Download Cancer Treatment Induced Bone Loss Fisiopatologia

Cancer Treatment Induced
Bone Loss
Fisiopatologia
Airoldi Mario
S.C. Oncologia Medica 2
Città della Salute e della Scienza di Torino
Il nuovo concetto di bone health nel paziente
neoplastico
METASTASI
OSSEA
OSTEOPOROSI
FRATTURE DA
FRAGILITÀ
SRE

Fratture

Radioterapia

Compressione spinale

Interventi ortopedici

Dolore
Il nuovo concetto di bone health nel paziente
neoplastico








Goserelin
Chemioterapia
Inibitori dell’aromatasi
Elevati livelli di citochine (IL-1, IL-6, IL-12, TNF-α)
Corticosteroidi
Menopausa
Invecchiamento
Ipovitaminosi D/Elevati livelli di PTH
ELEVATO TURNOVER OSSEO
Il rimodellamento osseo: l’unità di rimodellamento BMU
CTX
NTX
DPD
HOProl
APOPTOSI
β-ALP
TGF-β1
IGF-1
BMP
PDGF
FGFs
OC
CROSS-LINK
COLLAGENO
TIPO I
Turnover osseo
ALP OC
NTX
CTX
ICTP
Turnover basso
Turnover medio
Turnover elevato
I prodotti
di catabolismo del collageno di tipo I (osseo)
derivanti dall’attività riassorbitiva degli osteoclasti
ICTP
Cat K
CTX
Cat K
Cat K
NTX sierico
GPP-SAGFDFSFLPQPPQEKAHDGGR α 1
N
N-TELOPEPTIDE
C
C-TELOPEPTIDE
Mod. da: Garnero P, et al. J Bone Miner Res 18: 859-867, 2003
NTX E CTX SIERICO
 NTX NORMALE
< 50
nmol/mmolCr
 NTX INTERMEDI 50-100
 NTX ELEVATI
> 100
 CTX NORMALE
< 0,400
 CTX INTERMEDI 0,400-0,800
 CTX ELEVATI
> 0,800
ng/mL
Il nuovo
concetto di bone health nel paziente neoplastico

Goserelin

Chemioterapia

Inibitori dell’aromatasi

Menopausa

Invecchiamento

Ipovitaminosi D
ELEVATO TURNOVER OSSEO
OSTEOPOROSI
FRATTURE DA
FRAGILITÀ
SRE

Fratture

Radioterapia

Compressione spinale

Chirurgia ortopedica

Dolore
METASTASI
OSSEA
Contribution of androgen deprivation therapy to
elevated bone turnover in men with metastatic
prostate cancer
40
35
ns
NTX nM BCE
30
25
20
*
15
10
0
ADT Meta -
ADT +
Meta -
ADT +
Meta +
Mod. da: Michaelson MD, et al. Clin Cancer Res. 10: 2705–2708, 2004
Osteoporosis and risk of fractures
Osteoporosis is asymptomatic, and it is associated to an
increase in the risk of fractures due to minor traumas (falls
from a height which is below one’s stature), but not due to
more important traumas (road accidents, falls from heights
above one’s stature).
Osteoporosis
Normal bone density
Mechanism of Bone Loss: Estrogen Dependence of
Bone Health in Both Women and Men
Sex hormone depletion by androgen deprivation (ADT) or aromatase inhibitors
(AI) leads to estrogen deficiency, resulting in deleterious bone effects1-3
Schematics adapted from Kawano et al. Proc Natl Acad Sci. USA. 2003;100: 9416-9421; 1. Riggs et al. Endocrine Rev.
2002;23:279-302; 2. Khosla et al. Calcif Tissue Int. 2001;69:189-192; 3. Smith et al. J Clin Endocrinol Metab. 2002;87:
599-603.
Treating bone metastases, reducing skeletalrelated events
Metastatic setting
Potential roles of osteoclasttargeting agents in breast cancer
Adjuvant setting
Preserving bone
mineral density,
preventing fractures
Preventing
recurrence and
deaths?
Osteoporosis and Bone Density
Normal
Osteoporotic
Cancer Treatment–Induced Bone Loss
 Rapid and severe bone loss resulting from cancer
therapies that lead to estrogen or androgen deprivation
 Various cancer therapies decrease BMD and increase
fracture risk
• Androgen-deprivation therapy
• Estrogen-deprivation therapy
• Chemotherapy
• Surgical (castration)
 CTIBL has significant clinical, social, and economic
consequences; treatment-related fractures are associated
with decreased quality of life and shorter survival
Oestrogen and bone loss
The effects of suppressed oestrogen
levels on bone loss
Oestrogen plays a key role in bone
loss caused by hormone ablation
therapy (testosterone is converted to
oestrogen by aromatase)
ADT causes a reduction in
testosterone, therefore suppressing
oestrogen levels
Low oestrogen levels lead to reduced
production of OPG and increased
RANK Ligand production by
osteoblasts
Increased levels of free RANK Ligand
lead to osteoclast activation and
increased bone resorption
Increased bone resorption leads to a
loss of BMD and an increased risk of
fracture
1
5
CTIBL-AD caused by ADT
ADT

T
T T

 

Oe
Oe Oe
ADT significantly
suppresses androgen
production, which
suppresses tumour
growth
T Testosterone


ADT shuts down
oestrogen production,
which causes significant
bone loss and increased
risk of fracture
Prostate cancer cell Oe Oestrogen
Key Slides on La bone health nel paziente neoplastico
Contribution
of androgen deprivation therapy to
elevated bone turnover in men with metastatic
prostate cancer
40
35
ns
NTX nM BCE
30
25
20
*
15
10
0
ADT Meta -
ADT +
Meta -
ADT +
Meta +
Mod. da: Michaelson MD, et al. Clin Cancer Res. 10: 2705–2708, 2004
© 2011 – FSE/ANM
18
Lumbar Spine BMD
Loss at 1 Year (%)
Bone Loss Induced by ADT for Prostate Cancer
Is Clinically Significant
Healthy Men1
Early
Menopausal
Women1
Women on
Aromatase
Inhibitor Therapy3
n = 308
Men After 1
Year of ADT2
n = 22
(N not available for 2 left bars)
1. Adapted from Hirbe et al. Clin Cancer Res. 2006;12(20 Pt2):6312s-6314s; 2. Michaelson et al. J Clin Oncol.
2007;25:1038-1042; 3. Eastell et al. J Bone Miner Res. 2002;17:S165. Abstract 1170.
ADT Effects on BMD in Men with PCa:
Pronounced Decreases Are a Consistent Finding
Study
Treatment
BMD (% decrease at 12 mo)
Eriksson1
Orchiectomy
Hip: - 9.6%
Radius: - 4.5%
Maillefert2
GnRH agonist
Hip: - 3.9%
L spine: - 4.6%
Daniell3
Orchiectomy or GnRH agonist
Hip: - 2.4%
Berrutti4
GnRH agonist
Hip: - 0.6%
L spine: - 2.3%
Higano5
LHRH agonist plus anti-androgen
Hip: - 2.7%
L spine: - 4.7%
Mittan6
GnRH agonist
Hip: - 3.3%
Radius: - 5.3%
1. Eriksson et al. Calcif Tissue Int. 1995;57:97-99; 2. Maillefert et al. J Urol. 1999;161:1219-1222;
3. Daniell et al. J Urol. 2000;163:181-86; 4. Berrutti et al. J Urol. 2002;167:2361-2367;
5. Higano et al. Proc Am Soc Clin Oncol. 1999;18:314a; 6. Mittan et al. J Clin Endocrinol Metab. 2002;87:3656-3661.
Bone Loss With Cancer Therapies
Bone Loss at 1 Yr
10
Naturally Occurring
Bone Loss
CTIBL
8
7.0
6
4.6
4
2
0
7.7
2.0
0.5
Normal
Men[1]
2.6
1.0
Menopausal
ADT[3]
Premature
[1]
Women
Menopause
Postmenopausal
Al Therapy in
Al Therapy Secondary to
[5]
Women[1]
Postmenopausal
+ GnRH Chemotherapy
Women[2]
Agonist in
Premenopausal
Women[4]
1. Kanis JA. Osteoporosis. 1997:22-55. 2. Eastell R, et al. J Bone Mineral Res. 2002. 3. Maillefert JF, et al.
J Urol. 1999;161:1219-1222. 4. Gnant M, et al. Lancet Oncol. 2008;9:840-849. 5. Shapiro CL, et al. J Clin
Oncol. 2001;19:3306-3311.
Bone loss in prostate cancer
 Why do bone complications occur in patients
with prostate cancer?
 Metastases
 As a result of the cancer treatment (CTIBL)
 Cancer treatment-induced bone loss (CTIBL)
is particularly associated with:
 Prostate cancer (CTIBL-AD)
 Breast cancer (CTIBL-AI)
 WHY?
 Because treatment often includes hormone
ablation that may interfere with normal bone
metabolism
Measuring bone loss
• Changes in bone mineral density
(BMD)
• Bone density classified using TScore
Classification
Normal
Low bone mass
(osteopenia)
Osteoporosis
Severe (established)
T-Score
-1 or greater
Between -1 and -2.5
-2.5 or lower
-2.5 or lower plus a
fragility fracture
• DXA (dual energy X-ray
absorptiometry) is the most
accurate and widely used technique
for measuring BMD, and typically
involves evaluating BMD of the
spine and/or hip
CTIBL-AD caused by ADT: evidence
 ADT also increases fracture risk, with 1
in 5 prostate cancer patients receiving
multiple doses of ADT experiencing a
fracture within 4 years of diagnosis
CTIBL bone loss vs normal bone
loss
 CTIBL-AD has very few symptoms, and
is not usually detected until a fracture
occurs
 ADT drops oestrogen to even lower
levels than those found in
postmenopausal women
 BMD loss of up to 4.6% has been
reported in the first year of ADT
treatment in prostate cancer patients
without metastases; this slows down
over time to a steady state
 ADT is associated with increased
fracture risk
ADT-related fracture risk in
prostate cancer
Bone turnover in breast cancer patients with or
without bone metastases
100
Breast cancer
90
AI
Meta -
70
Meta +
60
50
Normal range
NTX nmol/mmol Cr
80
40
30
20
10
1
2
3
4
1. Coleman RE, et al. J Clin Oncol. 23: 4925–4935, 2005
2. Eastell R,et al. J Bone Min Res 2: 1215–1223, 2006
3. Coleman RE, et al. Lancet Oncol 8: 119–127, 2007
4. Gonnelli S, et al. Bone 40: 205–210, 2007
Steroidal and Nonsteroidal AIs Increase Fracture Risk
Compared With Tamoxifen
14
P < .0001
Fractures (%)
12
11.0
Tamoxifen
Anastrozole
Exemestane
Letrozole
10
8
7.7
6
P = .003
7.0
5.0
4
P < .001
5.7
4.0
2
0
ATAC[1]
(68 Mos)
IES[2]
(58 Mos)
BIG 1-98[3]
(26 Mos)
1. Howell A, et al. Lancet. 2005;365:60-62. 2. Coleman RE, et al. Lancet Oncol. 2007;8:119-127.
3. Thürlimann B, et al. N Engl J Med. 2005;353:2747-2757.
Adjuvant Studies With AIs in Breast Cancer:
Increased Fracture Rate
N
Median F/U,
Mos
Aromatase
Inhibitor, %
Tamoxifen, %
P Value
ATAC[1]
6186
68
11.0
7.7
< .0001
BIG 1-98[2]
8010
26
5.8
4.1
.0006
IES[3]
4724
56
7.0
4.9
.003
ARNO[4]
3224
28
2.4
1.2
NR
Placebo %
MA.17[5]
5187
30
5.3
4.6
.25
In the ATAC trial, after 2 yrs of anastrozole treatment, BMD decreased at lumbar spine
(median loss: 4.1%) and total hip (median loss: 3.9%)[6]
BMD increases of 2.2% and 1.2% were observed with tamoxifen in lumbar spine
and total hip, respectively[6]
1. Howell A, et al. Lancet. 2005;365:60-62. 2. Thürlimann B, et al. N Engl J Med. 2005;353:2747-2757.
3. Coombes RC, et al. ASCO 2006. Abstract LBA527. 4. Jakesz R, et al. Breast Cancer Res Treat.
2004;88:S7. Abstract 2. 5. Goss PE, et al. J Natl Cancer Inst. 2005;97:1262-1271. 6. Eastell R, et al. J
Bone Miner Res. 2006;21:1215-1223.
AI-induced estrogen deficiency

The AIs are divided into steroidal inactivators
(exemestane) and nonsteroidal inhibitors (letrozole,
anastrozole).
 At clinical doses, these third-generation AIs are
successful in inhibiting greater than 97 percent of
aromatase activity in vivo .
27
27
…AI-induced estrogen deficiency
 In vivo animal studies suggest that exemestane may be more
bone sparing than letrozole, owing to its androgenic structure .
 However, there are no human trials showing a differential effect of
the individual AIs on bone.
 The MA-27 trial is a comparative trial of exemestane versus
anastrozole as adjuvant therapy in postmenopausal women. The
results are likely to provide more conclusive information about the
skeletal effects of the steroidal versus nonsteroidal AIs.
Effect of AIs on bone loss
 Having a postmenopausal
status is a risk factor for
increased bone loss
 Use of AIs is an additional
risk factor
• AI use is associated with a
BMD loss that is 2-3% more
per year than the normal
decrease in BMD seen in
postmenopausal women
2
9
A 44% increase in relative risk of fracture with the AI
anastrozole was reported from a trial comparing
anastrozole with tamoxifen
Cancer Treatment Induced
Bone Loss
Epidemiologia
Incidence of menopause in breast cancer
patients
Osteoporosis – Incidence in Breast Cancer
Patients
• Women’s Health Initiative-observational Study
(5.000 Breast Cancer Patients and 80.000
Controls)
• Breast Cancer survivors had a 28% increased
risk of non hip fracture after adjustment for age,
weight, length of menopause
Chen Z et al; Arch Intern Med 2005; 165:552-558
Annual Incidence (%) and severity (±SEM)
of vertebral fractures in controls and
Breast Cancer Patients
EPIDEMIOLOGIA DEL CANCRO DELLA MAMMELLA E
DELL’UTILIZZO DEGLI INIBITORI DELL’AROMATASI (IA)
In ITALIA 38.000 donne / anno si ammalano di cr della mammella.
200 nuovi casi/100.000 donne oltre i 50 anni (AIRTUM 2011)
L’85% sopravvive a 5 anni (89-90% al Nord/ 81-83% Sud) (AIRTUM 2011)
Il 40% circa inizia IA. La durata della terapia con IA è per 5 anni
Nel 2010 vi erano 125.000 donne in terapia con IA
( OSMED 2010)
Considerando l’incidenza di fratture negli RCT con IA tra 5-11%, si
Possono stimare nel 2010 tra 6.000 e 14.000 pazienti con fratture
da fragilità.
PROSTATE CANCER EPIDEMIOLOGY
TSE: 149/100.000 persone / anno
EPIDEMIOLOGIA DELL’ UTILIZZO DEL BLOCCO
ORMONALE ADIUVANTE
Conti G , Dogliotti et al , Eur Soc Med Oncol 2008
In breast cancer:
Survival improvement has necessitated refocus on
preserving patients overall health , functional autonomy ,and
quality of life throughout the extended disease course.
Fracture risk is elevated in patients with newly diagnosed
breast cancer compared with age – matched women without
breast cancer , and breast cancer itself as well as long –
term adjuvant therapies for this disease may further increase
the risk of fractures.
SKELETAL OUTCOMES
 Bone loss is most rapid in pre-menopausal women receiving
both ovarian suppression therapy (GnRH agonist) and an AI.
As a consequence, the risk of fracture is
substantially increased
Fractures may
↑ mortality, DVT
↓ QoL, Mobility
Bone health during adjuvant therapy for early
breast cancer
Some chemotherapeutic agents may directly affect bone ,
resulting in a rapid decrease in BMD; however , indirect
effects of chemotherapy may also result in rapid BMD
decline.
For example, ovarian dysfunction is common with
chemotherapy in premenopausal women, leading to
premature menopause.