Calcium and vitamin D supplementation and loss of bone mineral density 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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Cited by (39)
Dietary Supplement Use in Women Diagnosed with Breast Cancer
2023, Journal of NutritionBone-modifying Agents (BMAs) in Breast Cancer
2021, Clinical Breast CancerCitation Excerpt :Trials of supplemental calcium and vitamin D in cancer treatment-induced bone loss or women receiving AIs are few in number. These trials show no effect mitigation of BMD.71 There is consensus among policy-making organizations (eg, National Osteoporosis Foundation [VA, USA], the US Preventative Services Task Force [MD, USA], the National Academy of Sciences, and the Institute of Medicine [both in Washington DC]) that women over the age of 50 years should receive 1000 to 1200 mg of calcium (including dietary and supplemental) and 800 to 1000 IU of vitamin D3 (cholecalciferol) per day.40
Impact of breast cancer and its treatment on bone loss and fracture risk-pathophysiology and management
2020, Marcus and Feldman’s OsteoporosisManagement of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG
2017, Journal of Bone OncologyCitation Excerpt :For other postmenopausal women receiving AI therapy, a dose of at least 800 (and up to 2000) IU of vitamin D every day is recommended to maintain replete levels. It is important to note, that a recent meta-analysis has underlined that the use of Vitamin D+/-calcium supplementation alone has been shown to be ineffective for fracture risk prevention in women with breast cancer (Evidence level 1 A) [125]. For patients initiating an AI treatment not receiving bisphosphonate for recurrence prevention, a BMD measurement is advised.
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.