REVIEW ARTICLE

Nothing Boring About Boron

Lara Pizzorno, MDiv, MA, LMT

Abstract
The trace mineral boron is a micronutrient with diverse biomolecules, such as S-adenosyl methionine (SAM-e)
and vitally important roles in metabolism that render it and nicotinamide adenine dinucleotide (NAD+);
necessary for plant, animal, and human health, and as (10) has demonstrated preventive and therapeutic
recent research suggests, possibly for the evolution of effects in a number of cancers, such as prostate, cervical,
life on Earth. As the current article shows, boron has and lung cancers, and multiple and non-Hodgkin’s
been proven to be an important trace mineral because it lymphoma; and (11) may help ameliorate the adverse
(1) is essential for the growth and maintenance of bone; effects of traditional chemotherapeutic agents. In none
(2) greatly improves wound healing; (3) beneficially of the numerous studies conducted to date, however, do
impacts the body’s use of estrogen, testosterone, and boron’s beneficial effects appear at intakes > 3 mg/d. No
vitamin D; (4) boosts magnesium absorption; estimated average requirements (EARs) or dietary
(5) reduces levels of inflammatory biomarkers, such as reference intakes (DRIs) have been set for boron—only
high-sensitivity C-reactive protein (hs-CRP) and tumor an upper intake level (UL) of 20 mg/d for individuals
necrosis factor α (TNF-α); (6) raises levels of antioxidant aged ≥ 18 y. The absence of studies showing harm in
enzymes, such as superoxide dismutase (SOD), catalase, conjunction with the substantial number of articles
and glutathione peroxidase; (7) protects against showing benefits support the consideration of boron
pesticide-induced oxidative stress and heavy-metal supplementation of 3 mg/d for any individual who is
toxicity; (8) improves the brains electrical activity, consuming a diet lacking in fruits and vegetables or who
cognitive performance, and short-term memory for is at risk for or has osteopenia; osteoporosis;
elders; (9) influences the formation and activity of key osteoarthritis (OA); or breast, prostate, or lung cancer.

Lara Pizzorno, MDiv, MA, LMT, is a senior medical editor help alleviate arthritis and improve brain function and has
at Integrative Medicine Advisors, LLC, in Seattle, demonstrated such significant anticancer effects that
Washington. boronated compounds are now being used in the treatment
of several types of cancer. A summary of the evidence
Corresponding author: Lara Pizzorno, MDiv, MA, LMT suggesting that boron should be given consideration as an
E-mail address: [email protected] essential micronutrient is provided, together with leading
dietary sources and intake recommendations.

T
he trace mineral boron is a micronutrient with Salient Effects
diverse and vitally important roles in metabolism Bone Growth and Maintenance
that render it necessary for plant, animal, and Scientists have known for many years that boron is
human health, and, possibly, as recent research suggests, essential for healthy bones. In 1985, the US Department of
for the evolution of life on Earth. The current review Agriculture (USDA) conducted an experiment in which
focuses primarily on boron’s most salient effects on postmenopausal women (n = 12) who had been put on a
human health, including its impact on bone development low-boron diet (0.25 mg/d for 119 d) were supplemented
and regeneration, wound healing, the production and with 3 mg/d of boron during two 28-day trials. In one trial,
metabolism of sex steroids and vitamin D, and the magnesium intake was low; in the other, magnesium
absorption and use of calcium and magnesium. In intake was adequate. With boron supplementation, the
addition, boron has anti-inflammatory effects that can women’s daily urinary excretion of calcium was reduced

Pizzorno—Boron Integrative Medicine • Vol. 14, No. 4 • August 2015 35

 by 44%. The reduction in calcium loss resulting from Expression of Extracellular-matrix Proteins
boron supplementation was 52 mg/d when the women Hakki et al7 extended understanding of the
were low in magnesium and 22 mg/d when magnesium mechanisms behind boron’s effects a step further, showing
levels were adequate.1 that boron regulates the messenger RNA (mRNA)
Boron plays an important role in osteogenesis, and its expression of a wide range of extracellular-matrix proteins,
deficiency has been shown to adversely impact bone not only those involved in wound repair but also the
development and regeneration.2 Boron influences the mineralized tissue-associated proteins, collagen type 1
production and activity of steroid hormones, actions via (COL1), osteopontin (OPN), bone sialoprotein (BSP), and
which this trace mineral is involved in the prevention of osteocalcin (OCN). The combined effects of these actions
calcium loss and bone demineralization. Boron boost osteoblast-cell viability, proliferation, and
supplementation has repeatedly been shown to markedly morphology as well as the mineralization of bone cells.
reduce urinary excretion of both calcium and magnesium Further research conducted by other investigators on
and to increase serum levels of estradiol and calcium human bone marrow stromal cells confirmed earlier
absorption in peri- and postmenopausal women.1,3 Boron discoveries of the mechanisms through which boron
also beneficially impacts vitamin-D utilization. boosts osteogenic differentiation and continued to add to
Supplementation with boron stimulates bone growth in the list. Boron was also found to increase mRNA expression
vitamin-D deficient animals and alleviates dysfunctions in of alkaline phosphatase and bone morphogenetic proteins
mineral metabolism characteristic of vitamin-D deficiency.4 (BMPs).11 Several other researchers have now confirmed
Animal studies published in 20085 and 20096 found that boron regulates protein levels of key BMPs—BMP-4,
that healing of the alveolar bone—a ridge of compact bone BMP-6, and BMP-7—plus the mRNA expression of runt-
that contains the tooth sockets on the maxillae and related transcription factor 2 (RUNX2).
mandible (ie, the bones that hold teeth)—was inhibited in The BMPs are multifunctional growth factors that
boron-deficient rats. Compared with boron-adequate rats belong to the transforming growth factor β (TGF-β)
(3 mg/kg/d of boron in the diet) when evaluated at 7 and superfamily, and several induce formation of new cartilage
14 days, boron-deficient animals (0.07 mg/kg/d boron in and bone. Of the 20 BMP family members that have been
the diet) had significant reductions in osteoblast surface identified and characterized to date,12,13 BMP-2, BMP-4,
(57% and 87% at 7 d and 14 d, respectively) concomitant BMP-6, and BMP-7, all of which show transcription and
with increases in quiescent surface (120% and 126% at activity regulated by boron, have been found necessary to
7 d and 14 d, respectively), indicating that boron deficiency induce osteoblastic differentiation in primary human,
can result in impaired bone healing due to a marked mesenchymal stem cells.14,15
reduction in osteogenesis. Boron was also determined to regulate production of
In 2010, Hakki et al7 published research investigating the RUNX2, also known as core-binding factor subunit α-1
mechanisms underlying boron’s effects on osteogenesis. (CBF-α1). RUNX2 is essential to osteoblastic differentiation
Boron was determined to induce mineralization of osteoblasts and bone formation and to bone maintenance. It is a
by regulating the expression of genes related to tissue transcription factor that works cooperatively with BMPs
mineralization and the actions of key hormones (17β-estradiol to stimulate osteoblast gene expression and the
[E2], testosterone, and vitamin D) involved in bone growth differentiation of mesenchymal stem cells into osteoblasts,
and turnover. Boron’s induction of tissue mineralization also and it remains active in mature osteoblasts. When active
underlies boron’s beneficial effects on wound healing. RUNX2 levels are reduced, expression of the genes
encoding the main bone-matrix proteins drops, including
Wound Healing BSP, OCN, OPN, and COL1.16-19
Since 1990, boron has been shown to significantly
improve wound healing. Application of a 3% boric acid Regulation of Sex Hormones
solution to deep wounds reduced the time required in Increased levels of sex steroids have been demonstrated
intensive care by two-thirds.8 In 2000, in vitro research in both men and women after boron supplementation.1,20
using human fibroblasts showed that a boric-acid solution In 1987, Nielsen et al1 reported that dietary boron repletion
improved wound healing through action on the extracellular in postmenopausal women (n = 13), who were previously
matrix.9 Further in vitro studies published in 2002 revealed on a low-boron diet, significantly increased their serum
that these beneficial effects of boron were due to direct estradiol (E2) and testosterone levels, particularly for those
actions on specific enzymes found in fibroblasts: elastase, women whose dietary intake of magnesium was low. In
trypsin-like enzymes, collagenase, and alkaline women on a low-magnesium diet, E2 almost doubled,
phosphatase.10 The most common cells in animal connective increasing from an average of 21.1 pg/mL to 41.4 pg/mL.
tissue, fibroblasts synthesize the extracellular matrix and Testosterone more than doubled, rising from an average of
collagen and play a critical role in wound healing. Boron 0.31 ng/mL to 0.83 ng/mL. Similar increases were seen in
facilitates the activity of these key enzymes in fibroblasts, the women on an adequate-magnesium diet: E2 rose from
thus improving extracellular-matrix turnover. an average of 15.5 pg/mL to 38.0 pg/mL, and testosterone

36 Integrative Medicine • Vol. 14, No. 4 • August 2015 Pizzorno—Boron

increased from 0.38 ng/mL to 0.65 ng/mL. In 1997, Naghii concluding by January; in other words, the study occurred
et al21 published findings of a similar increase in serum during the fall transition to winter, a time when vitamin-D
levels of E2 in healthy males (n = 18) after 4 weeks of status would be expected to worsen. Yet, with boron
dietary supplementation with boron. supplementation, 25(OH)D3 levels rose significantly, with
After only 1 week of boron supplementation of an average rise of 20%.27
6 mg/d, a further study by Naghii et al20 of healthy males How does boron exert its hormonal effects? In sum,
(n = 8) found (1) a significant increase in free testosterone, boron increases the biological half-life and bioavailability
which rose from an average of 11.83 pg/mL to 15.18 pg/mL; of E2 and vitamin D.
and (2) significant decreases in E2, which dropped from Boron Increases Half-life and Bioavailability of Sex
42.33 pg/mL to 25.81 pg/mL. All of the inflammatory Hormones and Vitamin D. Boron’s beneficial effects on
biomarkers that were measured also decreased: bone metabolism are due in part to the roles it plays in
(1) interleukin (IL) 6, from 1.55 pg/mL to 0.87 pg/mL; both producing E2 and in increasing its biological half-life
(2) high-sensitivity C-reactive protein (hs-CRP) by and that of vitamin D. Regarding 17β-estradiol, the
approximately 50%, a remarkable decrease, from 1460 ng/mL simplest and preferred pathway for its production is
to 795 ng/mL; and (3) tumor necrosis factor α (TNF-α) by reduction of the keto group of estrone by a tetrahydroborate
approximately 30%, from 12.32 to 9.97 pg/mL. Levels of salt, potassium borohydride.28
dihydrotestosterone, cortisol, and vitamin D increased Regarding vitamin D, Miljkovic et al27 proposed in an
slightly. excellent paper in Medical Hypotheses that boron suppresses
The significant decrease in the men’s plasma E2 after the activity of 24-hydroxylase, the microsomal enzyme
1 week of boron supplementation suggests a higher rate of primarily responsible for catabolism of 25(OH)D3.
conversion of total testosterone (T) to free testosterone A number of recent papers, which are discussed in the
(FT) in the testosterone metabolic pathway. In support, following text, have provided evidence to support this
the ratios of FT/T, T/E2, and FT/E2 were all significantly hypothesis.
increased, indicating boron had androgen amplifier effects: The hypothesis by Milijkovic et al27 also accounts for
(1) FT/T (pg/mL/ng/mL) increased from 3.62 to 4.66; boron’s well-recognized upregulation of 17β-estradiol levels
(2) T/E2 (ng/mL) rose from 91.68 to 148; and in women, including postmenopausal women receiving
(3) FT/E2 (ng/mL) from 0.31 to 0.67. hormone replacement therapy, because catabolism of
It is well known that approximately 98% of testosterone 17β-estradiol is also achieved by microsomal enzymes
molecules are bound to proteins in the blood, principally to catalyzing vicinal hydroxylations (eg, 24-hydroxylase). This
sex hormone–binding globulin (SHBG), and are not suggests a more general hypothesis: Nutritional boron can
bioavailable because bound hormones cannot exit inhibit a range of microsomal enzymes that insert hydroxyl
capillaries.22 Thus, the elevation of unbound free testosterone groups vicinal to existing hydroxyls in steroids, which
seen with boron supplementation may have significant include enzymes that catabolize 17β-estradiol, 25(OH)D3,
beneficial ramifications, particularly in aging men in whom, and 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3).29 As
typically, levels of SHBG increase and levels of FT decrease.23 noted by Miljkovic et al27:

Prevention of Vitamin-D Deficiency Boron readily forms covalent complexes with

Boron has been shown to increase serum levels of cis-vicinal dihydroxy compounds. Thus, it is
25-hydroxyvitamin D3 (25[OH]D3) in animal studies4,24 and conceivable that it can form such a complex with
24,25-dihydroxyvitamin D, the end product of the
of vitamin D–deficient individuals in human studies.25,26 In
reaction of 25(OH)D3 with 24-hydroxylase. This
a clinical trial25 in which middle-aged men and women postulated complex might either act as a competitive
(n = 15) were placed on a low-boron diet, which was also inhibitor of the 24-hydroxylase reaction, or
marginal in magnesium and copper status, for 63 days alternatively, perhaps could act to down-regulate
(0.23 mg B/2000 kcal), 25(OH)D3 rose significantly after expression of the enzyme. Another possibility is that
boron supplementation (3 mg/d as sodium borate) for an boron is a direct inhibitor of the enzyme at very
additional 49 days. Levels of 25(OH)D3 rose from an modest concentrations; indeed, boron can inhibit
average of 44.9 nM after the 63 days of boron deprivation to numerous enzymes …
62.4 nM after the 49 days of boron repletion, a 39% increase.
Similar results were seen in an open pilot study of Therefore, boron’s beneficial hormonal effects are likely to
middle-aged individuals (n = 13) predetermined to be be a result of its general impact on vicinal hydroxylations
vitamin D deficient (serum 25[OH]D3 < 12 ng/mL). Levels of steroids.
of 25(OH)D3 were studied during boron supplementation In chemistry, vicinal stands for any 2 functional groups
of 6 mg/d for 60 days using calcium fructoborate, that are bonded to 2 adjacent carbon atoms. Hydroxylation
Ca([C6H10O6]2B)2∙4H2O, a boron-containing complex that is the addition of a hydroxyl group (-OH). Boronic acids’
occurs naturally in fruit.26 The study took place in Serbia unique feature is their ability to form reversible covalent
with supplementation beginning in October and complexes with molecules containing vicinal hydroxyl

Pizzorno—Boron Integrative Medicine • Vol. 14, No. 4 • August 2015 37

Deactivation of Vitamin D groups. Boronic acids act as Lewis acids, substances that can
Cholecalciferol (vitamin D3) is both activated and degraded via accept a lone pair of electrons from another molecule in
hydroxylation. Synthesis of vitamin D begins in the skin as a completing the stable group of one of their own atoms. For
nonenzymatic process when the absorption of ultraviolet B (UVB) example, H+ is a Lewis acid because it can accept a lone pair,
radiation in sunlight results in conversion of 7-dehydrocholesterol, a completing its stable form, which requires 2 electrons. The
metabolite of cholesterol stored in the skin, to precholecalciferol. current definition of a Lewis acid is:
Precholecalciferol is immediately converted into cholecalciferol
(vitamin D3) and transported to the liver where it undergoes … a molecular entity (and the corresponding chemical
hydroxylation by 25-hydroxylase. Actually, 75% of serum 25(OH)D3 species) that is an electron-pair acceptor, and therefore, able
arises from the action of 1,25-dihydroxyvitamin D3 24-hydroxylase to react with a Lewis base to form a Lewis adduct by sharing
the electron pair furnished by the Lewis base. A Lewis base
(CYP2R1), and an, as yet, unidentified enzyme is responsible for the
is any species that donates a pair of electrons to a Lewis acid
remaining 25% of 25-hydroxylation of cholecalciferol.30
to form a Lewis adduct.33
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 As already mentioned, serum concentrations of both
(CYP27B1) at the C-1 position to form the hormonal, most-active 25(OH)D3 and 17β-estradiol increase when boron is
metabolite, calcitriol (1,25[OH]2D3). The 24-hydroxylation of supplemented. Because this effect is seen in postmenopausal
25(OH)D3 and calcitriol, which is accomplished by women receiving hormone replacement therapy, a
1,25-dihydroxyvitamin D3 24-hydroxylase (CYP24A1), leads to the reduction in E2 catabolism, rather than increased E2
degradation of these vitamin-D metabolites.31 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
Boron May Improve the Effects of Vitamin D Supplementation 17β-estradiol), which is already hydroxylated at the 3 and
in “Nonresponders” 17 positions. This addition indicates that boron is a potent
Support for boron’s potential for beneficial effects on vitamin inhibitor for microsomal enzymes that catalyze the
D levels is suggested by recent research investigating the relationship insertion of hydroxyl groups vicinal to existing hydroxyl
between levels of DNA methylation of CYP24A1, a 24-hydroxylase groups in steroids.
enzyme, and CYP2R1, a 25-hydroxylase enzyme, and also by Two specific examples of that process are the E2
examining postmenopausal women’s ability to increase serum hydroxylases and 24-hydroxylase, the enzymes that catalyze
25(OH)D3 in response to vitamin-D supplementation.32 the conversion of 25(OH)D3 and 1,25-dihydroxyvitamin D3
Researchers randomly assigned 446 white, postmenopausal (1,25[OH]2D3) into 24-hydroxylated products, which
women to a calcium and vitamin D intervention, 1100 IU/day, for constitute the degradation products of the vitamin-D
at least 12 months. From these subjects, 18 with the highest molecule. A summary of the activation and deactivation of
12-month increase in serum 25(OH)D3 were selected as responders, vitamin D.34
and 18 with the lowest 12-month increase in serum 25(OH)D3 were
selected as nonresponders. Levels of deoxyribonucleic acid (DNA) Magnesium Absorption
methylation for the 2 groups were compared. Boron significantly improves magnesium absorption
Methylation silences or shuts down activity in these CpG sites; and deposition in bone, yet another beneficial effect of
thus, greater methylation leads to lessened production of the boron’s inhibition of 17β-estradiol degradation. Thus,
hydroxylase. Responders had significantly lower baseline levels of boron is a factor in magnesium’s myriad beneficial effects.
DNA methylation in the promoter region of CYP2R1—a Magnesium’s importance, in bone alone, is illustrative of
25-hydroxylase that activates vitamin D—than nonresponders had, the widespread ramifications of boron insufficiency.
8% versus 30%, respectively. That finding indicated a greater Approximately 60% of the magnesium in the human
production of 25-hydroxylase, and, thus, greater potential for body is found in bone, where it is a cofactor for key
vitamin-D activation. enzymes that regulate calcium metabolism. The majority
Responders also had lower baseline levels of DNA methylation of magnesium in bone resides on cortical bone, an integral
in the promoter region of CYP24A1, a 24-hydroxylase that degrades part of the structure of apatite crystal.35 Apart from its
vitamin D, than the nonresponders had, 13% versus 32%, structural role in apatite crystals, magnesium is required
respectively. This finding possibly indicates a balance in responders’ in osteoblasts and osteoclasts and in all living cells, within
ability to both activate and then degrade vitamin D. Although which magnesium is fundamental for adenosine
nonresponders’ levels of DNA methylation of CYP24A1 were triphosphate (ATP) production and serves as the cofactor
greater, it is unknown whether the 24-hydroxylase enzymes that of more than 300 enzymes involved in lipid, protein, and
they produced had a higher-than-average rate of activity. Boron nucleic acid synthesis. Because of its positive charge,
was not included in this investigation, but it would have been magnesium stabilizes cell membranes, balances the actions
germane to have assayed subjects’ boron intake and serum levels of calcium, and functions as a signal transducer.31
because boron inhibits the activity of 24-hydroxylase.

38 Integrative Medicine • Vol. 14, No. 4 • August 2015 Pizzorno—Boron

Anti-inflammatory Effects Clinical Effects of Hypomagnesemia
A number of papers have indicated that boron reduces In addition to its direct effects on the structure and cells of
levels of inflammatory biomarkers.20,36,37 In a recent human the skeleton, magnesium impacts bone indirectly by affecting
trial involving healthy male volunteers (n = 8), a significant the homeostasis of the 2 master regulators of calcium
increase in concentrations of plasma boron occurred homeostasis (ie, parathyroid hormone [PTH] and
6 hours after supplementation with 11.6 mg of boron, 1,25[OH]2D3).59 PTH signaling involves the increase of cyclic
coupled with significant decreases in levels of hs-CRP and adenosine monophosphate (cAMP) through the activation of
TNF-α. One week of boron supplementation 10 mg/d adenylate cyclase, which requires magnesium.
resulted in a 20% decrease in the plasma concentration of Hypomagnesemia impairs secretion of PTH and renders
TNF-α, from 12.32 to 9.97 pg/mL, and in remarkable target organs refractory to PTH. Reduced secretion of PTH or
decreases (approximately 50%) in plasma concentration of impaired peripheral response to the hormone leads to low
hs-CRP, from 1460 to 795 ng/mL, and of IL-6, from 1.55 serum concentrations of 25(OH)D3. In addition, the
to 0.87 pg/mL. hydroxylase enzyme 25-hydroxycholecalciferol-1-hydroxylase,
Is boron adequacy important? Consider that elevated which is responsible for production of the most active,
hs-CRP is associated with an increased risk for breast hormonal form of vitamin D, calcitriol, requires magnesium as
cancer,38 obesity and metabolic syndrome (MetS) in its cofactor. Consequently magnesium deficiency impairs
children,39 atherosclerosis, unstable angina, insulin calcitriol production.
resistance, type 2 diabetes,40,41 nonalcoholic fatty liver Hypomagnesemia promotes inflammation.60 Substance P
disease (NAFLD),42,43 metastatic prostate cancer,44 lung is released at high levels in magnesium deficiency, and the
cancer,45 adult depression, depression in childhood and levels of proinflammatory cytokines—TNF-α, IL-1, and IL-6—
psychosis in young adult life,46,47 coronary heart disease, increase both in the serum and the bone marrow. Magnesium
and stroke.48-51 also plays an important role in carbohydrate metabolism; its
deficiency provokes and worsens insulin resistance.
Anti-inflammatory Effects in Osteoarthritis Insulin resistance and resulting high glucose
Epidemiological evidence, case reports, and controlled concentrations (>12 mM) alter the biomineralization process
animal and human studies have provided evidence for the in osteoblastic cells so that although a number of factors
use of boron as a safe and effective treatment for promoting osteoblast activity are triggered, less calcium is
osteoarthritis (OA).52-54 Examining the relationship deposited. High glucose increases mRNA expression of the
between boron administration and OA prevalence around receptor activator of nuclear factor kappa Β ligand (RANKL),
the world, researchers discovered that in areas where OCN, BSP, and RUNX2, but it decreases expression of the
boron intake is greater than or equal to 1 mg/d, the decoy for RANKL (ie, osteoprotegerin) and increases mRNA
estimated incidence of arthritis ranges from 20% to 70%. expression of proinflammatory cytokines (eg, IL-6, IL-10,
In contrast, in areas where boron intake is usually 3 to 10 and TNF-α). Osteoblastic cells cultured in normal glucose
mg/d, estimated incidence of arthritis ranges from 0% to conditions had a Ca/P ratio of 1.48 and 1.60 at 7 days and
10%.55 The boron concentration has been found to be 14 days, respectively. In contrast, mineral deposits formed by
lower in the femur heads, bones, and synovial fluid of OA osteoblastic cells cultured with high d-(+)-glucose
patients compared with individuals without OA.56 concentrations had Ca/P ratios of 0.78 and 1.29 at 7 days and
Analysis of animal studies, in which rats with induced 14 days, respectively. These findings represent just a few of
arthritis benefited from orally or intraperitoneally the ways in which hypomagnesemia causes accelerated bone
administered boron, revealed that boron downregulates loss. Adequate boron intake of 3 mg/d can help prevent
production and activity of serine protease enzymes hypomagnesemia.
involved in the inflammatory response.57 Human studies
of boron deprivation and repletion have shown that boron
significantly increases erythrocyte superoxide dismutase decahydrate) was seen in 20 subjects with OA; 50% of
(SOD) activity. In a study in which 63 days of boron subjects receiving supplemental boron improved compared
depletion were followed by 49 days of boron with only 10% of those receiving the placebo.61
supplementation 3 mg/d, SOD rose from 3091 U/g Hb to In vitro studies have shown anti-inflammatory effects
3231 U/g Hb in men older than 45 years, from of calcium fructoborate—a naturally occurring, plant-
2666 U/g Hb to 3169 U/g Hb in postmenopausal women, based, boron-carbohydrate complex—on cellular
and from 2520 U/g Hb to 3327 U/g Hb in postmenopausal cultures,62 and an open-label pilot study (n = 20) found
women on estrogen therapy.58 that calcium fructoborate had highly positive effects on
Human clinical evidence for boron’s use in the OA symptoms.26 In the 8-week pilot study, OA patients
treatment of OA patients was first provided by a double- were divided into 2 groups, those with mild and medium
blind, placebo-controlled supplementation trial conducted forms of OA and those with severe cases. Two assessment
in Australia, in which a significantly favorable response to measures were used, the Western Ontario and McMaster
a supplement of 6 mg of boron per day (sodium tetraborate Universities Arthritis Index (WOMAC) and the Newnham

Pizzorno—Boron Integrative Medicine • Vol. 14, No. 4 • August 2015 39

 criteria. Mild-to-medium cases received 6 mg/d of
High-sensitivity C-reactive Protein supplemental boron; severe cases received 12 mg/d. In
C-reactive protein (CRP) is an acute-phase protein subjects with mild and medium OA, average pain
produced in the liver in response to increased immune-cell reduction was 62.5% in 4 weeks and 70.8% in 8 weeks. In
production of proinflammatory cytokines (eg, IL-1, IL-6, IL-8, the first 4 weeks, 80% of mild-to-medium OA subjects
and TNF-α). CRP is a known predictor of risk for cardiovascular reduced or eliminated their analgesic (ibuprofen) use. By
disease (CVD), heart attack, and stroke. Studies have also 8 weeks, 67% had stopped using the nonsteroidal anti-
shown a clear link between above-normal levels of CRP and inflammatory drug (NSAID) medication. Joint rigidity
OA, periodontal disease, and risk for fracture. In Japan, where disappeared in one-half of the mild and medium OA
women typically have substantially lower levels of CRP than patients in the first 4 weeks and decreased in the remaining
their Caucasian counterparts, women whose CRP levels were one-half by 87.5% on average. By week 8, all subjects with
above what is normal for the Japanese had more than double mild- and medium-level OA were rigidity free. Mobility
the risk for fracture—2.22 if in the medium quartile and 2.40 if and flexibility were significantly improved in 71.4% of
in the quartile with the highest CRP levels.63 subjects at 4 weeks and in 77.8% at 8 weeks.
Two tests can be used to evaluate CRP: CRP and hs-CRP. In the severe OA group, average pain reduction was
Both tests measure the same molecule in the blood. CRP is the 47.9% at 4 weeks and 64.5% at 8 weeks. In the first 4 weeks,
standard test and measures a much wider, higher range of CRP 40% of subjects with severe OA reduced or eliminated their
levels than hs-CRP, but CRP does not do well in capturing the analgesic (ibuprofen) use. By week 8, 75% had quit using
lower ranges, which are important in determining whether their NSAID medication (ibuprofen). Joint rigidity
low-level, chronic inflammation is present and which may be a disappeared in one-half of the severe OA patients in the first
contributing factor to an ongoing disease process. The test for 4 weeks. In the remaining one-half, joint rigidity decreased
hs-CRP accurately detects the lower concentrations of CRP. significantly, an average rigidity reduction of 50%. Mobility
People with chronically elevated inflammation (eg, individuals and flexibility were significantly improved in 50% of severe
with conditions such as arthritis or periodontal disease) should OA subjects at 4 weeks and in 62.5% at 8 weeks.
have the CRP, not the hs-CRP test run. Their CRP levels will be Based on the results of animal studies,62 the
very high, often too high to be meaningful or even measured researchers hypothesized that boron’s anti-inflammatory
using the hs-CRP test. The hs-CRP test is the better choice for effects result from inhibition of the oxidative burst by
apparently healthy people to determine whether they have low- scavenging cells (leukocytes) and excessive activity by
grade chronic inflammation. The hs-CRP test measures CRP neutrophils (ie, white cells that scavenge debris) and
in the range from 0.5 to 10 mg/L. The standard CRP test invaders outside of the circulatory system. Boron also
measures CRP in the range from 10 to 1000 mg/L. boosts free-radical scavenging by raising levels of a
Hs-CRP usually is ordered as one of several tests in a triumvirate of antioxidant enzymes in blood and cells:
cardiovascular risk profile, often together with tests for SOD, catalase, and glutathione peroxidase.
cholesterol and triglycerides, because the best way to predict Scorei et al54 then conducted a double-blind, placebo-
cardiovascular risk is to combine a good marker for inflammation, controlled pilot study to evaluate the effects of different
such as hs-CRP, with the lipid profile. Research has now shown dosages of calcium fructoborate on systemic inflammation
that healthy people whose hs-CRP results are in the high end of and dyslipidemia markers in middle-aged people with
the normal range, above 3.0 mg/L, have 1.5 to 4 times the risk of primary OA. Study subjects (n = 72) were randomly
having a heart attack compared with those whose hs-CRP values assigned to 4 groups: (1) group 1 received 1.5 mg of boron,
are at the low end of the normal range, 1.0 mg/L or less. 2 ×/d; (2) group 2 was given 3 mg, 2 ×/d; (3) group
Because the hs-CRP test serves as a marker for inflammation, 3 received 6 mg, 2 ×/d; and (4) group 4 received placebo,
it is important that the patient is not recently recovering from a 2 ×/d. Fifteen days of dietary supplementation with
cold, flu, other infection, or injury when the test is run. As noted calcium fructoborate lowered inflammatory biomarkers—
earlier, CRP is an acute-phase protein, so levels dramatically rise CRP, fibrinogen (FBR), and erythrocyte sedimentation
in response to any recent illness, infection, or trauma, including rate (ESR)—in all groups except the placebo group; no
dental work. For that reason, any acute inflammation will raise effect was seen on lipids. In groups 1, 2, and 3 (ie, those
the amount of CRP and give a falsely elevated estimate of risk. supplemented with boron in the form of calcium
Also, patients should be instructed not to take an NSAID, as fructoborate), significant decreases occurred in ESR levels:
those medications will temporarily depress CRP levels, as will a drop of -10.25%, -11.9%, and -8.5% in groups 1, 2, and
statins, giving a falsely lowered estimate of risk. 3, respectively, compared with baseline. In the placebo
Women on conventional hormone replacement therapy group, the ESR level rose 36.36%. FBR also dropped in
(HRT) (eg, Premarin or Provera), but not on bioidentical those supplemented: -13.73 in group 1, -2.05 in group 2,
hormone replacement therapy (BHRT), have been shown to and -4.18 in group 3. In the placebo group, FBR rose 4.10.
have elevated hs-CRP levels, yet another reason to consider use CRP also dropped in all supplemented groups: -60.25 in
of BHRT rather than HRT. group 1, -26.66 in group 2, and -17.54 in group 3. In the
placebo group, CRP increased 5.47.

40 Integrative Medicine • Vol. 14, No. 4 • August 2015 Pizzorno—Boron

 Most recently, calcium fructoborate 110 mg 2 ×/d, performance on tasks of motor speed and dexterity,
which provides approximately 3 mg of boron 2 ×/d or attention, and short-term memory. A series of experiments
6 mg/d, was shown to improve knee discomfort within the conducted in otherwise healthy older men and women
first 14 days of treatment. In this study, subjects with self- found that relatively short periods, 42 to 73 days, of
reported knee discomfort (n = 60) were randomized into restricted boron intake adversely affected brain function
2 groups given either calcium fructoborate or placebo.64 At and cognitive performance. The most consistent EEG
both 7 days and 14 days, significant reductions in the mean, finding was that low boron intake resulted in a shift
within-subject changes in scores, as measured using the toward more activity in the low frequencies and less
WOMAC index and the McGill Pain Questionnaire (MPQ), activity in the high, dominant frequencies of the EEG
were seen in the group supplemented with calcium spectrum, the same effect typically observed in response
fructoborate when compared with the placebo group. to nonspecific malnutrition and heavy-metal toxicity.
Estimated treatment differences for the MPQ score were Increased low frequency activity is characteristic of states
-5.8 and -8.9 at days 7 and 14, respectively. Estimated of reduced mental alertness, is associated with lowered
differences for the WOMAC score were -5.3 and -13.73 at ability to perform vigilance and psychomotor tasks, and
days 7 and 14, respectively. Negative values indicate greater has been related to impaired memory performance.
reductions in reported discomfort. No changes in the
WOMAC or MPQ scores were seen in the placebo group.65 Heavy-metal Toxicity
CRP levels are typically higher in patients with OA The effectiveness of some boron compounds—boric
compared with normal controls, and CRP levels with acid, borax, colemanite, and ulexite—on the genotoxicity
reference values above 0.5 mg/dL in OA patients are induced by heavy metals—arsenic trioxide, colloidal
associated with disease progression.66,67 As noted earlier, in bismuth subcitrate, cadmium chloride, mercury chloride,
addition to OA and CVD, higher levels of CRP are also and lead chloride—was assessed in human blood cultures.71
associated with NAFLD, MetS, type 2 diabetes, obesity, Sister chromatid exchange (SCE) and micronuclei (MN)
depression, kidney disease, and osteoporosis. Boron, in assays were performed to establish DNA damage in
combination with plant-sourced calcium, as calcium lymphocytes, and oxidative stress was evaluated by
fructoborate, has been shown to significantly reduce estimating the changes in the main, antioxidant, enzyme
blood levels of CRP in humans.68 activities and in the levels of total glutathione in
erythrocytes. Heavy-metal treatments increased the
Protection Against Malathion-induced Oxidative Stress frequency of both SCE and MN and the plasma levels of
In a recent study, boron protected animals chronically malondialdehyde, a marker of oxidative stress, and
exposed to low levels of malathion, a widely used pesticide decreased the antioxidant enzyme activities and the level
that causes oxidative stress even at the low levels at which of total glutathione compared to controls. All boron-tested
humans are exposed to it in the food supply.69 Malathion compounds (5-20 ppm) significantly reduced all genotoxic
administration 100 mg/kg/d by gastric gavage increased effects that were induced by low doses of heavy metals.
malondialdehyde, nitric oxide and 8-hydroxy-2’-
deoxyguanosine (8-OHdG) levels, and markers of liver Production of Key Biomolecules
damage. It decreased acetylcholinesterase and reduced Not only is boron an inhibitor of 24-hydroxylase, but
glutathione; superoxide dismutase; and catalase activities it also influences the formation and activity of boroesters
in blood, liver, kidney, and brain tissues. Administration in biomolecules containing cis-hydroxyl groups. Such
of boron 5, 10, and 20 mg/kg/d reversed malathion- boron-containing biomolecules include those that contain
induced oxidative stress, lipid peroxidation, and ribose (eg, S-adenosyl methionine [SAM-e], diadenosine
suppression of antioxidant enzyme activity. Boron phosphates, and nicotinamide adenine dinucleotide
decreased malathion-induced oxidative stress, enhanced [NAD+]). These biomolecules are key players required in a
antioxidant defense mechanisms, and regenerated multitude of fundamental biochemical processes.72,73
damaged liver, kidney, and brain tissues in rats. First, let us examine SAM-e. A key methyl donor,
SAM-e is one of the most frequently used enzyme
Brain Activation and Psychological Function substrates in human metabolism.74 Approximately 95% of
Assessments of brain electrical activity in both animals SAM-e is used in methylation reactions that influence the
and humans have shown that boron deprivation—0.12 μg/g activity of DNA, RNA, proteins, phospholipids, hormones,
in the diet as boric acid—results in decreased brain electrical and transmitters. SAM-e methylation reactions result in
activity.70 In mature rats, boron deprivation was associated the formation of S-adenosyl homocysteine, which can be
with decreased high-frequency and increased low-frequency hydrolyzed into homocysteine. The hypothesis that boron
brain electrical activity, consistent with decreased arousal, bioactivity occurs in part through an effect on SAM-e
suggesting that boron may play an important role in the formation and/or use is supported by findings that plasma
maintenance of brain activation in animals. In humans, homocysteine increased and liver SAM-e decreased in rats
boron deprivation (<0.3 mg/d) resulted in poorer fed 0.05 to 0.15 mg/kg of boron compared with rats

Pizzorno—Boron Integrative Medicine • Vol. 14, No. 4 • August 2015 41

 supplemented with 3 mg/kg in their diets.75 High-
circulating homocysteine and depleted SAM-e have been Figure 1. Structure of boric acid.
implicated in many of the disorders that can be beneficially
affected by intakes of boron of greater than or equal to
3 mg/d, including arthritis, osteoporosis, cancer, diabetes,
and impaired brain function.
Boron strongly binds oxidized NAD+,76 and, thus,
might influence reactions in which NAD+ is involved,
which include ATP production, calcium signaling, and the
actions of the sirtuins, which are NAD-dependent
deacetylases. Blocking NAD+ utilization, yet another
beneficial action of boron, boosts NAD+ levels, activates
sirtuins, and promotes healthy aging.77
Boron also forms boroester complexes with
phosphoinositides, glycoproteins, and glycolipids.
Glycolipids are biomolecules that act as calcium chelators
and redox modifiers and affect cell-membrane integrity
and function.78 Phosphoinositides are involved in the
regulation of lipid kinases.79 Glycoproteins are important,
integral membrane proteins, where they play a role in cell-
to-cell interactions. Glycolipids, which are found on the
outer surface of all eukaryotic cell membranes, extend
from the phospholipid bilayer into the aqueous including prostate, breast, cervical, and lung cancers.
environment outside the cell and act as a recognition site Boron-enriched diets have been found to result in
for specific chemicals, help maintain the stability of the significant decreases in risk for prostate and cervical
membrane, and attach cells to one another to form tissues. cancer and to decrease risk of lung cancer in smoking
Through the boroester complexes formed with these women. In the last few years, the use of natural and
biomolecules, boron impacts all the above actions. synthetic boron-containing compounds as anticancer
agents has increased, particularly in inoperable cancers
A Possible Histone Deacetylase Inhibitor? and those with high malignancy. Boron-containing
As research into the chemistry of boron-containing compounds interfere with the physiology and reproduction
compounds has increased, they have been shown to be of cancer cells through diverse mechanisms, including
potent antiosteoporotic, anti-inflammatory, and inhibition of serine proteases, NAD-dehydrogenases,
antineoplastic agents both in vitro and in vivo. One mRNA splicing and cell division, receptor binding
potential explanation for the diversity in beneficial effects mimicry, and induction of apoptosis.81
is that some boronated compounds are histone deacetylase Prostate Cancer. Dietary boron is inversely correlated
inhibitors (HDIs). with prostate cancer incidence.82 According to National
HDIs are potential therapeutic agents for cancer and Health and Nutrition Examination Survey (NHANES) III
neurological diseases because of their abilities to alter gene data, risk of prostate cancer was 52% lower in men whose
expression, induce growth arrest or apoptosis of tumor diets supplied more than 1.8 mg/d of boron compared
cells, and stimulate normal cell differentiation. Several with those whose dietary boron intake was less than or
HDIs promote osteoblast maturation by enhancing equal to 0.9 mg/d. High correlation (r = 0.63) was found
RUNX2-dependent transcriptional activation, causing an between boron concentration in subsurface water and the
increase in the expression levels of osteoblast-maturation distribution of prostate cancer in Texas.83 Analysis of
genes, type 1 collagen, OPN, BSP, and OCN.80 What do all NHANES III data also found that increased dietary intake
of these increases have in common? All have been shown, of boron was associated with a decreased risk of prostate
as noted earlier, to be activities of boron. HDIs are being cancer, with a dose-response pattern. The adjusted odds
considered as a new class of bone anabolic agents for the ratio was 0.46 for the highest quartile of boron intake
treatment of diseases associated with bone loss, such as compared with the lowest quartile.82 No correlation with
osteoporosis and cancer. prostate cancer frequency has been observed when boron
consumption was less than 1.17 mg/d.84
Anticancer Effects Boric acid inhibits human prostate cancer cell
An increasing number of papers have indicated that proliferation in vitro.85,86 In one study, boric acid
boron possesses anticarcinogenic properties. Boron-rich decreased the size of prostate tumors in mice and
diets and regions where the soil and water are rich in markedly reduced levels of insulin-like growth factor 1
boron correlate with lower risks of several types of cancer, (IGF-1) in tumor tissue and of serum prostate specific

42 Integrative Medicine • Vol. 14, No. 4 • August 2015 Pizzorno—Boron

antigen (PSA).87 In this study, 2 groups with 10 animals beneficially modulate estrogen receptors, selectively
per group were dosed with boric-acid solutions binding to ER-β.99,100
(1.7, 9.0 mg boron/kg/d) by gavage. The control group Cervical Cancer. Cervical cancer is the second most
received only water. Tumor sizes were measured weekly frequent cancer in women worldwide, yet in Turkey it
for 8 weeks. The size of tumors decreased in mice ranks only ninth, which is 2 to 5 times lower than in
exposed to the low and high dose of boric acid by 38% Europe and North America.101 Although the reasons for
and 25%, respectively. Serum PSA levels for the two this difference surely involve a combination of factors,
dosages decreased by 88.6% and 86.4%, respectively, including sociocultural differences, lack of population-
compared with the control group. In boron-dosed based screening programs, or a lower human
animals, a significantly lower incidence of mitotic figures, papillomavirus (HPV) prevalence rate in Turkey, it has
the term used in cellular pathology to describe the been suggested that the low incidence of cervical cancer in
microscopic appearance of a cell undergoing mitosis, was Turkey correlates with its boron-rich soil.102 HPVs are the
seen. Circulating IGF-1 levels did not differ among main cause of cervical cancer. HPV-16 and HPV-18 cause
groups, but expression of IGF-1 in the tumors was approximately 95% of all cervical cancers, and boron
significantly reduced by boron treatment. interferes in the life cycle of HPV.
PSA is an androgen-regulated serine protease Serine protease inhibitors reduce the immortalizing
(enzyme) produced by both normal and cancerous and transforming capacity of the HPV E7 oncogene.103-106
prostate epithelial cells88 and is still the most commonly Boron exists in the human body mostly in the form of
used serum marker for prostate cancer. Boronic acid has boric acid, a serine protease inhibitor. After conducting
been shown to inhibit PSA activity.89,90 research that revealed incidence of cervical cancer-related
histopathological findings correlated with boron-rich and
boron-poor areas, Korkmaz et al107 suggested that higher
CLINICAL PEARL: Several modifications to PSA amounts of boron in drinking water may help inhibit HPV
biomarker detection have been suggested to improve its transformation, reducing incidence of cervical cancer.
sensitivity and specificity, including PSA density, In that study, 107 incidence of adverse cytological
free:total PSA, PSA velocity/doubling time, and findings in cervical smears was evaluated for 1059 women
different PSA isoforms. In addition, new biomarkers, of low socioeconomic status who were living in boron-rich
including genetic and blood or urine based biomarkers, (472 women) and boron-poor (587 women) regions in
are now available. The most advanced is prostate cancer Turkey. Mean dietary intake of boron was 8.41 mg/d for
gene 3, which is found in urine and was developed into women from the boron-rich regions and 1.26 mg/d for
a commercial test in 2006.91 women living in the boron-poor regions. None of the
women from the boron-rich regions had any
cytopathological indications of cervical cancer;
The IGF-1 signaling pathway promotes cancer cytopathological findings were present in 15 women from
progression; its downregulation is associated with the boron-poor areas.
lowered risk.92 Lung Cancer. Boron may have cancer-preventive
Additional insight into the cellular mechanisms actions similar to those of HRT, which is known to reduce
underlying boron’s antiprostate-cancer effects is provided lung cancer.108,109 A 10-year study (1995-2005), conducted
by Barranco et al,93,94 whose work revealed that boric acid at the University of Texas’s MD Anderson Cancer Center,
inhibits the growth of prostate-cancer cells both by in Houston, on the joint effects of boron intake and HRT
decreasing expression of A-E cyclin and through boron’s use on lung-cancer risk, found that boron intake was
influence on estrogen and testosterone. Cells treated with inversely associated with lung cancer in women. Women
boric acid also showed decreased adhesion and migration, whose intake of boron was low and who did not use HRT
indicating lowered metastatic potential.21,95-97 were at substantially increased risk. For all women,
It has been thought that high estradiol levels correlate decreased boron intake was associated with increasing
with low prostate-cancer risks,97 a supposition that forms odds of lung cancer corresponding to a 39%, 64%, and
the basis of aromatase-inhibition therapy. Recently, 95% increase by decreasing quartile of intake. Compared
however, papers have begun to appear that suggest with women with high dietary boron intake who used
estrogen’s role in the prostate is complicated by the HRT, the odds ratio for lung cancer for low dietary boron
differential actions of the estrogen receptors (ERs), ER-α intake and no HRT use was 2.07.110 One explanation
and ER-β. Stimulation of ER-α promotes aberrant proposed by the researchers for boron’s reduction in lung
proliferation, inflammation, and premalignant pathology, cancer risk was that postmenopausal women with high
whereas activation of ER-β has beneficial effects regarding dietary boron intakes, as well as HRT users, have higher
cellular proliferation and plays a protective role against levels of estradiol competing for estrogen receptors with
carcinogenesis.98 Research in this area is just beginning, polycyclic aromatic hydrocarbons (PAHs) from cigarette
but it appears that boron-containing compounds may smoke carcinogens. If correct, then increasing boron

Pizzorno—Boron Integrative Medicine • Vol. 14, No. 4 • August 2015 43

 intake during HRT will also reduce the carcinogenic increased, and the nuclear-division index (ie, the cytotoxic
potential of PAHs from cigarette smoke. effect) was decreased in lymphocyte cultures exposed to
Inhibition of Tumor-induced Angiogenesis. Boronic paclitaxel. The addition of boric acid (2.5 or 5 mg/L)
acid, and a series of boron-containing phenoxyacetanilide significantly diminished the paclitaxel-induced increases
derivatives, have also been shown to greatly inhibit in genotoxicity, returning levels to close to control values
hypoxia-inducible factor (HIF) 1.111 HIFs are heterodimeric and fully restoring cytotoxicity indices to control values.81
(α/β) transcriptional factors and are major physiological
stimuli for expression of angiogenesis factors. Angiogenesis, Life on Earth
the formation of new blood vessels sprouting from existing Due to its importance in the so-called sugars world,
host capillaries, must occur for tumors to grow beyond a boron may have played an essential role in the prebiotic
certain critical size. Inhibition of tumor-induced origins of genetic material. Borates (ie, boron compounds
angiogenesis prevents growth of many types of solid such as boric acid) influence the formation of ribofuranose
tumors and provides a novel approach for cancer treatment; from formaldehyde, which feeds the prebiotic metabolic
thus, HIF-1 is a target of antineoplastic therapy. cycle. Borates, by forming complexes with organic cis-diols,
Induction of Cancer-cell Apoptosis. Sugar-borate are thought to have provided the thermal and chemical
esters act as boron vehicles, increasing the concentration stability necessary for the development of life on Earth.117
of borate inside cancer cells relative to normal cells. The development of the RNA world, in which RNA
Increased intracellular concentration of borate not only acted as a catalyst as well as an informational
activates borate transporters but also leads to growth macromolecule, assumes a large prebiotic (pre-RNA)
inhibition and apoptosis. In normal cells, the 2 latter, cell- source of ribose. However, the generally accepted prebiotic
destructive effects do not occur because the amount of synthesis of ribose, the formose reaction, yields numerous
borate present in a healthy diet, 1 to 10 mg/d, is easily sugars without any selectivity, and even if ribose were
exported from normal cells. Cancer cells, however, selectively synthesized, ribose and other sugars are
commonly overexpress sugar transporters and/or unstable. Thus, it has been thought that the first genetic
underexpress borate export, rendering sugar-borate esters material could not have contained ribose or other sugars
as promising chemopreventive agents.112 because of their instability.118
Treatment of Multiple Myeloma and Non- Nonetheless, during evolution, ribose was selected as
Hodgkin’s Lymphoma. Boron-based drugs are now being the exclusive sugar component of nucleic acids. Ribose’s
developed for use as therapeutic agents with anticancer, choice is explained by using molecular models to look at
antiviral, antibacterial, antifungal, and other disease- the chemical structure of aldopentoses (common sugars)
specific activities. Bortezomib (marketed as Velcade by and envisioning how they would fit in a nucleic-acid
Millennium Pharmaceuticals and Cytomib by Venus model. Comparisons indicate that ribose was not randomly
Remedies), which contains boron as an active element, has selected but was the only choice because β-D-ribose best
been approved as a proteasome inhibitor for the treatment fits into the structure of the physiological forms of nucleic
of multiple myeloma and non-Hodgkin’s lymphoma,113 acids.119 Ribose is the only sugar present in both early
and several other boron-based compounds are in various RNA-based biochemistry and contemporary DNA-based
phases of clinical trials, with the expectation of better life. Therefore, the stability of ribose is of fundamental
efficacy and potency than existing drugs.114 concern for determining the origin of early RNA-based
Lessening Side Effects of Traditional biochemistry. Borates stabilize ribose and can form borate-
Chemotherapeutic Agents. Traditional chemotherapeutic ester nucleotides.
agents are cytotoxic (ie, they act by killing cells that divide Borate selectively increases the stability of ribose over
rapidly), a key feature of most cancer cells. Unfortunately, all other aldopentoses. Without boron’s stabilizing
other rapidly dividing cells, including cells produced in influence, ribose is the least stable of all the aldopentoses
the bone marrow, are also destroyed, resulting in produced by the formose reaction. A current theory is that
myelosuppression (ie, decreased production of blood cells, ribose accumulation occurred in borate-rich environments
and, hence, a number of adverse effects, including in the pre-RNA world, setting the stage for the development
immunosuppression).115 An in vitro study found that boric of ribose-based nucleotides (RNA).120 This borate-complex
acid can help protect against genotoxicity and cytotoxicity formation might have sequestered ribose from the
that are induced in lymphocytes by paclitaxel, an anticancer isomerization and decomposition reactions, resulting in
drug commonly used to treat breast, ovarian, and lung its selective stabilization. These findings indicate that
cancers.116 ribose could have accumulated in borate-rich environments
Paclitaxel (10 or 20 μg/L) was added to human on the early Earth and suggest that ribose-based
peripheral lymphocytes in blood cultures, and its genotoxic nucleotides, combined with phosphate and nucleobases,
and cytotoxic effects were assessed by SCE and MN tests. formed abiotically.
Compared with controls, the frequencies of SCEs and the
formation of MNs (ie, the genotoxic effects) were greatly

44 Integrative Medicine • Vol. 14, No. 4 • August 2015 Pizzorno—Boron

Typical Intake of Boron/Supplemental Table 1. (Food Processor/Overestimated) Boron Content of
Recommendations Richest Food Sources
Table 1 lists the boron content of its richest
food sources. Unfortunately, the numbers are Food mg/100 g mg in a Typical Serving
thought to be inaccurate, with an estimation of
Avocado 2.06 2.06
their being up to 3 to 4 times higher than the
values found using chemical analysis. 121 Apricots (dried) 2.11 0.53
Meacham et al122,123 have shown that Currants 1.74 0.26
currently available computer software databases Grapes (red) 0.50 0.50
such as Food Processor (ESHA, Salem, OR,
USA) greatly overestimate the boron content of Peach 0.52 0.57
foods. When a chemical analysis of foods was Prunes 1.88 0.94
compared with analysis of dietary records in Raisins 4.51 0.67
Food Processor, chemical analysis of the
Red kidney beans 1.4 1.82
foodstuffs noted in the dietary records found
1.2 mg/d of boron, whereas Food Processor Lentils 0.74 0.96
reported boron content as 4.5 mg/d (version Almonds 2.82 0.42
7.32), 5.0 mg/d (version 8.1), and 5.3 mg/d Brazil nuts a
1.72 0.34
(version 9.9). Using chemical analysis, the
Cashew nuts 1.15 0.17
researchers reported the boron content of the
10 foods richest in boron (Table 2). Hazelnuts 2.77 0.68
Boron is part of the normal human diet, Peanut butter 1.92 0.38
but daily intake varies widely depending on the Pistachio nuts 1.20 0.18
proportions of various food groups in the diet
and on the boron concentrations in the soil.124 Walnuts (California) 1.63 0.24
Reported values for mean overall boron intake Wine (Shiraz Cabernet) 0.86 0.86
vary: 1.7 to 7.0 mg/d in the United States; 1.75
to 2.12 mg/d in Mexico; 0.8 to 1.9 mg/d in the Note: Adapted from Naghii et al.121
European Union; 2.16 to 2.28 mg/d in Australia;
and approximately 0.93 mg/d in Korea.125,126 a
Brazil nuts are the richest food source of selenium. Consumption
The dissimilarities correlate with regional of more than 2 Brazil nuts/d may result in selenium toxicity.
differences in the soil and consumption of fiber
and protein-rich plant foods.
A diverse, plant-food-rich diet is estimated to provide
approximately 1.5 to 3 mg/d of boron.125,127 Foods of plant
origin, especially fruits, leafy vegetables, nuts, and legumes, Table 2. Chemical Analysis of Boron Content (mg/100 g)
are rich in boron as are plant-derived fermented beverages in the Top 10 Foods
(ie, wine, cider, and beer). Meat, fish, and dairy products,
however, are poor sources. Peanuts and peanut butter, Food mg/100 g
other nuts, raisins, wine, and avocado are also top
Avocado 1.43
contributors to boron intake. Although coffee and milk
are low in boron, they provide 12% of the total boron Peanut butter 0.59
intake in the United States due to the volume consumed Peanuts, dry 0.58
and to the fact that the standard American diet contains so Prune juice 0.56
few servings of fruits, vegetables, and legumes.125,128 No
recommended levels have been set for boron, only an Chocolate powder 0.43
upper intake level (UL) of 20 mg/d. 129 Red wine 0.36
Although Rainey et al125 stated that “very large variations Granola-raisin cereal 0.36
in boron intakes occur across the US adult population,”
Grape juice 0.34
ranging as high as 9 mg/d, the researchers’ estimates of mean
and 95th-percentile intakes of boron in the United States Pecans 0.26
were 1.17 to 2.42 mg/d for men and 0.96 to 1.94 mg/d for Raisin bran 0.26
women. It is important to note that the US population is
consuming fewer boron-rich plant foods today than in 1998,
when the research conducted by Rainey et al125 was done. It Note: Adapted Meacham et al.122
seems likely that average boron intake has dropped.

Pizzorno—Boron Integrative Medicine • Vol. 14, No. 4 • August 2015 45

 In 1988 to 1994, only 27% of adults met the USDA enzymes, such as SOD, catalase, and glutathione peroxidase;
guidelines for fruit—2 or more servings, and only 35% (7) protects against pesticide-induced oxidative stress and
met the guidelines for vegetables—3 or more servings; in heavy-metal toxicity; (8) improves brain electrical activity,
1999 to 2002, 28% and 32% of adults met fruit and cognitive performance, and short-term memory in elders;
vegetable guidelines, respectively. Only 11% met USDA (9) influences the formation and activity of key biomolecules,
guidelines for both fruits and vegetables in 1988 to 1994 such as SAM-e and NAD+; (10) has demonstrated preventive
and 1999 to 2002, indicating no change in consumption.130 and therapeutic effects in a number of cancers, such as
By 1999 to 2002, only 40% ± 2% of the US population met prostate, cervical, and lung cancers and multiple and non-
the then-current recommendation to eat an average of 5 or Hodgkin’s lymphoma; and (11) may help ameliorate the
more servings of fruits and vegetables per day. Among adverse effects of traditional chemotherapeutic agents.
subpopulations, the percentages consuming at least that Americans’ daily dietary intake of boron was estimated to
much ranged from a low of 10% ± 3% of girls aged 4 to 8 be approximately 1 mg/d in 1999.
years to a high of 60% ± 4% of men aged 51 to 70 years. In none of the numerous studies conducted to date,
As of 2006, the new combined recommended amounts however, do boron’s beneficial effects appear at intakes of
of fruits and vegetables ranged from 2 to 6.5 cups. less than 3 mg/d. No EARs or DRIs have been set for boron;
Assuming 2 servings per cup, the proportions of the only a UL of 20 mg/d for individuals aged 18 years or older.
subpopulations meeting the combined new The absence of studies showing harm in conjunction with
recommendations for fruits and vegetables are estimated the substantial number of articles showing benefits support
to range from a low of 0.7% ± 0.4% of boys aged 14 to 18 the consideration of boron supplementation of 3 mg/d for
years, whose combined recommendation is 5 cups, to a any individual who is consuming a diet low in fruits and
high of 48% ± 4% of children aged 2 to 3 years, whose vegetables or who is at risk for or has osteopenia;
combined recommendation is 1 cup. Only 17% ± 3% of osteoporosis; OA; or breast, prostate, or lung cancer.
women aged 51 to 70 years meet their combined
recommendation, and all other sex–age groups have fewer
than 11% meeting them.131 References
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