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Bone Density and Breast Cancer

The Link between Bone Density and Breast Cancer Risk

Understanding and Monitoring Risk Factors

Bone density, or bone mineral density ( BMD ), is the amount of bone mineral in bone tissue.  Bone mineral density (BMD) is a lifetime marker of estrogen exposure in a woman's body and has been associated with increased breast cancer risk. Estrogen is a crucial factor in maintaining bone density and gradually decreases over age. While there are many factors that influence bone density and bone health, the presence of estrogen contributes to the capacity of bone to continuously remodel and maintain the dynamic balance between bone resorption and bone formation.  A woman’s exposure to estrogen over the life cycle may contribute to her risk of breast cancer.

Bone density measurement is used in clinical medicine as an indirect indicator of osteoporosis and fracture risk.  There is a clear association between poor bone density and a higher probability of fracture.  There is a clear association between poor bone density and low estrogen levels.  Conversely, there is a clear association between increased and healthy bone density and higher estrogen levels.

Screening for risk of breast cancer should ALSO include assessment of estrogen levels and bone density along with well-recognized risk factors which include first degree relatives, obesity, increased visceral fat, smoking, alcoholism, early menarche, late menopause, sedentary lifestyle, hormone replacement therapy, and prolonged estrogen exposure, increased density of breast tissue. 

I would also add exposure to environmental endocrine disruptors and imbalances in the intestinal microbiome influencing estrogen metabolism.  Breast density and bone density are related to endogenous and exogenous estrogen exposure in a woman’s body.  There is a correlation between estrogen exposure, high breast density, high bone density, and increased risk of breast cancer.

 

Bone is living metabolically active tissue. “Bone remodeling is the process by which bone is renewed to maintain bone strength and mineral homeostasis. Remodeling involves continuous removal of discrete packets of old bone, replacement of these packets with newly synthesized proteinaceous matrix, and subsequent mineralization of the matrix to form new bone begins before birth and continues until death.  Bone remodeling increases in perimenopausal and early postmenopausal women and then slows with further aging, but continues at a faster rate than in premenopausal women. Bone remodeling is thought to increase mildly in aging men.”  Normal Bone Anatomy and Physiology 10.2215/CJN.04151206

Engaging in a health model for all patients includes assessing and managing bone health to promote healthy bone over the life cycle. A health model for cancer patients, due to the typically older age demographics will inherently include a large population of patients already at risk for loss of bone mass, osteopenia and osteoporosis. Screening for bone mineral density and managing bone health should be part of whole-person, whole health care. Taking a thorough history that includes family history, bone health and bone mineral density can bring attention to patients at higher risk for low bone density and fracture as well as patients with a higher risk of estrogen driven breast cancers.

Bone density measurement is used in clinical medicine as an indirect indicator of osteoporosis and fracture risk.  There is a clear association between poor bone density and higher probability of fracture.  There is a clear association between poor bone density and low estrogen levels.  Conversely there is a clear association between increased and healthy bone density and higher estrogen levels.

The Most Common Risk Factors for Low Bone Density and Primary Considerations for a Bone Density Test include:

  • Females age 65 or older
  • Males aged 70 or older
  • People over age 50 with
    • previous bone fracture from minor trauma
    • rheumatoid arthritis
    • low body weight
    • a parent with a hip fracture
  • Individuals with vertebral abnormalities
  • Individuals receiving, or planning to receive, long-term glucocorticoid therapy
  • Individuals with primary hyperparathyroidism
  • Individuals being monitored to assess the response or efficacy of an approved osteoporosis drug therapy
  • Individuals receiving androgen deprivation therapy 
  • Individuals with a history of eating disorders

Additional factors that are related to the risk of low bone density and the need for assessment include smoking, alcohol intake, long-term use of corticosteroid drugs, sedentary or convalescent lifestyle, protein status, mineral status, digestion, and absorption function, chronic inflammation and vitamin D status.  

For cancer patients and survivors also consider periods of poor nutrition, calorie, protein status, convalescence, lack of exercise, effect of hormonal therapies, oophorectomy, orchiectomy, chemotherapy, immunotherapy, treatment induced thyroiditis, gastritis, enteritis and colitis,  chronic pain impacting appetite, digestive and absorptive dysfunction, surgical loss of gastrointestinal organs and function as contributors to risk of loss of bone density and as well as multiple and varied adverse effects of cancer physiology and cancer treatments upon nutritional status and active lifestyle.

Selected References 

Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol. 2008 Nov;3 Suppl 3(Suppl 3):S131-9. doi: 10.2215/CJN.04151206. PMID: 18988698; PMCID: PMC3152283.

Fraenkel M, Novack V, Mizrakli Y, Koretz M, Siris E, Norton L, Shafat T, Geffen DB. Bone mineral density in women newly diagnosed with breast cancer: a prospective cohort study. NPJ Breast Cancer. 2022 Feb 17;8(1):21. doi: 10.1038/s41523-022-00388-z. PMID: 35177701; PMCID: PMC8854387.

Zain NM, Seriramulu VP, Chelliah KK. Bone Mineral Density and Breast Cancer Risk Factors among Premenopausal and Postmenopausal Women A Systematic Review. Asian Pac J Cancer Prev. 2016;17(7):3229-34. PMID: 27509955.

Resveratrol, Estrogen and Breast Cancer

Resveratrol, Estrogen and Breast Cancer

Phytochemical Aromatase Inhibition

Estrogen Receptor Positive is a prevalent form of breast cancer that has been effectively treated by targeting the proliferative estrogen pathway. .   Typically pre-menopausal women will be given SERMS (Selective Estrogen Receptor Modifiers such as Tamoxifen) which blocks the effect of circulating estrogen on receptor binding, thus inhibiting estrogen stimulation and function.  Tamoxifen and SERMS also have significant adverse effects:  increasing thrombosis, endometrial proliferation, and cancer stem cells.   

Another category of hormonal therapies includes SEEMS ( Selective Estrogen Enzyme Modulators, such as Aromatase Inhibitors) including letrozole and Arimidex, which block the conversion of androgens to estrogens in the tissue by inhibiting the aromatase enzyme. SEEMS are primarily recommended to post-menopausal women.  While most studies on resveratrol and its impact on cancer metabolism are murine or cell studies, the evidence is compelling.   Most human studies have been focused on the cell-protective, anti-aging, anti-oxidant and anti-inflammatory properties of resveratrol. Here we take a look at the aromatase inhibition properties of resveratrol.

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a phytochemical that belongs to the stilbenoids group of phytophenolsIt is a natural plant compound found in the skin of red grapes, red wine, red grape juice, Japanese Knotweed (Polygonum cuspidatum), and in small amounts in some berries such as blueberries, mulberries, lingonberries, bilberries, red currants, cranberries and in small amounts in pistachios and peanuts. 

In one study both resveratrol, as well as melatonin, were found to be aromatase inhibitors and to have an inhibitory effect equivalent to letrozole, a commonly prescribed aromatase inhibitor drug.

Although this was true in cell culture, it has not been seen in human studies, primarily due to the fact that resveratrol has a low absorption rate when taken orally.   

Estrogen receptor-positive Anti-aromatase effect of resveratrol and melatonin on hormonal positive breast cancer cells co-cultured with breast adipose fibroblasts.

 

Another cell culture study demonstrated that resveratrol could inhibit aromatase at both the enzyme and mRNA expression levels and that there was a significant transcriptional control of the CYP19 gene which promotes cell proliferation in breast tissue. The research concluded that these phytochemicals can be used to target allosteric binding sites on the aromatase enzyme.

A more recent study demonstrated the anti-proliferative effect on Estrogen Receptor positive (ER+)  breast cancer cells by effectively targeting allosteric binding sites on the aromatase enzyme by resveratrol, chrysin, and apigenin. The study also included berberine and pomiferin as promising phytochemical aromatase inhibitors.  High-quality berberine is readily available and has a broad range of therapeutic actions including impacting over 20 pathways involved in cancer cell metabolism, inflammation, and bacterial pathogen control.  

Wang Y, Lee KW, Chan FL, Chen S, Leung LK. The red wine polyphenol resveratrol displays bilevel inhibition on aromatase in breast cancer cells. Toxicol Sci. 2006 Jul;92(1):71-7. doi: 10.1093/toxsci/kfj190. Epub 2006 Apr 11. PMID: 16611627.

A similar study showed that resveratrol can inhibit the CYP19 promoter gene via transcriptional control by reducing estradiol mRNA abundance through aromatase inhibition.  This leads to an anti-proliferative effect.

Wang Y, Ye L, Leung LK. A positive feedback pathway of estrogen biosynthesis in breast cancer cells is contained by resveratrol. Toxicology. 2008 Jun 27;248(2-3):130-5. doi: 10.1016/j.tox.2008.03.017. Epub 2008 Mar 29. PMID: 18462857.

The research on the impact of resveratrol on estrogen receptor-positive breast cancer proliferation and aromatase inhibition has fueled the development of several “enhanced” more bioactive resveratrol steroid analogues which may be more effective and have greater absorption than the form found in nature. 

In my clinical experience, resveratrol is a weak aromatase inhibitor and does not offer the level of protection provided by pharmaceuticals, but is also well-tolerated and without many of the adverse effects of aromatase inhibitors drugs. (Joint pain, fatigue, sleep disruption, vaginal dryness, hot flashes).  I will give 3-5 grams of pure resveratrol powder daily in 2 divided doses. To overcome the low absorption rate of resveratrol.  I always give it a high-fat food such as nut butter or full-fat yogurt and mix in cinnamon and ginger not only to improve the taste but also to enhance digestion and absorption.  This may be a good option for women who stop taking aromatase inhibitors due to unacceptable side effects negatively impacting their Quality of Life. Pharmacologic dosing of resveratrol can offer a mild aromatase inhibitory protective effect to these women along with over 50 additional pathways contributing to health and longevity.

Alhadrami HA, Sayed AM, Melebari SA, Khogeer AA, Abdulaal WH, Al-Fageeh MB, Algahtani M, Rateb ME. Targeting allosteric sites of human aromatase: a comprehensive in-silico and in-vitro workflow to find potential plant-based anti-breast cancer therapeutics. J Enzyme Inhib Med Chem. 2021 Dec;36(1):1334-1345. doi: 10.1080/14756366.2021.1937145. PMID: 34139914; PMCID: PMC8759730.

Kang H., Xiao X., Huang C., Yuan Y., Tang D., Dai X., Zeng X. Potent aromatase inhibitors and molecular mechanism of inhibitory action. Eur. J. Med. Chem. 2018;143:426–437. doi: 10.1016/j.ejmech.2017.11.057. - DOI - PubMed

Sainsbury R. The development of endocrine therapy for women with breast cancer. Cancer Treat. Rev. 2013;39:507–517. doi: 10.1016/j.ctrv.2012.07.006. - DOI - PubMed

Zhao H., Zhou L., Shangguan A.J., Bulun S.E. Aromatase expression and regulation in breast and endometrial cancer. J. Mol. Endocrinol. 2016;57:R19–R33. doi: 10.1530/JME-15-0310. - DOI - PMC - PubMed

The Connection Between Breast Cancer and The Environment

Breast Cancer is the most commonly diagnosed malignancy in women.

Image Credit - Ribbon vector created by pikisuperstar - www.freepik.com

There is a continually expanding and compelling volume of data linking breast cancer to exposure to environmental toxins, radiation and endocrine disrupters lead to increased incidence of breast cancers.

When taking a thorough history of our patients we must include a review of their “Exposome”

Genetic and Genomic factors, Reproductive history, lifestyle factors such as weight, alcohol consumption, smoking and lack of physical exercise all contribute to increased risk profiles. Socioeconomic status as well as psychological health and resilience, all influence outcomes. Racial and ethnic minorities are often exposed to a disproportionately higher level of environmental toxins in the US. Immigrants may have lived in areas where there are no environmental regulations or controls.

Exposures to common chemicals found in products used every day contribute to a lifetime burden of toxic chemicals. The greatest rise in the incidence of breast cancers occurred in the decades after World War II when there were exponential increases in the use of herbicides, pesticides, plastics, cosmetics and body care products.

Cancer is often a perfect storm of genetics and environment. While studies are done on single agents, the reality is that we are living in a toxic chemical soup in modern life exposing us to a myriad of chemicals from multiple sources on a daily basis.

A common chemical BPA (Bisphenol A) is an endocrine disruptor. Exposure to BPA early in life contributes to breast displasias later in life due to its impact on mammary gland gene expression. BPA is found in plastics, linings of canned food containers and credit card receipts.

Limit exposure to plastics, polycarbonate food and water containers and canned foods to reduce BPA exposures. Breastfeeding women should be cautious as BPA is found in human breast milk.

Parabens, p-hydroxybenzoic acid esters, are widely used preservatives in personal care products and cosmetics. Parabens are endocrine disruptors. Parabens enable the Hallmarks of Cancer, characteristics of tumor cell survival and proliferation through multiple pathways. Parabens are also found in human breast milk. Parabens bind to estrogen receptors, inhibit apoptosis, promote proliferation, angiogenesis and metastasis. A lifelong commitment to avoiding all products that contain parabens will dramatically reduce exposures. Many European countries have banned the use of parabens. European made products are often paraben free as well as select brands made in the US.

Visit the Environmental Working Group Cosmetics Data base https://www.ewg.org/skindeep/ for a list of safe and not so safe products.

Single Nucleotide Polymorphisms in P450 enzymes, particularly CYP1BI metabolism. Mulitple methylation pathways also influence detoxificaton pathways and estrogen metabolism.

A healthy microbiome, particularly rich in Bifidobacteria and butyrate support normal estrogen conjugation and excretion. MANY breast cancer treatments contribute to dysbiosis, increased inflammation and alterations in estrogen metabolism and mood.

Pelvic and Abdominal radiotherapy, surgeries, chemotherapy agents, steroids, antibiotics administered to cancer patients and compromise gut health, immunity and inflammation control. Increasing butryate in the intestines improves the health of the microbiome.

Butyrate and the health of intestinal microbiome can be easily increased by ingesting 6-8 grams of soluble fibers daily. The Onion-Garlic family and the Brassica-Cabblage family vegetables are high in soluble fibers.

The use of oral contraceptives, fertility drugs and hormone replacement therapy all alter breast tissue. Thus, medical care itself leads to nosocomial trends in breast cancer. Patients BEWARE!!!

Many pesticides and herbicides cause endocrine disruption. Commercial production of many animal food sources including the additional of estrogens and growth hormones to feed.

Patients should be well versed and take a tour of their home room by room to identify toxic, endocrine disrupting chemical exposures.

Patients can be overwhelmed when we give them a long list of products and foods to avoid.

In our clinic we employ nutritional health coaches to assist patients in successfully implementing a lifestyle and diet that reduces exposures to estrogenic environmental chemicals.

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