https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712861/
Nothing Boring About Boron
Lara Pizzorno, MDiv, MA, LMT
The trace mineral boron is a micronutrient with diverse and vitally important roles in metabolism that render it necessary for plant, animal, and human health, and as recent research suggests, possibly for the evolution of life on Earth. As the current article shows, boron has been proven to be an important trace mineral because it (1) is essential for the growth and maintenance of bone; (2) greatly improves wound healing; (3) beneficially impacts the body’s use of estrogen, testosterone, and vitamin D; (4) boosts magnesium absorption; (5) reduces levels of inflammatory biomarkers, such as high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor α (TNF-α); (6) raises levels of antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase; (7) protects against pesticide-induced oxidative stress and heavy-metal toxicity; (8) improves the brains electrical activity, cognitive performance, and short-term memory for elders; (9) influences the formation and activity of key biomolecules, such as S-adenosyl methionine (SAM-e) and nicotinamide adenine dinucleotide (NAD+); (10) has demonstrated preventive and therapeutic effects in a number of cancers, such as prostate, cervical, and lung cancers, and multiple and non-Hodgkin’s lymphoma; and (11) may help ameliorate the adverse effects of traditional chemotherapeutic agents. In none of the numerous studies conducted to date, however, do boron’s beneficial effects appear at intakes > 3 mg/d. No estimated average requirements (EARs) or dietary reference intakes (DRIs) have been set for boron—only an upper intake level (UL) of 20 mg/d for individuals aged ≥ 18 y. The absence of studies showing harm in conjunction with the substantial number of articles showing benefits support the consideration of boron supplementation of 3 mg/d for any individual who is consuming a diet lacking in fruits and vegetables or who is at risk for or has osteopenia; osteoporosis; osteoarthritis (OA); or breast, prostate, or lung cancer.
The trace mineral boron is a micronutrient with diverse and vitally important roles in metabolism that render it necessary for plant, animal, and human health, and, possibly, as recent research suggests, for the evolution of life on Earth. The current review focuses primarily on boron’s most salient effects on human health, including its impact on bone development and regeneration, wound healing, the production and metabolism of sex steroids and vitamin D, and the absorption and use of calcium and magnesium. In addition, boron has anti-inflammatory effects that can help alleviate arthritis and improve brain function and has demonstrated such significant anticancer effects that boronated compounds are now being used in the treatment of several types of cancer. A summary of the evidence suggesting that boron should be given consideration as an essential micronutrient is provided, together with leading dietary sources and intake recommendations.
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Salient Effects
Bone Growth and Maintenance
Scientists have known for many years that boron is essential for healthy bones. In 1985, the US Department of Agriculture (USDA) conducted an experiment in which postmenopausal women (n = 12) who had been put on a low-boron diet (0.25 mg/d for 119 d) were supplemented with 3 mg/d of boron during two 28-day trials. In one trial, magnesium intake was low; in the other, magnesium intake was adequate. With boron supplementation, the women’s daily urinary excretion of calcium was reduced by 44%. The reduction in calcium loss resulting from boron supplementation was 52 mg/d when the women were low in magnesium and 22 mg/d when magnesium levels were adequate.1
Boron plays an important role in osteogenesis, and its deficiency has been shown to adversely impact bone development and regeneration.2 Boron influences the production and activity of steroid hormones, actions via which this trace mineral is involved in the prevention of calcium loss and bone demineralization. Boron supplementation has repeatedly been shown to markedly reduce urinary excretion of both calcium and magnesium and to increase serum levels of estradiol and calcium absorption in peri- and postmenopausal women.1,3 Boron also beneficially impacts vitamin-D utilization. Supplementation with boron stimulates bone growth in vitamin-D deficient animals and alleviates dysfunctions in mineral metabolism characteristic of vitamin-D deficiency.4
Animal studies published in 20085 and 20096 found that healing of the alveolar bone—a ridge of compact bone that contains the tooth sockets on the maxillae and mandible (ie, the bones that hold teeth)—was inhibited in boron-deficient rats. Compared with boron-adequate rats (3 mg/kg/d of boron in the diet) when evaluated at 7 and 14 days, boron-deficient animals (0.07 mg/kg/d boron in the diet) had significant reductions in osteoblast surface (57% and 87% at 7 d and 14 d, respectively) concomitant with increases in quiescent surface (120% and 126% at 7 d and 14 d, respectively), indicating that boron deficiency can result in impaired bone healing due to a marked reduction in osteogenesis.
In 2010, Hakki et al7 published research investigating the mechanisms underlying boron’s effects on osteogenesis. Boron was determined to induce mineralization of osteoblasts by regulating the expression of genes related to tissue mineralization and the actions of key hormones (17β-estradiol [E2], testosterone, and vitamin D) involved in bone growth and turnover. Boron’s induction of tissue mineralization also underlies boron’s beneficial effects on wound healing.
Wound Healing
Since 1990, boron has been shown to significantly improve wound healing. Application of a 3% boric acid solution to deep wounds reduced the time required in intensive care by two-thirds.8 In 2000, in vitro research using human fibroblasts showed that a boric-acid solution improved wound healing through action on the extracellular matrix.9 Further in vitro studies published in 2002 revealed that these beneficial effects of boron were due to direct actions on specific enzymes found in fibroblasts: elastase, trypsin-like enzymes, collagenase, and alkaline phosphatase.10 The most common cells in animal connective tissue, fibroblasts synthesize the extracellular matrix and collagen and play a critical role in wound healing. Boron facilitates the activity of these key enzymes in fibroblasts, thus improving extracellular-matrix turnover.
Expression of Extracellular-matrix Proteins
Hakki et al7 extended understanding of the mechanisms behind boron’s effects a step further, showing that boron regulates the messenger RNA (mRNA) expression of a wide range of extracellular-matrix proteins, not only those involved in wound repair but also the mineralized tissue-associated proteins, collagen type 1 (COL1), osteopontin (OPN), bone sialoprotein (BSP), and osteocalcin (OCN). The combined effects of these actions boost osteoblast-cell viability, proliferation, and morphology as well as the mineralization of bone cells.
Further research conducted by other investigators on human bone marrow stromal cells confirmed earlier discoveries of the mechanisms through which boron boosts osteogenic differentiation and continued to add to the list. Boron was also found to increase mRNA expression of alkaline phosphatase and bone morphogenetic proteins (BMPs).11 Several other researchers have now confirmed that boron regulates protein levels of key BMPs—BMP-4, BMP-6, and BMP-7—plus the mRNA expression of runt-related transcription factor 2 (RUNX2).
The BMPs are multifunctional growth factors that belong to the transforming growth factor β (TGF-β) superfamily, and several induce formation of new cartilage and bone. Of the 20 BMP family members that have been identified and characterized to date,12,13 BMP-2, BMP-4, BMP-6, and BMP-7, all of which show transcription and activity regulated by boron, have been found necessary to induce osteoblastic differentiation in primary human, mesenchymal stem cells.14,15
Boron was also determined to regulate production of RUNX2, also known as core-binding factor subunit α-1 (CBF-α1). RUNX2 is essential to osteoblastic differentiation and bone formation and to bone maintenance. It is a transcription factor that works cooperatively with BMPs to stimulate osteoblast gene expression and the differentiation of mesenchymal stem cells into osteoblasts, and it remains active in mature osteoblasts. When active RUNX2 levels are reduced, expression of the genes encoding the main bone-matrix proteins drops, including BSP, OCN, OPN, and COL1.16–19
Regulation of Sex Hormones
Increased levels of sex steroids have been demonstrated in both men and women after boron supplementation.1,20 In 1987, Nielsen et al1 reported that dietary boron repletion in postmenopausal women (n = 13), who were previously on a low-boron diet, significantly increased their serum estradiol (E2) and testosterone levels, particularly for those women whose dietary intake of magnesium was low. In women on a low-magnesium diet, E2 almost doubled, increasing from an average of 21.1 pg/mL to 41.4 pg/mL. Testosterone more than doubled, rising from an average of 0.31 ng/mL to 0.83 ng/mL. Similar increases were seen in the women on an adequate-magnesium diet: E2 rose from an average of 15.5 pg/mL to 38.0 pg/mL, and testosterone increased from 0.38 ng/mL to 0.65 ng/mL. In 1997, Naghii et al21 published findings of a similar increase in serum levels of E2 in healthy males (n = 18) after 4 weeks of dietary supplementation with boron.
After only 1 week of boron supplementation of 6 mg/d, a further study by Naghii et al20 of healthy males (n = 8) found (1) a significant increase in free testosterone, which rose from an average of 11.83 pg/mL to 15.18 pg/mL; and (2) significant decreases in E2, which dropped from 42.33 pg/mL to 25.81 pg/mL. All of the inflammatory biomarkers that were measured also decreased: (1) interleukin (IL) 6, from 1.55 pg/mL to 0.87 pg/mL; (2) high-sensitivity C-reactive protein (hs-CRP) by approximately 50%, a remarkable decrease, from 1460 ng/mL to 795 ng/mL; and (3) tumor necrosis factor α (TNF-α) by approximately 30%, from 12.32 to 9.97 pg/mL. Levels of dihydrotestosterone, cortisol, and vitamin D increased slightly.
The significant decrease in the men’s plasma E2 after 1 week of boron supplementation suggests a higher rate of conversion of total testosterone (T) to free testosterone (FT) in the testosterone metabolic pathway. In support, the ratios of FT/T, T/E2, and FT/E2 were all significantly increased, indicating boron had androgen amplifier effects: (1) FT/T (pg/mL/ng/mL) increased from 3.62 to 4.66; (2) T/E2 (ng/mL) rose from 91.68 to 148; and (3) FT/E2 (ng/mL) from 0.31 to 0.67.
It is well known that approximately 98% of testosterone molecules are bound to proteins in the blood, principally to sex hormone–binding globulin (SHBG), and are not bioavailable because bound hormones cannot exit capillaries.22 Thus, the elevation of unbound free testosterone seen with boron supplementation may have significant beneficial ramifications, particularly in aging men in whom, typically, levels of SHBG increase and levels of FT decrease.23
Prevention of Vitamin-D Deficiency
Boron has been shown to increase serum levels of 25-hydroxyvitamin D3 (25[OH]D3) in animal studies4,24 and of vitamin D–deficient individuals in human studies.25,26 In a clinical trial25 in which middle-aged men and women (n = 15) were placed on a low-boron diet, which was also marginal in magnesium and copper status, for 63 days (0.23 mg B/2000 kcal), 25(OH)D3 rose significantly after boron supplementation (3 mg/d as sodium borate) for an additional 49 days. Levels of 25(OH)D3 rose from an average of 44.9 nM after the 63 days of boron deprivation to 62.4 nM after the 49 days of boron repletion, a 39% increase.
Similar results were seen in an open pilot study of middle-aged individuals (n = 13) predetermined to be vitamin D deficient (serum 25[OH]D3 < 12 ng/mL). Levels of 25(OH)D3 were studied during boron supplementation of 6 mg/d for 60 days using calcium fructoborate, Ca([C6H10O6]2B)2·4H2O, a boron-containing complex that occurs naturally in fruit.26 The study took place in Serbia with supplementation beginning in October and concluding by January; in other words, the study occurred during the fall transition to winter, a time when vitamin-D status would be expected to worsen. Yet, with boron supplementation, 25(OH)D3 levels rose significantly, with an average rise of 20%.27
How does boron exert its hormonal effects? In sum, boron increases the biological half-life and bioavailability of E2 and vitamin D.
Boron Increases Half-life and Bioavailability of Sex Hormones and Vitamin D Boron’s beneficial effects on bone metabolism are due in part to the roles it plays in both producing E2 and in increasing its biological half-life and that of vitamin D. Regarding 17β-estradiol, the simplest and preferred pathway for its production is reduction of the keto group of estrone by a tetrahydroborate salt, potassium borohydride.28
Regarding vitamin D, Miljkovic et al27 proposed in an excellent paper in Medical Hypotheses that boron suppresses the activity of 24-hydroxylase, the microsomal enzyme primarily responsible for catabolism of 25(OH)D3. A number of recent papers, which are discussed in the following text, have provided evidence to support this hypothesis.
The hypothesis by Milijkovic et al27 also accounts for boron’s well-recognized upregulation of 17β-estradiol levels in women, including postmenopausal women receiving hormone replacement therapy, because catabolism of 17β-estradiol is also achieved by microsomal enzymes catalyzing vicinal hydroxylations (eg, 24-hydroxylase). This suggests a more general hypothesis: Nutritional boron can inhibit a range of microsomal enzymes that insert hydroxyl groups vicinal to existing hydroxyls in steroids, which include enzymes that catabolize 17β-estradiol, 25(OH)D3, and 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3).29 As noted by Miljkovic et al27:
Boron readily forms covalent complexes with cis-vicinal dihydroxy compounds. Thus, it is conceivable that it can form such a complex with 24,25-dihydroxyvitamin D, the end product of the reaction of 25(OH)D3 with 24-hydroxylase. This postulated complex might either act as a competitive inhibitor of the 24-hydroxylase reaction, or alternatively, perhaps could act to down-regulate expression of the enzyme. Another possibility is that boron is a direct inhibitor of the enzyme at very modest concentrations; indeed, boron can inhibit numerous enzymes …
Therefore, boron’s beneficial hormonal effects are likely to be a result of its general impact on vicinal hydroxylations of steroids.
In chemistry, vicinal stands for any 2 functional groups that are bonded to 2 adjacent carbon atoms. Hydroxylation is the addition of a hydroxyl group (-OH). Boronic acids’ unique feature is their ability to form reversible covalent complexes with molecules containing vicinal hydroxyl groups. Boronic acids act as Lewis acids, substances that can accept a lone pair of electrons from another molecule in completing the stable group of one of their own atoms. For example, H+ is a Lewis acid because it can accept a lone pair, completing its stable form, which requires 2 electrons. The current definition of a Lewis acid is:
… a molecular entity (and the corresponding chemical species) that is an electron-pair acceptor, and therefore, able to react with a Lewis base to form a Lewis adduct by sharing the electron pair furnished by the Lewis base. A Lewis base is any species that donates a pair of electrons to a Lewis acid to form a Lewis adduct.33
Deactivation of Vitamin D
Cholecalciferol (vitamin D3) is both activated and degraded via hydroxylation. Synthesis of vitamin D begins in the skin as a nonenzymatic process when the absorption of ultraviolet B (UVB) radiation in sunlight results in conversion of 7-dehydrocholesterol, a metabolite of cholesterol stored in the skin, to precholecalciferol. Precholecalciferol is immediately converted into cholecalciferol (vitamin D3) and transported to the liver where it undergoes hydroxylation by 25-hydroxylase. Actually, 75% of serum 25(OH)D3 arises from the action of 1,25-dihydroxyvitamin D3 24-hydroxylase (CYP2R1), and an, as yet, unidentified enzyme is responsible for the remaining 25% of 25-hydroxylation of cholecalciferol.30
The result of this 25-hydroxylation is the formation of calcidiol (25[OH]D3). A second hydroxylation takes place in the kidney, where calcidiol undergoes hydroxylation by 1α-hydroxylase (CYP27B1) at the C-1 position to form the hormonal, most-active metabolite, calcitriol (1,25[OH]2D3). The 24-hydroxylation of 25(OH)D3 and calcitriol, which is accomplished by 1,25-dihydroxyvitamin D3 24-hydroxylase (CYP24A1), leads to the degradation of these vitamin-D metabolites.31
As already mentioned, serum concentrations of both 25(OH)D3 and 17β-estradiol increase when boron is supplemented. Because this effect is seen in postmenopausal women receiving hormone replacement therapy, a reduction in E2 catabolism, rather than increased E2 synthesis, is responsible. Each of the major routes of E2 catabolism involve hydroxylations (ie, the introduction of a vicinal hydroxyl group at the 2, 4, or 16 position of 17β-estradiol), which is already hydroxylated at the 3 and 17 positions. This addition indicates that boron is a potent inhibitor for microsomal enzymes that catalyze the insertion of hydroxyl groups vicinal to existing hydroxyl groups in steroids.
Boron May Improve the Effects of Vitamin D Supplementation in “Nonresponders”
Support for boron’s potential for beneficial effects on vitamin D levels is suggested by recent research investigating the relationship between levels of DNA methylation of CYP24A1, a 24-hydroxylase enzyme, and CYP2R1, a 25-hydroxylase enzyme, and also by examining postmenopausal women’s ability to increase serum 25(OH)D3 in response to vitamin-D supplementation.32
Researchers randomly assigned 446 white, postmenopausal women to a calcium and vitamin D intervention, 1100 IU/day, for at least 12 months. From these subjects, 18 with the highest 12-month increase in serum 25(OH)D3 were selected as responders, and 18 with the lowest 12-month increase in serum 25(OH)D3 were selected as nonresponders. Levels of deoxyribonucleic acid (DNA) methylation for the 2 groups were compared.
Methylation silences or shuts down activity in these CpG sites; thus, greater methylation leads to lessened production of the hydroxylase. Responders had significantly lower baseline levels of DNA methylation in the promoter region of CYP2R1—a 25-hydroxylase that activates vitamin D—than nonresponders had, 8% versus 30%, respectively. That finding indicated a greater production of 25-hydroxylase, and, thus, greater potential for vitamin-D activation.
Responders also had lower baseline levels of DNA methylation in the promoter region of CYP24A1, a 24-hydroxylase that degrades vitamin D, than the nonresponders had, 13% versus 32%, respectively. This finding possibly indicates a balance in responders’ ability to both activate and then degrade vitamin D. Although nonresponders’ levels of DNA methylation of CYP24A1 were greater, it is unknown whether the 24-hydroxylase enzymes that they produced had a higher-than-average rate of activity. Boron was not included in this investigation, but it would have been germane to have assayed subjects’ boron intake and serum levels because boron inhibits the activity of 24-hydroxylase.
Two specific examples of that process are the E2 hydroxylases and 24-hydroxylase, the enzymes that catalyze the conversion of 25(OH)D3 and 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) into 24-hydroxylated products, which constitute the degradation products of the vitamin-D molecule. A summary of the activation and deactivation of vitamin D.34
Magnesium Absorption
Boron significantly improves magnesium absorption and deposition in bone, yet another beneficial effect of boron’s inhibition of 17β-estradiol degradation. Thus, boron is a factor in magnesium’s myriad beneficial effects. Magnesium’s importance, in bone alone, is illustrative of the widespread ramifications of boron insufficiency.
Approximately 60% of the magnesium in the human body is found in bone, where it is a cofactor for key enzymes that regulate calcium metabolism. The majority of magnesium in bone resides on cortical bone, an integral part of the structure of apatite crystal.35 Apart from its structural role in apatite crystals, magnesium is required in osteoblasts and osteoclasts and in all living cells, within which magnesium is fundamental for adenosine triphosphate (ATP) production and serves as the cofactor of more than 300 enzymes involved in lipid, protein, and nucleic acid synthesis. Because of its positive charge, magnesium stabilizes cell membranes, balances the actions of calcium, and functions as a signal transducer.31
Anti-inflammatory Effects
A number of papers have indicated that boron reduces levels of inflammatory biomarkers.20,36,37 In a recent human trial involving healthy male volunteers (n = 8), a significant increase in concentrations of plasma boron occurred 6 hours after supplementation with 11.6 mg of boron, coupled with significant decreases in levels of hs-CRP and TNF-α. One week of boron supplementation 10 mg/d resulted in a 20% decrease in the plasma concentration of TNF-α, from 12.32 to 9.97 pg/mL, and in remarkable decreases (approximately 50%) in plasma concentration of hs-CRP, from 1460 to 795 ng/mL, and of IL-6, from 1.55 to 0.87 pg/mL.
Is boron adequacy important? Consider that elevated hs-CRP is associated with an increased risk for breast cancer,38 obesity and metabolic syndrome (MetS) in children,39 atherosclerosis, unstable angina, insulin resistance, type 2 diabetes,40,41 nonalcoholic fatty liver disease (NAFLD),42,43 metastatic prostate cancer,44 lung cancer,45 adult depression, depression in childhood and psychosis in young adult life,46,47 coronary heart disease, and stroke.48–51
