[(boron OR boric) AND (vitamin D)]
________________________________________________________________

Boron enhances odontogenic and osteogenic differentiation 
of human tooth germ stem cells (hTGSCs) in vitro. 

Taşlı PN, Doğan A, Demirci S, Şahin F.

Biol Trace Elem Res. 2013 Jun;153(1-3):419-27 

Stem cell technology has been a great hope for the treatment of many common 
problems such as Parkinson's disease, Alzheimer's disease, diabetes, cancer, and 
tissue regeneration. Therefore, the main challenge in hard tissue engineering is 
to make a successful combination of stem cells and efficient inductors in the 
concept of stem cell differentiation into odontogenic and osteogenic cell types. 
Although some boron derivatives have been reported to promote bone and teeth 
growth in vivo, the molecular mechanism of bone formation has not been 
elucidated yet. Different concentrations of sodium pentaborate pentahydrate 
(NaB) were prepared for the analysis of cell toxicity and differentiation 
evaluations. The odontogenic, osteogenic differentiation and biomineralization 
of human tooth germ stem cells (hTGSCs) were evaluated by analyzing the mRNA 
expression levels, odontogenic and osteogenic protein expressions, alkaline 
phosphatase (ALP) activity, mineralization, and calcium deposits. The 
NaB-treated group displayed the highest ALP activity and expression of osteo- 
and odontogenic-related genes and proteins compared to the other groups and 
baseline. In the current study, increased in vitro odontogenic and osteogenic 
differentiation capacity of hTGSCs by NaB application has been shown for the 
first time. The study offers considerable promise for the development of new 
scaffold systems combined with NaB in both functional bone and tooth tissue 
engineering. 
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Pivotal role of boron supplementation on bone health: 
A narrative review. 

Rondanelli M, Faliva MA, Peroni G, Infantino V, Gasparri C, 
Iannello G, Perna S, Riva A, Petrangolini G, Tartara A

J Trace Elem Med Biol. 2020 Dec;62:126577 

BACKGROUND: Boron is a trace element that plays an important role in numerous 
biological functions, including calcium metabolism, growth and maintenance of 
bone tissue. However, there are still no precise indications regarding a 
possible role of boron supplementation, and its amount of supplementation, to 
maintain bone health. So the aim of this narrative review was to consider the 
state of the art on the effectiveness of boron supplementation (alone or with 
other micronutrients) on growth and maintenance of bone in humans through 
control of calcium, vitamin D and sex steroid hormone metabolism in order to 
suggest a daily dosage of boron supplementation.
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.
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Effect of boron on vitamin D deficient rats.

Hegsted M, Keenan MJ, Siver F, Wozniak P.

Biol Trace Elem Res. 1991 Mar;28(3):243-55 

The effects of different levels of dietary boron were determined in vitamin D 
deficient rats. Vitamin D deficient diets containing either 0.158 ppm or 2.72 
ppm of boron were fed to rats for 11 w, and calcium, magnesium, and phosphorus 
apparent absorption and balance were measured in the twelfth week. Higher 
apparent absorption and balance values for calcium and phosphorus were observed 
in the rats with higher dietary boron, but very few differences were seen in 
body wt, organ wt, and bone parameters. Balance measurements represented the 
present status of the rats after 12 w on the diets, but other measurements 
represented an accumulation over the lifetime of the rat, including a suckling 
period with ample vitamin D and boron. The data demonstrated that when rats are 
vitamin D deficient, as indicated by hypocalcemia, the level of boron in the 
diet affects mineral balance.
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Effects of dietary boron in rats fed a vitamin D-deficient diet.

Dupre JN, Keenan MJ, Hegsted M, Brudevold AM.

Environ Health Perspect. 1994 Nov;102 Suppl 7(Suppl 7):55-8 

Although boron has long been known to be a required nutrient for plants, it was 
not until recently that there was any suggestion of a nutritional requirement 
for animals and humans. Addition of boron to the diet of vitamin D-deficient 
chicks indicated that boron may play a role in animal nutrition. Studies with 
rats have demonstrated that supplemental dietary boron has most marked effects 
when the diet is deficient in known nutrients. We observed higher 
apparent-balance values of calcium, magnesium, and phosphorus for rats fed a 
vitamin D-deprived diet with dietary supplemental boron (2.72 ppm), than for 
rats fed the same diet without added boron (0.16 ppm). The treatment group with 
dietary supplemental boron demonstrated a high degree of variability in response 
to boron. We hypothesize that relatively large and variable vitamin D stores in 
weanling rats from a colony supplemented with 3000 IU vitamin D/kg diet 
accounted for the observed variable response. A recent, unpublished study using 
weanling rats from a low-vitamin D colony appears to support this hypothesis.
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The effect of supplementation of calcium, vitamin D, boron, and increased 
fluoride intake on bone mechanical properties and metabolic hormones in rat.

Ghanizadeh G, Babaei M, Naghii MR, Mofid M, Torkaman G, Hedayati M 

Toxicol Ind Health. 2014 Apr;30(3):211-7 

Evidence indicates that optimal nutrition plays a role in bone formation and 
maintenance. Besides major components of mineralization such as calcium, 
phosphorus, and vitamin D, other nutrients like boron and fluoride have 
beneficial role, too. In this study, 34 male Wistar rats were divided into five 
groups: control diet, fluoride, fluoride + boron, fluoride + calcium + vitamin 
D, and fluoride + boron + calcium + vitamin D. Boron equal to 1.23 mg, calcium 
and vitamin D equal to 210 mg + 55 IU and fluoride equal to 0.7 mg/rat/day was 
added to their drinking water for 8 weeks. Plasma blood samples and bones were 
collected. Findings are evidence that fluoride + boron intake revealed 
significant positive effects on bone mechanical properties and bone metabolic 
hormones. These findings suggest that combined intake of these two elements has 
beneficial effects on bone stiffness and breaking strength comparing to even 
calcium + vitamin D supplementation. This evidence dealing with health problems 
related to bone and skeletal system in humans should justify further 
investigation of the role of boron and fluoride with other elements in relation 
to bone.
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Up-regulatory impact of boron on vitamin D function -- 
does it reflect inhibition of 24-hydroxylase? 

Miljkovic D, Miljkovic N, McCarty MF.

Med Hypotheses. 2004;63(6):1054-6 

Nutritional intakes of boron have been shown to lessen the adverse consequences 
of vitamin D deficiency in rodents. Pilot clinical studies suggest that this 
effect may be mediated, in whole or in part, by an increase in serum 
25-hydroxyvitamin D. We propose that, in concentrations achievable with good 
diets, boron suppresses the activity of the microsomal enzyme 24-hydroxylase, 
chiefly responsible for catabolism of this steroid. This inhibition may reflect 
a direct interaction with the enzyme, or perhaps boron's ability to form a 
covalent complex with the product of its activity, 24,25-dihydroxyvitamin D. An 
up-regulatory impact of boron on 25-hydroxyvitamin D is potentially beneficial 
in light of the fact that the vitamin D status of many individuals is poor 
during winter months, and traditional supplemental doses of this vitamin are 
often too low to correct this problem. There is growing evidence that good 
vitamin D status -- as reflected by 25-hydroxyvitamin D levels -- may reduce 
risk for a host of prominent disorders; thus, boron may have the ability to 
potentiate this protection. Clinical studies also suggest that nutritional boron 
can up-regulate 17beta-estradiol levels in women, including postmenopausal women 
receiving hormone replacement therapy. The catabolism of this hormone is 
achieved by microsomal enzymes catalyzing vicinal hydroxylations -- a 
description that also applies to 24-hydroxylase. This suggests the more general 
hypothesis that nutritional boron can inhibit a range of microsomal enzymes 
which insert hydroxyl groups vicinal to existing hydroxyls in steroids -- 
including the enzymes which catabolize estradiol and 25-hydroxyvitamin D.
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Trace elements and bone health.

Zofková I, Nemcikova P, Matucha P 

Clin Chem Lab Med. 2013 Aug;51(8):1555-61 

The importance of nutrition factors such as calcium, vitamin D and vitamin K for 
the integrity of the skeleton is well known. Moreover, bone health is positively 
influenced by certain elements (e.g., zinc, copper, fluorine, manganese, 
magnesium, iron and boron). Deficiency of these elements slows down the increase 
of bone mass in childhood and/or in adolescence and accelerates bone loss after 
menopause or in old age. Deterioration of bone quality increases the risk of 
fractures. Monitoring of homeostasis of the trace elements together with the 
measurement of bone density and biochemical markers of bone metabolism should be 
used to identify and treat patients at risk of non-traumatic fractures. Factors 
determining the effectivity of supplementation include dose, duration of 
treatment, serum concentrations, as well as interactions among individual 
elements. Here, we review the effect of the most important trace elements on the 
skeleton and evaluate their clinical importance.
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Effect of combination therapy of fatty acids, calcium, vitamin D and boron 
with regular physical activity on cardiovascular risk factors in rat. 

Naghii MR, Darvishi P, Ebrahimpour Y, Ghanizadeh G, 
Mofid M, Hedayati M, Asgari AR.

J Oleo Sci. 2012;61(2):103-11 

The effect of consumption of fatty acids and selected nutrients, along with 
regular physical activity, on cardiovascular risk factors in rats was 
investigated.Male rats were divided into the seven groups: Group 1: regular food 
and drinking water, Group 2: same as Group. 1 + physical activity (whole body 
vibration; WBV), Group 3: same as Group. 2 + calcium, vitamin D, boron, Group 4: 
same as Group. 3 + canola oil, Group 5: same as Group. 3 + sunflower oil, Group 
6: same as Group. 3 + mix of sunflower oil and canola oil, Group 7: same as 
Group. 3 + coconut oil. Rats were treated for 8 weeks, and analysis of the 
frozen plasmas was performed. A- Analysis between the treatment groups and 
control revealed that vibration training in Group 2 increased body weight (P = 
0.04), plasma creatin kinase (CK), (P = 0.02), and estradiol (E2), (P = 0.03). 
Rats in Group 5 consumed less food and plasma levels of cholesterol and 
LDL-cholesterol (LDL-C) increased significantly (P = 0.02) in Group 6 and in 
Group 7 (p<0.05). B- Analysis of data among Group 4 - 7 (the oil consuming 
groups) and Group 3 revealed significant differences in cholesterol (Chol), 
LDL-C, HDL-cholesterol (HDL-C), triglycerides (TG), C- reactive protein 
(hs-CRP), estradiol (E2), atherogenic index (AI), and risk factor (RF), 
(p<0.05). In addition, plasma levels of testosterone (T) and free testosterone 
(FT) in Group 7 had a remarkable but non-significant increase. As a result of 
vibration training, a similar trend was observed for vitamin D in Group 2-7. The 
findings show that WBV is effective in improving health status by influencing 
cardiovascular disease (CVD) risk factors. Moreover, canola oil and sunflower 
oil, separately, showed beneficial impacts on CVD risk factors; whereas their 
combination had negative impacts on lipid profile. Coconut oil revealed to be 
efficient to provide health benefits in terms of CVD treatments.
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Effects of dietary boron supplementation on some biochemical parameters, 
peripheral blood lymphocytes, splenic plasma cells and bone characteristics 
of broiler chicks given diets with adequate or inadequate cholecalciferol 
(vitamin D3) content. 

Kurtoğlu F, Kurtoğlu V, Celik I, Keçeci T, Nizamlioğlu M.

Br Poult Sci. 2005 Feb;46(1):87-96 

(1) The effects of 5 and 25 mg/kg boron supplementation of diets with inadequate 
(6.25 microg/kg) or adequate (50 microg/kg) cholecalciferol (vitamin D3) content 
on some biochemical parameters, tibia characteristics, peripheral blood 
lymphocyte and splenic plasma cell counts of broilers were investigated. (2) 
Supplementation of the diet with boron affected plasma concentrations of boron, 
iron, copper and zinc and also tibia boron, zinc and calcium concentrations but 
did not have any effect on tibia iron or copper concentrations or tibia ash and 
tibia weight values. (3) Boron supplementation caused significant increases in 
splenic plasma cell count but decreased the proximal and distal tibia growth 
plate widths. There was no effect of boron supplementation on peripheral blood 
alpha-naphthyl acetate esterase (ANAE) content. Whole blood haematocrit and 
haemoglobin counts were significantly increased by boron supplementation but 
there were no effects on leucocyte ratios such as eosinophil, basophil, 
monocyte, lymphocyte and thrombocyte. (4) In general, the findings of the 
present study support the hypothesis that boron has an important biological role 
that affects the mineral metabolism of animals by influencing both biochemical 
and haematological mechanisms.
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Relation of boron to the composition and mechanical properties of bone.

McCoy H, Kenney MA, Montgomery C, Irwin A, Williams L, Orrell R.

Environ Health Perspect. 1994 Nov;102 Suppl 7(Suppl 7):49-53 

A review of the experimental studies relating boron to biological effects on 
appendicular and axial bones in animal models suggests that numerous influences, 
known and unknown, affect the responsiveness of bone to dietary boron. Degrees 
of skeletal response to boron are modified by other nutritional variables that 
include calcium, magnesium, vitamin D, and fluoride. Evidence suggests that 
appendicular and axial bones may differ in their responses. Tests of the 
mechanical properties of bones may provide useful criteria for assessing the 
impacts of boron status on bone. These tests might resolve questions about 
optimal intakes of boron because mechanical properties sometimes respond to 
boron when composition of bones does not. Difficulty in interpreting some of the 
existing research arises because of the incipient state of knowledge regarding 
boron nutriture, to analytical problems associated with determining accurately 
the small quantities of boron in feed and tissues, and to technological 
difficulties in controlling extraneous exposure of experimental animals to 
boron. Yet there is considerable evidence that both compositional and functional 
properties of bone are affected by boron status.
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Dietary boron modifies the effects of vitamin D3 nutrition on indices 
of energy substrate utilization and mineral metabolism in the chick. 

Hunt CD, Herbel JL, Idso JP.

J Bone Miner Res. 1994 Feb;9(2):171-82 

An experiment was designed to test part of the hypothesis that physiologic 
amounts of dietary boron enhance utilization of or, alternatively, compensate 
for, inadequate concentrations of active vitamin D metabolites to normalize 
energy substrate utilization and mineral metabolism. Day-old cockerel chicks 
were fed a ground corn, high-protein casein, corn oil-based diet (< or = 0.18 mg 
B/kg) supplemented with physiologic amounts of boron (as orthoboric acid) at 0 
(non-PSB) or 1.4 (PSB) mg/kg and vitamin D3 (as vitamin D3 powder in corn 
endosperm carrier) at 3.13 (inadequate, IVD) or 15.6 (adequate, AVD) 
micrograms/kg. After 26 days, IVD decreased food consumption and plasma calcium 
concentrations and increased plasma concentrations of glucose, 
beta-hydroxybutyrate, triglycerides, triiodothyronine, cholesterol, and alkaline 
phosphatase activity. In the IVD chicks, PSB returned plasma glucose and 
triglycerides to concentrations exhibited by the AVD chicks and increased food 
consumption in both IVD and AVD chicks. Histologic findings suggested that PSB 
enhanced maturation of the growth plate. A ninefold increase in dietary boron 
yielded only a two-fold increase in plasma boron concentration and no increase 
in femur boron concentration, which suggests that boron is under homeostatic 
control. The findings suggest that boron acts on at least three separate 
metabolic sites because it compensates for perturbations in energy substrate 
utilization induced by vitamin D3 deficiency, enhances major mineral content in 
bone, and, independently of vitamin D3, enhances some indices of growth 
cartilage maturation.
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Effect of consumption of fatty acids, calcium, vitamin D and boron 
with regular physical activity on bone mechanical properties and 
corresponding metabolic hormones in rats. 

Naghii MR, Ebrahimpour Y, Darvishi P, Ghanizadeh G, 
Mofid M, Torkaman G, Asgari AR, Hedayati M 

Indian J Exp Biol. 2012 Mar;50(3):223-31.

The consumption of fatty acids, nutrients, and regular physical activity, 
individually influence bone mechanical properties in rats. To investigate their 
effects in combination, male rats were divided into the seven groups: G1: 
regular food and drinking water; G2: same as Gr.1 + physical activity (Whole 
body vibration; WBV); G3: same as Gr.2 + Calcium, Vit. D, Boron; G4: same as 
Gr.3 + canola oil; G5: same as Gr.3 + sunflower oil; G6: same as Gr.3 + mix of 
sunflower oil and canola oil; and G7: same as Gr.3 + coconut oil; and treated 
for 8 weeks. Analysis between the control with the groups 2 and 3 revealed that 
vibration in the G2 increased the body weight (P = 0.04), with no other major 
difference in plasma and bone indices. Comparison between the control with the 
G4-G7 (the oil groups) revealed that the rats in the G5 had a lower body weight 
(15 % less) and a significant increase in plasma levels of Estradiol in the G7 
was noted. In addition, levels of Testosterone in the G4 and G7, and Free 
Testosterone in the G7 had a remarkable increase. Similar trend was observed for 
plasma levels of Vit. D in the G4 and G5. The stiffness and the breaking 
strength of the femur in the G7, and the breaking strength of the lumbar in the 
G7 compared to the control and the G4 and G5 was significantly higher and tended 
to increase in comparison to the G6. Better and stronger measurements observed 
for coconut oil is warranted to further study its effect on biomechanical 
properties of bones.
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Effects of boron supplementation of adequate and inadequate vitamin 
D3-containing diet on performance and serum biochemical characters 
of broiler chickens. 

Kurtoğlu V, Kurtoğlu F, Coşkun B.

Res Vet Sci. 2001 Dec;71(3):183-7 

In this study, supplementation of two levels (5 and 25 parts per million; ppm) 
of boron into broiler diets including 125 IU kg(-1) (inadequate) and 2000 IU 
kg(-1) (adequate) vitamin D3 was investigated. The effects of supplementation on 
performance and biochemical characters (Ca, P, Mg, glucose and AP) of broilers 
from 1 to 45 days of age were evaluated. Boron provided significant increases in 
performances of chicks fed both adequate and inadequate vitamin D3-containing 
diets. The improvements in the inadequate vitamin D3-containing group were 
higher than that of adequate vitamin D3-containing group. The boron addition had 
a positive effect on Ca, P and alkaline phosphatase levels of chicks. Boron 
might be regarded as beneficial in inadequate vitamin D3-containing broiler 
feed.
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Trace elements have beneficial, as well 
as detrimental effects on bone homeostasis. 

Zofkova I, Davis M, Blahos J.

Physiol Res. 2017 Jul 18;66(3):391-402 

The protective role of nutrition factors such as calcium, vitamin D and vitamin 
K for the integrity of the skeleton is well understood. In addition, integrity 
of the skeleton is positively influenced by certain trace elements (e.g. zinc, 
copper, manganese, magnesium, iron, selenium, boron and fluoride) and negatively 
by others (lead, cadmium, cobalt). Deficiency or excess of these elements 
influence bone mass and bone quality in adulthood as well as in childhood and 
adolescence. However, some protective elements may become toxic under certain 
conditions, depending on dosage (serum concentration), duration of treatment and 
interactions among individual elements. We review the beneficial and toxic 
effects of key elements on bone homeostasis.
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The relationship between boron and magnesium status 
and bone mineral density in the human: a review. 

Volpe SL, Taper LJ, Meacham S.

Magnes Res. 1993 Sep;6(3):291-6.

Osteoporosis is a disease that characteristically afflicts postmenopausal women. 
It is estimated that millions of people are plagued yearly with this 
debilitating disease. Associated health care costs are in the billions of 
dollars, annually. Much research has been conducted in the area of osteoporosis 
and mineral supplementation, mainly focusing on calcium and vitamin D. 
Nonetheless, more recent studies have reported possible improvements in bone 
mineral density in women who were supplemented with the ultratrace mineral, 
boron. Boron may play a role in bone metabolism, but its role is most likely to 
be associated with its interactions with other minerals and vitamins such as 
calcium, magnesium and vitamin D. Although the focus of this review will be to 
discuss the interactive role of boron with magnesium and bone metabolism, some 
discussion of its interactive role with vitamin D is also necessary.
________________________________________________________________

High Doses of Boron Have No Protective Effect Against 
Nephrolithiasis or Oxidative Stress in a Rat Model. 

Ergul AB, Kara M, Karakukcu C, Tasdemir A, Aslaner H, 
Ergul MA, Muhtaroglu S, Zararsiz GE, Torun YA 

Biol Trace Elem Res. 2018 Nov;186(1):218-225 

Boron plays roles in the metabolism of calcium, vitamin D, steroid hormones, 
healthy bone development, and maintenance of cell membranes. The biological 
effects of boron are dose-dependent but follow a U-shaped pattern, rendering it 
important to define the active range. The studies of Bahadoran et al. on rats 
and Naghii et al. on humans showed that low doses of boron (3 and 10 mg/day) 
prevented kidney stone formation. The aim of this study was to determine whether 
high doses of boron have an anti-urolithiatic or antioxidant effect on 
nephrolithiasis in an experimental rat model. The study was conducted on 50 
adult male Wistar rats randomized to five groups. Nephrolithiasis was induced 
with water containing 0.75% ethylene glycol (EG) and 2% ammonium chloride (AC). 
This treatment was given to animals in all groups for 10 days, except the 
positive and negative controls. Simultaneously, groups 2, 3, and 4 were given 
boric acid via gavage at doses of 25, 50, and 100 mg/kg/day (equivalent to 
4/8/16 mg boron respectively) as the source of boron. Animals in the negative 
and positive control groups were given 6 μL/g distilled water without boric 
acid. At day 10, intra-cardiac blood samples were drawn from all animals. The 
right and left kidneys were removed for biochemical and histopathological 
examinations, respectively. The groups were compared with respect to serum urea, 
creatinine, calcium, phosphorous, total antioxidant status (TAS), total oxidant 
status (TOS), serum paraoxonase (PON1) activity, tissue calcium and oxalate 
levels, and stone burden as determined by histopathological examination. Serum 
urea and creatinine levels were significantly higher (p < 0.001 and p < 0.05, 
respectively), while serum calcium and phosphorous levels were significantly 
lower (p < 0.001 and p < 0.001, respectively), in animals given EG/AC compared 
to negative controls. No significant differences were detected in serum calcium, 
phosphorous, urea, or creatinine levels between animals treated with boron and 
positive controls (p > 0.05). Serum PON1 activity was significantly lower in 
animals given EG/AC than in negative controls (p < 0.001), while no significant 
difference in serum PON1 level was detected between rats treated with boron and 
positive controls. No significant differences were detected in vitamin D, TAS, 
TOS, tissue calcium, or tissue oxalate levels among groups. No stone formation 
was detected on histopathological examination in negative controls. No 
significant differences were found in stone formation between rats treated with 
boron and positive controls. Based on this study, high doses of boron had no 
protective effect against nephrolithiasis and oxidative stress.
________________________________________________________________

The physiological effects of dietary boron.

Devirian TA, Volpe SL.

Crit Rev Food Sci Nutr. 2003;43(2):219-31 

Boron may be an essential nutrient for animals and humans. Dietary boron 
influences the activity of many metabolic enzymes, as well as the metabolism of 
steroid hormones and several micronutrients, including calcium, magnesium, and 
vitamin D. Boron supplementation in rats and chicks has been shown to increase 
bone strength. Boron may also play a role in improving arthritis, plasma lipid 
profiles, and brain function. Additional research is necessary to further 
clarify boron's influence in human and animal physiology, as well as determine a 
dietary requirement for humans.
________________________________________________________________

The biochemical effects of physiologic amounts 
of dietary boron in animal nutrition models. 

Hunt CD 

Environ Health Perspect. 1994 Nov;102 Suppl 7(Suppl 7):35-43 

This review summarizes evidence that supports working hypotheses for the roles 
of boron in animal model systems. It is well established that vascular plants, 
diatoms, and some species of marine algal flagellates have acquired an absolute 
requirement for boron, although the primary role of boron in plants remains 
unknown. Recent research findings suggest that physiologic amounts of 
supplemental dietary boron (PSB) affect a wide range of metabolic parameters in 
the chick and rat model systems. Much of the current interest in boron animal 
nutrition began with the initial finding that PSB stimulates growth in 
cholecalciferol (vitamin D3)-deficient chicks, but does not markedly affect 
growth in chicks receiving adequate vitamin D3 nutriture. The finding suggests 
that boron affects some aspect of vitamin D3 metabolism or is synergistic with 
vitamin D3 in influencing growth. Vitamin D3 regulates energy substrate 
utilization, and current research findings indicate that dietary boron modifies 
that regulatory function. The concentration of circulating glucose, the most 
thoroughly investigated metabolite to date, responds to PSB, especially during 
concomitant vitamin D3 deficiency. In chicks, PSB substantially alleviated or 
corrected vitamin D3 deficiency-induced elevations in plasma glucose 
concentrations. The influence of vitamin D3 on cartilage and bone mineralization 
is mediated in part through its role as a regulator of energy substrate 
utilization; calcification is an energy-intensive process. There is considerable 
evidence that dietary boron alleviates perturbations in mineral metabolism that 
are characteristic of vitamin D3 deficiency. In rachitic chicks, PSB alleviated 
distortion of the marrow sprouts of the proximal tibial epiphysial plate, a 
distortion characteristic of vitamin D3 deficiency. 
(ABSTRACT TRUNCATED AT 250 WORDS)
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[Diet, nutrition and bone health].[Italian]

Miggiano GA, Gagliardi L.

Clin Ter. 2005 Jan-Apr;156(1-2):47-56.

Nutrition is an important "modifiable" factor in the development and maintenance 
of bone mass and in the prevention of osteoporosis. The improvement of calcium 
intake in prepuberal age translates to gain in bone mass and, with genetic 
factor, to achievement of Peak Bone Mass (PBM), the higher level of bone mass 
reached at the completion of physiological growth. Individuals with higher PBM 
achieved in early adulthood will be at lower risk for developing osteoporosis 
later in life. Achieved the PBM, it is important maintain the bone mass gained 
and reduce the loss. This is possible adopting a correct behaviour eating 
associated to regular physical activity and correct life style. The diet is 
nutritionally balanced with caloric intake adequate to requirement of 
individual. This is moderate in protein (1 g/kg/die), normal in fat and the 
carbohydrates provide 55-60% of the caloric intake. A moderate intake of 
proteins is associated with normal calcium metabolism and presumably does'nt 
alter bone turnover. An adequate intake of alkali-rich foods may help promote a 
favorable effect of dietary protein on the skeleton. Lactose intolerance may 
determinate calcium malabsorption or may decrease calcium intake by elimination 
of milk and dairy products. Omega3 fatty acids may "down-regulate" 
pro-inflammatory cytokines and protect against bone loss by decreasing 
osteoclast activation and bone reabsorption. The diet is characterized by food 
containing high amount of calcium, potassium, magnesium and low amount of 
sodium. If it is impossible to reach the requirement with only diet, it is need 
the supplement of calcium and vitamin D. Other vitamins (Vit. A, C, E, K) and 
mineral (phosphorus, fluoride, iron, zinc, copper and boron) are required for 
normal bone metabolism, thus it is need adequate intake of these dietary 
components. It is advisable reduce ethanol, caffeine, fibers, phytic and ossalic 
acid intake. The efficacy of phytoestrogens is actually under investigation. 
Some drugs may interfere with calcium and other nutrients and produce an 
unfavourable effect on bone health.
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Nutrition and osteoporosis prevention for the orthopaedic surgeon: 
A wholefoods approach. 

Higgs J, Derbyshire E, Styles K 

EFORT Open Rev. 2017 Jun 23;2(6):300-308 

Osteoporosis is a prevalent and debilitating condition with no signs of 
subsiding. Rising numbers of people consuming nutrient-poor diets coupled with 
ageing populations and sedentary lifestyles appear to be the main drivers behind 
this. While the nutrients calcium and vitamin D have received most attention, 
there is growing evidence that wholefoods and other micronutrients have roles to 
play in primary and potentially secondary osteoporosis prevention. Until 
recently, calcium and vitamin D were regarded as the main nutrients essential to 
bone health but now there are emerging roles for iron, copper and selenium, 
among others. Fruit and vegetables are still not being eaten in adequate amounts 
and yet contain micronutrients and phytochemicals useful for bone remodelling 
(bone formation and resorption) and are essential for reducing inflammation and 
oxidative stress. There is emerging evidence that dried fruits, such as prunes, 
provide significant amounts of vitamin K, manganese, boron, copper and potassium 
which could help to support bone health. Just 50 g of prunes daily have been 
found to reduce bone resorption after six months when eaten by osteopaenic, 
postmenopausal women. Dairy foods have an important role in bone health. 
Carbonated drinks should not replace milk in the diet. A balanced diet containing 
food groups and nutrients needed for bone health across the whole lifecycle may 
help to prevent osteoporosis. Greater efforts are needed to employ preventative 
strategies which involve dietary and physical activity modifications, if the 
current situation is to improve. 
________________________________________________________________

Effects of boric acid supplementation on bone health 
in crossbred calves under tropical condition.

Singh AK, Kewalramani N, Mani V, Sharma A, Kumari P, Pal RP

J Trace Elem Med Biol. 2021 Jan;63:126647 

INTRODUCTION: Boron (B) is thought to play key role in proper bone growth and 
development as well as have some role in regulation of minerals such as calcium 
(Ca), phosphorus (P) and magnesium (Mg) which act synergistically with vitamin D. 
OBJECTIVE: Present study was planned in two phases to assess the effect of 
optimum and supranutritional levels of (B) in the form of boric acid (BA) 
supplementation on bone health of growing cross bred calves.
METHOD: During Phase-1, twenty four male crossbred calves were blocked into four 
groups (n = 6) on the basis of their body weight (154.83 ± 8.5 kg), age (7-9 
months) and were supplemented with 0 (C), 2.6 (T-1), 5.4 (T-2) and 10.7 (T-3) g 
BA for appropriate B (0.175 adjustment factor to calculate B form BA) 
consumption i.e. 0, 100, 200 and 400 ppm in each group respectively, for 90 
days. During phase 2, twenty-one male crossbred calves were divided into 3 
groups (n = 7) on the basis of their body weight (103.76 ± 4.34 kg) and age (5-8 
months). All the groups were on similar dietary regimen with additional 
supplementation of boric acid as 0 g (control); 3.6 g (200 ppm B; T-1) and 
10.8 g (600 ppm B; T-2), respectively for a period of 120 d.
RESULTS: From the first experiment it is reported that plasma levels of bovine 
alkaline phosphatase (BALP), type I collagen cross-linked N-telopeptide (NTx) 
and Ca were significantly (P < 0.05) affected in T-2 and T-3 groups as compared 
to T-1 and control groups. Whereas, plasma osteocalcin (OCN) concentration was 
found to be higher in T-2 and T-3 groups as compared to control group. However, 
plasma concentrations (ng/mL) of tartrate resistant acid phosphatase (TRAP) 
remained unaltered due to dietary treatments. Based on the results, another 
experiment was conducted to validate the above findings and further to determine 
the effect of still higher i.e supranutritional levels of BA supplementation on 
bone health of calves. Results revealed that supplementation of BA in T-2 group 
had no beneficial effect on bone health as the plasma concentration of BALP, 
OCN, NTx, 25 (OH) vitamin D and Ca as compared to T-1 group in phase 2. Other 
possible attributes of bone health i.e. plasma concentration of Mg, P, 
parathyroid hormone (PTH), and calcitonin were not affected by BA 
supplementation at any levels.
CONCLUSION: Overall from present study it can be concluded that supplementation 
of boric acid 3.6 g/d (equivalent to 200 ppm B) in the diet of growing animals 
has positive effect on bone health related biomarkers (OCN, NTx and BALP) and 
supplementation of supranutritional level of BA i.e. 10.8 g (equivalent to 
600 ppm B) level had neither additional beneficial nor harmful effect on bone 
health of calves.
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The role of nutrition in osteoporosis.

Bunker VW 

Br J Biomed Sci. 1994 Sep;51(3):228-40.

Osteoporosis-related bone fractures are a significant cause of mortality and 
morbidity, with women being particularly affected. Osteoporosis is a condition 
of bone fragility resulting from micro-architectural deterioration and decreased 
bone mass; adult bone mass depends upon the peak attained and the rate of 
subsequent loss; each depends on the interaction of genetic, hormonal, 
environmental and nutritional factors. An adequate supply of calcium is 
essential to attain maximum bone mass, and adult intakes below about 500 mg/day 
may predispose to low bone mass. Supplementation with calcium may conserve bone 
at some skeletal sites, but whether this translates into reduced fracture rates 
is not clear. Chronically low intakes of vitamin D--and possibly magnesium, 
boron, fluoride and vitamins K, B12, B6 and folic acid (particularly if 
co-existing)--may pre-dispose to osteoporosis. Similarly, chronically high 
intakes of protein, sodium chloride, alcohol and caffeine may also adversely 
affect bone health. The typical Western diet (high in protein, salt and refined, 
processed foods) combined with an increasing sedentary lifestyle may contribute 
to the increasing incidence of osteoporosis in the elderly.
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Boron supplementation in peripartum Murrah buffaloes: 
The effect on calcium homeostasis, bone metabolism, 
endocrine and antioxidant status.

Sharma A, Mani V, Pal RP, Sarkar S, Datt C

J Trace Elem Med Biol. 2020 Dec;62:126623 

BACKGROUND: Calcium homeostasis and immuno-endocrine system undergoes drastic 
changes in peripartum dairy animals and failure to adapt these physiological 
changes causes major impact on animal health as well as productivity. Boron (B), 
a newer trace element, influences calcium (Ca), phosphorus (P) and magnesium 
(Mg) metabolism as well as immune system by manipulating several hormones or 
enzyme systems. Present study was conducted to determine the effect of dietary B 
supplementation on Ca homeostasis, bone metabolism, endocrine and antioxidant 
status in peripartum Murrah buffaloes.
METHODS: Thirty advanced pregnant Murrah buffaloes (8th month pregnant) were 
allocated into three groups based on their most probable producing ability 
(MPPA) and parity (n = 10 in each group) viz. B0, B200 and B400 and supplemented 
with 0, 200 and 400 ppm of B in the form of boric acid. Blood samples were 
collected at periodic intervals (-45, -30, -21, -15, -7, 0, 7, 15, 30, 60, 90 
and 120 day relative to expected date of calving) and analysed for minerals 
concentration, hormonal profile, bone health biomarkers and antioxidant enzymes.
RESULTS AND CONCLUSION: Boron supplementation at 200 and 400 ppm increased 
(p < 0.05) plasma Ca, Mg and osteocalcin (OCN) concentration during postpartum 
stage. Higher (p < 0.05) levels of plasma 25-hydroxy vitamin D3 were observed in 
both B supplemented groups as compared to B unsupplemented group irrespective of 
physiological stages. Plasma parathyroid hormone (PTH) and cortisol levels were 
lower (p < 0.05) in both B supplemented groups than B unsupplemented group, 
especially during postpartum stage. Whereas, plasma ferric reducing total 
antioxidant power (FRAP) activity was found to be higher (p < 0.05) in B 
supplemented groups as compared to B unsupplemented group. Furthermore, 
antioxidant enzymes (erythrocytic superoxide dismutase; SOD, catalase, 
glutathione peroxidase; GPx), plasma level of total immunoglobulins (TIg), bone 
specific alkaline phosphatase (BALP) and tartrate resistant acid phosphatase 
(TRAP) remained unaffected by dietary B supplementation. Overall, it can be 
concluded that supplementation of B at 200 ppm in the diet of peripartum Murrah 
buffaloes helped to induce metabolic adaptations for improving Ca homeostasis, 
bone metabolism and antioxidant status without much additional benefits at 
higher level used in the present study.
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Zebrafish as a Model to Unveil the Pro-Osteogenic Effects 
of Boron-Vitamin D3 Synergism.

Sojan JM, Gundappa MK, Carletti A, Gaspar V, 
Gavaia P, Maradonna F, Carnevali O

Front Nutr. 2022 Apr 29;9:868805 

The micronutrient boron (B) plays a key role during the ossification process as 
suggested by various in vitro and in vivo studies. To deepen our understanding 
of the molecular mechanism involved in the osteogenicity of B and its possible 
interaction with vitamin D3 (VD), wild-type AB zebrafish (Danio rerio) were used 
for morphometric analysis and transcriptomic analysis in addition to taking 
advantage of the availability of specific zebrafish osteoblast reporter lines. 
First, osteoactive concentrations of B, VD, and their combinations were 
established by morphometric analysis of the opercular bone in alizarin 
red-stained zebrafish larvae exposed to two selected concentrations of B (10 and 
100 ng/ml), one concentration of VD (10 pg/ml), and their respective 
combinations. Bone formation, as measured by opercular bone growth, was 
significantly increased in the two combination treatments than VD alone. 
Subsequently, a transcriptomic approach was adopted to unveil the molecular key 
regulators involved in the synergy. Clustering of differentially expressed genes 
revealed enrichment toward bone and skeletal functions in the groups co-treated 
with B and VD. Downstream analysis confirmed mitogen-activated protein kinase as 
the most regulated pathway by the synergy groups in addition to transforming 
growth factor-β signaling, focal adhesion, and calcium signaling. The 
best-performing synergistic treatment, B at 10 ng/ml and VD at 10 pg/ml, was 
applied to two zebrafish transgenic lines, Tg(sp7:mCherry) and Tg(bglap:EGFP), 
at multiple time points to further explore the results of the transcriptomic 
analysis. The synergistic treatment with B and VD induced enrichment of 
intermediate (sp7+) osteoblast at 6 and 9 days post fertilization (dpf) and of 
mature (bglap +) osteoblasts at 15 dpf. The results obtained validate the role 
of B in VD-dependent control over bone mineralization and can help to widen the 
spectrum of therapeutic approaches to alleviate pathological conditions caused 
by VD deficiency by using low concentrations of B as a nutritional additive.
________________________________________________________________

Dietary boron modified the effects of magnesium and molybdenum 
on mineral metabolism in the cholecalciferol-deficient chick.

Hunt CD 

Biol Trace Elem Res. 1989 Nov;22(2):201-20 

The metabolic effects of dietary boron, magnesium, and molybdenum on mineral 
metabolism in the cholecalciferol-deficient chick, with emphasis on growth 
cartilage histology, were studied. One-day-old cockerel chicks were assigned to 
groups in a fully-crossed, three factor, 2 x 2 x 2 design. The basal diet was 
based on ground corn, high-protein casein, and corn oil and contained 125 IU 
cholecalciferol (inadequate), 0.465 mg B, 2.500 mg Mg, and 0.420 mg Mo/kg. The 
treatments were the supplementation of the basal diet with B at O or 3; Mg at 
300 (inadequate) or 500 (adequate); and Mo at 0 or 20 mg/kg. At d 25, B 
depressed mortality, alleviated the cholecalciferol-deficiency induced 
distortion of the marrow sprouts (MS) of the proximal tibial epiphysial plate, 
and elevated the numbers of osteoclasts within the MS. Adequate Mg exacerbated 
the cholecalciferol-deficiency induced bone lesions. Mo widened the MS markedly. 
In Mg-deficient chicks, B elevated plasma Ca and Mg concentrations and growth, 
but inhibited initiation of cartilage calcification; B had the opposite effect 
in Mg-adequate chicks. An interaction among B, Mg, and Mo affected plasma uric 
acid and glucose concentrations. B may function to modify mineral metabolism in 
cholecalciferol deficiency, suppressing bone anabolism in concurrent Mg 
deficiency and bone catabolism in concurrent Mg adequacy.
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The proteasome inhibitor bortezomib stimulates osteoblastic 
differentiation of human osteoblast precursors via upregulation 
of vitamin D receptor signalling. 

Kaiser MF, Heider U, Mieth M, Zang C, von Metzler I, Sezer O.

Eur J Haematol. 2013 Apr;90(4):263-72 

Interactions of myeloma cells with the bone marrow microenvironment lead to 
enhanced osteoclast recruitment and impaired osteoblast activity. Recent 
evidence revealed that the proteasome inhibitor bortezomib stimulates osteoblast 
differentiation, but the mechanisms are not fully elucidated. We hypothesised 
that bortezomib could influence osteoblastic differentiation via alteration of 
vitamin D signalling by blocking the proteasomal degradation of the vitamin D 
receptor (VDR). This is of clinical importance, as a high rate of vitamin D 
deficiency was reported in patients with myeloma. We performed cocultures of 
primary human mesenchymal stem cells (hMSCs) and human osteoblasts (hOBs) with 
myeloma cells, which resulted in an inhibition of the vitamin D-dependent 
differentiation of osteoblast precursors. Treatment with bortezomib led to a 
moderate increase in osteoblastic differentiation markers in hMSCs and hOBs. 
Importantly, this effect could be strikingly increased when vitamin D was added. 
Bortezomib led to enhanced nuclear VDR protein levels in hMSCs. Primary hMSCs 
transfected with a VDR luciferase reporter construct showed a strong increase in 
VDR signalling with bortezomib. In summary, stimulation of VDR signalling is a 
mechanism for the bortezomib-induced stimulation of osteoblastic 
differentiation. The data suggest that supplementation of vitamin D in patients 
with myeloma treated with bortezomib is crucial for optimal bone formation.
________________________________________________________________

The influence of a low-boron diet and boron supplementation on bone, 
major mineral and sex steroid metabolism in postmenopausal women.

Beattie JH, Peace HS 

Br J Nutr. 1993 May;69(3):871-84 

An increase in dietary intake of B from 0.25 to 3.25 mg/d has been reported to 
increase plasma oestradiol and testosterone and decrease urinary Ca excretion in 
postmenopausal women. Consequently, it is suggested that the higher level of B 
intake could reduce bone loss associated with the menopause and cessation of 
ovarian function. The present study was designed to investigate the effect of a 
B supplement on bone mineral absorption and excretion, plasma sex steroid levels 
and urinary excretion of pyridinium crosslink markers of bone turnover in 
healthy postmenopausal volunteers. The women were accommodated in a metabolic 
unit, given a low-B diet (LBD; 0.33 mg/d) for 3 weeks and were asked to take a B 
supplement of 3 mg/d in addition to the LBD for a further 3 weeks. Changing B 
intake from 0.33 to 3.33 mg/d had no effect on minerals, steroids or crosslinks. 
However, the LBD appeared to induce hyperabsorption of Ca since positive Ca 
balances were found in combination with elevated urinary Ca excretion. This 
phenomenon may have inhibited or obscured any effect of B.
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Excerpt from "The Borax Conspiracy — How the Arthritis Cure 
has been stopped." by Walter Last 

Boron deficiency causes the parathyroids to become overactive, 
releasing too much parathyroid hormone which raises the blood 
level of calcium by releasing calcium from bones and teeth. 
This then leads to osteoarthritis and other forms of arthritis, 
osteoporosis and tooth decay. With advancing age high blood 
levels of calcium lead to calcification of soft tissues causing 
muscle contractions and stiffness; calcification of endocrine 
glands, especially the pineal gland and the ovaries; 
arteriosclerosis, kidney stones, and calcification of the 
kidneys ultimately leading to kidney failure. Boron deficiency 
combined with magnesium deficiency is especially damaging to 
the bones and teeth. 
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Boric acid inhibits alveolar bone loss in rat experimental periodontitis 
through diminished bone resorption and enhanced osteoblast formation.

Shalehin N, Hosoya A, Takebe H, Hasan MR, Irie K

J Dent Sci. 2020 Dec;15(4):437-444 

BACKGROUND/PURPOSE: Inhibition of bone resorption is essential for periodontal 
treatment. Recently, it has been suggested that boric acid suppresses 
periodontitis, but the mechanism of this inhibition is still not well 
understood. Therefore, to analyze the cellular response to boric acid 
administration, we histologically evaluated alveolar bone in experimental 
periodontitis of rats administered boric acid.
MATERIALS AND METHODS: 5-0 silk ligatures were placed around the cervix of the 
second maxillary molars of 4 week-old rats treated with or without boric acid. 
Five and 14 days after ligature placement, the periodontal tissues between first 
and second molars were investigated histologically and immunohistochemically 
using antibodies to CD68, cathepsin K, and α-smooth muscle actin (SMA).
RESULTS: Five days after the beginning of the experiment, many CD68-positive 
cells appeared in the periodontal tissues with ligature placement without boric 
acid administration. Also, the number of cathepsin K-positive osteoclasts had 
increased on the surface of alveolar bone. However, boric acid administration 
prevented severe bone resorption and reduced the number of cells positive for 
CD68 and cathepsin K. At day 14 post treatment, cells positive for α-SMA were 
seen in the periodontal tissues after boric acid administration, whereas no such 
cells were found around the alveolar bone without the administration of boric 
acid.
CONCLUSION: Boric acid inhibited the inflammation of ligature-induced 
periodontitis. This agent might reduce bone resorption by inhibiting 
osteoclastogenesis and also could accelerate osteoblastogenesis. 
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Substitution of strontium and boron into hydroxyapatite crystals: 
Effect on physicochemical properties and biocompatibility 
with human Wharton-Jelly stem cells.

Kolmas J, Velard F, Jaguszewska A, Lemaire F, 
Kerdjoudj H, Gangloff SC, Kaflak A

Mater Sci Eng C Mater Biol Appl. 2017 Oct 1;79:638-646 

Hydroxyapatite (HA) enriched with strontium and boron ions was synthesized using 
two different methods: the precipitation method (Sr,B-HAw) and the dry method 
(Sr,B-HAd). Additionally, for the sake of comparison, the "pure" unsubstituted 
HA was prepared together with HAs substituted only with one type of a foreign 
ion. The obtained materials were subjected to physicochemical analysis with the 
use of various analytical methods, such as powder X-ray diffraction (PXRD), 
transmission electron microscopy (TEM), inductively coupled plasma optical 
emission spectroscopy (ICP-OES), Fourier transform infrared spectroscopy (FT-IR) 
and solid-state proton nuclear magnetic resonance (1H ssNMR). All the obtained 
materials were also biologically tested for their potential cytotoxicity. The 
obtained materials (Sr,B-HAw and Sr,B-HAd) were homogeneous and respectively 
showed nano- and microcrystal apatitic structures. The simultaneous introduction 
of Sr2+ and BO33- ions turned out to be more effective in respect of the dry 
method. Of importance, doped materials obtained using both synthesis routes have 
been demonstrated to be biocompatible, opening the way for medical applications. 
________________________________________________________________

Effects of boric acid on experimental periodontitis 
and alveolar bone loss in rats.

Demirer S, Kara MI, Erciyas K, Ozdemir H, Ozer H, Ay S.

Arch Oral Biol. 2012 Jan;57(1):60-5 

OBJECTIVE: The goal of the present study was to evaluate the histopathologic and 
morphometric effects of systemic boric acid in a rat periodontitis model.
DESIGN: Twenty-four Wistar rats were divided into three groups of eight animals 
each: non-ligated (NL), ligature only (LO), and ligature and treated with boric 
acid (BA) (3mg/kg per day for 11 days). A 4/0 silk suture was placed in a 
subgingival position around the mandibular first molars; after 11 days the rats 
were sacrificed, and changes in alveolar bone levels were measured clinically 
and tissues were histopathologically examined to assess the differences amongst 
the study groups.
RESULTS: The ratio of presence of inflammatory cell infiltration (ICI) and 
osteoclast number in the LO group was significantly higher than that of the NL 
and BA groups (p<0.05). The ratio of presence of osteoblastic activity in the LO 
group was significantly lower than that of the NL and BA groups (p<0.05). 
Alveolar bone loss was also significantly higher in the LO group compared to the 
BA and NL groups (p<005).
CONCLUSIONS: This study has demonstrated that systemic administration of boric 
acid reduced periodontal inflammation and alveolar bone loss in periodontal 
disease in rats. 
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