Paris, November 1st 2016 Integrated care: guidance on fracture prevention in cancer-associated bone disease; treatment options René Rizzoli MD International Osteoporosis Foundation and Division of Bone Diseases Geneva University Hospitals and Faculty of Medicine Geneva, Switzerland
Bone Disease in Cancer 1. Malignancy-associated 1. Cancer Treatment-associated For review: Rizzoli et al Osteoporos Int 2013
Rapid Bone Loss in Patients with - Ovarian Failure after Adjuvant Chemotherapy (particularly with cyclophosphamide) - Hormone Ablative Therapy - Surgical Castration - Irradiation - Glucocorticoid Therapy Highest Rate of Bone Loss in Premenopausal Women with Acute Ovarian Failure (-> 8% at the Spine and -> 4% at the Hip within the First Year)
Changes of Bone Loss without/ with treatment Bone Loss at 1 Yr (%) 10 8 6 4 2 0 Naturally Occurring Bone Loss 0.5 1.0 2.0 Normal Men 1 Postmenopausal Women 1 Menopausal Women 1 2.6 Al Therapy in Postmenopausal Women 2 Cancer-Treatment Induced Bone Loss ADT 3 Al Therapy + GnRH Antagonist in Premenopausal Women 4 Premature Menopause Secondary to Chemotherapy 5 1. Kanis JA et al. Osteoporosis 1997, 22-55; 2. Eastell RJ et al. Bone Mineral Res. 2006;21:1215-23 3. MaillefertJF et al. J Urol. 1999;161:1219-22 4. Gnant M et al. Lancet Oncol. 2008;9:840-49 5. Shapiro CL. J Clin Oncol. 2001;19:3306-11 4.6 7.0 7.7
Fracture Associated with Breast Cancer Therapy WHI: Fracture RR in Breast Cancer Survivors = 1.31 Chen et al Arch Int Med 2005 From Edwards et al 2011
Fracture Risk Is Increased by 28% in Breast Cancer Survivors* P <.001 Cumulative fracture risk (%) 14 12 10 8 6 4 2 0.6 Control (n=80,848) Breast cancer survivors (n=5,298) 0.6 P =.0049 1.0 1.4 P =.001 2.3 3.2 P <.001 7.6 9.7 10.5 13.6 0 Hip Clinical spine Lower arm/wrist Other osteoporotic fracture Total fractures *Average length of follow-up = 5.1 years. Chen Z, et al. J Bone Miner Res. 2003;18(suppl 2):S22. Abstract 1077.
Incidence of Fractures in AI trials (on Treatment) Trial Primary adjuvant therapy versus tamoxifen Incidence (%) in tamoxifen/ai group p value Follow-up (months) ATAC 1 (anastrozole) 7.7/11.0 <0.0001 68 BIG 1-98 2 (letrozole) 5.8/8.6 <0.001 51 Adjuvant therapy switched to AI from tamoxifen IES 3 (exemestane) 3.1/4.3 0.03 55.7 ABCSG 8/ARNO 95 4 (anastrozole) 1.0/2.0 0.015 28 Extended adjuvant therapy following 5 years tamoxifen MA.17 5 (letrozole) 4.6/5.3 0.25 30 1. ATAC Trialists Group. Lancet 2005; 2. Coates et al. J Clin Oncol 2007; 3. Coombes RC et al. Lancet 2007; 4. Jakesz R et al. Lancet 2005; 5. Goss PE. JNCI 2005
351 W, 61.3 Yrs Cheung et al Lancet Oncol 2012
Cuzick et al Lancet Oncol 2010 Reversibility Fracture OR: 1.33 OR: 0.98 Anastrozole vs Tamoxifen 5 Years Treatment + 5 Years Follow-up Kaplan-Meier: Time to Recurrence
Sestak et al Lancet Oncol 2014
Zoledronic Acid Reduces Accelerated Bone Loss During Three Years of Adjuvant HT Lumbar spine T score 0-0. 1-0. 2-0. 3-0. 4-0. 5-0. 6-0. 7-0. 8-0. 9-1 - 1. 1-1. 2-1. 3-1. 4-1. 5 3-year data Months Tamoxifen + Zoledronic acid Anastrozole + Zoledronic acid Tamoxifen P <.0001 Anastrozole 0 1 2 2 4 3 6 Gnant M, et al. J Clin Oncol. 2006..
Z-FAST: Zoledronic Acid Increases Bone Mineral Density in Patients With AIBL* 6% 1-year data % Change in BMD 4% 2% 0% 2% 4% Upfront group Delayed group 6% 8% P <.0001 Lumbar spine P <.0001 Total hip *Mean (SD) percentage change in bone mineral density (g/cm 2 ) from baseline to 12 months (4 mg zoledronic acid every 6 mo). Brufsky et al. J Clin Oncol. 2005;23(supp;16):533.
Fractures: - 15% (p=0.02) Coleman et al Lancet 2015
Percentage change from baseline in lumbar spine BMD vs Placebo (HALT-Br, Freedom) Aromatase Inhibitors Change From Baseline (± 95% CI) 8 7 6 5 4 3 2 1 0-1 -2-3 * * *P < 0.0001 versus Placebo Placebo (n = 122) Denosumab (n = 123) * * 5.5% Difference at Month 12 1 3 6 12 24 Months Data from the FREEDOM trial; cannot be directly compared * 7.6% Difference at Month 24 Ellis GK et al. JCO. 2008;26:4875-4882. Cummings SR, et al. NEJM 2009;361:756-65
Lancet 2015
Fractures After Androgen Deprivation: Fracture-Free Survival Kaplan-Meier fracture-free survival curves in PC patients with orchiectomy, GnRH agonists, or no androgen deprivation 100 Fracture-Free Survival (%) 90 80 70 60 50 40 30 20 10 1. 2. 3. 4. 5. No androgen deprivation GnRH agonist, 1-4 doses GnRH agonist, 5-8 doses GnRH agonist, > 9 doses RR = 1.45 (1.36-1.56) Orchiectomy, RR = 1.54 (1.42-1.68) 0 1 2 3 4 5 6 7 8 9 10 2 1 3 4 5 Shahinian et al NEJM 2005 Y ears After Diagnosis
Effect of Denosumab on New Vertebral Fracture in Men With Prostate Cancer Receiving Androgen Deprivation Therapy 62% Reduction in Subject Incidence of New Vertebral Fracture Over 36 Months (Adjusted P = 0.0125) Placebo (n = 673) Denosumab (n = 679) Month 12 Month 24 Month 36 Percent of Subjects 6 4 2 0 RR 0.15 P = 0.004 1.9% 0.3% RR 0.31 P = 0.004 3.3% 1.0% RR 0.38 P = 0.006 3.9% 1.5% Subject incidence 13 2 22 7 26 10 Adapted from: Smith MR, et al N Engl J Med. 2009;361:745-55.
Guidelines for Osteoporosis Management in Cancer Survivors Group Population Screening Interval Indications for OP Treatment Lustberg et al JCO 2012
Management of Women with Sex Hormone Deprivation Rizzoli et al Osteoporos Int 2013
Management of Men with Sex Hormone Deprivation Rizzoli et al Osteoporos Int 2013