| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Departments of Medicine (S.L.G., A.B., V.G.V.), Epidemiology (S.M.S., V.G.V.), Health and Community Systems (S.M.S.), and Biostatistics (S.M.S.) and Magee Women’s Hospital/University of Pittsburgh Breast Program (V.G.V., A.B.), University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and Department of Medicine (R.K.B.), University of Kansas, Kansas City, Kansas 66160
Address all correspondence and requests for reprints to: Susan L. Greenspan, M.D., Professor of Medicine, University of Pittsburgh, 3471 Fifth Avenue, Suite 1110, Pittsburgh, Pennsylvania 15213-3221. E-mail: greenspans{at}dom.pitt.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Objective: Our objective was to determine whether risedronate, 35 mg weekly, is efficacious and safe in preventing bone loss associated with chemotherapy-induced menopause.
Design: The study was a randomized, double-blind, placebo-controlled clinical trial over 12 months.
Setting and Participants: Participants included 87 newly postmenopausal women with status post chemotherapy, recruited from a breast cancer clinic in an academic medical center.
Intervention: Participants were randomly assigned to receive risedronate 35 mg/wk or placebo.
Main Outcome Measures: The primary outcomes were the 12-month changes in spine and hip bone mineral density. Secondary outcomes included changes in markers of bone resorption (urine N-telopeptide cross-linked collagen type I) and formation (osteocalcin, N-terminal propeptide of type I procollagen, and bone-specific alkaline phosphatase).
Results: After 12 months, bone mineral density increased by 1.2% at the spine and 1.3% at the hip in women on risedronate vs. significant decreases for women in the placebo group of 0.9% at the spine and 0.8% at the hip (P < 0.01, difference between groups). N-telopeptide cross-linked collagen type I, a marker of bone resorption, decreased by 19.3%, and N-terminal propeptide of type I procollagen, a marker of bone formation, decreased by 26.6% in participants on active therapy compared with increases in the control group. Risedronate was well tolerated, and the retention rate was 95% at 1 yr.
Conclusions: Risedronate once weekly prevented bone loss and reduced bone turnover in women with breast cancer treated with chemotherapy. Early measures to prevent bone loss should be considered in this cohort of breast cancer survivors.
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Previous studies have demonstrated bone loss and fractures in women with chemotherapy-induced early menopause for breast cancer (2, 3, 4, 5, 6, 7, 8). Shapiro et al. (7) reported a 7.7% decrease in bone mineral density (BMD) at the spine and a 4.6% decrease at the femoral neck in 35 women 1 yr after chemotherapy-induced ovarian failure. Bone loss was not found in the 14 patients who retained ovarian function. In an observational study, Chen et al. (8) reported a 15% increased rate of fractures in breast cancer survivors. Women diagnosed before age 55 had an increased relative risk of 1.78 for vertebral compression fractures (8).
There have been a limited number of studies that have examined prevention of chemotherapy-induced bone loss (9, 10, 11, 12, 13, 14). Investigators have treated patients with clodronate (oral or iv) or iv pamidronate with inconsistent efficacy on bone mass. Delmas et al. (9) reported that high-dose, cyclical risedronate, given in an unconventional manner, prevented both trabecular and cortical bone loss in women with menopause induced by chemotherapy for breast cancer. Untreated women experienced a decrease in lumbar spine, femoral neck, and trochanter BMD, regardless of concomitant tamoxifen administration. In the placebo group, the mean decrease in spine BMD was approximately 1.5% during the first year and 2.5% at the end of the second year. Bone density was maintained in the women receiving risedronate.
Few data are available on the prevention of bone loss with FDA-approved, once-weekly oral bisphosphonate therapy. Furthermore, there is a paucity of data elucidating the impact of concurrent use of tamoxifen, a bone-protective agent in postmenopausal women, or aromatase inhibitors (agents resulting in bone loss) with bisphosphonates in the prevention of chemotherapy-induced bone loss.
The Risedronate’s Effect on Bone Loss in Breast Cancer Study (ReBBeCa Study) was designed to test the hypothesis that risedronate, 35 mg once weekly, an oral antiresorptive agent, prevents bone loss or improves bone mass in newly postmenopausal women with breast cancer treated with chemotherapeutic agents with or without the concomitant use of tamoxifen or aromatase inhibitors.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
We screened women age 18 yr and older from the greater Pittsburgh area with breast cancer who were newly postmenopausal (up to 8 yr) after being treated with chemotherapy with or without tamoxifen or aromatase inhibitors. Women were consecutively screened from clinics or self-referred from breast cancer support groups and evaluated at an academic medical center. We excluded women with stage 4 breast cancer (presence of distant metastases), a history of any illness known to affect bone and mineral metabolism (renal failure or hepatic failure), malignancy (excluding breast cancer), hyperparathyroidism, and malabsorption. Women were allowed to begin or continue with tamoxifen or an aromatase inhibitor if prescribed by their physician. Participants who had been treated with other medications known to affect bone and mineral metabolism were excluded. Women with an adult fragility fracture or with an initial BMD T-score of –2.5 or below at the hip or spine were counseled about therapy but given the option to participate in the study. Eighty-seven women were eligible and randomized. The protocol was approved by the University of Pittsburgh Institutional Review Board. Participants were advised of the nature of the study and provided written informed consent before participation.
Study design
This study was a double-blind (double-masked), placebo-controlled, randomized clinical trial over 12 months with a 12-month extension. Participants were recruited from May 2003 to July 2004. This report presents the preplanned, primary analyses at 1 yr. Participants were randomly assigned with equal allocation to either active treatment once weekly or a matched placebo using permuted block randomization within strata based on the participant’s age (less than 52 yr old and 52 yr or older). Assignments were computer generated by the study statistician using permuted block randomization within strata using random block sizes of 2k (i.e. 2, 4, or 6). The randomization schedule was given to the research pharmacy service that prepared the study prescriptions, thus maintaining the blinding to both the patient and study staff/investigators. The primary outcome variable was change in posteroanterior (PA) spine BMD over 1 yr. Secondary endpoints included BMD at the lateral spine, hip, forearm, and total body. Additional outcome measures were biochemical markers of bone turnover assessed at baseline and 6 and 12 months.
All participants had an assessment of their dietary calcium intake using a validated questionnaire (15), and those with daily calcium intake less than 1200 mg received supplementary calcium with vitamin D in the form of calcium carbonate, 500 mg, with 200 IU vitamin D (Oscal Plus D; Glaxo SmithKline, Pittsburgh, PA). Participants were randomized to oral risedronate, 35 mg once weekly, or placebo. Adherence was assessed by pill count.
Outcome variables
BMD was measured at the spine (PA and lateral projections), hip (femoral neck, total hip, trochanter, and intertrochanter), one-third distal radius, and total body by dual-energy x-ray absorptiometry using a QDR-4500A bone densitometer (Hologic, Inc., Bedford, MA) at baseline and months 6 and 12. The coefficients of variation of BMD in adults using our densitometer are 1.3% for the PA spine and 1.4% for the total hip (16). To assess resorption, we measured a second morning urine for creatinine and urine N-telopeptide cross-linked collagen type I (NTX, nmol bone collagen equivalents/mmol creatinine) (Osteomark; Ostex International, Seattle, WA). Markers of formation included serum osteocalcin (ng/ml) (Novocalcin; Quidel Corp., Mountain View, CA), serum intact N-terminal propeptide of type I procollagen (PINP, ng/ml) (Orion Diagnostica, Inc., Espoo, Finland), and bone-specific alkaline phosphatase (bone ALP, U/liter) (Alkphase-B; Quidel). We also measured serum 25-hydroxyvitamin D by RIA (ng/ml) (Nichols Advantage; Nichols Institute Diagnostics, San Juan Capistrano, CA) and intact PTH (pg/ml) (Bayer Centaur PTH Immunoassays; Bayer, Tarrytown, NY).
Sample size
A priori, we specified that the study needed 90 subjects with 45 subjects randomized each to placebo and risedronate, 35 mg/wk. The sample size for this study was designed to have sufficient statistical power (
0.80) to test the primary hypothesis concerning the efficacy of risedronate, 35 mg, after 12 months of treatment relative to placebo, allowing for a 15% attrition rate.
Statistical analysis
When analyzing data, an intention-to-treat approach was used where all subjects were analyzed to the groups to which they were assigned via randomization. An exploratory analysis was conducted initially to identify data anomalies (e.g. outliers and missing data) and to evaluate whether underlying statistical assumptions would be reasonably satisfied. Descriptive statistics were computed to characterize the two treatment groups of subjects (placebo and risedronate) using measures of central tendency and dispersion considering the level of measurement and the empirical distribution of the variable. Continuous baseline descriptive variables were reported as mean ± SD for the total sample and by group, whereas categorical descriptors were reported as frequency counts and percentages for the total sample and by group. To assess for group differences on continuous-type baseline subject characteristics and outcomes, Student’s t tests (or the separate variance t test if group variances are unequal or the nonparametric Wilcoxon rank-sum procedure if dependent variables were nonnormally distributed and not transformable) were applied. 
2 tests of independence (or Fisher’s exact test if cell sizes were smaller than expected) were used for categorical baseline characteristics, attrition, and the occurrence of adverse events. The effect of treatment on the longitudinal endpoints of bone mass, bone metabolism, and markers of resorption and formation was analyzed using repeated-measures analysis with a mixed modeling approach (17, 18). This flexible repeated-measures method allows for data that are missing at random, which occurred to a limited extent in this study due to attrition. The PROC MIXED procedure in SAS (version 8.2; SAS Institute, Cary, NC) was employed for fitting these models. Based on these analyses, changes in endpoints over time relative to their baseline levels by treatment group were reported as mean ± SE. Additionally the effect of prescribed tamoxifen or aromatase inhibitors (anastrozole, exemestane, and letrozole) on the efficacy of risedronate was explored using mixed-effects modeling. The level of statistical significance was set at 0.05 for two-sided hypothesis testing.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
). At baseline, the two groups were similar in clinical characteristics, including age, body mass index, dietary calcium, breast cancer treatment, and bone metabolism (Table 1). All women received chemotherapy, 63 (72%) received radiation therapy, and 55 (63%) had a lumpectomy. Twenty-eight women had stage I breast cancer, 51 had stage II, five had stage III, and one had a small lesion in the liver but was reviewed and approved by the data safety and monitoring board for inclusion in the study. Two women did not know their stage. There were no significant differences between the groups with respect to cancer therapy and stage of cancer. There was no statistically significant difference between the two groups in baseline BMD or T-scores of the hip and spine (Table 1). By World Health Organization classification (lowest BMD at the spine, total hip, or femoral neck) (19), 49% were classified as normal, 48% had low bone mass or osteopenia, and 2% had osteoporosis. The marker of bone resorption, urinary NTX, was similar in the two groups. Osteocalcin, a marker of bone formation, was similar; however, PINP and bone ALP were higher in the women treated with risedronate (Table 1).
|
|
). Of the participants who discontinued the intervention, all discontinued because of medical reasons. In the treatment group, this included two patients with gastroesophageal reflux diseases, one with chronic urticaria, and one with recurrence of breast cancer. In the placebo group, one woman discontinued due to resumption of menses.
After 1 yr, BMD in the spine increased by 1.2 ± 0.5% in participants treated with risedronate and decreased by 0.9 ± 0.5% in the placebo group (P < 0.01, difference between groups at 12 months, Fig. 2). Total hip BMD increased 1.3 ± 0.3% in women on risedronate therapy and decreased 0.8 ± 0.3% in those who received placebo (P < 0.001, difference between groups at 6 and 12 months, Fig. 2). Similar trends were observed in the lateral spine and trochanter. At the distal radius and total body, BMD remained stable in the treatment group but decreased in the placebo group (0.8 ± 0.4 and 0.8 ± 0.3%, respectively, both differences between groups, P < 0.05). When the rates of change in BMD were adjusted for baseline bone turnover markers (individually as well as simultaneously), similar results were found. At baseline, approximately 70% of women in each group were on tamoxifen, as prescribed by their physician. At 12 months, 31% were on tamoxifen. BMD changes at the spine, hip, and all other skeletal sites for women on tamoxifen and risedronate were similar to changes for women on risedronate alone. However, in the placebo group, the rate of change for total hip BMD was 1.2 ± 0.05% greater (P < 0.05) in women on tamoxifen compared with those who were not. There were no significant differences in the PA spine between those on or off tamoxifen in the placebo group.
|
Markers of bone formation and resorption were significantly different (P < 0.05) in the treatment group vs. the placebo group as early as 6 months and remained suppressed through 12 months in women on risedronate. Risedronate decreased PINP by an average of 26.6 ± 6.0%, osteocalcin by 24.2 ± 5.2%, bone ALP by 21.7 ± 3.7%, and NTX by 19.3 ± 10.6% at 1 yr, with minimal or no change in the placebo group (Fig. 3). There was no difference for women on risedronate and tamoxifen vs. those who were on risedronate alone. The addition of an aromatase inhibitor had no significant impact on bone turnover markers in either group.
|
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
The suppression of bone turnover markers is another indicator of the skeletal response to bisphosphonate therapy. Although the placebo group experienced an increase or maintenance of bone turnover while receiving calcium and vitamin D, women treated with risedronate had significant decreases in all bone turnover markers as early as 6 months with confirmed suppression out to 12 months. The decrease of 20–30% of bone turnover with risedronate may have been less than the expected 40% decrease noted in other studies of postmenopausal women (20) because 70% of women were on tamoxifen, an agent that has a mild antiresorptive effect. Patients were also on calcium and vitamin D. Bone turnover is an independent risk factor for fracture (21) and can provide surrogate information for fracture protection (22). The decrease in bone turnover markers observed in our patients in risedronate provides additional information regarding the benefit of this antiresorptive agent for this cohort of women. In women treated with iv pamidronate, suppression of bone markers was not observed (14). However, this may have been due to the random timing of the measurement.
Data from the ATAC study, published in 2002, demonstrated improved disease-free survival in over 9000 breast cancer patients on anastrozole (an aromatase inhibitor) alone compared with tamoxifen or the combination of tamoxifen and anastrozole (23). This information has resulted in women converting from tamoxifen (a bone-protective agent) to aromatase inhibitors. Although aromatase inhibitors have provided significant clinical benefit for protection against breast cancer recurrence, they have also increased fracture risk (23). The women who received an aromatase inhibitor had over twice the number of fractures in the spine compared with the women in the tamoxifen group and almost a 50% increased risk of wrist fractures (23). Eastell and Hannon (24) measured bone density in 308 of these participants and described a 2.6% reduction in the lumbar spine and a 1.7% reduction in total hip BMD. Additional studies reporting the use of aromatase inhibitors as initial adjuvant therapy (25) or after 2–5 yr of tamoxifen therapy (26, 27, 28) have established aromatase inhibitors as the treatment of choice for postmenopausal women with hormonally responsive breast cancer (29). Several of the studies have documented increased fracture risk with the use of aromatase inhibitors (25, 26), and the incidence of fractures in this population will increase with wider use of the aromatase inhibitors. Approximately 37% of our participants were on aromatase inhibitors during the 12 months. Risedronate prevented bone loss in these women, but the number of participants was too small to draw a definitive conclusion.
There are some important limitations of our study. At baseline, the average time from menopause was 3.3 yr. This may have resulted in a heterogeneous population of women. However, this inclusion criterion allows the results to be generalizable to a broader population of breast cancer survivors. Also, because of the timing of the study, during the clinical trial, more women were placed on an aromatase inhibitor by their own physician. The impact of an aromatase inhibitor on bone loss in the placebo group may have been less than what would have been seen had they been treated for 12 months with an aromatase inhibitor. However, this was not the primary objective of the study.
There are several important strengths of this study. First, it was conducted in a single center, using a single bone densitometer. Second, all of the markers were assessed in samples that were collected in the morning. Third, we enrolled a larger group of participants than previous studies (9, 10, 15). Finally, we had an acceptable retention rate of 95% and the medication was well tolerated.
In summary, once-weekly risedronate prevented bone loss and reduced bone turnover in women with breast cancer and chemotherapy-induced menopause. These results have important clinical ramifications for breast cancer survivors who go into remission after early, aggressive therapy. Because of the long-term survival of this cohort, they are at risk for bone loss and osteoporosis. Skeletal integrity needs to be assessed and considered as part of their long-term management. Additional research is needed to evaluate the efficacy of risedronate in preventing bone loss in women taking long-term aromatase inhibitors.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Disclosure Statement: S.L.G. consults for Merck, Procter and Gamble, and NPS. S.L.G. has received lecture fees from Merck and Procter and Gamble. S.L.G. has received grant support from Merck and Procter and Gamble. R.K.B. has received lecture fees from GlaxoSmithKline, Roche, and Procter and Gamble. R.K.B. has received grant support from Procter and Gamble. S.M.S. has nothing to declare. V.G.V. has received consulting fees, lecture fees, and grant support form Astra-Zeneca. A.B. has received consulting fees and lecture fees from Astra-Zeneca.
First Published Online October 17, 2006
Abbreviations: BMD, Bone mineral density; bone ALP, bone alkaline phosphatase; NTX, N-telopeptide cross-linked collagen type I; PA, posteroanterior; PINP, N-terminal propeptide of type I procollagen.
Received June 15, 2006.
Accepted October 10, 2006.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  S. L. Hines, B. A. Mincey, J. A. Sloan, S. P. Thomas, E. Chottiner, C. L. Loprinzi, M. D. Carlson, P. J. Atherton, M. Salim, and E. A. Perez Phase III Randomized, Placebo-Controlled, Double-Blind Trial of Risedronate for the Prevention of Bone Loss in Premenopausal Women Undergoing Chemotherapy for Primary Breast Cancer J. Clin. Oncol., March 1, 2009; 27(7): 1047 - 1053. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Saad, J. D. Adachi, J. P. Brown, L. A. Canning, K. A. Gelmon, R. G. Josse, and K. I. Pritchard Cancer Treatment-Induced Bone Loss in Breast and Prostate Cancer J. Clin. Oncol., November 20, 2008; 26(33): 5465 - 5476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Hershman, D. J. McMahon, K. D. Crew, S. Cremers, D. Irani, G. Cucchiara, L. Brafman, and E. Shane Zoledronic Acid Prevents Bone Loss in Premenopausal Women Undergoing Adjuvant Chemotherapy for Early-Stage Breast Cancer J. Clin. Oncol., October 10, 2008; 26(29): 4739 - 4745. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Qaseem, V. Snow, P. Shekelle, R. Hopkins Jr., M. A. Forciea, D. K. Owens, and for the Clinical Efficacy Assessment Subcommittee Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures: A Clinical Practice Guideline from the American College of Physicians Ann Intern Med, September 16, 2008; 149(6): 404 - 415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Saarto, L. Vehmanen, C. Blomqvist, and I. Elomaa Ten-Year Follow-Up of 3 Years of Oral Adjuvant Clodronate Therapy Shows Significant Prevention of Osteoporosis in Early-Stage Breast Cancer J. Clin. Oncol., September 10, 2008; 26(26): 4289 - 4295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Hadji, J. -J. Body, M. S. Aapro, A. Brufsky, R. E. Coleman, T. Guise, A. Lipton, and M. Tubiana-Hulin Practical guidance for the management of aromatase inhibitor-associated bone loss Ann. Onc., August 1, 2008; 19(8): 1407 - 1416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Greenspan, A. Brufsky, B. C. Lembersky, R. Bhattacharya, K. T. Vujevich, S. Perera, S. M. Sereika, and V. G. Vogel Risedronate Prevents Bone Loss in Breast Cancer Survivors: A 2-Year, Randomized, Double-Blind, Placebo-Controlled Clinical Trial J. Clin. Oncol., June 1, 2008; 26(16): 2644 - 2652. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Parton and I. E. Smith Controversies in the Management of Patients With Breast Cancer: Adjuvant Endocrine Therapy in Premenopausal Women J. Clin. Oncol., February 10, 2008; 26(5): 745 - 752. [Full Text] [PDF]
|
|
|
|
|
|
C. MacLean, S. Newberry, M. Maglione, M. McMahon, V. Ranganath, M. Suttorp, W. Mojica, M. Timmer, A. Alexander, M. McNamara, et al. Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis Ann Intern Med, February 5, 2008; 148(3): 197 - 213. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Eastell Breast Cancer and the Risk of Osteoporotic Fracture: A Paradox J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 42 - 43. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
, P < 0.05; 
, P < 0.01 comparison between risedronate and placebo groups.