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Breast Cancer and Bone Health

Breast Cancer and Bone Health. Tracy S. d’Entremont, MD Bryn Mawr Medical Specialists. 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 ). Osteoporosis.

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Breast Cancer and Bone Health

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  1. Breast Cancer and Bone Health Tracy S. d’Entremont, MD Bryn Mawr Medical Specialists

  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).

  3. 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.

  4. A- Normal BoneB- Osteoporosis

  5. 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

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

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

  8. Detection

  9. 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

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

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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 1st vertebral fracture of 2.4% • Decrease Rate of subsequent fractures of 6% JAMA. 1999; 282:637-645.

  19. Bisphosphonates

  20. 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

  21. 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 zoledronatevs placebo. • The study demonstrated 3.2% absolute decrease in disease progression in the patients treated with bisphosphonate therapy. NEJM 09; 360:679-691.

  22. ZO-FAST • ZoledronateFemara Adjuvant Synergy Trial • > 1000 Women treated with AI therapy randomized to immediate Bisphosphonate therapy vsbisphosphonates 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.

  23. 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.

  24. 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

  25. Rank Ligand’s Role in Bone Metastases

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