osteoporosi e ctibl: quali novità...elevato turnover osseo nei pazienti con carcinoma elevato...
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Osteoporosi e CTIBL:
Quali novità
Francesco Bertoldo
Dipartimento di Medicina
Universita’ di Verona
TERAPIE MEDICHE DELL’OSSO:UPDATE
Servitja S et al ,The Breast 2012 1
T-score > -1
T-score < -1 > - 2.5
T-score < -2.5
(Mean age 62.5)
Nuova metastasi
Elevato turnover osseo nei pazienti con carcinoma
ELEVATO TURNOVER OSSEO
(menopausa + terapia ormonale adiuvante + metastasi)
Perdita ossea Homing delle cellule
tumorali
Crescita della
metastasi ossea
CTIBL
FRAGILITÀ
PROGRESSIONE
OSSEA
CTX
NTX
P1NP
SDF-1
TGF b
PDGF
IGF-1
OP
CTX
NTX
P1NP
SDF-1
TGF b
PDGF
OP
CTX
NTX
P1NP
SDF-1
TGF b
PDGF
OP
SRE
Scheletro non metastatico Nicchia preneoplastica Metastasi ossea
Bertoldo F
Hormonal Adiuvant Therapy
Chemotherapy
Age
Low vitamin D levels
High Bone Turnover
The “Bone Health” concept in Cancer Patients
Bone
Metastasis
SRE Fracture
Radiotherapy
Spinal Compression
Orth. Surg.
Pain Fragility Fracture
Bone Fragility
Bone Loss/Bone
Quality Bone
Metastasis
SRE Fracture
Radiotherapy
Spinal Compression
Orth. Surg.
Pain
0 2 4 6 8
Normal men
Late menop. women
Early menop women
Aromatase Inhibitor
Bone Marrow transpl
Androgen deprivation
AI + GNrh agonist
Ovarian failure due
chemiother
1%
2 %
2.6%
3.3%
4.6%
7.0%
7.6%
Lumbar spine BMD (% /year Bone Loss)
0.5%
CANCER TREATMENT INDUCED BONE LOSS
Rate of BMD Loss
High Bone Turnover
Loss of Bone Mass Qualitative /
Microarchitectural
Damage
Bone Fragility
Fracture
Boivin G et al. Connect Tissue Res. 2002;43:535-537.
SLOW
REVERSIBLE
RAPID
IRREVERSIBLE
High prevalence of vertebral fractures in women with breast cancer starting aromatase inhibitor therapy
Bouvard B et al; Annals of Oncology, 2012
19.1 % non vertebral Fx 19.7% > 1 vertebral Fx
ETA’ < 60 aa 60-70 aa >70 aa
% > 1 VFX 10.1 18.4 32.8
497 women 63 y.o
1
Page 10
AC Lassemiante et al. Endocrine 2014
Page 11
CATEGORIE AD ALTO RISCHIO DI CTIBL / FX
•BC premenopausa dopo Kemio o K+ GnrH + TAM
( anche dopo la sospensione della terapia adiuvante)
•BC pre- o postmenopausa alla sospensione TAM
•BC postmenopausa con switch TAM- AI
•BC postmenopausa in AI “ giovani” ( < 65 aa)
•PC men
Bertoldo F
ALGORITMO DECISIONALE NELLA CTIBL
Presenza di frattura
da fragilità
SI NO
TERAPIA
CON BP o DNB
(Secondo le indicazioni
della nota 79)
ETA’
< 60 aa 60-75aa > 75aa
DEXA
T-score
< -2
TRATTAMENTO
BPs ( denosumab)
T-score <- 1
+ 1 fattore di rischio
T-score <- 1
T-score < 0 + 1 fattore
di rischio
Grado di evidenza II
Raccomandazione B
DEXA
Linee Guida
AIOM 2013
Coleman R et al.
ALGORITMO DECISIONALE NELLA CTIBL
Linee Guida
AIOM 2013
Presenza di frattura
da fragilità
SI NO
TERAPIA
CON BP o DNB
indicazioni (Secondo le
della nota 79)
ETA’
< 60 aa 60-75aa > 75aa
DEXA
T-score
< -2
TRATTAMENTO
BPs ( denosumab)
T-score <- 1
+ 1 fattore di rischio
T-score <- 1
T-score < 0 + 1 fattore
di rischio
DEXA
GUIDELINES Therapeutic Threshold Treatment
EAU 2013 DEXA T-score <-2.5 DNB 60 mg/6 mo.
ZOL 4 mg /6 mo.
NCCN 2013 FRAX HIP > 3%
FRAX major FX >20%
AL 70 mg / week
ZOL 5 mg /Year
DNB 60mg/6 mo.
CTIBL IN PROSTATE CANCER- SPECIFIC GUIDELINES
QUALI EVIDENZE PER PREVENZIONE/ TRATTAMENTO
DELLA CTIBL?
• Le attuali linee guida indicano l’utilizzo dei bisfosfonati (BP) e DNB
•Tutti gli studi in BC con BPs e DNB hanno come end-point la prevenzione
della perdita di BMD
•Vi è un unico studio (PC) con end-point la riduzione del rischio
di frattura (DNB)
• Non è definita la posologia del BPs da utilizzare
(quella utilizzata per la PMO? Maggiore?)
• Non vi sono BPs registrati con indicazione CTIBL
•. E’ registrato ( ma non rimborsabile ) denosumab (PROLIA 60mg/6 mesi)
in PC in ADT
Effects of Antiresorptive therapy on
BMD in BC Women treated with AI
0
1
2
3
4
5
Risedronate 35mg/w
%
fro
m b
as
eli
ne
4.4%
2.1%
Ibandronate 150 mg/mo
Zoledronate 4 mg 6 mo
Denosumab 60 mg/6 mo
0.6
Hip
3%
Spine Ellis JCO 2008
6
3.5%
6.5%
1.%
4%
Eidtman Ann Oncol 2010 Lester Clin Can Res 2008 Van Poznak JCO 2010
J Clin Oncol 2008
Lester JE Clin Canc Res 2008
Zoledronic acid (zoledronate) for postmenopausal
women with early breast cancer receiving adjuvant
letrozole (ZO-FAST study): final 60-month results
Coleman R et al Annals of Oncology 24: 398–405, 2013
Primary Endpoint: Percentage change from baseline
in lumbar spine BMD vs Placebo
*P < 0.0001 versus Placebo Months
BM
D M
ea
n P
erc
en
t C
ha
ng
e F
rom
Ba
se
lin
e
(± 9
5%
CI)
Ellis GK et al. J Clin Oncol. 2008;26:4875-4882. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.
8
6
4
2
0
-2
7
5
3
1
-1
-3
*
* *
*
*
1 3 6 12 24
Denosumab (n = 123) Placebo (n = 122)
7.6% Difference
at Month 24
21
5.5% Difference
at Month 12
Denosumab 60 mg/ 6 mo. in PMO Women with BC and AI
Denosumab 60 mg/ 6 mo.
Effect on BMD at Cortical Bone Sites
Total Hip and Distal 1/3 Radius
* P < 0.0001 versus Placebo
Months
Total Hip (Proximal Femur)
-2
5
-1
1 3 6 12 24
4
2
0
3
1
* *
* *
Months
Distal 1/3 Radius
12 24
2
-4
-5
4
0
-2
3
1
-1
-3
* *
Ellis GK et al. J Clin Oncol. 2008;26:4875-4882.
Placebo (N = 122)
Denosumab (N = 123)
Placebo (N = 106)
Denosumab (N =115)
4.7% Difference
at Month 24
6.1% Difference
at Month 24
22
BM
D M
ea
n P
erc
en
t C
ha
ng
e F
rom
Ba
se
lin
e
(± 9
5%
CI)
BM
D M
ea
n P
erc
en
t C
ha
ng
e F
rom
Ba
se
lin
e
(± 9
5%
CI)
RRR of fractures in ad hoc pivotal trials
AL
N (
FIT
1)
AL
N (
FIT
1)
AL
N (
FIT
1)
RIS
(V
ER
T)
RIS
(V
ER
T)
RIS
(V
ER
T)
RA
L (
MO
RE
)
RA
L (
MO
RE
)
RA
L (
MO
RE
)
IBA
(B
ON
E)
IBA
(B
ON
E)
IBA
(B
ON
E)
Str
Ra
n(T
RO
PO
S)
Str
Ra
n(T
RO
PO
S)
Str
Ra
n(T
RO
PO
S)
ZO
L (
Ho
rizo
n)
ZO
L (
Ho
rizo
n)
ZO
L (
Ho
rizo
n)
-80
-70
-60
-50
-40
-30
-20
-10
0
Vertebral Non-Vertebral Hip
% R
RR
NICE, modif
Den
osu
ma
b
Den
osu
ma
b
Den
osu
ma
b
Persistenza d’effetto di singola infusione di acido zoledronico
5 mg/5anni
Grey et al. Bone 2012
> 70% hip fracture reduction
0
1
2
3
4
5
Risedronate 35mg
%
fro
m b
as
eli
ne
4.7%
2.4%
Alendronate 70 mg)
Zoledronate 4 mg once y
Zoledronate 4mg/ 3 mo
DNB 60 mg/6 mo
. 4.2%
2%
Hip
4%
2%
4.6%
5.3%
1.1% 1.1%
Spine
)
Ishizako K 2007 Smith NEJM 2009 Michaelson MD 2007; Satoh T 2009 Smith MR 2003; Campbell 2010
Bhoopalam 2009
4.1%
3.2%
4.8%
6
7
Bone target agents: effects on BMD in Men with ADT Induced Bone Loss
Greenspan S J Clin Oncol 2008
Primary Endpoint: Percentage Change in Lumbar Spine BMD at Month 24
Screen/Randomize Treatment Follow-up/EOS
Study Month 1 18 24
Secondary Objectives: Efficacy of denosumab compared with placebo on: Fractures and BMD at nonvertebral sites
Key elegibility Criteria • Prostate cancer
subjects on ADT • Subjects ≥ 70 years
of age or < 70 with T-score < -1.0
• No previous IV and limited oral BP use
• Planned N = 1226
Denosumab 60 mg SC, Day 1 of
Months 6, 12, 18, 24 30
Prevention of Cancer Treatment Induced Bone Loss (CTIBL)
Smith M et al. N Engl J Med, 361:745-55, 2009. Enrico Cortesi
HALT-PC (20040138): Denosumab in ADT-Treated Prostate Cancer
Placebo 60 mg SC, Day 1
of Months 6, 12, 18, 24 30
Follo
w-u
p
End
of
stu
dy
RA
ND
OM
IZAT
ION
Baseline Characteristics (cont’d)
Characteristic Placebo
(n = 734)
SC Denosumab
(n = 734)
Subjects with T-score < –2.5 at any sitea, n (%) 111 (15.1) 105 (14.3)
Lumbar spine BMD T-score
Median (range) –0.6 (–4.8-7.6) –0.5 (–6.8-7.3)
Mean ±SD –0.4 ± 1.8 –0.3 ± 1.8
Total hip BMD T-score
Median (range) –1.0 (–3.6-3.1) –0.9 (–3.6-3.3)
Mean ±SD –0.9 ± 1.0 –0.9 ± 1.0
Femoral neck BMD T-score
Median (range) –1.5 (–3.5-1.9) –1.5 (–3.8-3.0)
Mean ±SD –1.4 ± 0.9 –1.4 ± 0.9
aAny site = lumbar spine, total hip, or femoral neck.
Smith MR, Egerdie B, Toriz NH, et al. N Engl J Med. 2009;361:745-755.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
*
Study Month
1 3 6 12 24 36
Placebo (n = 734)
Denosumab (n = 734) 10
8
6
4
2
0
–2
–4
–6
0
Primary/Secondary End Point: BMD
Total Hip Lumbar Spine
Study Month
1 3 6 12 24 36
Placebo (n = 734)
Denosumab (n = 734)
0
*
*
*
*
*
*
6.7% difference
at 24 moa
*
* *
*
*
4.8% difference
at 24 mo
10
8
6
4
2
0
–2
–4
–6
aPrimary end point
*P ≤.001 at all measured sites
Smith MR, Egerdie B, Toriz NH, et al. N Engl J Med. 2009;361:745-755.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
20040138
Secondary End Point: New Vertebral Fractures
0
2
4
6
1 . 9 % 0 . 3 % 3 . 3 % 1 . 0 % 3 . 9 % 1 . 5 %
RR 0.15 P = .004
RR 0.31
P = .004
RR 0.38
P = .006
Subject Incidence
2 6 1 0 1 3 2 2 2 7
Inc
ide
nc
e o
f N
ew
Ve
rte
bra
l
Fra
ctu
re
RR = relative risk.
SC Denosumab (n = 679) Placebo (n = 673)
12 24 36
Month
Smith MR, Egerdie B, Toriz NH, et al. N Engl J Med. 2009;361:745-755.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
Nb patients
*
Study Month
1 3 6 12 24 36
Placebo (n = 734)
Denosumab (n = 734) 10
8
6
4
2
0
–2
–4
–6
0
Primary/Secondary End Point: BMD
Total Hip Lumbar Spine
Study Month
1 3 6 12 24 36
Placebo (n = 734)
Denosumab (n = 734)
0
*
*
*
*
*
*
6.7% difference
at 24 moa
*
* *
*
*
4.8% difference
at 24 mo
10
8
6
4
2
0
–2
–4
–6
aPrimary end point
*P ≤.001 at all measured sites
Smith MR, Egerdie B, Toriz NH, et al. N Engl J Med. 2009;361:745-755.
Copyright © 2009 Massachusetts Medical Society. All rights reserved.
TOREMIFENE REDUCES FRACTURE RISK IN MEN
RECEIVING ANDROGEN DEPRIVATION THERAPY
FOR PROSTATE CANCER
Smith MR, J Urol 2010
10_ 9 _ 8 _ 7 _ 6_ 5 _ 4 – 3 – 2 – 1 –
0 _
23
11
RRR 50% (CI 1.5-75) P<0.05
2 years
47
28
New vertebral fx
RRR 38% (CI 2.2-60) P 0.036
Inci
den
ce n
ew f
ract
ure
(%
)
Smith MR, J Urol 2010
TOREMIFENE REDUCES FRACTURE RISK IN MEN RECEIVING
ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER
all fractures
Goserelin
Chemotherapy
Aromatase inhibitors
Menopause
Age
Low vitamin D levels
High Bone Turnover
The “Bone Health” concept in Cancer Patients
Bone
Metastasis
SRE Fracture
Radiotherapy
Spinal Compression
Orth. Surg.
Pain
Fragility Fracture
Bone Loss
Homing Cancer cell
Premetastatic niche
CONCLUSIONI
•LA normalizzazione del turnover ( entro range 30-40
anni/premenopausale) permette la prevenzione della perdita di
massa ossea , la prevenzione delle fratture ( probabilmente
l’effetto adiuvante (DSF e OS)
• Questo si puo’ realizzare con amino BP e denosumab
( indicazioni, rimborsabilità) alle dosi utilizzate per
l’OP.Postmenop.
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