1. Breast Cancer and Bone Health

2. Bone Homeostasis Bone is a living tissue which is constantly renewing via a balance of resorption of old bone (via Osteoclasts) and deposition of new bone (via Osteoblasts).

4. Osteoporosis Disruption to this balance can result in weak or brittle bones that are subject to fractures with little to no trauma or stress. Fractures associated with postmenopausal osteoporosis have been associated with increased morbidity and mortality. Aromatase Inhibitor associated bone loss has been demonstrated to occur at twice the rate of normal postmenopausal bone loss.

5. A- Normal Bone B- Osteoporosis

6. Risk Factors of Osteoporosis Female Advanced Age White and Asian Ethnicity Family History of Osteoporosis Small Frame Decreased Estrogen Levels Decreased Testosterone Levels Increased Thyroid Hormones Increased Parathyroid Hormones Increased Adrenal Hormones Steroid Use

7. Breast Cancer Specific Risk Factors Chemotherapy Induced Menopause Aromatase Inhibitor associated decreased Estrogen Levels Ovarian Suppression – GnRh Agonists – Oophorectomy

8. Lifestyle Risk Factors Low Calcium Intake Smoking Sedentary Lifestyle Excessive Alcohol Eating Disorders or Poor Dietary Habits

9. Detection

10. Interpretation of Dexa Scans T-Score: the number of standard deviations above or below the mean for a healthy 30 year old adult of the same sex and ethnicity as the patient Normal Density: T-score > -1 SD Osteopenia: T-score -2.5 to -1 SD Osteoporosis: T-score < -2.5 SD

11. Who Should Be Scanned? All women aged 65 and older regardless of risk factors Younger postmenopausal women with one or more risk factors.postmenopausal Postmenopausal women who present with fractures (to confirm the diagnosis and determine disease severity). Estrogen deficient women at clinical risk for osteoporosis. Estrogen Individuals receiving, or planning to receive, long-term glucocorticoid (steroid) therapy.steroid Individuals with primary hyperparathyroidism.hyperparathyroidism Individuals being monitored to assess the response or efficacy of an approved osteoporosis drug therapy. Individuals with a history of eating disorders

12. Which Breast Cancer Patients Should be Scanned? All Women Over the Age of 65 All Women with Medically Induced Menopause Baseline Prior to Initiation of AI therapy

13. WHO Fracture Risk Assessment (FRAX) Tool http://www.sheffield.ac.uk/FRAX/ Retrospective case-controlled study of 400 postmenopausal women with newly diagnosed breast cancer revealed that >28% of women were candidates for bone directed therapy when risk factors were taken into account in addition to BMD; where as BMD alone only identified < 10% at risk patients. Br J Ca 2010; 102:645-650.

14. Treatments to Prevent Bone Loss Exercise – Weight bearing and Resistence Adequate Calcium Intake (at least 1300 mg/day) Adequate Vitamin D Levels (at least 800 IU/day) Low Caffeine Quit Smoking Maintain Healthy Weight Tamoxifen Raloxifene Bisphosphonates

15. Vitamin D The Women’s Health Initiative is the largest study looking at supplemental Calcium and Vitamin D use in order to decrease Bone Loss and decrease Fracture Risk. Subgroup analysis has also looked at the incidence of certain cancers in those 36,000 postmenopausal women who took Ca + D supplements.

16. Women’s Health Initiative Initial data seemed to be negative: – 1306 cancers in the supplemental group – 1333 cancers in the placebo group However reevaluation of the data taking into account the number of women who were already taking calcium and Vitamin D supplements at study entry soon revealed that Calcium and Vitamin D does decrease the risk of total, breast and colorectal cancers by roughly 14-20%. Am J. Clin. Nutr. 2010 Jan; 95(1):258-9

17. Tamoxifen Although Tamoxifen has been shown to preserve BMD in postmenopausal women, it has not been shown to do the same in premenopausal women. In at least one population based study in Canada, current use of Tamoxifen in post menopausal women was associated with a decreased incidence in osteoporotic fracture risk. JCO Nov 10, 2008; 26(32):5227-5232.

18. Raloxifene SERM approved for the treatment of osteoporosis in postmenopausal women Approved for the prevention of Breast Cancer in High Risk Women or in Women with Osteoporosis

19. MORE Trial Greater than 7700 postmenopausal women Randomized to placebo, 60 mg, or 120 mg of Raloxifene for 3 years Results demonstrate BMD of 2-3% increase compared with placebo Decrease Rate of 1 st vertebral fracture of 2.4% Decrease Rate of subsequent fractures of 6% JAMA. 1999; 282:637-645.

20. Bisphosphonates

21. Trials of Antiresorptive Agents for Preventing AIBL in Postmenopausal Women with Breast Cancer Antiresorptive agent N BMD Dosing Treatment Follow-Up, Mean BMD change from baseline (trial) study, n duration, years months LS TH Zoledronate (ZO-FAST) 1065 1065 4 mg i.v. q6mo 5 36 +4.39 +1.9 Zoledronate (Z-FAST) 602 602 4 mg i.v. q6mo 5 61 +6.19 +2.57 Zoledronate (E-ZO-FAST) 527 527 4 mg i.v. q6mo 5 36 +5.98 NR Zoledronate (N03CC) 558 395 4 mg i.v. q6mo 5 24 +4.94 +1.22 Denosumab (HALT-BC) 252 252 60 mg s.c. q6mo 2 24 +6.2 +3.7 Risedronate (SABRE) 154 111 35 mg p.o./week 2 24 +2.2 +1.8 Risedronate 87 87 35 mg p.o./week 2 24 +0.4 +0.9 Clodronate 61 61 1600 mg p.o./day 3 60 -1.0 -0.1 Risedronate (ARBI) 213 70 35 mg p.o./week 2 24 +5.7 +1.6 Risedronate (IBIS-II) 613 59 35 mg p.o./week 5 12 +0.32 +0.67 Ibandronate (ARIBON) 131 5 150 mg p.o./mo 2 24 +2.98 +0.6 Risedronate 118 11 35 mg p.o./week 1 12 +4.1 +1.8

22. Do Bisphosphonates Have Anti-Tumor Activity as Well? European Study looked at 1800 premenopausal women taking goserelin + tamoxifen or goserelin + anastrazole and randomized them to zoledronate vs placebo. The study demonstrated 3.2% absolute decrease in disease progression in the patients treated with bisphosphonate therapy. NEJM 09; 360:679-691.

23. ZO-FAST Zoledronate Femara Adjuvant Synergy Trial > 1000 Women treated with AI therapy randomized to immediate Bisphosphonate therapy vs bisphosphonates only after a fracture or when the BMD dropped to < -2.0 Demonstrated 41% relative risk reduction in disease recurrence in the group treated immediately with zoledronate Ann Oncol 2010; 21:2188-2194.

24. Long Term Risks of Bisphosphonates There have been many case reports in the literature lately to suggest that long term bisphosphonate use is associated with atypical femoral fractures. Fractures usually occur in the subtrochanteric region The theory is that inhibition of osteoclasts may inhibit bone turnover and lead to increased bone deposition by osteoblasts, but is this bone sturdy bone or just dense, brittle bone? Very little data exists to support the use of bisphosphonates beyond 5 yrs The current recommendation is to discontinue use by 5 yrs.

25. Denosumab Monoclonal Antibody to RANK-ligand HALT-BC – Hormone Ablation Bone Loss Trial in Breast Cancer – 52 Women – Denosumab vs. placebo was given prophylactically to prevent AIBL – Demonstrated effective increase in BMD by 7.6% in 2 yrs although no change in fracture risk in this small population – Larger ABCSGT-18 is Currently Accruing over 3400 women to confirm this data. JCO 08;26(30): 4875-82

26. Rank Ligand’s Role in Bone Metastases

27. Patient with Breast Cancer Initiating or Receiving AI Therapy T-Score > -2.0 No Additional Risk Factors Exercise Calcium Vitamin D Supplements Monitor Risk Status and BMD at 1 year Any 2 of the Following Risk Factors: T-Score < -1.5 Age > 65 Low BMI Family History of Hip Fx Personal Hx of Fragility Fx Smoking Steroid Use > 6 months T-Score < -2.0 Exercise Bisphosphonate Therapy Calcium + Vitamin D Supplements Monitor BMD 1-2 years while on Bisphosphonate Therapy