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

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

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

The Structure of Bone Cortical Bone Vascular Supply Trabecular Bone Marrow

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).

Bone Remodeling Osteoclast Osteoblasts 6

Bone Remodeling

Components of Bone Strength quality Bone density + Architecture Bone turnover Accumulation of lesions (microfractures) Secondary mineralisation aBMD = g/cm2 vBMD = g/cm3 This slide summarizes concepts outlined in the National Institutes of Health (NIH) consensus statement.1 Compromised bone strength leads to an increased risk of fracture. Bone strength depends on bone quality and bone density. Bone quality is affected by the bone architecture and turnover, and the accumulation of bone damage (e.g. micro-fractures) and mineralization. Bone density is expressed as grams of mineral per area (aBMD) or volume (vBMD) Though not mentioned in the NIH statement, the quantity as well as the quality of the bone matrix (including type 1 collagen and other proteins) also affects bone quality. Reference: 1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785-795. NIH Consensus Development Panel. JAMA 2001; 285 (6): 785-795

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

Interpretation of a DEXA Scan T score Z score

Diagnosis of Osteoporosis The WHO and the International Osteoporosis Foundation have developed the following guidelines for women, for assessments with DEXA scanning. This scale is based on a mean value based on a young female BMD. As a person’s BMD level decreases past this mean value, so their risk of developing osteopenia and/or osteoporosis (and suffering a fracture) increases. A 1.0 SD (standard deviation) decrease from the mean BMD equals a T-score of -1. A 2.5 SD decrease equals a T-score of -2.5. Reference: 1. Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet. 2002 Jun 1;359(9321):1929-36 Adapted from Kanis, JA. Lancet 2002; 359(9321):1929-36

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

80% of Fractures Occur in Patients Who Have Normal or Osteopenic BMD 50 45 40 35 30 25 20 15 10 5 Fracture rate per 1,000 person-years >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 < –3.5 450 400 350 300 250 200 150 100 50 Number of women with fractures Fracture rate No. of women with fractures BMD distribution 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):1108-1112. 13 13 13

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

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 Relative risk 0.50 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.

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 Normal men1 Postmenopausal Women >551 Menopausal Women <551 AI therapy in postmenopausal women2 AI therapy plus GnRH agonist in premenopausal women3 Premature menopause secondary to chemotherapy4 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.

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

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 Key point: The increase in fracture rates appears to only be associated with the active treatment period and does not continue after treatment completion. Q: Why is the carryover effect not seen with bones ? Q: Were any of these patients receiving bisphosphonates or other relevant medications ? Q: How do these fracture rates compare with an age-matched population ? Q: Wouldn’t you expect the tamoxifen patients to begin to do worse with respect to fractures as they come off treatment and the protective effect of tamoxifen is lost ? 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 18

Fracture Rates in Adjuvant Trials of Aromatase Inhibitors Tamoxifen / Placebo % Increase Reference ATAC (Anastrozole) 340 (11%) 237 (7.7%) 43% Howell et al Lancet 2005 BIG 1-98 (Letrozole) 211 (8.6%) 141 (5.8%) 50% Coates et al JCO 2007 IES (Exemestane) 162 (7.0%) 115 (4.9%) 41% Coombes et al Lancet 2007 ABCSG (Anastrozole) 34 (2.0%) 16 (1.0%) 113% Jakesz et al Lancet 2005 MA17 137 (5.3%) 119 (4.6%) 15% Perez et al JCO 2006

ATAC -Percentage Change in BMD Over Time Anastrozole (n=81) Tamoxifen (n=86) Lumbar spine Total hip Estimated % change (mean and 95% CI) 4 4 2 2 -2 -2 -4 -4 -6 -6 -8 -8 -10 -10 Baseline 1 2 5 Baseline 1 2 5 Time (years) Time (years) 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 Eastell et al J Clin Oncol 26:1051, 2008.

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

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

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 redundant 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. 23 23

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) 4% P < .0001* P < .0001* P < .0001* P < .0001* P < .0001* P < .0001* 3% 2% Δ 4,4% 1% Δ 5.9% Δ 6.7% Δ 3.3% Δ 4.7% Δ 5.2% Mean (SEM) % change BMD 0% –1% –2% Results from the Z-FAST study show that after 12, 24, and 36 months of therapy, upfront zoledronic acid (4 mg every 6 months) treatment increases bone mineral density (BMD) from baseline at the lumbar spine and total hip In contrast, the delayed group experienced declines in BMD from baseline at 12 and 24 months at both lumbar spine and total hip Patients receiving upfront zoledronic acid (4 mg/ 6 months) continued to gain BMD over 2 years of treatment The overall difference between the upfront and delayed groups was increasing over 24 and 36 months of therapy –3% –4% Month 12† Month 24† Month 36‡ Month 12† Month 24† 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. 24 24

ARIBON Study Design - Monthly Oral Ibandronate Lester et al. Clin Cancer Res, in press, 2008

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

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. 8

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 In the ABCSG-12 trial, premenopausal patients receiving endocrine therapy alone (either tamoxifen + goserelin or anastrozole + goserelin) had 17.3% and 11.6% reductions in bone mineral density (BMD) from baseline, respectively, at 36 months In contrast, patients who received zoledronic acid (4 mg every 6 months) had BMD measurements that remained stable over 36 months ABCSG-12 = Austrian Breast and Colorectal Cancer Study Group Trial 12. Gnant MF, et al. Lancet Oncology 2008

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

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

Denosumab For Treatment of Bone Loss on Aromatase Inhibitors RANKL stimulates osteoclasts and bone resorption Denosumab Novel fully human monoclonal antibody to RANKL RANKL RANK Cancer Cells in Bone Direct effects on tumor? Cytokines and Growth Factors (IL-6, IL-8, IL-1b, PGE-2, TNF-a, CSF-1, PTHrP) Growth Factors (TGF-b, IGFs, FGFs, PDGFs, BMPs) Osteoclast RANKL RANKL AI, aromatase inhibitor; BMP, bone morphogeneic protein; FGF, fibroblast growth factor; IGF, insulin-like growth factor; IL, interleukin; CSF, colony stimulating factor; PDGF, platelet derived growth factor; PGE, prostaglandin E; PTHrP, parathyroid hormone release hormone; RANKL, receptor activator of NF-κB ligand; TGF tissue growth factor; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand. Bone Resorption Osteoblast Lineage Bone

Denosumab: Effect on Lumbar Spine Bone Mineral Density BMD, bone mineral density; Ellis G, et al. J Clin Oncol 2008

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

ASCO Guidelines on Bone Health ASCO Guidelines 2003 Hillner, B. E. et al. J Clin Oncol; 21:4042-4057 2003

Reid et al. Cancer Treatment Reviews 2008. 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.

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

Reid et al. Cancer Treatment Reviews 2008 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

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

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, no risk factors T-score < –2.0 Calcium and vitamin D supplements Zoledronic acid (4 mg / 6 months) calcium and vitamin D supplements Monitor risk status and BMD every 1 to 2 yearsa 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 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.

WHO FRAX Index (www.shef.ac.uk/FRAX) SPEAKER’S NOTES: This slide summarizes the musculoskeletal and other adverse events for patients on the IES at 55.7 months follow-up. Incidence rates per 1000 women years (99% CI) for fractures (allowing more than one fracture event per patient) are E=19.2 (15.9, 23.1) and T=15.1 (12.2, 18.7). Fracture rates, osteoporosis, and musculoskeletal adverse events all differ between treatment arms, with the majority in favor of tamoxifen. Muscle cramps significantly favors exemestane (P≤0.001). Note: Box sizes in the plot indicate the precision of the estimate, with a larger box indicating better precision. Reference 1. Coombes RC, Kilburn LS, Snowdon CF et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 2007;369:559-70. .

Bone Metastases in Cancer BM are frequent in metastatic cancers; there are various types (lytic, blastic).

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

Bone Metastases Can Lead to SREs Patients who will likely develop an SRE without treatment % of patients Left untreated, patients with bone metastases are at high risk of experiencing an SRE, such as pathologic fracture or spinal cord compression. This chart shows the incidence of SREs in patients with bone metastases from various tumor types without treatment. A majority of untreated patients with renal cell carcinoma1 or multiple myeloma2 experienced an SRE, as did half of patients with breast cancer3 and nearly half of patients with prostate cancer4 or non-small cell lung cancer (NSCLC).5 References: 1. Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer. 2003;98:962-969. 2. Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol. 1998;16:593-602. 3. Kohno N, Aogi K, Minami H, et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol. 2005;23:3314-3321. 4. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96:879-882. 5. Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial. Cancer. 2004;100:2613-2621. 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.

The Vicious Cycle of Bone Destruction Growth factors and cytokines released by tumor cells Tumor Cells Osteoclastic resorption stimulated PTHrP IL-6 IL-8, PGE2 TNF- 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 Osteoclast Bone Adapted from Mundy GR, Yoneda T. N Engl J Med. 1998;339:398-400. Courtesy John Mackey 44

Effect of Bisphosphonates on Vicious Cycle of Bone Destruction Decrease activity of osteoclasts Tumor Cells PTHrP IL-6 IL-8, PGE2 TNF- CSF-1 Reduction in release of peptides BMP PDGF FGFs IGFs TGF-β BMP PDGF FGFs IGFs TGF-β Slowed tumor-cell growth Reduced production of PTHrP and other factors Osteoclast Decrease in bone resorption Bone Adapted from Mundy GR, Yoneda T. N Engl J Med. 1998;339:398-400. Courtesy John Mackey 45

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; 88:3033-3037; Rosen LS, et al Cancer 2003;100:36-43.

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