Breast Cancer and Bone Health. Robert Coleman, Cancer Research Centre, Weston Park Hospital, Sheffield

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1 Breast Cancer and Bone Health Robert Coleman, Cancer Research Centre, Weston Park Hospital, Sheffield

2 Breast Cancer and Bone Health Normal Bone Health Impact of Cancer Therapies on Bone Health Therapeutic Strategies Management Guidelines QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

3 Breast Cancer and Bone Health Normal Bone Health Impact of Cancer Therapies on Bone Health Therapeutic Strategies Management Guidelines QuickTime and a TIFF (Uncompressed) decompressor are needed to see this picture.

4 The Structure of Bone Cortical Bone Vascular Supply Trabecular Bone Marrow

5 Properties of the skeleton Skeleton composition: 80% cortical bone (mostly in the appendicular skeleton) 20% trabecular bone (mostly in the axial skeleton) Trabecular bone: large surface area / unit volume highly responsive to metabolic processes turnover is 8x that of cortical bone more sensitive for measuring changes in BMD due to bone loss or therapy annual turnover rate of 25% compared with 5 6% for cortical bone. Fractures commonly occur in trabecular bone (e.g. vertebra, femoral neck, distal radius).

6 Bone Remodeling Osteoclast Osteoblasts

7 Bone Remodeling QuickTime and a TIFF (LZW) decompressor are needed to see this picture.

8 Components of Bone Strength Bone strength Bone quality + Bone density Architecture Bone turnover Accumulation of lesions (microfractures) Secondary mineralisation abmd = g/cm 2 vbmd = g/cm 3 NIH Consensus Development Panel. JAMA 2001; 285 (6):

9 Lifetime Changes in Bone Mass BMD Gain Consolidation Loss Cancer Treatments Cancer Men Women Age

10 Interpretation of a DEXA Scan T score Z score

11 Diagnosis of Osteoporosis QuickTime and a TIFF (LZW) decompressor are needed to see this picture. Adapted from Kanis, JA. Lancet 2002; 359(9321):

12 BMD and Fracture Risk in the Normal Population Average 35 years 16X 8X 4X 1X 2X T score

$of women with fractures BMD distribution 450 400 350 300 250 200 150 100 50 Number of women with fractures 0 >1.0 1.0 to 0.5 0.5 to 0.0 0.0 to 0.5 0.5 to 1.0 1.0 to 1.5 1.5 to 2.0 2.0 to 2.5 2.5 to 3.$

13 Fracture rate per 1,000 person-years 80% of Fractures Occur in Patients Who Have Normal or Osteopenic BMD Fracture rate No. of women with fractures BMD distribution Number of women with fractures 0 > to to to to to to to to to 3.5 < BMD Fracture rate increases ~2-fold in osteopenic women Majority of fractures occur in osteopenic women (T-score 1.0 to 2.5) BMD, bone mineral density. Reprinted from Siris ES, et al. Arch Intern Med. 2004;164(10):

14 Bioavailable E2, pmol/l Sex, Age and Treatment Effects on Bioavailable Oestradiol Concentrations Premenopausal women Postmenopausal women Normal men Androgen Deprivation Therapy Aromatase Inhibitor Therapy Adapted from: Khosla et al. J Clin Endocrinol Metab 2001;86:

15 Relative risk Low Oestrogen Levels Increase Relative Fracture Risk Women 65 years with undetectable estrogen levels (< 5 pg/ml) have a 2.5-fold increased risk for subsequent hip or vertebral fractures a Spine fracture Hip fracture a. Compared with women with detectable estrogen levels. Adapted from Cummings SR, et al. N Engl J Med. 1998;339(11): < Endogenous serum estradiol level, pg/ml

16 Bone loss at I year Normal and Cancer Treatment Related Bone Loss Rates 10 8 Naturally occurring bone loss CTIBL Normal men 1 Postmenopausal Women >55 1 Menopausal Women <55 1 AI therapy in postmenopausal women 2 AI therapy plus GnRH agonist in premenopausal women 3 Premature menopause secondary to chemotherapy 4 1. Kanis JA. Osteoporosis.1997: Eastell R et al. J Bone Mineral Res Gnant M. San Antonio Breast Cancer Symposium, Shapiro CL et al. J Clin Oncol. 2001;19:

17 Breast Cancer and Bone Health Normal Bone Health Impact of Cancer Therapies on Bone Health Therapeutic Strategies Management Guidelines

18 Fracture Episode Rates Throughout the ATAC Study Annual fracture episode rates (%) Anastrozole (A) Tamoxifen (T) End of Treatment 146 v 143 fractures 375 v RR=1.55 fractures P < RR=1.03 P = Time since randomization (years) At risk: A T Forbes et al Lancet Oncology 2008

19 Fracture Rates in Adjuvant Trials of Aromatase Inhibitors Aromatase Inhibitor Tamoxifen / Placebo % Increase Reference ATAC (Anastrozole) BIG 1-98 (Letrozole) IES (Exemestane) ABCSG (Anastrozole) MA17 (Letrozole) 340 (11%) 237 (7.7%) 43% Howell et al Lancet (8.6%) 141 (5.8%) 50% Coates et al JCO (7.0%) 115 (4.9%) 41% Coombes et al Lancet (2.0%) 16 (1.0%) 113% Jakesz et al Lancet (5.3%) 119 (4.6%) 15% Perez et al JCO 2006

20 ATAC -Percentage Change in BMD Over Time Estimated % change (mean and 95% CI) Lumbar spine -10 Baseline Time (years) Anastrozole (n=81) Tamoxifen (n=86) Significantly more BMD loss on anastrozole than tamoxifen p< for both lumbar spine and total hip BMD primary analysis No patient with normal baseline BMD developed osteoporosis Total hip -10 Baseline Time (years) Eastell et al J Clin Oncol 26:1051, 2008.

21 Breast Cancer and Bone Health Normal Bone Health Impact of Cancer Therapies on Bone Health Therapeutic Strategies Management Guidelines

22 Overall Structure of Bisphosphonates PO 3 H 2 R 2 Chain R 1 Chain C Osteoclast PO 3 H 2

23 Z-FAST / ZO-FAST / E-ZO-FAST: Trial design Key endpoints: Primary: Bone mineral density (BMD) at 12 mo Secondary : Fracture, disease recurrence, disease free-survival, bone markers 2,193 patients Breast cancer Stage I to IIIa Postmenopausal or amenorrheic due to cancer treatment ER + and/or PgR + T-score 2 SD R Letrozole + zoledronic acid 4 mg every 6 months Letrozole Delayed zoledronic acid If 1 of the following occurs: BMD T-score < 2 SD Clinical fracture Asymptomatic fracture at 36 months Treatment duration 5 years BMD = Bone mineral density; ER = Oestrogen receptor; PgR = Progesterone receptor; R = Randomisation; SD = Standard deviation.

24 Z-FAST: Immediate Zoledronic Acid Increases BMD in Lumbar Spine and Hip Mean (SEM) % change BMD Upfront ZOL (4 mg/6 months) Delayed ZOL (4 mg/6 months) (N = 602) 4% P <.0001* P <.0001* P <.0001* P <.0001* P <.0001* P <.0001* 3% 2% 1% 0% 1% 2% 3% Δ 4,4% Δ 5.9% Δ 6.7% Δ 3.3% Δ 4.7% Δ 5.2% 4% Month Month Month Month Month Month Lumbar spine Total hip SEM = Standard error of the mean; BMD = Bone mineral density; ZOL = Zoledronic acid. *P values correspond to intergroup comparisons. Intragroup comparisons from baseline to month 12 or 24 for all treatment groups were significant (P <.0001 for all). Adapted from Brufsky A, et al. Presented at: 29th SABCS 2006, Abstract #5060. Brufsky A, et al. Presented at: 30th SABCS 2007, Abstract #27.

25 ARIBON Study Design - Monthly Oral Ibandronate NORMAL T-score > -1 N=68 Anastrozole Calcichew D3 Forte Repeat DXA in 2 Years N=20 Placebo OSTEOPENIC T-score -1 to -2.5 N=50 Anastrozole Calcichew D3 Forte RANDOMSATION 1:1 N=25 Oral Ibandronate 150mg q 28 days Repeat DXA at 12 and 24 months OSTEOPOROTIC T-score -2.5 N=13 Anastrozole Calcichew D3 Forte N=25 Oral Ibandronate 150mg q 28 days N=12 Serum and Urine for markers of bone turnover Lester et al. Clin Cancer Res, in press, 2008

26 ARIBON Study Results - Monthly Oral Ibandronate 150mg SPINE HIP Lester et al. Clin Cancer Res, in press 2008

27 ABCSG-12 - Bone Protection Study with Zoledronic Acid Premenopausal women with early breast cancer No chemotherapy Tamoxifen 20 mg/d Surgery (+RT) Goserelin 3.6mg q28d Randomize 1 : 1 : 1: 1 Tamoxifen 20 mg/d + Zoledronic Acid 4mg q6m Anastrozole 1 mg/d Anastrozole 1 mg/d + Zoledronic Acid 4mg q6m Gnant MF, et al. J Clin Oncol. 2007;25:

28 ABCSG XII: 6 Monthly Zoledronic Acid Reduces Bone Loss END OF TREATMENT Ana + ZA: p< Tam + ZA: p=0.049 Tamoxifen alone: p< Anastrozole alone: p< ABCSG-12 = Austrian Breast and Colorectal Cancer Study Group Trial 12. Gnant MF, et al. Lancet Oncology 2008

29 Patients, % Patients, % Zoledronic Acid Preserves BMD During 3 Years of Adjuvant Therapy 100 Goserelin/Anastrozole 100 Goserelin/Anastrozole + ZOL Time, mo BMD = Bone mineral density; ZOL = Zoledronic acid. Adapted from Gnant MF, et al. J Clin Oncol. 2007;25(7): Osteoporosis Osteopenia Normal Time, mo

30 First event per patient, n First DFS Events (ITT Population) No ZOL vs ZOL Death without prior recurrence Secondary malignancy Contralateral breast cancer Distant recurrence Locoregional recurrence H.R. 0.65; p= No ZOL ZOL (n = 904) (n = 899) DFS = Disease-free survival; ITT = Intent-to-treat; ZOL = Zoledronic acid. Gnant M, et al. NEJM 2009

RANKL Denosumab For Treatment of Bone Loss on Aromatase Inhibitors RANKL stimulates osteoclasts and bone resorption Denosumab Novel fully human monoclonal antibody to RANKL Cytokines and Growth

31 RANKL Denosumab For Treatment of Bone Loss on Aromatase Inhibitors RANKL stimulates osteoclasts and bone resorption Denosumab Novel fully human monoclonal antibody to RANKL Cytokines and Growth Factors (IL-6, IL-8, IL-1b, PGE-2, TNF-a, CSF-1, PTHrP) Osteoblast Lineage RANKL RANK Cancer Cells in Bone Direct effects on tumor? Osteoclast Growth Factors (TGF-b, IGFs, FGFs, PDGFs, BMPs) Bone Resorption Bone

32 Denosumab: Effect on Lumbar Spine Bone Mineral Density Ellis G, et al. J Clin Oncol 2008

33 Breast Cancer and Bone Health Normal Bone Health Impact of Cancer Therapies on Bone Health Therapeutic Strategies Management Guidelines

34 ASCO Guidelines on Bone Health Copyright American Society of Clinical Oncology ASCO Guidelines 2003 Hillner, B. E. et al. J Clin Oncol; 21:

35 UK Management for Bone Loss in Breast Cancer - NOS/NCRI Post-menopausal women >age 45 Baseline DEXA scan and risk assessment if for AI therapy Risk adapted strategy Lifestyle advice and adequate calcium and vitamin D 1 g calcium and 800iu vitamin D Reassure if T score > -1 and no risk factors No monitoring required Monitor BMD of osteopaenic patients every 2 years Baseline T score <-1 Intervention with bisphosphonates > age 75 and > 1 risk factor for osteoporotic fracture T score < -2 either at baseline or on follow-up T score < -1 at baseline and annual bone loss >4% Reid et al. Cancer Treatment Reviews 2008.

36 UK Guidance Algorithm on Management of Bone Loss in Early Breast Cancer POST-MENOPAUSAL WOMEN Reid et al. Cancer Treatment Reviews 2008

37 UK Management for Bone Loss in Breast Cancer - NOS/NCRI Premature menopause at age <45 Baseline DEXA scan and risk assessment Lifestyle advice and adequate calcium and vitamin D 1g calcium and 800iu vitamin D Risk adapted strategy Reassure if T score > -1 and not on concomitant AI No monitoring required Monitoring of BMD Perform every 2 years if: T score < -1 without an AI All patients if concomitant AI Intervention with bisphosphonates Concomitant AI and T score < -1 T score < -2 either at baseline or on follow-up Annual bone loss >4% on serial BMD monitoring Reid et al. Cancer Treatment Reviews 2008

38 UK Guidance Algorithm on Management of Bone Loss in Early Breast Cancer PREMATURE MENOPAUSE BEFORE AGE 45 Reid et al. Cancer Treatment Reviews 2008

39 European Recommendations for Women Initiating Aromatase Inhibitor Therapy T-score 2.0, no risk factors Calcium and vitamin D supplements Any 2 of the following risk factors: T-score < 1.5 Age > 65 years Low BMI (< 20 kg/m 2 ) Family history of hip fracture Personal history of fragility fracture after age 50 Oral corticosteroid use of > 6 months Smoking (current or history of) T-score < 2.0 Zoledronic acid (4 mg / 6 months) calcium and vitamin D supplements Monitor risk status and BMD every 1 to 2 years a a. 5% drop in BMD should trigger zoledronic acid treatment (4 mg / 6 mo). Use lowest T-score from 3 sites. BMI = Body mass index; BMD = Bone mineral density; AI = Aromatase inhibitor. Adapted from Hadji P, et al. Ann Oncol. 2008;19(8): Monitor BMD every 2 years Data for oral bisphosphonates are emerging Evidence from 4 clinical trials indicates that zoledronic acid prevents AI-associated bone loss

40 WHO FRAX Index (

41 Bone Metastases in Cancer

42 Consequences of Bone Metastases Poor functional capacity Economic Burden Impaired mobility Severe bone pain Metastatic Bone Disease Long and painful recovery from fractures Hypercalcaemia Inconvenient hospital/clinic visits Pain and paralysis from spinal cord compression

43 % of patients Bone Metastases Can Lead to SREs Patients who will likely develop an SRE without treatment 90 74% 60 51% 50% 49% 46% 30 0 Renal cell carcinoma (n=74) Multiple myeloma (n=179) Breast (n=114) Prostate (n=208) NSCLC (n=250) Data are from placebo-controlled arms of bisphosphonate trials. Lipton A et al. Cancer. 2003;98: Berenson JR et al. J Clin Oncol. 1998;16: Kohno N et al. J Clin Oncol. 2005;23: Saad F et al. J Natl Cancer Inst. 2004;96: Rosen LS et al. Cancer. 2004;100:

44 The Vicious Cycle of Bone Destruction Growth factors and cytokines released by tumor cells Osteoclastic resorption stimulated PTHrP IL-6 IL-8, PGE 2 TNF-a CSF-1 BMP PDGF FGFs IGFs TGF-β Peptides (eg, TGF-β) released by bone resorption Tumor cell production of factors increased More bone resorption Tumor cell proliferation Adapted from Mundy GR, Yoneda T. N Engl J Med. 1998;339: Courtesy John Mackey

Effect of Bisphosphonates on Vicious Cycle of

osteoclasts PTHrP IL-6 IL-8, PGE 2 TNF-a CSF-1

of peptides Slowed tumor-cell growth Reduced

in bone resorption Adapted from Mundy GR,

45 Effect of Bisphosphonates on Vicious Cycle of Bone Destruction Decrease activity of osteoclasts PTHrP IL-6 IL-8, PGE 2 TNF-a CSF-1 BMP PDGF FGFs IGFs TGF-β Reduction in release of peptides Slowed tumor-cell growth Reduced production of PTHrP and other factors Decrease in bone resorption Adapted from Mundy GR, Yoneda T. N Engl J Med. 1998;339: Courtesy John Mackey

46 Added Benefit of Zoledronic Acid Over Pamidronate in Breast Cancer 64% risk of skeletal complication with no bisphosphonate at 2 years Approx 33% risk reduction with pamidronate Further 20% risk reduction with zoledronic acid 64% 43% 34% Lipton A, et al Cancer 2000; 88: ; Rosen LS, et al Cancer 2003;100:36-43.

47 Conclusions Important effects of cancer treatments on bone health Ovarian suppression Aromatase inhibitors Effective management and treatment strategies emerging DEXA baseline assessment required Risk adapted monitoring and intervention Bisphosphonates effective in preventing bone loss Bone metastases cause considerable morbidity Bisphosphonates markedly reduce number and severity of skeletal complications

Integrated care: guidance on fracture prevention in cancer-associated bone disease; treatment options

$Integrated care: guidance on fracture prevention in cancer-associated bone disease; treatment options$ Paris, November 1st 2016 Integrated care: guidance on fracture prevention in cancer-associated bone disease; treatment options René Rizzoli MD International Osteoporosis Foundation and Division of Bone