Cancer Treatment Induced Bone Loss

Fisiopatologia

Airoldi MarioS.C. Oncologia Medica 2

Città della Salute e della Scienza di Torino

Il nuovo concetto di bone health nel paziente neoplastico

FRATTURE DA FRAGILITÀ

OSTEOPOROSI METASTASIOSSEA

SRE Fratture

Radioterapia

Compressione spinale

Interventi ortopedici

Dolore

Il nuovo concetto di bone health nel paziente neoplastico

ELEVATO TURNOVER OSSEO

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

Il rimodellamento osseo: l’unità di rimodellamento -BMU

TGF-β1IGF-1BMPPDGFFGFs

CROSS-LINK COLLAGENO

TIPO I

APOPTOSI

CTXNTXDPDHOProl

β-ALP OC

Turnover osseo

Turnover basso

Turnover medio

Turnover elevato

ALP OC

NTXCTXICTP

N-TELOPEPTIDE

NTX sierico

N C

C-TELOPEPTIDE

GPP-SAGFDFSFLPQPPQEKAHDGGR α 1

I prodotti di catabolismo del collageno di tipo I (osseo) derivanti dall’attività riassorbitiva degli osteoclasti

Mod. da: Garnero P, et al. J Bone Miner Res 18: 859-867, 2003

Cat K Cat K Cat K

ICTP CTX

NTX E CTX SIERICO

NTX NORMALE < 50 nmol/mmolCr

NTX INTERMEDI 50-100

NTX ELEVATI > 100

CTX NORMALE < 0,400 ng/mL

CTX INTERMEDI 0,400-0,800

CTX ELEVATI > 0,800

FRATTURE DA FRAGILITÀ

OSTEOPOROSI

METASTASIOSSEA

SRE Fratture

Radioterapia

Compressione spinale

Chirurgia ortopedica

Dolore

ELEVATO TURNOVER OSSEO

Goserelin Chemioterapia Inibitori dell’aromatasi Menopausa Invecchiamento Ipovitaminosi D

Il nuovo concetto di bone health nel paziente neoplastico

Contribution of androgen deprivation therapy to elevated bone turnover in men with metastatic prostate cancer

Mod. da: Michaelson MD, et al. Clin Cancer Res. 10: 2705–2708, 2004

0

10

15

20

25

30

35

40N

TX n

M B

CE

ADT -Meta -

ADT + Meta -

ADT + Meta +

*

ns

Osteoporosis Normal bone density

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 and risk of fractures

Mechanism of Bone Loss: Estrogen Dependence of Bone Health in Both Women and Men

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.

Sex hormone depletion by androgen deprivation (ADT) or aromatase inhibitors (AI) leads to estrogen deficiency, resulting in deleterious bone effects1-3

Potential roles of osteoclast-targeting agents in breast cancer

Preventing recurrence and

deaths?

Preserving bonemineral density,

preventing fractures

Treating bone metastases, reducing skeletal-related events

Adjuvant setting

Metastatic setting

Normal Osteoporotic

Osteoporosis and Bone Density

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

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 levelsLow oestrogen levels lead to reduced production of OPG and increased RANK Ligand production by osteoblastsIncreased levels of free RANK Ligand lead to osteoclast activation and increased bone resorptionIncreased bone resorption leads to a loss of BMD and an increased risk of fracture

15

The effects of suppressed oestrogen levels on bone loss

CTIBL-AD caused by ADT

ADT

TT

T

Oe

OeOe

T Testosterone Oe Oestrogen Prostate cancer cell

ADT significantly suppresses androgen

production, which suppresses tumour

growth

ADT shuts down oestrogen production,

which causes significant bone loss and increased

risk of fracture

Key Slides on La bone health nel paziente neoplastico

© 2011 – FSE/ANM

Contribution of androgen deprivation therapy to elevated bone turnover in men with metastatic prostate cancer

0

10

15

20

25

30

35

40N

TX n

M B

CE

Mod. da: Michaelson MD, et al. Clin Cancer Res. 10: 2705–2708, 2004

ADT -Meta -

ADT + Meta -

ADT + Meta +

*

ns

18

Bone Loss Induced by ADT for Prostate Cancer Is Clinically Significant

(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.

Healthy Men1 Early Menopausal

Women1

Women on Aromatase

Inhibitor Therapy3

n = 308

Men After 1Year of ADT2

n = 22

Lum

bar S

pine

BM

D

Loss

at 1

Yea

r (%

)

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

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.

Bon

e Lo

ss a

t 1 Y

r

Naturally Occurring Bone Loss

CTIBL

0

2

4

6

8

10

Normal Men[1]

Postmenopausal Women[1]

Menopausal Women[1]

Al Therapy inPostmenopausal

Women[2]

ADT[3]

Al Therapy+ GnRH

Agonist inPremenopausal

Women[4]

Premature Menopause

Secondary toChemotherapy[5]

0.51.0

2.02.6

4.6

7.07.7

Measuring bone loss• Changes in bone mineral density

(BMD)• Bone density classified using T-

Score

• 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

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

Classification T-Score

Normal -1 or greater

Low bone mass (osteopenia) Between -1 and -2.5

Osteoporosis -2.5 or lower

Severe (established) -2.5 or lower plus a fragility fracture

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-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

CTIBL-AD caused by ADT: evidenceCTIBL bone loss vs normal bone

loss

ADT-related fracture risk in prostate cancer

100

90

80

70

60

50

40

30

20

10

1 2 3 4

NTX

nm

ol/m

mol

Cr

Meta -

Meta +

Breast cancer

AI

1. Coleman RE, et al. J Clin Oncol. 23: 4925–4935, 20052. Eastell R,et al. J Bone Min Res 2: 1215–1223, 2006

3. Coleman RE, et al. Lancet Oncol 8: 119–127, 20074. Gonnelli S, et al. Bone 40: 205–210, 2007

Bone turnover in breast cancer patients with or without bone metastases

Nor

mal

rang

e

TamoxifenLetrozoleAnastrozole

Frac

ture

s (%

)

11.0

7.7

5.7

4.0

7.0

5.0

P < .0001

P < .001

0

2

4

6

8

10

12

14

P = .003

Exemestane

ATAC[1]

(68 Mos)IES[2]

(58 Mos)BIG 1-98[3]

(26 Mos)

Steroidal and Nonsteroidal AIs Increase Fracture Risk Compared With Tamoxifen

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.

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.

Adjuvant Studies With AIs in Breast Cancer: Increased Fracture Rate

N Median F/U,Mos

AromataseInhibitor, %

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

27

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

…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

29

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 EDELL’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.

TSE: 149/100.000 persone / anno

PROSTATE CANCER EPIDEMIOLOGY

Conti G , Dogliotti et al , Eur Soc Med Oncol 2008

EPIDEMIOLOGIA DELL’ UTILIZZO DEL BLOCCO ORMONALE ADIUVANTE

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

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.

Bone health during adjuvant therapy for early breast cancer