slobodan vukičević: osteoporoza u žena od alendronata do osteogrowa brijuni, 8-11 rujan 2011
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Slobodan Vukičević: Osteoporoza u ženaOd Alendronata do OsteogrowaBrijuni, 8-11 rujan 2011
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
Gideon Rodan
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.
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
Alendronat: Prijetnje i uspjesi
Phase III OsteoporosisTreatment Study
1995 odobren u Americi
GO
Liberman i sur NEJM 1995
Alendronat: Prijetnje i uspjesi
FIT 3236
1993/2003
biomehanikakosti
Phase III OsteoporosisTreatment Study
1995 odobren u Americi
GO
Alendronat: Prijetnje i uspjesi
FIT 3236 FLEX 2852
1993/2003 1998/2003
biomehanikakosti
gubitak kosti prestankom
Ther
BMD: Slabinska kralježnica 5 godina nakon prestanka uzimanja alendronata
FITFLEX
placeboalendronatalendronat
3.81%
5.26%
9.54%
1.52%
14.80%
10.99%
5-10%gube neliječenežene iste dobi
BMD: Vrat bedrene kosti 5 godina nakon prestanka uzimanja alendronata
FIT FLEX
placeboalendronatalendronat
1.94%
4.10%
Alendronat: Prijetnje i uspjesi
FIT 3236 FLEX 2852
1993/2003 1998/2003
biomehanikakosti
gubitak kosti prestankon
Ther
2005
osteonekrozačeljusti
Intraoralni aspekt izložene kosti na mjestu prethodno izvađenog zuba
Osteonekroza čeljusti
• ONJ=komplikacija ovisna o LIJEKU a ne samo o BISFOSFONATU
Alendronat: Prijetnje i uspjesi
FIT 3236 FLEX 2852
1993/2003 1998/2003
biomehanikakosti
gubitak kosti prestankom
Ther
2005
osteonekrozačeljusti
rak jednjaka
2006
Alendronat: Prijetnje i uspjesi
FIT 3236 FLEX 2852
1993/2003 1998/2003
biomehanikakosti
gubitak kosti prestankom
Ther
2005
osteonekrozačeljusti
rak jednjaka
fibrilacija atrija
2006 2007
Alendronat: Prijetnje i uspjesi
FIT 3236 FLEX 2852
1993/2003 1998/2003
biomehanikakosti
gubitak kosti prestankom
Ther
2005
osteonekrozačeljusti
rak jednjaka
fibrilacija atrija
atipični prijelomi
2006 2007 2008
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
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
83g žena nakon 9g liječenja 77g žena nakon 5g liječenja
Kortikalni kljun
Zadebljani korteks
Kwek EB, et al. NEJM 359:316, 2008 .
Subtrohanterni stres prijelom
Kwek EB, et al. NEJM 359:316, 2008 .
Povezanost između subtrohanteričkih ili prijeloma dijafize femura i liječenja bisfosfonatima nije potvrđena epidemiološkim studijama ili u prospektivnim randomiziranimkontrolnim studijama
Osugi i sur. Acta Orthop 82:112, 2011
Odvina et al J Clin Endocrinol Metab 90:1294, 2005
Bolesnica liječena bisfosfonatom 10g Koštana biopsija zdrave osobe
Odvina et al J Clin Endocrinol Metab 90:1294, 2005Koštana biopsija u UV svjetlu
Bolesnica liječena bisfosfonatom 10g Koštana biopsija zdrave osobe
Armamento-Villareal et al. NEJM 355:2048, 2006
Koštane biopsije prije i nakon liječenjabisfosfonatom
PRIJE NAKON
4
MSC
OB precursor
HSC
OC precursor
5
3
2
Osteocytes
OC
OB
1
5
By courtesy of Jack Martin
Bone morphogenetic proteins in tissue engineering
Simic & Vukicevic EMBO rep 2007
TGF- or BMP superfamily
BMP-1
1
UNIVIN
VG-1 B
MP-2
BMP-4
dppGDF-3
GDF-6
GDF-7
BMP-9
DORSALIN
BMP-1
0
SCREW
GDF-1
GDF-10
BMP-3
TGF-3
TGF-1
TGF-5
TGF-4
ACTIVIN
NODAL
INHIB
IN-
A
INHIB
IN-
B
BMP-5BM
P-6
60ABM
P-8
GDF-5 B
MP-7
BMP Books 2002, 2004 and 2008
Ectopic bone formation
OSTEOGROW
2009 Nature Genetics
Identification of a single residue in BMP6 that is responsible for increased resistance to noggin inhibition
c
c
Generation of BMPs with superior agonistic activity
Song et al JBC 2010
K60 is associated with BMP6 resistantce to noggin
Engineering BMPswith super-agonistactivity
in vivo in vitro
PLASMA SERUM
BMP6*
* * * * *
PK of BMP6 from rat serum/plasma
*
Vukičević S, Grgurevic L, Oppermann H. Whole blood derived coagulum device for treating bone defects. WO2008/011192 A2.
OSTEOGROW: The principle of treating bone fractures in men
Bone fracture
OSTEOGROW
FULL BLOOD
blood clot
BMP6 incorporates into blood clot
Blood clot is injected between broken bone ends
OSTEOGROW: Whole blood modified coagulum (WBDC) + recombinant human bone morphogenetic protein6 (BMP6)
Preclinical testing of safety and efficacy
Control2 weeks
Control
8 weeks
Commercial bone device
2 weeks
Commercial bone device
4 weeks
Commercial bone device
8 weeks
OSTEOGROW: WBCD + 50 µg BMP6
2 weeks
OSTEOGROW: WBCD + BMP6
4 weeks
OSTEOGROW: WBCD + BMP6
8 weeks
OSTEOGROW: Comparison
Control
Commercial device
Osteogrow
8 weeks
Financiranje
Smiljka Vikić-Topić
Mihaela Perić Ivančica Bastalić
Donatella Verbanac
OSTEOGROW project co-authors
Igor Erjavec
Martina PaukJelena Brkljačić
Genadij Razdorov
Đurđa Car
Mirjana Palcic
OSTEOGROW team members: Preclinical testing and bioassays for BMP6 validation
GMP quality of BMP6 for clinical trials
Genera Research in Kalinovica
OSTEOGROW consortium partners (11) Country (7)Sveuciliste u Zagrebu, Medicinski Fakultet (University of Zagreb School of Medicine, UZSM)
Croatia
Genera Istraživanja d.o.o.(Genera Research, GEN) Croatia
Linköpings Universitet (Linköping University, LIU) Sweden
Biotest s.r.o. (BT) Czech Republic
Medizinische Universitaet Wien (Medical University of Vienna, MUW) Austria
Klinika za Ortopediju i traumatologiju KCU Sarajevo (University of Sarajevo Clinical Center, Orthopedic and Traumatology Clinic, USCC)
Bosnia and Herzegovina
Paul Regulatory Services UK Ltd (PRS) United Kingdom
KB Sestre milosrdnice Klinika za traumatologiju (University of Zagreb Trauma Clinic, THZ)
Croatia
Smart Medico d.o.o. (SMED) Croatia
Vitrology Limited (VITR) United Kingdom
European Research and Project Office GmbH (Eurice, EUR) Germany
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