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. Author manuscript; available in PMC: 2018 Feb 1.
Published in final edited form as: Obesity (Silver Spring). 2016 Dec 27;25(2):346–351. doi: 10.1002/oby.21729

The Effect of Exercise on Body Composition and Bone Mineral Density in Breast Cancer Survivors taking Aromatase Inhibitors

Gwendolyn A Thomas 1, Brenda Cartmel 2, Maura Harrigan 2, Martha Fiellin 2, Scott Capozza 2, Yang Zhou 2, Elizabeth Ercolano 2, Cary P Gross 2, Dawn Hershman 3, Jennifer LIgibel 4, Kathryn Schmitz 5, Fang-yong Li 2, Tara Sanft 2, Melinda L Irwin 2
PMCID: PMC5450163  NIHMSID: NIHMS829801  PMID: 28026901

Abstract

Objective

We examined the effect of 12 months aerobic and resistance exercise vs. usual care on changes in body composition in postmenopausal breast cancer survivors taking aromatase inhibitors (AIs).

Methods

121 breast cancer survivors were enrolled in the Hormones and Physical Exercise (HOPE) study and randomized to either supervised twice-weekly resistance exercise training and 150 minutes per week of aerobic exercise (N=61) or a usual care (N=60) group. Dual energy X-ray absorptiometry (DXA) scans were conducted at baseline, 6-months, and 12-months to assess changes in body mass index (BMI), percent body fat (%FM), lean body mass (LBM) and bone mineral density (BMD).

Results

At 12-months, the exercise group relative to the usual care group had a significant increase in LBM (0.32 vs −0.88 kg, p=0.03), a decrease in %FM (−1.4 vs 0.48 %, p=0.03), and a decrease in BMI (−0.73 vs 0.17 kg/m2, p=0.03). Change in BMD was not significantly different between groups at 12 months (0.001 g/cm2 vs. −0.006 g/cm2, p=0.37).

Conclusions

A combined resistance and aerobic exercise intervention improved body composition in breast cancer survivors taking AIs. Exercise interventions may help to mitigate the negative side effects of AIs and improve health outcomes in breast cancer survivors.

Keywords: aromatase inhibitors, body composition, breast cancer

Introduction

Breast cancer is the most common cancer diagnosis among American women, accounting for 30% of cancer diagnoses with an estimated 231,840 invasive cases diagnosed in 2015, as well as an estimated 60,290 additional cases of in situ breast cancer(1). Approximately 65% of all breast cancer survivors are overweight or have obesity as defined by a BMI ≥25 (2,3)(2,3)(2,3), and few breast cancer survivors exercise at recommended levels of physical activity.(4,5) Not only are obesity and sedentary lifestyle believed to cause between 25%–33% of all breast cancer cases (6), these risk factors are also associated with poorer outcomes after diagnosis, in both pre and postmenopausal breast cancer and a significant increase in recurrence and elevated total mortality (1). Findings from a recent meta-analysis have shown that in comparison with lean participants, participants with obesity had a 35% higher risk of breast cancer related death and a 41% higher risk of all-cause mortality(7). Additionally, breast cancer treatment is related to increases in body fat as well as decreases in lean body mass and bone mineral density (8,9). These changes can put these women at increased risk for frailty fractures and osteoporosis, as well further risk for comorbid chronic disease and cancer recurrence (10,11).

Furthermore, 80% of breast cancers in postmenopausal women are hormone receptor positive (11) and the current standard of care is taking an aromatase inhibitor (AI) for five years, which increases disease free survival by 10 to 40% compared with tamoxifen(12–14). While AIs are associated with clinically meaningful recurrence and mortality risk reductions (10), a side effect is loss of BMD(15–17). Postmenopausal breast cancer survivors taking AIs lose about 2.6% of their BMD annually, which is double the amount of BMD loss in healthy postmenopausal women(18,19). Research examining the effects of AIs on other components of body composition have been mixed, with some studies showing loss of LBM and increases in body fat or maintenance of total body fat, while other studies showing no changes in body weight nor LBM(12–14,20–22). Side effects from AIs, such as arthralgia or bone loss, lead some women to stop taking AIs, thereby greatly increasing their chance of recurrence (23). Importantly, individuals with obesity have significantly higher incidences of arthralgia, putting them at greater risk for non-compliance with AI treatment (24).

The potential negative side effects to body composition and bone loss from AIs may be diminished or eliminated through the implementation of regular physical activity and exercise(25). However, to our knowledge no study has examined the effect of exercise vs. usual care on body composition and BMD in breast cancer survivors taking AIs. Given the efficacy of AIs and the large proportion of women diagnosed with breast cancer recommended to take AIs, it is important to have interventions available to improve AI side effects as well as quality of life and all-cause mortality. Thus, we sought to examine the effect of a 12-month combined aerobic and resistance exercise intervention vs. usual care on changes in BMI, % body fat, LBM and BMD in postmenopausal breast cancer survivors taking AIs.

METHODS

The Hormones and Physical Exercise (HOPE) study was a randomized control trial of exercise vs. usual care on the primary endpoint of AI-associated arthralgia, and the secondary endpoint of body composition(25). The study protocol was approved by the Yale School of Medicine Human Investigation Committee and the Connecticut Department of Health Human Investigation Committee. All participants provided written informed consent. Breast cancer survivors were recruited via a field arm of the Connecticut Tumor Registry, the Rapid Case Ascertainment Shared Resource (RCA) of the Yale Cancer Center from June 2010 to December 2012.

Participants were 121 postmenopausal women within 0.5–4.0 years of diagnosis of hormone receptor positive stage I to III breast cancer who were taking an AI for at least six months prior to enrollment. Inclusion criteria required participating in less than 90 minutes of physical activity per week in the past six months and no strength training in the past year. Additionally, participants had to be experiencing at least mild arthralgias (as defined by a score of 3 out of 10 on the worst pain item of the Brief Pain Inventory) for at least two months prior to enrollment.

Exercise Intervention

Participants who were assigned to the yearlong exercise intervention participated in a twice-weekly supervised resistance training program at a local health club and were instructed to complete 150 minutes of moderate-intensity aerobic at home. The strength training was performed under the supervision of an American College of Sports Medicine certified cancer exercise trainer and the 150 minutes per week aerobic exercise program is in accordance with current exercise recommendations for cancer survivors. (26) The aerobic exercise intervention consisted primarily of brisk walking (on a treadmill or outside), although participants were able to perform other types of sustained aerobic exercise such as cycle ergometers and elliptical trainers. Exercise started at 50% of predicted maximal heart rate (220-age) and was gradually increased in accordance with American College of Sports Medicine guidelines to approximately 60–80% of predicted maximal heart rate and was verified by heart rate monitors (Polar Electro, Woodbury, NY). After each exercise session, participants recorded type, duration, and average heart rate in physical activity logs which served as a measure of exercise adherence. The strength training program was a total body program for the lower and upper extremities. Each strength training session consisted of three sets of 8–12 repetitions of six exercises (e.g. leg press, leg extension, leg curl, bench press and seated row) using a linear progressive approach. Participants progressed up to three sets per exercise over the first four weeks of training. If the participant performed two sessions in which the same weight could be performed 12 times, the weight was then increased in the next training session.

Usual Care Group

Women in the usual care group were instructed to continue with their usual activities. Participants in both groups were provided with a breast cancer specific educational booklet developed for the HOPE study, which discussed such topics as lymphedema and fatigue. This booklet was individually discussed during the exercise training for the exercise group and in a monthly phone call for the usual care group.

Assessment of Study Endpoints and Covariates

An interviewer-administered questionnaire was completed at baseline to collect relevant medical history as well as current medication usage, health habits and comorbidities. Additional information on disease stage, hormone-receptor status, histological grade, therapy and completion date, and surgery was provided by all participants at baseline. Information on recurrence of breast cancer and treatment were collected at 6 and 12 months and confirmed by the participant’s physician and review of medical records. Participants recorded their daily aromatase inhibitor use in a log that was reviewed monthly with study staff by phone or in person. Participants also completed an interview-administered physical activity questionnaire, which assessed the past 6 months of recreational activity including the type, frequency, and duration of activities (27). This questionnaire was completed at baseline, 6 and 12 months to determine between groups physical activity levels. Aerobic fitness was evaluated at baseline and 12 months using standard VO2 maximum testing(28).

A dual x-ray absorptiometry (DXA) scan was obtained at baseline and 12 months for the assessment of whole body fat, lean tissue and BMD using a QDR 4500W (Hologic 4500 with a “Discovery” upgrade, Hologic Inc, Waltham, Mass) with daily calibration. Body weight was measured on an electronic scale and recorded to the nearest 0.1 kg and height was measured with a standard standiometer, rounding up to the nearest 0.5cm. Body weight and standing height were measured at baseline, 6 and 12 months without shoes and taken twice and averaged.

Sample Size

Sample size was estimated at the design stage to detect a difference in the primary end point arthralgia. We powered our study with 60 patients per group to detect a difference of standard deviation (SD) of 1.5 (SD, 2.5) in the Brief Pain Inventory worst pain change score with 90% power at a two-sided significance level of. 05 based on results of the study by Hershman and colleagues (24).

Statistical Analyses

Participants were grouped according to the intention-to-treat principle. Permuted block randomization (at 1:1 ratio) with random block size was performed, stratified by current bisphosphonate use and joint pain before AI therapy. Intervention effects were evaluated by differences in mean changes at follow-up time points between exercise and usual-care groups using mixed–model repeated measures analysis. Group-by time interaction was also included as a fixed effect. Analyses were performed using SAS software (version 9.3; SAS Institute, Cary, NC). Statistical significance was set at P <.05 using two-sided tests.

RESULTS

As described previously (25), a total of 1,537 estrogen receptor–positive breast cancer survivors were identified through the Rapid Case Ascertainment Shared Resource of the Yale Cancer Center. Screening telephone calls were completed with 1,016 women (66% of patients with estrogen receptor-positive breast cancer treated at five Connecticut hospitals). From 1016 screening calls made, 121 (11.9%) women were eligible, interested, and randomized (Figure 1).

Figure 1.

Figure 1

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Consolidated Standards of Reporting Trials (CONSORT) Diagram: Flow of participants through Hormones and Physical Exercise (HOPE) study, June 2010–December 2012. AI, aromatase inhibitor; BPI, Brief Pain Index.

Baseline characteristics

On average women were 62.0 ± 7.0 years old, 2.7 ± 3.1 years from cancer diagnosis and had been taking an AI for 1.9 ± 1.3 years (Table 1). Women were also physically inactive and overweight with an average BMI of 29.0 ± 5.9 (Table 2). The two groups did not differ in terms of demographics, clinical, or body composition variables or age since menopause.

Table 1.

Baseline characteristics by randomization groupa

Exercise
N=61		 Usual Care
N=60
Age (years) 62.0 (7.0) 60.5 (7.0)
Ethnicity
  Non-Hispanic White 85% 84%
  Hispanic 2% 5%
  African-American 10% 7%
  Asian/Pacific Islander 2% 2%
  American Indian 0% 2%
Education
  High school graduate 10% 15%
  Some school after high school 33% 42%
  College graduate + 57% 43%
Time since diagnosis (years) 2.7 (3.1) 3.3 (3.9)
Time since initiating AI therapy (years) 1.9 (2.9) 1.8 (1.3)
Disease stage (%)
  Stage I 56% 53%
  Stage II 28% 30%
  Stage III 10% 7%
  Don’t Know 6% 10%
Chemotherapy
  Yes 54% 43%
  No 46% 57%
Radiation
  Yes 82% 75%
  No 18% 25%
Physical Activity (minutes per week) 54.8 (93.0) 60.7 (99.0)
VO2 Max (mL/kg/min) 23.0 (5.3) 23.1(3.5)
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a

Values are mean ± SD or N (%); no statistically significant baseline differences between groups

Table 2.

Baseline body composition characteristics by randomization groupa

Exercise N=61 Usual Care
N=60		 P value
Weight (kg) 78.4 (18.0) 75.9 (14.8) 0.40
BMI (kg/m2) 30.0 (6.8) 28.7 (5.5) 0.27
Fat Mass (kg)b 32.6 (10.8) 32.7 (9.5) 0.95
Lean Mass (kg)b 43.6 (7.8) 42.2 (5.8) 0.25
Percent Body Fat (%)b 40.8 (6.3) 40.7 (6.3) 0.90
BMD (g/cm2)b 1.137 (0.114) 1.115 (0.116) 0.31
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a

Values are mean ± SD

b

DXA Measures

Change in physical activity levels and adherence to the exercise intervention

At baseline, both the exercise group and the usual care group had low levels of physical activity. Specifically, the exercise group averaged 54.8 minutes per week (36.5% of the recommended 150 minutes per week) and the usual care group averaged 60.7 minutes per week (40.5% of the recommended 150 minutes per week). Over the course of the intervention, women assigned to the exercise intervention increased their physical activity to an average 159 ± 136 min/week, compared with 49 ± 86 min/week in the usual-care group (P < .001). Additionally, their aerobic fitness as measured by V02 max increased by 6.5% ± 3.7% in women randomized to exercise versus a 1.8% ± 11.2% decrease in women randomized to usual care (P < .001).

Changes in body composition by randomized group

Table 3 shows mean changes in body composition variables at twelve months for both groups. At twelve months, the exercise group had a significant increase in LBM compared to the usual care group (0.32 kg vs −0.88 kg, p=.03). The exercise group also had favorable changes in percent body fat at 12 months, with a reduction of 1.4%, as opposed to an increase in the usual care group of 0.5% (p=0.03). Additionally, exercisers had a decrease in BMI at 12 months as opposed to the usual care group who had an increase in BMI (−0.73 kg/m2 vs 0.17kg/m2, p=0.03). BMD did not change in either the exercise or usual care groups at twelve months (0.001 g/cm2 vs. −0.006 g/cm2, p=0.37). However, in post-hoc analyses, bisphosphonate use (N=20; Exercise =11, Usual Care =9) modified the effect of exercise on BMD such that in women on bisphosphonates randomized to exercise experienced an increase in BMD compared to women randomized to usual care (0.03 g/cm2 vs 0.01 g/cm2, p=0.09). BMD changes in women not taking bisphosphonates did not differ by randomization in those women in the exercise or usual care groups (−0.01 g/cm2 vs. −0.01 g/cm2, p=0.76).

Table 3.

Twelve-month effect of exercise on body composition by randomization group.

Exercise N=60 Usual Care N= 61
Change
from
Baseline		 95% CI Change
from
Baseline		 95% CI P
value
Weight (kg) −1.8 (−3.3 to −0.39) −0.32 (−1.9 to 1.24) 0.16
BMI (kg/m2) −0.73 (−1.3 to −0.17) 0.17 (−0.44 to
0.77)		 0.03
Fat Mass
(kg)		 −2.7 (−4.4 to −1.1) −1.5 (−3.5 to 0.49) 0.37
Lean Mass
(kg)		 0.32 (−0.43 to 1.07) −0.88 (−1.7 to −0.07) 0.03
Percent
Body Fat
(%)		 −1.4 (−2.5 to −0.25) 0.48 (−0.74 to
1.71)		 0.03
BMD
(g/cm2)		 0.001 (−0.009 to
0.010)		 −0.006 (−0.017 to
0.004)		 0.37
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Effect of Exercise Versus Usual Care on BPI-Assessed Pain at Baseline and 12 Months

As previously described (28), the BPI-assessed worst joint pain scores averaged 5.6 (SD 2.1) for exercisers and 5.9 (SD1.9) those in the usual care condition at baseline. At 12 months, BPI scores decreased by 1.6 points in the exercise group (a 29% decrease), whereas the usual care group experienced an increase of 0.2 points (a 3% increase).

DISCUSSION

In our study, 12 months of a combined aerobic plus resistance exercise intervention was associated with a decrease in percent body fat and BMI and an increase in LBM in postmenopausal breast cancer survivors taking an AI. These favorable changes in body composition may be particularly helpful for women with obesity taking AIs. It has been reported that AIs may be less effective in women with a BMI > 30 kg/m2, which may be due to altered endocrine function in adipose tissue as well as comorbidities common to obesity(29). It is also well documented that over two-thirds of breast cancer survivors are overweight or have obesity (2–4), and few participate in recommended amounts of exercise(4). Current guidelines advise overweight women to avoid gaining weight and women with obesity to lose weight after treatment to improve breast cancer outcomes(26). Therefore, reducing BMI and percent body fat while maintaining or increasing lean body mass may have strong clinical benefits.

It is important to note that the usual care group demonstrated evidence of the expected age-related decline in LBM. Dietary-induced weight loss is often associated with loss of LBM (30), but we found exercise to be associated with weight and percent body fat loss, yet a favorable increase in LBM. However, neither the exercise nor usual care groups experienced changes in BMD over 12 months. The women enrolled in the HOPE study were taking an AI for an average of 1.9 years, thus, AI-associated changes in BMD may have occurred prior to enrollment into the HOPE Study. However, it is interesting to note that those women taking bisphosphonates and exercising had a trend towards an increase in BMD, a change which could have been enhanced by exercise. Future studies need to examine the impact of exercise vs. usual care on changes in BMD upon initiation of AI therapy, and whether and what type of exercise can be considered a treatment for AI-induced BMD losses.

Our findings support the effectiveness of a combined exercise intervention for promoting beneficial body composition changes in post-menopausal women with breast cancer who are taking AIs. Given the high levels of obesity and inactivity in breast cancer survivors this could be a particularly relevant finding (3–5) as they could be at significant risk for additional chronic disease and cancer mortality. These findings are consistent with findings that combined exercise interventions promote changes in adiposity across clinical groups. A recent meta-analysis examining different exercise interventions on anthropometric outcomes in participants with a BMI ≥ 25 kg/m2 found that combined training was most effective in reducing fat mass and raising LBM, as compared with aerobic exercise only(31,32). Additionally, performing resistance training twice a week for a six month period can increase LBM by 1–2 kg, a change which may prevent or reverse age associated lean mass losses (33). Previous investigations have demonstrated that intentional weight loss due to exercise is often associated with a loss of fat mass (34) and unchanged or increased lean mass.(35,36) In the HOPE study, BMI and percent body fat was reduced while lean mass was increased in postmenopausal breast cancer survivors.

Study limitations include that we only measured total BMD. Additionally, five participants had to discontinue used of aromatase inhibitors over the course of the intervention due to joint pain (2), length of time on an AI (1), gastric distress (1), and belief that cognition was being affected (1). Our study may also have issues with generalizability to other study populations, as participants were predominantly non-Hispanic white and highly educated.

There are several strengths to this study including a randomized study design, yearlong trial, and focus on body composition changes in women at risk of adverse changes in body composition, i.e., women taking AIs. In postmenopausal women combined aerobic and resistance exercise has been shown to promote increased BMD in the lumbar spine, femoral neck and femoral neck.(37) Future research is necessary to better understand the impact of AIs on body composition and if exercise can prevent any potential adverse body composition changes due to AI therapy. Follow-up is also necessary to determine the long-term benefits of these body composition improvements on chronic disease risk and cancer recurrence. Research that enrolls women at AI initiation may enhance the impact of exercise on beneficial changes in BMD and body composition.

What is already known

  • -

    65% of breast cancer survivors are overweight or have obesity and are highly sedentary

  • -

    obesity and sedentary lifestyle are associated with poorer outcomes in breast cancer survivors

  • -

    aromatase inhibitors are the current standard of care for hormone receptor positive breast cancer survivors (80%) and can negatively affect bone mineral density and body composition

What this paper adds

  • -

    No prior studies have examined whether a combined resistance and aerobic exercise intervention can reduce the detrimental effects on body composition in breast cancer survivors takings AIs. This is particularly important given the associations between obesity and breast cancer recurrence.

  • -

    a combined resistance and aerobic exercise intervention promoted beneficial body composition changes in post-menopausal women with breast cancer taking aromatase inhibitors

  • -

    a combined exercise intervention reduced BMI and percent body fat, while increasing lean mass which could promote changes that could be beneficial in preventing further chronic disease and cancer recurrence in this at risk population.

Acknowledgments

FUNDING: This research was supported by National Cancer Institute Grant No. R01 CA132931 and in part by a grant from the Breast Cancer Research Foundation (M.L.I.), Yale Cancer Center Support Grant No. P30 CA016359, and Clinical and Translational Science Award Grant No. UL1 TR000142 from the National Center for Advancing Translational Science, a component of the National Institutes of Health. Certain data used in this study were obtained from the Connecticut Tumor Registry, located in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data

Cary P. Gross declares research funding from 21st century oncology, Pfizer, Johnson & Johnson and Medtronic.

Footnotes

CLINICAL TRIALS REGISTRATION: clinicaltrials.gov: NCT02056067

DISCLOSURE: All other authors none reported.

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