This article is part of the 2019 Oncology Special Issue of Natural Medicine Journal. Read the full issue here.
Zheng N, Hsieh E, Cai H, et al. Soy food consumption, exercise, and body mass index and osteoporotic fracture risk among breast cancer survivors: the Shanghai Breast Cancer Survival Study. JNCI Cancer Spectr. 2019;3(2):1-8.
To assess associations between soy food intake, exercise, and BMI and osteoporosis-related bone fractures in women with a history of breast cancer (stages 0-III)
Population-based, longitudinal study (Shanghai Breast Cancer Survival Study)
Participants are part of the ongoing Shanghai Breast Cancer Survival Study. A total of 4,139 women, all with a diagnosis of breast cancer (stages 0-III), were evaluated (1,987 were pre/perimenopausal, 2,152 women were postmenopausal)
Study Parameters Assessed
Osteoporosis-related bone fractures were evaluated at 18 months and 3, 5, and 10 years post-diagnosis. Exercise and soy isoflavone intake was assessed at 6 and 18 months post-diagnosis. Weight and height were taken at baseline.
Primary Outcome Measures
Outcome measures were the number of osteoporotic fractures, defined as “fractures caused by falls from standing height and at sites associated with osteoporosis” relative to menopausal status, soy intake and BMI.
The overall risk for osteoporotic fracture was 2.9% and 4.4% for pre/perimenopausal women and postmenopausal women, respectively. High soy isoflavone intake was associated with less risk of fracture for pre/perimenopausal women but not postmenopausal women. Specifically, pre/perimenopausal women who consumed >56.06 mg/d of isoflavones had significantly lower risk of fracture (hazard ratio [HR]: 0.22, 95% confidence interval [CI]: 0.09-0.53) compared to pre/perimenopausal women who consumed <31.31 mg/d (P<0.001). Being overweight (BMI >25 kg/m2) was associated with a higher risk for fracture (HR: 1.81, 95% CI: 1.04-3.14) for pre/perimenopausal women, but being overweight/obese was not an associated risk for the postmenopausal cohort. Exercise was inversely associated with osteoporotic fractures in postmenopausal women (HR: 0.56, 95% CI: 0.33-0.97 for metabolic equivalent hours >12.6 vs <4.5), and exercise followed a dose-response pattern (Ptrend=0.035).
Risk for osteoporosis and bone fracture increases in women who have been diagnosed with estrogen-receptor-positive breast cancer.1 Selective estrogen receptor modulators (SERMs, such as tamoxifen) for pre/perimenopausal women and aromatase inhibitors in postmenopausal women result in lowering the estrogenic milieu within bone.2–7 The publication currently under review is the first to suggest that higher isoflavone intake is associated with fewer osteoporotic fractures in pre/perimenopausal women. This study also confirms that exercise is inversely associated with fracture risk in a dose-dependent manner.
Osteoporosis, and the risk of fracture that comes with lowered bone mineral density (BMD), are a consequence of several other types of cancer therapies. Androgen deprivation, stem cell transplantation, and ovarian failure secondary to treatment with chemotherapy are all associated with treatment-induced bone loss.8 Primary care providers are often tasked with monitoring bone health in many of these patient populations since standards of care within oncology often do not provide such guidance.
In bone, estrogen has a protective effect from the loss of BMD. When estrogen binds to its receptor, there is a reduction in the activity of osteoclasts; thus anything that limits estrogenic effects in bone results in greater osteoclastic activity and reduction of BMD. Antiestrogenic drugs that universally lower estrogen, such as aromatase inhibitors, reliably lead to bone loss through this mechanism. Similarly, premenopausal women who undergo ovarian ablation due to drugs or surgery lose the bone-protective effect of their endogenous estrogens.
Unlike aromatase inhibitors, which universally lower estrogen by >95%,9 SERMs have a differential effect on estrogen receptors, either as an antagonist or an agonist, depending on the tissue/organ. Tamoxifen, the most widely used SERM, is an antagonist when bound to estrogen receptors in breast tissue, while having a slight agonist effect when binding to receptors in bone.10 This slight agonist effect leads to increased BMD in postmenopausal women who take tamoxifen.11 Premenopausal women who take tamoxifen, however, will not derive this benefit. Premenopausally, endogenous estrogens are still circulating at relatively high levels, making the weak agonist effect of tamoxifen a net reduction in estrogenic effects on bone.12
The publication currently under review is the first to suggest that higher isoflavone intake is associated with fewer osteoporotic fractures in pre/perimenopausal women.
While isoflavones are commonly referred to as phytoestrogens, they are more akin to “phyto-SERMs,” with effects that are dependent on the estrogen receptors expressed (alpha/beta) as well as the tissue type.13 Previous studies on isoflavone intake from soy foods in women with a history of breast cancer have suggested an inverse relationship with recurrence as well as overall mortality.14–19 We know less about high-dose, isolated soy isoflavones; experimental studies suggest that isoflavones as isolates in high doses have unique risks and lack proof of safety.20
Given that this study tracked the consumption of isoflavones from whole foods, it is possible that other constituents in soy are responsible for the reduced risk of osteoporotic fracture observed in premenopausal women. In the current study, there was a lack of any associated decrease in osteoporotic fractures in the postmenopausal cohort, further implying the presence of non-estrogen-mediated mechanism(s). Like any plant, soy has a complex array of thousands of phytochemicals. For example, soy-derived flavonoids have dozens of known physiological effects, although none of them alone can account for the observation on bone health observed in the current study.20
This study took place in China where consumption of soy foods is dramatically higher than in Western populations. Intake of isoflavones per day in the Shanghai Breast Cancer Survival Study had a mean [SD] value of 45.9 [38.3]. In comparison, in the Women’s Healthy Eating and Living (WHEL) study, a US-based cohort that assessed soy intake in women with a history of breast cancer, the mean [SD] intake was 2.6 [7.9] mg. In the Life After Cancer Epidemiological (LACE) study, women consumed a mean [SD] 4.1 [11.9] mg per day.16 While these studies did show associations for benefit of soy consumption on mortality and recurrence of breast cancer at these low levels, it is unclear if the effects translate to bone health at all.
There are several limitations of this study, as outlined by the authors: The data collection was dependent on self-reporting of osteoporotic fractures, which has been suggested to be reliable but inherently has risks of misclassification. Also, there was no information collected on osteoporosis screening, bisphosphonate use, or compliance with guidelines for osteoporosis prevention. This study used data prior to the widespread adoption of monitoring bone health in those with a history of breast cancer in China. Similarly, bisphosphonate use was unlikely, although possible, given the years of enrollment into this study were 2002-2006.
There is no doubt that bone health is a top priority in women with a history of breast cancer and that active surveillance should be done with sequential bone density scans over time. Given the preponderance of evidence that whole soy food can benefit these women, we now have yet another reason to assure them that a serving or 2 daily of soy is not only okay, it is encouraged. While studies on soy do not delineate between conventional and organic sources, it goes without saying that organic sourcing is advisable.
- Body J-J. Increased fracture rate in women with breast cancer: a review of the hidden risk. BMC Cancer. 2011;11(1):384.
- Reid DM, Doughty J, Eastell R, et al. Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK expert group. Cancer Treat Rev. 2008;34(Suppl 1):S3-S18.
- Rabaglio M, Sun Z, Price KN, et al. Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol. 2009;20(9):1489-1498.
- Bruning P, Pit M, de Jong-Bakker M, van den Ende A, Hart A, van Enk A. Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer. Br J Cancer. 1990;61(2):308-310.
- Delmas P, Fontana A. Bone loss induced by cancer treatment and its management. Eur J Cancer. 1998;34(2):260-262.
- Eastell R, Hannon RA, Cuzick J, Dowsett M, Clack G, Adams JE. Effect of an aromatase inhibitor on BMD and bone turnover markers: two-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) Trial (18233230). J Bone Miner Res. 2006;21(8):1215-1223.
- JM Lappe ST. Prevention of osteoporosis in women treated for hereditary breast and ovarian carcinoma: a need that is overlooked. Cancer. 1998;83:830-834.
- Guise TA. Bone loss and fracture risk associated with cancer therapy. Oncologist. 2006;11(10):1121-1131.
- Brueggemeier RW, Hackett JC, Diaz-Cruz ES. Aromatase inhibitors in the treatment of breast cancer. Endocr Rev. 2005;26(3):331-345.
- Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J, Nilsson S. Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol Pharmacol. 1998;54(1):105-112.
- Clines GA, Choksi P, Van Poznak C. Adjuvant endocrine therapy and bone health in breast cancer. Curr Osteoporos Rep. 2015;13(5):263-273.
- Vehmanen L, Elomaa I, Blomqvist C, Saarto T. Tamoxifen treatment after adjuvant chemotherapy has opposite effects on bone mineral density in premenopausal patients depending on menstrual status. J Clin Oncol. 2006;24(4):675-680.
- Mangalath DL, Sadasivan C. Selective estrogen receptor modulators (SERMs) from plants. In: Brahmahari G, ed. Bioactive Natural Products: Chemistry and Biology. Weinheim, Germany: 2015 Wiley‐VCH; 2014. Published online 2015 https://onlinelibrary.wiley.com/doi/abs/10.1002/9783527684403.ch13. Accessed September 25, 2019.
- Messina M. Impact of soy foods on the development of breast cancer and the prognosis of breast cancer patients. Complement Med Res. 2016;23(2):75-80. http://www.karger.com/DOI/10.1159/000444735. Accessed September 25, 2019.
- Shu XO, Zheng Y, Cai H, et al. Soy food intake and breast cancer survival. JAMA. 2009;302(22):2437.
- Nechuta SJ, Caan BJ, Chen WY, et al. Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of US and Chinese women. Am J Clin Nutr. 2012;96(1):123-132.
- Chi F, Wu R, Zeng Y-C, Xing R, Liu Y, Xu Z-G. Post-diagnosis soy food intake and breast cancer survival: a meta-analysis of cohort studies. Asian Pac J Cancer Prev. 2013;14(4):2407-2412.
- Guha N, Kwan ML, Quesenberry CP Jr, Weltzien EK, Castillo AL, Caan BJ. Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: the Life After Cancer Epidemiology study. Breast Cancer Res Treat. 2009;118(2):395-405.
- Caan BJ, Natarajan L, Parker B, et al. Soy food consumption and breast cancer prognosis. Cancer Epidemiol Biomarkers Prev. 2011;20(5):854-858.
- Uifălean A, Schneider S, Ionescu C, Lalk M, Iuga CA. Soy isoflavones and breast cancer cell lines: molecular mechanisms and future perspectives. Molecules. 2015;21(1):E13.