osteonecrosi dei mascellari (onj): prevenzione, … · osteonecrosi dei mascellari (onj):...
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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
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
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)
Ellis GK et al. J Clin Oncol, 26:4875-82, 2008
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
Ellis GK et al. J Clin Oncol, 26:4875-82, 2008
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.
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
Smith M et al. N Engl J Med, 361:745-55, 2009.
Denosumab therapy was also associated with significant
decreases of new vertebral fractures at 12, 24, 36 months
New treatments
• Anti RANKL MoAb (Denosumab)
• Cathepsin K inhibitors (Odanacatib)
• SERM
• Anti Sclerostin Ab
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
• Anti RANKL MoAb (Denosumab)
• Cathepsin K inhibitors
• SERM (Bazedoxifene, Lasofoxifene)
• Anti Sclerostin Ab
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
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