Journal of Trace Elements in Medicine and Biology 62 (2020) 126577

Contents lists available at ScienceDirect

Journal of Trace Elements in Medicine and Biology

journal homepage: www.elsevier.com/locate/jtemb

Review

Pivotal role of boron supplementation on bone health: A narrative review T

a,b c c, b
Mariangela Rondanelli , Milena Anna Faliva , Gabriella Peroni *, Vittoria Infantino ,
Clara Gasparric, Giancarlo Iannellod, Simone Pernae, Antonella Rivaf, Giovanna Petrangolinif,
Alice Tartarac
a
IRCCS Mondino Foundation, Pavia, 27100, Italy
b
Department of Public Health, Experimental and Forensic Medicine, Unit of Human and Clinical Nutrition, University of Pavia, Pavia, 27100, Italy
c
Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita’’, University of Pavia, Pavia, 27100, Italy
d
General Management, Azienda di Servizi alla Persona “Istituto Santa Margherita’’, Pavia, 27100, Italy
e
Department of Biology, College of Science, University of Bahrain, 32038 Sakhir, Bahrain
f
Research and Development Unit, Indena, Milan, Italy

ARTICLE INFO ABSTRACT

Keywords: Background: Boron is a trace element that plays an important role in numerous biological functions, including
Boron calcium metabolism, growth and maintenance of bone tissue. However, there are still no precise indications
Bone regarding a possible role of boron supplementation, and its amount of supplementation, to maintain bone health.
Dietary supplementation So the aim of this narrative review was to consider the state of the art on the effectiveness of boron supple-
Bone mineral density
mentation (alone or with other micronutrients) on growth and maintenance of bone in humans through control
Nutrients
of calcium, vitamin D and sex steroid hormone metabolism in order to suggest a daily dosage of boron sup-
plementation.
Main findings: This review included 11 eligible studies: 7 regarding the supplementation with boron alone and 4
regarding supplementation with boron and other nutrients. Despite the number of studies considered being low,
the number of subjects studied is high (594) and the results are interesting.
Conclusions: The studies considered in this narrative review have evaluated the positive effectiveness on bone, in
humans, through control of calcium, vitamin D and sex steroid hormone metabolism, considering a dietary
supplementation of 3 mg/day of boron (alone or with other nutrients); this supplementation is demonstrably
useful to support bone health (in order to prevent and maintain adequate bone mineral density), also considering
the daily dose of 3 mg is much lower than the Upper Level indicated by EFSA in the daily dose of 10 mg.

1. Introduction the steroid ring. This role would be particularly evident in case of in-
sufficient dietary intake of vitamin D, magnesium or both [2].
Boron is a semiconductor element, with metal and non-metal The main sources of boron for humans are food and drinking water
properties, not present on Earth in elementary form, but in the form of [3,4]. The greatest contribution is generally obtained through the in-
borates in sedimentary rocks, clay, oceans, in soil and in coal [1]. Boron take of coffee (boron content equal to 29 μg / 100 g) and milk (18 μg /
is a trace element that plays an important role in numerous biological 100 g) (for the abundant quantities consumed), peanuts (1700 μg /
functions, including calcium metabolism, growth and maintenance of 100 g) and peanut butter (1450 μg / 100 g), wine (610 μg / 100 g), and
bone tissue. In fact, from what emerged from a review that considered sultanas (2200 μg / 100 g) [5]. The most important commercial pro-
both animal and human studies, boron seems to influence the meta- ducts containing boron in inorganic form include: borax (or sodium
bolism of various nutrients and steroid hormones, such as 1.25 (OH) 2 tetraborate), borax pentahydrate, sodium perborate, colemanite (a
vitamin D, testosterone and 17- β estradiol, according to the hypothesis calcium borate hydrate), boric acid and ulexite (a sodium and calcium
that this element would be necessary for the hydroxylation reactions of borate hydrate) [1]. Among all the numerous active natural organic

Corresponding author.
⁎

E-mail addresses: [email protected] (M. Rondanelli), [email protected] (M.A. Faliva), [email protected] (G. Peroni),
[email protected] (V. Infantino), [email protected] (C. Gasparri), [email protected] (G. Iannello),
[email protected] (S. Perna), [email protected] (A. Riva), [email protected] (G. Petrangolini),
[email protected] (A. Tartara).

https://doi.org/10.1016/j.jtemb.2020.126577
Received 21 April 2020; Received in revised form 26 May 2020; Accepted 4 June 2020
Available online 06 June 2020
0946-672X/ © 2020 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
M. Rondanelli, et al. Journal of Trace Elements in Medicine and Biology 62 (2020) 126577

compounds containing boron present in products of plant origin, sugars weight of the food): avocado (14.3 ± 0.4), peanut butter (5.9 ± 0.2),
and polyalcohol borate esters, pectic polysaccharide borate esters, or- dried peanuts (5.8 ± 0.6), plum juice (5.6 ± 0.0), chocolate powder
ganic acid-borate esters and aminoacid-borate esters are particularly (4.3 ± 0.4), wine (3.6 ± 0.0), muesli-raisin (3.6 ± 0.3), grape juice
represented in animal feed and being human [6]. Currently there are (3.4 ± 0.0), pecan nuts (2.6 ± 0.1), and raisin cereals (2.6 ± 0.6) [20].
also organic boron compounds sold as supplements: calcium fruitate However, studies conducted on the US population have shown that, in
and boron gluconate chelates, boron aspartate, boron citrate, boron terms of percentage of total daily boron intake, the greatest contribu-
ascorbate, boron glycinate [6]. However, only plants are able to me- tion to the dietary contribution of this element comes from drinks,
tabolize inorganic boron compounds (such as boric acid or borates) and especially wine (3.52 ± 0.27), coffee (0.24 ± 0.07 μg B / g of food) and
to convert them, for example, to mono- or di-saccharide borate esters beer (0.13 ± 0.06), juices (plum juice 5.19 ± 0.21; apple juice
(mono- or di-sugar borate esters, SBEs), which are then effectively as- 2.38 ± 0, 10; orange juice 0.17 ± 0.04), milk and dairy products (yo-
similated by animal and human cells [1]. Calcium fructoborate, in gurt 0.46 ± 0.03 whole milk 0.13 ± 0.05), fruit (e.g. cherries 7.0 ± 0,
particular, in addition to being produced and marketed as an active 3; peaches 4.49 ± 0.07; fruit salad with syrup 2.45 ± 0.17) and vege-
component of various dietary supplements, represents the sugar-borate tables and legumes (red beans 3.14 ± 0.04; carrots 2.59 ± 0.09; broc-
ester complex most commonly found in nature, mainly contained in coli 2.47 ± 0.03; spinach 2.40 ± 0.09; and mixed canned vegetables
vegetables, fruit, seeds and honey [1,7]. 1.11 ± 0.19) [20,21].
According to the WHO, the amount of boron absorbed by man
through inhaled air is 0.44 μg / day, the quota introduced through the 1.2. Boron and bone development: in vitro and in animal model studies
diet is on average 1.2 mg / day while drinking water contributes with
an average concentration of 0.1−0.3 mg / l of boron [8]. Studies have Boron appears to have a positive effect on bone regeneration, as
shown, in both animals and in humans, that boron taken orally is about demonstrated by some in vitro and animal research [22,23]. In the
90 % absorbed [9]. Absorption through intact skin, on the other hand, study of Hakki et al. an increase in mineralization nodules, an increase
is minimal [10]. in the expression of the gene coding for collagen type I, osteopontin,
Boron is then mainly eliminated through urine, to a lesser extent via bone sialoprotein and osteocalcin, and an increase in bone morphoge-
the stool (2%) and only in small quantities with sweat, breath and bile netic protein levels have been observed on boron-treated pre-osteo-
[11]. blastic cells BMPs-4, -6 and -7, important growth factors that induce
Animal studies have shown that boron does not accumulate in sig- bone neoformation [22]. In the study of Uysal et al., conducted on
nificant quantities in the soft tissues, while it tends to reach much rabbits, daily supplementation of the diet with 3 mg of boron / kg was
higher levels than those found in the blood and soft tissues themselves, associated with a significant increase in the mineralization area and in
in the bone [12]. According to research by Tibbits et al. in dogs, the the number of osteoblasts at the level of the median palatal suture [23].
other tissues at which high levels of boron are reached are mainly the A further 2016 in vitro study showed that boron is able to promote the
liver, lymph nodes, adrenals and kidneys (minimum concentrations at proliferation and differentiation of mammalian osteoblasts by accel-
the level of the tissues of the head region) [13]. In the bone, in parti- erating the flow of calcium ions [24], and a study conducted on pig
cular, this element appears almost completely and exclusively localized bone marrow mesenchymal stromal cells showed how calcium fructo-
at the level of the mineral portion, and the manifestations of its defi- borate can stimulate the differentiation of osteoblasts from the spinal
ciency, completely non-specific, can include arthritis, bone loss and cord by increasing the activity of alkaline phosphatase [25]. Boron
osteoporosis [7]. deficiency, on the other hand, seems to lead to impaired growth and
abnormal bone development [2]. Research conducted on mice has
1.1. Daily intake of boron with the diet highlighted how reduced dietary boron intake can alter bone re-
modeling and inhibit bone neoformation: through a histomorphometric
To date, due to insufficient data available, recommended intake analysis on the periodontal alveolar bone, have been observed a re-
levels (RDA) for boron have not yet been established [14,15]; however, duction in the surface of the osteoblasts and an increase in the quiescent
the World Health Organization (WHO) has estimated an "boron intake" surface in the group of animals subjected to a low boron diet. This
of 1−13 mg / day as an "acceptable safety interval" for adults [16]. suggests that boron introduced with diet may exert a positive action
Oral exposure to high concentrations of boron in humans was re- against bone growth and maintenance by affecting the presence and
sponsible for minimal or little toxicity phenomena, and chronic ex- growth of osteoblasts and / or osteoclasts [26].
posure to ≥ 84 mg B / kg body weight / day could cause neurological, In a study on ostrich chicks, supplementation of drinking water with
gastrointestinal pathological manifestations, cardiovascular and he- boron (0 mg / l, 100 mg / l, 200 mg / l, 400 mg / l) was shown to be
patic, as well as diarrhea, anorexia, kidney damage and testicular useful for bone development, with improvement of several tibial bone
atrophy [1]. parameters, including bone mineral density, length, weight, cortical
Based primarily on the negative effects of excess boron on re- bone thickness (with the greatest benefit observed for 200 mg / l sup-
productive function and development in animal models, the U.S. Food plementations) [27]. In the same study, an increase in the serum con-
and Nutrition Board set the tolerable upper limit (UL) for this micro- centration of leptin, a hormone that affects bone metabolism by redu-
element at 20 mg / day [9]. EFSA (European Food Safety Agency), cing its reabsorption and stimulating its turnover, was also observed
however, following a critical analysis of boron toxicokinetics and tox- with high levels of boron introduced in the diet [27].
icodynamics data, has declared as safe for adults a maximum dose of Furthermore, it would seem that boron supplementation is able to
10 mg / day (in the form of boric acid and borates) [17]. correct the mineral metabolism alterations induced by a deficiency of
The average daily consumption of boron in the US population was vitamin D: in fact, the supplementation (3 ppm) of this microelement, in
assessed by survey, in different age groups, using the "Boron Nutrient fact, in rats fed a diet low in vitamin D determined an increase in serum
Data Base" and a two-day food diary. The average intake of boron was calcium levels [28], and the addition of 3 mg of boron / kg of food to
between 0.75 and 0.96 mg / day for school-age children and between the diet stimulated the growth of vitamin D deficient chicks compared
0.87 and 1.35 mg / day for adults [9]. These values are in line with to a low boron diet (≤ 0.3 mg / kg of food) [29].
what is highlighted by Biego G.H. et al. for the French population In a study carried out on rabbits, animals fed a high-calorie low-
(1.6 mg / day) [18] and slightly lower than those reported by Naghii boron diet (3.88 mg B / kg) were compared with animals receiving
M.R. et al. for the Australian population (2.23 ± 1.23 mg / day) [19]. increasing supplements (10, 30 and 50 mg B / kg body weight). It was
By using inductively coupled plasma spectrometry (ICP), Meacham thus observed that rabbits with the highest supplementation (50 mg B /
S.L. et al. have identified the 10 richest foods in boron (μg of B / g of dry kg) had the highest maximum femoral rupture force value and that

2
M. Rondanelli, et al. Journal of Trace Elements in Medicine and Biology 62 (2020) 126577

supplementations with 30 and 50 mg boron / kg were associated with hormone metabolism, in order to suggest a daily dosage of boron sup-
greater compressive strength of the tibia. The addition of boron to the plementation.
feeding also resulted in a significant increase in all rabbits’ concentra-
tions of calcium and magnesium at the tibial level, with an increase in
phosphorus in the groups supplemented with 30 and 50 mg / kg; sup- 2. Materials and methods
plementation with 30 mg B / kg was also associated with an increase in
the femoral concentrations of calcium, magnesium and phosphorus The present narrative review was performed following the steps by
[30]. Egger et al. [37] as follows:
Other animal research has shown that boron deficiency can com-
promise the bone healing process through a marked reduction in os- 1 Configuration of a working group: three operators skilled in clinical
teogenesis [31,32]. In this study, conducted on male mice after the nutrition (one acting as a methodological operator and two parti-
extraction of the first lower right molar tooth, histological and histo- cipating as clinical operators).
morphometric analyzes were performed on the periodontal alveolar 2 Formulation of the revision question on the basis of considerations
bone after 7 and 14 days of diet containing 3 mg B / kg (+ B, adequate made in the abstract: “the state of the art on effectiveness of boron
diet) or 0.07 mg B / kg (-B, B-deficient diet). In animals + B, after 7 and supplementation (alone or with other micronutrients) on growth
14 days, active osteogenesis was highlighted with the formation of new and maintenance of bone in humans through control of calcium,
trabeculae occupying almost entirely the alveolus, unlike the animals vitamin D and sex steroid hormones metabolism, in order to suggest
-B, in which few trabeculae were present with poor bone formation a daily dosage of boron supplementation.
activity; moreover, the -B mice showed a reduction in the osteoblastic 3 Identification of relevant studies: a research strategy was planned on
surface and a statistically significant increase in the quiescent surface PubMed (Public MedIine run by the National Center of
[31]. Boron deficiency would therefore seem to alter the alveolar bone Biotechnology Information (NCBI) of the National Library of
repair process that begins immediately after a dental extraction, sug- Medicine of Bethesda (USA)) as follows: (a) Definition of the key-
gesting that this microelement is able to promote normal trabecular words (boron, bone health, humans, supplementation, bone mineral
formation or bone microarchitecture [32]. In addition, an in vitro study density), allowing the definition of the interest field of the docu-
has shown a favorable role of boron towards osteoblastic function, ments to be searched, grouped in quotation marks (“…”) and used
positively regulating proteins such as type I collagen, osteopontin, bone separately or in combination; (b) use of: the Boolean (a data type
sialoprotein, osteocalcin [22]. with only two possible values: true or false) AND operator, that
Finally, a study conducted on rats by Ghanizadeh et al. Deserves allows the establishments of logical relations among concepts; (c)
mention. in 2014, where 34 male animals were divided into 5 groups: a Research modalities: advanced search; (d) Limits: time limits: papers
control group fed a standard diet containing 650 mg of calcium / 100 g published in the last 20 years; humans; adults; languages: English;
of food and 80 I.U. of vitamin D3 / 100 g of food, and 4 intervention (e) Manual search performed by the senior researchers experienced
groups supplemented daily with, respectively: fluoride, in clinical nutrition through the revision of articles on effectiveness
fluoride + boron, fluoride + calcium + vitamin D and of boron supplementation (alone or with other micronutrients) on
fluoride + boron + calcium + vitamin D. Supplementation provided a growth and maintenance of bone in humans through control of
total of 0.7 mg of fluorine per animal per day, 1.23 mg of boron, 210 mg calcium, vitamin D and sex steroid hormones metabolism, in order
of calcium and 55 IU of vitamin D. After 8 weeks of treatment, the to suggest a daily dosage of boron supplementation.
measurements carried out on the mechanical properties of the bone 4 Published in journals qualified in the Index Medicus.
showed that the combined intake of fluorine and boron is associated 5 Analysis and presentation of the outcomes: we create paragraphs
with greater stiffness and breaking force at the femoral level and with a about effectiveness of boron supplementation alone or in combina-
higher maximum load for the lumbar vertebrae compared to the intake tion with other nutrients, and the data extrapolated from the “re-
of calcium and vitamin D. The blood concentration of calcium was also vised studies” were collocated in tables; in particular, for each study
significantly higher in animals supplemented with fluorine and boron, we specified the author and year of publication and study char-
while higher levels of free testosterone and estradiol were found in all acteristics.
intervention groups at comparison with the control group, indicating 6 The analysis was carried out in the form of a narrative review of the
the existence of a positive relationship between minerals and steroid reports. At the beginning of each section, the keywords considered
hormones. Overall, these results suggest the importance of carrying out and the type of studies chosen are reported. We evaluated, as is
further investigations to clarify the role of boron and fluorine, possibly suitable for the narrative review, studies of any design which con-
in association with other elements, in influencing bone health [33]. sidered the effectiveness of boron supplementation (alone or with
Finally, bioactive glass technology has also shown how boron plays other micronutrients) on growth and maintenance of bone in hu-
an important role in promoting osteoblast proliferation [34]. mans through control of calcium, vitamin D and sex steroid hor-
mone metabolism.
1.3. Boron and magnesium

About 60 % of the magnesium present in the human body is found 3. Results

in the bone, where it acts as a cofactor for numerous enzymes that
regulate the metabolism of calcium [35]. Boron appears to significantly 3.1. Effectiveness of boron supplementation on maintenance of bone in
improve the absorption of magnesium and its deposition at the bone humans
level, as suggested by a study conducted in rats in which a significant
increase in the bone content of magnesium (in mg / g) was observed in This research was conducted based on the keywords: “boron” AND
the animals to which it had been given as part of a diet low in vitamin “supplementation” AND “bone” AND “humans”.
D, but supplemented in boron compared to those fed a diet low in both For the present review we have analyzed a total of seven studies:
vitamin D and boron [36]. one observational clinical trial [38], one cross-sectional observational
Given this background, the aim of this narrative review was to clinical trial [39], two double-blind clinical trials [40,41], one single-
consider the state of the art on effectiveness of boron supplementation blind cross-over clinical trial [42], one experimental controlled study
(alone or with other micronutrients) on growth and maintenance of [43] and one follow-up clinical trial [44]. The results of these seven
bone in humans through control of calcium, vitamin D and sex steroid studies have been shown in Table 1.

3
 Table 1
Studies regarding boron supplementation and bone health in humans.
First author, Study design Setting Inclusion criteria Intervention Parallel treatments/ Number of Duration of the Primary outcomes Secondary Results
year placebo subjects (M-F) intervention outcomes
M. Rondanelli, et al.

Beattie J.H., Observational Human Nutrition Helthy; no history of Low boron diet (LBD, Self-selected diet 6 healthy 3 weeks + 3 Bone mineral Urinary calcium, During LBD: increased urinary
1993 clinical trial Unit of the Rowett alcohol or drug 0.33 mg/d) for the first (acclimation-period postmenopausal weeks absorption and magnesium and Ca and Mg excretion;
Research abuse; no more than 3 weeks; then daily diet, APD) volunteers excretion; plasma phosphorous hyperabsorption of Ca
Institute, 20 years since the supplement of 3 mg B/ sex steroid levels; (positive Ca balances in
Buckburn, menopause; BMI 8 MJ energy intake for urinary excretion combination with elevated
Aberden 25 kg/m2); other 3 weeks of pyridinium urinary Ca Excretion).
postmenopausal crosslink markers Changing boron intake: no
of bone turnover effect on minerals, steroids or
crosslinks.
Boyacioglu Cross-sectional Two different All su bjects free 25 subjects consuming 28 subjects consuming 53 All subjects in Serum osteocalcin // Serum osteocalcin levels in
O., observational regions of Turkey, from spontaneous drinking water with a drinking water with a postmenopausal the boron levels; expression the boron exposed regions
2018 study with natural menses for at least a boron concentration of boron concentration women (50−60 exposed group of osteocalcin gene significantly higher
exposure to high year 1.59 ± 0.04 mg/L of 0.012 ± 0.05 mg/L years old) living in the rs1800247 (27.55 ± 3.20 ng/mL)
(≥1 mg/L) or low boron-rich area polymorphism compared to that of control
(< 1 mg/L) boron for an average group (23.47 ± 12.55 ng/
concentration in of 57.5 ± 12.0 mL).
drinking water years
Hunt C.D., Double-blind Metabolic unit Healthy Basal diet Conventional basal 11 women 48 days Fecal and urinary B Serum levels of During B supplementation:
1997 (except for under close postmenopausal supplemented with diet (daily average (48−82 years) and Ca loss B, Ca, Mg and K increased faecal B loss,
boron) clinical supervision for women; normal 3 mg B/d for 48 days: 6 intake of 0.36 mg of B) regardless of Mg intake;
trial 167 days bone, kidney and women with a boron for the first 119 days decreased urinary Ca loss
liver function; diet low in Mg, 5 without supplemental Mg;
normal blood women with a boron increased urinary Ca loss with
pressure; negative diet supplemented with supplemental Mg; increased

4
lung scan; normal 200 mg Mg/d plasma B concentrations (1.5-
plasma Ca and Mg folds). Supplemental B
levels without supplemental Mg:
decreased serum Mg
concentrations. Supplemental
B with supplemental Mg:
increased serum Mg
concentrations.
Naghii Single blind Free-living Healthy subjects 5 mg of B (as sodium Placebo tablets 8 healthy male 4 weeks Boron and calcium Plasma lipids In the treatment group:
M.R., cross-over trial subjects tetrabaorate) twice a (containing lactose subjects excretion in 24-h and increased mean concentration
1997 day only) urine sample susceptibility to of urinary B; reduced calcium
oxidation; excretion. No difference in
plasma steroid plasma lipids or the
hormones oxidizability of LDL.
(estradiol and Significant increase in plasma
testosterone) estradiol concentration; trend
for plasma testosterone levels
to be increased.
Naghii Experimental Free-living apparently healthy 10 mg of boron (as Habitual diet and, for 8 male volunteers 7 days Plasma boron Plasma levels of Following hours and weekly B
M.R., controlled subjects non-smoker subjects sodium tetraborate)/d only one day, a (mean age concentrations total and free consumption: significant
2011 study capsule containing 41.3 ± 7.5 years) testosterone, increase in plasma B. After six
lactose powder as DHT, estradiol, hours B supplementation:
placebo SHBG, cortisol, decrease of SHBG, hsCRP and
LH, vitamin D; TNF-α; after one week:
hsCRP, IL-6, increase of mean plasma free
TNF-α testosterone and decrease of
mean plasma estradiol. After
supplementation: increase of
all inflammatory biomarkers
(continued on next page)
Journal of Trace Elements in Medicine and Biology 62 (2020) 126577
M. Rondanelli, et al. Journal of Trace Elements in Medicine and Biology 62 (2020) 126577

3.2. Effectiveness of boron in association with other nutrients,

was low); decreased P urinary

17β-estradiol and testosterone

marked when dietary Mg was

excretion only by the low-Mg
decreased Ca and Mg urinary

women; marked elevation of

significantly higher levels of

depression when dietary Mg

serum concentrations (more

supplementation on maintenance of bone in humans

After B supplementation:
DHT, cortisol and vit. D.

excretion (more marked

This research was conducted based on the keywords: “boron” AND
concentrations; non

“supplementation” AND “nutrients” AND “bone” AND “humans”.

Four studies have included about nutritional supplements con-
taining boron in combination with other nutrients: two comparative
Results

effectiveness research (CER) studies [45,46], one single-blind, un-

low).
controlled, prospective clinical trial [47] and one longitudinal trial
[48]. The results of these four studies have been shown in Table 2.
Fig. 1 shows the flow chart of literature research.
Secondary
outcomes

4. Discussion
//

4.1. Effectiveness of boron supplementation on calcium metabolism, growth

Primary outcomes

and maintenance of bone in humans

17β-estradiol and
Urinary excretion

concentrations of
of Ca, Mg and P;

testosterone

A study conducted on 12 postmenopausal women, aged between 48

and 82 years, showed that a 3 mg / day boron supplementation (as
serum

sodium borate) for 48 days, after 119 days of low boron diet (0.25 mg /
die), is able to reduce the urinary excretion of calcium and magnesium
Duration of the

and to increase the serum levels of 17-β estradiol and testosterone, to a

intervention

greater extent in case of low dietary intake of magnesium [40]. On the

48 days

other hand, a diet low in boron would induce an increase in urinary

calcium excretion, as emerged from a study conducted on 6 post-me-
nopausal women (53–65 years), after administration of a diet con-
taining 0.33 mg / day of boron for 3 weeks: urinary calcium excretion
subjects (M-F)

(48−82 years

increased rapidly, in some cases, to double, following the transition

Number of

12 women

from a free diet to a low boron diet [38].

In order to further investigate the effects of a boron supplement on
old)

serum levels and on the excretion of boron, calcium and magnesium,

Hunt C.D. and colleagues enrolled 11 postmenopausal women, aged
d) for an initial period
(0.25 mg/2000 kcal/
Parallel treatments/

48–82, who were given a low boron diet (on average 0.36 mg / day) for
Diet low in boron

119 days, followed by an integration period with 3 mg B (as disodium

tetraborate decahydrate) / day for 48 days. During this second period of
of 119 days

the study, 5 of the 11 volunteers also received supplementation of

placebo

200 mg / day of magnesium. The data collected showed that a 9-fold

increase in boron introduced with the diet was associated with a 1.5-
fed with a B diet low in

with 200 mg of Mg/day

fold increase in its plasma concentration; the urinary and faecal losses
Mg, 5 women fed with
borate)/day: 7 women

a B diet supplemented
3 mg of B (as sodium

of boron also more than 100 % compensated the doses taken with the
supplemented with

diet, thus indicating that boron was affected, in the human body, by
Intervention

homeostatic regulation phenomena. In women not supplemented with

Basal diet

magnesium, boron supplementation decreased serum Magnesium con-

centrations, while in women who received 200 mg / day of Mg, sup-
plementation with boron tended to increase circulating levels.
Furthermore, boron supplementation decreased urinary calcium losses
Caucasian women in

emotionally suited

informed consent

only in women in whom Mg was also not integrated, while it was as-
Inclusion criteria

good health and

Postmenopausal

sociated with an increase in urinary calcium excretion in women taking

for the study;

magnesium supplementation, thus suggesting that the effects of boron

on calcium excretion depended on the simultaneous intake or not of
magnesium [41].
A study by Boyacioglu O. and colleagues on 53 postmenopausal
Metabolic unit for

women aged between 50 and 60 also investigated the relationship be-

tween daily intake of boron, blood levels of osteocalcin and poly-
167 days

morphisms of the gene coding for it. Osteocalcin is a sensitive and

Setting

specific indicator of osteoblastic function; its levels, in fact, appear high

in all those clinical conditions characterized by an accelerated bone
turnover, such as hyperparathyroidism, hyperthyroidism, acromegaly
Observational
Study design

and Paget's disease [39]. In the study in question 25 women, from re-
clinical trial

gions of Turkey considered "rich in boron", took drinking water with

Table 1 (continued)

concentrations of B (types of boron compounds not specified) equal to

1.59 ± 0.04 mg / L (average daily intake of boron 6.99 ± 2, 90 mg),
First author,

while the remaining 28 women, coming from "poor boron" regions, took
1987
F.H.,

drinking water with concentrations of this microelement equal to

Nielsen

0.012 ± 0.05 mg / L (average daily intake of boron 1.20 ± 0.12 mg).

year

Analysis of the data showed significantly higher serum levels of

5
 Table 2
Studies regarding boron, in association with other nutrients, supplementation and bone health in humans.
First Study design Setting Inclusion criteria Intervention Parallel treatments Number of subjects Duration of Primary outcomes Secondary Results
author, (M-F) the outcomes
year intervention
M. Rondanelli, et al.

Cook A., Single-blind, Free- Women within 1–10 years Product 1, a vitamin/ // 12 women (mean age 2 years BMD of the lumbar spine Relief of No effects on BMD over
2002 uncontrolled, living after menopause, no mineral blend 53.4 years, SD 4.96) (L1-L4), total hip, and menopausal a 2-year period of
prospective trial subjects congenital or other disease containing Ca, Mg, Mn, distal one third of the symptoms treatment. Mean
known to affect bone Cu, Cr, Se, Mo, B forearm (nondominant, annualized bone loss:
density, no medication that (2 mg), Si, Sr, Zn, unfractured) (by DEXA); 1.42 % in the spine;
depletes or enhances bone vitamin B1, B2, B3, B6, annualized percent BMD 1.42 % in the forearm;
density, T score < -1.0 SD B12, D, K, pantothenic loss no significant losses at
at lumbar spine, hip, or acid, folic acid, ascorbic the hip (0.42 %) (no
forearm (measured by DXA) acid, betaine HCl; and protective effect of the
Product 2, an herbal treatment against the
blend containing dong predictable acceleration
quai extract, licorice of bone mineral losses
root extract, chaste tree associated with early
berry (Vitex agnus- post-menopause). Relief
castus), black cohosh of menopausal
(Cimicifuga racemosa), symptoms: reported by
false unicorn extract 4 of 4 women
(Helonias opulus), experiencing symptoms
fennel seed extract at the start of the trial.
(Foeniculum vulgare),
hesperidin complex.
Kaats G.R., Comparative Free- no medical conditions Plan 1: plant-sourced Plan 2: AlgaeCal, 172 healthy women 1 year Mean annualized percent MAPC of BMD in In the compliant sub-
2011 effectiveness living precluding participation calcium (AlgaeCal, AC), 720 mg; Mg, 72 mg; (> 40 years) change (MAPC) of BMD the entire cohort groups, increase in

6
research study subjects 750 mg; Mg, 65 mg; vit vit D-3, 800 IU plus among highly compliant for each plan MAPC of BMD: plan
D-3, 1000 IU; no vit K-2 and Sr citrate; subjects; safety in all three 1 = 1.30 %; plan
activity program; no activity program; Plan plans (assessed by a 2 = 2.00 %; plan
health literacy 3: AlgaeCal, 756 mg; Quality of Life inventory, 3 = 4.1 %. In all
information Mg, 350 mg; vit D-3, a blood chemistry panel subjects, increase in
1600 IU plus vit K-7, and daily tracking self- MAPC of BMD: plan
Sr citrate, B (3 mg), reports) 1 = 1.20 %; plan
vit C; activity 2 = 0.33 %; plan
program; 3 = 2.5 %. In all three
groups, no statistically
significant differences
between baseline and
ending blood chemistry
tests or the QoL self-
reports.
Kaats G.R., Longitudinal Free- Healthy adult women; AlgaeCal (AC) // 172 females (mean From 1–7 Baseline-ending BMD // AC supplement
2016 trial living reported use of AlgaeCal for supplement containing: age 65.1 y, SD 7.8) to years annualized changes. associated with a
subjects one to 7 years; at least one elemental Sr (from assess efficacy; 125 Safety assessed by 45- statistically significant
total body DEXA during the citrate), Ca, Mg, females to assess measurement blood annualized and linear
past 7 years; no vitamin D3, vitamin K- safety chemistry panel. increase in BMD (1.04
bisphosphonates or other 7, vitamin C, B (3 mg). % per year, 7.3 % over
bone building medications. the 7-year study
period). No adverse
effects or safety
concerns.
Michalek Comparative Free- no medical conditions Bone-health plan 1 Bone-health plan 2 AlgaeCal 1: 125 6 months Changes in BMD (MAPC, Measures of Positive MAPC in BMD
J.E., effectiveness living precluding participation (AlgaeCal 1): (AlgaeCal 2): healthy adults mean annualized percent safety, volunteer compared to baseline in
2011 research study subjects pedometer-based pedometer program; (86.4% F; mean age changes, measured by biases, dropout both groups, but
activity program; health Sr citrate, AlgaeCal, 55.2 ± 11.2 years). DXA total body) effects, and significant change only
(continued on next page)
Journal of Trace Elements in Medicine and Biology 62 (2020) 126577
M. Rondanelli, et al. Journal of Trace Elements in Medicine and Biology 62 (2020) 126577

osteocalcin in postmenopausal subjects naturally exposed to higher

and in self-reported QoL

compliant and partially

blood chemistry panel

concentrations of food boron than those found in subjects from "poor

compliant subjects for

significant changes in
in AlgaeCal 2 group.

MAPC in AlgaeCal 2
Significantly greater

than in AlgaeCal 1.
boron" regions, while no correlation was found statistically significant

Significant MAPC
contrast between

in either group.
between the levels of exposure to boron and the presence of particular

both plans. No
polymorphisms of the gene coding for osteocalcin [39].
Results

4.2. Effectiveness of boron supplementation on vitamin D and sex steroid

hormones metabolism in humans

Studies in middle-aged men and women have shown that boron is

compliance
Secondary
outcomes

effects of

capable of inducing an increase in serum levels of 25 (OH) vitamin D

(similar to estrogen therapy in postmenopausal women) [44,49]. In the
study of Nielsen et al., 15 subjects between 44 and 70 years of age
(including 5 men, 5 postmenopausal women on estrogen therapy, 4
postmenopausal women not on estrogen therapy and 1 pre-menopausal
woman) followed a 2000 kcal / Western diet die containing 0.23 mg of
Primary outcomes

boron for 63 days and, subsequently, a diet supplemented with 3 mg /

day of boron (in the form of sodium borate) for 49 days; serum values of
ionized calcium and 25-hydroxycholecalciferol were lower during the
boron-poor diet than that associated with its supplementation [44]. In a
pilot study conducted in Serbia on 13 middle-aged subjects deficient in
vitamin D (25 (OH) vitamin D < 12 ng / ml), following boron supple-
intervention
Duration of

mentation of 6 mg / day (in the form of calcium fructoborate) for 60

days, a significant average increase in 25 (OH) vitamin D levels of 20 %
the

was observed [49].

In another double-blind placebo-controlled pilot clinical trial of 20
(78.4% F; mean age
56.7 ± 13.2 years).
Number of subjects

volunteers with osteoarthritis of the knee, aged 44–65 years, daily ad-
ministration of 108 mg of calcium fructoborate for 14 days was asso-
AlgaeCal 2: 51
healthy adults

ciated with an increase significant levels of 125 (OH) 2 vitamin D

compared to baseline, an effect not observed in the placebo group.
(M-F)

However, no significant changes were found in serum 25 (OH) vitamin

D levels [50].
vit D-3, vit K-7, vit C,
AlgaeCal, Ca, Mg, Mg

Furthermore, several authors have observed that boron introduced

from Mg carbonate,
Parallel treatments

in the diet can lead to an increase in the plasma concentrations of 17-β

trace minerals in

estradiol and / or testosterone [40,42,43]. In a 1997 study by Naghii

and colleagues, a supplement of 10 mg of boron (as sodium tetraborate)
B (3 mg).

was administered to 18 healthy male subjects for 4 weeks: at the end of

this period, a statistically significant increase was found of plasma es-
tradiol levels and a growth trend (albeit not statistically significant) of
literacy information; Sr
citrate, AlgaeCal, trace

free testosterone levels [42]. In a second 2011 study by Naghii et al.,

minerals in AlgaeCal,
Ca, Mg, vitamin D-3,

the diet of 8 healthy male volunteers, aged between 29 and 50 years,

was supplemented for 7 days with 10 mg / day of sodium tetraborate.
vitamin K-2.
Intervention

At the end of the supplementation, a significant increase in plasma le-

vels of boron and free testosterone was observed, while the con-
centration of estradiol was shown to be reduced; dihydrotestosterone,
cortisol and vitamin D were elevated at the end of the study, but not
statistically significantly [43]. To explain these effects, it has been hy-
pothesized that boron can act as a powerful inhibitor of some micro-
somal enzymes that catalyze the insertion of hydroxyl groups in steroids
Inclusion criteria

such as, for example, 24-hydroxylase (which catalyzes 25OH vitamin D)

and estradiol -hydroxylase (responsible for the catabolism of 17-β es-
tradiol). It may therefore be reasonable in the future to test this hy-
pothesis through in vitro studies on hepatocytes or other cells expres-
sing 24-hydroxylase activity [49].
Setting

4.3. Effectiveness of boron supplementation in combination with other

nutrients on calcium metabolism, growth and maintenance of bone in
humans
Study design

Nutraceutical products (represented by individual nutrients, dietary

Table 2 (continued)

supplements, herbal products, etc.) have recently been strongly pro-

moted and recommended, as they are considered to be able to bring
health benefits, including bone health [51]. Research and studies aimed
at evaluating the effects of different nutritional supplements on bio-
author,

markers associated with chronic diseases and health status are therefore
First

year

increasing. Among these, bone mineral density (BMD) is often

7
M. Rondanelli, et al. Journal of Trace Elements in Medicine and Biology 62 (2020) 126577

Fig. 1. Flow chart of literature research.

considered to be the "gold standard" for assessing bone health [46]. calcium of vegetable origin (AlgaeCal) also containing 65 mg of Mg and
In this context, the study by Michalek et al. is inserted, a com- 1000 IU cholecalciferol; Plan 2 included integration with AlgaeCal to-
parative effectiveness research (CER) in which a first group (AlgaeCal1) gether with 72 mg of Mg, 800 I.U. cholecalciferol, strontium citrate and
of 125 healthy volunteers (average age 55.2 ± 11.2 years) of both sexes vitamin K-2; finally, Plan 3 provided for the intake of AlgaeCal together
(86.4 % women) a calcium-based supplement of plant origin (AlgaeCal, with 350 mg of Mg, 1600 I.U. of cholecalciferol, strontium citrate, vi-
obtained from a seaweed from the coasts of South America) was daily tamin K-7, vitamin C and 3 mg of boron (form of boron compound not
administered for 6 months, also containing magnesium, strontium ci- specified). In addition, both Plan 2 and Plan 3 included a physical ac-
trate, 800 IU of cholecalciferol and vitamin K-2. A second group tivity program (measured by pedometer) and the delivery of bone
(AlgaeCal2) of 51 volunteers (average age 56.7 ± 13.2; 78.4 % female) health information material. Within each group, the subjects were
was instead given, again for a period of 6 months, an alternative version further divided also according to the degree of compliance with the
of the same supplement based of AlgaeCal, which contained similar treatment (two subgroups, above the median: "compliant"; below the
amounts of strontium citrate, calcium and magnesium, but 1600 IU of median: "partially compliant"). Since the duration of Plan 1 was 1 year,
cholecalciferol, vitamin K-7 instead of vitamin K-2 and, in addition, while that of Plans 2 and 3 was 6 months, in this study the changes in
275 mg of magnesium carbonate, 3 mg of boron (type of boron com- the BMD were calculated as "mean annualized percentage change” or
pound not specified by the authors) and 50 mcg of vitamin C. To MAPC. Lacking a control group, the study sponsor chose to compare the
evaluate the effectiveness, the BMD value at the baseline and at the end changes in the BMD in the three intervention groups with data deriving
of the 6 months of treatment was obtained by DXA examination (dual- from previous studies in the literature, according to which after middle
energy x-ray absorptiometry). In both groups there was a positive in- age there would be an annual loss of bone mass linked to the same age,
crease in BMD compared to the baseline (calculated as the "mean an- in both sexes, of about 1% and an even more accelerated loss, up to 2%
nualized percentage change", mean annualized percent change or per year, in women during the first 14 years after menopause; also
MAPC), but only in the second group was this change statistically sig- based on additional data from three different databases (DXA ma-
nificant. In both groups, moreover, greater compliance with integration chinery manufacturer, researchers themselves and National
has been shown to be associated with higher BMD values [46]. Osteoporosis Foundation), a change in BMD was also estimated in the
In a second comparative efficacy research (CER) by Kaats G.R. et al., absence of treatment of 0.75 % / year. At the end of the study, a sig-
172 healthy volunteer female subjects over 40 years of age were di- nificantly greater increase in BMD was observed in all three interven-
vided into three groups and assigned to as many plans for promoting tion groups compared to the expected change values (MAPC Plan 1:
bone health: Plan 1 included the only intake of a supplement based of 1.20 %; Plan 2: 0.33 %; Plan 3: 2, 5%) and the group belonging to Plan

8
M. Rondanelli, et al. Journal of Trace Elements in Medicine and Biology 62 (2020) 126577

3, the most complete from a nutritional point of view, showed far providing further beneficial effects.
greater values than the other two, especially considering, for each
group, the only voluntary subjects with greater compliance (MAPC Plan 4.4. Boron and bone: possible mechanisms of action
1: 1.30 %; Plan 2: 2.00 %; Plan 3: 4.1 %) [45].
The increase in BMD values that emerged in all intervention groups The various boron-containing compounds (BCCs) can each exercise
in both of these research appears, therefore, in contrast to previous different biological actions, from the modulation of enzymatic activities
studies according to which calcium and vitamin D3 supplementation to the interactions with proteins and molecules containing ribose [6].
was associated with a slowdown in age-related BMD loss, but not to an Some of them (such as boric acid and borate) have shown affinity to-
increase [45,46]. wards hydroxyl groups in the cis position, such as those contained in
In 2016 Kaats G.R. et al. then published a further study on the ef- some biologically important sugars (in particular ribose), and this
ficacy and safety of the vitamin-mineral supplement based on AlgaeCal could, at least in part, explain the mechanism behind some biological
(containing 680 mg of strontium, 720 mg of calcium, 72 mg of magne- effects of boron [1,52]. For example, the function of ribose-containing
sium, 1600 IU of vitamin D3, 100 mcg of vitamin K-7, 3 mg of boron molecules, such as S-adenosylmethionine, diadenosine phosphate,
(form of boron compound not specified) and 50 mg of vitamin C). A NAD + and its metabolite ADP cyclic ribose (cADPR), could be mod-
total of 172 healthy adult women (average age 65.1 years) were re- ified by boron; these biochemical entities are involved, in addition to
cruited who had hired the integrator for 1–7 years and who had per- cardiovascular health and neurological functions, also in the formation
formed at least one assessment of BMD via DXA in the same time in- and maintenance of bone, to which boron seems to bring beneficial
terval. After making a second BMD measurement (not less than one year effects [52].
and no more than 7 years from the first), the annualized average per- Boron also appears to interfere in the metabolism of human steroid
centage change (MAPC) was calculated, which was then compared with hormones, thus affecting the levels of estrogen and testosterone; in fact,
the expected or "normal" values obtained, similar to the previous study, it has been hypothesized that it can facilitate their hydroxylation and
from data from three different databases (Centers for Disease Control protect them from rapid degradation. Vitamin D3, which contributes to
(CDC), GE Lunar Norms, Integrative Health Technologies, Inc. (IHTI)). joint and bone health, is also affected by boron and its compounds,
To assess the safety of the same supplement, a total of 125 women from which tend to increase serum concentrations [53]. As already men-
the same intervention group performed a panel of 45 blood chemistry tioned, boron can form covalent complexes with compounds containing
tests on two occasions, 1–4 years apart. The results showed a statisti- two hydroxyl groups close together in the cis position; it has therefore
cally significant increase in BMD during the entire study period, both in been hypothesized that it may inhibit a series of microsomal enzymes
comparison with the baseline data and in comparison with the expected that catalyze, in steroid compounds, the insertion of hydroxyl groups
values obtained from the databases (-0.4 % per year): BMD MAPC was close to existing hydroxyl groups (such as 24-hydroxylase and estradiol-
in fact 1.04 % per year (7.3 % in the 7 years of study). However, no hydroxylase, responsible for the catabolism of the vitamin D 25 OH and
adverse effects or safety problems related to the intake of this supple- estradiol), or forming complexes that act as competitive inhibitors or,
ment have emerged [48]. alternatively, causing a down-regulation of the expression of these en-
In contrast to the results of the studies just described are those that zymes [49].
emerged from a prospective, uncontrolled, single-blind, two-year trial Considering the evidence currently available, it seems reasonable to
conducted in 2002 by Cook A. et al. on a sample of 12 post-menopausal assume that boron also plays a favorable role in calcium metabolism, a
initial women (average age 53.4 years). Two products were adminis- figure of great importance for the prevention of osteoporosis and bone
tered daily to each subject: the first, a vitamin-mineral mixture con- loss. A connection between boron and the signal pathways mediated by
taining calcium 600 mg, magnesium 250 mg, manganese 20 mg, copper calcium (Ca2 +) was also hypothesized, as the latter would counteract
2 mg, chromium 200 mcg, selenium 100 mcg, molybdenum 50 mcg, the expression of some genes also influenced by a boron deficiency;
boron (chelated) 2 mg, silicon 1 mg, strontium 500 mcg, zinc 20 mg, further investigations are necessary to determine whether boron defi-
vitamins B1 20 mg, B2 20 mg, B3 50 mg, B6 25 mg, B12 20 mcg, D 200 ciency can alter the influence and release system of Ca2 + ions [53].
IU, K 300 mcg, pantothenic acid 20 mg, folic acid 800 mcg and betaine Finally, calcium fructoborate can exert a protective effect against
hydrochloride 20 mg; the second represented by a mixture of herbs inflammatory molecules at cellular and enzymatic level, being able to
including Angelica sinensis, licorice root extract, Vitex agnus-castus, chemically bind to specific glycoprotein receptors of cytokines present
Cimicifuga racemosa, Helonia opulus, Foeniculum vulgare, hesperidin. on the surface of cell membranes; administered orally, it appears to be
The study participants were then subjected to BMD detection of the effective in improving the manifestations of the physiological response
lumbar spine (L1-L4), hip and distal third of the forearm via DXA at the to stress (including, among other things, discomfort and joint stiffness
baseline and then at 6, 12 and 24 months. Lacking a control group, the and bone loss), modulating the serum levels of reactive protein C (CRP)
comparison of the data obtained was made with the placebo groups of and other cytokines [7]. In fact, there is a strong association between
other trials performed on women in the initial post-menopause and chronic inflammation and bone loss: inflammation can help decouple
compared to a "non-response" (modification of the BMD equal to zero). the formation from bone resorption in favor of excessive resorption,
The bone mineral loss detected, on an annual basis during the study, thus leading to decreased BMD. In fact, proinflammatory cytokines such
was -1.42 % per year for the lumbar spine, -0.43 % for the hip and as IL-1, IL-6 and TNF-α seem to stimulate osteoclastogenesis while the
−1.42 % for the forearm; these values were not significantly different levels of reactive protein C (CRP) are positively associated with the
from those of the controls of the other trials used for the comparison. total serum concentration of alkaline phosphatase (ALP) and with
The authors therefore concluded that a combined treatment based on higher rates of bone turnover [54]. However, further studies are needed
vitamins, minerals and herbs would seem ineffective in countering the to improve understanding, even at the molecular level, of the various
acceleration of bone mineral loss that occurs in the early stages of post- possible mechanisms of action with which boron and its compounds
menopause [47]. affect bone health.
One of the limitations of the literature available today could be
represented by the fact that studies conducted in humans do not con- 5. Conclusions
sider the intake of boron as the only ingredient of the dietary supple-
ment (the products previously described and compared, in fact, con- To date, unfortunately, due to insufficient data available, re-
tained, for example, also quotas different cholecalciferol); in this way it commended intake levels (RDA) for boron have not yet been estab-
is difficult to establish whether the addition of boron to multivitamin lished [14,15]; however, the World Health Organization (WHO) has
and mineral supplements for bone health can be responsible for estimated an "boron intake" of 1−13 mg / day as an "acceptable safety

9
M. Rondanelli, et al. Journal of Trace Elements in Medicine and Biology 62 (2020) 126577

interval" for adults [16]. EFSA (European Food Safety Agency), how- 10665/37931/9241561734_eng.pdf.
ever, following a critical analysis of boron toxicokinetics and tox- [17] European Food Safety Authority, Tolerable Upper Intake Levels for Vitamins and
Minerals, Scientific Committee on Food; Scientific Panel on Dietetic Products,
icodynamics data, has declared as safe for adults a maximum dose of Nutrition and Allergies, 2006 (Accessed 19 March 2020), http://www.efsa.eu.int.
10 mg / day (in the form of boric acid and borates) [17]. [18] G.H. Biego, M. Joyeux, P. Hartemann, G. Debry, Daily intake of essential minerals
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