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Breast cancer survivors are at an increased risk for osteoporotic fractures not explained by lower BMD: a retrospective analysis

Breast cancer survivors are at an increased risk for osteoporotic fractures not explained by... www.nature.com/npjbcancer All rights reserved 2374-4677/15 ARTICLE OPEN Breast cancer survivors are at an increased risk for osteoporotic fractures not explained by lower BMD: a retrospective analysis 1 2 3 3 3 2 4 5 Merav Fraenkel , David B Geffen , Victor Novack , Tali Shafat , Yuval Mizrakli , Samuell Ariad , Michael Koretz , Larry Norton and Ethel Siris BACKGROUND: An association between higher bone mineral density (BMD) and the diagnosis of breast cancer (BC) has been reported. Data on the risk of osteoporotic fractures in women with BC are conflicting. AIMS: The objective of this study was to assess fracture risk adjusted for BMD in women with and without BC, and to assess whether fracture risk in BC patients is attributed to BMD or BC characteristics. METHODS: Using electronic medical records of patients who underwent dual energy X-ray absorptiometry BMD studies at Soroka University Medical Center between February 2003 and March 2011, we identified women with subsequent diagnosis of osteoporotic fractures. BC status, demographic, health characteristics, BMD, and other laboratory findings were assessed. In BC patients data on grade, stage, and treatment were collected. Primary outcome was osteoporotic fracture, analyzed by Cox proportional hazards regression models. RESULTS: During a median follow-up of 4.9 years in 17,110 women with BMD testing (658 BC patients), 1,193 women experienced an osteoporotic fracture (62 in BC and 1,131 in no-BC groups). In multivariate analysis adjusted for age, body mass index (BMI) and BMD, hazard ratio (HR) for any osteoporotic fracture in women with BC was 1.34 (P = 0.026). BMD was similar among women with and without BC who fractured. BC patients who experienced an osteoporotic fracture had a trend for less-advanced BC, lower rates of chemotherapy treatment, and higher rates of tamoxifen treatment. CONCLUSIONS: BC survivors are at increased risk of an osteoporotic fracture, which is not explained by worse BMD. Chemotherapy or aromatase inhibitors did not contribute substantially to fracture risk among our BC survivors. npj Breast Cancer (2015) 1, 15010; doi:10.1038/npjbcancer.2015.10; published online 22 July 2015 INTRODUCTION In view of these conflicting data, we conducted this retro- spective study with the primary objective to compare the rates of Several observational studies have suggested that a higher bone 1,2 osteoporotic fractures adjusted for bone mineral density (BMD) in mass is associated with increased breast cancer (BC) risk. BC patients and controls. We further examined whether fracture However, data on the risk of osteoporotic fractures in women with risk in BC patients is attributed to BMD or BC treatment. BC are conflicting. Early studies did not find a lower risk for 3–5 osteoporotic fracture among patients who developed BC. Large epidemiological studies demonstrated an increased fracture risk in MATERIALS AND METHODS BC patients. In a study comparing fracture rates in postmenopau- sal women with and without a history of BC in the Women’s Population Health Initiative cohort, BC patients were at a 15% increased risk of We identified all women who underwent BMD measurement at Soroka clinical fracture compared with controls. Furthermore, in the University Medical Center, Beer Sheva, Israel, a 1,000-bed tertiary-care same study, 146,959 postmenopausal women were followed for hospital, between January 2003 and March 2011. We excluded those under age 18. Only the initial test was included for women who underwent up to 9 years, and incident BC carried a 55% increase in risk of hip more than one BMD measurement. The electronic medical records of the fracture. patients were assessed. “Clalit” Health Services, the largest of the four Several other contemporary reports demonstrated an health maintenance organizations in Israel, maintains a comprehensive unchanged or even lower risk for osteoporotic fractures in BC electronic medical record system where the patient is identified by the survivors. A study conducted in the Mayo Clinic showed no single national identification number. All medical encounters are recorded increase in hazard ratio (HR) for an osteoporotic fracture among in the system. 608 BC patients. Two studies from Denmark and the United We screened the electronic medical record for an osteoporotic fracture States each separately reported on lower total and hip fracture risk (fracture of hip, proximal humerus, ribs, spine, or distal radius) diagnosed 10,11 (respectively) in BC survivors. following the BMD test. Non-osteoporotic, pathologic, and high-velocity 1 2 Endocrine Unit, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; Department of Oncology, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; Clinical Research Center, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; Breast Health Center, Soroka University Medical Center and the Faculty of Health 5 6 Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; Breast Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA and Division of Endocrinology, Columbia University Medical Center, New York, NY, USA. Correspondence: M Fraenkel (meravfr@bgu.ac.il) Received 12 March 2015; revised 30 April 2015; accepted 10 June 2015 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited High fracture risk in breast cancer survivors M Fraenkel et al trauma fractures were excluded. In addition, the electronic charts were phase, two-site chemiluminescent enzyme-labeled immunometric assay. screened for BC diagnosis, using International classification of disease-9 Results were expressed as pg/ml with a normal range of 14–72 pg/ml. codes (233.0, 174.0–175.9), pathology diagnoses (biopsy), and surgical procedures. For BC patients, oncology department medical charts were Primary outcome manually reviewed to obtain the additional clinical information. Data were The primary outcome was osteoporotic fracture defined as fracture of hip, collected on demographics, mortality, body mass index (BMI), laboratory proximal humerus, ribs, spine, or distal radius diagnosed after BMD was results, medication purchase, and BC characteristics (risk factors, histolo- performed. gical diagnosis, stage, grade, and treatment modalities). The study protocol was approved by the Soroka Medical Center Institutional Review Board. Statistical analysis The results are presented as the mean ± s.d. for continuous variables, as BMD measurement total patients (percentage of total patients) for categorical data, and BMD was measured by dual energy X-ray absorptiometry using a Prodigy median and interquartile range for variables with non-normal distribution. densitometer (GE-Lunar, Milwaukee, WI, USA) at the lumbar spine, femur 2 The t-test was used for comparison of continuous variables and χ -or neck, and total hip. The results were expressed as bone density (in g/cm ), Fisher’s exact tests were used for categorical data. We utilized the Mann– T-score (s.d. from the mean for young women), and Z-score (s.d. from the Whitney test for the comparison of variables with non-normal distribution. mean for age-matched women adjusted for body mass). Multivariate analyses for osteoporotic fracture risk factors were performed using Cox proportional hazards regression models. Variables found to be associated with the outcome in the univariate analysis with P valueo0.1 25-hydroxyvitamin D assay and clinically significant factors were included in the models after verifying Vitamin D status was reported when available. Vitamin D levels were the proportionality of the hazards. determined by measuring patients’ serum 25-hydroxyvitamin D levels by A two-tailed P value of ⩽ 0.05 was considered significant. The statistical the IDS Octavia 25-OH-D Kit (Immunodiagnostic Systems, Boldon, UK). analysis was done using SPSS version 21 (IBM Corp Armonk, NY, USA). Results were expressed as ng/ml with a normal range of 20–58 ng/ml. RESULTS PTH assay Study population Parathyroid hormone (PTH) status was reported when available. Serum A total of 17,110 women underwent BMD testing at Soroka PTH levels were determined by using the Immulite 2000 intact PTH Kit (Siemens, Los Angeles, CA, USA). This determination is based on a solid University Medical Center between February 2003 and March N=17110 BMD tests N=2302 N=14808 Fracture after No fractures BMD test after BMD test N=1072 N=187 Not N=25 osteoporotic Metastatic fracture Metastatic disease or MM disease or MM N=12 N=14621 High energy No fractures fractures after BMD test N=14025 N=596 non-Breast N=1193 Breast cancer cancer patients patients *Osteoporotic fracture after BMD test N=1131 N=62 non-Breast Breast cancer cancer patients patients Figure 1. Flow chart of study population. *Osteoporotic fracture defined as hip, vertebral, distal radius, humerus, and ribs fractures. npj Breast Cancer (2015) 15010 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited High fracture risk in breast cancer survivors M Fraenkel et al Table 1. Baseline characteristics of patients with osteoporotic fracture according to BC diagnosis (n= 1193) Variable BC (n = 62) No BC (n = 1,131) P value Age at first fracture 68.8 (±8.8) 68.8 (±10.2) 0.969 BMI 29.3 (±4.8) 29.6 (±5.6) 0.735 BMI ⩽ 30 39 (62.9) 637 (56.3) 0.658 30.1–35 15 (24.2) 309 (27.3) 35.1–40 7 (11.3) 139 (12.3) ⩾ 40.1 1 (1.6) 46 (4.1) BMD, g/cm Femoral neck 0.77 (±0.11) 0.76 (±0.12) 0.317 Total hip 0.84 (±0.13) 0.82 (±0.13) 0.164 Spine 0.96 (±0.15) 0.95 (±0.16) 0.450 BMD T-score Femoral neck − 1.72 (±0.94) − 1.85 (±1.00) 0.330 Total hip − 1.32 (±1.12) − 1.52 (±1.10) 0.169 Spine − 1.80 (±1.23) − 1.94 (±1.36) 0.450 BMD Z-score Femoral neck − 0.37 (±0.84) − 0.46 (±0.88) 0.401 Total hip − 0.16 (±1.03) − 0.31 (±0.94) 0.220 Spine − 0.29 (±1.34) − 0.43 (±1.36) 0.425 VitD, ng/ml (n= 465) 21.4 (±9.9) (n= 28) 19.9 (±9.7) (n= 437) 0.431 VitD, ng/ml o20 14 (50.0) 234 (53.5) 0.715 ⩾ 20 14 (50.0) 203 (46.5) PTH, pg/ml (n= 203) 48.7 (±34.0) (n= 9) 65.7 (±58.1) (n= 194) 0.384 PTH, pg/ml ⩽ 72 6 (66.7) 143 (73.7) 0.640 472 3 (33.3) 51 (26.3) Medication use (N,%) Topical steroids (46 months, during 2 years before BMD) 2 (3.2) 55 (4.9) 0.556 Systemic steroids (43 months, during 2 years before BMD) 2 (3.2) 96 (8.5) 0.142 Hormone replacement therapy (during 2 years before BMD) 13 (21.0) 244 (21.6) 0.910 Vitamin D (during the last 12 months before BMD) 1 (1.6) 106 (9.4) 0.037 Bisphosphonates (during 2 years before BMD) 8 (12.9) 296 (26.2) 0.020 Bisphosphonates (ever) 39 (62.9) 694 (61.4) 0.808 Anticonvulsants (during 2 years before BMD) 4 (6.5) 62 (5.5) 0.745 Abbreviations: BC, breast cancer; BMI, body mass index; BMD, bone mineral density; PTH, parathyroid hormone; VitD, vitamin D. Statistical analysis: Student's t-test. b 2 Statistical analysis: χ -test. 2011. Figure 1 presents the study population flow chart. During a BC diagnosis to BMD testing was 6.2 years (interquartile range median follow-up of 4.9 years, 2,302 women experienced any 3.3–9.4 years). fracture following BMD, while 14,808 remained free of fracture. In the present study we focused on the 1,193 patients with BC patients with and without osteoporotic fractures osteoporotic fractures comprising 62 women with BC and 1,131 Baseline characteristics of BC patients with and without an BC-free women. osteoporotic fracture are presented in Table 3. BC patients who Table 1 presents the baseline characteristics of the women with fractured were slightly older than those without fractures, but had an osteoporotic fracture according to BC status. Women with and similar BMI. Rates of prior usage of hormone replacement therapy without BC experienced an osteoporotic fracture at a similar age and oral contraceptives were not different among BC patients and BMI. Before BMD test women without BC had higher rates of with and without fracture (Table 3a). During study follow-up 71 BC vitamin D and bisphosphonate use as compared with women with patients died. BC. BMD at all three sites, lumbar spine, femur neck, and total hip, was similar between women who fractured with and without BC Stage and grade of among BC patients with and without an as measured by three methods of assessment: g/cm , T-score and osteoporotic fracture Z-score. Women with fractures had a trend toward less-advanced BC (lower Table 2 presents fracture characteristics compared between tumor node metastasis stage and grade) compared with those who women with and without BC. Anatomic location of osteoporotic fracture did not differ according to BC status. The median remained free of fracture (Table 3b). Hormone receptor and Her-2 time from BMD testing to first osteoporotic fracture did not receptor status by immune-histochemistry did not differ between BC differ between women with and without BC. Median time from patients who fractured compared with those who did not fracture. © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited npj Breast Cancer (2015) 15010 High fracture risk in breast cancer survivors M Fraenkel et al Table 2. Population of patients with osteoporotic fractures—fracture location (n= 1,193) Variable All subjects BC (n = 62) No BC (n = 1,131) P value Hip fracture (N, %) 231 (19.4) 10 (16.1) 221 (19.5) 0.508 Vertebral fracture (N, %) 436 (36.5) 20 (32.3) 416 (36.8) 0.471 Distal radius fracture (N, %) 241 (20.2) 16 (25.8) 225 (19.9) 0.295 Ribs fracture (N, %) 126 (10.6) 11 (17.7) 115 (10.2) 0.059 Humerus fracture (N, %) 277 (23.2) 16 (25.8) 261 (23.1) 0.620 Time from BMD to first osteoporotic fracture (median, interquartile range, years) 2.01 (0.1–4.2) 2.14 (0.9–4.5) 2.01 (0.1–4.2) 0.222 Abbreviations: BC, breast cancer; BMD, bone mineral density. Some patients had more than one fracture type. a 2 Statistical analysis: χ -test. Statistical analysis: a parametric test (Mann–Whitney). 1,2 Treatment for BC and BMD among women with and without an protect BC patients from osteoporotic fractures. Early reports osteoporotic fracture from Sweden and the United States were not protected from 3,4 osteoporotic fractures. Data on the BC treatment are presented in Table 3b. A lower Osteoporotic fracture risk was assessed in a prospective cohort percentage of BC patients who fractured as compared with of women (5.1 years’ follow-up) from the Women’s Health women without fracture received chemotherapy (either adjuvant Initiative study; after adjusting for demographic parameters and or neo-adjuvant) for their BC, while a higher percentage received various risk factors, BC survivors (n = 5,298) had a HR of 1.15 for tamoxifen. Rates of aromatase inhibitors use did not differ any fracture compared with controls (n = 80,848). In our cohort the between BC patients with and without fractures (Table 3b). Rates HR for fracture among BC survivors was even higher (1.34), and of radiotherapy and use of trastuzumab did not differ according to was not explained by worse BMD in BC patients. fracture status (Table 3b). As expected, BMD in the lumbar spine, We found that vertebral fractures were the most common femur neck, and total hip expressed as g/cm , T- and Z-scores osteoporotic fracture in BC survivors. An elevated risk for vertebral were lower among BC patients who fractured compared with those without fracture (Table 3c). fracture was found in a cohort of BC patients from the United Kingdom. This increased risk was related to the diagnosis of BC and to the excessive bone loss secondary to the treatment for BC. Factors associated with osteoporotic fracture This was not true for BC survivors in our cohort, who experienced We used Cox survival regression models for multivariate analysis an osteoporotic fracture despite having a trend for less-aggressive of factors associated with osteoporotic fractures (Table 4). and less-advanced BC compared with BC survivors who did not Parsimonious model showed that adjusted for age, BMI, and fracture. In addition, BC survivors who fractured were less heavily BMD, BC conferred an excess risk for fracture of 34% (HR 1.34, treated with chemotherapy or aromatase inhibitors rather a larger confidence interval 1.04–1.73, P = 0.026). proportion received tamoxifen, which is considered protective for bone health. Similar to our work, fracture risk was assessed in a BC cohort of 608 women treated at the Mayo Clinic. In this work, a DISCUSSION standardized incidence ratio of 0.9 (95% confidence interval 0.7– Our results show that BC survivors are at 34% increased risk of 1.2) for osteoporotic fracture risk in BC patients was found. After suffering from an osteoporotic fracture. This increased risk is not adjustment for age, they found that advanced disease (stage III/ explained by worse BMD, as BMD tended to be slightly higher in IV), any chemotherapy, alcoholism, and use of bisphosphonates BC patients who fractured as compared with those without BC were risk factors for osteoporotic fractures in BC survivors. It may who fractured. It is also not explained by higher rates of vitamin D be that underlying clinical characteristics prompting specific deficiency or use of certain medications that are considered as treatments may have been partially responsible for the associated detrimental for bone health such as systemic or topical steroids or fracture outcomes in this study and in our work (indication bias). anticonvulsants. Compared with women who fractured but did There are several limitations to our study, part of which rely on not suffer from BC, a smaller percentage of women with BC who the retrospective nature of data collection from patients files. The fractured were treated with vitamin D or bisphosphonates before database from which patients with and without BC who fractured BMD, which may reflect that these women were not considered was from all women who performed BMD at Soroka Medical at high risk for fractures. The results of our work underscore Center and does not represent all women with BC who were the importance of appreciating fracture risk in BC survivors and treated in Soroka Medical Center during the same time period, treating them according to the updated osteoporosis/BC and there may have been a selection bias in patient referral to guidelines. BMD. Retrospective nature of the data assessment carried inherent In subgroup analysis of BC patients, those who fractured had a limitations of the data availability: for example, there was the lack trend toward older age, but did not differ from BC women who of data on estrogen exposure (gravidity, parity, age at menarche did not fracture in rates of hormone replacement therapy use. and menopause, and more). Finally, the possibility of the selection Thus, fracture risk is not explained by lack of estrogen treatment in bias should be considered: that is, women with the history of BC the menopause. Furthermore, BC women who fractured had a may have a closer medical follow-up leading to the better trend of less-aggressive disease, were less frequently treated with diagnosis of the osteoporotic fractures. chemotherapy or aromatase inhibitors compared with BC women The studies’ strength is based on the unique structure of Israeli who did not fracture. As expected, BC women who fractured had Clalit health insurance system that allows access to a fully lower BMD compared with those with BC who did not fracture, computerized medical record system, which maximizes availability which contributed to their fracture risk. of baseline and follow-up data including clinical data, lab workup, The conclusions that have been reached in our population and medication use. In addition, Soroka Medical Center is unique support other studies that showed higher rates of fracture in BC survivors. This is contrary to the assumption that higher BMD may in the sense that all BC patients are treated in a single institute npj Breast Cancer (2015) 15010 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited High fracture risk in breast cancer survivors M Fraenkel et al Table 3. BC patients stratified by osteoporotic fracture occurrence Variable Osteoporotic fracture (n = 62) No osteoporotic fracture (n = 596) P value a: Baseline characteristics (n = 658) Age at BC diagnosis (mean± s.d.) 62.6± 9.3 60.0± 11.1 0.082 BMI (mean± s.d.) 29.3± 4.8 29.9± 5.8 0.343 BMI, N (%) ⩽ 30 39 (62.9) 337 (56.5) 0.442 30.1–35 15 (24.2) 147 (24.7) 35.1–40 7 (11.3) 73 (12.2) ⩾ 40.1 1 (1.6) 39 (6.5) HRT treatment, N (%) (n= 296) per history 6 (25.0) (n= 24) 71 (26.1) (n= 272) 0.906 HRT (during 2 years before BMD) according to drug purchase, N (%) 13 (21.0) 127 (21.3) 0.950 Past/current oral contraceptives use, N (%) (n= 125) 3 (25.0) (n= 12) 26 (23.0) (n= 113) 0.877 b: BC grade, stage, and treatment T stage, N (%) (n= 638) T in situ 7 (11.9) 48 (8.3) 0.394 T0 0 (0) 7 (1.2) T1 39 (66.1) 331 (57.2) T2 12 (20.3) 160 (27.6) T3 0 (0) 21 (3.6) T4 0 (0) 6 (1.0) Tx 1 (1.7) 6 (1.0) Stage, N (%) (n = 636) 0/I 37 (63.8) 302 (52.2) 0.038 II 21 (36.2) 225 (38.9) III/IV 0 (0) 51 (8.8) Histology, N (%) (n = 639) DCIS (only) 7 (11.9) 48 (8.3) 0.467 Invasive duct carcinoma 47 (79.7) 468 (80.7) Invasive lobular carci 2 (3.4) 41 (7.1) Other 3 (5.1) 24 (4.2) Histological grade, N (%) (n = 429) Low 6 (14.0) 106 (27.5) 0.048 Intermediate 25 (58.1) 154 (39.9) High 12 (27.9) 126 (32.6) Immunohistochemistry, N (%) ER positive (n= 562) 46 (86.8) 426 (83.7) 0.558 PR positive (n= 552) 42 (80.8) 352 (70.4) 0.115 Her-2 (n= 436) 0/+1 30 (76.9) 313 (78.8) 0.192 +2 and CISH negative 0 (0) 12 (3.0) +2 and CISH unknown 6 (15.4) 28 (7.1) +3/CISH positive 3 (7.7) 44 (11.1) Triple negative (n= 526) 1 (2.0) 28 (5.9) 0.253 Chemotherapy (neo or adjuvant) N (%)(n= 636) 15 (25.0) 260 (45.1) 0.003 Hormonal therapy (neo or adjuvant) (n = 636) N (%) Tamoxifen alone 31 (51.7) 198 (34.4) 0.007 Aromatase inhibitors alone 1 (1.7) 46 (8.0) Tamoxifen+aromatase inhibitors 20 (33.3) 206 (35.8) Other 1 (1.7) 1 (0.2) Any tamoxifen treatment, N (%) 51 (85.0) 404 (70.1) 0.015 Any aromatase inhibitors treatment, N (%) 21 (35.0) 252 (43.8) 0.193 Radiotherapy (neo or adjuvant), N (%) (n= 636) 42 (70.0) 440 (76.4) 0.272 Trastuzumab (neo or adjuvant), N (%) (n= 635) 0 (0) 16 (2.8) 0.195 c: BMD BMD, g/cm (mean± s.d.) Femoral neck 0.77± 0.11 0.83± 0.12 o0.001 Total hip 0.84± 0.13 0.91± 0.14 o0.001 Spine 0.96± 0.15 1.03± 0.17 0.002 BMD T-score (mean± s.d.) Femoral neck − 1.72± 0.94 − 1.22± 1.04 o0.001 Total hip − 1.32± 1.12 − 0.79± 1.13 o0.001 Spine − 1.80± 1.23 − 1.23± 1.42 0.002 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited npj Breast Cancer (2015) 15010 High fracture risk in breast cancer survivors M Fraenkel et al Table 3. (Continued ) Variable Osteoporotic fracture (n = 62) No osteoporotic fracture (n = 596) P value BMD Z-score (mean± s.d.) Femoral neck − 0.37± 0.84 − 0.05± 0.93 0.010 Total hip − 0.16± 1.03 0.18± 1.02 0.013 Spine − 0.29± 1.34 0.13±1.49 0.035 Abbreviations: BC, breast cancer; BMD, bone mineral density; BMI, body mass index; CISH, chromogenic in situ hybridization; DCIS, ductal carcinoma in situ; ER, estrogen receptor; HRT, hormone replacement therapy; PR, progesterone receptor. Statistical analysis: Student's t-test. b 2 Statistical analysis: χ -test. CONTRIBUTIONS Table 4. Multivariable analysis (Cox regression) to first osteoporotic ES, VN, LN, MF, DBG, and MK conceived and designed the experiments. TS, VN, and fracture YM: performed the experiments. TS, VN, MF, DBG, and ES: analyzed the data. DBG, SA, and MK: contributed reagents/materials/analysis tools. MF, VN, TS, ES, and DBG: wrote Variable HR 95% CI HR P value the manuscript. Age at BMD 1.02 1.02–1.03 1.02 o0.001 BMI 1.03 1.02–1.04 1.03 o0.001 COMPETING INTERESTS BMD T-score The authors declare no conflict of interest. Total hip 0.71 0.66–0.76 0.71 o0.001 Spine 0.94 0.89–0.99 0.94 0.014 BC 1.34 1.04–1.73 1.34 0.026 REFERENCES 1 Fraenkel M, Novack V, Liel Y, Koretz M, Siris E, Norton L et al. Association between Abbreviations: BC, breast cancer; BMI, body mass index; BMD, bone mineral bone mineral density and incidence of breast cancer. PLoS One 2013; 8: e70980. density; CI, confidence interval; HR, hazard ratio. 2 Qu X, Zhang X, Qin A, Liu G, Zhai Z, Hao Y et al. Bone mineral density and risk of breast cancer in postmenopausal women. Breast Cancer Res Treat 2013; 138: 261–271. with access to patient’s records that cover complete treatment 3 Utz JP, Melton LJ 3rd, Kan SH, Riggs BL. Risk of osteoporotic fractures in women scheme. This is also the first study to the best of our knowledge with breast cancer: a population-based cohort study. J Chronic Dis 1987; 40: that correlated fracture risk in BC survivors with BMD data. 105–113. 4 Adami HO, Zack M, Kressner U, Persson I, Berglund A, Naessen T et al. Hip fractures in women with breast cancer. Am J Epidemiol 1990; 132:877–883. CONCLUSIONS 5 Kanis JA, McCloskey EV, Powles T, Paterson AH, Ashley S, Spector T. A high incidence of vertebral fracture in women with breast cancer. Br J Cancer 1999; 79: In summary we found that BC survivors are at increased risk for 1179–1181. osteoporotic fractures and that this increased risk is not explained 6 Chen Z, Maricic M, Bassford TL, Pettinger M, Ritenbaugh C, Lopez AM et al. by worse BMD compared with women who fractured but did not Fracture risk among breast cancer survivors: results from the Women’s Health suffer from BC. There may be a qualitative defect in bone of BC Initiative Observational Study. Arch Intern Med 2005; 165:552–558. patients that is not apparent with BMD testing similar to other 7 Chen Z, Maricic M, Aragaki AK, Mouton C, Arendell L, Lopez AM et al. Fracture risk processes that affect bone quality such as diabetes and obesity. increases after diagnosis of breast or other cancers in postmenopausal women: More novel qualitative technologies that estimate the trabecular results from the Women’s Health Initiative. Osteoporos Int 2009; 20: 527–536. microarchitecture, such as the trabecular bone score, might be 8 Pawloski PA, Geiger AM, Haque R, Kamineni A, Fouayzi H, Ogarek J et al. Fracture useful in assessing the risk fracture for these patients. risk in older, long-term survivors of early-stage breast cancer. J Am Geriatr Soc 2013; 61:888–895. We also found that treatment with chemotherapy or aromatase 9 Melton LJ 3rd, Hartmann LC, Achenbach SJ, Atkinson EJ, Therneau TM, Khosla S. inhibitors did not contribute substantially to fracture risk among Fracture risk in women with breast cancer: a population-based study. J Bone Miner our BC survivors. This leads us to believe that lower past estrogen Res 2012; 27: 1196–1205. exposure leading to less-aggressive BC and therefore less 10 Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk in patients with different chemotherapy as well as inherent factors from BC that directly types of cancer. Acta Oncol 2009; 48: 105–115. negatively affect bone are the main contributors for increased 11 Lamont EB, Lauderdale DS. Low risk of hip fracture among elderly breast cancer fragility in a subset of BC patients. survivors. Ann Epidemiol 2003; 13: 698–703. 12 Leslie WD, Aubry-Rozier B, Lamy O, Hans D. TBS (trabecular bone score) and diabetes-related fracture risk. J Clin Endocrinol Metab 2013; 98: 602–609. FUNDING This study was funded by an unrestricted research grant from the This work is licensed under a Creative Commons Attribution 4.0 Cure Breast Cancer Foundation. International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons DISCLAIMER license, users will need to obtain permission from the license holder to reproduce the The funders had no role in study design, data collection and material. To view a copy of this license, visit http://creativecommons.org/licenses/ analysis, decision to publish, or preparation of the manuscript. by/4.0/ npj Breast Cancer (2015) 15010 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Breast Cancer Springer Journals

Breast cancer survivors are at an increased risk for osteoporotic fractures not explained by lower BMD: a retrospective analysis

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www.nature.com/npjbcancer All rights reserved 2374-4677/15 ARTICLE OPEN Breast cancer survivors are at an increased risk for osteoporotic fractures not explained by lower BMD: a retrospective analysis 1 2 3 3 3 2 4 5 Merav Fraenkel , David B Geffen , Victor Novack , Tali Shafat , Yuval Mizrakli , Samuell Ariad , Michael Koretz , Larry Norton and Ethel Siris BACKGROUND: An association between higher bone mineral density (BMD) and the diagnosis of breast cancer (BC) has been reported. Data on the risk of osteoporotic fractures in women with BC are conflicting. AIMS: The objective of this study was to assess fracture risk adjusted for BMD in women with and without BC, and to assess whether fracture risk in BC patients is attributed to BMD or BC characteristics. METHODS: Using electronic medical records of patients who underwent dual energy X-ray absorptiometry BMD studies at Soroka University Medical Center between February 2003 and March 2011, we identified women with subsequent diagnosis of osteoporotic fractures. BC status, demographic, health characteristics, BMD, and other laboratory findings were assessed. In BC patients data on grade, stage, and treatment were collected. Primary outcome was osteoporotic fracture, analyzed by Cox proportional hazards regression models. RESULTS: During a median follow-up of 4.9 years in 17,110 women with BMD testing (658 BC patients), 1,193 women experienced an osteoporotic fracture (62 in BC and 1,131 in no-BC groups). In multivariate analysis adjusted for age, body mass index (BMI) and BMD, hazard ratio (HR) for any osteoporotic fracture in women with BC was 1.34 (P = 0.026). BMD was similar among women with and without BC who fractured. BC patients who experienced an osteoporotic fracture had a trend for less-advanced BC, lower rates of chemotherapy treatment, and higher rates of tamoxifen treatment. CONCLUSIONS: BC survivors are at increased risk of an osteoporotic fracture, which is not explained by worse BMD. Chemotherapy or aromatase inhibitors did not contribute substantially to fracture risk among our BC survivors. npj Breast Cancer (2015) 1, 15010; doi:10.1038/npjbcancer.2015.10; published online 22 July 2015 INTRODUCTION In view of these conflicting data, we conducted this retro- spective study with the primary objective to compare the rates of Several observational studies have suggested that a higher bone 1,2 osteoporotic fractures adjusted for bone mineral density (BMD) in mass is associated with increased breast cancer (BC) risk. BC patients and controls. We further examined whether fracture However, data on the risk of osteoporotic fractures in women with risk in BC patients is attributed to BMD or BC treatment. BC are conflicting. Early studies did not find a lower risk for 3–5 osteoporotic fracture among patients who developed BC. Large epidemiological studies demonstrated an increased fracture risk in MATERIALS AND METHODS BC patients. In a study comparing fracture rates in postmenopau- sal women with and without a history of BC in the Women’s Population Health Initiative cohort, BC patients were at a 15% increased risk of We identified all women who underwent BMD measurement at Soroka clinical fracture compared with controls. Furthermore, in the University Medical Center, Beer Sheva, Israel, a 1,000-bed tertiary-care same study, 146,959 postmenopausal women were followed for hospital, between January 2003 and March 2011. We excluded those under age 18. Only the initial test was included for women who underwent up to 9 years, and incident BC carried a 55% increase in risk of hip more than one BMD measurement. The electronic medical records of the fracture. patients were assessed. “Clalit” Health Services, the largest of the four Several other contemporary reports demonstrated an health maintenance organizations in Israel, maintains a comprehensive unchanged or even lower risk for osteoporotic fractures in BC electronic medical record system where the patient is identified by the survivors. A study conducted in the Mayo Clinic showed no single national identification number. All medical encounters are recorded increase in hazard ratio (HR) for an osteoporotic fracture among in the system. 608 BC patients. Two studies from Denmark and the United We screened the electronic medical record for an osteoporotic fracture States each separately reported on lower total and hip fracture risk (fracture of hip, proximal humerus, ribs, spine, or distal radius) diagnosed 10,11 (respectively) in BC survivors. following the BMD test. Non-osteoporotic, pathologic, and high-velocity 1 2 Endocrine Unit, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; Department of Oncology, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; Clinical Research Center, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; Breast Health Center, Soroka University Medical Center and the Faculty of Health 5 6 Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; Breast Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA and Division of Endocrinology, Columbia University Medical Center, New York, NY, USA. Correspondence: M Fraenkel (meravfr@bgu.ac.il) Received 12 March 2015; revised 30 April 2015; accepted 10 June 2015 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited High fracture risk in breast cancer survivors M Fraenkel et al trauma fractures were excluded. In addition, the electronic charts were phase, two-site chemiluminescent enzyme-labeled immunometric assay. screened for BC diagnosis, using International classification of disease-9 Results were expressed as pg/ml with a normal range of 14–72 pg/ml. codes (233.0, 174.0–175.9), pathology diagnoses (biopsy), and surgical procedures. For BC patients, oncology department medical charts were Primary outcome manually reviewed to obtain the additional clinical information. Data were The primary outcome was osteoporotic fracture defined as fracture of hip, collected on demographics, mortality, body mass index (BMI), laboratory proximal humerus, ribs, spine, or distal radius diagnosed after BMD was results, medication purchase, and BC characteristics (risk factors, histolo- performed. gical diagnosis, stage, grade, and treatment modalities). The study protocol was approved by the Soroka Medical Center Institutional Review Board. Statistical analysis The results are presented as the mean ± s.d. for continuous variables, as BMD measurement total patients (percentage of total patients) for categorical data, and BMD was measured by dual energy X-ray absorptiometry using a Prodigy median and interquartile range for variables with non-normal distribution. densitometer (GE-Lunar, Milwaukee, WI, USA) at the lumbar spine, femur 2 The t-test was used for comparison of continuous variables and χ -or neck, and total hip. The results were expressed as bone density (in g/cm ), Fisher’s exact tests were used for categorical data. We utilized the Mann– T-score (s.d. from the mean for young women), and Z-score (s.d. from the Whitney test for the comparison of variables with non-normal distribution. mean for age-matched women adjusted for body mass). Multivariate analyses for osteoporotic fracture risk factors were performed using Cox proportional hazards regression models. Variables found to be associated with the outcome in the univariate analysis with P valueo0.1 25-hydroxyvitamin D assay and clinically significant factors were included in the models after verifying Vitamin D status was reported when available. Vitamin D levels were the proportionality of the hazards. determined by measuring patients’ serum 25-hydroxyvitamin D levels by A two-tailed P value of ⩽ 0.05 was considered significant. The statistical the IDS Octavia 25-OH-D Kit (Immunodiagnostic Systems, Boldon, UK). analysis was done using SPSS version 21 (IBM Corp Armonk, NY, USA). Results were expressed as ng/ml with a normal range of 20–58 ng/ml. RESULTS PTH assay Study population Parathyroid hormone (PTH) status was reported when available. Serum A total of 17,110 women underwent BMD testing at Soroka PTH levels were determined by using the Immulite 2000 intact PTH Kit (Siemens, Los Angeles, CA, USA). This determination is based on a solid University Medical Center between February 2003 and March N=17110 BMD tests N=2302 N=14808 Fracture after No fractures BMD test after BMD test N=1072 N=187 Not N=25 osteoporotic Metastatic fracture Metastatic disease or MM disease or MM N=12 N=14621 High energy No fractures fractures after BMD test N=14025 N=596 non-Breast N=1193 Breast cancer cancer patients patients *Osteoporotic fracture after BMD test N=1131 N=62 non-Breast Breast cancer cancer patients patients Figure 1. Flow chart of study population. *Osteoporotic fracture defined as hip, vertebral, distal radius, humerus, and ribs fractures. npj Breast Cancer (2015) 15010 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited High fracture risk in breast cancer survivors M Fraenkel et al Table 1. Baseline characteristics of patients with osteoporotic fracture according to BC diagnosis (n= 1193) Variable BC (n = 62) No BC (n = 1,131) P value Age at first fracture 68.8 (±8.8) 68.8 (±10.2) 0.969 BMI 29.3 (±4.8) 29.6 (±5.6) 0.735 BMI ⩽ 30 39 (62.9) 637 (56.3) 0.658 30.1–35 15 (24.2) 309 (27.3) 35.1–40 7 (11.3) 139 (12.3) ⩾ 40.1 1 (1.6) 46 (4.1) BMD, g/cm Femoral neck 0.77 (±0.11) 0.76 (±0.12) 0.317 Total hip 0.84 (±0.13) 0.82 (±0.13) 0.164 Spine 0.96 (±0.15) 0.95 (±0.16) 0.450 BMD T-score Femoral neck − 1.72 (±0.94) − 1.85 (±1.00) 0.330 Total hip − 1.32 (±1.12) − 1.52 (±1.10) 0.169 Spine − 1.80 (±1.23) − 1.94 (±1.36) 0.450 BMD Z-score Femoral neck − 0.37 (±0.84) − 0.46 (±0.88) 0.401 Total hip − 0.16 (±1.03) − 0.31 (±0.94) 0.220 Spine − 0.29 (±1.34) − 0.43 (±1.36) 0.425 VitD, ng/ml (n= 465) 21.4 (±9.9) (n= 28) 19.9 (±9.7) (n= 437) 0.431 VitD, ng/ml o20 14 (50.0) 234 (53.5) 0.715 ⩾ 20 14 (50.0) 203 (46.5) PTH, pg/ml (n= 203) 48.7 (±34.0) (n= 9) 65.7 (±58.1) (n= 194) 0.384 PTH, pg/ml ⩽ 72 6 (66.7) 143 (73.7) 0.640 472 3 (33.3) 51 (26.3) Medication use (N,%) Topical steroids (46 months, during 2 years before BMD) 2 (3.2) 55 (4.9) 0.556 Systemic steroids (43 months, during 2 years before BMD) 2 (3.2) 96 (8.5) 0.142 Hormone replacement therapy (during 2 years before BMD) 13 (21.0) 244 (21.6) 0.910 Vitamin D (during the last 12 months before BMD) 1 (1.6) 106 (9.4) 0.037 Bisphosphonates (during 2 years before BMD) 8 (12.9) 296 (26.2) 0.020 Bisphosphonates (ever) 39 (62.9) 694 (61.4) 0.808 Anticonvulsants (during 2 years before BMD) 4 (6.5) 62 (5.5) 0.745 Abbreviations: BC, breast cancer; BMI, body mass index; BMD, bone mineral density; PTH, parathyroid hormone; VitD, vitamin D. Statistical analysis: Student's t-test. b 2 Statistical analysis: χ -test. 2011. Figure 1 presents the study population flow chart. During a BC diagnosis to BMD testing was 6.2 years (interquartile range median follow-up of 4.9 years, 2,302 women experienced any 3.3–9.4 years). fracture following BMD, while 14,808 remained free of fracture. In the present study we focused on the 1,193 patients with BC patients with and without osteoporotic fractures osteoporotic fractures comprising 62 women with BC and 1,131 Baseline characteristics of BC patients with and without an BC-free women. osteoporotic fracture are presented in Table 3. BC patients who Table 1 presents the baseline characteristics of the women with fractured were slightly older than those without fractures, but had an osteoporotic fracture according to BC status. Women with and similar BMI. Rates of prior usage of hormone replacement therapy without BC experienced an osteoporotic fracture at a similar age and oral contraceptives were not different among BC patients and BMI. Before BMD test women without BC had higher rates of with and without fracture (Table 3a). During study follow-up 71 BC vitamin D and bisphosphonate use as compared with women with patients died. BC. BMD at all three sites, lumbar spine, femur neck, and total hip, was similar between women who fractured with and without BC Stage and grade of among BC patients with and without an as measured by three methods of assessment: g/cm , T-score and osteoporotic fracture Z-score. Women with fractures had a trend toward less-advanced BC (lower Table 2 presents fracture characteristics compared between tumor node metastasis stage and grade) compared with those who women with and without BC. Anatomic location of osteoporotic fracture did not differ according to BC status. The median remained free of fracture (Table 3b). Hormone receptor and Her-2 time from BMD testing to first osteoporotic fracture did not receptor status by immune-histochemistry did not differ between BC differ between women with and without BC. Median time from patients who fractured compared with those who did not fracture. © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited npj Breast Cancer (2015) 15010 High fracture risk in breast cancer survivors M Fraenkel et al Table 2. Population of patients with osteoporotic fractures—fracture location (n= 1,193) Variable All subjects BC (n = 62) No BC (n = 1,131) P value Hip fracture (N, %) 231 (19.4) 10 (16.1) 221 (19.5) 0.508 Vertebral fracture (N, %) 436 (36.5) 20 (32.3) 416 (36.8) 0.471 Distal radius fracture (N, %) 241 (20.2) 16 (25.8) 225 (19.9) 0.295 Ribs fracture (N, %) 126 (10.6) 11 (17.7) 115 (10.2) 0.059 Humerus fracture (N, %) 277 (23.2) 16 (25.8) 261 (23.1) 0.620 Time from BMD to first osteoporotic fracture (median, interquartile range, years) 2.01 (0.1–4.2) 2.14 (0.9–4.5) 2.01 (0.1–4.2) 0.222 Abbreviations: BC, breast cancer; BMD, bone mineral density. Some patients had more than one fracture type. a 2 Statistical analysis: χ -test. Statistical analysis: a parametric test (Mann–Whitney). 1,2 Treatment for BC and BMD among women with and without an protect BC patients from osteoporotic fractures. Early reports osteoporotic fracture from Sweden and the United States were not protected from 3,4 osteoporotic fractures. Data on the BC treatment are presented in Table 3b. A lower Osteoporotic fracture risk was assessed in a prospective cohort percentage of BC patients who fractured as compared with of women (5.1 years’ follow-up) from the Women’s Health women without fracture received chemotherapy (either adjuvant Initiative study; after adjusting for demographic parameters and or neo-adjuvant) for their BC, while a higher percentage received various risk factors, BC survivors (n = 5,298) had a HR of 1.15 for tamoxifen. Rates of aromatase inhibitors use did not differ any fracture compared with controls (n = 80,848). In our cohort the between BC patients with and without fractures (Table 3b). Rates HR for fracture among BC survivors was even higher (1.34), and of radiotherapy and use of trastuzumab did not differ according to was not explained by worse BMD in BC patients. fracture status (Table 3b). As expected, BMD in the lumbar spine, We found that vertebral fractures were the most common femur neck, and total hip expressed as g/cm , T- and Z-scores osteoporotic fracture in BC survivors. An elevated risk for vertebral were lower among BC patients who fractured compared with those without fracture (Table 3c). fracture was found in a cohort of BC patients from the United Kingdom. This increased risk was related to the diagnosis of BC and to the excessive bone loss secondary to the treatment for BC. Factors associated with osteoporotic fracture This was not true for BC survivors in our cohort, who experienced We used Cox survival regression models for multivariate analysis an osteoporotic fracture despite having a trend for less-aggressive of factors associated with osteoporotic fractures (Table 4). and less-advanced BC compared with BC survivors who did not Parsimonious model showed that adjusted for age, BMI, and fracture. In addition, BC survivors who fractured were less heavily BMD, BC conferred an excess risk for fracture of 34% (HR 1.34, treated with chemotherapy or aromatase inhibitors rather a larger confidence interval 1.04–1.73, P = 0.026). proportion received tamoxifen, which is considered protective for bone health. Similar to our work, fracture risk was assessed in a BC cohort of 608 women treated at the Mayo Clinic. In this work, a DISCUSSION standardized incidence ratio of 0.9 (95% confidence interval 0.7– Our results show that BC survivors are at 34% increased risk of 1.2) for osteoporotic fracture risk in BC patients was found. After suffering from an osteoporotic fracture. This increased risk is not adjustment for age, they found that advanced disease (stage III/ explained by worse BMD, as BMD tended to be slightly higher in IV), any chemotherapy, alcoholism, and use of bisphosphonates BC patients who fractured as compared with those without BC were risk factors for osteoporotic fractures in BC survivors. It may who fractured. It is also not explained by higher rates of vitamin D be that underlying clinical characteristics prompting specific deficiency or use of certain medications that are considered as treatments may have been partially responsible for the associated detrimental for bone health such as systemic or topical steroids or fracture outcomes in this study and in our work (indication bias). anticonvulsants. Compared with women who fractured but did There are several limitations to our study, part of which rely on not suffer from BC, a smaller percentage of women with BC who the retrospective nature of data collection from patients files. The fractured were treated with vitamin D or bisphosphonates before database from which patients with and without BC who fractured BMD, which may reflect that these women were not considered was from all women who performed BMD at Soroka Medical at high risk for fractures. The results of our work underscore Center and does not represent all women with BC who were the importance of appreciating fracture risk in BC survivors and treated in Soroka Medical Center during the same time period, treating them according to the updated osteoporosis/BC and there may have been a selection bias in patient referral to guidelines. BMD. Retrospective nature of the data assessment carried inherent In subgroup analysis of BC patients, those who fractured had a limitations of the data availability: for example, there was the lack trend toward older age, but did not differ from BC women who of data on estrogen exposure (gravidity, parity, age at menarche did not fracture in rates of hormone replacement therapy use. and menopause, and more). Finally, the possibility of the selection Thus, fracture risk is not explained by lack of estrogen treatment in bias should be considered: that is, women with the history of BC the menopause. Furthermore, BC women who fractured had a may have a closer medical follow-up leading to the better trend of less-aggressive disease, were less frequently treated with diagnosis of the osteoporotic fractures. chemotherapy or aromatase inhibitors compared with BC women The studies’ strength is based on the unique structure of Israeli who did not fracture. As expected, BC women who fractured had Clalit health insurance system that allows access to a fully lower BMD compared with those with BC who did not fracture, computerized medical record system, which maximizes availability which contributed to their fracture risk. of baseline and follow-up data including clinical data, lab workup, The conclusions that have been reached in our population and medication use. In addition, Soroka Medical Center is unique support other studies that showed higher rates of fracture in BC survivors. This is contrary to the assumption that higher BMD may in the sense that all BC patients are treated in a single institute npj Breast Cancer (2015) 15010 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited High fracture risk in breast cancer survivors M Fraenkel et al Table 3. BC patients stratified by osteoporotic fracture occurrence Variable Osteoporotic fracture (n = 62) No osteoporotic fracture (n = 596) P value a: Baseline characteristics (n = 658) Age at BC diagnosis (mean± s.d.) 62.6± 9.3 60.0± 11.1 0.082 BMI (mean± s.d.) 29.3± 4.8 29.9± 5.8 0.343 BMI, N (%) ⩽ 30 39 (62.9) 337 (56.5) 0.442 30.1–35 15 (24.2) 147 (24.7) 35.1–40 7 (11.3) 73 (12.2) ⩾ 40.1 1 (1.6) 39 (6.5) HRT treatment, N (%) (n= 296) per history 6 (25.0) (n= 24) 71 (26.1) (n= 272) 0.906 HRT (during 2 years before BMD) according to drug purchase, N (%) 13 (21.0) 127 (21.3) 0.950 Past/current oral contraceptives use, N (%) (n= 125) 3 (25.0) (n= 12) 26 (23.0) (n= 113) 0.877 b: BC grade, stage, and treatment T stage, N (%) (n= 638) T in situ 7 (11.9) 48 (8.3) 0.394 T0 0 (0) 7 (1.2) T1 39 (66.1) 331 (57.2) T2 12 (20.3) 160 (27.6) T3 0 (0) 21 (3.6) T4 0 (0) 6 (1.0) Tx 1 (1.7) 6 (1.0) Stage, N (%) (n = 636) 0/I 37 (63.8) 302 (52.2) 0.038 II 21 (36.2) 225 (38.9) III/IV 0 (0) 51 (8.8) Histology, N (%) (n = 639) DCIS (only) 7 (11.9) 48 (8.3) 0.467 Invasive duct carcinoma 47 (79.7) 468 (80.7) Invasive lobular carci 2 (3.4) 41 (7.1) Other 3 (5.1) 24 (4.2) Histological grade, N (%) (n = 429) Low 6 (14.0) 106 (27.5) 0.048 Intermediate 25 (58.1) 154 (39.9) High 12 (27.9) 126 (32.6) Immunohistochemistry, N (%) ER positive (n= 562) 46 (86.8) 426 (83.7) 0.558 PR positive (n= 552) 42 (80.8) 352 (70.4) 0.115 Her-2 (n= 436) 0/+1 30 (76.9) 313 (78.8) 0.192 +2 and CISH negative 0 (0) 12 (3.0) +2 and CISH unknown 6 (15.4) 28 (7.1) +3/CISH positive 3 (7.7) 44 (11.1) Triple negative (n= 526) 1 (2.0) 28 (5.9) 0.253 Chemotherapy (neo or adjuvant) N (%)(n= 636) 15 (25.0) 260 (45.1) 0.003 Hormonal therapy (neo or adjuvant) (n = 636) N (%) Tamoxifen alone 31 (51.7) 198 (34.4) 0.007 Aromatase inhibitors alone 1 (1.7) 46 (8.0) Tamoxifen+aromatase inhibitors 20 (33.3) 206 (35.8) Other 1 (1.7) 1 (0.2) Any tamoxifen treatment, N (%) 51 (85.0) 404 (70.1) 0.015 Any aromatase inhibitors treatment, N (%) 21 (35.0) 252 (43.8) 0.193 Radiotherapy (neo or adjuvant), N (%) (n= 636) 42 (70.0) 440 (76.4) 0.272 Trastuzumab (neo or adjuvant), N (%) (n= 635) 0 (0) 16 (2.8) 0.195 c: BMD BMD, g/cm (mean± s.d.) Femoral neck 0.77± 0.11 0.83± 0.12 o0.001 Total hip 0.84± 0.13 0.91± 0.14 o0.001 Spine 0.96± 0.15 1.03± 0.17 0.002 BMD T-score (mean± s.d.) Femoral neck − 1.72± 0.94 − 1.22± 1.04 o0.001 Total hip − 1.32± 1.12 − 0.79± 1.13 o0.001 Spine − 1.80± 1.23 − 1.23± 1.42 0.002 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited npj Breast Cancer (2015) 15010 High fracture risk in breast cancer survivors M Fraenkel et al Table 3. (Continued ) Variable Osteoporotic fracture (n = 62) No osteoporotic fracture (n = 596) P value BMD Z-score (mean± s.d.) Femoral neck − 0.37± 0.84 − 0.05± 0.93 0.010 Total hip − 0.16± 1.03 0.18± 1.02 0.013 Spine − 0.29± 1.34 0.13±1.49 0.035 Abbreviations: BC, breast cancer; BMD, bone mineral density; BMI, body mass index; CISH, chromogenic in situ hybridization; DCIS, ductal carcinoma in situ; ER, estrogen receptor; HRT, hormone replacement therapy; PR, progesterone receptor. Statistical analysis: Student's t-test. b 2 Statistical analysis: χ -test. CONTRIBUTIONS Table 4. Multivariable analysis (Cox regression) to first osteoporotic ES, VN, LN, MF, DBG, and MK conceived and designed the experiments. TS, VN, and fracture YM: performed the experiments. TS, VN, MF, DBG, and ES: analyzed the data. DBG, SA, and MK: contributed reagents/materials/analysis tools. MF, VN, TS, ES, and DBG: wrote Variable HR 95% CI HR P value the manuscript. Age at BMD 1.02 1.02–1.03 1.02 o0.001 BMI 1.03 1.02–1.04 1.03 o0.001 COMPETING INTERESTS BMD T-score The authors declare no conflict of interest. Total hip 0.71 0.66–0.76 0.71 o0.001 Spine 0.94 0.89–0.99 0.94 0.014 BC 1.34 1.04–1.73 1.34 0.026 REFERENCES 1 Fraenkel M, Novack V, Liel Y, Koretz M, Siris E, Norton L et al. Association between Abbreviations: BC, breast cancer; BMI, body mass index; BMD, bone mineral bone mineral density and incidence of breast cancer. PLoS One 2013; 8: e70980. density; CI, confidence interval; HR, hazard ratio. 2 Qu X, Zhang X, Qin A, Liu G, Zhai Z, Hao Y et al. 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Osteoporos Int 2009; 20: 527–536. microarchitecture, such as the trabecular bone score, might be 8 Pawloski PA, Geiger AM, Haque R, Kamineni A, Fouayzi H, Ogarek J et al. Fracture useful in assessing the risk fracture for these patients. risk in older, long-term survivors of early-stage breast cancer. J Am Geriatr Soc 2013; 61:888–895. We also found that treatment with chemotherapy or aromatase 9 Melton LJ 3rd, Hartmann LC, Achenbach SJ, Atkinson EJ, Therneau TM, Khosla S. inhibitors did not contribute substantially to fracture risk among Fracture risk in women with breast cancer: a population-based study. J Bone Miner our BC survivors. This leads us to believe that lower past estrogen Res 2012; 27: 1196–1205. exposure leading to less-aggressive BC and therefore less 10 Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk in patients with different chemotherapy as well as inherent factors from BC that directly types of cancer. Acta Oncol 2009; 48: 105–115. negatively affect bone are the main contributors for increased 11 Lamont EB, Lauderdale DS. Low risk of hip fracture among elderly breast cancer fragility in a subset of BC patients. survivors. Ann Epidemiol 2003; 13: 698–703. 12 Leslie WD, Aubry-Rozier B, Lamy O, Hans D. TBS (trabecular bone score) and diabetes-related fracture risk. J Clin Endocrinol Metab 2013; 98: 602–609. FUNDING This study was funded by an unrestricted research grant from the This work is licensed under a Creative Commons Attribution 4.0 Cure Breast Cancer Foundation. International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons DISCLAIMER license, users will need to obtain permission from the license holder to reproduce the The funders had no role in study design, data collection and material. To view a copy of this license, visit http://creativecommons.org/licenses/ analysis, decision to publish, or preparation of the manuscript. by/4.0/ npj Breast Cancer (2015) 15010 © 2015 Breast Cancer Research Foundation/Macmillan Publishers Limited

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npj Breast CancerSpringer Journals

Published: Jul 22, 2015

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