1. De afbeelding kan niet worden weergegeven. Mogelijk is er onvoldoende geheugen beschikbaar om de afbeelding te openen of is de afbeelding beschadigd. Start de computer opnieuw op en open het bestand opnieuw. Als de afbeelding nog steeds wordt voorgesteld door een rode X, kunt u de afbeelding verwijderen en opnieuw invoegen. Prof Dr Willem F Lems Department of Rheumatology EULAR Centre of Excellence: VU University medical centre and Reade, Amsterdam, the Netherlands De afbeelding kan niet worden weergegeven. Mogelijk is er onvoldoende geheugen beschikbaar om de afbeelding te openen of is de afbeelding beschadigd. Start de computer opnieuw op en open het bestand opnieuw. Als de afbeelding nog steeds wordt voorgesteld door een rode X, kunt u de afbeelding verwijderen en opnieuw invoegen. De afbeelding kan niet worden weergegeven. Mogelijk is er onvoldoende geheugen beschikbaar om de afbeelding te openen of is de afbeelding beschadigd. Start de computer opnieuw op en open het bestand opnieuw. Als de afbeelding nog steeds wordt voorgesteld door een rode X, kunt u de afbeelding verwijderen en opnieuw invoegen. Een terugblik op ASBMR (en ACR) 2013 IWO-meeting Zwolle, 30 November 2013

2. (poten(le)belangenverstrengeling Geen Voorbijeenkomstmogelijkrelevante rela(esmetbedrijven EliLilly,Novar(s,MSD,Servier,Will Pharma,Takeda Sponsoringofonderzoeksgeld Honorariumofandere(nancile) vergoeding Aandeelhouder Andererela(e,namelijk EliLilly,Novar(s,MSD,Servier,WillPharma, Takeda EliLilly,Novar(s,MSD,Servier,WillPharma, Takeda - - DisclosurebelangensprekerProfDrWFLems 3. Watistegenwoordigdemeestgesteldevraagbijnascholing osteoporose?: wattedoenna5jaarbehandeling? NieuweOntwikkelingenDiagnos(ek(VFA,TBS:albesproken) VergelijkendeStudiestussenan(-osteoporosemedica(e Botkwaliteit Ontwikkelingnieuwemedicamenten FractureOutpa(entClinic Enook:nieuwtjesvoordeprak(serendeosteoporose- deskundige 4. Meestgesteldevraagbijnascholingosteoporose: wattedoenna5jaarbehandeling? 5. Na5jaartherapie*: herevalua1e,inclusief klinischerisicofactoren enDXA (enVFAofRXWKbij vermoedenvannieuwe wervelbreuk) Hoogrisico: -T-2.5infemurhals Verder bisfosfonaatof anderemedica1e ofSC,IV -Leefs1jladviezen -Medica1estaken Opvolgingna2-3jaar ofbijnieuwefracturen eninclusiefklinische risicofactoren,DXA(enVFA ofRXWKbijvermoedenvan nieuwewervelbreuk) Herevalua(ena5-jaartherapie;expertopinion!!! Aanbevolen Sterkaanbevolen Kanzinvolzijn Gestructureerdeklinische followup Na2jaartherapiemet teripara1de/PTH(1-84): herevalua1e,inclusief klinischerisicofactoren enDXA (enVFAofRXWKbij vermoedenvannieuwe wervelbreuk) Bisfosfonaatof raloxifeen *Bisfosfonaten,stron(umranelaat,raloxifeen CBO 2011 6. HORIZON-PFTExtension2: StudyDesign 3-yearinterna(onal,mul(center,randomized,double-blindextensionstudyenrolled190 pa(entswithPMOwhohadbeentreatedwithZOLforupto6con(nuousyearsinthecore andrstextensionstudies *All patients received calcium 10001500 mg/d and vitamin D 4001200 IU/d and follow-up telephone calls every 3 months; Core = CZOL446H2301; First extension study = CZOL446H2301E1; ZOL = Zoledronic acid; PMO = Postmenopausal osteoporosis Core treatment assignment (ZOL 5mg, N=3889) (Z6, N=616) (Z3P3, N=617) Year 3 (Z6P3, N=95) (Z9, N=95) p 1st dose q p 2nd dose q p 3rd dose q p last visit q Year 7 Year 8 Year 9 Year 6 Core treatment assignment (PBO, N=3876) (P3Z3, N=1223) Ca & Vit D* Z=Zoledronicacid;P=Placebo NP4requestnumber:162307 7. Between-treatment comparison in percentage change in total hip BMD from Core Study Baseline to Year 9 (ITT) ITT = Intent-to-treat; BMD = Bone mineral density; Bracketed value is P value, ZOL vs placebo; n = Number of patients with values at Year 0 and the follow-up visit NP4requestnumber:162307 0 1 2 3 4 5 6 7 0 0,5 1 1,5 2 2,5 3 3,5 4 4,5 5 5,5 6 6,5 7 7,5 8 8,5 9 Changefrombaseline(%) Time (years) Z9 Z6P3 Z9 n = 94 94 94 91 91 92 83 72 67 Z6P3 n = 91 93 93 90 92 92 75 71 68 LS Mean = 0.15 0.29 0.92 0.58 0.55 0.56 1.08 1.71 0.96 Difference [0.738] [0.568] [0.116] [0.336] [0.416] [0.219] [0.069] [0.351] [0.446] Core Extension-1 Extension-2 8. Incidence of new Vertebral Morphometric Fractures in the core study, Years 3-6 and Years 6-9 (ITT) ITT = Intent-to-treat; Bracketed value is (n/N) n= Number of patients with the event; N = Number of patients in the analysis population with x-rays; (%)= n/N*100; E2 - relative risk reduction of 40% (95% CI: -144% to 85%). The relative risk reduction and the lower CI is negative that is quite different from core and extension 1 0 2 4 6 8 10 12 %Patients ZOL PBO Z6 Z3P3 Z9 Z6P3 10.9% [310/2853] 3.3% [92/2822] 3.0% [14/469] 6.2% [30/486] 5.3% [5/95] 3.2% [3/95] Morphometric vertebral fractures Core Extension-1 Extension-2 70%* (62, 76) 49% (26, 95) *P < 0.001 vs. placebo P = 0.035 vs. Z3P3 P = 0.461 vs. Z6P3 40% (-144, 85) NP4requestnumber:162307 9. OverallSafetyResultsoftheZol-Extension2Study Category Z9, n = 92 n (%) Z6P3, n = 95 n (%) Total subjects with any AEs 80 (87.0) 80 (84.2) Total subjects with any SAEs 24 (26.1) 28 (29.5) Total deaths 1 (1.1) 5 (5.3) Total discontinuations due to AEs 5 (5.4) 8 (8.4) AE = Adverse event; PMO = Postmenopausal osteoporosis; SAE = Serious adverse event NP4requestnumber:162307 10. EightYearsofDenosumabTreatmentinPostmenopausalWomen WithOsteoporosis:ResultsFromtheFirstFiveYearsofthe FREEDOMExtension FREEDOM EXTENSION 1 2 3Year 0 5 6 74 8 9 10 1 2 30 5 6 74Year Denosumab 60 mg SC Q6M (N = 3902) Placebo SC Q6M (N = 3906) Calcium andVitamin D Long-term Denosumab Cross-over Denosumab Denosumab 60 mg SC Q6M (N = 2343) Denosumab 60 mg SC Q6M (N = 2207) R A N D O M I Z A T I O N 11. RESULTS:PercentageChangeinBMD LS means and 95% confidence intervals. n = number of subjects with values at baseline and the time point of interest. *P < 0.05 vs FREEDOM baseline; P < 0.0001 vs FREEDOM baseline and extension baseline. Represents subjects from the FREEDOM DXA substudy. 12. RESULTS:Figure4.YearlyIncidenceof NewVertebralFractures n = number of subjects with 1 fracture. N = number of randomized subjects who remained on study at the beginning of each period. *Annualized incidence: (2-year incidence) / 2. Lateral radiographs (lumbar and thoracic) were not obtained at years 4 and 7 (years 1 and 4 of the extension). Placebo Long-term Denosumab Cross-over Denosumab 1/2* 4/5*3 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 YearlyIncidenceof NewVertebralFractures(%) Years of Denosumab Treatment 1980 34 1514 25 1496 50 N n 3691 82 3186 98 3702 3247 35 3453 24 3400 32 107 2.2 3.1 3.1 0.9 0.7 1.1 0.9 1.7 1.7 FREEDOM EXTENSION 2101 58 1614 18 1567 38 4/5* 7/8*6 N n 3691 82 3186 98 3702 3247 35 3453 24 3400 32 107 2.2 3.1 3.1 0.9 0.7 1.1 1.4 1.1 1.2 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 YearlyIncidenceof NewVertebralFractures(%) Years of Denosumab Treatment FREEDOM EXTENSION 1 2 3 13. RESULTS:Figure5.YearlyIncidenceof NonvertebralFractures n = number of subjects with 1 fracture. N = number of randomized subjects who remained on study at the beginning of each period. Percentages for nonvertebral fractures are Kaplan-Meier estimates. Placebo Long-term Denosumab Cross-over Denosumab 3.1 2.9 2.52.6 2.1 2.2 1.5 1.2 1.8 1.6 0.7 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 YearlyIncidenceof NonvertebralFractures(%) Years of Denosumab Treatment FREEDOM EXTENSION 2343 2244N n 34 27 2067 34 1867 28 3906 116 3454 83 3902 98 3487 73 3682 75 3688 103 1742 12 1 2 3 4 5 7 86 YearlyIncidenceof NonvertebralFractures(%) FREEDOM EXTENSION 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years of Denosumab Treatment 2207 2105N n 55 41 1965 46 1756 20 3906 116 3454 83 3902 98 3487 73 1646 22 3682 75 3688 103 1 2 3 4 5 3.1 2.9 2.52.6 2.1 2.2 2.5 2.0 2.6 1.2 1.4 14. RESULTS:Table2.Exposure-adjusted SubjectIncidenceofAdverseEvents (Ratesper100Subject-years) N = number of subjects who received 1 dose of investigational product. Treatment groups are based on the original randomized treatments received in FREEDOM. Rate = exposure-adjusted subject incidence per 100 subject-years. AEs coded using MedDRA v13.0. ONJ = osteonecrosis of the jaw. Cumulative ONJ cases: 3 cross- over, 5 long-term. Cumulative atypical femoral fracture cases: 1 cross-over, 1 long-term. Denosumab Extension Study Years 15 Cross-over Denosumab Long-term Denosumab N = 2206 N = 2343 Rate Rate All AEs 99.7 100.8 Infections 22.3 21.1 Malignancies 1.9 2.0 Eczema 0.9 0.9 Hypocalcemia 0.1 < 0.1 Pancreatitis < 0.1 < 0.1 Serious AEs 10.2 10.7 Infections 1.3 1.4 Cellulitis or erysipelas < 0.1 < 0.1 Fatal AEs 0.7 0.8 ONJ < 0.1 < 0.1 Atypical femoral fracture < 0.1 < 0.1 15. FurtherReduc(oninNonvertebralFractureRateIsObserved Following3YearsofDenosumabTreatment: ResultsWithUp to7YearsintheFREEDOMExtension SFerrari1,etal ASBMR: 1018. Baltimore, MD, USA; October 47, 2013 16. FREEDOMExtensionStudyDesign Key Inclusion Criteria for the Extension: Completed the FREEDOM study (completed their 3-year visit, did not discontinue investigational product, and did not miss > 1 dose). Not receiving any other osteoporosis medications. FREEDOM EXTENSION 1 2 3Year 0 5 6 74 8 9 10 1 2 30 5 6 74Year R A N D O M I Z A T I O N DMAb 60 mg SC Q6M (N = 3902) Placebo SC Q6M (N = 3906) Long-term DMAb Treatment Cross-over DMAb Treatment DMAb 60 mg SC Q6M (N = 2343) DMAb 60 mg SC Q6M (N = 2207) Calcium and Vitamin D 17. n=numberofsubjectswhohave1nonvertebralfracture.PercentagesfornonvertebralfracturesareKaplan-Meieres1mates. Yearly Nonvertebral Fracture Incidence With DMAb Treatment for Up to 7 Years Long-term DMAb Treatment Long-term DMAb Cross-over DMAb YearlyIncidenceof NonvertebralFractures(%) Years of DMAb Treatment 2066 1867 43 47 33 27 31 2746 2207 2105 1964 1755 FREEDOM EXTENSION Cross-over DMAb Treatment n N 2343 2343 2343 22432343 N n 53 40 40 17 YearlyIncidenceof NonvertebralFractures(%) Years of DMAb Treatment EXTENSION 18. 1017 19. Furtherreduc(oninNonvertebralFractureRatebydenosumab: 7yeardata,anewanalysis(1018). KlinischeConsequen(es: Bijdeafwegingoverwelofnietdoorgaanmetbehandelen na5jaar,zijnernugegevensovereec(viteitbeschikbaar over7-8jaaroverdenosumab. Anderegegevensspelenookeenrol: kansopbijwerkingen; achtergrond-risico:highriskpa(ent?; wensvandepa(ent; Kosten; Langetermijneecten. 20. Ac(evecomparators 21. ALongitudinalStudyofSkeletalHistomorphometryinSubjects OnTeripara(de(TPTD)orZoledronicAcid(ZOL),TheSHOTZ Study Objective: To evaluate the biological effects of TPTD and ZOL in postmenopausal women with osteoporosis, based on histomorphometric indices and material properties Study Design A2-yeartrialwithpairedbiopsydesign Pa(entswhocompleted1-yearrandomizedtrialwereeligiblefor1-year, open-label,extensionstudy Postmenopausalwomen withosteoporosis N=19 TPTD 20g/d,SC n=10 Aper6and24months,transiliaccrestbonebiopsieswereperformedapertetracycline labeling SC, subcutaneous; TPTD, teriparatide; ZOL, zoledronic acid. Dempster D, et al. Columbia University, USA. A longitudinal Study of Skeletal Histomorphometry in Subjects On Teriparatide (TPTD) or Zoledronic acid (ZOL), the SHOTZ Study. Abstract [1020]. Presented at the 2013 Annual Meeting of The American Society for Bone and Mineral Research. October 5, 2013. ZOL5mg/y, IVinfusion n=9 Assessments 22. 1020 AlongitudinalstudyofSkeletalHistomorphometryinsubjectsOnTeripara(de (TPTD)orZoledronicacid(ZOL),theSHOTZstudy.David Dempsteretal. 23. Objec1ve:TotestthehypothesisthatBMDincreasesfollowingdenosumabadministra(on,whichisseendespite lowboneturnovermarkersandlimitediliaccresttetracyclinelabeling,resultfromanon-remodelingdependent mechanismthataccruesbonematrix Thehypothesiswastestedbyexaminingtheuorochromelabelingparerninproximalfemursec(onsfrom ovariectomizedcynomolgusmonkeystreatedwithdenosumabfor16months Dempster D, et al. Columbia University, USA. Continuous Modeling-Based Bone Formation: A Novel Mechanism That Could Explain the Sustained Increases in Hip Bone Mineral Density (BMD) With Denosumab Treatment. Abstract [LB-MO30]. Presented at the 2013 Annual Meeting of The American Society for Bone and Mineral Research. October 7, 2013. Matureovariectomizedcynomolgus monkeys(N=34;age>9years) Vehicle(n=20) Denosumab 25mg/kg(n=14) Administra(onofourochromelabelswasatmonths6,12,and16 Doseofdenosumabwas25xclinicaldose BMD, bone mineral density. Continuous Modeling-Based Bone Formation: A Novel Mechanism That Could Explain the Sustained Increases in Hip Bone Mineral Density (BMD) With Denosumab Treatment 24. Figure: Epifluorescent micrograph from denosumab-treated cynomolgus monkeys femur sections Boththesuperiorendocortexandtheinferiorperiostealsurfacecontainedmul(plesuperimposedlabelsoversmooth cementlineswhichopenspannedmonths6to16(seegure),sugges(ngthatmodeling-basedboneforma(onoccurred con(nuouslyduringdenosumabadministra(on Signicantincreaseinbonestrengthwasduetoaugmenta(onofbonemass,whichoccurredatbiomechanicallyrelevant sitesonthesuperiorandinferioraspectsofthefemurneck Source: Dempster D, et al. Presented at the 2013 Annual Meeting of The ASBMR. October 7, 2013. Dempster D, et al. Columbia University, USA. Continuous Modeling-Based Bone Formation: A Novel Mechanism That Could Explain the Sustained Increases in Hip Bone Mineral Density (BMD) With Denosumab Treatment. Abstract [LB-MO30]. Presented at the 2013 Annual Meeting of The American Society for Bone and Mineral Research. October 7, 2013. Continuous Modeling-Based Bone Formation: A Novel Mechanism That Could Explain the Sustained Increases in Hip Bone Mineral Density (BMD) With Denosumab Treatment Results 25. Objec1ve:Todeterminethecompara(veeectsofTPTD,DMAB,andcombina(on therapy(COMBO)onperipheralcompartmentalbonedensityandmicroarchitecture Tsai J, et al. Massachusetts General Hospital, USA. Comparative Effects of Teriparatide, Denosumab, and Combination Therapy on Peripheral Compartmental Bone Density and Microarchitecture: the DATA-HRpQCT Study. Abstract [FR0372]. Presented at the 2013 Annual Meeting of The American Society for Bone and Mineral Research. October 4, 2013. Postmenopausal women age(5191) randomized (N=100) TPTD 20-ugSCQD DMAB SCQ6months COMBO 12months Measurementsatdistalradiusand (biabyHR-pQCT DTot,DTrab,DCort Tb.Th,Tb.Sp,Tb.N Ct.Th,Ct.Po Ct.Th, cortical thickness; Ct.Po, cortical porosity; DMAB, denosumab; DTot, total density; Dtrab, trabecular density; Dcort, cortical density; HR-pQCT, high-resolution peripheral quantitative computed tomography; QD, once a day; SC, subcutaneous; Tb.TH, trabecular thickness; Tb.Sp, trabecular spacing; Tb.N, trabecular number; TPTD, teriparatide. Compara(veEectsofTeripara(de,Denosumab,and Combina(onTherapyonPeripheralCompartmental BoneDensityandMicroarchitecture:TheDATA-HRpQCTStudy 26. 1019.TheDATAExtensionStudy:2YearsofCombinedDenosumaband Teripara(deinPostmenopausalWomenwithOsteoporosis:ARandomized ControlledTrial.BenjaminLederetal. 27. Mean percent change (SD) from baseline in bone density and microarchitecture at 12 months at the radius IncreaseinDcortwasobservedintheCOMBOgroupversusTPTDgroup(P