Osteoporosi e CTIBL: Quali novità...Elevato turnover osseo nei pazienti con carcinoma ELEVATO TURNOVER OSSEO (menopausa + terapia ormonale adiuvante + metastasi) Perdita ossea Homing - [PDF Document] (2024)

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

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

-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

3

1

* *

* *

Months

Distal 1/3 Radius

12 24

2

-4

-5

4

-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

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

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

–2

–4

–6

Primary/Secondary End Point: BMD

Total Hip Lumbar Spine

Study Month

1 3 6 12 24 36

Placebo (n = 734)

Denosumab (n = 734)

*

*

*

*

*

*

6.7% difference

at 24 moa

*

* *

*

*

4.8% difference

at 24 mo

10

8

6

4

2

–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

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

–2

–4

–6

Primary/Secondary End Point: BMD

Total Hip Lumbar Spine

Study Month

1 3 6 12 24 36

Placebo (n = 734)

Denosumab (n = 734)

*

*

*

*

*

*

6.7% difference

at 24 moa

*

* *

*

*

4.8% difference

at 24 mo

10

8

6

4

2

–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.