managementof(osteoporosis(in( paents(with(breastcancer(on ... ·...
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Management of Osteoporosis in Pa1ents with Breast Cancer on
Aromatase Inhibitor Rukshini Puvanendran
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Kandang Kerbau Hospital • KKH
• Women and Children’s Hospital
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Breast Cancer and Bone Loss
• Pa1ents with breast cancer are at an increase in risk for bone loss
• Gluco-‐cor1coids, chemotherapy, GNRH agonists
• Estrogen depriva1on: Aromatase inhibitors/ oophrectomy/ ovarian abla1on.
• As there is an increase in survival of breast cancer pa1ents it is important to ensure bone health for cancer survivors
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American Society of Clinical Oncology 2014
• American Society of Clinical Oncology (ASCO) clinical prac1ce guidelines reflect this, recommending that postmenopausal women with early ER-‐posi1ve breast cancer be offered either Tamoxifen for 10 years, an aromatase inhibitor for 5 years, Tamoxifen ini1ally for 5 years followed by an aromatase inhibitor for up to a further 5 years, or Tamoxifen for 2–3 years followed by an aromatase inhibitor for up to a further 5 years.
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Aromatase inhibitors versus tamoxifen in early breast cancer: pa7ent-‐level meta-‐analysis of the randomized trials
• Advances in adjuvant therapy has been shown to increase breast cancer survival • Tamoxifen has been the cornerstone of adjuvant therapy for several decades. • Recently aromatase inhibitors have been shown to reduce recurrence for ER+ • Early Breast Cancer Trialists' Collabora7ve Group (EBCTCG): Meta-‐analysis • Aromatase inhibitors reduce recurrence rates by about 30% (propor1onately)
compared with tamoxifen. • 5 years of an aromatase inhibitor reduces 10-‐year breast cancer mortality rates by
about 15% compared with 5 years of tamoxifen, hence by about 40% (propor1onately) compared with no endocrine treatment.
• Lancet 2014
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Management of BONE HEALTH in pa1ents on AROMATASE
INHIBITORS Post menopausal Women with Breast
Cancer without bone metastasis
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Aromatase inhibitors
• Highly potent • Inhibits conversion of androgens to estrogen in the peripheral 1ssues (adrenal glands and fats cells)
• Unable to block estrogen produc1on by the ovaries. • Suppress circula1ng estrodiol levels to undetectable • Use predominantly in post menopausal women • reduc1on in estrogen levels and up regula1on of RANK ligand signal in bone.
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Effect of Anastrozole on Bone Mineral Density: 5-‐Year Results From the Anastrozole, Tamoxifen, Alone or in Combina7on Trial : Estell et al (UK)
A: Lumbar spine; B: Total Hip
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Screening
• All pa1ents should have a baseline BMD screen before star1ng Aromatase Inhibitors
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Osteoporosis
• Defini1on: • WHO BMD T score < -‐2.5 SD • WHO FRAX score: Osteopenia with Hip fracture risk > 3%, major fracture risk >20
• Less than age 50: BMD Z score < 2.0 SD
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Decision for specific treatment of post menopausal women on aromatase inhibitors
• Osteoporosis: BMD < -‐2.5 SD Universally accepted
• BMD < -‐2.0 SD : Because of speed of AI induced bone loss
• BMD SD < -‐1.0 to -‐ 2.0 – FRAX – 2 or more risk factors
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Bone Related risk factors • Age > 65 • Previous fragility fractures • BMI : 20 kg/m 2 • Use of gluco-‐cor1costeroids (>
5.0 or 7.5 mg prednisolone daily for 3 months)
• Alcohol abuse ( > 3 standard drinks/ day)
• Smoking • History of hip fracture in first
degree rela1ves • Secondary causes of
osteoporosis
• Treatment with AI > 6 months • Chemotherapy induced
menopause • Radiotherapy • Tamoxifen use in pre-‐
menopausal women – (T reduces risk in post
menopausal women but increases risk in pre-‐menopausal women)
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Ini1al Evalua1on
• History and Physical Examina1on – Clinical risk factors for fracture – Lifestyle factors
• Bone Mineral Density and FRAX analysis at baseline
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FRAX
• WHO Fracture Risk Assessment Tool
FRAX IS NOT VALIDATED F
OR AI USE
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Ini1al Evalua1on of pa1ent with low bone mass ini1a1ng AI
• Screen for secondary causes of osteoporosis: – Ca/ Vitamin D – Renal func1on – Thyroid func1on – Liver func1on tests: Albumin/ total protein/Alkaline phosphatase/ Liver enzymes
– Bone scan evalua1ons if needed – 24 hr urine calcium
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Treatment
• Universal Recommenda1ons for all pa1ents • Adequate calcium and vitamin D in diet • Smoking cessa1on/ alcohol modera1on • Fall preven1on strategies • Weight bearing and strength building exercises. Balance exercises
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Treatment with specific an1 osteoporo1c medica1ons
• Vitamin D • Suggest keep levels at 30 ng/ml • Possible lower incidence of AI related arthralgia in pa1ents with Vit D level > 40 ng/ml
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Specific treatment of Osteoporosis
• Bisphosphonates: • Oral: • Risendronate
– IBIS II trail (Anastrazole and Risendronate) ( N= 1410 placebo vs anastrazole)
– SABRE trail (Anastrazole and Risendronate)(N=234) • Alendronate
– (Hiroaki Inoue et al N= 92) • Ibandronate
– ARBON trial ( N= 25)
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Specific therapy for Osteoporosis
• IV Bisphosphonates (Zolendronate 4 mg 6 monthly)
• Largest concentra1on of data • Bone substudy of ABCSG-‐12 trial (n= 401) over 3 years
• Zometa®-‐Femara® Adjuvant Synergy Trials – (Z-‐FAST, N = 602; ZO-‐FAST, N= 1066; E-‐ZO-‐FAST, N = 527)
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IV Zolendronate
• Z-‐FAST (post-‐menopausal women with early ER + breast cancer. Analysis at mth 36)
• Up-‐front group: Administer together with AI • Delayed group: Administer aqer BMD < -‐2.0 SD • Only 25% of pa7ents in delayed group required
treatment • Women receiving upfront treatment con1nued to gain
BMD aqer 36 months (BMD 6.7% vs 5.2% p < 0.001)
• Trend to reduced fracture in upfront group, but no sta1s1cally significant. (5.7% vs 6.3% p = 0.002)
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The effect of anastrozole on bone mineral density during the first 5 years of adjuvant treatment in postmenopausal women with early breast cancer
Hiroaki Inoue et al
BMD changes of lumbar spine according to upfront, delayed or without Bis. In pa1ents treated with upfront Bis (bold line; n = 19), 5.4% BMD increase from baseline was noted at the lumbar spine whereas in those without Bis (thin line; n = 21) BMD decreased by 4.3% from baseline within 24 months (p < 0.0001).
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Denosumab
• Ellis et al: ( N= 125) • ER+ post menopausal women with T score -‐2.5 SD, Tx with Ca and Vit D
• Randomised into placebo or Denosumab • Lumbar spine BMD increased 5.5% and 7.7 % at 12 mths and 24 mths vs placebo
• J Clinical Oncology 2008
• Not many RCTs and small numbers
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Osteoporosis Treatments NOT recommended for AI induced Bone loss
• Estrogen therapy: Contra-‐indicated in pa1ents with ER +breast cancer
• SERMS: Raloxifene. Not recommended as Tamoxifen has been shown to reduce effec1veness of aromatase inhibitors (? increase in AI metabolism).
• Recombinant human PTH : Not recommended as radia1on is a risk factor for osteogenic sarcoma ( possible effect of human PTH)
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Na1onal Comprehensive Cancer Network (US)
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European Society for Clinical and Economical Aspects of Osteoporosis and Osteoarthri1s
(ESCO)
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Summary • Pa1ent with breast cancer are at increase risk of bone loss
• Aromatase inhibitors accelerate bone loss • Screening BMD recommended before ini1a1on of AI
• Universal tx for all • Specific Tx: BMD < -‐2.0 SD T score (post menopausal)
• BMD -‐1.0 to 2.0 SD with 2 or more risk factors/ FRAX
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Treatment op1ons • IV Zolendronate supported by RCTs. • Only 25% of delayed pa1ents required treatment, so upfront treatment unlikely necessary.
• Oral bisphosphonates: IBIS II trail – likely beuer pa1ent acceptance, but concern about insufficient data and possibility of reduced compliance.
• SC Denosumab not many studies. – Maybe for pa1ents intolerant of bisphosphonates.
• No RCT comparing bisphosphonates to Denosumab
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THANK YOU The End
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Recommenda1on University of Marburg, Baldingerstrasse