Calcium and vitamin D supplementation and loss of bone mineral density in women undergoing breast cancer therapy

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Abstract

An unintended consequence of breast cancer therapies is an increased risk of osteoporosis due to accelerated bone loss. We conducted a systematic review of calcium and/or vitamin D (Ca ± D) supplementation trials for maintaining bone mineral density (BMD) in women with breast cancer using the “before–after” data from the Ca ± D supplemented comparison group of trials evaluating the effect of drugs such as bisphosphonates on BMD. Whether Ca ± D supplements increase BMD in women undergoing breast cancer therapy has never been tested against an unsupplemented control group. However, results from 16 trials indicate that the Ca ± D doses tested (500–1500 mg calcium; 200–1000 IU vitamin D) were inadequate to prevent BMD loss in these women. Cardiovascular disease is the main cause of mortality in women with breast cancer. Because calcium supplements may increase cardiovascular disease risk, future trials should evaluate the safety and efficacy of Ca ± D supplementation in women undergoing breast cancer therapy.

Introduction

Osteoporosis is a significant health concern in postmenopausal women, especially women with breast cancer. Breast cancer therapies that reduce estrogen levels (e.g. oophorectomy, chemotherapy, aromatase inhibitors (AIs)), increase bone resorption without a corresponding increase in bone formation [1], [2] resulting in loss of bone mineral density (BMD) [1], [3]. Compared to healthy postmenopausal women who may lose ∼1% BMD per year, women with breast cancer lose 2–3 fold more BMD [1], increasing the risk of fractures, including fractures at an earlier age [4], [5]. Hip and vertebral fractures are associated with significant declines in function, in health-related quality of life (HRQOL) [5], [6], [7], [8], and in higher mortality rates [9], [10]. Consequently, management of accelerated bone loss in women with breast cancer is a pressing oncologic need. We recently reviewed evidence indicating that 500–1000 mg supplemental calcium and 200–500 IU vitamin D/day were ineffective in preventing loss of BMD in men undergoing androgen deprivation therapy for prostate cancer [11]. Here we evaluated the effectiveness of supplemental calcium and/or vitamin D (Ca ± D) in preventing bone loss in women undergoing treatment for breast cancer.

Section snippets

Calcium and vitamin D intake among women

The dietary reference intakes of nutrients for Americans are established by the Institute of Medicine (IOM) which recommends a daily intake of 1000 mg and 1200 mg calcium for women between 19–50 and ≥51 years, respectively. The recommended vitamin D intake for women <70 and >70 years is 600 and 800 IU/day [12]. The tolerable Upper Limit [UL], the level below which a nutrient can be consumed without adverse effects, for calcium in women between 19–50 years is 2500 mg and is 2000 mg for women ≥51

Calcium physiology

The adult human body contains approximately 1 kg of calcium, of which more than 99% is stored in bones and teeth. Longitudinal studies have shown that calcium intake is a minor but significant predictor of total bone mass in adults. Data from NHANES indicate that Caucasian women with low milk intake during childhood and adolescence had low BMD during adulthood and a higher risk of fracture [16]. Although a protective effect of youthful calcium intake on fracture risk in adulthood is established,

Treatment options for breast cancer

Breast cancer is a heterogeneous group of diseases with distinct clinical, morphological and molecular phenotypes [23]. Its treatment depends upon molecular subtype and hormone receptor status (e.g., estrogen and/or progesterone receptors) [24]. Hormonal therapies for premenopausal women include selective estrogen receptor modulators (SERMs) or ovarian suppression/ablation [24]. Tamoxifen, a SERM, is the standard for premenopausal women with or without chemotherapy [24]. Ovarian

Role of estrogen in breast cancer and bone loss

Estradiol (E2) and estrone (E1) are the dominant circulating estrogens before and after menopause, respectively [26], [27]. The ovaries maintain circulating estrogen levels in premenopausal women, but as ovarian estrogen synthesis decreases post-menopause, estrogen is produced peripherally by the aromatization of androgens [28] by cytochrome P450 aromatase monooxygenase enzymes that are expressed in the ovaries, placenta, adipose tissue, skin, chondrocytes and osteoblasts [27], [29]. Because

Review of clinical practice guidelines

We reviewed clinical practice guidelines for bone health in women with breast cancer by searching the websites of professional organizations including the National Comprehensive Cancer Network (NCCN) [25], the American Society of Clinical Oncology (ASCO) [41], and the National Guidelines Clearinghouse [42]. For example, to counter treatment-related bone loss, the Belgian Bone Club recommends 400–800 IU vitamin D and supplemental calcium to maintain daily calcium intake between 1200 and 1500 mg

Clinical trial evidence

We evaluated clinical trial evidence for calcium and vitamin D supplementation in maintaining skeletal health of women with breast cancer. We searched PUBMED for publications in English during 1990–2012 using the MeSH terms “clinical trial”, “breast neoplasm”, “osteoporosis”, “calcium”, “calcium, dietary”, “vitamin D”, and “25-hydroxyvitamin D”. We excluded drug trials (e.g. bisphosphonates) that did not include a comparison group [52], [53] or those that simultaneously gave antiresorptive

Nonskeletal disease outcomes in breast cancer and with calcium and vitamin D supplementation

Because Ca ± D did not show a benefit in preserving BMD in women undergoing treatment for breast cancer, we evaluated potential non-skeletal risks associated with Ca ± D supplementation in these women.

Discussion

Ca ± D supplements are widely recommended by lay and professional groups for the prevention and management of osteoporosis in healthy women and in women with breast cancer undergoing treatment. We found no clinical trial evidence comparing Ca ± D supplements vs. no supplements in preventing BMD loss in women with breast cancer. However, results from 16 trials of Ca ± D supplements at doses commonly recommended, indicate that 500–1500 mg calcium and 200–1000 IU vitamin D/day were inadequate to inhibit

Conclusion

Ca ± D supplements are the mainstay of osteoporosis management in women and are commonly recommended to women undergoing treatment for breast cancer. However, at doses currently recommended, supplements of vitamin D (200–1000 IU) and calcium (500–1500 mg)/day failed to prevent loss of BMD in women with breast cancer. Breast cancer therapies increase the risk of CVD [75], [76], the primary cause of death in women with breast cancer [73], [104]. Besides an increased risk of CVD from breast cancer

Conflict of interest

The authors have declared no conflicts of interest.

Reviewers

Professor Ingo J. Diel, CGG-Klinik GmbH, Institute for Gynecological Oncology, Quadrat P7 16-18, DE-68161 Mannheim, Germany.

Professor Guy Jerusalem, CHU Liège, BE-4000 Liège, Belgium.

Professor Peyman Hadji, Philipps University of Marburg, Dept of Gynecology, Gynecological Oncology & Endocrinology, Pilgrimstein 3, DE-35037 Marburg, Germany.

Acknowledgements

Mridul Datta is supported by the Comprehensive Cancer Center of Wake Forest University Cancer Control Traineeship – NCI/NIH Grant # R25CA122061.

Gary G. Schwartz, Ph.D., M.P.H., Ph.D. is Associate Professor of Cancer Biology and Epidemiology and Prevention at Wake Forest School of Medicine. He has contributed to studies in basic science, epidemiology, and clinical trials in the area of calcium/vitamin D and cancer.

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    Gary G. Schwartz, Ph.D., M.P.H., Ph.D. is Associate Professor of Cancer Biology and Epidemiology and Prevention at Wake Forest School of Medicine. He has contributed to studies in basic science, epidemiology, and clinical trials in the area of calcium/vitamin D and cancer.

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