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