OSTEONECROSI DEI MASCELLARI (ONJ): PREVENZIONE, … · OSTEONECROSI DEI MASCELLARI (ONJ): PREVENZIONE, DIAGNOSI, TRATTAMENTO UPDATE 2010 Alessandria, 5 giugno 2010 Stefania Boldini

OSTEONECROSI DEI MASCELLARI (ONJ):

PREVENZIONE, DIAGNOSI, TRATTAMENTO

UPDATE 2010

Alessandria, 5 giugno 2010

Stefania Boldini Francesco Bertoldo

Dipartimento di Scienze Biomediche e Chirurgiche

Università di Verona

Novità nel trattamento dell’osteoporosi

Many Factors Stimulate Osteoblast

Expression of RANK-Ligand1,2

Activated

Osteoclast

RANKL

RANK

OPG

Osteoclast PrecursorColony-Forming

Unit-Macrophage Multinucleated

Osteoclast

+mCSF+mCSF

Abbreviations: IL, interleukin; mCSF, macrophage colony-stimulating factor; PTH, parathyroid hormone;

PTHrP, parathyroid hormone-related protein.

.1. Boyle WJ, et al. Nature. 2003;423:337-342. 2. Hofbauer LC, et al. JAMA. 2004;292:490-495.

PTH

PGE2

Glucocorticoids

Vitamin D

IL-11

IL-6

IL-1

PTHrP

TNF-

OsteoblastsOsteoblastsand and

Bone Marrow Bone Marrow Stromal CellsStromal Cells

Bone Formation Bone Resorption

New and Emerging Treatments

Antiresorptive (anticatabolic)

• Denosumab

• Odanacatib

• Lasofoxifene

• Bazedoxifene

• New delivery systems – oral

salmon calcitonin

Osteo-anabolic (bone-forming)

• Sclerostin inhibitor

• Variations of PTH

• Endogenous PTH stimulation – calcium sensing receptor antagonist (calcilytic)

• New delivery systems –transdermal PTH

Strontium ranelate

Combinations of antiresorptive and anabolic

Osteoprotegerin Prevents RANKL Binding to

RANK and Inhibits Osteoclast Activity

Activated

Osteoclast

Osteoclast

Precursor

Multinucleated

Osteoclast

Osteoblasts

Bone Resorption

RANKL

RANK

OPG

X

XBoyle WJ, et al. Nature. 2003;423:337-342.

Colony-Forming

Unit-Macrophage

Hormones

Growth Factors

Cytokines

X

Ab anti

catepsina K

SERMAb anti

Sclerostina

Ab anti

RANK-L

New treatments

• Anti RANKL MoAb (Denosumab)

• Cathepsin K inhibitors

• SERM

• Anti Sclerostin Ab

Denosumab: anti RANKL MoAb

• Fully human monoclonal antibody

• IgG2 isotype

• High affinity for human RANKL

• High specificity for RANKL

– No detectable binding to TNFα,

TNFβ, TRAIL, or CD40L

• No neutralizing antibodies detected

in clinical trials to date

Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066.

Data on file, Amgen.

Elliott R, et al. Osteoporos Int. 2007;18:S54. Abstract

P149.

McClung MR, et al. New Engl J Med. 2006;354:821-31.

Model of Denosumab

TNF = tumor necrosis factor;

TRAIL = TNFα-related apoptosis-inducing Ligand

Dmab Mechanism of Action

Growth Factors

Hormones

Cytokines

Bone

Abbreviation: CFU-M, colony forming unit macrophage.

Osteoblast

Lineage

Osteoclast

CFU-M

Pre-Fusion

Osteoclast

Multinucleated

Osteoclast

RANK

RANKL

OPG

Dmab

Dmab Serum Levels

(1 mg/kg s.c.)

With permission from Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066.

11 33 55 99

Study MonthStudy Month

00 22 44 6600

1010

11

1010

22

1010

33

1010

44

Seru

m L

evel

(ng

/m)

ECEC5050

Cummings SR et al N. Eng.J. Med 2009: 361:1-10

-68% p <.000

Cummings SR et al N. Eng.J. Med 2009: 361:1-10

Denosumab in post menopausal

osteoporosis: the Freedom trial

-20% p< .011 -40% p< .036

Denosumab and potential applications

in medical oncology

• Denosumab and SREs in metastatic disease

• Denosumab and CTIBL (Cancer treatment-

induced bone loss)

• Denosumab and adjuvant setting

Denosumab Oncology Programme Overview

1Body J J, et al. Clin. Cancer Res 2006; 12:1221-1228; 2Lipton A, et al. J Clin Oncol 2007; 25:4431-4437; 3Suarez T et al. J

Clin Oncol 2006;24(S18):6S:8562; 4Fizazi K, et al. J Clin Oncol 2009;27:1564-71 5Vij et al. Blood 2007; 110(11):3604; 6Thomas et al. CTOS, 2007:787; 7Ellis G, et al. J Clin Oncol 2008;26:4875-82; 8Smith MR et al. N Engl J Med, 2009

Phase 1 Phase 2 Phase 3

BrCa & MM - PK/PDBreast cancer - PK/PD

(Bisphosphonate naïve)2

Solid tumours & MM - PK/PD

(Bisphosphonate treated)3,4

Multiple myeloma5

Giant cell tumour6

Solid tumours & MM - SRE

Prostate cancer - SRE

Breast cancer - SRE

Prostate cancer – delay bone mets

Prostate cancer – ADT bone loss8

Breast cancer – AI bone loss7

SRE = skeletal-related event

Final results published

ECCO Meeting, 2009

Study

Design:

Multi-center, randomized, double-blind, placebo-

controlled study conducted in the United States and

Canada

N = 125 Placebo SC every

6 months (x 4 doses)

N = 127 Denosumab 60 mg SC

every 6 months (x 4 doses)

Baseline 12 month 24 month

Women Receiving

Aromatase Inhibitor

Therapy For Hormone-

Receptor-Positive, Non-

Metastatic Breast Cancer

•T-score of -1.0 to -2.5 at

lumbar spine, total hip

(proximal femur), or

femoral neck

(osteopenia)

•Exclusion: BPs

Phase 3 Study of Denosumab in Women

Receiving Aromatase Inhibitor Therapy

Ellis GK et al. J Clin Oncol, 26:4875-82, 2008

* P < 0.0001 versus Placebo

Perc

en

tag

e C

ha

ng

e (

±95

% C

I) F

rom

Baseli

ne

in L

um

bar

Sp

ine B

on

e M

inera

l D

en

sit

y 8

6

4

2

0

-2

7

5

3

1

-1

-3

*

**

*

*

7.6% Difference

at Month 24

1 3 6 12 24Months

5.5% Difference

at Month 12

Denosumab (N = 123)Placebo (N = 122)


Primary endpoint: lumbar spine BMD changes at 12 m

* P < 0.0001 versus Placebo

Months Months

Total Hip (Proximal Femur)

Pe

rce

nta

ge C

han

ge

(±

95

% C

I) F

rom

Ba

se

line

in B

on

e M

ine

ral D

en

sity

1 3 6 12 24

4

2

0

-2

5

3

1

-1

Placebo (N = 122) Denosumab (N = 123)

**

**

Distal 1/3 RadiusPlacebo (N = 106) Denosumab (N =115)

12 24

4

2

0

-2

3

1

-1

-3

-4

-5

* *

3.7% Difference

at Month 12

4.7% Difference

at Month 24

3.8% Difference

at Month 12

6.1% Difference

at Month 24


At 12 and 24 months, total hip and distal radius BMD increased

in the denosumab group versus placebo

Phase 3 Study of Denosumab in ADT nonmetastatic

hormone-sensitive prostate cancer men

Study

Design:

Multi-center, randomized, double-blind, placebo-

controlled study conducted in the United States and

Canada

Men Receiving Adrogen

Deprivation Therapy For

Non-Metastatic hormone-

sensitive Prostate Cancer

•T-score of -1.0 to -2.5 at

lumbar spine, total hip

(proximal femur), or

femoral neck

(osteopenia)

•Exclusion: BPs

N = 734 Denosumab 60 mg SC

every 6 months (x 4 doses)

N = 734 Placebo SC every

6 months (x 4 doses)

Baseline 12 month 24 month

Smith M et al. N Engl J Med, 361:745-55, 2009.


Denosumab therapy was also associated with significant

increases in bone mineral density at all bone sites in ADT prostate

cancer patients

p<0.001 p<0.001

p<0.001p<0.001


Denosumab therapy was also associated with significant

decreases of new vertebral fractures at 12, 24, 36 months

Safety of Dmab in

Freedom trial

New treatments


• Cathepsin K inhibitors (Odanacatib)

• SERM


Bone H. et al, JBMR 2010; 25(5):937-47

Weekly dose of Odonacatib increase BMD

in all sites in a phase III with 400 PMO trial

New treatments



• SERM (Bazedoxifene, Lasofoxifene)


New SERMs for Postmenopausal

Osteoporosis

• Efficacy

– Increases BMD

– Reduces BTMs

– Decreases risk of VFs and NVFs

– Decreases risk of ER+ breast cancer

– Improves signs and symptoms of vulvovaginal atrophy

• Safety

– Increases risk of venous thromboembolisms (VTEs), hot flushes, muscle spasm, and vaginal bleeding

• Efficacy

– Increases BMD

– Reduces BTMs

– Decreases risk of VFs

• Safety

– Increases risk of VTEs, hot flushes,

muscle cramps

Cummings SR, et al. J Bone Miner Res. 2008;23:S81.

Silverman SL, et al. J Bone Miner Res. 2008;23:1923-1934.

Eastell R, et al. J Bone Miner Res. 2008;23:S81.

Lasofoxifene Bazedoxifene

Oral Bazedoxifene 20-40 mg/die increase BMD in

Lumbar spine (A) and in Total hip (B) in a phase

7492 PMO III trial

Silverman SL et al. JBMR 2008;23 (12):1923-34

A) Lumbar spine B) Total hip

Reduction on vertebral fracture incidence

in oral Bazedoxifene

20-40 mg/die

Silverman SL et al. JBMR 2008;23 (12):1923-34

Risk reduction for new/worsening vertebral (A)

and non v. fracture (B) after 3 years of LAS

treatment in PMO compared to placebo (phase III PEARL trial)

Gennari L. et al. Clinical Interventions in Aging 2010; 5:19-29

New treatments



•

• SERM


Dkk SclerostinSclerostin Wnt

Frizzled

Liganded

State

APC

axin

Gsk3

-Catenin-Catenin

-Catenin

DshFrat-1

-Catenin p300/CBP

SMRT/

NCoR

Tcf/Lef

Altered

Transcription

of Genes

Nuclear

LocalizationNucleus

OSTEOBLAST

BONE

FORMATION

WIF sFRP

APC

P

Proteosomal

Degradation

LRP

Frizzled

axin -Catenin

Gsk3

(No New

Bone Made)

Dkk SclerostinSclerostinUnliganded

State

~Pathway Dead~

With permission from

Shoback D. J Clin Endocrinol Metab. 2007;92:747-753.

Sclerostin MAb Increases BMD in Rats

0,20

0,22

0,24

0,26

0,28

0,30

0,32

0,34

Lumbar Spine Tibia-Femur

BM

D (

g/c

m2)

Sham Vehicle PTH Mab

Warmington K, et al. J Bone Miner Res. 2005;20(suppl 1):S22.

Li X, et al. J Bone Miner Res. 2009;24:578-588.

1.5-year-old rats 1 year post-ovariectomy

MAb 25 mg/kg 2x/wk x 5 wk

PTH 1-34 100 mcg/kg 5x/wk x 5 wk

There is a lot ongoing work …..

And much remains to be done…..

Target Potential

Therapy

RANKL Anti-RANKL

MIP-1a CCR1

antagonist

DKK1/sFRP-

2

Wnt Agonist,

anti-DKK1,

bortezomib

Activin A ACE-011

Documents

OSTEONECROSI DEI MASCELLARI (ONJ): PREVENZIONE, … · OSTEONECROSI DEI MASCELLARI (ONJ): PREVENZIONE, DIAGNOSI, TRATTAMENTO UPDATE 2010 Alessandria, 5 giugno 2010 Stefania Boldini