Fructoborate

Other Names

bis(fructose) ester of boric acidBorate(1-), bis(beta-D-fructofuranosato(2-)-kappaO2,kappaO3)-, calcium (2:1), (T-4)-CaFBcalcium bis(β-D-fructopyranose) boratecalcium fructoboratecalcium fructoborate tetrahydratecalcium salt of bis(fructose) boratecalcium;(1S,1'S,5R,5'R,7R,7'R,8S,8'S)-5,5',7,7'-tetrakis(hydroxymethyl)-3,3'-spirobi[2,4,6-trioxa-3-boranuidabicyclo[3.3.0]octane]-8,8'-diolCFCFBFrXBnature-identical boron complexorganoboron-fructose complexplant-based dietary boronsugar-borate ester

Synopsis

Fructoborate (Calcium Fructoborate)

1. Identity: Chemical Name, Natural Source, and Common Forms

Chemical Identity

Calcium fructoborate is a salt of an organoboron compound containing boron, fructose, and calcium. Results of thermal analysis, together with X-ray powder diffraction (XRD), Fourier Transform Infrared (FTIR) spectroscopy, and Raman spectroscopy, led to the conclusion that the commercially produced form is a nature-identical product with the molecular composition Ca[(C₆H₁₀O₆)₂B]₂·4H₂O, containing 2.5 ± 0.1% boron and 4.6 ± 0.1% calcium. This molecular formula is also commonly represented as Ca[(C₆H₁₀O₆)₂B]₂ in the peer-reviewed literature. The structure involves two molecules of fructose bound to a single boron atom, with a calcium ion stabilizing the complex.

Its chemical structure is similar to one of the natural forms of boron — the bis-manitol, bis-sorbitol, bis-fructose, and bis-sucrose borate complexes found in edible plants. Sugar-borates (SBs) are mono- or di-sugar-borate esters (SBEs) comprised of one or two monosaccharide molecules linked to a boron atom. Calcium fructoborate contains three forms of borate — diester, monoester, and boric acid — and all are biologically active, both at the intracellular (as free boric acid) and extracellular level (as fructose-borate diester and monoester).

Boron (B) is a trace element with distinctive coordination chemistry that enables the formation of reversible esters with cis-diol-containing ligands, particularly carbohydrates and polyols. As boric acid/borate enters the human or animal cell, it blocks other biomolecules that contain cis-diols, for example, nicotinamide adenine dinucleotide (NAD), S-adenosyl methionine (SAM), flavin adenine dinucleotide (FAD), and ribonuclease (RNase).

Natural Source and Occurrence

Calcium fructoborate, the most common form of the fructoborate ester (FBE), is naturally found in fresh fruits, vegetables, and honey, and in dried fruits such as plums, raisins, and apricots. Sugar-borate esters are found in fruits, vegetables, certain nuts, and legumes, and are naturally absorbed by animal cells. Calcium fructoborate is the most common SBE, typically manifesting as the specific bis-fructose ester. In foods, they serve as a source of soluble borate.

The mean daily intake of fructoborate and related complexes is estimated to be about 35 mg (1.05 mg elemental boron), and the 95th percentile intake is estimated at about 75 mg (2.25 mg elemental boron). Fructoborate is also found as a protonated diester fructoborate (PFB) resulting from the sorbitol metabolic pathway in the phloem and extracellular peach nectar.

Commercial Forms and Preparations

Today, calcium fructoborate (CaFB) is industrially manufactured in a nature-identical form using a chemical synthesis according to Miljkovic (1999) and Hunter (2016) patents. CF is manufactured as a "nature-identical" complex and is commercially marketed as FruiteX-B® Brand calcium fructoborate. Although calcium fructoborate is naturally occurring and found in commonly ingested fruits and vegetables, the commercially produced FrXB calcium fructoborate complex is formed by a proprietary reaction of boric acid with fructose and calcium carbonate.

The novel food product used in the EFSA assessment is produced by chemical synthesis and contains a maximum of 2.9% boron, on average 4.7% calcium, and 84.2% fructose. In dietary supplements, boron is present in many different forms, including sodium borate, sodium tetraborate, boron amino acid chelate, and calcium fructoborate. Calcium fructoborate is the most scientifically studied boron-based dietary supplement, with over a dozen published studies on its unique chemical and clinical properties.

2. Traditional and Historical Use

Boron-containing minerals appeared incidentally in traditional mineral waters and remedies, but intentional therapeutic use of boron is a modern phenomenon rooted in nutritional science rather than folk medicine. Traditionally, boric acid and some of the inorganic borates have been used for boron supplementation. Recently, other boron compounds have been introduced to the pharmaceutical industry market for the same purpose.

Calcium fructoborate as a specifically identified compound does not have a documented history of use in traditional ethnobotanical or traditional medicine systems. Its identification as a discrete dietary ingredient is a product of modern analytical chemistry. Initially identified in fruits and vegetables and subsequently developed as a stable calcium salt, CaFB provides a practical model for understanding how boron's biological effects may depend on chemical form in addition to elemental intake. The earliest interest in dietary boron for human health came from nutritional science in the late 1980s, when a seminal metabolic ward study by Nielsen et al. showed that boron supplementation (3 mg/day) in postmenopausal women reduced urinary calcium excretion by 44% and urinary magnesium excretion, while significantly elevating serum 17β-estradiol concentrations.

Interest in boron for human nutrition surged in the 1970s–1990s, particularly following studies suggesting effects on calcium and magnesium metabolism and bone health. From the 2000s to the present, expanded clinical research has been conducted into boron's roles in steroid hormone metabolism, anti-inflammatory pathways, and cognitive function. Calcium fructoborate as a distinctive supplemental form entered commercial markets in the late 1990s following the foundational patent work of Miljkovic (1999).

3. Key Constituents, Active Compounds, and Mechanisms of Action

Compositional Chemistry

Calcium fructoborate contains three forms of borate — diester, monoester, and boric acid — and all are biologically active, both at the intracellular level (as free boric acid) and at the extracellular level (as fructose-borate diester and monoester). The relative molar concentrations of these three types of boron-containing molecules were found to be approximately 5%, 85%, and 10%, respectively.

Chemically, CaFB comprises mono- and di-ester fructoborates stabilized by calcium, supporting aqueous handling and storage stability. Results show that calcium fructoborate, starting from pH 6.86, gradually releases boric acid, and the dissociation is complete at pH 4, indicating that it is largely hydrolyzed under the acidic conditions of the stomach.

Mechanism of Action: Anti-inflammatory Activity

The mechanisms by which calcium fructoborate exerts its anti-inflammatory effects are not entirely clear, but some of its molecular biological in vitro activities are understood: inhibition of superoxide within the cell; inhibition of interleukin-1β (IL-1β), interleukin-6 (IL-6), and nitric oxide release in culture media; and increase of tumor necrosis factor-α (TNF-α) production. Calcium fructoborate also has no effects on lipopolysaccharide-induced cyclooxygenase-2 (COX-2) protein expression.

At the cellular and molecular level, CF is superior to boric acid/borate, exhibiting a complex "protective" effect against inflammatory response. CF is superior to boric acid/borate due to its complex action mechanism, both at the intracellular (as free boric acid) and extracellular level (as fructose-borate esters). Moreover, the free boric acid resulting from hydrolysis of the fructoborate complex may be less toxic than dietary supplement intake of regular boric acid/borax/sodium borate.

Calcium fructoborate can exert a protective effect against inflammatory molecules at cellular and enzymatic levels, being able to chemically bind to specific glycoprotein receptors of cytokines present on the surface of cell membranes.

Mechanism of Action: Mineral Metabolism and Vitamin D

Boron participates in key physiological processes, including mineral metabolism, bone homeostasis, hormonal regulation, immune modulation, and redox balance. One review indicates that boron influences the activity of 25-hydroxyvitamin D and may modify calcium metabolism by influencing parathyroid hormone and calcitonin secretion. In the functioning of the osteoarticular system, boron acts by regulation of calcium and magnesium metabolism, enhancing the vitamin D activation process, and influencing serum steroid hormone levels.

Mechanism of Action: Antioxidant Activity

In vitro studies revealed that calcium fructoborate is a superoxide ion scavenger and anti-inflammatory agent. Inside cells, CF acts as an antioxidant and induces the overexpression of apoptosis-related proteins and eventually apoptosis. A boron-based dietary supplement study found that calcium fructoborate regulates antioxidant metabolism by strengthening biochemical metabolic profiles against oxidation, and also has a protective effect against DNA damage caused by oxidation.

Proposed Steroid Hormone Interactions

Several authors have observed that boron introduced in the diet can lead to an increase in the plasma concentrations of 17-β estradiol and/or testosterone. In a 1997 study by Naghii and colleagues, a supplement of 10 mg of boron (as sodium tetraborate) was administered to 18 healthy male subjects for 4 weeks; at the end of this period, a statistically significant increase was found in plasma estradiol levels and a growth trend (albeit not statistically significant) of free testosterone levels. These specific hormone findings were reported for inorganic boron forms and the extent to which they specifically apply to calcium fructoborate has not been established in dedicated clinical trials.

4. Scientific Evidence by Area of Use

4.1 Joint Health and Osteoarthritis

These findings suggest that boron, particularly as calcium fructoborate, might hold promise for reducing osteoarthritis symptoms, but confirmation is needed from additional controlled trials, as noted by the NIH Office of Dietary Supplements.

Pilot clinical study (2011/2012): In an early study, FruiteX-B® was tested for 14 days at a serving of 108 mg twice a day on subjects diagnosed with minor osteoarthritis conditions of the knees by CT scan. On Day 14, WOMAC and McGill indexes were reduced by an average of 29% and 14% respectively over Day 1 pre-ingestion values. Blood level of C-Reactive Protein (CRP) in 7 out of 10 subjects was found reduced up to 37% compared to Day 1 baseline levels. The study also showed that blood level of endogenous 1,25(OH) vitamin D was increased more than 19% compared to baseline, although no significant changes were found in serum 25(OH) vitamin D levels. This was a small double-blind, placebo-controlled pilot study with a very limited sample size of 10 subjects per group, and results should be interpreted with caution.

Comparative double-blind, placebo-controlled clinical study (2014): Calcium fructoborate (CFB) at a dose of 110 mg twice per day was evaluated in 60 participants with self-reported knee discomfort, who were randomized into two groups receiving CFB or placebo. A previous pilot clinical trial had reported a statistically significant reduction of Western Ontario and McMaster Universities Arthritis Index (WOMAC) score and McGill Pain Questionnaire (MPQ) index values. Seven days' supplementation with CFB resulted in statistically significant improvement of knee comfort as measured by MPQ, while reduction of WOMAC index values indicated a strong trend (P=0.06) at 7 days, suggesting that CFB could improve knee distress as a result of short-term treatment. This study had significant limitations, including a short 2-week intervention window and reliance on self-reported symptoms.

Double-blind, placebo-controlled pilot study on inflammation and dyslipidemia markers in osteoarthritis (Scorei et al., 2011): This study, cited by the NIH ODS and indexed on PubMed (PMID: 21556821), examined the effect of calcium fructoborate on systemic inflammation and dyslipidemia markers in middle-aged people with primary osteoarthritis. Published clinical research has demonstrated CF's ability to modulate key markers associated with the body's inflammatory response mechanism. In particular, studies indicate that CF significantly modulates elevated serum levels of CRP in humans and some cytokines.

Overall evidence quality for joint health: The joint health data consists primarily of small, short-term (7–14 day) clinical trials, some of which are industry-sponsored. While results are directionally consistent, the trials are limited by small sample sizes, short durations, and a need for independent replication. The NIH ODS characterizes this evidence as preliminary.

4.2 Inflammation Biomarkers (CRP and Cytokines)

Double-blind, placebo-controlled study on CRP, cholesterol, and cytokines (Rogoveanu et al., 2015): Data from this study indicate that 30-day supplementation with 112 mg/day CFB resulted in a significant reduction of LDL, triglycerides, total cholesterol, IL-1β, IL-6, MCP-1, and CRP, while HDL levels were increased compared to baseline and placebo. These results suggest that CFB might provide beneficial support to healthy cardiovascular systems by positively affecting these blood markers. The study was registered on ClinicalTrials.gov (ISRCTN90543844).

CF supplementation tested over a 14-day period at a serving of 108 mg (2.91 mg boron and 5.4 mg calcium) twice per day reduced CRP by 37% versus pre-supplementation baseline value. CF also induced a 19% increase in endogenous levels of calcitriol, the active form of vitamin D₃ (1,25-dihydroxyvitamin D).

Overall evidence quality: CRP reductions are among the most replicated findings for calcium fructoborate across several small clinical trials. However, all studies to date have been of short duration (14–60 days), with modest sample sizes, and require confirmation in larger, longer independent RCTs.

4.3 Cardiovascular Health

Randomized, double-blind, active-controlled parallel clinical trial in stable angina pectoris (Militaru et al., 2013): This study aimed to evaluate the effects of short-term (60-day) oral supplementation with calcium fructoborate, resveratrol, and their combination on the clinical and biological statuses of subjects with stable angina pectoris, as a randomized, double-blinded, active-controlled, parallel clinical trial. Of the total subjects included (n = 166), 87 completed the 60-day test treatment period and 29 followed their usual medical care in parallel. Primary outcomes included high-sensitivity CRP, N-terminal prohormone of brain natriuretic peptide, and lipid markers.

Orally administered CF has been reported effective in ameliorating symptoms of physiological response to stress, including inflammation of the mucous membranes, discomfort associated with osteoarthritis disorders, and bone loss, and for supporting cardiovascular health. Clinical studies have exhibited the ability of CF to significantly modulate molecular markers associated with inflammatory mechanisms, mainly on elevated serum levels of CRP.

Overall evidence quality: Cardiovascular evidence for calcium fructoborate is preliminary. Observed improvements in LDL, total cholesterol, triglycerides, and CRP are biologically plausible, but the trials are small, of short duration, and often combine calcium fructoborate with other agents (e.g., resveratrol), making it difficult to attribute effects to calcium fructoborate alone. No long-term cardiovascular outcome trials (e.g., measuring myocardial infarction or stroke incidence) have been conducted.

4.4 Bone Health

Calcium fructoborate, as a naturally occurring boron dietary derivative, when administered orally, has been reported effective in ameliorating symptoms including inflammation of the mucous membranes, discomfort and stiffness associated with osteoarthritis disorders, and bone loss.

Boron might be important for bone growth and formation, possibly by affecting osteoblast and/or osteoclast activity or by influencing serum steroid hormone levels and calcium metabolism. Animal studies indicate that boron deficiency causes abnormal limb development; delayed maturation of growth plates; and decreased bone strength, bone volume fraction, and trabecular thickness. Experimental data show that boron-deficient diets in animals lead to poorer bone mineralization, suggesting boron's involvement in osteogenesis and bone mass maintenance.

However, in an observational study in 134 Korean women (average age 41 years), boron intakes (mean of 0.9 mg/day) were not significantly correlated with bone mineral density in the lumbar spine or femoral regions, reflecting the inconsistency in the human evidence base for boron and bone mineral density. No large-scale randomized controlled trials specifically using calcium fructoborate as the tested intervention for bone mineral density endpoints have been reported in the peer-reviewed literature.

Overall evidence quality: Mechanistic and animal evidence for boron's role in bone metabolism is reasonably consistent. Human clinical data specifically for calcium fructoborate on bone mineral density endpoints is lacking; most inference is extrapolated from broader boron research. Evidence is preliminary and insufficient to establish efficacy for bone loss prevention in humans.

4.5 Cancer (Preliminary, Preclinical)

A review identified other promising research directions for boron-based chemoprevention and chemotherapy using calcium fructoborate, with targets including breast cancer, prostate cancer, lung cancer, and cervical cancer. CF showed inhibitory effects on MDA-MB-231 breast cancer cells, appearing to enter the cell most likely by a co-transport mechanism via a sugar transporter. Inside cells, CF acts as an antioxidant and induces the overexpression of apoptosis-related proteins and eventually apoptosis.

Overall evidence quality: Evidence for calcium fructoborate in cancer is entirely preclinical (cell culture and animal models). No human clinical trials have evaluated calcium fructoborate for any cancer indication. These findings are exploratory only.

4.6 Antioxidant Activity

In vitro studies revealed that calcium fructoborate is a superoxide ion scavenger and anti-inflammatory agent. It may influence macrophage production of inflammatory mediators, can be beneficial for the suppression of cytokine production, and inhibits progression of endotoxin-associated diseases, as well as boric acid and other boron sources.

Overall evidence quality: Antioxidant activity has been demonstrated in cell culture and animal models. Human data on antioxidant endpoints are limited and embedded within the clinical trials conducted for other primary endpoints (osteoarthritis, cardiovascular).

5. Body Systems and Health Areas

Musculoskeletal system: CaFB is widely used as a dietary supplement for joint health, specifically for modulation of the symptoms of age-related joint discomfort and degeneration.
Cardiovascular system: According to some recent clinical trials, CaFB can also be used to prevent cardiovascular disorders.
Immune system / systemic inflammation: It may influence macrophage production of inflammatory mediators and can be beneficial for the suppression of cytokine production.
Endocrine system / mineral metabolism: Current evidence suggests beneficial effects of boron on bone mineral density, cognitive function, inflammation, antioxidant defenses, and metabolic regulation; studies suggest that boron intake is associated with increased calcium and magnesium retention in the body and influences vitamin D activity.
Cellular / antioxidant defense: CF is a natural product with effects in oxidative metabolism and cell apoptosis.
Oncology (preclinical only): CF has been identified as a natural product from plants and has been investigated for the prevention and treatment (as adjuvant) of osteoporosis and osteoarthritis, with exploratory interest in cancer.

6. Dosage Forms and Dosages Reported in Studies

In dietary supplements, calcium fructoborate is among the forms in which boron is commercially present. The Supplement Facts label on a dietary supplement product declares the amount of elemental boron, not the weight of the entire boron-containing compound.

Pilot clinical study (knee osteoarthritis, 2011): FruiteX-B® tested for 14 days at a serving of 108 mg twice a day.
Comparative double-blind clinical study (knee discomfort, 2014): CFB at a dose of 110 mg twice per day was evaluated for 14 days.
Double-blind, placebo-controlled study (CRP and lipid markers, 2015): 30-day supplementation with 112 mg/day CFB was the primary treatment arm.
Animal and human dose-range studies: Studies on animals and humans with a dose range of 1–7 mg calcium fructoborate (0.025–0.175 mg elemental boron) per kg body weight per day exhibited good anti-inflammatory activity and negligible adverse effects on humans.
EFSA-assessed maximum use level: The EFSA assessment recommended calcium fructoborate for the general adult population at a maximum level of 220 mg/day (maximum boron intake of 6.4 mg per day).
EU regulatory submission conditions: Under specified conditions of use, a daily serving of 220 mg calcium fructoborate would contribute 6 mg boron.

Calcium fructoborate is available commercially in capsule and tablet forms, typically as part of joint health or bone health supplement formulations, and is also used as an ingredient in combination products (e.g., combined with glucosamine and chondroitin sulfate in some trials). Calcium fructoborate is one of several forms in which boron is available in dietary supplements; scientists do not currently know if one form of boron is better than others.

7. Safety Considerations and Interactions

Toxicological Profile

A branded calcium fructoborate product was evaluated in a 90-day dietary toxicity study and two genotoxicity studies. In the 90-day study, four groups of 10 male and 10 female rats were fed diets with FrxB at concentrations providing mean overall daily intakes of up to approximately 1,161 mg/kg bw/day in male rats and 1,171 mg/kg bw/day in female rats. There were no mortalities, no clinical or ophthalmologic signs, body weight, or other findings associated with administration of the test substance. The no-observed-adverse-effect level (NOAEL) was 1,161.3 and 1,171.1 mg/kg bw/day in male and female rats, respectively.

Bacterial mutagenicity studies and a micronucleus test using Chinese hamster V79 cells demonstrated no mutagenic or genotoxic potential of the tested brand of calcium fructoborate. Calcium fructoborate is neither mutagenic nor genotoxic based on the results of a reverse mutation assay and an in vitro mammalian micronucleus assay. On the basis of a 90-day oral toxicity study in rats, a NOAEL of 1,200 mg/kg body weight/day (highest dose tested) was established, which is well above the intended use level of 3 mg/kg body weight/day in consideration of a 70 kg individual consuming 220 mg calcium fructoborate per day.

EFSA Novel Food Opinion (2021)

The EFSA Panel concluded that calcium fructoborate is safe for the adult population, excluding pregnant and lactating women, at intake levels up to 220 mg/day (3.14 mg/kg bw per day). Under conditions mimicking the gastrointestinal environment, the novel food is fully hydrolysed, and the Panel considered boron toxicity relevant for the safety assessment. The Panel considers that there is no concern with respect to genotoxicity of the novel food.

Considering that the combined intake of boron from the novel food and the background diet (0.14 mg/kg bw per day) does not exceed the ADI of 0.16 mg/kg bw per day, the intake of 220 mg/day in adults, containing up to 6.4 mg boron, does not raise safety concerns.

Tolerable Upper Intake Levels for Elemental Boron

According to a literature review, the tolerable upper intake level (UL) for adults has been established at approximately 20 mg/day in the USA/Canada. The relative contribution of the individual components under the intended conditions of use of calcium fructoborate as an ingredient in food supplements would result in exposures well within the tolerable upper intake levels derived from various authoritative opinions and/or background dietary exposure levels.

Despite numerous toxicological and epidemiological studies, significant knowledge gaps remain regarding the long-term effects of exposure to various forms of boron in humans — especially at low, chronic exposures and in sensitive groups such as pregnant women and individuals with renal failure. Data from toxicological analyses indicate possible reproductive and developmental effects at high doses, but the epidemiological evidence remains inconclusive and limited by the lack of precise exposure measurements.

Gastrointestinal Hydrolysis and Boron Bioavailability

The novel food is comprised of calcium, fructose, and boron, and it is expected that under gastrointestinal conditions, the low pH in the stomach and/or non-specific enzymes may catalyse the hydrolysis of the ester bonds in the fructofuranose borate to form fructose and boric acid, which are readily absorbed. In a human single-dose study, five human subjects received 216 mg of the novel food. The total amount of boron measured in blood serum at baseline and after 60, 120, and 180 minutes from administration was 56, 160, 140, and 127 ng/mL, respectively.

Specific Populations and Exclusions

The EFSA recommended uses are intended for food supplements targeting the general adult population, excluding pregnant and lactating women, at a maximum level of 220 mg/day. Significant knowledge gaps remain regarding long-term effects at low, chronic exposures and in sensitive groups, particularly pregnant women and individuals with renal failure.

Interactions

In a small human study, boron as sodium tetraborate significantly increased plasma boron levels within 4–6 hours of consumption, but no data are available on the relative bioavailability of different forms of supplemental boron. Because calcium fructoborate is hydrolyzed to boric acid and fructose under gastrointestinal conditions, any interactions documented for boron in general — including effects on steroid hormone metabolism — are considered potentially relevant. Several authors have observed that boron introduced in the diet can lead to an increase in plasma concentrations of 17-β estradiol and/or testosterone, which has implications for individuals on hormone-related medications or with hormone-sensitive conditions, though this has not been specifically evaluated for calcium fructoborate in dedicated interaction studies. Boron exhibits its most clinically relevant synergies with magnesium, vitamin D, and calcium — the three primary nutrients in bone mineral metabolism — making combination bone-health formulations a rational supplementation strategy.

Evidence Quality and Research Limitations — Overall Assessment

Calcium fructoborate is the most scientifically studied boron-based dietary supplement, with over a dozen published studies on its unique chemical and clinical properties. However, the body of clinical evidence is characterized by small sample sizes, short study durations (largely 14–60 days), a limited number of independent research groups, and concentration in specific populations (predominantly middle-aged individuals with osteoarthritis). Limitations include small sample sizes, heterogeneous endpoints, and lack of long-term data. No large-scale, multi-center randomized controlled trials or systematic reviews with meta-analysis specifically focused on calcium fructoborate have been published as of the date of this article. Scientists do not currently know if one form of boron is better than others.

References

Health Conditions

Health conditions that Fructoborate may help support.

No conditions available.

Body Systems

Body systems that Fructoborate may help support.

No body systems available.