Silicon Supplementation for Bone Health: An Umbrella Review Attempting to Translate from Animals to Humans

Studies have attempted to demonstrate the benefits of silicon on bone health using a wide range of Si amounts—provided in the diet or through supplementation—and several different animal species. Previous studies in humans have also demonstrated a positive correlation between Si intake and bone health measures. The aim of the current review is to determine the effective levels of Si intake or supplementation that influence bone health to better inform future study designs and guidelines. Articles were identified using one of two search terms: “silicon AND bone” or “sodium zeolite A AND bone”. Articles were included if the article was a controlled research study on the effect of Si on bone health and/or mineral metabolism and was in English. Articles were excluded if the article included human subjects, was in vitro, or studied silica grafts for bone injuries. Silicon type, group name, Si intake from diet, Si supplementation amount, animal, and age at the start were extracted when available. Dietary Si intake, Si supplementation amount, and the amount of Si standardized on a kg BW basis were calculated and presented as overall mean ± standard deviations, medians, minimums, and maximums. Studies that left out animal weights, amount of food or water consumed, or nutrient profiles of the basal diet were excluded from these calculations. Standardized Si intakes ranged from 0.003 to 863 mg/kg BW, at times vastly exceeding current human Si intake recommendations (25 mg/d). The lack of data provided by the literature made definitively determining an effective threshold of supplementation for skeletal health difficult. However, it appears that Si consistently positively influences bone and mineral metabolism by around 139 mg Si/kg BW/d, which is likely unfeasible to attain in humans and large animal species. Future studies should examine this proposed threshold more directly and standardize supplemental or dietary Si intakes to kg BW for better study replication and translation.


Introduction 1.Role of Silicon in Bone Development
Silicon plays a role in bone and cartilage development.Early studies demonstrated that basal diets deficient in Si reduced the overall growth in chicks and rats [1,2] and altered long bone and skull formation in chicks [3,4], producing more-porous, less-mineralized bone.Typically, Si associates more with the organic matrix of bone and soft tissue [5,6], and declining Si concentrations in connective tissue may also be an indicator of decreasing collagen content [7].In vitro, Si stimulates the production of type I collagen and mineralization activity in osteoblasts [8,9].Through its association with type I collagen, Si contributes to the early calcification of bone's organic matrix by providing a low solubility matrix to attract and contain other ions, such as Ca, at the organic-inorganic interface [10].

Effects of Silicon Supplementation
While deficiency proves harmful, supplementation may be beneficial.Silicon supplementation in the form of sodium zeolite A has increased distances accumulated during training before bony or soft-tissue injury in horses [11], possibly due to reduced resorption during periods of disuse or other alterations in bone turnover [12].Silicon supplementation in calves has increased hydroxyproline content, an early marker for collagen formation, in skin [13], since Si stimulates type I collagen synthesis [8,14].During both normal conditions and Ca deficiency, Si supplementation inhibits bone resorption [15] by reducing osteoclast formation and activity [16] as well as increasing osteoblastogenesis [17] and osteoblast activity [8,9,18].The direct effects on bone cells and collagen synthesis could assist in cartilage repair and bone strength and demonstrate the importance of Si within the diet.In humans, silica-based nanomaterials have been used for bone tissue engineering and repair [19] due to these effects, and higher Si intake has been associated with greater bone mineral density [20][21][22].However, the effects of Si supplementation above adequate intakes on bone and cartilage measures have been lacking.
Silicon can also alter mineral metabolism.These effects can be beneficial when it comes to binding metals like aluminum to generate aluminosilicates to prevent absorption and harmful accumulation in tissues [23].The effects of Si on serum Ca concentrations in supplemented animals are mixed, with some studies showing greater concentrations [13,24], but more recent studies show no difference or decreased Ca concentrations with Si supplementation [25,26].Magnesium retention [27] and serum concentrations [24,26] can also be reduced with Si supplementation.However, these alterations in serum or plasma minerals do not always translate into changes in mineral concentrations in bone or soft tissue.Silicon in the diet increases Ca concentration in bone above amounts in a deficient diet [28,29], but other studies supplementing Si on top of an adequate diet show no changes in the Ca concentration of bones [26,30].By altering both mineral metabolism and collagen synthesis, Si supplementation may increase bone density [5,15] and strength [30][31][32].All these direct and indirect effects play a central role in improving and maintaining bone and cartilage quality during growth and later life, demonstrating Si's importance as a micromineral.

Clinical Relevance
A visualized summary of Si effects related to bone health from previous animal experiments has been provided in Figure 1.In humans, Si intake ranges between 12 to 62 mg/day, depending on diet and location [33].Greater dietary Si intake correlates with greater bone mineral density in men and pre-menopausal women [34], indicating that Si plays an essential role in bone health in humans as well as animals.However, dietary Si retention from various sources appears relatively low, with less than 10% accounted for in serum and around 40% excreted in urine, though a full study of Si balance was not conducted [35].In combination with Vitamin D and calcium, supplemental Si can positively influence bone turnover and increase femoral BMD in post-menopausal women [33], indicating the need to establish an effective threshold for supplementation to improve clinical outcomes.
Despite the promise of Si to address various musculoskeletal issues in animals and its correlation with better bone health in humans, experimental results can be mixed.A wide range of animals have been used in studies to demonstrate the essentiality or benefits of Si with an even wider range of Si amounts provided in the diet or through supplementation.The aim of the current review is to determine the effective levels of Si that influence skeletal health to better inform future study design and guidelines.

Inclusion/Exclusion Criteria
Articles that met the following inclusion criteria were incl controlled research study on the effect of Si on bone health a and (b) the article was in English.Articles were excluded if they (a) The article included human subjects, (b) the article was in vit silica grafts for bone injuries.

Search Strategy
The authors identified articles for this review from PubMe 1967 to April 2023, using one of two search terms: "silicon AND A AND bone", due to the authors' research experiences.

Article Selection
Studies were screened in two stages.Initially, the authors

Inclusion/Exclusion Criteria
Articles that met the following inclusion criteria were included: (a) The article was a controlled research study on the effect of Si on bone health and/or mineral metabolism and (b) the article was in English.Articles were excluded if they met the following criteria: (a) The article included human subjects, (b) the article was in vitro, or (c) the article studied silica grafts for bone injuries.

Search Strategy
The authors identified articles for this review from PubMed, published from January 1967 to April 2023, using one of two search terms: "silicon AND bone" or "sodium zeolite A AND bone", due to the authors' research experiences.

Article Selection
Studies were screened in two stages.Initially, the authors reviewed article titles and abstracts for inclusion and exclusion criteria.Articles that met the inclusion criteria were sought for full-text retrieval and assessed for eligibility.Articles that met inclusion criteria but were not available for full-text retrieval or tested external stressors, such as bacterial or viral infections, were further excluded.Figure 2 shows a flow chart of the literature search and selection.

Data Extraction
Silicon type, group name, Si intake from diet, Si supplementation amount, animal, and age at the start were extracted from each study to the extent these data were reported.Silicon type was extracted as reported, and treatments were sorted and standardized into Deficient, Control, or Si-supplemented.Additionally, mineral and bone outcomes were summarized and recorded.Dietary Si intake, Si supplementation amount, and amount of Si standardized on a kg BW basis were calculated based on the information provided.If bodyweight or food intake data were not reported or were unable to be retrieved or estimated by species standards, calculations were not performed, and those treatments were excluded from further analysis.If daily dietary Si intakes were not provided or were unable to be calculated, these treatments were also excluded; however, if dietary Si intake was provided on a mg/kg BW basis, this value was included in the analysis of standardized Si but not dietary Si intake.

Data Extraction
Silicon type, group name, Si intake from diet, Si supplementation amount, ani and age at the start were extracted from each study to the extent these data were repo Silicon type was extracted as reported, and treatments were sorted and standardized Deficient, Control, or Si-supplemented.Additionally, mineral and bone outcomes w summarized and recorded.Dietary Si intake, Si supplementation amount, and amou Si standardized on a kg BW basis were calculated based on the information provide bodyweight or food intake data were not reported or were unable to be retrieved or mated by species standards, calculations were not performed, and those treatments w excluded from further analysis.If daily dietary Si intakes were not provided or were able to be calculated, these treatments were also excluded; however, if dietary Si in was provided on a mg/kg BW basis, this value was included in the analysis of stand

Analysis
For clarity, experimental groups or treatments from each included study will be referred to as "treatments", and the assigned terms-Deficient, Control, or Si-supplemented-will be referred to as "groups".The means and standard deviations of dietary Si intake and standardized Si for Deficient, Control, and Si-supplemented groups was tabulated overall via JMP 16 (Location), while the mean (±SD) Si supplementation amount was calculated only for the Si-supplemented group.Counts were performed for Si forms and research species.Additionally, Si treatments were noted either as having "No Effect" or a "Positive Effect" on bone or mineral measures, to attempt to determine an effective standardized Si dose.Outliers were explored via interquartile range calculations, and data points were excluded if they were more than three times the interquartile range.A Mann-Whitney U test was conducted to compare dietary Si intake and standardized Si amounts between Control and Si-supplemented groups as well as between No Effect and Positive Effect doses.

Results
Tables 1-3 show the studies grouped by animals included for this literature review along with summary information and results.The counts for Si forms and research species are as follows: Sodium metasilicate was the most reported form (n = 20), followed by sodium zeolite A (n = 11).The remaining forms included monosilicic acid, orthosilicic acid, aluminosilicates, silicon-collagen complex, chelated silica, tetraethyl-orthosilicate, monomethyl-silanetriol, and silanol, but these forms were only used in four or fewer groups or studies.Rats were the most common animal studied (n = 18 treatments), followed by chicks (n = 13 treatments) and horses (n = 6 treatments), with mice (n = 4 treatments), calves (n = 2 treatments), pigs (n = 2 treatments), and turkeys (n = 1 treatment) making up the rest of the experiments.Two papers [26,36] each included two experiments with two different species.Overall mean ± standard deviations, as well as minimums, maximums, and medians for total standardized Si, Si supplementation amounts, and dietary Si intake, are presented in Table 4.Of the 45 articles included in this review, only 20 contained enough information to calculate a standardized Si dose to kg BW, while 22 provided enough information for estimated daily dietary intake and 16 for estimated doses per day.There was not enough information to report these values for treatments labeled as Deficient.There were differences in sums of dietary Si intake and standardized total Si between Control and Si treatments (p < 0.01).Additionally, there was also a difference in the sums of standardized Si and daily Si doses between "No Effect" and "Positive Effect" treatments (p < 0.05 for both variables; Table 5), with "Positive Effect" doses and standardized Si (116 mg and 139 mg/kg BW, respectively) being substantially higher than "No Effect" (12 mg and 73 mg/kg BW, respectively).
Table 1.Brief summaries of studies using chicks or turkeys included in this review. 1Article contained multiple experiments, and amounts for each group were averaged based on the number of experiments in which they appeared.X indicates information not applicable; "-" denotes missing or not enough information to calculate.

Discussion
Value reporting varied dramatically across the included studies, making this review difficult.Nearly half the studies left out animal weights, amount of food or water consumed, or the nutrient profiles of the basal diet.Without this information, the total amount of Si could not be standardized to kg BW, limiting the ability to translate amounts and results to other species, including humans.
The age of the animal at the time of Si supplementation could impact the influence of Si on bone and cartilage outcomes.Early studies examined deficiencies versus Si-adequate diets in chicks during growth and demonstrated the essentiality of Si for bone and cartilage development [1,3,4,6,37].However, when later experiments did not use purified diets with Si removed and usually studied Si supplementation to already adequate diets, results were mixed even in growing animals.
Sodium metasilicate was the most reported form of Si used for supplementation, likely because many of the early studies with chicks and rats repeatedly used this form to demonstrate the importance of Si for skeletal development.However, these Si species contained metals like Al, which made it difficult to distinguish Si influence on bone versus its ability to suppress Al absorption.
Standardized Si intakes ranged from 0.003 to 863 mg/kg BW.One aim of this review was to determine an "effective dose" on a mg per kg BW basis in order to translate results across species.Unfortunately, due to the lack of critical information reported in many of the studies included in this review, this dose may not be able to be determined on a conclusive basis.Sums of standardized Si intakes in studies demonstrating positive effects on bone and/or mineral metabolism did rank higher in the Mann-Whitney U test than standardized Si intakes in studies showing no effects on bone or mineral metabolism.The difference between these two groups indicates that there may be a level above essentiality at which supplemented Si positively influences these outcomes, though some studies have reported no greater outcomes with increased supplementation [15,26,40,43,45,55].Previous experiments that have achieved improvements in bone or cartilage quality in adult animals [5,15,27,48,49,[53][54][55] fed Si in large amounts, which, when expressed on a per kg BW basis at 18 to 462 mg Si/kg BW, is difficult to translate into use with large animals.Supplemented mature horses receiving a total of 54 mg Si/d or 0.1 mg Si/kg BW had no change in collagen metabolism in synovial fluid, indicating that cartilage turnover remained unaffected, and lameness did not improve [61].Once expressed on a kg BW basis, this amount is much lower than previously successful experimental levels of Si.Based on current data gathered by this review, it appears that standardized Si intake above 139 mg/kg BW/d may positively influence bone or mineral metabolism outcomes; this is over double the current estimated human intake on a whole-body basis.
Even without an "effective dose", the standardization of intakes would facilitate research and results translation across species.The current recommendation for human Si intake for bone health is 25 mg/d [23,33].If a human weighing 65 kg consumed this amount of Si, it would only be around 0.4 mg/kg BW-this is a small amount, even for control treatments in this review.Additionally, the higher end of Si intakes may not be feasible for large animals, including humans.If a human weighing 65 kg consumed the mean standardized Si intake from Si treatments, this would be 7.8 g Si, eclipsing the recommendation from the literature for this mineral as well as the daily recommended allowance for macrominerals like calcium [62].Supplementing at these amounts would likely alter the metabolism of other crucial minerals [24,27,43,55] and would likely be difficult, if not impossible, to achieve in humans.
Silicon sources for humans include water and diet [22].Plant-based foods contribute a significant amount of Si, with the largest contribution coming from cereals and cereal products, especially oat bran and oat cakes, which contain roughly 23.4 and 18.3 mg Si/100 g [63].Silicon in fruits and vegetables ranges from non-detectable to 16.6 mg/100 g.Water, especially mineral water, may contain up to 40 mg Si/L [22].Even at these amounts, humans will likely struggle to achieve experimental levels of Si, especially if the threshold for consistent positive outcomes is at 139 mg Si/kg BW/d.For a 65 kg human, this amount would be equivalent to eating roughly 38.6 kg of oat bran or drinking 225 L of water.If this threshold is unachievable via normal diet and water intake, supplementation would likely be necessary.
A recent review examining Si intake and bone mineral density in humans came to similar results as this current review [33].The upper intakes noted in that review were around 40 mg/d for adults, which would be on the low side of Si intakes for studies included in the current review.Supplementation studies in humans included in the recent review included doses from 3 to 86 mg Si per day, in addition to a likely adequate diet.During supplementation, these amounts produced little to no effect on bone or mineral parameters, and these amounts were similar to treatments marked as "No Effect" in the current review, indicating that far greater amounts may be necessary to influence bone health in adults.While the previous review did not note average BW in its included studies, the supplemental and typical Si intakes were likely much lower on a per kg BW basis than experimental amounts in animals, as the animal studies included in the current review averaged 120 mg Si/kg BW.
Limitations of the current review include the lack of effect size, bias estimations for meta-analysis, and the small number of studies from which data could be extracted.While excluding data due to missing information meant several studies were eliminated from final calculations and analysis, the authors felt that estimations of missing data would add to the uncertainty of an already limited data set.Additionally, the authors were unable to explore the effects of Si type and age at the start of supplementation on bone and mineral outcomes due to the previously noted difficulties of inconsistent data reporting.
It is likely that many of the experimental amounts of Si providing some benefits in animals will prove difficult to translate to humans.Providing Si on top of an already adequate diet likely does not influence bone health measures in healthy adult animals, despite changes to mineral metabolism, but a lack of Si during growth is associated with negative changes to bones and cartilage.The lack of data provided by the literature made definitively determining an effective threshold of supplementation for skeletal health difficult, though it appears that Si consistently positively influences bone and mineral metabolism measures at around 139 mg/kg BW/d.Future studies should examine this threshold more directly to determine if positive bone or mineral effects can be consistently achieved above it.Ultimately, studies should standardize supplemental or dietary intakes of this micromineral to kg BW for better study replication and translation.

2024, 16 ,Figure 1 .
Figure 1.Summary of effects of silicon supplementation (+Si) or deficie to bone health.Direction of arrow indicates either increase, decreas outcome.

Figure 1 .
Figure 1.Summary of effects of silicon supplementation (+Si) or deficiency (−Si) on outcomes related to bone health.Direction of arrow indicates either increase, decrease, or no change in measured outcome.

Nutrients 2024 , 4 Figure 2 .
Figure 2. Flow chart of literature search and selection.

Figure 2 .
Figure 2. Flow chart of literature search and selection.

Table 2 .
Brief summaries of studies using rats or mice included in this review.X indicates information not applicable; "-" denotes missing or not enough information to calculate.

Table 3 .
Brief summaries of studies using horses, pigs, or calves included in this review.X indicates information not applicable; "-" denotes missing or not enough information to calculate.

Table 4 .
Minimums (Min), maximums (Max), medians, and means (±SD) of daily dietary Si intake, Si supplementation dose, and standardized total Si intake from control (Con) and supplemented (Si) groups from animal studies included in this review.

Table 5 .
Mean (±SD) amounts of daily Si supplementation doses and standardized total Si intake from studies resulting in "No Effect" or "Positive Effect" on bone or mineral metabolism, excluding controls.