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OSTEOPOROSE Teraptic update

OSTEOPOROSE Teraptic update. Erik Fink Eriksen Oslo University Hospital. AGENDA. Osteoporose Byrde for samfunn Underbehandling Behandlings effektivitet Østrogener og SERMS Bisfosfonater Langtidsbehandling Bivirkninger Seponering PTH. Osteoporose – byrde og omkostninger i Norge.

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OSTEOPOROSE Teraptic update

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  1. OSTEOPOROSETerapticupdate Erik Fink Eriksen Oslo University Hospital

  2. AGENDA • Osteoporose • Byrde for samfunn • Underbehandling • Behandlingseffektivitet • Østrogenerog SERMS • Bisfosfonater • Langtidsbehandling • Bivirkninger • Seponering • PTH

  3. Osteoporose – byrdeogomkostningeriNorge • 50% avkvinnerog 15% avmenn over 50 vilfå en osteoporotiskfraktur • Basertpå BMD har 240,000 nordmennosteoporose • 9000 hoftebruddog 15000 håndleddsbruddårlig • Behandlingavhoftebruddkoster 250,000-400,000 kr • Total omkostninger 4 mia/år • Under 20% med osteoporosebehandlesmedisinsk • Medisinomkostninger 110 mill kr/år • RA (0,7% avbefolkningen) 1,7 miakr/år

  4. Osteoporoseogunderbehandling • Helsedirektoratetog mange leger mener at osteoporoseer en livsstilssykdomsomskalforebyggesogbehandles med endringer I kostholdogmosjon • Tvilling-studier viser at genetikkeransvarlig for 2/3 avbentapogbrudd • Mosjonogkostholdsendringerer kun effektivt I barndomogpubertet • Deterikkevist at mosjonharsignifikanteeffekterpåskjelettet hos eldre (aldrigpåvisteffektpåbrudd), - men deterfortsatteffektivtpåmusklerog CV risiko • Ca+vitamin D fortsatviktigprofylakse hos eldre, men ogsåbegrenseteffektsommonoterapi • Risiko for kardiovaskulærsykdom?

  5. Treatmentofosteoporosis

  6. 1 1 2 Source: WPDF# DWD200308a FACT StudyTetracycline Labels after 6 Months Cancellous Bone Review: David Donley (20Aug2003) TPTD20 ALN10 Reviewer Memo: Tetracycline labels Newly formed bone Meunier, et al. ECTS 2003 (Poster Presentation #P-294) Image from ME Arlot, Laboratoire d’Histodynamique Osseuse Lyon, France Slide Modified: on: 8/15/2003 2:47:48 PM SL24 Rev: 12 Memo: moved labels up, moved pink arrow 15Aug-3 - MR

  7. BONE MARKERS - ORIGIN • Pyridinium kollagen • crosslinks • C-telopeptide (CTX) • N-telopeptide (NTX) Ben resorption Ben formation Markers: • Osteocalcin • Procollagentype I propeptides: • C-terminal (P1CP) • N-terminal (P1NP) • Bone-specific alkaline phosphatase

  8. Alendronate OC OB Bal Source: WPDF# DWD200308a Bone Formation and Resorption Markers after anabolics, antiresorptives and dual action agents Review: David Donley (20Aug2003) Formation (PINP) Resorption (NTx) * Teriparatide Dual action 250 Reviewer Memo: 200 150 100 50 0 -50 * -100 0 1 3 6 12 Months OC OB Bal OC OB Bal on: 9/9/2003 10:20:29 AM SL1 Rev: 405 (ASBMR 2003) Memo:

  9. Classes of Pharmacologic Agents for the Treatment of Osteoporosis • Antiresorptive agents • ET/ERT-SERMs • Calcitonin • Bisphosphonates • Anti-RANKL MAb (Denosumab) • Dual actionAgents • Cathepsin K antagonists • Chloride channelinhibitors • Anabolic agents • Teriparatide [rhPTH(1-34), rhPTH(1-84)]] • Anti- Sclerostin MAb • Other mechanism • Strontium ranelate

  10. ANTI RESORPTIV BEHANDLING

  11. 18 16 14 12 10 8 6 ZOL 5 mg (n = 1065) 28% 4 Placebo (n = 1062) Hazard ratio, 0.72 (95% CI, 0.56–0.93) P = .0117 2 0 Cumulative Incidence (%) 0 4 8 12 16 20 24 28 32 36 Month Risiko reduksjon ved hjertesykdom og osteoporose BP1 BP2 BP3 BP4 PTH 19 Months Years Years Years Years 0-1 0-3 0-1 0-2 0-3 0-1 0-2 0-3 0-1 0-2 0-3 0-2 0 10 20 30 40 41% 50 48% 52% 55% 60 58% 60% 61% 62% 65% 65% 65% 70

  12. EFFECTS OF ANTIRESORPTIVE DRUGS X Healthy Human Iliac Crest Biopsy Osteoporotic Human Iliac Crest Biopsy

  13. HORMONBEHANDLING

  14. WHI E+MPA fracture outcome Rossouw et al. JAMA 2002

  15. Østrogener beskytter mot hoftebrudd - WHI

  16. Profile of the two WHI studies Estrogen + MPA – 5 yrs Estrogen only – 7 yrs Combined – 50-59 yrs

  17. DOPS - 10 year dataRandomized cohorts Schierbeck et al. BMJ 2012;35:e6409

  18. Structural Comparison of Estradiol, Raloxifene, and Other SERMs O OH N O OH S HO HO Raloxifene Estradiol N O N N O O Cl Cl Tamoxifen Toremifene Clomiphene

  19. Raloxifen reduserer fraktur risiko MORE Trial - 4 Years Raloxifene Placebo 3 Hip 2 RR 0.66 (95% CI = 0.55, 0.81) 1 30 BMD % change 0 Placebo -1 25 Hip Raloxifene 60 mg/d -2 20 Months -3 % Incident Vertebral Fracture 0 6 12 18 24 15 RR 0.51 (95% CI = 0.35, 0.73) 10 3 Spine 2 49% 5 1 BMD % change 0 0 -1 Without Prevalent Vertebral Fractures With Prevalent Vertebral Fractures -2 Months -3 0 6 12 18 24 Eastell R, et al. J Bone Miner Res. 2000;15(suppl 1):S229.

  20. BISFOSFONATER

  21. Actions of Bisphosphonates on Osteoclasts and Osteocytes BP = bisphosphonates BP BP bind to bone mineral osteoclast BP BP BP BP BP BP BP BP Bone Concentrate at sites of bone resorption and inhibit osteoclasts Bisphosphonate (bone surface) Osteoclast membrane osteocyte BPs may act on osteocytes and prevent apoptosis Haversian canal Images by courtesy of Fraser Coxon and Mike Rogers

  22. Effect of Long-term AlendronateTreatment on Total Hip BMD FIT FLEX 16 FLEX treatment group* 14 Placebo 12 Alendronate (pooled) 10 8 Mean Change from FIT Baseline (%) Mean difference (95% CI): 2.36 (1.81, 2.90) P < 0.001 6 4 2 0 -2 0 1 2 3 4 0 1 2 3 4 5 Time (Years) Alendronate, n = 662 660 658 656 460† 657 642 628 599 580 553 Placebo, n = 437 435 436 432 297† 437 428 415 401 380 361 BMD = bone mineral density; CI = confidence interval; *All patients included in FLEX received alendronate in FIT, and results from the alendronate group was pooled from the alendronate 5 mg/day and 10 mg/day groups; †Measured in clinical fracture arm only.Black DM, et al. JAMA. 2006;296:2927–2938.

  23. Effect of Long-term Alendronate Treatment on Serum PINP FIT FLEX 60 FLEX treatment group* 50 Placebo Alendronate (pooled) 40 Mean PINP (ng/mL) 30 20 10 0 0 1 2 3 4 0 1 2 3 4 5 Time (Years) Alendronate, n = 130 61‡ 44† 130 126 130 Placebo, n = 87 48‡ 34† 87 87 87 PINP = procollagen I N-terminal propeptide; *All patients included in FLEX received alendronate in FIT, and results from the alendronate group was pooled from the alendronate 5 mg/day and 10 mg/day groups; †Measured in clinical fracture arm only; ‡Measured in vertebral fracture arm only.Black DM, et al. JAMA. 2006;296:2927–2938.

  24. Effect of Long-term Alendronate Treatment on Clinical Fracture Risk (1) Clinical Vertebral Fracture Risk Clinical Nonvertebral Fracture Risk FLEX treatment group:* Placebo Alendronate (pooled) 20 20 15 15 Cumulative Incidence (%) 10 10 RR, 0.45 (95% CI, 0.24, 0.86) 5 RR, 1.00 (95% CI, 0.76, 1.32) 5 0 0 0 12 24 36 48 60 72 0 12 24 36 48 60 72 Time to First Fracture (Month) Time to First Fracture (Month) No. at Risk Placebo 437 428 429 421 417 414 Alendronate 662 659 657 654 650 646 437 421 410 396 373 355 662 642 619 585 565 537 RR = relative risk; *All patients included in FLEX received alendronate in FIT, and results from the alendronate group was pooled from the alendronate 5 mg/day and 10 mg/day groups. Black DM, et al. JAMA. 2006;296:2927–2938.

  25. Placebo ZOL 5 mg Zoledronic Acid Reduced 3-Year Risk of Morphometric Vertebral Fractures (Stratum I) by 70% 70%*(62%, 76%) 15 10.9%(310/2853) 71%*(62%, 78%) 10 7.7%(220/2853) 60%*(43%, 72%) % Patients With New Vertebral Fractures 3.7%(106/2853) 3.3%(92/2822) 5 2.2%(63/2822) 1.5%(42/2822) 0 0–1 0–2 0–3 Years *P < .0001, relative risk reduction vs placebo (95% confidence interval) Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.

  26. Placebo ZOL 5 mg Zoledronic Acid Reduced Cumulative 3-Year Risk of Clinical Fractures (Hip, Clinical Vertebral, Non-vertebral) 25%‡(13%, 36%) 15 10.7%(388/3861) 77%†(63%, 86%) 10 41%*(17%, 58%) 8.0%(292/3875) Cumulative Incidence (%) of New Clinical Fractures Over 3 Years 5 2.6%(84/3861) 2.5%(88/3861) 1.4%(52/3875) 0.5%(19/3875) 0 HipFracture Clinical Vertebral Fracture Non-vertebral Fracture§ Values above bars are 3-year cumulative event rates based on Kaplan-Meier estimates. *P = .0024; †P < .0001; ‡P = .0002; relative risk reduction vs placebo §Hip fracture was not excluded from analysis of non-vertebral fracture. Black DM, et al. N Engl J Med. 2007;356:1809-1822.

  27. Fx. Incidence and turnover changeThe Alendronate experience ZOL 5 mg Placebo 0.40 0.30 0.20 Risk and 95% CI 0.10 0.00 T-score PINP at 1 year PINP at 1 year ng/mL -3 -2 -1 0 1 2 3 4 5 6 10 30 60 80 100 130 Due to the non-linearity of the relationship, a quadratic model best explains the association Data on file, Novartis

  28. 6 Years of ZOL Treatment Maintains Reduction in β-CTX at a Lower Level Than 3 Years of Treatment (ITT) Z3P3 Z6 0.6 0.5 Start of extension trial 0.4 Mean β-CTX (ng/mL) 0.3 * 0.2 0.1 0 0.5 1.5 3 3.5 4.5 5 0 2 2.5 4 5.5 6 1 Time (years) • Mean values remained within the premenopausal reference range throughout *P < 0.05. No significant difference at any other time point in the extension study. Horizontal dashed lines represent premenopausal reference range (Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822). ITT = intention to treat, Z3P3 = ZOL for 3 years and placebo for 3 years, Z6 = ZOL for 6 years

  29. Continuous ZOL Treatment Resulted in Significantly Fewer New Morphometric Vertebral Fractures in Years 3-6 Than Discontinuation of Treatment (ITT) PBO ZOL Core Study (Yr 0-3) Z3P3 Z6 15 10.9%(310/2853) 70%†(62, 76) 10 52%*(10, 74) 6.2%(30/486) % Patients 3.3%(92/2822) 5 3.0%(14/469) 0 Core study1 Extension study Morphometric Vertebral Fractures Core study:†P < 0.001 relative risk reduction vs placebo (PBO) *P =0.0348,relative risk reduction vs Z3P3; n = the number of patients in the analysis population with X-rays at Year 3 and Year 6 ITT = intention to treat , Z3P3 = ZOL for 3 years and placebo for 3 years, Z6 = ZOL for 6 years 1. Black DM, et al. N Engl J Med. 2007;356:1809–1822.

  30. 18 16 14 12 10 8 6 ZOL 5 mg (n = 1065) 4 Placebo (n = 1062) 2 0 0 4 8 12 16 20 24 28 32 36 Zoledronic Acid 5 mg Reduced Risk of All-Cause Mortality by 28% Over Time 28% Hazard ratio, 0.72 (95% CI, 0.56–0.93) P = .0117 Cumulative Incidence (%) Month

  31. BP in CV disease in RA Wolfe et l. JBMR 2012

  32. Osteonecrosis of the Jaw • No spontaneous AE reports • AE database search of 50 MedDRA terms, with adjudication • Case definition: exposed bone in the mouth > 6 weeks • 1 in ZOL, 1 in placebo • Both cases healed with antibiotic therapy and/or debridement

  33. Frequency of ONJ – Benign indications Retrospective assessment ASBMR consensusrep. 1/10,000-1/100,000 German study < 1/13,600 ADA < 1/100,000 Canadianstudy < 1/100,000 Prospective assessment ZOL (>10,000 pts) 1 BP/1 placebo – DEN 0 Extension studies: ZOL 1 ONJ case Z6, 0 in Z3P3 – DEN 1 > 1,000,000 ptsused Aclasta so far No ONJ casereported Risk in oncology trials 1-5% In oncology trials Denosumab has the same risk of ONJ than ZOL

  34. Atypical femoral fractures 4% of hip fx. aresubtrochanteric Case reports: transversal fx. prodromal pain focalor diffuse cort. thickening periostealreaction fx. usually nor related to falls bilat. affectionoftenseen Risk factors: Vitamin D deficiency, gluco corticoids, long term BP use

  35. Atypical femoral fractures • Swedish register study • Risk increasesimmediately • Risk decreasesimmediatelyafterdiscontinuation • BP treatmentincreases risk 40X • Study from Kaiser Permanente foundincreased risk withprolonged BP use (X-raybasedanalysis) • 1 yr ALN 2/100,000 • 12 yr ALN 250/100,000 • Risk verylow 1-3 ATFF per 100 hip fracturesavoided

  36. Predictors of Risk for Vertebral Fracture Overveiebeh pause når: BMD T-score I ryggoghofteer > -2,5 Ingennyebrudd under beh, OR = odds ratio. FDA Advisory Committee. September 9, 2011: Joint Meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM271911.pdf

  37. Anabolicdrugs

  38. PTH Liningcells once-daily  osteoblast apoptosis bone lining cells • Wnt • BMP • PPAR • IGF 1,2  RANKL  OPG  Lining cell dedifferentiation  bone formation  bone mass/strength

  39. TPTD20 (n = 26) ALN10 (n = 23) Source: RMP.B3DSGHBM.SASPGM (ASMBR03) WPDF# DWD200308a PTH/ALN COMPARISONLumbar Spine Cancellous BMD - QCT Review: David Donley (20Aug2003) † 19.0 * Reviewer Memo: % change (mean ±SE) 3.8 *P<0.05, †P<0.01 ALN10 vs.TPTD20 McClung, et al, ASBMR 2003 Slide Modified: on: 9/18/2002 12:45:37 PM SL10 Rev: 272 Memo:

  40. Source: Effect of Teriparatide onSkeletal Architecture Review: Hong Ren Reviewer Memo: Female, age 65 Duration of therapy: 637 days (approx 21 mos) BMD Change: Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%) Total Hip: +5.2% (group mean = 2.6 ± 4.9%) Patient treated with 20µg Slide Modified: on: 10/22/2002 12:55:03 PM SL10 Rev: 147 Memo: ACR 2002

  41. Source: Manuscript WPDF#OW200206b Zanchetta (JBMR2003) Slideset WPDF#JA20034a Cortical Bone Parameters Assessed by pQCT Review: J. Alam 041003; K. Engstrom 041003 *P=0.005 †P<0.001 †P<0.001 Reviewer Memo: †P<0.001 †P<0.001 Zanchetta, et al. J Bone Miner Res. 2003 Slide Modified: on: 4/10/2003 2:30:40 PM SL9 Rev: 35 Memo:

  42. Mild Severe Moderate Mild Severe Moderate New VFx with Increasing Prevalent VFx Grade TPTD20 Group Placebo Group RR = 3.6, P<0.001 30 25 20 % of women with new VFx P=0.20 15 10 5 27 23 14 0 Prevalent VFx Grade Fracture Prevention Trial

  43. ANABOLIC DRUGSAntifracture efficacy over time First Non - traumatic Non - Vertebral Fracture versus Time on Therapy 1.8% 1 Placebo PTH 1.6% 0.9 0.8 1.4% 0.7 1.2% 0.6 Ratio of Percent with Fracture 1.0% Patients with Fracture 0.5 as Percent of Patients at Risk 0.8% 0.4 0.6% 0.3 0.4% 0.2 0.2% 0.1 0 0.0% [0,6) [6,12) [12,18) >=18 [0,6) [6,12) [12,18) >=18 Months of Therapy Months on Therapy Data from Fracture Prevention Trial N: Placebo=544, TPTD20=541,TPTD40=552

  44. Combination treatment - 68 yr oldmale LS-BMD (% change) Oct 04 June 06 PTH 1-34 ZOL

  45. Behandlingog alder • 50-60 • HRT ogAlendronat • Intermitterende iv. Aclasta • Svær OP: Forsteo • 60-75 • Alendronat • Iv. Aclasta • Svær OP: Forsteo • (Prolia) • > 75 • Prolia • Iv. Aclasta • Svær OP: Forsteo

  46. Nye Behandlingsregimer Erik Fink Eriksen Oslo Universitetssykehus

  47. Agenda • The new entrants in the market - parenteral administration • Denosumab (Prolia®) • Dual action agents – a new MOA • New Anabolics • Anti-Sclerostin

  48. Osteoprotegerin (OPG) and RANK ligand (RANKL) are the principal regulators of osteoclast formation Denusomab M-CSF E2,-IF 1,25 Vit D RANK RANKL PGE2 nF-B JNK TRAF-6 OPG IL-11 PTH, PTHrp IL-1, TNF- Osteoblast Mononuclear cell Osteoclast

  49. Prolia®viser en raskogvedvarendereduksjonavbeinresorpsjonen Gjennomsnittligendringfra baseline iserumnivåav C-telopeptid1 Adapted from Lewiecki EM et al, 2007. 1. Lewiecki EM et al. J Bone Miner Res 2007;22:1832–1841. 49

  50. HISTOMORPHOMETRY FREEDOM TRIAL Reid et al. JBMR 2010

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