak zones) Increase in perforations Loss of connectivity Increasing + charge Zeta otential Ibandronate Bisphosphonate otency Inhibition of enzyme FS farnesyl pyrophosphate synthase Ibandronate amidronate Increasing enzyme inhibition Bone Strength hysiological Range Increasing - charge Bone Turnover From Arrain, Masud, Dental Update, 9; :-9 Adapted from Weinstein RS, J Bone Miner Res ;. ational steoporosis Guideline Group The RAK/RAK Ligand/G Concept Receptor Ligand Decoy Receptor RAK (Receptor Activator of uclear factor-kappab) RAK Ligand A ligand is a small molecule that binds to a site on a macromolecular surface by intermolecular forces G (steorotegerin) provides an alternative binding site for RAK Ligand Ligand binding activates cellular signalling Ligand bound to decoy receptor can not activate cellular signalling BMD at Month for All Measured Skeletal Sites hase : The DECIDE Trial ercent Change From Baseline (%) in BMD Least Squares Mean (9% CI).%.%.% 7 mg QW Denosumab mg QM.%.% Total Hip Lumbar Spine Trochanter Femoral eck / Radius.. Brown J, et al. J Bone Miner Res. 9;:-. Brown J, et al. resented at: th Annual European Symposium on Calcified Tissues; May -, ; Barcelona, Spain. Late breaking abstract LB. 9 Amgen. All rights reserved. Do not copy or distribute. Median (Q, Q) Change From Baseline (%) Effect of Treatment on Bone Turnover Markers hase : The DECIDE Trial mg QW sctx Study Month.. Adapted from Brown J, et al. J Bone Miner Res. 9;:-. Median (Q, Q) Change From Baseline (%) Denosumab mg QM - s - 9 Study Month 9 Amgen. All rights reserved. Do not copy or distribute

5 //7 Denosumab mg s/c x year Fracture Data: Effect on vertebral and non-vertebral fractures Absolute risk year FREEDM trial (7 women mean age 7.). %. ew vertebral fracture ew non-vert fracture Hip fracture. %. p <. p <. p <..7 Mean F/ T score -. Mean L/S T score -. % prevalent VCF % Denosumab mg Vertebral Fracture Risk Reduction With Denosumab in atients With Renal Impairment ivotal FREEDM Trial A Retrospective Analysis of atients From the ivotal FREEDM Trial According to Baseline Renal Function Incidence at Month (%) Denosumab All Creatinine Clearance (ml/min) Cummings SR et al. J Bone Miner Res () :S Incidence is based on crude incidence. umber of subjects with an evaluation during the time period of interest. Statistical analysis was not performed. Adapted from: Jamal AS, et al. oster presented at: 7th Congress of European Symposium on Calcified Tissues; June -, ; Glasgow, UK. Amgen Inc. All rights reserved ercentage Change From Baseline The Relationship Between Gains in Total Hip BMD and Fracture Incidence at Spine and on-spine Sites Was Assessed Total Hip BMD FREEDM EXTESI 7.% Yearly Crude Incidence of ew Vertebral Fracture (%) Yearly Incidence of onvertebral Fractures (%) %.%.9% FREEDM.% ew Vertebral Fracture.7%.%.% Years of Treatment Exposure.% Denosumab FREEDM.9%.%.%.% EXTESI. Year.. Years of Treatment Exposure <. vs FREEDM baseline. <. vs FREEDM baseline and Extension baseline. ʌ Annualized rate: (-year rate) / ; vertebral fractures were not assessed at year..% / ʌ onvertebral Fracture.%.% EXTESI.%.% Summary of Adverse Events (AE) of Interest Subject Rates per atient-years FREEDM Years - = Rate (n) FREEDM Years - = 79 Rate (n) Denosumab EXT Long-term Years - = Rate (n) EXT Cross-over Years - = Rate (n) All AEs. (). (9). (9). () Infections.7 () 9. (). (7) 7. () Eczema. (7). (9).(7).9 (9) Hypocalcemia <. () <. () <. () Serious AEs. (97). (). (). () Infections. (). (). (). () Cellulitis or Erysipelas <. (). () <. () <. () Fatal AEs. (9). (7). (). () J: There were four adjudicated cases of J in the extension study: Two cases in the cross-over and two cases in the continued denosumab group Atypical fracture: two cases of atypical femoral fractures have been reported from the FREEDM Extension trial 9 = umber of subjects who received >/= dose of investigational product. Treatment groups are based on the original randomized treatments received in FREEDM. All subjects in the extension are receiving denosumab; Rate = Exposure-adjusted subject incidence per subject-years; n = Total number of subjects with an adverse event. Adapted from: apapoulos S, et al. JBMR ;7():9-7 Current Therapeutic ptions Anti-resorptive (Calcitriol) (Calcitonin)x Estrogens SERMs Bisphosphonates Denosumab Anabolic - stimulators of bone formation arathyroid Hormone - arathyroid Hormone - Calcium + Vit D Human arathyroid Hormone - and - H - Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Glu Trp Val Arg Glu Met Ser Asn Leu Gly Lys Leu Arg Lys Lys Leu Gln Asp Val His Asn he 7 His Dual action? Strontium ranelate -C

6 //7 % change (mean ± SE) TTD in Women: Effects on LS BMD Effects on Lumbar Spine BMD Teriparatide in Women: End of Months Treatment TTD Study (LCF) Marcus, et al. J Bone Miner Res ;:- <. Effect of Teriparatide on the Risk of ew Vertebral Fractures Risk Reduction % % % 7% % RR. (9% CI,.9 to.) RR. (9% CI,. to.) 9 (n=) % 9% TTD (n=) TTD (n=) o. of women who had > fracture <. vs. % of Women % of Women Effect of Teriparatide on the Risk of onvertebral Fragility Fractures 7 RR. (9% CI,. to.) RR.7 (9% CI,. to.) % % TH TH (=) (=) (=) =. vs. =. vs. o. of women who had > nonvertebral fragility fracture Baseline Teriparatide atient Fracture revention Trial Follow-Up Female, age 9 Duration of therapy: days (approx mos) BMD Change: ÞLumbar Spine: +7.9% (group mean = 9.7 ± 7.%) ÞTotal Hip: +.% (group mean =. ±.9%) Jiang Y et al. JBMR Changes in bone density years after cessation of TTD treatment: Immediate treatment with bisphosphonates versus delayed bisphosphonate therapy. Teriparatide and Denosumab, Alone or Combined, in Women with ostmenopausal steoporosis: the DATA Study Randomised Trial. Tsai J, et al. Lancet ;:. Bone Mineral Density Changes end of teriparatide treatment Spine Total Hip Comparison is between men who took bisphosphonates immediately and six men who delayed initiation of bisphosphonates until year after TTD withdrawal. =., <. Kurland ES et al. steoporos Int ;: Cumulative lumbar spine bone density change: baseline through year after TTD withdrawal. Cumulative % change±sem in lumbar spine density for men who took bisphosphonates immediately after completing TTD (n=, gray bar) and men who took no medication for year after TTD withdrawal (n=7, black bar). Comparison is from baseline, prior to beginning hth ( ) treatment, until year after discontinuing hth ( ). p< vs baseline; p< vs denosumab alone; p< vs denosumab alone; p< vs teriparatide alone; p< vs teriparatide alone.

7 //7 Combination of zoledronate and teriparatide Combination of zoledronate and teriparatide LSM change in lumbar spine BMD from baseline (%) 9 7 =7 = = = = = = 9 Time (weeks) = = LSM change in femoral neck BMD from baseline (%) - =7 = = = = = = 9 Time (weeks) =9 =9 Serum (ng/ml) = = = =9 = = =9 = = = = =7 = = = 9 Time (weeks) Serum b-ctx (ng/ml) = = =. =9. = =. = = =9. = = =7 =9 = = 9 Time (weeks) mg + teriparatide µg/day + teriparatide µg/day mg mg + teriparatide µg/day + teriparatide µg/day mg p<., vs. teriparatide alone and vs. zoledronate alone; p<., vs. zoledronate alone; p<., vs. teriparatide alone; p<., vs. zoledronate alone. BMD, bone mineral density; LSM, least-squares mean. Cosman F, et al. J Bone Miner Res. ;:. β-ctx, β-c-telopeptide of type I collagen;, -terminal propeptide of type I collagen. Cosman F, et al. J Bone Miner Res. ;:. Current Therapeutic ptions Anti-resorptive (Calcitriol) (Calcitonin)x Estrogens SERMs Bisphosphonates Denosumab Anabolic - stimulators of bone formation arathyroid Hormone - arathyroid Hormone - Dual action? Strontium ranelate Calcium + Vit D Sr - C ++ Strontium Ranelate CH - C S C C H C H C - C Sr ++ Strontium Effects on vertebral fracture risk in patients with prevalent vertebral fracture atients (%) STI ver year Meunier J et al. Engl J Med ;:9-. RR: - 9% RR: - %. %. %. % ver years.9 % - year - years ver year: RR =., 9% CI [.;.7] ver years: RR =.9, 9% CI [.;.7] rotelos g/day <. = Kaplan-Meier; RR: Cox model Strontium- Effects on hip fracture risk ver years atients (%) = 977 RR: - % Months Reginster J.Y et al. J of Clin Endoc Metab ;9():-. rotelos g/day steoporotic patients aged 7 years and over and T<- RR =. 9% CI [.;.997] <. 7

8 //7 Strontium effects on lumbar spine bone mineral density STI +.% - - Months Meunier J et al. Engl J Med ;:9-. Reginster J.Y et al. data on file. Relative change from baseline Strontium g/day <., hierarchical step-down procedure TRS +.7% MHRA Warnings on Strontium Ranelate Increased risk of cardiovascular disorders (RR for MI. ) (on top of known previous risk of VTE) Use now restricted to treatment of severe osteoporosis in postmenopausal women at high risk of fracture in men at increased risk of fracture Treatment should only be initiated by a physician with experience in the treatment of osteoporosis Should not be used in patients with: ischaemic heart disease, peripheral arterial disease; cerebrovascular disease; a history of these conditions; or in patients with uncontrolled hypertension Treatment should be stopped if the patient develops any of the above conditions Regular Monitoring for the development of the above conditions Summary: Strategies for prevention and treatment of osteoporosis ral bisphosphonates are associated with reduced mortality after hip fracture Bone Mass Healthy diet, Exercise, ptimum body weight uberty Bisphosphonates, Denosumab,SERMs, Strontium Ranelate, TH, Exercise eak Bone Mass Menopause Falls assessment Calcium + Vit D Ageing Men Women Fracture zone Beaupre et al; steoporos Int, : 9 9 % reduction in mortality per year of use. 7 Age (years) Effect of steoporosis Treatment on Mortality: A Meta-Analysis (Bolland et al; J Clin Endocrinol Metab, ) Incidence of osteoporotic fractures Strontium Strontium Denosumab Incidence per person-years Hip Spine Best Available Grade A Evidence for Treatment Hip? Spine Wrist deaths in approx, subjects Wrist 7 9 Men 7 9 Women Cooper & Melton 99

9 //7 Treatment is Associated with Reduced Hip Fracture Risk and Maintained Safety in the ldest ld Axelson et al ASBMR Sept Adverse events were not more common in the older age quartiles Future? Cathepsin K Inhibition ew SERMS (arzoxifene, bazedoxifene, lasofoxifene) Cathepsin K inhibition Sclerostin pathway TH type receptor pathway Calcilytics (ca receptor antagonists) pathway SARMS Sarcopenia otential difference to other anti-resorptive therapies? steoclast function suppressed but osteoclast survival not impaired Effect on osteoblast function and bone formation? danacatib month dose-ranging study LR/Wnt athway and Sclerostin - - LS-BMD danacatib mg TH-BMD U-Tx danacatib mg ostmenopausal women (=99, mean age:. ± 7. years) with BMD T-scores -. at the lumbar spine, femoral neck, trochanter, or total hip and -. at all sites. McClung et al ASBMR I Monoclonal Ab 9

10 //7 Future Treatments Romosozumab Cosman EJM Age range -9 (% > 7years) 7% reduction in new Vertebral fracture % reduction in Clinical fractures Abaloparatide Cosman JBMR Selective activator of TH type receptor. Daily subcut injections Age 9- years (9% > 7 years) months % reduction in Vertebral fractures % reduction in onvertebral fractures Miller JAMA ACTIVE trial Abaloparatide vs placaebo v s open label teriparatide Less hypercalcaemia than teriparatide Future? ew SERMS Cathepsin K inhibition Sclerostin pathway TH type receptor Calcilytics (ca receptor antagonists) pathway SARMS Sarcopenia IMRTAT T T FRGET Lifestyle Factors Smoking Lack of exercise oor diet especially lack of calcium Excess alcohol Thank You Any Questions? Fall revention