Cancer Treatment Induced Bone Loss Fisiopatologia. Airoldi Mario S.C. Oncologia Medica 2 Città della Salute e della Scienza di Torino

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1 Cancer Treatment Induced Bone Loss Fisiopatologia Airoldi Mario S.C. Oncologia Medica 2 Città della Salute e della Scienza di Torino

2 Il nuovo concetto di bone health nel paziente neoplastico OSTEOPOROSI METASTASI OSSEA FRATTURE DA FRAGILITÀ Fratture SRE Radioterapia Compressione spinale Interventi ortopedici Dolore

3 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

4 Il rimodellamento osseo: l unità di rimodellamento - BMU CTX NTX DPD HOProl β-alp APOPTOSI OC TGF-β1 IGF-1 BMP PDGF FGFs CROSS-LINK COLLAGENO TIPO I

5 Turnover osseo ALP OC NTX CTX ICTP Turnover basso Turnover medio Turnover elevato

6 I prodotti di catabolismo del collageno di tipo I (osseo) derivanti dall attività riassorbitiva degli osteoclasti ICTP CTX Cat K 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: , 2003

7 NTX E CTX SIERICO NTX NORMALE < 50 nmol/mmolcr NTX INTERMEDI NTX ELEVATI > 100 CTX NORMALE < 0,400 ng/ml CTX INTERMEDI 0,400-0,800 CTX ELEVATI > 0,800

8 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

9 Contribution of androgen deprivation therapy to elevated bone turnover in men with metastatic prostate cancer ns NTX nm BCE * ADT - Meta - ADT + Meta - ADT + Meta + Mod. da: Michaelson MD, et al. Clin Cancer Res. 10: , 2004

$Osteoporosis and risk of fractures Osteoporosis is asymptomatic, and it is$ from a height which is below one s stature), but not due to more important

from a height which is below one s stature), but not due to more important

10 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

Schematics adapted from Kawano et al. Proc Natl Acad Sci. USA. 2003;100: 9416-9421; 1. Riggs et al. Endocrine Rev.

11 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 effects 1-3 Schematics adapted from Kawano et al. Proc Natl Acad Sci. USA. 2003;100: ; 1. Riggs et al. Endocrine Rev. 2002;23: ; 2. Khosla et al. Calcif Tissue Int. 2001;69: ; 3. Smith et al. J Clin Endocrinol Metab. 2002;87:

12 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?

13 Osteoporosis and Bone Density Normal Osteoporotic

14 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 1 5 The effects of suppressed oestrogen levels on bone loss Oestrogen

oestrogen by aromatase) ADT causes a reduction in testosterone, therefore suppressing oestrogen

production by osteoblasts Increased levels of free RANK Ligand lead to osteoclast activation and

15 Oestrogen and bone loss 1 5 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

CTIBL-AD caused by ADT ADT T T T Oe Oe Oe ADT

$fracture T Testosterone Prostate cancer cell$

16 CTIBL-AD caused by ADT ADT T T T Oe Oe Oe ADT significantly suppresses androgen production, which suppresses tumour growth ADT shuts down oestrogen production, which causes significant bone loss and increased risk of fracture T Testosterone Prostate cancer cell Oe Oestrogen

17 Key Slides La bone health nel paziente neoplastico Contribution of androgen deprivation therapy to elevated bone turnover in men with metastatic prostate cancer ns NTX nm BCE * ADT - Meta - ADT + Meta - ADT + Meta + Mod. da: Michaelson MD, et al. Clin Cancer Res. 10: , FSE/ANM

18 18

bars) 1. Adapted from Hirbe et al. Clin Cancer Res. 2006;12(20 Pt2):6312s-6314s; 2. Michaelson et al.

19 Bone Loss Induced by ADT for Prostate Cancer Is Clinically Significant Lumbar Spine BMD Loss at 1 Year (%) Healthy Men 1 Early Menopausal Women1 Women on Aromatase Inhibitor Therapy 3 n = 308 (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: ; 3. Eastell et al. J Bone Miner Res. 2002;17:S165. Abstract Men After 1 Year of ADT 2 n = 22

20 ADT Effects on BMD in Men with PCa: Pronounced Decreases Are a Consistent Finding Study Treatment BMD (% decrease at 12 mo) Eriksson 1 Orchiectomy Hip: - 9.6% Radius: - 4.5% Maillefert 2 GnRH agonist Hip: - 3.9% L spine: - 4.6% Daniell 3 Orchiectomy or GnRH agonist Hip: - 2.4% Berrutti 4 GnRH agonist Hip: - 0.6% L spine: - 2.3% Higano 5 LHRH agonist plus anti-androgen Hip: - 2.7% L spine: - 4.7% Mittan 6 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: ; 3. Daniell et al. J Urol. 2000;163:181-86; 4. Berrutti et al. J Urol. 2002;167: ; 5. Higano et al. Proc Am Soc Clin Oncol. 1999;18:314a; 6. Mittan et al. J Clin Endocrinol Metab. 2002;87:

21 Bone Loss With Cancer Therapies Bone Loss at 1 Yr Normal Men [1] Naturally Occurring Bone Loss 1.0 Postmenopausal Women [1] 2.0 Menopausal Women [1] 2.6 Al Therapy in Postmenopausal Women [2] 4.6 ADT [3] CTIBL 7.0 Al Therapy + GnRH Agonist in Premenopausal Women [4] 7.7 Premature Menopause Secondary to Chemotherapy [5] 1. Kanis JA. Osteoporosis. 1997: Eastell R, et al. J Bone Mineral Res Maillefert JF, et al. J Urol. 1999;161: Gnant M, et al. Lancet Oncol. 2008;9: Shapiro CL, et al. J Clin Oncol. 2001;19:

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 T- Score

22 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 T- Score Classification Normal Low bone mass (osteopenia) Osteoporosis Severe (established) T-Score -1 or greater Between -1 and 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

$CTIBL-AD caused by ADT: evidence ADT also increases fracture risk, with 1 in 5 prostate cancer patients receiving multiple doses of ADT experiencing a fracture$ $oestrogen to even lower levels than those found in postmenopausal women ADT-related fracture risk in prostate cancer BMD loss of up to 4.$

23 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 ADT-related fracture risk in prostate cancer 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

24 Bone turnover in breast cancer patients with or without bone metastases Breast cancer 80 AI Meta - NTX nmol/mmol Cr Normal range Meta Coleman RE, et al. J Clin Oncol. 23: , Eastell R,et al. J Bone Min Res 2: , Coleman RE, et al. Lancet Oncol 8: , Gonnelli S, et al. Bone 40: , 2007

25 Steroidal and Nonsteroidal AIs Increase Fracture Risk Compared With Tamoxifen P < Tamoxifen Anastrozole Exemestane Letrozole 10 Fractures (%) P = P < ATAC [1] (68 Mos) IES [2] (58 Mos) BIG 1-98 [3] (26 Mos) 1. Howell A, et al. Lancet. 2005;365: Coleman RE, et al. Lancet Oncol. 2007;8: Thürlimann B, et al. N Engl J Med. 2005;353:

26 Adjuvant Studies With AIs in Breast Cancer: Increased Fracture Rate N Median F/U, Mos Aromatase Inhibitor, % Tamoxifen, % P Value ATAC [1] <.0001 BIG 1-98 [2] IES [3] ARNO [4] NR Placebo % MA.17 [5] 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: Thürlimann B, et al. N Engl J Med. 2005;353: Coombes RC, et al. ASCO Abstract LBA Jakesz R, et al. Breast Cancer Res Treat. 2004;88:S7. Abstract Goss PE, et al. J Natl Cancer Inst. 2005;97: Eastell R, et al. J Bone Miner Res. 2006;21:

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

28 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 AI use is associated with a BMD loss that is 2-3% more

$women A 44% increase in relative risk of fracture with the AI$

29 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 A 44% increase in relative risk of fracture with the AI anastrozole was reported from a trial comparing anastrozole with tamoxifen 2 9

30 Cancer Treatment Induced Bone Loss Epidemiologia

31 Incidence of menopause in breast cancer patients

32 Osteoporosis Incidence in Breast Cancer Patients Women s Health Initiative-observational Study (5.000 Breast Cancer Patients and 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:

$vertebral fractures in controls and Breast Cancer$

33 Annual Incidence (%) and severity (±SEM) of vertebral fractures in controls and Breast Cancer Patients

34 EPIDEMIOLOGIA DEL CANCRO DELLA MAMMELLA E DELL UTILIZZO DEGLI INIBITORI DELL AROMATASI (IA) In ITALIA donne / anno si ammalano di cr della mammella. 200 nuovi casi/ 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 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 e pazienti con fratture da fragilità.

35 PROSTATE CANCER EPIDEMIOLOGY TSE: 149/ persone / anno

36 EPIDEMIOLOGIA DELL UTILIZZO DEL BLOCCO ORMONALE ADIUVANTE Conti G, Dogliotti et al, Eur Soc Med Oncol 2008

37 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.

38 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

39 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.

Breast Cancer and Bone Loss. One in seven women will develop breast cancer during a lifetime

Breast Cancer and Bone Loss. One in seven women will develop breast cancer during a lifetime Breast Cancer and Bone Loss One in seven women will develop breast cancer during a lifetime Causes of Bone Loss in Breast Cancer Patients Aromatase inhibitors Bil Oophorectomy Hypogonadism Steroids Chemotherapy