Phytotherapy and Nutritional Supplements on Breast Cancer 用于乳腺癌治疗的植物疗法和营养补充剂

4.2.5. Vitamin D and Calcium

Vitamin D is a liposoluble vitamin mainly acquired through endogenous synthesis via sun exposure of the skin (ultraviolet B rays); a daily sunlight exposure can generate the equivalent of a 10,000 IU oral dose of vitamin D3 [188]. It can also be obtained from dietary sources (e.g., fatty fish and fortified food products, cereal, milk and dairy products, beef, and liver) or as a nutritional supplement (ergocalciferol (D2) or cholecalciferol (D3)) [422]. Either of these forms needs to be metabolized via hydroxylation in the liver and kidney to the active form known as calcitriol. Our levels of vitamin D are mainly affected by the limited sun exposure (darker skin, use of sunscreen, season, latitude, and time of day) and limited physical activity. However, daily recommended intake (DRI) values generally consider vitamin D levels in persons with limited sun exposure as adequate to restore levels. Several other biological systems (e.g., heart, brain, muscle, immune, pancreas, and control cell cycle) present vitamin D receptors. Physiologically, appropriate levels of vitamin D are essential in skeletal mineralization, regulation of parathyroid hormone production, and maintenance of calcium and phosphorous plasmatic concentrations [423]. Vitamin D regulates intestinal calcium absorption and bone and renal calcium resorption [422]. Regarding the topic of cancer, it presents promising actions [424]: regulating the expression of genes that are involved in development and progression of cancer; being able to stimulate cell differentiation and apoptosis; inhibiting proliferation, angiogenesis, invasion, inflammation, and metastatic potential; suppressing aromatase activity leading to reduce estrogen levels and reduced breast cancer risk. Blood levels of 25-hydroxy-vitamin D can be measured to determine a deficiency of vitamin D [423].

Vitamin D deficiency is common among cancer patients, namely, in breast cancer cases [135, 154, 160, 167, 170, 425]. Some authors found no association between breast cancer risk and vitamin D/calcium intake [136, 138–140, 142] or serum levels [145–147]. Studies about intake or serum vitamin D and/or calcium levels found controversial results: dietary vitamin D or serum levels were associated with a decrease of breast cancer risk in several countries such as Pakistan [154], Iran [161], Korea [162], USA [163, 164], Europe [165], Australia [156], France [150], Italy [153], and Germany [166]; dietary calcium and vitamin D had no association with breast cancer risk in a large cohort study performed in Europe [141] but other authors found a significant evidence of the inverse relationship between vitamin D and calcium intake and breast cancer risk, related or not to menopausal status [157, 158], a U-shape association between plasma vitamin D levels and breast cancer risk while an inverse association was observed with serum calcium levels [171–173]. Serum calcium levels were inversely associated with breast cancer in premenopausal women and the opposite occurred in overweight postmenopausal women [169]. However, in Asian population calcium serum levels and breast cancer were not related [148]. The risk of breast cancer also appears to vary with menopausal status. While no relation between vitamin D serum levels was found in premenopausal women, an inverse association seems to be evident in postmenopause with threshold serum values of 27 ng/ml [168]. Lee et al. found that vitamin D has a protective effect on premenopausal women [155]. Despite the fact that age may be a risk factor, Mohr et al. showed no relationship between vitamin D levels and breast cancer in young military women [137], and results in postmenopausal women revealed no association either [136, 145]. Until now there is no agreement about the optimal dietary vitamin D and calcium intake to diminish breast cancer risk. However, based in existing studies, some authors suggested that daily intake of 600 mg calcium + 400 IU vitamin D and a target of 30–50 ng/ml of serum vitamin D may achieve the lowest risk of breast cancer in women [153, 166, 426].

Discordant data about the dietary source of those nutrients have been also discussed. Dietary but not vitamin D supplement was positively associated with increased breast cancer risk [176]. Other studies found no association with dairy products consume and breast cancer risk [149, 151, 427]. Sun exposure is also a relevant source of vitamin D and it seems to be an important protective factor when combined with dietary vitamin D, especially in postmenopausal women at northern latitudes with poor UV light [152].

Nonetheless, there are no adequate clinical trials that support the promising outcomes of supplementation breast cancer patients, in the case of a shortfall, with vitamin D. Most of the studies referred to the fact that the results required cautious interpretations. In accordance with Goodwin et al. [181], vitamin D deficiency in these patients is a negative prognostic factor. Women with aggressive subtypes of breast cancer have lower serum vitamin D levels which can be an indicator of poor prognostic [177, 183, 184]. For example, in a multiethnic cohort, Villaseñor and collaborators revealed that higher serum of 25-hydroxy vitamin D may be associated with improved survival, but the results were not statistically significant, referring to the need of including additional endpoints in future larger studies [182]. Calcium serum levels were positively related to breast cancer aggressiveness in premenopausal women with or without overweight [185]. The calcium/magnesium ratio appears to be also important since they have antagonist effects on absorption-resorption cycle. Magnesium intake has been related to an improved breast cancer survival and this effect is potentiated with higher calcium/magnesium ratios [180].

Vitamin D intake was not related to breast cancer recurrence independently of menopausal status [179].

Some studies related the lower risk of breast cancer and vitamin D to the inhibition of cell proliferation via nuclear vitamin D receptor (VDR). Polymorphism of VDR may be determinant in the breast cancer risk and may also explain the controversial data from different epidemiologic studies [176, 178, 428]. However, despite contradictory results reported in different studies, polymorphism of this receptor has been pointed as responsible for individual sensitivity to vitamin D [174, 429]. This relation might be also dependent on breast cancer subtype and menopausal status [175].

As with other nutritional supplements, in vitro and in vivo studies using vitamin D in breast cancer patients demonstrated contradictory results. Because a high concentration of calcitriol induces the hormone transcriptional targets and presents antiproliferative effects in culture breast cancer lineages, Urata et al. evaluated the outcomes of calcitriol supplementation in postmenopausal breast cancer specimens [430]. However, the authors could not extrapolate the effects observed in vitro to in vivo analyses.

In this context, a universal benefit from vitamin D supplementation among patients with cancer will be influenced by various factors, including the baseline vitamin D status, vitamin D receptor polymorphisms, and variable target effects dependent on the vitamin D receptor status of the tumour [383].

Many breast cancer patients have different risk factors for the development of osteoporosis such as age or aromatase inhibitor therapy. The use of aromatase inhibitor in postmenopausal women can generate a harmful effect on bone mass and an augmentation in fracture risks. These musculoskeletal symptoms appear probably due to estrogen deficiency caused by aromatase inhibitor [431]. Vitamin D is a promising and effective approach to reduce the incidence and severity of arthralgia resulting from aromatase inhibitor treatment [186, 190, 191, 193]. Sometimes, even with the supplementation of 500–1.000 UI women present a vitamin D deficit [186, 431]. Khan et al. [190] successfully supplemented patients with high doses of vitamin D (50,000 IU per week) for several weeks to control joint pain and fatigue associated with letrozole (i.e., an aromatase inhibitor). Other authors achieve similar improvement with calcium and/or vitamin D supplementation [187, 192, 432].

Amir and colleagues [188] explored the effects of high dose vitamin D3 (10,000 IU/day for 4 months) in breast cancer patients with bone metastases. In this phase 2 trial, the authors suggested the safety of supplementation but neither significant palliative benefit nor significant change in bone resorption occurred.

In breast cancer patients, whose bone density can be affected by chemotherapy-induce menopause and aromatase inhibitor, clinical practices guidelines recommend the supplementation not only with vitamin D but also with calcium [189]. Calcium is the most prevalent mineral in the body. Chung et al. reported no benefits for bone density or risk of fractures in breast cancer patients supplemented only with vitamin D and limited benefits for combination higher doses of vitamin D (>10 μg/day) with calcium (>1,000 mg) in noninstitutionalized individuals [433]. In a systematic review, results from trials point to insufficient calcium and vitamin D supplementation doses (i.e., 500–1500 mg for calcium and 200–1000 IU vitamin D) to prevent bone mineral density loss [189]. Vitamin D supplementation was associated with an improvement in bone loss if target serum levels of 30 ng/ml were achieved [194], but some negative results are also reported. Doses of 500–1500 mg calcium and 200–1000 IU vitamin D were not sufficient to prevent bone mineral loss [189]. Some of the studies reported associated calcium supplementation with the enhanced risk of cardiovascular disease, so future validated trials should be considered to evaluate the safety and efficacy of these regimens of supplementation in women undergoing breast cancer therapy. Another aspect to consider is the confounding factor in human trials. Deschasaux et al. found that body mass index and alcohol consumption may modify the effect of vitamin D on breast cancer risk, which can be the reason for discrepant results between studies [159].

There are very few randomized placebo-controlled trials that proved the efficacy, safety, and optimum dosage of vitamin D and calcium supplementation for cancer patients. Rohan et al. found no benefit in the administration of daily use of 1000 mg of calcium carbonate and 400 IU of vitamin D3 for 7 years, in postmenopausal women and the risk of benign proliferative breast disease [143]. The same study concluded that daily doses used were not associated with a protective effect related to breast cancer risk [144].

Vitamin D deficiency has also been linked with increased toxicity from bisphosphonate therapy, which can provoke hypocalcaemia [434]. Currently, researchers investigate the need to supplement vitamin D and calcium simultaneously with bisphosphonate therapy [435]. In a double-blind, randomized, placebo-controlled study, Rhee et al. proved the efficacy of combined alendronate (5 mg) and calcitriol (0.5 µg) to prevent bone loss due to aromatase inhibitor in Korean postmenopausal women with early breast cancer.

Despite the huge data from experimental and observational studies, a better understanding of the biologic effect of vitamin D in breast tissue and a more careful clinical design will be useful for making recommendations for vitamin D supplementation among breast cancer prevention or treatment.