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Slobodan Vukičević: Osteoporoza u žena Od Alendronata do Osteogrowa Brijuni, 8-11 rujan 2011

Slobodan Vukičević: Osteoporoza u žena Od Alendronata do Osteogrowa Brijuni, 8-11 rujan 2011

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Slobodan Vukičević: Osteoporoza u žena Od Alendronata do Osteogrowa Brijuni, 8-11 rujan 2011

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  1. Slobodan Vukičević: Osteoporoza u ženaOd Alendronata do OsteogrowaBrijuni, 8-11 rujan 2011

  2. Tolerancija i sigurnost • prospektivne RCT studije • bisfosfonati grupa lijekova najopsežnije proučena u povjesti medicine • od 1969 sigurnost i učinkovitost proučavana u nizu opsežnih RCT studija u bolesnika sa osteoporozom, Padgetovom bolesti, mijelomom i koštanim metastazama. Bisfosfonati koji sadrže dušik proučeni su u više od 60,000 bolesnika u trajanju od 3 ili više godina • do 201. prepisano je više od 330 milijuna oralnih bisfosfonata širom svijeta

  3. Gideon Rodan • vodio alendronat od oktrića do FDA odobrenja • čovjek največeg moralnog integriteta i zato su klinički rezultati alendronata 100% pouzdani i bez post-hoc prilagodbi • otvorio put za novu klasu lijekova His outstanding scientific contributions included: isolation and characterization of the first transformed osteoblastic cell line (ROS 17), the dissection of the PTH signal transduction mechanisms, the concept of osteoblast-osteoclast interactions, the cloning of alkaline phosphatase, and the roles of steroids and prostaglandins in bone metabolism. As Director of the Department of Bone Biology and Osteoporosis Research at Merck, he fostered the development of the first bisphosphonate approved for treatment of osteoporosis and provided detailed studies of the mechanisms of action of the bisphosphonates.

  4. Alendronat: Prijetnje i uspjesi GO 1995 odobren u Americi Phase III Osteoporosis Treatment Study Liberman i sur NEJM 1995

  5. Alendronat: Prijetnje i uspjesi GO biomehanika kosti 1995 odobren u Americi 1993/2003 Phase III Osteoporosis Treatment Study FIT 3236

  6. Alendronat: Prijetnje i uspjesi gubitak kosti prestankom Ther biomehanika kosti 1998/2003 1993/2003 FIT 3236 FLEX 2852

  7. BMD: Slabinska kralježnica 5 godina nakon prestanka uzimanja alendronata 14.80% 5.26% 3.81% FLEX FIT 10.99% 1.52% 9.54% 5-10% gube neliječene žene iste dobi alendronat placebo alendronat

  8. BMD: Vrat bedrene kosti 5 godina nakon prestanka uzimanja alendronata FLEX FIT 4.10% 1.94% placebo alendronat alendronat

  9. Alendronat: Prijetnje i uspjesi gubitak kosti prestankon Ther osteonekroza čeljusti biomehanika kosti 1998/2003 1993/2003 2005 FIT 3236 FLEX 2852

  10. Osteonekrozačeljusti Intraoralni aspekt izložene kosti na mjestu prethodno izvađenog zuba

  11. ONJ=komplikacija ovisna o LIJEKU a ne samo o BISFOSFONATU

  12. Alendronat: Prijetnje i uspjesi gubitak kosti prestankom Ther rak jednjaka osteonekroza čeljusti biomehanika kosti 1998/2003 2006 1993/2003 2005 FIT 3236 FLEX 2852

  13. Alendronat: Prijetnje i uspjesi gubitak kosti prestankom Ther fibrilacija atrija rak jednjaka osteonekroza čeljusti biomehanika kosti 1998/2003 2006 1993/2003 2005 2007 FIT 3236 FLEX 2852

  14. Alendronat: Prijetnje i uspjesi gubitak kosti prestankom Ther atipični prijelomi fibrilacija atrija rak jednjaka osteonekroza čeljusti biomehanika kosti 1998/2003 2006 1993/2003 2005 2007 2008 FIT 3236 FLEX 2852

  15. Atipični prijelomi bedrene kosti: slučajevi i serije Lenart et al NEJM 358:1304, 2008 Neviaser et al J Orthop Trauma 22:346, 2008 Visekruna et al J Clin Endocrinol Metab 93:2948, 2008 Odvina et al J Clin Endocrinol Metab 90:1294, 2005 Goh et al J Bone Joint Surg Br 89:349, 2007 Armamento-Villareal et al NEJM 355:2048, 2006 Cheung et al Hong Kong Med J 13:485, 2007 Armamento-Vilareal et al Calcif Tissue Int 85:37, 2009 Somford et al J Bone Miner Res 24:1736, 2009 Odvina et al Clin Endocrinol 2009 Capeci et al J Bone Joint Surg Am 91:2556, 2009 Kwek et al Injury 39:224, 2008 Ing-Lorenzini et al Drug Saf 32:775, 2009 Abrahamsen et al J Bone Miner Res 24:1095, 2009

  16. Atipični prijelomi bedrene kosti radiološki spiralni prijelomi kortikalni kljun u gornjoj i srednjoj trećini sa poprečnim ili kosim prijelomom zadebljanje kortikalne kosti: kost deblja lateralno često obostrano

  17. Zadebljani korteks Kortikalni kljun 83g žena nakon 9g liječenja 77gžena nakon 5g liječenja Kwek EB, et al.NEJM 359:316, 2008 .

  18. Subtrohanterni stres prijelom Kwek EB, et al.NEJM 359:316, 2008 .

  19. Osugi i sur. Acta Orthop 82:112, 2011 Povezanost između subtrohanteričkih ili prijeloma dijafize femura i liječenja bisfosfonatima nije potvrđena epidemiološkim studijama ili u prospektivnim randomiziranim kontrolnim studijama

  20. Odvina et al J Clin Endocrinol Metab 90:1294, 2005 Bolesnica liječena bisfosfonatom 10g Koštana biopsija zdrave osobe

  21. Odvina et al J Clin Endocrinol Metab 90:1294, 2005Koštana biopsija u UVsvjetlu Bolesnica liječena bisfosfonatom 10g Koštana biopsija zdrave osobe

  22. NAKON PRIJE Koštane biopsije prije i nakon liječenja bisfosfonatom Armamento-Villareal et al. NEJM 355:2048, 2006

  23. HSC MSC OB precursor 3 OC precursor 2 1 OC 4 OB Osteocytes 5 5 By courtesy of Jack Martin

  24. Bone morphogenetic proteins in tissue engineering Simic & Vukicevic EMBO rep 2007

  25. TGF- or BMP superfamily BMP-7 BMP-6 BMP-2 dpp BMP-4 60A BMP-8 BMP-11 BMP-9 BMP-10 TGF-3 DORSALIN SCREW BMP-3 GDF-3 GDF-5 GDF-6 GDF-7 GDF-1 GDF-10 NODAL INHIBIN-A INHIBIN-B ACTIVIN TGF-4 TGF-1 TGF-5 BMP-5 UNIVIN VG-1

  26. BMP Books 2002, 2004 and 2008

  27. Ectopic bone formation

  28. OSTEOGROW

  29. 2009 Nature Genetics

  30. Identification of a single residue in BMP6 that is responsible for increased resistance to noggin inhibition c c Vukicevic and Grgurevic, Cyt Growth Fact Res, 2009 Song et al, J Biol Chem, 2010

  31. Generation of BMPs with superior agonistic activity

  32. K60 is associated with BMP6 resistantce to noggin Engineering BMPs with super-agonist activity Song et al JBC 2010

  33. PK of BMP6 from rat serum/plasma * * * * * * * BMP6 PLASMA SERUM in vivo in vitro Vukičević S, Grgurevic L, Oppermann H. Whole blood derived coagulum device for treating bone defects. WO2008/011192 A2.

  34. OSTEOGROW: The principle of treating bone fractures in men Bone fracture

  35. OSTEOGROW FULL BLOOD blood clot Blood clot is injected between broken bone ends BMP6 incorporates into blood clot

  36. OSTEOGROW: Whole blood modified coagulum (WBDC) + recombinant human bone morphogenetic protein6 (BMP6)

  37. Preclinical testing of safety and efficacyControl 2 weeks

  38. Control 8 weeks

  39. Commercial bone device 2 weeks

  40. Commercial bone device 4 weeks

  41. Commercial bone device 8 weeks

  42. OSTEOGROW: WBCD + 50 µg BMP6 2 weeks

  43. OSTEOGROW: WBCD + BMP6 4 weeks

  44. OSTEOGROW: WBCD + BMP6 8 weeks

  45. OSTEOGROW: Comparison 8 weeks Control Commercial device Osteogrow

  46. Financiranje

  47. OSTEOGROW project co-authors Smiljka Vikić-Topić Donatella Verbanac Mihaela Perić Ivančica Bastalić

  48. OSTEOGROW team members: Preclinical testing and bioassays for BMP6 validation Mirjana Palcic Igor Erjavec Genadij Razdorov Đurđa Car Jelena Brkljačić Martina Pauk

  49. GMP quality of BMP6 for clinical trials