|Home | About | Journals | Submit | Contact Us | Français|
Targeted exercise training could reduce risk factors for fracture and obesity-related diseases that increase from breast cancer treatment, but has not been sufficiently tested. We hypothesized that progressive, moderate-intensity resistance + impact training would increase or maintain hip and spine bone mass, lean mass and fat mass and reduce bone turnover compared to controls who participated in a low-intensity, non-weight bearing stretching program. We conducted a randomized, controlled trial in 106 women with early stage breast cancer who were >1 year post-radiation and/or chemotherapy, ≥50 years of age at diagnosis and postmenopausal, free from osteoporosis and medications for bone loss, resistance and impact exercise naïve, and cleared to exercise by a physician. Women were randomly assigned to participate in 1 year of thrice-weekly progressive, moderate-intensity resistance + impact (jump) exercise or in a similar frequency and length control program of progressive, low-intensity stretching. Primary endpoints were bone mineral density (BMD; g/cm2) of the hip and spine and whole body bone-free lean and fat mass (kg) determined by DXA and biomarkers of bone turnover—serum osteocalcin (ng/ml) and urinary deoxypyrodiniline cross-links (nmol/mmolCr). Women in the resistance + impact training program preserved BMD at the lumbar spine (0.47 vs. −2.13%; P = 0.001) compared to controls. The resistance + impact group had a smaller increase in osteocalcin (7.0 vs. 27%, P = 0.03) and a larger decrease in deoxypyrodinoline (−49.9 vs. −32.6%, P = 0.06) than controls. Increases in lean mass from resistance + impact training were greatest among women currently taking aromatase inhibitors compared to controls not on this therapy (P = 0.01). Our combined program of resistance + impact exercise reduced risk factors for fracture among postmenopausal breast cancer survivors (BCS) and may be particularly relevant for BCS on aromatase inhibitors (AIs) because of the additional benefit of exercise on muscle mass that could reduce falls.
There are approximately 2.5 million breast cancer survivors (BCS) in the U.S. . Compared to their cancer-free peers, BCS are at higher risk of fracture [2, 3]. Prior to their cancer diagnosis and treatment, BCS are no more likely to fracture than other women; however, systemic treatment increases fracture risk . Chemotherapy, chemotherapy-induced menopause, and aromatase inhibitor (AI) treatment accelerate bone loss and bone turnover [5–10]. In addition, inactivity related to cancer treatment can weaken the skeleton [11, 12] cause muscle loss and lead to fat gain [13–16]. These changes in body composition place BCS at higher risk of obesity-related disease  breast cancer recurrence , frailty , and fractures . There is no pharmacologic strategy to concomitantly improve all three components of body composition affected by breast cancer treatment. Further, current clinical guidelines do not endorse routine use of bisphosphonates for BCS with low bone mass (e.g., osteopenia), but rather recommend lifestyle advice to prevent bone further bone loss .
Exercise improves all three components of body composition in women without a cancer diagnosis; but it is not clear if exercise has the same effects in BCS [21, 22]. A combination of resistance plus impact training is specifically suited to reverse or slow age-related declines in bone and muscle mass and can also reduce body fat [23–26] but, the combined intervention has not been evaluated in BCS . We conducted a randomized controlled trial in postmenopausal BCS comparing a 12-month resistance + impact exercise training program to a 12-month control condition of flexibility (stretching) sessions. We hypothesized that moderate-intensity resistance + impact exercise would increase muscle and bone mass, reduce fat mass, and lower bone turnover compared to flexibility exercise that places little stress on the musculoskeletal and metabolic systems. Our study targeted non-osteoporotic women who were at increased risk for bone loss due to age and cancer treatment  and for whom few evidence-based, non-pharmacologic strategies currently exist .
We conducted a 12-month single-blind randomized controlled trial comparing two parallel groups receiving progressive, supervised exercise: (1) moderate-intensity resistance + impact training (experimental) and (2) flexibility training (control). Primary outcomes were measured at baseline, 6 and 12 months. All testing and exercise training took place at Oregon Health & Science University (OHSU) between October 2006 and January 2009. The study was approved by the OHSU Institutional Review Board.
Women were recruited through the Oregon State Cancer Registry, clinician referral, community events, study advertisements, and information sessions. Interested women were screened to determine if they met the following eligibility criteria: diagnosis of stage 0–3a breast cancer at or after age 50, postmenopausal, ≥1 year post-chemotherapy or radiotherapy, non-osteoporotic, no bone altering medication other than adjuvant hormone therapy, physician clearance to exercise and, no regular participation in resistance and/or impact exercise (less than two 30-min sessions per week) in the past month, physical and cognitive ability to complete study testing.
The PASS 2000 program  was used to conduct the power analysis based on a 2 × 3 mixed-design analysis of variance using initial and change values for primary outcome measures from our prior work . At n = 35 per group, we had power of 0.81 to 0.99 to detect a significant group by time interaction for bone, lean and fat mass measures at α < 0.01. To protect against 20% attrition [29, 30] we planned to randomize at least 44 participants per group.
Participants in both groups were prescribed an exercise program consisting of two supervised classes and one home-based session per week for 12 months. Each exercise session lasted 45–60 min. Certified exercise instructors were trained and supervised by the research team to deliver the exercise protocols. Session completion was tracked in training logs for both class and home programs. Home programs began after 1 month of supervised classes to provide time to learn proper form and safety before exercising at home. Women followed a written manual that outlined each week’s exercise program.
The resistance plus impact intervention (POWIR: Prevent Osteoporosis With Impact + Resistance) used in this study was based on our prior interventions in women without cancer [31, 32]. POWIR complied with the American College of Sports Medicine (ACSM) recommendations for preserving bone health in postmenopausal women by using resistance and/or impact exercise at moderate to high bone loading forces [23, 33] and with ACSM recommendations for resistance training at loads corresponding to 60–70% of 1-RM for 1–3 sets of 8–12 repetitions to build lean mass and strength in novice weightlifters and older adults [34, 35]. Free weights were used to apply resistance—dumbbells for upper body, weighted vests for lower body, and a barbell for one combined upper + lower body exercise. Initial intensity and progression were based on our previous studies  (Table 1). Selected exercises utilized musculature with attachments directly on the skeletal sites of interest [31, 36] and included wall-sits, 90° squats, bent-knee dead lifts, forward lunges, lateral lunges, 1-arm row, chest press, lateral raise, and push-ups. Impact exercise consisted of two-footed jumps from the ground to a target height 1″ from the floor with a bent-knee landing, performed with weighted vests on and in sets of 10. During a single exercise session participants warmed up, performed 1–6 jump sets, 1–2 sets of 3–4 upper body, and 3–4 lower body exercises, then cooled down. At home the same exercises that were performed in class were done except the deadlift, resistance bands replaced free weights for upper-body exercises, and lower body exercises were performed without weighted vests because of the inconvenience of transporting them. Training volume progressively increased by increasing band thickness, squat and lunge depth, and sets and repetitions.
Participants in the control group (FLEX) performed a series of whole body stretching and relaxation exercises in a seated or lying position. Selected exercises were chosen to minimize weight-bearing forces so that little stimulus to the musculoskeletal system was applied and energy expenditure was minimal.
Each woman had physician clearance to participate in either exercise program. Participants reported any training-related injury to the training team and in training logs. If necessary, adjustments in the training program were made on an individual basis and recorded. Any woman with serious or persistent symptoms was asked to refrain from exercise until her physician cleared her return to training. Women who were prescribed compression sleeves for lymphedema (n = 5) wore their sleeves during exercise training. To document any effect of the program on lymphedema we compared circumferences between arms measured at the base of the middle finger, wrist, and distal forearm at 0, 3, 6, and 12 months of training . Women reported symptoms of lymphedema to the trainer and in training logs.
At baseline, written informed consent was obtained followed by completion of questionnaires, body composition testing, and blood/urine collection. Providing biological specimens was offered as an optional part of the study. Tests followed standard operating procedures, were administered by trained technicians blinded to group assignment, and were repeated at 6 and 12 months. Randomization was stratified by adjuvant hormone therapy use (AI or SERM vs. none) and current aerobic activity (≥90 vs. <90 min/week). Group assignments were placed in sealed, sequentially numbered envelopes and opened by the participant following the completion of baseline testing.
Bone mineral density (g/cm2) of the proximal femur (total hip, greater trochanter, femoral neck) and anterior–posterior lumbar spine (L1–L4), bone-free lean mass (kg), and fat mass (kg) were assessed by dual energy X-ray absorptiometry (DXA; Hologic QDR Discovery Wi; software version 12.0). DXA scans were performed by licensed technicians blinded to participant group and were analyzed by the same technician. Coefficients of variation for DXA measures in our laboratory are 1–1.5% .
Bone turnover was assessed by serum osteocalcin (ng/ml), a byproduct of bone formation and urinary deoxypyrodinoline cross-links (nmol/l), a byproduct of bone degradation adjusted for urine volume (creatinine: mmol/l). Blood and urine samples were collected in the morning after 12-h fast and stored at −70°C for analysis. Analyses were conducted in batch by ELISA with commercial kits (Diagnostic Systems Laboratory, Inc). Inter-assay CVs from our laboratory are 5.7 and 6.2% and intra-assay CVs are 8 and 4.8% for deoxypyridinoline and osteocalcin, respectively.
Demographic and clinical history was obtained by self-report. Medication use was updated at 6 and 12-month visits. Chronic medical conditions were assessed by the Charlson Comorbidity Index . Menopausal status of participants in each group was confirmed by FSH >30 mIU/ml and estradiol <20 pg/ml based on radioimmunoassay of baseline samples. To account for changes in physical activity and diet outside of the intervention that could affect primary outcomes, we measured habitual physical activity with the Community Health Activity Model Program for Seniors (CHAMPS) physical activity questionnaire for older adults  (kcal/day in all activities) and habitual calcium (dietary + supplemental) and total energy intake with the 2005 Block Food Frequency Questionnaire at each visit .
To characterize the sample, we computed means and standard deviations for continuous variables and frequencies and percentages for categorical variables. Separate one-way ANOVAs were conducted to check the validity of randomization and identify covariates. To account for the potential influence of age, time since diagnosis, and adjuvant hormone therapy on changes in outcome variables over time, these variables were included as covariates in all analyses. The intent-to-treat (ITT) analysis was performed using Hierarchical Linear Modeling (HLM; HLM 6.08 software)  analyzing each participant according to her originally assigned group and regardless of missing 6 or 12-month data. HLM is superior to other approaches to handling missing data, such as mean imputation or last observation carried forward [42, 43]. In addition to ITT analysis, data from participants with complete baseline and 12-month data were considered to evaluate intervention effects in participants who completed the study using separate 2 (group) × 3 (time) mixed-design analysis of covariance (MD-ANCOVA) for each outcome. To examine the influence of adjuvant hormone therapy use on the impact of the intervention on primary outcomes, HLM was repeated to examine effect modification. Significant interactions were graphed and interpreted to determine the nature of the effect moderation.
In response to recruitment efforts 359 women showed interest in the study. Of these, 106 women enrolled in the trial and were randomized to POWIR (n = 52) or FLEX (n = 54). Eighty-eight participants consented for biological specimen collection. Participant flow is outlined in Fig. 1. Women who withdrew from the program did not differ from those who remained in the study on any baseline characteristic or outcome. Participants were older (>60 years), had high BMI, normal skeletal health (T score ≥ −1.0) and an additional chronic condition other than cancer (Table 2). Most women had stage I or II breast cancer and varied in their time since breast cancer diagnosis (SD = 3.1 years). Nearly all participants received radiation therapy, about 60% also received chemotherapy and about half were currently taking adjuvant hormone therapy—mostly AIs. Women consumed slightly less than the RDI for calcium, most likely related to their modest self-report caloric intake, and were active (Table 3). Intervention groups were not different at baseline. Energy intake and calcium intake did not change over time for either group and were not included as covariates in subsequent analyses (Table 3). Ten women changed their adjuvant hormone therapy regimen during the 1-year intervention, either discontinuing AIs (n = 4) or SERMs (n = 4) altogether or switching from a SERM to an AI (n = 2). The distribution of women changing therapy was equal between study groups. Removing these women from analyses did not alter statistical outcomes.
Total, supervised-only and home-only attendance averaged 57, 76, and 23% for POWIR and 62, 72, and 44% for FLEX groups. Attendance to home sessions was significantly better in FLEX than POWIR, t(64) = 3.60, P < 0.01. Final intensity for lower body resistance exercises was just shy of the planned progression, stopping at 13% of body weight in weighted vests and 10–12 RM for upper body exercises by month 9. There were no injuries or adverse events associated with participation in either intervention and no significant change in upper-extremity circumference measures over time (data not shown).
Using the ITT approach, there were significant differences over time between POWIR and FLEX groups for lumbar spine BMD (Coefficient on slope of time = 0.013, SE = 0.004, t(99) = 3.64, P < 0.01). Based on observed values from participants with complete data sets, BMD at the spine was preserved in the POWIR group compared to a 2% loss in controls (Table 3). There were no significant group differences over time at any hip site. Over time, BMD was maintained at both skeletal sites compared with consistent declines in BMD at each 6-month interval (Fig. 2). Changes in serum osteocalcin over time differed by group (Coefficient on slope of time = −1.07, SE = 0.49, t(83) = 2.17, P = 0.03) and a trend was apparent for deoxypyridinoline (Coefficient on slope of time = −0.10, SE = 0.05, t(84) = 1.92, P = 0.06). Osteocalcin increased in FLEX but remained steady in POWIR, while deoxypyridinoline cross-links decreased more in POWIR than FLEX (Table 3). In per protocol analyses, significance was maintained for both lumbar spine BMD and osteocalcin (Table 3), with significant linear trends (P < 0.01).
Changes in whole body fat mass and % body fat did not differ between groups. Lean mass increased in the POWIR group to a greater extent among women currently taking AIs than POWIR participants not on AI treatment, whereas lean mass did not change appreciably among FLEX regardless of AI use (Coefficient of group by AI vector on slope of time = 922.50, SE = 367.98, t(95) = −2.51, P = 0.01 see Fig. 3). There was no effect modification of AI use on bone or fat measures or of SERM use on any primary outcome.
In contrast to BCS who participated in stretching exercise and consistently lost BMD at the lumbar spine over 1 year, women who participated in a program of combined resistance + impact training (e.g., POWIR) maintained BMD at this site. In addition to BMD, the POWIR program caused more favorable changes in bone turnover, resembling that achieved by anti-resorptive therapy . POWIR did not improve lean or fat mass; however, moderator analysis detected differences between groups that depended upon adjuvant hormone therapy use. That is, women who were in the POWIR group and on AIs had the greatest increase in lean mass, while women in the FLEX group who were not on AIs appeared to have a slight decrease in lean mass.
The efficacy of our resistance + impact exercise program to prevent declines in BMD at the spine is consistent with the results from our previous trial in premenopausal women without cancer . We are the first to report that exercise can preserve bone mass at the lumbar spine, a clinically relevant fracture site in BCS, though we failed to achieve similar results at the hip. Programs at our achieved training volume have increased hip BMD in premenopausal women when performed 3–5 times per week [31, 45], but the postmenopausal hip may require a greater load to adapt . Combined programs of impact plus resistance training better target the spine than the hip in postmenopausal women without cancer . Studies with conservative jump training programs have not improved hip BMD in cancer-free older women [45, 46], whereas those employing atypical loading , more jumps or more intense resistance exercise were effective [48, 49]. The lower intensity of home exercises, lower adherence to the home program and modest jump number in our study may have contributed to an overall suboptimal stimulus at the hip. The hip may also simply require a longer time period to adapt to moderate-intensity training in older women. Snow et al.  reported that a similar exercise program to ours did not affect hip BMD after 9 months, but was later found to have preserved BMD at a 5-year follow-up in women continuing to exercise compared to losses among inactive women. Future studies should consider longer training programs, inclusion of exercises that load the hip in unusual patterns, greater jump number, increased frequency of supervised sessions and/or strategies to maintain training intensity at home.
The POWIR program did not favorably shift body composition; however, our results suggest that current AI use influences changes in body composition in response to resistance training. The ability of exercise of any type to improve body composition in BCS of any age is unclear since results from RCTs tend to be mixed . Schmitz et al.  reported significant gains in lean body mass among recently treated BCS who strength trained for 6 months, but did not replicate these findings among BCS with or at risk for lymphedema, who also notably did not use AIs [51, 52]. In our study, we found greater between group differences in lean body mass over 1 year among AI users that suggest a potentiating influence of AIs on training-induced hypertrophy. Recently, AI use has been shown to increase free testosterone and lean mass in BCS without concomitant changes in % body fat . Kenney et al.  reported preservation of lean mass with a combination of dihydroepiandrostenedione supplementation plus exercise in frail older women compared to losses in controls. A possible synergistic effect of AIs and resistance training on lean mass in BCS is an intriguing finding that is worth further study.
The strengths of our study are the translation of a targeted bone loading program shown effective in non-clinical populations to improve BMD in cancer survivors, our study of older BCS who are rarely the focus of exercise trials, and exclusion of bisphosphonate use to reduce confounding. Notable limitations of our study include a lack of a usual care control group, inclusion of aerobically active women, and modest attrition. Given the known benefits of physical activity we felt it would be unethical to assign women to a non-exercise control group. We selected an exercise type, e.g., stretching, that was the least likely to produce an osteogenic stimulus to bone and expend energy, but that could produce benefits for range of motion and well being. The 12-month changes in controls were minimal or followed age-expected trends and so we felt the flexibility program was appropriate. We did not exclude women who were aerobically active from participating because impact and resistance exercise load the skeleton in distinctly different ways than aerobic exercise and are superior for osteogenesis [36, 55]. However, aerobically active participants may have replaced their habitual activity with the intervention program causing no net change in energy expenditure or body fat (Table 3). Retention in the study was modest (62%) and this may have affected the ability of the program to shift lean and fat mass and bone mass at the hip, leaving us potentially underpowered for these variables. However, we fell only three participants short of the estimated sample size for the per protocol analysis, and we did not have any borderline P values where an inadequate sample size might bring into question whether or not we were underpowered to detect significance. Exercise studies that include a BMD outcome should ideally last a year or longer to allow for completion of bone remodeling cycles , but the tradeoff to longer programs is risk of attrition and waning adherence over time. Only three randomized, controlled trials with center-based training programs in BCS have lasted for 1 year and all reported lower attrition [51, 56, 57]; however, ours was the only study specific to older women and that required women to attend scheduled group exercise classes. Most women cited logistical issues for dropping out (Fig. 1), which we largely attribute to the constrained schedule, unusual class times, inconvenient parking and travel to the facility. Clearly, we need to better understand the conditions that will yield optimal adherence to resistance training in older in BCS to promote this program in clinical practice. Adherence among women who stayed in the program was comparable to the other center-based trials [51, 56, 57]. Even with drop out, retention in our study is better than that reported for bisphosphonate use with approximately 50% of patients who are prescribed this medication discontinuing use within 6–12 months .
Our program was able to preserve bone mass at the spine and lower bone turnover rates, both factors that translate to reductions in fracture risk. Fracture risk at the spine and hip increases 26 and 55% after breast cancer diagnosis, respectively , and both fracture types are associated with excess mortality and morbidity [59, 60]. Fractures in BCS add to the economic and personal costs that already result from treatment aimed to eradicate disease, particularly for older women [61, 62]. Our POWIR program was able to preserve bone and slow turnover and each could contribute to lower fracture risk at the spine. A 1–2% increase in BMD translates to a 7–14% decrease in fracture risk  and slowing of bone turnover can lower fracture risk at the hip and spine independent of BMD . It was encouraging that the training effect on spine BMD and turnover were independent of adjuvant hormone therapy use so that women on bone-depleting AIs still benefited from exercise. Whether exercise can offer a lifestyle strategy to reduce hip fracture risk by preserving bone mass at the hip in BCS remains unclear.
Supported by Susan G. Komen for the Cure and the National Cancer Institute (1R01 CA120123, to Dr. Winters-Stone) and with partial support from the Oregon Clinical and Translational Research Institute (OCTRI), Grant number UL1 RR024140 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. We thank the Oregon State Cancer Registry for their assistance with recruitment efforts for the study. Theraband provided elastic bands for home exercise programs. We thank Ms. Ann Reiner for helping to manage the study and Mr. Nathan Brooks, Ms. Camella Potter, and Mr. Anton Stupnitskiy for their assistance with data collection. We also thank Ms. Janice Hoffman, Ms. Laurie Iverson, and Ms. Lisa Domenico for their assistance with exercise training.
Kerri M. Winters-Stone, School of Nursing, Oregon Health & Science University, 3455 SW US Veteran’s Hospital Rd., Mailcode: SN-ORD, Portland, OR 97239, USA.
Jessica Dobek, School of Nursing, Oregon Health & Science University, 3455 SW US Veteran’s Hospital Rd., Mailcode: SN-ORD, Portland, OR 97239, USA.
Lillian Nail, School of Nursing, Oregon Health & Science University, 3455 SW US Veteran’s Hospital Rd., Mailcode: SN-ORD, Portland, OR 97239, USA.
Jill A. Bennett, School of Nursing, Oregon Health & Science University, 3455 SW US Veteran’s Hospital Rd., Mailcode: SN-ORD, Portland, OR 97239, USA.
Michael C. Leo, School of Nursing, Oregon Health & Science University, 3455 SW US Veteran’s Hospital Rd., Mailcode: SN-ORD, Portland, OR 97239, USA.
Arpana Naik, School of Medicine, Oregon Health & Science University, Portland, OR, USA.
Anna Schwartz, School of Nursing, University of Washington, Seattle, WA, USA.