Osteoporosis and rate of bone loss among ... - Wiley Online Library

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Osteoporosis and Rate of Bone Loss among Postmenopausal Survivors of Breast Cancer Results from a Subgroup in the Women’s Health Initiative Observational Study Zhao Chen, Ph.D., M.P.H.1 Michael Maricic, M.D.2 Mary Pettinger, M.S.3 Cheryl Ritenbaugh, Ph.D., M.P.H.4 Ana Maria Lopez, M.D.5 David H. Barad, M.D.6 Margery Gass, M.D.7 Meryl S. LeBoff, M.D.8 Tamsen L. Bassford, M.D.4 1

Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona.

2

Department of Medicine, University of Arizona, Tucson, Arizona.

3

Clinical Coordinating Center for Women’s Health Initiative, Fred Hutchinson Cancer Research Center, Seattle, Washington.

4

Department of Family and Community Medicine, University of Arizona, Tucson, Arizona.

5

Arizona Cancer Center, University of Arizona, Tucson, Arizona.

6

Women’s Health Initiative Clinic Center, Albert Einstein College of Medicine, Bronx, New York.

7 Women’s Health Initiative Clinic Center, University of Cincinnati, Cincinnati, Ohio. 8

Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. The Women’s Health Initiative Program is funded by the National Heart, Lung and Blood Institute, United States Department of Health and Human Services. Short list of Women’s Health Initiative investigators: Program Office (National Heart, Lung, and Blood Institute, Bethesda, Maryland): Barbara Alving, Jacques Rossouw, Linda Pottern. Clinical Coordinating Center (Fred Hutchinson Cancer Research Center, Seattle, WA) Ross Prentice, Garnet Anderson, Andrea LaCroix, Ruth E. Patterson, Anne McTiernan; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker, Pentti Rautaharju; (Medical Research Labs, Highland Heights, KY) Evan Stein; (University of California at San Francisco, San Francisco, CA) Steven Cummings; (University of Minnesota, Minneapolis, MN) John Himes; (University of Washington, Seattle, WA) Bruce Psaty. Clinical Centers: (Albert Einstein College of Medicine, Bronx, NY) Sylvia Wassertheil-Smoller; (Bay-

BACKGROUND. Breast cancer diagnosis and treatment may put women at higher risk for osteoporosis in later life. METHODS. In a subgroup of participants in the Women’s Health Initiative Observational Study, authors of the current study investigated differences in bone mineral density (BMD, measured by dual-energy x-ray absorptiometry) between breast cancer survivors (n ⫽ 209) and a noncancer reference group (n ⫽ 5759). RESULTS. In comparison to the reference group, breast cancer survivors had significantly lower total body BMD value (0.989 vs. 1.013 g/cm2, P ⫽ 0.001) and total hip BMD value (0.823 vs. 0.845 g/cm2, P ⫽ 0.02) at baseline after adjustment for age, race/ethnicity, years since menopause, and clinical center. These lower BMD levels were largely explained by lower usage of hormone therapy (HT) among

lor College of Medicine, Houston, TX) Jennifer Hays; (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA) JoAnn Manson; (Brown University, Providence, RI) Annlouise R. Assaf; (Emory University, Atlanta, GA) Lawrence Phillips; (Fred Hutchinson Cancer Research Center, Seattle, WA) Shirley Beresford; (George Washington University Medical Center, Washington, DC) Judith Hsia; (Harbor-UCLA Research and Education Institute, Torrance, CA) Rowan Chlebowski; (Kaiser Permanente Center for Health Research, Portland, OR)Evelyn Whitlock; (Kaiser Permanente Division of Research, Oakland, CA) Bette Caan; (Medical College of Wisconsin, Milwaukee, WI) Jane Morley Kotchen; (MedStar Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Northwestern University, Chicago/Evanston, IL) Linda Van Horn; (Rush-Presbyterian St. Luke’s Medical Center, Chicago, IL) Henry Black; (Stanford Center for Research in Disease Prevention, Stanford University, Stanford, CA) Marcia L. Stefanick; (State University of New York at Stony Brook, Stony Brook, NY) Dorothy Lane; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Alabama at Birmingham, Birmingham, AL) Cora Beth Lewis; (University of Arizona, Tucson/Phoenix, AZ) Tamsen Bassford; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of California at Davis, Sacramento, CA) John Robbins; (University of California at Irvine, Orange, CA) Allan Hubbell; (University of California at Los Angeles, Los Angeles, CA) Howard Judd; (University of California at San Diego, LaJolla/Chula Vista, CA) Robert D. Langer; (University of Cincinnati, Cincinnati, OH) Margery Gass; (University of Florida, Gainesville/ Jacksonville, FL) Marian Limacher; (University of Hawaii, Honolulu, HI) David Curb; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University

© 2005 American Cancer Society DOI 10.1002/cncr.21335 Published online 18 August 2005 in Wiley InterScience (www.interscience.wiley.com).

of Massachusetts/Fallon Clinic, Worcester, MA) Judith Ockene; (University of Medicine and Dentistry of New Jersey, Newark, NJ) Norman Lasser; (University of Miami, Miami, FL) Mary Jo O’Sullivan; (University of Minnesota, Minneapolis, MN) Karen Margolis; (University of Nevada, Reno, NV) Robert Brunner; (University of North Carolina, Chapel Hill, NC) Gerardo Heiss; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (University of Tennessee, Memphis, TN) Karen C. Johnson; (University of Texas Health Science Center, San Antonio, TX) Robert Brzyski; (University of Wisconsin, Madison, WI) Gloria Sarto; (Wake Forest University School of Medicine, Winston-Salem, NC) Denise Bonds; (Wayne State University School of Medicine/Hutzel Hospital, Detroit, MI) Susan Hendrix. Zhao Chen, Ph.D. received support through an award (R01 AR049411) from the National Institute of Arthritis, Musculoskeletal and Skin Diseases, United States Department of Health and Human Services Margery Gass, M.D. has received recent research grants and contracts from GlaxoSmithKline, Pfizer, Organon, Proctor & Gamble Pharmaceuticals, Roche, and WyethAyerst, and has received honoraria or consultation fees from Aventis, GlaxoSmithKline, Organon, Merck, Proctor & Gamble Pharmaceuticals, and Wyeth-Ayerst. Additionally, Dr. Gass is a member of advisory boards to Eli Lilly, Merck, and Proctor & Gamble Pharmaceuticals. Address for reprints: Zhao Chen, Ph.D., M.P.H., Division of Epidemiology and Biostatistics, Mel and Enid Zuckerman Arizona College of Public Health, University of Arizona, PO Box 245203, 1540 E. Drachman, Tucson, AZ 85724; Fax: (520) 6269011; E-mail: [email protected] Received February 28, 2005; revision received April 1, 2005; accepted April 26, 2005.

Osteoporosis among Breast Cancer Survivors/Chen et al.

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survivors: after additional statistical adjustment for HT, hip BMD values were 0.834 versus 0.844 g/cm2 (P ⫽ 0.26), and total body values were 1.005 versus 1.013 g/cm2 (P ⫽ 0.33) for survivors and reference women, respectively. More than 77% of survivors with osteoporosis were undiagnosed by their healthcare providers, and this was similar to the undiagnosed rate in the reference group (85.7%). Longitudinally, breast cancer survivors in this study did not demonstrate an accelerated rate of bone loss compared with the reference population. CONCLUSIONS. Associated with lower HT usage, postmenopausal survivors of breast cancer were more likely to have low BMD in comparison to other women of the same age; and many of these survivors with osteoporosis were undiagnosed. Cancer 2005;104:1520 –30. © 2005 American Cancer Society.

KEYWORDS: BMD, bone mineral density, bone loss, osteoporosis, breast cancer survivor, undiagnosed rate for osteoporosis.

I

ncreasingly, it has been recognized that breast cancer diagnosis and treatments may compromise many breast cancer survivors’ health and may increase their risk for other chronic diseases, such as osteoporosis. Although studies have suggested a correlation between high bone mineral density and increased risk of breast cancer,1,2 there is some evidence that breast cancer survivors are at an increased risk of accelerated bone loss,3–5 which could lead to a higher risk of fractures.6,7 An increased rate of bone turnover and loss may occur among breast cancer survivors, because of early menopause induced by adjuvant chemotherapy,3,4 oophorectomy in premenopausal women, and/or from the inability to receive postmenopausal hormone therapy (HT). In addition, direct toxic effects of chemotherapy agents on bone formation cells8 –10 and breast cancer itself may also cause reductions of bone mineral density (BMD) in this population. Breast cancer survivors are a growing population, and currently there are over 2 million breast cancer survivors in the United States. Given that breast cancer has become a chronic disease for many women, preventing bone loss may have a significant role in reducing comorbidity and in improving health-related quality of life during the long survival time after a breast cancer diagnosis. However, there has been very limited prospective data demonstrating whether postmenopausal survivors of breast cancer continue to have lower BMD and an accelerated rate of bone loss in comparison to other women of their age.11 In this study, we compared bone density and rate of changes in BMD between breast cancer survivors and women without any cancers from a postmenopausal subcohort in the Women’s Health Initiative Observational Study (WHI-OS). We also examined the undiagnosed rate for osteoporosis in this population by survivor status and by age (grouped) at breast cancer diagnosis. We hypothesized that breast cancer sur-

vivors would have low BMD and an increased risk for osteoporosis in comparison to women of the same age who did not have any cancer history; however, as is the case in the reference population, osteoporosis is significantly underdiagnosed among breast cancer survivors.

MATERIALS AND METHODS Study Population Participants in this study were a subgroup of women from the WHI-OS who received BMD testing at 3 of the 40 WHI participating clinical centers (Pittsburgh, PA; Birmingham, AL; and sister facilities in Tucson and Phoenix, AZ). Details of the design and data collection methods used in the WHI-OS have been published previously.12,13 Women were included in this analysis if they had a baseline BMD measurement for the total hip, spine, or total body. Women who reported having had a breast cancer diagnosis in a baseline questionnaire were defined as breast cancer survivors; women who had no cancer history at baseline and who did not develop any cancer during the WHI-OS follow-up period were defined as a no-cancer reference group in statistical analysis. Other women were excluded from the current study’s analysis.

Study Procedure Self-administered or interviewer-administered questionnaires for eligibility screening and baseline characteristics (such as demographic, reproductive, and health status data) were completed by each of the WHI-OS participants at baseline. At the time of enrollment, physical examinations, including weight and height measurements, were conducted by trained WHI staff. During follow-up, women were sent questionnaires annually to update medical and other lifestyle information. The WHI-OS participants visited their WHI clinical center at annual Visit 3 (AV-3) and at

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annual Visit 6 (AV-6) to get additional physical measurements.

BMD Measurements Bone mineral density (BMD) at the posterior-anterior spine, total hip, and total body were measured as areal density (g/cm2) at three WHI BMD clinical centers by dual-energy x-ray absorptiometry (DXA) (QDR 2000, 2000⫹ and 4500, Hologic Inc., Waltham, MA). Standard DXA protocols were used for participants’ positioning and analysis of DXA scans by radiology technicians who were trained and certified by both the Hologic Company and the WHI Bone Density Coordinating Center at the University of California, San Francisco. The ongoing WHI quality assurance program monitors machine and technician performance by reviewing phantom scans, randomly sampling all scans, and flagging scans with specific problems, and by controlling hardware and software changes. In addition to daily and weekly phantom scans at each clinic, a set of calibration phantoms were also circulated and scanned across DXA instruments used in the WHI-OS. In each DXA scan, BMD T-scores were automatically calculated by the Hologic program using the young adult reference group (non-Hispanic white women aged 20 –29 yrs) from the National Health and Nutrition Examination Survey for the hip, and the manufacturer’s database for the spine and total body (T-score ⫽ [individual BMD ⫺ Mean of the young adult reference BMD population]/standard deviation of the young reference BMD population). A T-score below ⫺2.5 was defined as osteoporosis.

Assessments of covariates At baseline and during follow-up, weight was measured to the nearest 0.1 kg on a balance-beam scale with the participant dressed in indoor clothing without shoes. Height was measured to the nearest 0.1 cm by using a wall-mounted stadiometer. Body mass index (BMI) was calculated as weight (kg) ⫼ height (m)2. Information on age, years since menopause, race/ethnicity, smoking habit, time spent walking, use of HT, history of diagnosis of osteoporosis, use of medications for osteoporosis, fracture history, health history, and nutrients intake were assessed from self- or interviewer-administered questionnaires at baseline. Osteoporosis medications included calcitonin, bisphosphonates, and selective estrogen receptor modulators (SERM). Hormone therapy (HT) was defined as postmenopausal estrogen therapy with or without progestin. Antiestrogens included tamoxifen and toremifene citrate (Fareston). Physical function was measured using the 10-item Medical Outcomes Study Scale,14 in which higher physical function scores mean better

physical functioning. We defined osteoporosis as undiagnosed when a woman’s BMD T-score was ⫺2.5 or lower at baseline BMD assessment in the WHI-OS and if, in the baseline questionnaire, she did not report being informed by her healthcare providers of an osteoporosis diagnosis before she began participation in the WHI-OS. Age at menopause is defined as the minimum age at which the participant last had any menstrual bleeding, or the date of a bilateral oophorectomy, or when she began using HT. If a woman had a hysterectomy but not a bilateral oophorectomy, then age at menopause is the earliest age at which she began using HT or began having menopausal symptoms. If a woman had a hysterectomy but not a bilateral oophorectomy, did not take HT, did not experience menopausal symptoms, and had her hysterectomy at age 50 years or older, her age at menopause is her age at hysterectomy. On the basis of this algorithm, if a participant’s age at menopause is ⬎ 60 years, then it is recoded as age 60 years.

Statistical Methods Baseline characteristics of breast cancer survivors and reference groups were compared by using chi-square tests for categoric variables and t tests for continuous variables. Change in bone density was defined as percentage changes from baseline to AV-3 or AV-6, respectively. These changes were calculated as [(BMD at follow-up time ⫺ BMD at baseline)/BMD at baseline] ⫻ 100. Linear regression models were used to compare mean BMD absolute and percent change values separately at each time point between breast cancer survivors and the reference group. Both unadjusted means and least-squares means for two adjusted models are reported. The first model makes statistical adjustments for age, race/ethnicity, clinical center, and years since menopause; and the second model adjusts all the above variables plus HT use at baseline. Statistical comparisons between the two study groups were based on the F statistic. Mixed effects models were also run to compare changes over time in BMD between the two study groups. These models used all available BMD measurements for each participant. An unstructured covariance pattern was assumed for the relation between serial measurements on the same participant. Regression intercept and slope were assumed to be random for each participant. Statistical comparisons of change in BMD between breast cancer survivors and the reference group were made by testing an interaction term of breast cancer survivor status by time. Adjustment was made for baseline variables of


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age, race/ethnicity, years since menopause, and clinical center. Adjustment for body weight, total calcium intake, and total vitamin D intake was made by including a covariate for the average measurement from the baseline and AV-3 visits. Information on medication use other than estrogen was available at baseline and at AV-3, and information on estrogen use was available at baseline, AV-1, AV-3, and AV-6. Two covariates for each medication were included in the models, one for some use (meaning use at some, but not all, of the visits), and a second for continuous use (meaning use at all visits). Further adjustment was made for occurrence of each of the following comorbid conditions during the follow-up period: myocardial infarction (MI), osteoarthritis, rheumatoid arthritis (RA), osteoporosis, emphysema, and diabetes. All statistical analyses were performed using SAS, version 9.0, using two-sided tests (SAS Institute, Inc., Cary, NC).

vors, contrasted with 19.4% of women in the reference group, were osteoporotic at one or more of the skeletal sites that were measured. In Model 2 (Fig. 1), when one additional variable, HT, was also statistically adjusted, the differences in prevalence rates of osteoporosis by survivor status disappeared. These results suggest that breast cancer survivors were at increased risk for osteoporosis at baseline, and this higher risk for osteoporosis among survivors was largely explained by the difference in HT use between survivors and the reference group. Figure 2 illustrates that among women who were osteoporotic, 12 of 54 survivors and 153 of 1070 women in the reference group reported having had a diagnosis for osteoporosis at baseline. The undiagnosed rate for osteoporosis was high for both survivors (77.8%) and for women in the reference group (85.7%). There was no statistically significant difference in osteoporosis diagnosis rate by survivor status (P ⫽ 0.1085).

RESULTS

Mean BMD and Rate of Changes in BMD

The average length of follow-up for women in the current study was 6.7 years as of August 2003. At baseline, there were 209 women in the survivor group and 5759 women in the reference group.

Table 2 displays mean BMD values at baseline, AV-3, and AV-6, as well as rates of change in BMD measurements by survivor status. Two adjusted models were presented: the first model statistically adjusted age, race/ethnicity, years since menopause, and clinical center; the second model statistically adjusted all these variables plus HT use. Results from the first model indicate that breast cancer survivors had lower BMD values for baseline total hip and total body measurements. There were several women in both the reference group and the survivor group who did not have follow-up BMD measurements. Group differences in BMD measurements at AV-3 or AV-6 were not found. The rate of change in total hip and spine BMD measurements were similar between the two groups; however, the rate of increase for total body BMD from baseline to AV-3 was significantly higher for breast cancer survivors than for women in the reference group (P ⫽ 0.03). The second model suggested that the difference in baseline BMD by survivor status was mainly because of the lower number of survivors who had used HT compared with the reference group.

Baseline Characteristics In Table 1, measurements of age, ethnicity, BMI, physical activities, medication use, health status, and other lifestyle factors were compared between the survivor group and the reference group. Breast cancer survivors were older (P ⫽ 0.01), less likely to be on HT, more likely to be on antiestrogen medications (P ⬍ 0.0001), and had poorer physical function (P ⫽ 0.005) measured by the physical function construct. About 54% of survivors in the current study were diagnosed with breast cancer before age 55 years.

Prevalence Rates of Osteoporosis Based on BMD and Undiagnosed Rate of Osteoporosis at Baseline Figure 1 shows that in Model 1 after statistically adjusting age, race/ethnicity, years since menopause, and clinical center, breast cancer survivors had a significantly higher prevalence rate of osteoporosis based on baseline total hip (adjusted P ⫽ 0.0039) or total body T scores (adjusted P ⫽ 0.0016), but the difference in prevalence of osteoporosis at the spine was not statistically different (adjusted P ⫽ 0.1627) between survivors and the no-cancer reference group. The overall prevalence rate of women who were osteoporotic, based on baseline T scores from any of the three measurements (total hip, lumbar spine, or total body) was significantly greater for breast cancer survivors (adjusted P ⫽ 0.0185). Approximately 27.2% of survi-

Missed Follow-up BMD Tests at AV-3 There were 44 breast cancer survivors (21% of total survivors in the current study) and 1118 women in the reference group (19.4% of women in the reference group) who did not have AV-3 BMD values. Transferring to other WHI-OS non-BMD clinics explained 1.4% (n ⫽ 16) of women in the reference group who had not AV-3 BMD. In addition, for survivors and the reference group, respectively, 15.9% (n ⫽ 7) versus 8.9% (n ⫽ 1118)

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TABLE 1 Baseline Characteristics by Survivor Group Breast cancer survivor (n ⴝ 209)

Age group at screening, yrs 50–59 60–69 70–79 Race/Ethnicity White Black Hispanic Asian/Pacific Islander American Indian Unknown Smoking Never Past Current Alcohol None Past ⬍ 1/month ⬍ 1/week 1-⬍ 7/week 7⫹/week Body mass index kg/m2 Underweight ⬍ 18.5 Normal ⬍ 18.5–24.9 Overweight 25–29.9 Obesity I ⱖ 30–34.9 Obesity II ⱖ 35–39.9 Extreme obesity III ⱖ 35–39.9 Hysterectomy at screening No Yes Years since menopause ⬍5 5-⬍ 10 10-⬍ 15 ⱖ 15 Oophorectomy No ovaries removed Partial, one, or unknown number Both ovaries removed ⬍ age 55 yrs Both ovaries removed ⱖ age 55 yrs Minutes/week spent walking None ⬎ 0–150 ⬎ 150 Physical function construct (⬎ 90)a No Yes Fracture history (any bone) No Yes Broke bone at age ⱖ 55 yrs No Yes HT usage Never Past Current

No-cancer reference (n ⴝ 5759)

No

%

No.

%

53 88 68

25.4 42.1 32.5

1825 2543 1391

31.7 44.2 24.2

146 37 19 2 2 3

69.9 17.7 9.1 1.0 1.0 1.4

4443 753 408 23 91 41

77.1 13.1 7.1 0.4 1.6 0.7

109 83 13

53.2 40.5 6.3

3095 2147 439

54.5 37.8 7.7

37 51 16 32 42 26

18.1 25.0 7.8 15.7 20.6 12.7

1041 1236 710 1067 1179 489

18.2 21.6 12.4 18.6 20.6 8.5

3 75 70 35 12 11

1.5 36.4 34.0 17.0 5.8 5.3

69 2114 1957 951 355 258

1.2 37.1 34.3 16.7 6.2 4.5

98 110

47.1 52.9

3081 2672

53.6 46.4

16 32 32 113

8.3 16.6 16.6 58.6

637 886 1055 2793

11.9 16.5 19.6 52.0

138 17 39 10

67.6 8.3 19.1 4.9

3965 598 879 173

70.6 10.7 15.7 3.1

96 83 28

46.4 40.1 13.5

2607 2203 850

46.1 38.9 15.0

156 47

76.8 23.2

3795 1821

67.6 32.4

128 76

62.7 37.3

3485 2085

62.6 37.4

133 28

82.6 17.4

3629 769

82.5 17.5

149 46 14

71.3 22.0 6.7

2534 821 2401

44.0 14.3 41.7

P value 0.01

0.10

0.63

0.10

0.99

0.07

0.22

0.19

0.83

0.005

0.96

0.98

⬍ 0.0001

(continued)


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TABLE 1 (Continued) Breast cancer survivor (n ⴝ 209)

Osteoporosis medication No Yes Antiestrogen use No Yes Total Ca, diet ⫹ supplements ⬍ 600 mg/day 600–1200 mg/day ⬎ 1200 mg/day Total vitamin D, diet ⫹ supplements ⬍ 4.66 mcg/day 4.66–12.36 mcg/day ⬎ 12.36 mcg/day Age at breast cancer diagnosis ⬍ 55 yrs ⱖ 55 yrs a

No-cancer reference (n ⴝ 5759)

No

%

No.

%

199 10

95.2 4.8

5660 99

98.3 1.7

158 51

75.6 24.4

5758 1

100.0 ⬍ 0.1

55 62 80

27.9 31.5 40.6

1391 2101 1973

25.4 38.4 36.1

65 61 71

33.0 31.0 36.0

1823 1825 1817

33.4 33.4 33.2

110 92

54.5 45.5

P value 0.001

⬍ 0.0001

0.14

0.71

Physical function construct of ⬎ 90 is a score indicating better physical functioning.

FIGURE 2. Undiagnosed rates of osteoporosis among women with a T score below ⫺2.5 from at least 1 of the baseline DXA scans (hip, spine, or total body scan). P ⫽ 0.1085 (for differences in diagnosis rates between breast cancer survivors and the no-cancer reference group).

Spine Total hip Total body Any site

Crude

Model 1

Model 2

Pcrude ⫽ 0.0425 Pcrude ⫽ 0.0023 Pcrude ⫽ 0.0002 Pcrude ⫽ 0.0056

Padjusted ⫽ 0.1627 Padjusted ⫽ 0.0039 Padjusted ⫽ 0.0016 Padjusted ⫽ 0.0185

Padjusted ⫽ 0.8359 Padjusted ⫽ 0.0718 Padjusted ⫽ 0.1196 Padjusted ⫽ 0.5662

Model 1 is adjusted for age, race/ethnicity, clinical center, and years since menopause. Model 2 is adjusted for age, race/ethnicity, clinical center, years since menopause, and hormone therapy use.

FIGURE 1. Comparison of prevalence of osteoporosis based on DXA measurements at baseline. Osteoporosis is defined by a T score ⬍ ⫺2.5 from spine, total hip, and total body BMD measurements or from any 1 of the 3 DXA scans at baseline.

died within 4 years of enrollment, 13.6% (n ⫽ 6) versus 9.6% (n ⫽ 107) were lost to follow-up within 4 years of enrollment, and 70.5% (n ⫽ 31) versus 80.1% (n ⫽ 895) did not have AV-3 DXA scans because of other reasons. However, among the other reasons category, 12 participants in the survivor group and 310 women in the reference group continued with the study after missing their DXA scans for BMD and had bone density measurements in subsequent clinical visits (AV-6 or AV-9).

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TABLE 2 Comparison of Adjusted BMD and Rates of Changes in BMD between Breast Cancer Survivors and the Reference Group Breast cancer survivor BMD Model 1a Total hip Baseline g/cm2 AV3 g/cm2 AV6 g/cm2 % AV3 change % AV6 change Spine (L2–L4) Baseline g/cm2 AV3 g/cm2 AV6 g/cm2 % AV3 change % AV6 change Total Body Baseline g/cm2 AV3 g/cm2 AV6 g/cm2 % AV3 change % AV6 change Model 2b Total Hip Baseline g/cm2 AV3 g/cm2 AV6 g/cm2 % AV3 change % AV6 change Spine (L2–L4) Baseline g/cm2 AV3 g/cm2 AV6 g/cm2 % AV3 change % AV6 change Total body Baseline g/cm2 AV3 g/cm2 AV6 g/cm2 % AV3 change % AV6 change

No-cancer reference group

No.

Mean (95% CI)

No.

Mean (95% CI)

P value

193 152 129 152 129

0.823 (0.805, 0.841) 0.833 (0.813, 0.853) 0.829 (0.807, 0.850) 0.058 (⫺0.587, 0.702) ⫺0.151 (⫺1.020, 0.719)

5350 4314 3537 4286 3502

0.845 (0.841, 0.848) 0.847 (0.843, 0.851) 0.842 (0.838, 0.846) 0.449 (0.329, 0.570) ⫺0.194 (⫺0.359, ⫺0.029)

0.02 0.17 0.23 0.24 0.92

189 152 127 152 127

0.959 (0.935, 0.983) 0.984 (0.957, 1.012) 0.997 (0.966, 1.029) 1.683 (0.883, 2.483) 3.659 (2.480, 4.838)

5220 4205 3389 4196 3377

0.980 (0.976, 0.985) 0.995 (0.989, 1.000) 1.010 (1.004, 1.016) 1.771 (1.620, 1.922) 3.262 (3.036, 3.488)

0.08 0.48 0.45 0.83 0.52

191 151 128 150 127

0.989 (0.975, 1.003) 1.013 (0.996, 1.030) 1.017 (0.998, 1.037) 1.559 (0.996, 2.122) 2.276 (1.448, 3.103)

5349 4291 3513 4271 3497

1.013 (1.010, 1.016) 1.022 (1.019, 1.026) 1.035 (1.031, 1.038) 0.905 (0.801, 1.010) 1.856 (1.699, 2.012)

⬍ 0.01 0.28 0.08 0.03 0.33

193 152 129 152 129

0.834 (0.816, 0.852) 0.847 (0.827, 0.867) 0.843 (0.822, 0.865) 0.212 (⫺0.439, 0.863) 0.262 (⫺0.612, 1.135)

5350 4314 3537 4286 3502

189 152 127 152 127

0.982 (0.959, 1.006) 1.010 (0.983, 1.037) 1.022 (0.991, 1.053) 1.758 (0.948, 2.567) 3.679 (2.486, 4.872)

5220 4205 3389 4196 3377

0.980 (0.975, 0.984) 0.994 (0.989, 0.999) 1.009 (1.003, 1.015) 1.769 (1.618, 1.920) 3.263 (3.037, 3.489)

0.84 0.25 0.41 0.98 0.50

191 151 128 150 127

1.005 (0.991, 1.020) 1.032 (1.015, 1.049) 1.035 (1.016, 1.054) 1.675 (1.106, 2.243) 2.389 (1.553, 3.226)

5349 4291 3513 4271 3497

1.013 (1.010, 1.015) 1.022 (1.019, 1.025) 1.034 (1.031, 1.038) 0.902 (0.797, 1.006) 1.852 (1.696, 2.008)

0.33 0.25 0.92 0.01 0.22

0.844 (0.841, 0.848) 0.847 (0.843, 0.850) 0.842 (0.838, 0.846) 0.442 (0.322, 0.562) ⫺0.214 (⫺0.378, ⫺0.050)

0.26 1.00 0.88 0.50 0.30

BMD: bone mineral density; CI: confidence interval; AV: annual visit. a Adjusted for age (linear), race/ethnicity (White/Hispanic, Black, Other), years since menopause, and clinical center. Years since menopause missing for 6.8% of participants. b Adjusted for age (linear), race/ethnicity (White/Hispanic, Black, Other), years since menopause, clinical center, and hormone therapy use (past, current). Years since menopause missing for 6.8% of participants

Comparison of Baseline BMD between Women With and Without AV-3 BMD On average, breast cancer survivors who did not have AV-3 BMD measurements had significantly (P ⬍ 0.05) lower total hip and total body BMD at baseline, and borderline significantly (P ⫽ 0.0773) lower BMD for spine, when compared with survivors who had followup BMD measurements at AV-3 after adjustment for age, race/ethnicity, year since menopause, and clinical center; in the reference group, there were no significant differences in baseline BMD measurements

between women with and without AV-3 BMD (data not shown). This suggests that loss of follow-up for survivors who had low baseline BMD may have contributed to the observed reduced discrepancies in mean BMD values between survivors and the reference group at the follow-up measurements.

Mixed Effects Models for Changes in BMD Mixed effects models were used to further examine group differences in rates of BMD changes by including all participants, even if their follow-up measure-


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TABLE 3 Comparison of BMD and Rates of Changes in BMD by Age at Diagnosis Among Breast Cancer Survivors < Age 55 yrs BMD Total hip Baseline g/cm2 AV3 g/cm2 AV6 g/cm2 % AV3 change % AV6 change Spine (L2–L4) Baseline g/cm2 AV3 g/cm2 AV6 g/cm2 % AV3 change % AV6 change Total body Baseline g/cm2 AV3 g/cm2 AV6 g/cm2 % AV3 change % AV6 change

> Age 55 yrs

No.

Mean (95% CI)

No.

Mean (95% CI)

P value

103 86 73 86 73

0.813 (0.784, 0.842) 0.816 (0.787, 0.846) 0.822 (0.794, 0.850) ⫺0.112 (⫺1.041, 0.818) 0.121 (⫺1.137, 1.379)

84 62 52 62 52

0.830 (0.797, 0.863) 0.851 (0.816, 0.887) 0.835 (0.801, 0.869) 0.231 (⫺0.899, 1.360) 0.330 (⫺1.205, 1.865)

0.49 0.18 0.57 0.67 0.85

103 86 71 86 71

0.939 (0.902, 0.975) 0.954 (0.915, 0.992) 0.971 (0.929, 1.014) 1.935 (0.666, 3.204) 3.171 (1.342, 5.001)

80 62 52 62 52

0.989 (0.947, 1.032) 1.024 (0.977, 1.071) 1.024 (0.973, 1.075) 1.174 (⫺0.369, 2.717) 4.268 (2.075, 6.461)

0.11 0.04 0.15 0.49 0.49

103 85 73 85 73

0.979 (0.958, 1.000) 1.001 (0.975, 1.026) 1.015 (0.987, 1.042) 1.704 (0.650, 2.758) 3.200 (1.636, 4.764)

82 62 51 61 50

1.006 (0.982, 1.030) 1.037 (1.006, 1.067) 1.053 (1.018, 1.087) 1.808 (0.523, 3.093) 3.965 (2.004, 5.925)

0.14 0.10 0.12 0.91 0.58

BMD: bone mineral density; CI: confidence interval; AV: annual visit. All results adjusted for age (linear) race/ethnicity (White/Hispanic, Black, Other), years since menopause, clinical center, and past and current hormone therapy use.

ments were incomplete (data not shown). All models were adjusted for body weight, total calcium intake, total vitamin D intake, medication use other than estrogen, estrogen use, MI, osteoarthritis, RA, osteoporosis, emphysema, and diabetes. Examining the results of statistical tests for interaction terms of time and case-status, we found that rates of change were similar for both the survivor group and the reference group at time points AV-3 and AV-6 in regard to total hip and spine BMD measurements. However, in comparison to the reference group, breast cancer survivors had a higher rate of increase in total body BMD measurement from baseline to AV-3 (P ⫽ 0.006) or AV-6 (P ⫽ 0.0003). These results from mixed effects models are in agreement with findings from the multiple linear regression analysis (Table 2), suggesting a faster rate of increase in total BMD measurement among breast cancer survivors than in the reference group. These findings may, at least partially, explain observed similar total body BMD values between survivors and the reference group at AV-3 and AV-6, even though survivors had lower total body BMD measurement at baseline.

Comparison of BMD Values and Rate of Changes in BMD by Age at Breast Cancer Diagnosis On the basis of results presented in Table 3, women who had a breast cancer diagnosis before age 55 years

appear to have a lower BMD compared with women whose breast cancer was diagnosed at or after age 55 years, but a statistically significant difference was found only between spine BMD measurements at baseline and AV-3 by age at breast cancer diagnosis. These results were adjusted for age, race/ethnicity, years since menopause, and clinical center. On the basis of T scores from any of the BMD measurement sites, approximately 25% of survivors in the younger diagnosis group were osteoporotic, and 30% of the survivors in the older diagnosis group had osteoporosis. The difference in the prevalence rate of osteoporosis was not statistically significant (P ⫽ 0.50) after adjustment for age, race/ethnicity, clinical center, and HT use. Further analysis suggests that among survivors who were osteoporotic based on their BMD measurements, 9 of 27 (33%) of the women in the younger cancer diagnosis group reported being diagnosed with osteoporosis by their healthcare providers at baseline. In contrast, 3 of 23 (11.5%) of women in the older cancer diagnosis group reported having an osteoporosis diagnosis at baseline. The undiagnosed rate was 66.7% and 88.5% for the younger and older diagnosis groups, respectively; however, the group difference for undiagnosed rate of osteoporosis had only borderline significance (P ⫽ 0.058) when adjusted for age, race/ethnicity, and clinical center.

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DISCUSSION Despite increasing concerns about bone health among cancer survivors, data on BMD and rate of changes in BMD values among breast cancer survivors compared with no-cancer reference groups are still scarce. The current study, conducted between breast cancer survivors and women without any cancer history from a subgroup of postmenopausal women in the WHI-OS, has added several direct epidemiologic observations to the understanding of bone health among postmenopausal survivors of breast cancer. On the basis of baseline measurements in our study, breast cancer survivors had an increased risk for low bone density and osteoporosis. This finding is in agreement with results from a small cross-sectional study among relatively young postmenopausal survivors of breast cancer (aged 42– 65 years), which found that 60% of survivors were osteopenic, and 20% of them were osteoporotic (based on T scores at total hip, femoral neck, spine, or forearm)11,15 after their cancer treatments, including surgery, adjuvant chemotherapy, and/or tamoxifen. The rate of osteoporosis among survivors was higher (27.2%) in our study in comparison to the 20% rate in the Twiss11 and Lindsey15 studies. This discrepancy may be due to older age of our participants and different BMD measurement sites used in the three studies. Several studies have suggested a significant association of higher BMD and increased risk of breast cancer among women with postmenopausal breast cancer.1,2,16 It is possible that the observed low mean BMD value was a consequence of breast cancer diagnosis and/or treatment for postmenopausal women, because these breast cancer survivors may have a higher BMD than the reference group before breast cancer diagnosis. However, it is unknown whether survivors who were diagnosed with breast cancer at a younger age already had low bone density at the time of the cancer diagnosis. Some observations suggest that stopping HT or restricting use of HT after breast cancer diagnosis among postmenopausal women,15 ovarian failure in women who take chemotherapy for breast cancer before menopause,4 and comprising bone health by direct toxic effects of chemotherapy agents on bone cells8,9 are some potential causes of reduced BMD in breast cancer survivors. In addition, cancer prognosis and lifestyle changes after cancer diagnosis may also contribute to the low BMD among breast cancer survivors. In our study, 71.3% of breast cancer survivors never used HT versus 44% never users in the reference group. The percentages of current HT users at baseline were 6.7% versus 41.7% for survivors and the reference group, respectively. Our re-

sults indicate that low baseline BMD level and high prevalence rate of osteoporosis among survivors were mainly due to lower usage of HT among these women. There were no statistically significant differences in these measures by group after adjusting for difference in HT use. We do not have information on cancer treatments or the exact age at cancer diagnosis; hence, we cannot determine the attributive role of chemotherapy-induced premature menopause or direct toxicity of chemotherapy agents on bone tissue in the observed low BMD among breast cancer survivors. There was an alarmingly high number of women with osteoporosis in our study who were undiagnosed. On average, the undiagnosed rate for osteoporosis was lower in breast cancer survivors (77.8%) than in the reference group (85.7%). However, a better detection of osteoporosis by health providers for breast cancer survivors was only a result of a higher osteoporosis diagnosis rate (33.3%) among women who had breast cancer before age 55 years. Survivors who had breast cancer at or after age 55 years had a similar (12%) diagnosis rate for osteoporosis compared with the reference group (14%). These striking results suggest that health providers pay more attention to monitoring bone health among younger women with breast cancer. However, close monitoring of bone health is also needed for the large number of women who had their breast cancer diagnosis after menopause. It has been reported that women who were postmenopausal when they developed breast cancer had lower bone density after adjuvant chemotherapy when compared with those who did not have chemotherapy.5 This finding suggests that chemotherapy also has detrimental effects on bone density in postmenopausal women, and special medical attention should be given to this group of women. We did not find an increased rate of bone loss among breast cancer survivors during follow-up. In fact, breast cancer survivors were catching up with women from the reference group in total body BMD measurement. It is possible that most of the reduction in BMD had occurred at the initial phase of the breast cancer diagnosis and treatments, such as at the time of HT cessation or at the time of starting chemotherapy. During the WHI-OS follow-up, most survivors had already passed their initial cancer diagnosis and treatment phase, and a significant percentage of them were using tamoxifen and medications for treating osteoporosis compared with women in the reference group. These factors may have contributed to the higher rate of increase in total body BMD among survivors. However, because survivors who did not have follow-up BMD measurements had significantly lower mean baseline BMD values in comparison to


survivors who had follow-up DXA scans for BMD, we cannot exclude that the increased BMD among survivors during the follow-up is a result of differential dropout in the survivor group by baseline BMD levels. In a previous study among the entire WHI-OS cohort, we observed a significantly increased rate of fractures among breast cancer survivors compared with WHI-OS participants who had no cancer history.7 Results from the current study, showing significantly lower BMD values at baseline and low BMD during follow-up among breast cancer survivors from a subgroup of WHI-OS participants, suggest that low BMD is a contributive factor to observed increased fracture risk among breast cancer survivors in the entire WHIOS cohort. Furthermore, in the current study, we found that baseline spinal BMD values were significantly lower among breast cancer survivors who had breast cancer diagnosis before age 55 years compared with women diagnosed with breast cancer at or after age 55 years, suggesting that, in contrast to women who had breast cancer in a later age, survivors in the younger diagnosis group have an increased risk for fractures of the spine. This result is in agreement with our findings on rates of clinical vertebral fractures in the entire WHI-OS cohort: a 78% increase of relative risk for clinical vertebral fractures in the younger cancer diagnosis group but no increased risk in the older diagnosis group. Our study has used both cross-sectional and longitudinal data to investigate levels of bone density and risk of osteoporosis in a relatively large sample of postmenopausal survivors of breast cancer, which has provided results that may be more generally applied. Additional strengths of this study include using stateof-the-art techniques and strict quality control procedures in assessing bone density, having available information on many lifestyle, medication, and health covariates, and studying multiethnic populations. However, factors, such as unknown exact age at breast cancer diagnosis, lack of information on cancer treatment regimens and prognosis, and loss of follow-up for a significant number of survivors, have limited our ability to investigate causes of low BMD and longitudinal changes in bone density among breast cancer survivors. Because the sample size of the breast cancer survivors was relatively small, we were unable to examine other clinically relevant questions, such as the impact of antiestrogen medications on BMD. It should be noted that the current study was based on data collected 3 to 10 years ago, and it may not reflect current clinical practice for screening and managing osteoporosis among breast cancer survivors. Adjuvant therapies for breast cancer survivors now often include aromatase inhibitors. The American Society of

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Clinical Oncology (ASCO) supports yearly DXA scans for postmenopausal breast cancer survivors at high risk, including those who are taking aromatase inhibitors.17 Whether the ASCO guideline will increase awareness among medical oncologists and have a positive impact on diagnosis and prevention of osteoporosis in breast cancer survivors remains to be studied. However, a recent review has reported that, despite a large number of practice guidelines on osteoporosis screening and treatment, BMD testing rates are low among at-risk patients, ranging from 1% to 32% of postfracture patients and 1% to 47% of oral glucocorticoid users.18 It is foreseeable that to increase osteoporosis screening, prevention and treatment among breast cancer survivors will face many challenges, and osteoporosis is unlikely to become an insignificant problem in this special population in the near future unless effective intervention strategies are developed and implemented. In summary, the current study has shown that postmenopausal survivors of breast cancer, especially those who had cancer diagnosis at a younger age, are a high-risk group of women for developing osteoporosis. This increased risk is largely explained in this population by lower usage of HT by survivors compared with other women. Approximately 75% of the total number of survivors who were osteoporotic were undiagnosed, and this undiagnosed rate is even higher (88%) for women who had a breast cancer diagnosis at or after age 55 years. Results of this study have demonstrated the need for screening, preventing, and treating osteoporosis in the large population of breast cancer survivors. Future studies are needed to investigate causes of bone loss among breast cancer survivors who are diagnosed with cancer at different ages.

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