Robert Coleman, Cancer Research Centre, Weston Park Hospital, Sheffield

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

3. Breast Cancer and Bone Health • Normal Bone Health • Impact of Cancer Therapies on Bone Health • Therapeutic Strategies • Management Guidelines

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

8. Bone strength Components of Bone Strength Bone quality Bone density + • Architecture • Bone turnover • Accumulation of lesions (microfractures) • Secondary mineralisation aBMD = g/cm2 vBMD = g/cm3 NIH Consensus Development Panel. JAMA2001; 285 (6): 785-795

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

10. Interpretation of a DEXA Scan Z score T score

11. Diagnosis of Osteoporosis Adapted from Kanis, JA. Lancet 2002; 359(9321):1929-36

12. BMD and Fracture Risk in the Normal Population Average BMD @ 35 years 16X 8X 4X 2X 1X -4.0 +1.0 0 -1.0 -2.0 -3.0 T score

13. Fracture rate increases ~2-fold in osteopenic women Majority of fractures occur in osteopenic women (T-score –1.0 to –2.5) 80% of Fractures Occur in Patients Who Have Normal or Osteopenic BMD 50 450 45 No. of women with fractures 400 BMD distribution 40 350 35 300 30 250 Fracture rate per 1,000 person-years 25 Number of women with fractures 200 20 150 15 100 10 50 5 0 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 –3.0 –3.0 to –3.5 < –3.5 BMD Fracture rate BMD, bone mineral density. Reprinted from Siris ES, et al. Arch Intern Med. 2004;164(10):1108-1112.

14. 200 160 Bioavailable E2, pmol/l 120 80 40 0 Premenopausal women Postmenopausal women Normal men Androgen Deprivation Therapy Sex, Age and Treatment Effects on Bioavailable Oestradiol Concentrations Aromatase Inhibitor Therapy Adapted from: Khosla et al. J Clin Endocrinol Metab 2001;86:3555-61

15. 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 fracturesa 1.0 1.0 1.00 Spine fracture Hip fracture 0.75 0.5 0.5 0.50 Relative risk 0.4 0.4 0.3 0.3 0.25 0.00 < 5 5 - 6 7 - 9 ≥ 10 Endogenous serum estradiol level, pg/mL a. Compared with women with detectable estrogen levels. Adapted from Cummings SR, et al. N Engl J Med. 1998;339(11):733-738.

16. Normal and Cancer Treatment Related Bone Loss Rates 10 Naturally occurring bone loss CTIBL 7.7 8 7.0 Bone loss at I year 6 4 2.6 2.0 2 1.0 0.5 0 Postmenopausal Women >551 Premature menopause secondary to chemotherapy4 AI therapy plus GnRH agonist in premenopausal women3 Normal men1 Menopausal Women <551 AI therapy in postmenopausal women2 • Kanis JA. Osteoporosis.1997:22-55. • Eastell R et al. J Bone Mineral Res. 2002. • Gnant M. San Antonio Breast Cancer Symposium, 2002. • Shapiro CL et al. J Clin Oncol. 2001;19:3306-3311.

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 4 End of Treatment Anastrozole (A)Tamoxifen (T) 146 v 143 fractures 3 Annual fracture episode rates (%) 2 375 v 234 fractures 1 RR=1.55 P <0.0001 RR=1.03 P =0.79 0 0 1 2 3 4 5 6 7 8 9 Time since randomization (years) At risk: A T 2984 2976 2859 2824 2745 2699 2640 2572 2496 2419 2306 2208 2077 2000 1713 1645 702 659 Forbes et al Lancet Oncology 2008

19. Fracture Rates in Adjuvant Trials of Aromatase Inhibitors

20. ATAC -Percentage Change in BMD Over Time Anastrozole (n=81) Tamoxifen (n=86) • Significantly more BMD loss on anastrozole than tamoxifen • p<0.0001 for both lumbar spine and total hip BMD primary analysis • No patient with normal baseline BMD developed osteoporosis Lumbar spine Total hip Estimated % change (mean and 95% CI) 4 4 2 2 0 0 -2 -2 -4 -4 -6 -6 -8 -8 -10 -10 Baseline 1 2 5 Baseline 1 2 5 Time (years) 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. Osteoclast Overall Structure of Bisphosphonates PO H 3 2 Chain R 2 Chain R 1 C PO H 3 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 • Delayed zoledronic acid • If 1 of the following occurs: • BMD T-score < –2 SD • Clinical fracture • Asymptomatic fracture at 36 months Letrozole 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 Upfront ZOL (4 mg/6 months) Delayed ZOL (4 mg/6 months) (N = 602) P < .0001* P < .0001* P < .0001* 4% P < .0001* P < .0001* P < .0001* 3% 2% Δ 4,4% Δ 6.7% Δ 5.9% 1% Δ 3.3% Δ 4.7% Δ 5.2% Mean (SEM) % change BMD 0% –1% –2% –3% –4% Month 12† Month 24† Month 36‡ Month12† Month24† Month 36‡ 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 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 Tamoxifen 20 mg/d + Zoledronic Acid 4mg q6m Surgery (+RT) Goserelin 3.6mg q28d Randomize 1 : 1 : 1: 1 Anastrozole 1 mg/d Anastrozole 1 mg/d + Zoledronic Acid 4mg q6m Gnant MF, et al. J Clin Oncol. 2007;25:820-828.

28. ABCSG XII: 6 Monthly Zoledronic Acid Reduces Bone Loss Ana + ZA: p<0.0001 END OF TREATMENT Tam + ZA: p=0.049 Tamoxifen alone: p<0.0001 Anastrozole alone: p<0.0001 Gnant MF, et al. Lancet Oncology 2008 ABCSG-12 = Austrian Breast and Colorectal Cancer Study Group Trial 12.

29. Osteoporosis 100 100 Osteopenia Normal 80 80 60 60 Patients, % Patients, % 40 40 20 20 0 0 0 6 12 36 0 6 12 36 Time, mo Time, mo Zoledronic Acid Preserves BMD During 3 Years of Adjuvant Therapy Goserelin/Anastrozole + ZOL Goserelin/Anastrozole BMD = Bone mineral density; ZOL = Zoledronic acid. Adapted from Gnant MF, et al. J Clin Oncol. 2007;25(7):820-828.

30. First DFS Events (ITT Population) No ZOL vs ZOL First event per patient, n H.R. 0.65; p=.017 (n = 904) (n = 899) DFS = Disease-free survival; ITT = Intent-to-treat; ZOL = Zoledronic acid. Gnant M, et al. NEJM 2009

31. RANKL RANK Denosumab For Treatment of Bone Loss on Aromatase Inhibitors • RANKL stimulates osteoclasts and bone resorption • Denosumab • Novel fully human monoclonal antibody to RANKL Cancer Cells in Bone Direct effects on tumor? Cytokines and GrowthFactors (IL-6, IL-8, IL-1b,PGE-2, TNF-a, CSF-1, PTHrP) Growth Factors (TGF-b, IGFs, FGFs,PDGFs, BMPs) Osteoclast RANKL RANKL BoneResorption OsteoblastLineage 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 ASCO Guidelines 2003 Hillner, B. E. et al. J Clin Oncol; 21:4042-4057 2003

35. UK Management for Bone Loss in Breast Cancer - NOS/NCRIPost-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/NCRIPremature 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 • Any 2 of the following risk factors: • T-score < –1.5 • Age > 65 years • Low BMI (< 20 kg/m2) • 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 T-score ≥ –2.0, no risk factors Calcium and vitamin D supplements Zoledronic acid (4 mg / 6 months)calcium and vitamin D supplements Monitor BMD every 2 years Monitor risk status and BMD every 1 to 2 yearsa • Data for oral bisphosphonates are emerging • Evidence from 4 clinical trials indicates that zoledronic acid prevents AI-associated bone loss 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):1407-1416.

40. WHO FRAX Index (www.shef.ac.uk/FRAX)

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. Bone Metastases Can Lead to SREs Patients who will likely develop an SRE without treatment % of patients 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;98:962-969. Berenson JR et al. J Clin Oncol. 1998;16:593-602. Kohno N et al. J Clin Oncol. 2005;23:3314-3321. Saad F et al. J Natl Cancer Inst. 2004;96:879-882. Rosen LS et al. Cancer. 2004;100:2613-2621.

44. The Vicious Cycle of Bone Destruction Growth factors and cytokines released by tumor cells Osteoclastic resorption stimulated Tumor Cells PTHrP IL-6 IL-8, PGE2 TNF- CSF-1 • Peptides (eg, TGF-β) released by bone resorption BMP PDGF FGFs IGFs TGF-β • Tumor cell production of factors increased • More bone resorption • Tumor cell proliferation Osteoclast Adapted from Mundy GR, Yoneda T. N Engl J Med. 1998;339:398-400. Courtesy John Mackey Bone

45. Effect of Bisphosphonates on Vicious Cycle of Bone Destruction Reduction in release of peptides PTHrP IL-6 IL-8, PGE2 TNF- CSF-1 BMP PDGF FGFs IGFs TGF-β BMP PDGF FGFs IGFs TGF-β Osteoclast • Decrease activity of osteoclasts Tumor Cells • Slowed tumor-cell growth • Reduced production of PTHrP and other factors • Decrease in bone resorption Bone Adapted from Mundy GR, Yoneda T. N Engl J Med. 1998;339:398-400. 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 34% 64% 43% Lipton A, et al Cancer 2000; 88:3033-3037; 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