Seminar 30-11-2013 Terugblik op ASBMR

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Terugblik op ASBMR

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Seminar 30-11-2013 Terugblik op ASBMR

  1. 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. 2. (poten(ële)  belangenverstrengeling   Geen     Voor  bijeenkomst  mogelijk  relevante   rela(es  met  bedrijven   Eli  Lilly,  Novar(s,  MSD,  Servier,  Will   Pharma,  Takeda   •  Sponsoring  of  onderzoeksgeld   •  Honorarium  of  andere  (financiële)   vergoeding   •  Aandeelhouder   •  Andere  rela(e,  namelijk  …       •  Eli  Lilly,  Novar(s,  MSD,  Servier,  Will  Pharma,   Takeda   •Eli  Lilly,  Novar(s,  MSD,  Servier,  Will  Pharma,   Takeda         •-­‐   •-­‐   Disclosure  belangen  spreker  Prof  Dr  WF  Lems    
  3. 3. •  Wat  is  tegenwoordig  de  meest  gestelde  vraag  bij  nascholing   osteoporose?:     wat  te  doen  na  5  jaar  behandeling?   •  Nieuwe  Ontwikkelingen  Diagnos(ek  (VFA,  TBS:  al  besproken)   •  Vergelijkende  Studies  tussen  an(-­‐osteoporose  medica(e   •  Botkwaliteit   •  Ontwikkeling  nieuwe  medicamenten   •  Fracture  Outpa(ent  Clinic   •  En  ook:  nieuwtjes  voor  de  prak(serende  osteoporose-­‐ deskundige  
  4. 4. Meest  gestelde  vraag  bij  nascholing  osteoporose:     wat  te  doen  na  5  jaar  behandeling?    
  5. 5. Na  5  jaar  therapie*:   herevalua1e,  inclusief   klinische  risicofactoren   en  DXA   (en  VFA  of  RX  WK  bij   vermoeden  van  nieuwe   wervelbreuk)   Hoog  risico:   -­‐   T  <-­‐2.5  in  femurhals   -­‐   Nieuwe  fractuur   -­‐   Erns1ge  secundaire   osteoporose   -­‐   Glucocor1coïden  ≥7.5  mg/d   Laag  risico:   -­‐   Geen  nieuwe  klinische   risicofactoren   -­‐   T  >-­‐2.5  in  femurhals   Verder   bisfosfonaat  of     andere  medica1e   of  SC,  IV   -­‐  Leefs1jladviezen   -­‐  Medica1e  staken   Opvolging  na  2-­‐3  jaar     of  bij  nieuwe  fracturen   en  inclusief  klinische   risicofactoren,  DXA  (en  VFA   of  RX  WK  bij  vermoeden  van   nieuwe  wervelbreuk)   Herevalua(e  na  5-­‐jaar  therapie;  expert  opinion!!!   Aanbevolen         Sterk  aanbevolen     Kan  zinvol  zijn       Gestructureerde  klinische     follow  up   Na  2  jaar  therapie  met   teripara1de/PTH  (1-­‐84):   herevalua1e,  inclusief   klinische  risicofactoren   en  DXA   (en  VFA  of  RX  WK  bij   vermoeden  van  nieuwe   wervelbreuk)   Bisfosfonaat  of     raloxifeen   *Bisfosfonaten,  stron(um  ranelaat,  raloxifeen   CBO 2011
  6. 6. HORIZON-­‐PFT  Extension  2:   Study  Design   •  3-­‐year  interna(onal,  mul(center,  randomized,  double-­‐blind  extension  study  enrolled  190   pa(ents  with  PMO  who  had  been  treated  with  ZOL  for  up  to  6  con(nuous  years  in  the  core   and  first  extension  studies     *All patients received calcium 1000–1500 mg/d and vitamin D 400–1200 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  =  Zoledronic  acid;  P  =  Placebo   NP4  request  number:  162307  
  7. 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 NP4  request  number:  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. 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) NP4  request  number:  162307  
  9. 9. Overall  Safety  Results  of  the  Zol-­‐Extension  2  Study   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 NP4  request  number:  162307  
  10. 10. Eight  Years  of  Denosumab  Treatment  in  Postmenopausal  Women     With  Osteoporosis:  Results  From  the  First  Five  Years  of  the     FREEDOM  Extension   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. 11. RESULTS:  Percentage  Change  in  BMD     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. 12. RESULTS:  Figure  4.  Yearly  Incidence  of     New  Vertebral  Fractures   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. 13. RESULTS:  Figure  5.  Yearly  Incidence  of     Nonvertebral  Fractures   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. 14. RESULTS:  Table  2.  Exposure-­‐adjusted     Subject  Incidence  of  Adverse  Events     (Rates  per  100  Subject-­‐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 1–5 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. 15. Further  Reduc(on  in  Nonvertebral  Fracture  Rate  Is  Observed   Following  3  Years  of  Denosumab  Treatment:     Results  With  Up     to  7  Years  in  the  FREEDOM  Extension   S  Ferrari1,  et  al   ASBMR: 1018. Baltimore, MD, USA; October 4–7, 2013
  16. 16. FREEDOM  Extension  Study  Design     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. 17. n  =  number  of  subjects  who  have  ≥  1  nonvertebral  fracture.  Percentages  for  nonvertebral  fractures  are  Kaplan-­‐Meier  es1mates.   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. 18. 1017    
  19. 19. Further  reduc(on  in  Nonvertebral  Fracture  Rate  by  denosumab:   7  year  data,  a  new  analysis  (1018).     Klinische  Consequen(es:   Bij  de  afweging  over  wel  of  niet  doorgaan  met  behandelen   na  5  jaar,  zijn  er  nu  gegevens  over  effec(viteit  beschikbaar   over  7-­‐8  jaar  over  denosumab.   Andere  gegevens  spelen  ook  een  rol:     •  kans  op  bijwerkingen;   •  achtergrond-­‐risico:  high  risk  pa(ent?;     •  wens  van  de  pa(ent;     •  Kosten;   •  Lange  termijn  effecten.  
  20. 20. Ac(eve  comparators    
  21. 21. A  Longitudinal  Study  of  Skeletal  Histomorphometry  in  Subjects     On  Teripara(de  (TPTD)  or  Zoledronic  Acid  (ZOL),  The  SHOTZ     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     • A  2-­‐year  trial  with  paired  biopsy  design   • Pa(ents  who  completed  1-­‐year  randomized  trial  were  eligible  for  1-­‐year,        open-­‐label,  extension  study   Postmenopausal  women   with  osteoporosis   N  =  19   TPTD     20  μg/d,  SC   n  =  10   Aper  6  and  24  months,  transiliac  crest  bone  biopsies  were  performed  aper  tetracycline   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. ZOL  5  mg/y,     IV  infusion   n  =  9   Assessments  
  22. 22. 1020   A  longitudinal  study  of  Skeletal  Histomorphometry  in  subjects  On  Teripara(de   (TPTD)  or  Zoledronic  acid  (ZOL),  the  SHOTZ  study.  David   Dempster  et  al.  
  23. 23. Objec1ve:  To  test  the  hypothesis  that  BMD  increases  following  denosumab  administra(on,  which  is  seen  despite   low  bone  turnover  markers  and  limited  iliac  crest  tetracycline  labeling,  result  from  a  non-­‐remodeling  dependent   mechanism  that  accrues  bone  matrix     The  hypothesis  was  tested  by  examining  the  fluorochrome  labeling  parern  in  proximal  femur  sec(ons  from   ovariectomized  cynomolgus  monkeys  treated  with  denosumab  for  16  months   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. Mature  ovariectomized  cynomolgus   monkeys  (N  =  34;  age  >9  years)   Vehicle  (n  =  20)   Denosumab     25  mg/kg  (n  =  14)   •  Administra(on  of  flourochrome  labels  was  at  months  6,  12,  and  16   •  Dose  of  denosumab  was  25x  clinical  dose   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. 24. Figure: Epifluorescent micrograph from denosumab-treated cynomolgus monkeys femur sections •  Both  the  superior  endocortex  and  the  inferior  periosteal  surface  contained  mul(ple  superimposed  labels  over  smooth   cement  lines  which  open  spanned  months  6  to  16  (see  figure),  sugges(ng  that  modeling-­‐based  bone  forma(on  occurred   con(nuously  during  denosumab  administra(on   •  Significant  increase  in  bone  strength  was  due  to  augmenta(on  of  bone  mass,  which  occurred  at  biomechanically  relevant   sites  on  the  superior  and  inferior  aspects  of  the  femur  neck   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. 25. Objec1ve:  To  determine  the  compara(ve  effects  of  TPTD,  DMAB,  and  combina(on   therapy  (COMBO)  on  peripheral  compartmental  bone  density  and  microarchitecture     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  (51–91)   randomized     (N  =  100)   TPTD   20-­‐ug  SC  QD   DMAB   SC  Q6  months   COMBO   12  months   Measurements  at  distal  radius  and   (bia  by  HR-­‐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(ve  Effects  of  Teripara(de,  Denosumab,  and   Combina(on  Therapy  on  Peripheral  Compartmental     Bone  Density  and  Microarchitecture:  The  DATA-­‐HRpQCT  Study      
  26. 26. 1019.  The  DATA  Extension  Study:  2  Years  of  Combined  Denosumab  and   Teripara(de  in  Postmenopausal  Women  with  Osteoporosis:  A  Randomized   Controlled  Trial.  Benjamin  Leder  et  al.  
  27. 27. Mean percent change (SD) from baseline in bone density and microarchitecture at 12 months at the radius •  Increase  in  Dcort  was  observed  in  the  COMBO  group  versus  TPTD  group  (P<.01)   •  Cor(cal  porosity  was  increased  more  with  TPTD  (18.0,  36.4%)  than  in  DMAB  (2.9,  18.8%)  and  COMBO  (3.0,   18.7%)   -­‐5   0   5   10   15   20   DTot   DTrab   DCort   Tb.Th   Tb.Sp   Tb.N   Ct.Th   Ct.Po   Mean  percent  change  from  the   baseline     HR-­‐pQCT   TPTD   DMAB   COMBO   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. Ct.Th, cortical thickness; Ct.Po, cortical porosity; Dcort, cortical density; DMAB, denosumab; DTot, total density; Dtrab, trabecular 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(ve  Effects  of  Teripara(de,  Denosumab,  and   Combina(on  Therapy  on  Peripheral  Compartmental     Bone  Density  and  Microarchitecture:  The  DATA-­‐HRpQCT  Study     Results  
  28. 28. Mean percent change (SD) from baseline in bone density and microarchitecture at 12 months at the tibia •  In  the  COMBO  group,  increased    DTot  was  observed  at  the  (bia  (3.1,  2.1%)  when  compared  with  the  TPTD   (0.0,  2.3%,  P<.0001)  and  DMAB  groups  (2.2,  2.0%,  P  =  .011)   •  Cor(cal  porosity  increased  more  at  (bia  in  TPTD  (5.6,  10.3%)  than  in  DMAB  (-­‐2.0,  10.6%)  and  COMBO  (-­‐1.0,   10.0%)   Ct.Th, cortical thickness; Ct.Po, cortical porosity; Dcort, cortical density; DMAB, denosumab; DTot, total density; Dtrab, trabecular 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. 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. Compara(ve  Effects  of  Teripara(de,  Denosumab,  and   Combina(on  Therapy  on  Peripheral  Compartmental     Bone  Density  and  Microarchitecture:  The  DATA-­‐HRpQCT  Study     Results  
  29. 29. Objec1ve:  To  assess  the  12-­‐month  effect  of  romosozumab  on  LS  and  TH  BMD,  and  bone  BMC  as   measured  by  QCT  in  postmemopausal  women  (aged  55–85  years)  with  LS,  TH,  or  femoral  neck  T-­‐ score  ≤-­‐2.0  and  ≥-­‐3.5   Genant HK, et al. USCF & Synarc Inc., USA. Effect of Romosozumab on Lumbar Spine and Hip Volumetric Bone Mineral Density (vBMD) as Assessed by Quantitative Computed Tomography (QCT). Abstract [1022]. Presented at the 2013 annual meeting of The American Society of Bone and Mineral Research. October 5, 2013. •  Interna(onal,  randomized,  placebo-­‐controlled,  Phase  II  study   •  Subjects  with  baseline  and  ≥1  post-­‐baseline  QCT  measurements  were  included  in  the   analyses   •  Measurements  were  performed  at  the  “total”  LS  (mean  of  L1  and  L2  en(re  vertebral   bodies)  and  TH  with  QCT     •  Percentage  change  from  baseline  in  integral  and  cor(cal  vBMD  and  BMC  and  trabecular   vBMD  was  evaluated  for  placebo,  20  µg  QD  subcutaneous  TPTD  and  210  mg  QM   romosozumab  at  12  months   Study  design     Par1cipants   Inves1ga1ons   BMC, bone mineral content; LS, lumbar spine; QCT, quantitative computed tomography; TH, total hip; TPTD, teriparatide; vBMD, volumetric bone mineral density. Effect  of  Romosozumab  on  Lumbar  Spine  and  Hip  Volumetric  Bone  Mineral   Density  (vBMD)  as  Assessed  by  Quan(ta(ve  Computed  Tomography  (QCT)    
  30. 30. Effect  of  Romosozumab  on  Lumbar  Spine  and  Hip  Volumetric  Bone  Mineral   Density  (vBMD)  as  Assessed  by  Quan(ta(ve  Computed  Tomography  (QCT)   Results   Percentage change in integral vBMD and BMC from baseline at 12 months *P<.05 compared with baseline, placebo, and TPTD BMC 25 20 15 10 5 0 -5 10 7.5 5 2.5 0 -2.5 -5 * * * * Placebo Teriparatide Romosozumab Percentagechange frombaseline LSmean(96%CI) Percentagechange frombaseline LSmean(95%CI) “Total” lumbar spine Total hip vBMD BMC vBMD n = 18 n = 19 n = 9n = 19 n = 9n = 18 n = 27 n = 30 n = 24 n = 27 n = 30 n = 24 vBMD, volumetric bone mineral density; BMC, bone mineral content; LS, lumbar spine; TH, total hip; TPTD, teriparatide. •  Significant  increases  in   integral  vBMD  and  BMC   were  observed  at  both  the   “total”  LS  and  TH  from   baseline  with   romosozumab  treatment   compared  with  placebo   and  TPTD   •  No  difference  between   TPTD  and  placebo  was   observed  for  TH   Genant HK, et al. USCF & Synarc Inc., USA. Effect of Romosozumab on Lumbar Spine and Hip Volumetric Bone Mineral Density (vBMD) as Assessed by Quantitative Computed Tomography (QCT). Abstract [1022]. Presented at the 2013 annual meeting of The American Society of Bone and Mineral Research. October 5, 2013.
  31. 31. •  Trabecular  vBMD  increased  from  baseline  with  romosozumab  and  TPTD  at  both  LS   and  TH  (P<.05  for  both)   –  At  LS,  gains  were  similar  with  both  romosozumab  and  TPTD  (18.3%  vs  20.1%,   respec(vely)   –  At  TH,  gains  were  greater  with  romosozumab  compared  with  TPTD  (10.8%  vs  4.2%,  P<. 05)   •  Cor(cal  vBMD     –  At  LS,  greater  increases  with  romosozumab  (13.7%)  compared  with  TPTD  (5.7%);  P<.0001   –  At  TH,  increases  with  romosozumab  (1.1%),  but  not  with  TPTD  (-­‐0.9%)   •  Cor(cal  BMC   –  At  LS,  increases  with  romosozumab  compared  with  TPTD  (23.3%  vs  10.9%,  P<.0001)   –   At  TH,  increase  with  romosozumab  was  3.4%  compared  with  0.0%  with  TPTD,  P<.05   vBMD, volumetric bone mineral density; BMC, bone mineral content; LS, lumbar spine; TH, total hip; TPTD, teriparatide. Genant HK, et al. USCF & Synarc Inc., USA. Effect of Romosozumab on Lumbar Spine and Hip Volumetric Bone Mineral Density (vBMD) as Assessed by Quantitative Computed Tomography (QCT). Abstract [1022]. Presented at the 2013 annual meeting of The American Society of Bone and Mineral Research. October 5, 2013. Effect  of  Romosozumab  on  Lumbar  Spine  and  Hip  Volumetric  Bone  Mineral   Density  (vBMD)  as  Assessed  by  Quan(ta(ve  Computed  Tomography  (QCT)   Results  
  32. 32. Objec1ve:  To  evaluate  the  effects  of  subcutaneous  blosozumab  treatment  on  non-­‐invasive   es(mates  of  spine  and  hip  strength  in  postmenopausal  women  (mean  age,  62  years)  with  low  areal   BMD  (lumbar  spine  T-­‐score  of  -­‐3.5  to  -­‐2.0)   Tony Keaveny, et al. University of California, Berkeley, USA. Effects of Blosozumab on Estimated Spine and Hip Strength in Postmenopausal Women with Low Bone Mineral Density: Finite Element Analysis of a Phase-II Dosing Study. Abstract [1023]. Presented at the 2013 annual meeting of The American Society of Bone and Mineral Research. October 5, 2013. Analyses  of  sub-­‐group  of  pa(ents  enrolled  in  a  double-­‐blind,  placebo-­‐controlled,  randomized,   mul(center,  1-­‐year  Phase-­‐II  dosing  study     •  To  es(mate  spine  and  hip  strength,  finite  element  analyses  were  performed  for  all  pa(ents   who  had  spine  and/or  hip  CTs  at  baseline  and  at  either  24  or  52  weeks,  using  the  VirtuOst   sopware  (O.N.  Diagnos(cs,  Berkeley,  CA)   •  Sta(s(cal  analyses  were  carried  out  using  a  mixed-­‐effect  model     Study  design     Postmenopausal  women  with  low  areal  BMD   (n  =  42;  all  receiving  calcium  +  vitamin  D)   Assessments   Placebo   Blosozumab  180  mg   every  4  weeks   Blosozumab  180  mg   every  2  weeks   Blosozumab  270  mg   every  2  weeks   BMD, bone mineral density. Effects  of  Blosozumab  on  Es(mated  Spine  and  Hip  Strength  in  Postmenopausal   Women  With  Low  Bone  Mineral  Density:  Finite  Element  Analysis  of  a  Phase-­‐II   Dosing  Study    
  33. 33. Effects  of  Blosozumab  on  Es(mated  Spine  and  Hip  Strength  in  Postmenopausal   Women  With  Low  Bone  Mineral  Density:  Finite  Element  Analysis  of  a  Phase-­‐II   Dosing  Study   Results   Change in finite element-estimated spine and hip strength Percent change from baseline; LS mean (95% CI) P<.05 at least, as compared with placebo (†) or baseline (*); n = number of patients. CI, confidence interval. •  Although  there  was  no  change  in  either  spine  or  hip  strength  from  baseline  in  the  placebo   group,  an  increase  in  both  spine  and  hip  strength  was  observed  at  both  week  24  and  week  52   in  the  treated  groups  (P<.05  at  least)   Placebo   Blosozumab  180  mg   every  4  weeks   Blosozumab  180  mg   every  2  weeks   Blosozumab  270  mg   every  2  weeks   Spine   24  weeks   -­‐0.4  (-­‐7.1,  6.3)   n  =  10   12.0†*  (5.5,  18.4)   n  =  11   27.5†*  (21.4,  33.7)   n  =  12   29.5†*  (21.3,  37.9)   n  =  7   52  weeks   0.7  (-­‐7.0,  8.5)   n  =  7   13.7†*  (6.3,  21.3)   n  =  8   32.0†*  (25.0,  38.5)   n  =  10   37.0†  (26.8,  47.2)   n  =  3   Hip   24  weeks   -­‐0.4  (-­‐2.3,  1.4)   n  =  11   0.7  (-­‐1.1,  2.5)   n  =  12   3.1†*  (  1.3,  4.9)   n  =  12   9.6†*  (7.1,12.1)   n  =  6   52  weeks   0.3  (-­‐1.9,  2.4)   n  =  8   1.4*  (-­‐0.6,  3.5)   n  =  9   5.4†*  (3.4,  7.4)   n  =  10   12.6†*  (9.3,  15.9)   n  =  3   Tony Keaveny, et al. University of California, Berkeley, USA. Effects of Blosozumab on Estimated Spine and Hip Strength in Postmenopausal Women with Low Bone Mineral Density: Finite Element Analysis of a Phase-II Dosing Study. Abstract [1023]. Presented at the 2013 annual meeting of The American Society of Bone and Mineral Research. October 5, 2013.
  34. 34. The  Pharmacokine(cs  of  Odanaca(b  50  mg  Are  Not  Affected     by  Severe  Renal  Insufficiency   Objective: To assess the impact of severe renal insufficiency on pharmacokinetics, pharmacodynamics, and tolerability of odanacatib 50 mg   Stoch A, et al. USA. The Pharmacokinetics of Odanacatib 50 mg are Not Affected by Severe Renal Insufficiency. Abstract [SA0390]. Presented at the 2013 Annual Meeting of The American Society for Bone and Mineral Research. October 5, 2013. Open-label, single-dose study; odanacatib orally administered to Subjects  (n=13)  with  severe  renal  insufficiency*   (aged  47–79  years)   Healthy  control  (n=12)  subjects**     (aged  40-­‐72  years)     Collection of plasma and urine samples (pre-dose and at specified time points over 15 days post- dose) for analyzing odanacatib concentrations and biomarkers *Defined as a creatinine clearance of <30 mL/min, **creatinine clearance ≥90 mL/min; both the groups were matched for age, gender, and body mass index. •  ANCOVA  model  to  determine  odanaca(b  AUC0-­‐∞  on  log  scale   •  AUC0-­‐∞  GMR  to  determine  pharmacokine(c  similarity  between  2  groups  based  on  the  90%  CI  for  the  GMR   contained  within  the  comparability  bounds  of  (0.40,  2.50)   •  Determina(on  of  Cmax,  Tmax,  and  apparent  terminal  t1/2   •  Analysis  of  serum  NTx  and  urine  NTx/Cr  to  determine  pharmacodynamics  by  linear  mixed  effect  model   •  AEs  analyzed  throughout  the  study   AEs, adverse events; ANCOVA, analysis of covariance; AUC, area under the curve; CI, confidence interval; Cr, creatinine; Cmax, maximum plasma concentration; GMR, geometric mean ratio; NTx, N-terminal telopeptide; Tmax, time to reach maximum concentration; t1/2, half-life.
  35. 35. The  Pharmacokine(cs  of  Odanaca(b  50  mg  Are  Not  Affected     by  Severe  Renal  Insufficiency   Results   95% CI -47.30, -23.38 95% CI -53.39, -30.76 95% CI -65.81, -51.51 95% CI -52.83, -32.08 AEs, adverse events; AUC, area under the curve; CI, confidence interval; Cmax, maximum plasma concentration; Cr, Creatinine; GMR, geometric mean ratio; NS, Non-sgnificant; NTx, N-terminal telopeptide; t1/2 , half-life. The  differences  in  serum  NTx  and  urine  NTx  levels  between  the  pa(ents  with  renal  insufficiency  and  healthy-­‐ matched  controls  were  non-­‐significant  (*P  =  NS)   Serum NTx and urine NTx/Cr values at 168 hours post-dose Stoch A, et al. USA. The Pharmacokinetics of Odanacatib 50 mg are Not Affected by Severe Renal Insufficiency. Abstract [SA0390]. Presented at the 2013 Annual Meeting of The American Society for Bone and Mineral Research. October 5, 2013.
  36. 36. Effect of Odanacatib on BMD and Fractures: Results From Bayesian Univariate and Bivariate Meta-Analyses Systema(c  review  of   Medline,  EMBASE,   Cochrane  library,   conference  proceedings,   and  bibliographies   31  poten(al  ar(cles   selected   6  ar(cles  on  4  RCT’s   included  (N  =  788)   Objective: Using Bayesian univariate and bivariate meta-analysis, this systematic review aimed to estimate the efficacy of ODN (50 mg/wk) in current trials and predicted its efficacy in future trials Gajic-Veljanoski O, et al. University Health Network, Canada. Effect of odanacatib on BMD and fractures: Results from Bayesian univariate and bivariate meta-analyses. Abstract [SA0384]. Presented at the 2013 Annual meeting of The American Society for Bone and Mineral Research. October 5, 2013. BMD, bone marrow density; ODN, odanacatib; RCT, randomized controlled trial.
  37. 37.   Bayesian  univariate  meta-­‐analyses:  Efficacy  of  ODN  on  BMD  or  all  fractures  (1-­‐3  yrs)     Effect  of  Odanaca1b  on  BMD  and  Fractures:  Results   From  Bayesian  Univariate  and  Bivariate  Meta-­‐Analyses   0 2 4 6 8 10 1.0 0.8 0.6 0.4 0.2 0.0 Density Mean Difference in LS BMD (% Change): ODN 1-3 Years De Villiers 2012 Brixen 2013 Nakamura 2013 Eisman 2011 POOLED MD FUTURE MD 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 10 De Villiers 2012 Nakamura 2013 Eisman 2011 Brixen 2013 POOLED MD FUTURE MD 0.0 0.5 1.0 1.5 2.0 2.5 3.0 6 5 4 3 2 1 0 De Villiers 2012 Brixen 2013 Eisman 2011 POPULATION OR FUTURE OR 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 10 De Villiers 2012 Nakamura 2013 Eisman 2011 Brixen 2013 POOLED MD FUTURE MD Density Mean Difference in TH BMD (% Change): ODN 1-3 Years Density Odds Ratio-All Fracture: ODN 2-3 years Density Mean Difference in FN BMD (% Change): ODN 1-3 Years BMD, bone marrow density; ODN, odanacatib. Gajic-Veljanoski O, et al. University Health Network, Canada. Effect of odanacatib on BMD and fractures: Results from Bayesian univariate and bivariate meta-analyses. Abstract [SA0384]. Presented at the 2013 Annual meeting of The American Society for Bone and Mineral Research. October 5, 2013.
  38. 38. How  to  TREAT  pa(ents  with  atypical  fractures?  
  39. 39. 1079   Histology  of  Atypical  Femoral  Fractures.  Jorg  Schilcher*1,   1080 Effect of Teriparatide on Healing of Incomplete Atypical Femur Fractures. Angela M. Cheung* et al
  40. 40. Histology  of  Atypical  Femoral  Fractures   Results   Histological  observa1ons   Fracture  gap  (X)     Amorphous  material  (+)   Thin  layer  of  amorphous   material  between  intact   bone  and  fragment   (lamellar  bone  tend  to   loosen);  white  arrows       Resorp(on  cavi(es   near  the  fracture  (black   arrows  )   Adapted from Schilcher J, et al. Presented at the 2013 Annual Meeting of The ASBMR. October 7, 2013. Schilcher  J,  et  al.  Linköping  University,  Sweden.  Histology  of  Atypical  Femoral  Fractures.  Abstract  [1079].  Presented  at  the  2013  Annual  Mee(ng  of  The  American  Society  for  Bone  and  Mineral  Research.   October  7,  2013.    
  41. 41. Effect  of  Teripara(de  on  Healing  of  Incomplete  Atypical     Femur  Fractures   Objec1ve:  To  evaluate  the  efficacy  of  teripara(de  in  pa(ents  with  incomplete  AFFs     AFF, atypical femur fracture; ASBMR, American Society for Bone and Mineral Research; CT, computed tomography. Cheung AM, et al. University Health Network-University of Toronto, CANADA. Effect of Teriparatide on Healing of Incomplete Atypical Femur Fractures. Abstract [1080]. Presented at the 2013 Annual Meeting of The American Society for Bone and Mineral Research. October 7, 2013. • Pa(ents  from  the  larger  Ontario  AFF  cohort  study  (N  =  22)  who  sa(sfied  the   criteria  for  the  defini(on  of  AFF  according  to  the  ASBMR  Task  Force  Par(cipants   • Fracture  healing  evaluated  by  CT  scans  and  plain  radiographs   • Measurement  of  depth  of  the  lucency  line  through  the  cortex  and  degree   of  extension  around  the  circumference  every  6  months  up  to  2  years   • Capture  of  progression/regression  of  fracture  line  up  to  last  follow-­‐up   Inves(ga(ons   • Descrip(ve  sta(s(cs  Sta(s(cal  analysis  
  42. 42. Effect  of  Teripara(de  on  Healing  of  Incomplete  Atypical  Femur  Fractures   Results   25(OH)D, 25-hydroxyvitamin D; AFF, atypical femur fracture; BMD, bone mineral density; BMI, body mass index; FN, femoral neck; LS, lumbar spine; PTH, parathyroid hormone; TH, total hip; TPD, teriparatide. •  All  pa(ents  were  postmenopausal  women  (mean  age  65.9  years;  range  26.0–80.8  years)  with  normal   ionized  calcium  and  intact  PTH   •  Mean  BMI  =  28.4  kg/cm2  and  mean  serum  25(OH)  D  =  110  nmol/L   •  77%  (n  =  17)  had  bilateral  AFFs  (12  complete  AFF  and  5  bilateral  incomplete  AFF)  and  23%   (n  =  5)  had  unilateral  incomplete  AFF   •  Mean  BMD  T-­‐scores  at  diagnosis  were   –  LS:  -­‐  1.76   –  TH:  -­‐  1.16   –  FN:  -­‐  1.78   •  Average  length  of  bisphosphonate  use  was  12  years   At  diagnosis     •  Average  dura(on  of  TPD  was  18.8  months   •  3  pa(ents  had  prophylac(c  surgical  repair   •  15  pa(ents  had  19  incomplete  AFFs  (2  healed,  5  healing,  and  12  stable  AFFs)   •  Worsening  of  fracture  was  not  observed  in  any  pa(ent   •  New  lucency  lines  in  the  same  femur  as  their  original  AFFs  developed  in  4  pa(ents   Aner  TPD  treatment   Cheung AM, et al. University Health Network-University of Toronto, CANADA. Effect of Teriparatide on Healing of Incomplete Atypical Femur Fractures. Abstract [1080]. Presented at the 2013 Annual Meeting of The American Society for Bone and Mineral Research. October 7, 2013.
  43. 43. Once-­‐Weekly  Teripara(de  Reduces  Vertebral  Fracture     Risk—Subgroup  Analysis  From  the  Teripara(de  Once-­‐Weekly     Efficacy  Research  (TOWER)  Trial,  542  Japanese    pa(ents  (RCT)   Results   BMD, bone mineral density; eGFR, estimated glomerular filtration rate; RR, relative risk; SD, standard deviation. •  2.7%  teripara1de  subjects  and  13.2%  placebo  subjects  had  incident  vertebral  fracture   •  RR  for  incident  vertebral  fracture  was  0.20  (P<.001)   •  Incident  vertebral  fractures  were  not  observed  in  subgroups  of  pa(ents  with  no  prevalent  vertebral   fractures,  with  vertebral  deformity  of  grade  0  to  2,  and  with  lumbar  BMD  ≥−2.5  SD  in  the  teripara(de   group     Subgroup  of  pa1ents   RR   P  value   <75  years   0.06   .007   ≥75  years   0.32   .015   1  vertebral  fracture   0.08   .015   ≥2  vertebral  fractures   0.29   .009   Grade  3  deformity   0.26   .003   Lumbar  BMD  <−2.5  SD   0.25   .035   eGFR  >70  mL/min/1.73  m2   0.13   .001   eGFR  <70  mL/min/1.73  m2   0.31   .004   Sugimoto T, et al. Shimane University School of Medicine, Japan. Once-weekly Teriparatide Reduces Vertebral Fracture Risk − Subgroup Analysis from the Teriparatide Once Weekly Efficacy Research (TOWER) Trial. Abstract [FR0376]. Presented at the 2013 Annual Meeting of The American Society for Bone and Mineral Research. October 4, 2013.
  44. 44. Objec1ve:  To  iden(fy  predictors  of  re-­‐fracture  amongst  a  specialist-­‐managed   popula(on     Ca + D, calcium and vitamin Study  design     • 7-­‐year  follow-­‐up  study   Par1cipants   • 212  subjects  who  were  treated  for  an  incident  osteoporo(c  fracture  (most  of  them  non-­‐ vertebral,  non-­‐hip)  for  at  least  4  years  (about  75%  were  put  on  bisphosphonates;  25%  on   Ca+D)   Inves1ga1ons   • Anthropometric,  clinical,  and  technical  data  were  documented  every  6  months   • Predictors  of  re-­‐fracture  were  iden(fied  by  logis(c  regression  analyses  before  and  aper   adjustment  for  poten(al  confounders   Ganda K, et al. Concord Hospital, Australia. Predictors of Re-fracture in Patients Managed within a Fracture Liaison Service: A 7-year Prospective Study. Abstract [SU0331]. Presented at the 2013 annual meeting of The American Society of Bone and Mineral Research. October 6, 2013. Predictors  of  Re-­‐Fracture  in  Pa(ents  Managed  Within  a     Fracture  Liaison  Service:  A  7-­‐Year  Prospec(ve  Study    
  45. 45. Predictors  of  Re-­‐Fracture  in  Pa(ents  Managed  Within  a     Fracture  Liaison  Service:  A  7-­‐Year  Prospec(ve  Study   Results   •  The  mean  dura(on  of  the  follow-­‐up  was  5.57  years  (4.02–7.51),  at  baseline,  mean  age  72.4  years,   mean  total  hip  T-­‐score  -­‐1.2   •  79%  female  and  38%  had  prevalent  fractures  at  the  (me  of  index  fracture   •  24%  of  the  treated  subjects  had  re-­‐fracture  during  the  study  (most  new  fractures  being  non-­‐ vertebral,  non-­‐hip),  and  in  a  group  of  similar  composi(on  the  re-­‐fracture  rates  were  35%  to  46%   over  2  to  6  years   •  In  unadjusted  analyses,  predictors  of  re-­‐fracture  were     –  Female  gender   –  Use  of  oral    glucocor(coid   –  Significant  comorbidi(es  (>3)   –  Gastro-­‐esophageal  reflux     –  Cardiovascular  disease   –  Body  weight,  <66.4  kg     –  Total  hip  T-­‐score,  <-­‐1.65  SD   –  Previous  falls       –  Maternal  history  of  hip  fracture   –  >2  prevalent  fractures   –  Sunlight  <30  min/d   SD, standard deviation; kg, kilogram. Ganda K, et al. Concord Hospital, Australia. Predictors of Re-fracture in Patients Managed within a Fracture Liaison Service: A 7-year Prospective Study. Abstract [SU0331]. Presented at the 2013 annual meeting of The American Society of Bone and Mineral Research. October 6, 2013.
  46. 46. Predictors  of  Re-­‐Fracture  in  Pa(ents  Managed  Within  a  Fracture  Liaison  Service:  A   7-­‐Year  Prospec(ve  Study   Results   •  Aper  adjus(ng  for  confounders,  the  following  factors  remained  significantly  associated  with   re-­‐fracture   –  Female  gender  (OR  7.3,  95%  CI  1.6–33.8,  P  =  .01)   –  Comorbidity  (OR  4.1,  95%  CI  1.9–9.1,  P<.01)   –  Total  hip  T-­‐score  <  –1.65  (OR  3.9,  95%  CI  1.8–8.3,  P<.01)   –  ≥1  fall  within  the  last  year  (OR  2.2,  95%  CI  1.0–4.8,  P  =  .04)   •  Prevalent  fracture  status  and  age  were  not  associated  with  re-­‐fracture   •  MPR  below  0.50  was  the  strongest  predictor  of  re-­‐fracture.   CI, confidence interval; MPR, medication possession rate; OR, odds ratio; SD, standard deviation. Ganda K, et al. Concord Hospital, Australia. Predictors of Re-fracture in Patients Managed within a Fracture Liaison Service: A 7-year Prospective Study. Abstract [SU0331]. Presented at the 2013 annual meeting of The American Society of Bone and Mineral Research. October 6, 2013.
  47. 47. •  E-­‐Consult  na  fracture:  medica(e  4.7%  ervoor,  5.9%   erna  (ns).  Lee  et  al,  SU  392.   •  System  based  interven(on  aper  fracture:  BMD   tes(ng  van  5%  naar  43.5%.  Bunta  et  al,  SU  391.   •  75.000  clinical  fractures  in  the  Netherlands  in  2010,     •  107.000  in  2025….  (SCOPE,  IOF  2013)  
  48. 48. OVERIGE  
  49. 49. •  62-­‐jarige  vrouw,  maakt  zich  zorgen  over  osteoporose,  omdat  haar  moeder   een  heupfractuur  had.     •  Ze  doet  regelma(g  aan  lichaamsbeweging,  neemt  1200  mg  aan   calciumsupplementen  per  dag  en  een  dieet  met  naar  scha‰ng  1040  mg   calcium  per  dag;   •  Ze  maakt  zich  zorgen  om  haar  cardiovasculaire  risico.   •  Wat  adviseert  U  haar?     •  Wie  (her)kent  deze  vrouw?   Bolland et al, BMJ 2008
  50. 50. New Engl J Med 2013 Areas of uncertainty: cardiovascular risk, differences between products in skeletal benefits and side effects, and requirements in premenopausal women, men and non caucasians.
  51. 51. Dietary and Supplemental Calcium Intake and the Risk of Mortality in Older Men: the MrOS Study n=5697 Results   *Adjusted for age, energy intake and calcium supplement use; ** Adjusted for age, ethnicity, education, BMI, walking speed, total energy intake, health habits, calcium supplements use, clinical center. RH, risk hazard; SD, standard deviation. •  Mean  age  (±SD),  74  ±  6  years   •  Mean  dietary  calcium  intake,  1142  ±  590  mg/d   •  Calcium  supplements  use,  65%  of  pa(ents   •  Men  with  higher  intake  were  older,  thinner,  berer  educated,  more  likely  to  be  Caucasian,  less  likely   to  smoke,  and  had  higher  gait  speed  compared  with  those  with  lower  total  calcium  intake  (P  trend   <.05  for  all)     At  baseline     •  2022  men  died,  of  which  687  deaths  were  due  to  cardiovascular  disease   –  Aper  par(al  adjustment*,  total  mortality  (RH  =  1.19,  CI:  1.02,  1.39)  was  higher  in  pa(ents   with  lowest  quar(le  of  total  calcium  intake  (<621  mg/d)  compared  with  pa(ents  in   highest  quar(le  (>1565  mg/d)   –  Aper  complete  adjustment**,  dietary  and  supplemental  calcium  intake  were  not   associated  with  total  or  cardiovascular  mortality  (see  the  figure  on  the  next  slide)   During  10-­‐year  follow-­‐up   Bauer D, et al. San Francisco, USA. Dietary and Supplemental Calcium Intake and the Risk of Mortality in Older Men: the MrOS Study. Abstract [1001]. Presented at the 2013 Annual Meeting of The American Society for Bone and Mineral Research. October 4, 2013.
  52. 52. Dietary and Supplemental Calcium Intake and the Risk of Mortality in Older Men: the MrOS Study Results   •  Calcium  intake  was  not  associated  with  total  or  cardiovascular  mortality  (P  trend  =  0.51,  0.79,  respec(vely)   •  Intake  of  calcium  supplements  was  also  not  associated  with  total  (RH  =  1.06,  CI:  0.96,  1.18)  or   cardiovascular  mortality  (RH  =  1.00,  CI:  0.83,  1.20)     *Adjusted for age, ethnicity, education, BMI, walking speed, total energy intake, health habits, calcium supplement use, and clinical center. BMI, body mass index; RH, risk hazard. 0 0.9 1.2 0.6 0.3 1.5 1.8 1.04 1.064 0.97 0.953 1 1.017 11 Q1: <681 Q2: 681-<1000 Q3: 1000-<1565 Q4: >1565 Quartiles of total calcium intake, mg/d Mortalityhazardratios*(95%Cl) Referent Total Mortality Cardiovascular Mortality Bauer D, et al. San Francisco, USA. Dietary and Supplemental Calcium Intake and the Risk of Mortality in Older Men: the MrOS Study. Abstract [1001]. Presented at the 2013 Annual Meeting of The American Society for Bone and Mineral Research. October 4, 2013.
  53. 53. Original Article Vitamin D–Binding Protein and Vitamin D Status of Black Americans and White Americans Camille E. Powe, M.D., Michele K. Evans, M.D., Julia Wenger, M.P.H., Alan B. Zonderman, Ph.D., Anders H. Berg, M.D., Ph.D., Michael Nalls, Ph.D., Hector Tamez, M.D., M.P.H., Dongsheng Zhang, Ph.D., Ishir Bhan, M.D., M.P.H., S. Ananth Karumanchi, M.D., Neil R. Powe, M.D., M.P.H., M.B.A., and Ravi Thadhani, M.D., M.P.H. N Engl J Med Volume 369(21):1991-2000 November 21, 2013
  54. 54. Levels of Total 25-Hydroxyvitamin D and Vitamin D–Binding Protein in Community-Dwelling White and Black Study Participants (n=904 and 1181). Powe CE et al. N Engl J Med 2013;369:1991-2000
  55. 55. Variant Vitamin D–Binding Proteins and Bioavailable 25-Hydroxyvitamin D. Powe CE et al. N Engl J Med 2013;369:1991-2000
  56. 56. Total and Bioavailable 25-Hydroxyvitamin D Levels among Homozygous Blacks and Whites with Similar Parathyroid Hormone Levels. Powe CE et al. N Engl J Med 2013;369:1991-2000
  57. 57. A  Randomized,  Double-­‐Blind,  Placebo-­‐Controlled  Trial  of  Alendronate   Treatment  for  Fibrous  Dysplasia  of  Bone     Objec1ve:  To  evaluate  the  efficacy  of  oral  alendronate  in  the  treatment  of  FD   Boyce A, et al. Children’s National Medical Center, USA. A Randomized, Double-blind, Placebo-controlled Trial of Alendronate Treatment for Fibrous Dysplasia of Bone. Abstract [SA0036]. Presented at the 2013 Annual Meeting of The American Society for Bone and Mineral Research. October 5, 2013. •  Randomized,  double-­‐blind,  placebo-­‐controlled  trial   Study  design   BMD, bone mineral density; FD, fibrous dysplasia. •  40  subjects  with  FD  (children  [n  =  15;  median  age  10,  range  6-­‐16]  and  adults     [n  =  23;  median  age  40,  range  20-­‐57])  enrolled   Par1cipants   •  Drug  or  placebo  for  6  months,  followed  by  6  months  off,  6  months  on  again,  and  6   months  off   •  Dosage:  40  mg/d  for  subjects  weighing  >50  kg,  20  mg  for  those  weighing  30  to  50  kg,  and   10  mg  for  those  weighing  20  to  30  kg   Treatment   •  Primary  end  point:  Change  from  baseline  in  N-­‐telopep(de  and  osteocalcin  at  18  months   •  Secondary  end  points:  Effects  on  pain  and  BMD  at  FD  and  non-­‐FD  sites     End  points  
  58. 58. A  Randomized,  Double-­‐Blind,  Placebo-­‐Controlled  Trial  of  Alendronate   Treatment  for  Fibrous  Dysplasia  of  Bone   Results   Wisconsin Brief Pain Questionnaire 10 8 6 4 2 0 0 6 12 18 24 Alendronate Placebo Treatment Period PainScore Months on Treatment There was no significant change in pain between the alendronate and placebo groups Boyce A, et al. Children’s National Medical Center, USA. A Randomized, Double-blind, Placebo-controlled Trial of Alendronate Treatment for Fibrous Dysplasia of Bone. Abstract [SA0036]. Presented at the 2013 Annual Meeting of The American Society for Bone and Mineral Research. October 5, 2013.
  59. 59. A  Randomized,  Double-­‐Blind,  Placebo-­‐Controlled  Trial  of  Alendronate   Treatment  for  Fibrous  Dysplasia  of  Bone   Results   •  Aper  18  months,  alendronate  decreased  N-­‐telopep(de  (P  =  .001),  with  no  change   in  osteocalcin  (P  =  .7)   •  BMD  increased  in  non-­‐FD  sites  (P  =  .003);     •  there  was  no  difference  at  the  FD  sites  (affected  femora  or  humeri)   -­‐  Fractures  were  observed  in  3  pa(ents  from  the  alendronate  group     -­‐  and  3  from  the  placebo  group   FD, fibrous dysplasia. Boyce A, et al. Children’s National Medical Center, USA. A Randomized, Double-blind, Placebo-controlled Trial of Alendronate Treatment for Fibrous Dysplasia of Bone. Abstract [SA0036]. Presented at the 2013 Annual Meeting of The American Society for Bone and Mineral Research. October 5, 2013.
  60. 60. SA0077   Varia(on  in  Bone  Turnover  Markers  in  Professional  Sport  Players  During   Training  is  Mediated  by  Changes  in  Scleros(n  Levels.  Ranuccio  Nu(*1  et  al.     University  of  Siena,  Italy,  University  of  Siena,  Italy,  Medical  Staff  Siena  Football  Club,   Italy   Before  Training   Before  Start  Season   Mid  Season   CTX   1,48   0,91   1,01   Bone  AF   12,1   17,5   15,8   Scleros(n     30.6   26.0  
  61. 61. Dank  voor  Uw  aandacht!  

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