Vitamin D, Calcium, Hormone Replacement Therapy (HRT) and Bone Health
Topic - Vitamin D, Calcium, Hormone Replacement Therapy (HRT) and Bone Health
Essence of the Article:
In postmenopausal women, supplementation with Vitamin D and calcium reduces the risk of hip fracture in women on hormone therapy (HT). Bone mineral density was unaffected. Study noted both increase in serum calcium and decrease in PTH after ingestion of supplements, which demonstrates reduced bone resorption.
While establishing that calcium, vitamin D and estrogen work together to reduce fracture risk, there are several ancillary points in this study that are worthy of discussion.
Forms of Calcium - Calcium carbonate was used in the study. This form has more elemental calcium by weight, but there are better options. Calcium citrate is better absorbed without the potential of digestive and intestinal issues. Better still for building bone is calcium hydroxyapatite (hydroxyl calcium phosphate) which comes from bone.
Additional Minerals - Why stop with just calcium when there are other minerals that will help produce a better outcome. Magnesium is an important consideration since it helps balance calcium in general, and keeps it from infiltrating the cells where it can wreak havoc. The intake of calcium and magnesium should be in 2:1 ratio.
Other beneficial minerals include boron, strontium and silicon.
Vitamin K2 helps prevent calcium deposition in the arteries by virtue of its role in Matrix G1a Protein (MGP), the most powerful and abundant inhibitor of arterial calcification.
More on calcium relationships to come in other reviews!
Estrogen - Helps mitigate bone loss caused by increased osteoclast numbers and by increased osteoclast activity.
Forms of Hormones - We'll discuss this in another review, but let's say we prefer a bioidentical form rather than one derived from horse urine.
A Vitamin D Story - A patient had his vitamin D tested and found it was low at 20 ng/mL . He then purchased some D3 - the correct form - at a retail store and took a large dose (10,000 I.U.) for 6 months with his second test slightly higher at 28 ng/mL. It was suggested he try an emulsified D3 from a trusted source a 4,000 I.U. (2 drops) per day for 2 months. The next test resulted in the mid 40s. 50-65 ng/mL seems a reasonable level to strive for at this point. Moral of the story - Always use supplements from a high quality manufacturer.
Women's Health Initiative clinical trials: interaction of calcium and vitamin D with hormone therapy
Robbins, John A.; Aragaki, Aaron; Crandall, Carolyn J.; Manson, Joann E.; Carbone, Laura; Jackson, Rebecca; Lewis, Cora Elizabeth; Johnson, Karen C.; Sarto, Gloria; Stefanick, Marcia L.; Wactawski-Wende, Jean
Menopause., POST EDITOR CORRECTIONS, 24 June 2013
Objective: This study aims to test the added value of calcium and vitamin D (CaD) in fracture prevention among women taking postmenopausal hormone therapy (HT).
Methods: This is a prospective, partial-factorial, randomized, controlled, double-blind trial among Women's Health Initiative postmenopausal participants aged 50 to 79 years at 40 centers in the United States with a mean follow-up of 7.2 years. A total of 27,347 women were randomized to HT (0.625 mg of conjugated estrogens alone, or 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily), and 36,282 women were randomized to 1,000 mg of elemental calcium (carbonate) plus 400 IU of vitamin D3 daily, each compared with placebo. A total of 16,089 women participated in both arms. The predefined outcomes were adjudicated hip fractures and measured bone mineral density.
Results: Interaction between HT and CaD on hip fracture (P interaction = 0.01) was shown. The effect of CaD was stronger among women assigned to HT (hazard ratio [HR], 0.59; 95% CI, 0.38-0.93) than among women assigned to placebo (HR, 1.20; 95% CI, 0.85-1.69). The effect of HT on hip fracture was stronger among women assigned to active CaD (HR, 0.43; 95% CI, 0.28-0.66) than among women assigned to placebo (HR, 0.87; 95% CI, 0.60-1.26). CaD supplementation enhanced the antifracture effect of HT at all levels of personal calcium intake. There was no interaction between HT and CaD on change in hip or spine bone mineral density.
Conclusions: Postmenopausal women at normal risk for hip fracture who are on CaD supplementation experience significantly reduced incident hip fractures beyond HT alone at all levels of personal baseline total calcium intake.
(C) 2013 by The North American Menopause Society.
Calcium Citrate Shown to Have Superior Bioavailability and Protects Against Bone Loss
Nov 21, 2000
New York (MedscapeWire) Nov 21 — An important follow-up study that reaffirms calcium citrate's superior bioavailability when compared with calcium carbonate also provides new evidence of calcium citrate's role in protecting against bone loss.
The study, published in the November issue of the Journal of Clinical Pharmacology, used 3 measures to determine calcium bioavailability — serum calcium, urinary calcium, and serum parathyroid hormone (PTH). This randomized crossover study compared the single-dose bioavailability and effects on PTH of commercial calcium citrate 250 mg (Citracal, Mission Pharmacal) and calcium carbonate 500 mg (Os-Cal, SmithKline Beecham) supplements in postmenopausal women.
"The initial study we conducted in 1999 showed that calcium citrate is more readily available to the body than calcium carbonate," explained study author Howard J. Heller, MD, assistant professor at the Center for Mineral Metabolism and Clinical Research at the University of Texas Southwestern Medical Center in Dallas. "We expanded the trial and our measurement methods to determine if one form of these commercially available calcium supplements was a better choice in postmenopausal women. We found that the tablet formulation of calcium citrate in the form of Citracal was more bioavailable than calcium carbonate, even when given with a meal. Several studies have established that calcium citrate is more bioavailable than calcium carbonate when the subject is fasting; however, some authors have previously suggested that the two forms of calcium are equally bioavailable when given with a meal.
"Moreover," Dr. Heller continued, "calcium citrate produced greater suppression of serum PTH by more than 50% over calcium carbonate. This provides physiological evidence that calcium citrate was better absorbed. We additionally found that calcium citrate may be particularly advantageous in those who absorb calcium poorly from calcium carbonate."
Parathyroid suppression is critical in maintaining bone because PTH is responsible for age-related bone loss. When the body senses a deficit in calcium, it responds to the challenge by increasing PTH levels and leaching calcium from the bones.
In another study from Mayo clinic, researchers found that calcium citrate supplementation effectively lowered serum PTH values to those found in premenopausal women, ultimately protecting them against bone loss.
Dr. Heller and his colleagues compared the calcium absorption of calcium citrate 350 mg (Citracal) and calcium carbonate 500 mg (Os-Cal) after a single oral load (500 mg calcium), taken with a meal, by calculating the peak and cumulative change in serum calcium from baseline, offering a direct measure of calcium bioavailability. Similarly, the curve of decline in serum PTH from baseline over time was used to assess the ability of calcium supplements to suppress parathyroid function. To adjust for daily biological variation and the effect of the meal alone, the value from the placebo phase was subtracted from the corresponding value for calcium citrate and calcium carbonate, allowing their actions to be compared independent of these variables.
Research participants were involved in 3 phases of randomized study. For 1 week prior to each phase, their diets contained an average amount of calcium (400 mg/day), were restricted in sodium (100 meq/day), and caffeine was not allowed. The purpose of these standardized diets was to reduce the influence of the diet on response. In 1 phase, subjects ingested a single dose, 500 mg calcium citrate. In another phase, research participants took a single dose of calcium carbonate. In the third phase, 2 placebo tablets were taken. In all phases, subjects were given the calcium supplement or placebo at the same time each morning with a standard breakfast in the clinical research setting. The participant's blood was drawn at baseline and obtained every hour for 6 hours to obtain a calcium bioavailability profile. Fasting and post-load urine samples were also collected.
This study was conducted as a follow-up to a previous study by Dr. Heller, published in the November 1999 issue of the Journal of Clinical Pharmacology, which was the first direct comparison of commercially available calcium supplements. In that study, it was proven that the calcium supplement formulation calcium citrate was 2.5 times more bioavailable than calcium carbonate, even when given with a meal, the optimum method of ensuring calcium carbonate absorption.
"It is very important for postmenopausal women to have sufficient intake of calcium (1200 to 1500 mg/day) and vitamin D (600 to 800 IU/day) in combination with a healthy, well-balanced diet and regular weight-bearing exercise," noted Dr. Heller. "However, since a serving of dairy only provides about 300 mg of calcium and up to 100 IU of vitamin D, most women are unable to achieve proper calcium and vitamin D intake via the diet alone. Our data suggests that there is an important difference in bioavailability between calcium supplements in postmenopausal women. Careful long-term studies should be done to determine if there is an equal difference in protection against bone loss and fracture."
J Clin Pharmacol. 2000;40:1237-12
Medscape Medical News © 2000
Cite this article: Calcium Citrate Shown to Have Superior Bioavailability and Protects Against Bone Loss. Medscape. Nov 21, 2000.
Dietary Supplement Fact Sheet:
See QuickFacts for easy-to-read facts about Vitamin D.
Vitamin D is a fat-soluble vitamin that is naturally present in very few foods, added to others, and available as a dietary supplement. It is also produced endogenously when ultraviolet rays from sunlight strike the skin and trigger vitamin D synthesis. Vitamin D obtained from sun exposure, food, and supplements is biologically inert and must undergo two hydroxylations in the body for activation. The first occurs in the liver and converts vitamin D to 25-hydroxyvitamin D [25(OH)D], also known as calcidiol. The second occurs primarily in the kidney and forms the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D], also known as calcitriol .
Vitamin D promotes calcium absorption in the gut and maintains adequate serum calcium and phosphate concentrations to enable normal mineralization of bone and to prevent hypocalcemic tetany. It is also needed for bone growth and bone remodeling by osteoblasts and osteoclasts [1,2]. Without sufficient vitamin D, bones can become thin, brittle, or misshapen. Vitamin D sufficiency prevents rickets in children and osteomalacia in adults . Together with calcium, vitamin D also helps protect older adults from osteoporosis.
Vitamin D has other roles in the body, including modulation of cell growth, neuromuscular and immune function, and reduction of inflammation [1,3,4]. Many genes encoding proteins that regulate cell proliferation, differentiation, and apoptosis are modulated in part by vitamin D . Many cells have vitamin D receptors, and some convert 25(OH)D to 1,25(OH)2D.
Serum concentration of 25(OH)D is the best indicator of vitamin D status. It reflects vitamin D produced cutaneously and that obtained from food and supplements  and has a fairly long circulating half-life of 15 days . 25(OH)D functions as a biomarker of exposure, but it is not clear to what extent 25(OH)D levels also serve as a biomarker of effect (i.e., relating to health status or outcomes) . Serum 25(OH)D levels do not indicate the amount of vitamin D stored in body tissues.
In contrast to 25(OH)D, circulating 1,25(OH)2D is generally not a good indicator of vitamin D status because it has a short half-life of 15 hours and serum concentrations are closely regulated by parathyroid hormone, calcium, and phosphate . Levels of 1,25(OH)2D do not typically decrease until vitamin D deficiency is severe [2,6].
There is considerable discussion of the serum concentrations of 25(OH)D associated with deficiency (e.g., rickets), adequacy for bone health, and optimal overall health, and cut points have not been developed by a scientific consensus process. Based on its review of data of vitamin D needs, a committee of the Institute of Medicine concluded that persons are at risk of vitamin D deficiency at serum 25(OH)D concentrations <30 nmol/L (<12 ng/mL). Some are potentially at risk for inadequacy at levels ranging from 30–50 nmol/L (12–20 ng/mL). Practically all people are sufficient at levels ≥50 nmol/L (≥20 ng/mL); the committee stated that 50 nmol/L is the serum 25(OH)D level that covers the needs of 97.5% of the population. Serum concentrations >125 nmol/L (>50 ng/mL) are associated with potential adverse effects  (Table 1).
|Table 1: Serum 25-Hydroxyvitamin D [25(OH)D] Concentrations and Health* |
|<30||<12||Associated with vitamin D deficiency, leading to rickets in infants and children and osteomalacia in adults|
|30–50||12–20||Generally considered inadequate for bone and overall health in healthy individuals|
|≥50||≥20||Generally considered adequate for bone and overall health in healthy individuals|
|>125||>50||Emerging evidence links potential adverse effects to such high levels, particularly >150 nmol/L (>60 ng/mL)|
* Serum concentrations of 25(OH)D are reported in both nanomoles per liter (nmol/L) and nanograms per milliliter (ng/mL).
** 1 nmol/L = 0.4 ng/mL
An additional complication in assessing vitamin D status is in the actual measurement of serum 25(OH)D concentrations. Considerable variability exists among the various assays available (the two most common methods being antibody based and liquid chromatography based) and among laboratories that conduct the analyses [1,7,8]. This means that compared with the actual concentration of 25(OH)D in a sample of blood serum, a falsely low or falsely high value may be obtained depending on the assay or laboratory used . A standard reference material for 25(OH)D became available in July 2009 that permits standardization of values across laboratories and may improve method-related variability [1,10].
Intake reference values for vitamin D and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of The National Academies (formerly National Academy of Sciences) . DRI is the general term for a set of reference values used to plan and assess nutrient intakes of healthy people. These values, which vary by age and gender, include:
Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy people.
Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.
Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects .
The FNB established an RDA for vitamin D representing a daily intake that is sufficient to maintain bone health and normal calcium metabolism in healthy people. RDAs for vitamin D are listed in both International Units (IUs) and micrograms (mcg); the biological activity of 40 IU is equal to 1 mcg (Table 2). Even though sunlight may be a major source of vitamin D for some, the vitamin D RDAs are set on the basis of minimal sun exposure .
|Table 2: Recommended Dietary Allowances (RDAs) for Vitamin D |
|0–12 months*||400 IU
|1–13 years||600 IU
|14–18 years||600 IU
|19–50 years||600 IU
|51–70 years||600 IU
|>70 years||800 IU
* Adequate Intake (AI)
Sources of Vitamin D
Very few foods in nature contain vitamin D. The flesh of fatty fish (such as salmon, tuna, and mackerel) and fish liver oils are among the best sources [1,11]. Small amounts of vitamin D are found in beef liver, cheese, and egg yolks. Vitamin D in these foods is primarily in the form of vitamin D3 and its metabolite 25(OH)D3 . Some mushrooms provide vitamin D2 in variable amounts [13,14]. Mushrooms with enhanced levels of vitamin D2 from being exposed to ultraviolet light under controlled conditions are also available.
Fortified foods provide most of the vitamin D in the American diet [1,14]. For example, almost all of the U.S. milk supply is voluntarily fortified with 100 IU/cup . (In Canada, milk is fortified by law with 35–40 IU/100 mL, as is margarine at ≥530 IU/100 g.) In the 1930s, a milk fortification program was implemented in the United States to combat rickets, then a major public health problem . Other dairy products made from milk, such as cheese and ice cream, are generally not fortified. Ready-to-eat breakfast cereals often contain added vitamin D, as do some brands of orange juice, yogurt, margarine and other food products.
Both the United States and Canada mandate the fortification of infant formula with vitamin D: 40–100 IU/100 kcal in the United States and 40–80 IU/100 kcal in Canada .
Several food sources of vitamin D are listed in Table 3.
|Table 3: Selected Food Sources of Vitamin D |
|Food||IUs per serving*||Percent DV**|
|Cod liver oil, 1 tablespoon||1,360||340|
|Swordfish, cooked, 3 ounces||566||142|
|Salmon (sockeye), cooked, 3 ounces||447||112|
|Tuna fish, canned in water, drained, 3 ounces||154||39|
|Orange juice fortified with vitamin D, 1 cup (check product labels, as amount of added vitamin D varies)||137||34|
|Milk, nonfat, reduced fat, and whole, vitamin D-fortified, 1 cup||115-124||29-31|
|Yogurt, fortified with 20% of the DV for vitamin D, 6 ounces (more heavily fortified yogurts provide more of the DV)||80||20|
|Margarine, fortified, 1 tablespoon||60||15|
|Sardines, canned in oil, drained, 2 sardines||46||12|
|Liver, beef, cooked, 3 ounces||42||11|
|Egg, 1 large (vitamin D is found in yolk)||41||10|
|Ready-to-eat cereal, fortified with 10% of the DV for vitamin D, 0.75-1 cup (more heavily fortified cereals might provide more of the DV)||40||10|
|Cheese, Swiss, 1 ounce||6||2|
* IUs = International Units.
** DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration to help consumers compare the nutrient contents among products within the context of a total daily diet. The DV for vitamin D is currently set at 400 IU for adults and children age 4 and older. Food labels, however, are not required to list vitamin D content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.
The U.S. Department of Agriculture's Nutrient Database Web site lists the nutrient content of many foods. It also provides a comprehensive list of foods containing vitamin D. A growing number of foods are being analyzed for vitamin D content. Simpler and faster methods to measure vitamin D in foods are needed, as are food standard reference materials with certified values for vitamin D to ensure accurate measurements .
Most people meet at least some of their vitamin D needs through exposure to sunlight [1,2]. Ultraviolet (UV) B radiation with a wavelength of 290–320 nanometers penetrates uncovered skin and converts cutaneous 7-dehydrocholesterol to previtamin D3, which in turn becomes vitamin D3 . Season, time of day, length of day, cloud cover, smog, skin melanin content, and sunscreen are among the factors that affect UV radiation exposure and vitamin D synthesis . Perhaps surprisingly, geographic latitude does not consistently predict average serum 25(OH)D levels in a population. Ample opportunities exist to form vitamin D (and store it in the liver and fat) from exposure to sunlight during the spring, summer, and fall months even in the far north latitudes .
Complete cloud cover reduces UV energy by 50%; shade (including that produced by severe pollution) reduces it by 60% . UVB radiation does not penetrate glass, so exposure to sunshine indoors through a window does not produce vitamin D . Sunscreens with a sun protection factor (SPF) of 8 or more appear to block vitamin D-producing UV rays, although in practice people generally do not apply sufficient amounts, cover all sun-exposed skin, or reapply sunscreen regularly [1,18]. Therefore, skin likely synthesizes some vitamin D even when it is protected by sunscreen as typically applied.
The factors that affect UV radiation exposure and research to date on the amount of sun exposure needed to maintain adequate vitamin D levels make it difficult to provide general guidelines. It has been suggested by some vitamin D researchers, for example, that approximately 5–30 minutes of sun exposure between 10 AM and 3 PM at least twice a week to the face, arms, legs, or back without sunscreen usually lead to sufficient vitamin D synthesis and that the moderate use of commercial tanning beds that emit 2%–6% UVB radiation is also effective [6,19]. Individuals with limited sun exposure need to include good sources of vitamin D in their diet or take a supplement to achieve recommended levels of intake.
Despite the importance of the sun for vitamin D synthesis, it is prudent to limit exposure of skin to sunlight  and UV radiation from tanning beds . UV radiation is a carcinogen responsible for most of the estimated 1.5 million skin cancers and the 8,000 deaths due to metastatic melanoma that occur annually in the United States . Lifetime cumulative UV damage to skin is also largely responsible for some age-associated dryness and other cosmetic changes. The American Academy of Dermatology advises that photoprotective measures be taken, including the use of sunscreen, whenever one is exposed to the sun . Assessment of vitamin D requirements cannot address the level of sun exposure because of these public health concerns about skin cancer, and there are no studies to determine whether UVB-induced synthesis of vitamin D can occur without increased risk of skin cancer .
In supplements and fortified foods, vitamin D is available in two forms, D2 (ergocalciferol) and D3 (cholecalciferol) that differ chemically only in their side-chain structure. Vitamin D2 is manufactured by the UV irradiation of ergosterol in yeast, and vitamin D3 is manufactured by the irradiation of 7-dehydrocholesterol from lanolin and the chemical conversion of cholesterol . The two forms have traditionally been regarded as equivalent based on their ability to cure rickets and, indeed, most steps involved in the metabolism and actions of vitamin D2 and vitamin D3 are identical. Both forms (as well as vitamin D in foods and from cutaneous synthesis) effectively raise serum 25(OH)D levels . Firm conclusions about any different effects of these two forms of vitamin D cannot be drawn. However, it appears that at nutritional doses vitamins D2 and D3 are equivalent, but at high doses vitamin D2 is less potent.
The American Academy of Pediatrics (AAP) recommends that exclusively and partially breastfed infants receive supplements of 400 IU/day of vitamin D shortly after birth and continue to receive these supplements until they are weaned and consume ≥1,000 mL/day of vitamin D-fortified formula or whole milk . Similarly, all non-breastfed infants ingesting <1,000 mL/day of vitamin D-fortified formula or milk should receive a vitamin D supplement of 400 IU/day . AAP also recommends that older children and adolescents who do not obtain 400 IU/day through vitamin D-fortified milk and foods should take a 400 IU vitamin D supplement daily. However, this latter recommendation (issued November 2008) needs to be reevaluated in light of the Food and Nutrition Board's vitamin D RDA of 600 IU/day for children and adolescents (issued November 2010 and which previously was an AI of 200 IU/day).
Vitamin D Intakes and Status
The National Health and Nutrition Examination Survey (NHANES), 2005–2006, estimated vitamin D intakes from both food and dietary supplements [4,23]. Average intake levels for males from foods alone ranged from 204 to 288 IU/day depending on life stage group; for females the range was 144 to 276 IU/day. When use of dietary supplements was considered, these mean values were substantially increased (37% of the U.S. population used a dietary supplement containing vitamin D.) The most marked increase was among older women. For women aged 51–70 years, mean intake of vitamin D from foods alone was 156 IU/day, but 404 IU/day with supplements. For women >70 years, the corresponding figures were 180 IU/day to 400 IU/day .
Comparing vitamin D intake estimates from foods and dietary supplements to serum 25(OH)D concentrations is problematic. One reason is that comparisons can only be made on group means rather than on data linked to individuals. Another is the fact that sun exposure affects vitamin D status; serum 25(OH)D levels are generally higher than would be predicted on the basis of vitamin D intakes alone . The NHANES 2005–2006 survey found mean 25(OH)D levels exceeding 56 nmol/L (22.4 ng/mL) for all age-gender groups in the U.S. population. (The highest mean was 71.4 nmol/L [28.6 ng/mL] for girls aged 1–3 years, and the lowest mean was 56.5 nmol/L [22.6 ng/mL] for women aged 71 and older. Generally, younger people had higher levels than older people, and males had slightly higher levels than females.) 25(OH)D levels of approximately 50 nmol/L (20 ng/mL) are consistent with an intake of vitamin D from foods and dietary supplements equivalent to the RDA .
Over the past 20 years, mean serum 25(OH)D concentrations in the United States have slightly declined among males but not females. This decline is likely due to simultaneous increases in body weight, reduced milk intake, and greater use of sun protection when outside .
Vitamin D Deficiency
Nutrient deficiencies are usually the result of dietary inadequacy, impaired absorption and use, increased requirement, or increased excretion. A vitamin D deficiency can occur when usual intake is lower than recommended levels over time, exposure to sunlight is limited, the kidneys cannot convert 25(OH)D to its active form, or absorption of vitamin D from the digestive tract is inadequate. Vitamin D-deficient diets are associated with milk allergy, lactose intolerance, ovo-vegetarianism, and veganism .
Rickets and osteomalacia are the classical vitamin D deficiency diseases. In children, vitamin D deficiency causes rickets, a disease characterized by a failure of bone tissue to properly mineralize, resulting in soft bones and skeletal deformities . Rickets was first described in the mid-17th century by British researchers [16,25]. In the late 19th and early 20th centuries, German physicians noted that consuming 1–3 teaspoons/day of cod liver oil could reverse rickets . The fortification of milk with vitamin D beginning in the 1930s has made rickets a rare disease in the United States, although it is still reported periodically, particularly among African American infants and children [3,16,21].
Prolonged exclusive breastfeeding without the AAP-recommended vitamin D supplementation is a significant cause of rickets, particularly in dark-skinned infants breastfed by mothers who are not vitamin D replete . Additional causes of rickets include extensive use of sunscreens and placement of children in daycare programs, where they often have less outdoor activity and sun exposure [16,25]. Rickets is also more prevalent among immigrants from Asia, Africa, and the Middle East, possibly because of genetic differences in vitamin D metabolism and behavioral differences that lead to less sun exposure.
In adults, vitamin D deficiency can lead to osteomalacia, resulting in weak bones [1,5]. Symptoms of bone pain and muscle weakness can indicate inadequate vitamin D levels, but such symptoms can be subtle and go undetected in the initial stages.
Groups at Risk of Vitamin D Inadequacy
Obtaining sufficient vitamin D from natural food sources alone is difficult. For many people, consuming vitamin D-fortified foods and, arguably, being exposed to some sunlight are essential for maintaining a healthy vitamin D status. In some groups, dietary supplements might be required to meet the daily need for vitamin D.
Vitamin D requirements cannot ordinarily be met by human milk alone [1,27], which provides <25 IU/L to 78 IU/L . (The vitamin D content of human milk is related to the mother's vitamin D status, so mothers who supplement with high doses of vitamin D may have correspondingly high levels of this nutrient in their milk .) A review of reports of nutritional rickets found that a majority of cases occurred among young, breastfed African Americans . A survey of Canadian pediatricians found the incidence of rickets in their patients to be 2.9 per 100,000; almost all those with rickets had been breast fed . While the sun is a potential source of vitamin D, the AAP advises keeping infants out of direct sunlight and having them wear protective clothing and sunscreen . As noted earlier, the AAP recommends that exclusively and partially breastfed infants be supplemented with 400 IU of vitamin D per day , the RDA for this nutrient during infancy.
Older adults are at increased risk of developing vitamin D insufficiency in part because, as they age, skin cannot synthesize vitamin D as efficiently, they are likely to spend more time indoors, and they may have inadequate intakes of the vitamin . As many as half of older adults in the United States with hip fractures could have serum 25(OH)D levels <30 nmol/L (<12 ng/mL) .
People with limited sun exposure
Homebound individuals, women who wear long robes and head coverings for religious reasons, and people with occupations that limit sun exposure are unlikely to obtain adequate vitamin D from sunlight [31,32]. Because the extent and frequency of use of sunscreen are unknown, the significance of the role that sunscreen may play in reducing vitamin D synthesis is unclear . Ingesting RDA levels of vitamin D from foods and/or supplements will provide these individuals with adequate amounts of this nutrient.
People with dark skin
Greater amounts of the pigment melanin in the epidermal layer result in darker skin and reduce the skin's ability to produce vitamin D from sunlight . Various reports consistently show lower serum 25(OH)D levels in persons identified as black compared with those identified as white. It is not clear that lower levels of 25(OH)D for persons with dark skin have significant health consequences. Those of African American ancestry, for example, have reduced rates of fracture and osteoporosis compared with Caucasians (see section below on osteoporosis). Ingesting RDA levels of vitamin D from foods and/or supplements will provide these individuals with adequate amounts of this nutrient.
People with fat malabsorption
As a fat-soluble vitamin, vitamin D requires some dietary fat in the gut for absorption. Individuals who have a reduced ability to absorb dietary fat might require vitamin D supplements . Fat malabsorption is associated with a variety of medical conditions including some forms of liver disease, cystic fibrosis, and Crohn's disease .
People who are obese or who have undergone gastric bypass surgery
A body mass index ≥30 is associated with lower serum 25(OH)D levels compared with non-obese individuals; people who are obese may need larger than usual intakes of vitamin D to achieve 25(OH)D levels comparable to those of normal weight . Obesity does not affect skin's capacity to synthesize vitamin D, but greater amounts of subcutaneous fat sequester more of the vitamin and alter its release into the circulation. Obese individuals who have undergone gastric bypass surgery may become vitamin D deficient over time without a sufficient intake of this nutrient from food or supplements, since part of the upper small intestine where vitamin D is absorbed is bypassed and vitamin D mobilized into the serum from fat stores may not compensate over time [34,35].
Vitamin D and Health
Optimal serum concentrations of 25(OH)D for bone and general health have not been established; they are likely to vary at each stage of life, depending on the physiological measures selected [1,2,6]. Also, as stated earlier, while serum 25(OH)D functions as a biomarker of exposure to vitamin D (from sun, food, and dietary supplements), the extent to which such levels serve as a biomarker of effect (i.e., health outcomes) is not clearly established .
Furthermore, while serum 25(OH)D levels increase in response to increased vitamin D intake, the relationship is non-linear for reasons that are not entirely clear . The increase varies, for example, by baseline serum levels and duration of supplementation. Increasing serum 25(OH)D to >50 nmol/L requires more vitamin D than increasing levels from a baseline <50 nmol/L. There is a steeper rise in serum 25(OH)D when the dose of vitamin D is <1,000 IU/day; a lower, more flattened response is seen at higher daily doses. When the dose is ≥1,000 IU/day, the rise in serum 25(OH)D is approximately 1 nmol/L for each 40 IU of intake. In studies with a dose ≤600 IU/day, the rise is serum 25(OH)D was approximately 2.3 nmol/L for each 40 IU of vitamin D consumed .
In March 2007, a group of vitamin D and nutrition researchers published a controversial and provocative editorial contending that the desirable concentration of 25(OH)D was ≥75 nmol/L (≥30 ng/ml) . They noted that approximately 1,700 IU/day of vitamin D are needed to raise serum 25(OH)D concentrations from 50 to 80 nmol/L (20–32 ng/mL).
However, the FNB committee that established DRIs for vitamin D extensively reviewed a long list of potential health relationships on which recommendations for vitamin D intake might be based . These health relationships included resistance to chronic diseases (such as cancer and cardiovascular diseases), physiological parameters (such as immune response or levels of parathyroid hormone), and functional measures (such as skeletal health and physical performance and falls). With the exception of measures related to bone health, the health relationships examined were either not supported by adequate evidence to establish cause and effect, or the conflicting nature of the available evidence could not be used to link health benefits to particular levels of intake of vitamin D or serum measures of 25(OH)D with any level of confidence.
More than 40 million adults in the United States have or are at risk of developing osteoporosis, a disease characterized by low bone mass and structural deterioration of bone tissue that increases bone fragility and significantly increases the risk of bone fractures . Osteoporosis is most often associated with inadequate calcium intakes, but insufficient vitamin D contributes to osteoporosis by reducing calcium absorption . Although rickets and osteomalacia are extreme examples of the effects of vitamin D deficiency, osteoporosis is an example of a long-term effect of calcium and vitamin D insufficiency. Adequate storage levels of vitamin D maintain bone strength and might help prevent osteoporosis in older adults, non-ambulatory individuals who have difficulty exercising, postmenopausal women, and individuals on chronic steroid therapy .
Normal bone is constantly being remodeled. During menopause, the balance between these processes changes, resulting in more bone being resorbed than rebuilt. Hormone therapy with estrogen and progesterone might be able to delay the onset of osteoporosis. However, some medical groups and professional societies recommend that postmenopausal women consider using other agents to slow or stop bone resorption because of the potential adverse health effects of hormone therapy [40,41,42].
Most supplementation trials of the effects of vitamin D on bone health also include calcium, so it is difficult to isolate the effects of each nutrient. Among postmenopausal women and older men, supplements of both vitamin D and calcium result in small increases in bone mineral density throughout the skeleton. They also help to reduce fractures in institutionalized older populations, although the benefit is inconsistent in community-dwelling individuals [1,2,43]. Vitamin D supplementation alone appears to have no effect on risk reduction for fractures nor does it appear to reduce falls among the elderly [1,2,43]; one widely-cited meta-analysis suggesting a protective benefit of supplemental vitamin D against falls  has been severely critiqued . However, a large study of women aged ≥69 years followed for an average of 4.5 years found both lower (<50 nmol/L [<20 ng/mL]) and higher(≥75 nmol/L [≥30 ng/mL]) 25(OH)D levels at baseline to be associated with a greater risk of frailty . Women should consult their healthcare providers about their needs for vitamin D (and calcium) as part of an overall plan to prevent or treat osteoporosis.
Laboratory and animal evidence as well as epidemiologic data suggest that vitamin D status could affect cancer risk. Strong biological and mechanistic bases indicate that vitamin D plays a role in the prevention of colon, prostate, and breast cancers. Emerging epidemiologic data suggest that vitamin D may have a protective effect against colon cancer, but the data are not as strong for a protective effect against prostate and breast cancer, and are variable for cancers at other sites [1,46,47]. Studies do not consistently show a protective or no effect, however. One study of Finnish smokers, for example, found that subjects in the highest quintile of baseline vitamin D status had a threefold higher risk of developing pancreatic cancer . A recent review found an increased risk of pancreatic cancer associated with high levels of serum 25(OH)D (≥100 nmol/L or ≥40 ng/mL) .
Vitamin D emerged as a protective factor in a prospective, cross-sectional study of 3,121 adults aged ≥50 years (96% men) who underwent a colonoscopy. The study found that 10% had at least one advanced cancerous lesion. Those with the highest vitamin D intakes (>645 IU/day) had a significantly lower risk of these lesions . However, the Women's Health Initiative, in which 36,282 postmenopausal women of various races and ethnicities were randomly assigned to receive 400 IU vitamin D plus 1,000 mg calcium daily or a placebo, found no significant differences between the groups in the incidence of colorectal cancers over 7 years . More recently, a clinical trial focused on bone health in 1,179 postmenopausal women residing in rural Nebraska found that subjects supplemented daily with calcium (1,400–1,500 mg) and vitamin D3 (1,100 IU) had a significantly lower incidence of cancer over 4 years compared with women taking a placebo . The small number of cancers (50) precludes generalizing about a protective effect from either or both nutrients or for cancers at different sites. This caution is supported by an analysis of 16,618 participants in NHANES III (1988–1994), in which total cancer mortality was found to be unrelated to baseline vitamin D status . However, colorectal cancer mortality was inversely related to serum 25(OH)D concentrations. A large observational study with participants from 10 western European countries also found a strong inverse association between prediagnostic 25(OH)D concentrations and risk of colorectal cancer .
Further research is needed to determine whether vitamin D inadequacy in particular increases cancer risk, whether greater exposure to the nutrient is protective, and whether some individuals could be at increased risk of cancer because of vitamin D exposure [46,55]. Taken together, however, studies to date do not support a role for vitamin D, with or without calcium, in reducing the risk of cancer .
A growing body of research suggests that vitamin D might play some role in the prevention and treatment of type 1  and type 2 diabetes , hypertension , glucose intolerance , multiple sclerosis , and other medical conditions [61,62]. However, most evidence for these roles comes from in vitro, animal, and epidemiological studies, not the randomized clinical trials considered to be more definitive . Until such trials are conducted, the implications of the available evidence for public health and patient care will be debated. One meta-analysis found use of vitamin D supplements to be associated with a statistically significant reduction in overall mortality from any cause [63,64], but a reanalysis of the data found no association . A systematic review of these and other health outcomes related to vitamin D and calcium intakes, both alone and in combination, was published in August 2009 .
Health Risks from Excessive Vitamin D
Vitamin D toxicity can cause non-specific symptoms such as anorexia, weight loss, polyuria, and heart arrhythmias. More seriously, it can also raise blood levels of calcium which leads to vascular and tissue calcification, with subsequent damage to the heart, blood vessels, and kidneys . The use of supplements of both calcium (1,000 mg/day) and vitamin D (400 IU) by postmenopausal women was associated with a 17% increase in the risk of kidney stones over 7 years in the Women's Health Initiative . A serum 25(OH)D concentration consistently >500 nmol/L (>200 ng/mL) is considered to be potentially toxic .
Excessive sun exposure does not result in vitamin D toxicity because the sustained heat on the skin is thought to photodegrade previtamin D3 and vitamin D3 as it is formed . In addition, thermal activation of previtamin D3 in the skin gives rise to various non-vitamin D forms that limit formation of vitamin D3 itself. Some vitamin D3 is also converted to nonactive forms . Intakes of vitamin D from food that are high enough to cause toxicity are very unlikely. Toxicity is much more likely to occur from high intakes of dietary supplements containing vitamin D.
Long-term intakes above the UL increase the risk of adverse health effects  (Table 4). Most reports suggest a toxicity threshold for vitamin D of 10,000 to 40,000 IU/day and serum 25(OH)D levels of 500–600 nmol/L (200–240 ng/mL). While symptoms of toxicity are unlikely at daily intakes below 10,000 IU/day, the FNB pointed to emerging science from national survey data, observational studies, and clinical trials suggesting that even lower vitamin D intakes and serum 25(OH)D levels might have adverse health effects over time. The FNB concluded that serum 25(OH)D levels above approximately 125–150 nmol/L (50–60 ng/mL) should be avoided, as even lower serum levels (approximately 75–120 nmol/L or 30–48 ng/mL) are associated with increases in all-cause mortality, greater risk of cancer at some sites like the pancreas, greater risk of cardiovascular events, and more falls and fractures among the elderly. The FNB committee cited research which found that vitamin D intakes of 5,000 IU/day achieved serum 25(OH)D concentrations between 100–150 nmol/L (40–60 ng/mL), but no greater. Applying an uncertainty factor of 20% to this intake value gave a UL of 4,000 IU which the FNB applied to children aged 9 and older, with corresponding lower amounts for younger children.
|Table 4: Tolerable Upper Intake Levels (ULs) for Vitamin D |
|0–6 months||1,000 IU
|7–12 months||1,500 IU
|1–3 years||2,500 IU
|4–8 years||3,000 IU
|≥9 years||4,000 IU
Interactions with Medications
Vitamin D supplements have the potential to interact with several types of medications. A few examples are provided below. Individuals taking these medications on a regular basis should discuss vitamin D intakes with their healthcare providers.
Corticosteroid medications such as prednisone, often prescribed to reduce inflammation, can reduce calcium absorption [66,67,68] and impair vitamin D metabolism. These effects can further contribute to the loss of bone and the development of osteoporosis associated with their long-term use [67,68].
Both the weight-loss drug orlistat (brand names Xenical® and alliTM) and the cholesterol-lowering drug cholestyramine (brand names Questran®, LoCholest®, and Prevalite®) can reduce the absorption of vitamin D and other fat-soluble vitamins [69,70]. Both phenobarbital and phenytoin (brand name Dilantin®), used to prevent and control epileptic seizures, increase the hepatic metabolism of vitamin D to inactive compounds and reduce calcium absorption .
Vitamin D and Healthful Diets
The federal government's 2010 Dietary Guidelines for Americans notes that "nutrients should come primarily from foods. Foods in nutrient-dense, mostly intact forms contain not only the essential vitamins and minerals that are often contained in nutrient supplements, but also dietary fiber and other naturally occurring substances that may have positive health effects. ...Dietary supplements…may be advantageous in specific situations to increase intake of a specific vitamin or mineral."
For more information about building a healthful diet, refer to the Dietary Guidelines for Americans and the U.S. Department of Agriculture's food guidance system, MyPlate.
The Dietary Guidelines for Americans describes a healthy diet as one that:
Emphasizes a variety of fruits, vegetables, whole grains, and fat-free or low-fat milk and milk products.
Milk is fortified with vitamin D, as are many ready-to-eat cereals and some brands of yogurt and orange juice. Cheese naturally contains small amounts of vitamin D.
Includes lean meats, poultry, fish, beans, eggs, and nuts.
Fatty fish such as salmon, tuna, and mackerel are very good sources of vitamin D. Small amounts of vitamin D are also found in beef liver and egg yolks.
Is low in saturated fats, trans fats, cholesterol, salt (sodium), and added sugars.
Vitamin D is added to some margarines.
Stays within your daily calorie needs.
Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010.
Cranney C, Horsely T, O'Donnell S, Weiler H, Ooi D, Atkinson S, et al. Effectiveness and safety of vitamin D. Evidence Report/Technology Assessment No. 158 prepared by the University of Ottawa Evidence-based Practice Center under Contract No. 290-02.0021. AHRQ Publication No. 07-E013. Rockville, MD: Agency for Healthcare Research and Quality, 2007. [PubMed abstract]
Holick MF. Vitamin D. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease, 10th ed. Philadelphia: Lippincott Williams & Wilkins, 2006.
Norman AW, Henry HH. Vitamin D. In: Bowman BA, Russell RM, eds. Present Knowledge in Nutrition, 9th ed. Washington DC: ILSI Press, 2006.
Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 2008;88:582S-6S. [PubMed abstract]
Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-81. [PubMed abstract]
Carter GD. 25-hydroxyvitamin D assays: the quest for accuracy. Clin Chem 2009;55:1300-02.
Hollis BW. Editorial: the determination of circulating 25-hydroxyvitamin D: no easy task. J. Clin Endocrinol Metab 2004;89:3149-3151.
Binkley N, Krueger D, Cowgill CS, Plum L, Lake E, Hansen KE, et al. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J Clin Endocrinol Metab 2004;89:3152-57. [PubMed abstract]
National Institute of Standards and Technology. NIST releases vitamin D standard reference material, 2009.
U.S. Department of Agriculture, Agricultural Research Service. 2011. USDA National Nutrient Database for Standard Reference, Release 24. Nutrient Data Laboratory Home Page, http://www.ars.usda.gov/ba/bhnrc/ndl.
Ovesen L, Brot C, Jakobsen J. Food contents and biological activity of 25-hydroxyvitamin D: a vitamin D metabolite to be reckoned with? Ann Nutr Metab 2003;47:107-13. [PubMed abstract]
Mattila PH, Piironen VI, Uusi-Rauva EJ, Koivistoinen PE. Vitamin D contents in edible mushrooms. J Agric Food Chem 1994;42:2449-53.
Calvo MS, Whiting SJ, Barton CN. Vitamin D fortification in the United States and Canada: current status and data needs. Am J Clin Nutr 2004;80:1710S-6S. [PubMed abstract]
Byrdwell WC, DeVries J, Exler J, Harnly JM, Holden JM, Holick MF, et al. Analyzing vitamin D in foods and supplements: methodologic challenges. Am J Clin Nutr 2008;88:554S-7S. [PubMed abstract]
Wharton B, Bishop N. Rickets. Lancet 2003;362:1389-400. [PubMed abstract]
Holick MF. Photobiology of vitamin D. In: Feldman D, Pike JW, Glorieux FH, eds. Vitamin D, Second Edition, Volume I. Burlington, MA: Elsevier, 2005.
Wolpowitz D, Gilchrest BA. The vitamin D questions: how much do you need and how should you get it? J Am Acad Dermatol 2006;54:301-17. [PubMed abstract]
Holick MF. Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health. Curr Opin Endocrinol Diabetes 2002;9:87-98.
International Agency for Research on Cancer Working Group on ultraviolet (UV) light and skin cancer. The association of use of sunbeds with cutaneous malignant melanoma and other skin cancers: a systematic review. Int J Cancer 2006;120:1116-22. [PubMed abstract]
American Academy of Dermatology. Position statement on vitamin D. November 1, 2008.
Wagner CL, Greer FR; American Academy of Pediatrics Section on Breastfeeding; American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 2008;122:1142-1152. [PubMed abstract]
Bailey RL, Dodd KW, Goldman JA, Gahche JJ, Dwyer JT, Moshfegh AJ, et al. Estimation of total usual calcium and vitamin D intakes in the United States. J Nutr 2010;140:817-822. [PubMed abstract]
Looker AC, Pfeiffer CM, Lacher DA, Schleicher RL, Picciano MF, Yetley EA. Serum 25-hydroxyvitamin D status of the US population: 1988-1994 compared with 2000-2004. Am J Clin Nutr 2008;88:1519-27. [PubMed abstract]
Chesney R. Rickets: an old form for a new century. Pediatr Int 2003;45: 509-11. [PubMed abstract]
Goldring SR, Krane S, Avioli LV. Disorders of calcification: osteomalacia and rickets. In: DeGroot LJ, Besser M, Burger HG, Jameson JL, Loriaux DL, Marshall JC, et al., eds. Endocrinology. 3rd ed. Philadelphia: WB Saunders, 1995:1204-27.
Picciano MF. Nutrient composition of human milk. Pediatr Clin North Am 2001;48:53-67. [PubMed abstract]
Weisberg P, Scanlon KS, Li R, Cogswell ME. Nutritional rickets among children in the United States: review of cases reported between 1986 and 2003. Am J Clin Nutr 2004;80:1697S-705S. [PubMed abstract]
Ward LM, Gaboury I, Ladhani M, Zlotkin S. Vitamin D-deficiency rickets among children in Canada. CMAJ 2007;177:161-166. [PubMed abstract]
American Academy of Pediatrics Committee on Environmental Health. Ultraviolet light: a hazard to children. Pediatrics 1999;104:328-33. [PubMed abstract]
Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3: Exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 1988;67:373-8. [PubMed abstract]
Webb AR, Pilbeam C, Hanafin N, Holick MF. An evaluation of the relative contributions of exposure to sunlight and of diet to the circulating concentrations of 25-hydroxyvitamin D in an elderly nursing home population in Boston. Am J Clin Nutr 1990;51:1075-81. [PubMed abstract]
Lo CW, Paris PW, Clemens TL, Nolan J, Holick MF. Vitamin D absorption in healthy subjects and in patients with intestinal malabsorption syndromes. Am J Clin Nutr 1985;42:644-49. [PubMed abstract]
Malone M. Recommended nutritional supplements for bariatric surgery patients. Ann Pharmacother 2008;42:1851-8. [PubMed abstract]
Compher CW, Badellino KO, Boullata JI. Vitamin D and the bariatric surgical patient: a review. Obes Surg 2008;18:220-4. [PubMed abstract]
Vieth R, Bischoff-Ferrari H, Boucher BJ, Dawson-Hughes B, Garland CF, Heaney RP, et al. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr 2007;85:649-50. [PubMed abstract]
National Institutes of Health Osteoporosis and Related Bone Diseases National Research Center. Osteoporosis overview. October 2010.
Heaney RP. Long-latency deficiency disease: insights from calcium and vitamin D. Am J Clin Nutr 2003;78:912-9. [PubMed abstract]
LeBoff MS, Kohlmeier L, Hurwitz S, Franklin J, Wright J, Glowacki J. Occult vitamin D deficiency in postmenopausal US women with acute hip fracture. JAMA 1999;251:1505-11. [PubMed abstract]
Kirschstein R. Menopausal hormone therapy: summary of a scientific workshop. Ann Intern Med 2003;138:361-4. [PubMed abstract]
American College of Obstetricians and Gynecologists. Frequently Asked Questions About Hormone Therapy. New Recommendations Based on ACOG's Task Force Report on Hormone Therapy.
North American Menopause Society. Role of progestrogen in hormone therapy for postmenopausal women: position statement of The North American Menopause Society. Menopause 2003;10:113-32. [PubMed abstract]
Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, et al. Vitamin D and calcium: a systematic review of health outcomes. Evidence Report/Technology Assessment No. 183 prepared by the Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-I. AHRQ Publication No. 09-E015. Rockville, MD: Agency for Healthcare Research and Quality, 2009.
Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ 2009;339:b3692. [PubMed abstract]
Ensrud KE, Ewing SK, Fredman L, Hochberg MC,Cauley JA, Hillier TA, et al. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J ClinEndocrinolMetab 2010;95:5266-5273. [PubMed abstract]
Davis CD. Vitamin D and cancer: current dilemmas and future research needs. Am J Clin Nutr 2008;88:565S-9S. [PubMed abstract]
Davis CD, Hartmuller V, Freedman M, Hartge P, Picciano MF, Swanson CA, Milner JA. Vitamin D and cancer: current dilemmas and future needs. Nutr Rev 2007;65:S71-S74. [PubMed abstract]
Stolzenberg-Solomon RZ, Vieth R, Azad A, Pietinen P, Taylor PR, Virtamo J, et al. A prospective nested case-control study of vitamin D status and pancreatic cancer risk in male smokers. Cancer Res 2006;66:10213-9. [PubMed abstract]
Kathy J. Helzlsouer for the VDPP Steering Committee. Overview of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol 2010;172:4-9. [PubMed abstract]
Lieberman DA, Prindiville S, Weiss DG, Willett W. Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals. JAMA 2003;290:2959-67. [PubMed abstract]
Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O'Sullivan MJ, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-96. [PubMed abstract]
Parfitt AM. Osteomalacia and related disorders. In: Avioli LV, Krane SM, eds. Metabolic bone disease and clinically related disorders. 2nd ed. Philadelphia: WB Saunders, 1990:329-96.
Freedman DM, Looker AC, Chang S-C, Graubard BI. Prospective study of serum vitamin D and cancer mortality in the United States. J Natl Cancer Inst 2007;99:1594-602. [PubMed abstract]
Jenab M, Bueno-de-Mesquita HB, Ferrari P, van Duijnhoven FJB, Norat T, Pischon T, et al. Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study. BMJ 2010;340:b5500. [PubMed abstract]
Davis CD, Dwyer JT. The 'sunshine vitamin': benefits beyond bone? J Natl Cancer Inst 2007;99:1563-5. [PubMed abstract]
Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358:1500-3. [PubMed abstract]
Pittas AG, Dawson-Hughes B, Li T, Van Dam RM, Willett WC, Manson JE, et al. Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care 2006;29:650-6. [PubMed abstract]
Krause R, Bühring M, Hopfenmüller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet 1998;352:709-10. [PubMed abstract]
Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004;79:820-5. [PubMed abstract]
Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006;296:2832-8. [PubMed abstract]
Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag K. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. Arthritis Rheum 2004;50:72-7. [PubMed abstract]
Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 2006;83:754-9. [PubMed abstract]
Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 2007;167:1730-7. [PubMed abstract]
Giovannucci E. Can vitamin D reduce total mortality? Arch Intern Med 2007;167:1709-10. [PubMed abstract]
Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-83. [PubMed abstract]
Buckley LM, Leib ES, Cartularo KS, Vacek PM, Cooper SM. Calcium and vitamin D3 supplementation prevents bone loss in the spine secondary to low-dose corticosteroids in patients with rheumatoid arthritis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1996;125:961-8. [PubMed abstract]
Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med 1990;112:352-64. [PubMed abstract]
de Sevaux RGL, Hoitsma AJ, Corstens FHM, Wetzels JFM. Treatment with vitamin D and calcium reduces bone loss after renal transplantation: a randomized study. J Am Soc Nephrol 2002;13:1608-14. [PubMed abstract]
McDuffie JR, Calis KA, Booth SL, Uwaifo GI, Yanovski JA. Effects of orlistat on fat-soluble vitamins in obese adolescents. Pharmacotherapy 2002;22:814-22. [PubMed abstract]
Compston JE, Horton LW. Oral 25-hydroxyvitamin D3 in treatment of osteomalacia associated with ileal resection and cholestyramine therapy. Gastroenterology 1978;74:900-2. [PubMed abstract]
Gough H, Goggin T, Bissessar A, Baker M, Crowley M, Callaghan N. A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in outpatients with epilepsy. Q J Med 1986;59:569-77. [PubMed abstract]
This fact sheet by the Office of Dietary Supplements provides information that should not take the place of medical advice. We encourage you to talk to your health care providers (doctor, registered dietitian, pharmacist, etc.) about your interest in, questions about, or use of dietary supplements and what may be best for your overall health. Any mention in this publication of a specific brand name is not an endorsement of the product.
Without Magnesium, Vitamin D & Calcium Alone Will Not Prevent Bone Fractures
LOS ANGELES, March 6, 2013 /PRNewswire/ -- The U.S. Preventive Services Task Force, a government-appointed panel of experts, recently issued a report stating that taking vitamin D and calcium supplements may not help prevent bone fractures in postmenopausal women, while also increasing the risk of kidney stones.1
"This is not surprising," says Carolyn Dean, MD, ND, magnesium expert and Medical Advisory Board member of the nonprofit Nutritional Magnesium Association (http://www.nutritionalmagnesium.org), "because adequate levels of magnesium in the body are essential for the absorption and metabolism of vitamin D and calcium. Magnesium converts vitamin D into its active form so that it can help calcium absorption and help prevent clogged arteries by drawing calcium out of the blood and soft tissues back into the bones where it is needed to build healthy bone structure."
Nutrients act in a synergetic way in the body. Absorption and metabolism of a particular nutrient will be affected, to a greater or lesser degree, by the other nutrients available to the body. This is also true with vitamin D.
According to the nonprofit Vitamin D Council, "In order to receive the most health benefit from increased levels of vitamin D, the proper cofactors must be present in the body. Vitamin D has many cofactors, but the ones listed here are the most important, with magnesium topping the list: Magnesium, Vitamin K, Vitamin A, Zinc and Boron."
According to research studies, magnesium has been found to influence the body's utilization of vitamin D in the following ways: Magnesium activates cellular enzymatic activity. In fact, all the enzymes that metabolize vitamin D require it.2,3 Low magnesium has been shown to alter, by way of decreasing, production of vitamin D's active form, 1,25(OH)2D (calcitriol).4
Magnesium is needed to exert positive influence over the human genome and may be involved in the genetic actions of vitamin D. Magnesium possibly has a role in vitamin D's effect on the immune system.5
Animal studies have shown magnesium is also necessary for vitamin D's beneficial actions on bone.6,7
Dr. Dean concurs: "It is vitally important that studies on the efficacy of vitamin D and calcium in relation to bone health are not done in isolation in the absence of magnesium. The fact that magnesium works synergistically with vitamin D and calcium by stimulating the specific hormone calcitonin—which helps to preserve bone structure and draws calcium out of the blood and soft tissues back into the bones, preventing osteoporosis, some forms of arthritis and kidney stones— cannot be overlooked."
Dr. Dean concludes, "The many studies pointing to the importance of these two nutrients to the prevention of both heart disease and osteoporosis, and the fact that magnesium can be found to increase the effectiveness of vitamin D and calcium, make finding out about this vital mineral that much more important."
A 32-page guide to the benefits of magnesium, along with magnesium deficiency symptoms, written by Dr. Dean, is available as a free download at http://www.nutritionalmagnesium.org.
About the Nutritional Magnesium AssociationThe nonprofit Nutritional Magnesium Association (NMA) is a trusted authority on the subject of magnesium and is a resource for all people affected by the widespread magnesium deficiency in our diets and the related health issues associated with this deficiency.
Moyer, V. A. Statement on behalf of the U.S. Preventive Services Task Force. Vitamin D and Calcium Supplementation to Prevent Fractures in Adults: U.S. Preventive Services Task Force Recommendation. Ann Intern Med. 2013, Feb 26. doi: 10.7326/0003-4819-158-9-201305070-00603. http://www.ncbi.nlm.nih.gov/pubmed/23440163
Zofkova, I., R. L. Kancheva. The Relationship between Magnesium and Calciotropic Hormones. Magnes Res. 1995 Mar; 8 (1): 77–84.
Carpenter, T. O. Disturbances of Vitamin D Metabolism and Action during Clinical and Experimental Magnesium Deficiency. Magnes Res. 1988 Dec; 1 (3–4): 131–39.
Saggese, G., S. Bertelloni, G. I. Baroncelli, G. Federico, L. Calisti, and C. Fusaro. Bone Demineralization and Impaired Mineral Metabolism in Insulin-Dependent Diabetes Mellitus. A Possible Role of Magnesium Deficiency. Helv Paediatr Acta. 1989 Jun; 43 (5–6): 405–14.
McCoy, H., and M. A. Kenney. Interactions between Magnesium and Vitamin D: Possible Implications in the Immune System. Magnes Res. 1996 Oct; 9 (3): 185–203.
Risco, F., and M. L. Traba. Bone Specific Binding Sites for 1,25(OH)2D3 in Magnesium Deficiency. J Physiol Biochem. 2004 Sep; 60 (3): 199–203.
Risco, F., M. L. Traba, and C. de la Piedra. Possible Alterations of the In Vivo 1,25(OH)2D3 Synthesis and Its Tissue Distribution in Magnesium-Deficient Rats. Magnes Res. 1995 Mar; 8 (1): 27–35.
SOURCE Nutritional Magnesium Association
Optimum Calcium Magnesium Ratio
The 2-to-1 Calcium-to-Magnesium Ratio
By A. Rosanoff, PhD, Director of Research & Science
Information Outreach, Center for Magnesium Education &
Research, LLC, www.MagnesiumEducation.com
As early as 1964, Dr. Mildred Seelig showed that calcium intake can be a factor in the body’s retention of dietary magnesium.1 This magnesium pioneer later considered the possible impact of high calcium with low magnesium intakes on heart and blood-vessel health,2, 3 and her predictive work was shown to be a serious consideration in 1978 when a population’s calcium-to-magnesium intake ratio was found to be associated with rates of heart disease death.4
The Two-to-One Ratio
The 2-to-1 calcium-to-magnesium ratio (2:1) was first suggested by the French magnesium researcher Jean Durlach as a high limit not to be exceeded, when he warned against excessive calcium relative to magnesium intakes; that is, one’s calcium intake from all sources including food, water and supplements should not exceed one’s total magnesium intake by more than 2 parts calcium to 1 part magnesium on a weight basis. 5
Thus, if one’s total magnesium intake per day is 300 mg, one’s total calcium intake for that day should not exceed 600 mg, according to Durlach. This would be a high level of calcium for the level of magnesium, not to be exceeded, according to this early and often-quoted recommendation. A lower calcium-to-magnesium ratio is thus safe, such as a one-to-one ratio or even less in some times of life or therapy.
It is important to note that this ratio is for weights of elemental calcium and elemental magnesium, not the weights of their compounds. It is also for all sources of calcium and magnesium intakes including food, water and supplements.
Calcium Cannot Be Optimally Utilized without a Proper Balance of Magnesium
Magnesium and calcium are two sides of a physiological coin: they are antagonistic to one another yet operate as a team.
• Calcium exists mainly outside the cells, whereas almost all magnesium is found inside the cells.
• Calcium excites nerves; magnesium calms them down.
• Calcium with potassium makes muscles contract, but magnesium is necessary for muscles to relax.
• Calcium is necessary to the clotting reaction—essential for wound healing—but magnesium keeps the blood
flowing freely and prevents abnormal thickening when clotting reactions would be dangerous.
• Calcium is mostly found in the bones and gives them much of their hardness, whereas magnesium is found
mainly in soft structures. Bone matrix, the soft structure within bone, contains protein and magnesium
and gives the bones some flexibility and resistance to brittleness.6
Without Adequate Magnesium, Too Much Calcium May Cause Damage to the Cells and the Body
Scientific study shows more and more that the underlying cellular change enabling the “fight or flight” stress response in the body is a low magnesium-to-calcium ratio caused by a large and sudden influx of calcium into the cells. The stress response subsides when the cells’ magnesium returns to its dominant presence inside the cells, moving extra calcium back to its “normal” position, thus restoring the cells’ natural ratio.
A low magnesium condition can be exacerbated by a high intake of calcium—promoted heavily today by many health professionals. Calcium cannot be optimally utilized without a proper balance of magnesium, and a high calcium intake without adequate magnesium nutrition and/or status can further drain any reserves of magnesium. Calcium is necessary at the cellular level for muscles to contract, for nerves to fire, for hormones to be secreted, and for the inflammation response to initiate. But calcium needs to be balanced with magnesium. If you take in too much calcium and too little magnesium over an extended time period and a cellular/physiological imbalance between calcium and magnesium occurs, what can happen is the excited firing state of biochemistry of the cell will tend to remain that way. In a stress situation, such as exercising more vigorously than usual or when someone is suddenly and unexpectedly frightened, muscle cells, nerve cells, hormone secreting cells or the inflammation response can go into an overreaction mode—the fight or flight mode. Without magnesium they don’t come back down to a resting state; they stay excited in that firing mode.
If calcium levels inside a cell get especially high because of low magnesium, the cell physically changes. High calcium tends to make things stiff and hard. But if soft tissue begins to get hard, it is a problem—the problem of calcification. In artery and heart cells, the stiffness caused by calcification hampers proper function and can lead to heart disease.
Calcium is an important essential nutrient, but it must be balanced by adequate magnesium or it may cause damage to the cells and the body as a whole.
Can there be too much magnesium and too little calcium? Of course. In this age of highly processed foods and the liberal use of essential nutrient supplementation, imbalances are always possible. A practicing physician or health professional must always be open to this possibility. This is especially difficult, as symptoms of “too much” of an essential nutrient often mimic symptoms brought on by “too little” of the same nutrient. But at this time, with a largely low magnesium diet and a general recommendation, especially to women, that they supplement their calcium, the imbalance of too much calcium to too little magnesium is one to regularly consider.7
1. Seelig, M. S. 1964. “The Requirement of Magnesium by the Normal Adult. Summary and Analysis of Published Data.” Am J Clin Nutr 14: 242–90. http://www.ncbi.nlm.nih.gov/pubmed/14168977.
2. Seelig, M. S. 1971. “Human Requirements of Magnesium; Factors That Increase Needs.” 1er Symposium International sur le Deficit Magnesique en Pathologie Humaine. Vittel, France. Ed. J. Durlach.
3. Seelig, M. S., and H. A. Heggtveit. 1974. “Magnesium Interrelationships in Ischemic Heart Disease: a Review.” Am J Clin Nutr 27(1): 59–79. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=4588182.
4. Karppanen, H., R. Pennanen, et al. 1978. “Minerals, Coronary Heart Disease and Sudden Coronary Death.” Adv Cardiol 25: 9–24. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=360793.
5. Durlach, J. 1989. “Recommended Dietary Amounts of Magnesium: Mg RDA.” Magnes Res 2(3): 195–203. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list _uids=2701269.
6. Seelig, M. S., and A. Rosanoff. 2003. The Magnesium Factor. New York: Avery Penguin Group.
7. Rosanoff, A., C. Weaver, et al. 2012. “Suboptimal Magnesium Status in the United States: Are the Health
Consequences Underestimated?” Nutrition Reviews 70(3): 153–64.
Indian J Clin Biochem. 2005 July; 20(2): 158–161.
Serum calcium measurement: Total versus free (ionized) calcium
Laxmayya Sava, Sandhya Pillai, Umesh More, and Alka Sontakke
Dept. of Biochemistry, Pad. Dr. D. Y. Patil Dental College and Hospital, C/O Dept. of Biochemistry, D. Y Patil Medical College, Pimpri, 411018 Pune,
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Measurement of serum free (ionized) calcium (Ca++) reflects true calcium status of the body in health and disease. Present study evaluates efficacy of Ca++ over total calcium (CaT) in serum for calcium status. 52 subjects were enrolled for study. Anaerobic fasting blood sample for Ca++ measurement and autoclaved plain bulb for estimation of CaT, Total protein (TP) and Albumin was used. CaT, Corrected CaT, Ca++, Calculated Ca++ were measured and correlated. Corrected CaT and calculated Ca++ were derived from the measured parameters. Study group showed significant difference between CaT and corrected CaT (p<0.006), Ca++ and calculated Ca++ (p<0.001). Negligible correlation was observed between Ca++ and serum protein. Positive correlation was observed between CaT and calculated Ca++, TP and albumin. Findings indicate that Ca++ levels are independent of serum protein status. With scrupulous sampling, Ca++ may be a better parameter than presently used CaT for assessing calcium status in serum.
Maturitas. 1996 May;23 Suppl:S65-9.
Estrogen and bone metabolism.
Department of Anatomy and Biocenter, University of Oulu, Finland.
Estrogen plays an important role in the growth and maturation of bone as well as in the regulation of bone turnover in adult bone. During bone growth estrogen is needed for proper closure of epiphyseal growth plates both in females and in males. Also in young skeleton estrogen deficiency leads to increased osteoclast formation and enhanced bone resorption. In menopause estrogen deficiency induces cancellous as well as cortical bone loss. Highly increased bone resorption in cancellous bone leads to general bone loss and destruction of local architecture because of penetrative resorption and microfractures. In cortical bone the first response of estrogen withdrawal is enhanced endocortical resorption. Later, also intracortical porosity increases. These lead to decreased bone mass, disturbed architecture and reduced bone strength. At cellular level in bone estrogen inhibits differentiation of osteoclasts thus decreasing their number and reducing the amount of active remodeling units. This effect is probably mediated through some cytokines, IL-1 and IL-6 being strongest candidates. Estrogen regulates the expression of IL-6 in bone marrow cells by a so far unknown mechanism. It is still uncertain if the effects of estrogen on osteoblasts is direct or is due to coupling phenomenon between bone formation to resorption.
Strontium Treatment for Osteoporosis
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If you are concerned about the bone-thinning disease osteoporosis, one treatment you may have heard of and considered is strontium. WebMD takes a look at the potential benefits and risks of this supplement purported to improve bone health.
What Is Strontium?
Strontium is a trace element found in seawater and soil. The main dietary source of strontium is seafood. Foods with lesser amounts of strontium include whole milk, wheat bran, meat, poultry, and root vegetables.
Strontium is chemically similar to calcium. It appears to play a role in the formation of new bone while slowing the breakdown of old bone, and thus may influence bone density. There is some evidence that women with osteoporosis may not absorb strontium as they should.
In several European countries and Australia, a patented form of strontium, called strontium ranelate (Protelos), is available as a prescription medication for the treatment and prevention of osteoporosis and related fractures. Protelos is not approved in the U.S.; however, unpatentable forms of the element, such as strontium citrate, are widely available as nutritional supplements in supermarkets and health food stores.
Possible Benefits of Strontium
A 2004 study from New England Journal of Medicine suggests strontium ranelate may be protective for women with osteoporosis. In the three-year study of postmenopausal women with osteoporosis, strontium ranelate increased bone density in the hip and spine and reduced the risk of fracturing a vertebra by 41% compared to placebo. A longer-term study published by the same group in 2009 showed strontium ranelate, compared to placebo, reduced the risk of vertebral fractures by 33% over four years.
Unfortunately, the supplement forms of strontium have not been tested in large studies like the prescription drug strontium ranelate. Furthermore, supplements are not regulated the same way as prescription drugs, so it's not always possible to know the quality of the supplement you are taking or the amount of the active ingredient in a product.
If you are interested in taking strontium supplement, ask your doctor to recommend one for you.
Possible Risks of Strontium
When taken in recommended doses, strontium supplements appear to be safe. Aside from occasional mild gastrointestinal upset, including diarrhea, side effects are rare. However, excessive doses of strontium may replace too much calcium in the bone and hurt vitamin D metabolism, causing them to weaken.
Use with caution if you have kidney problems or history of blood clots.
What Else You Should Know About Strontium
The optimal strontium dose is not known. If you are on medication treatment for osteoporosis, it is not known whether strontium supplements will enhance or diminish the benefits.
Also, it's important to note that while strontium may increase bone density, improvements seen on bone density testing may appear more impressive than they really are. That's because strontium in bone can affect interpretation of bone mineral testing. If you are taking strontium regularly, you should let the radiologist know before you have the bone mineral density test.
WebMD Medical Reference
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Boron is a trace element which has an important influence on both calcium and magnesium metabolism. Boron is concentrated in the bone, spleen, and thyroid indicating boron’s functions in bone metabolism and suggesting a potential role for boron in hormone metabolism. Boron is thought to be useful to increase muscle mass; increase muscle strength; maintain bone density; improve calcium absorption; decrease body fat.
According to the USDA, boron is a trace mineral that helps bones develop and grow normally. Boron becomes especially important when there is not enough vitamin D in the diet. Boron may also prevent arthritis in the elderly.
Research has shown that low boron diets have been associated with reduced testosterone levels and boron supplements have been shown to increase serum levels of testosterone in postmenopausal women. This finding caused an increase in boron supplements targeting athletes and bodybuilders for boosting testosterone levels, strength and muscle mass. However, specific research on athletes has not yet confirmed this association that boron alone will boost testosterone.
Dietary Sources: Dried fruits, nuts, dark green leafy vegetables, applesauce, grape juice, and cooked dried beans and peas. Meat and fish are poor dietary sources of boron. One mg of boron is found in 1.5 ounces of raisins or prunes; 2 ounces of almonds or peanuts; 4 ounces of red wine
Dosage: Daily needs for boron probably fall somewhere around 1 mg.
Side Effects: 1-10 mg per day is considered safe, but caution is warranted at higher intake levels as consumption of 50 mg or more may be linked to toxicity, loss of appetite, nausea, vomiting, skin rashes, lethargy, and diarrhea.
(Source: http://www.nal.usda.gov/ttic/tektran/data/000009/61/0000096130.html and www.supplementwatch.com)
A review of animal and human research on boron yielded the following information which points to a much more comprehensive view of boron.
Deficiency in boron has been shown to contribute to:
Boron supplementation was found to:
Some information about Boron:
Boron Citations (38)
J Nutr Health Aging. Author manuscript; available in PMC 2009 March 20.
Published in final edited form as:
J Nutr Health Aging. 2007 Mar-Apr; 11(2): 99–110.
SILICON AND BONE HEALTH
Rayne Institute, Gastrointestinal Laboratory, St Thomas' Hospital, London SE1 7EH; Department of Nutrition, King's College London, 150 Stamford Street, London SE1 9NN; MRC Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL.
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Low bone mass (osteoporosis) is a silent epidemic of the 21st century, which presently in the UK results in over 200,000 fractures annually at a cost of over one billion pounds. Figures are set to increase worldwide. Understanding the factors which affect bone metabolism is thus of primary importance in order to establish preventative measures or treatments for this condition. Nutrition is an important determinant of bone health, but the effects of the individual nutrients and minerals, other than calcium, is little understood. Accumulating evidence over the last 30 years strongly suggest that dietary silicon is beneficial to bone and connective tissue health and we recently reported strong positive associations between dietary Si intake and bone mineral density in US and UK cohorts. The exact biological role(s) of silicon in bone health is still not clear, although a number of possible mechanisms have been suggested, including the synthesis of collagen and/or its stabilization, and matrix mineralization. This review gives an overview of this naturally occurring dietary element, its metabolism and the evidence of its potential role in bone health.
Keywords: Silicon, orthosilicic acid, human exposure, dietary sources, silicon metabolism, bone health
Osteoporosis is a leading cause of morbidity and mortality in the elderly, and is an increasing drain on healthcare resources (over 1 billion pounds in the UK) (1, 2). The major clinical effect is bone fracture, especially of the femur, but also of vertebrae and the radius, causing pain, disability and loss of independence, and often a rapid sequence of events leading to death (1-5).
The aetiology of osteoporosis is multifactorial, and although genetic and hormonal factors strongly influence the rate of decline of bone mass with age, nevertheless poor nutrition, smoking and excessive alcohol use, and lack of physical exercise all also greatly affect it (1, 3-7). Although ideally these non-genetic factors could be altered, in practice this is difficult, and hence drugs are extensively used to try to slow, or reverse, osteoporosis, now chiefly calcium and vitamin D supplementation, bisphosphonates and oestrogens, and oestrogen receptor modulators (5, 8-11). Osteoporosis is an imbalance between bone resorption by osteoclast cells and bone formation by osteoblasts (2, 12) - oestrogens and bisphosphonates slow bone resorption, by reducing bone turnover, but few drugs (rhPTH, strontium renelate and sodium fluoride being exceptions) can increase osteoblast activity and hence bone formation (2).
There has also been interest in other bone minerals (magnesium, potassium and fluoride) and nutritional trace elements (zinc, copper, boron and manganese) in the diet; their intake is positively associated with bone mass, while deficiency has been correlated either with reduced bone mass or slow healing of fractures (6, 7, 12-14). Zinc, copper and manganese are essential cofactors for enzymes involved in the synthesis of the constituents of bone matrix (6, 7).
Another trace element that may be important is silicon (Si), but although there is 1-2 g present in the body (the most abundant trace element after iron and zinc, two other elements of physiological importance) its function is still surprisingly unclear. Silicon was long thought to be an inert universal contaminant that ‘washes through’ biology with no biological or toxicological properties; “a fortuitous reminder of our geochemical origin or an indicator of environmental exposure” (15). Animal studies in the 1970's reported that dietary silicon deficiency produces defects in connective and skeletal tissues (16-18), and that silicon is concentrated at the mineralisation front of growing bone (18). Work over the last 30 years has added to these findings to suggest that dietary silicon may be important, or at least beneficial, for bone formation and to bone health. This review gives an overview of silicon, human exposure to this element, its metabolism and the evidence of its potential role in bone health.
Silicon (Si) is a non-metallic element with an atomic weight of 28. It is the second most abundant element in the Earth's crust at 28 wt %, (19, 20) but it is rarely found in its elemental form due to its great affinity for oxygen, forming silica and silicates, which at 92%, are the most common minerals. Quartz (12%) and the aluminosilicates, plagioclase (39%) and alkaline feldspar (12%) are the most prevalent silicates (21). These are present in igneous and sedimentary rocks and soil minerals and are highly stable structures that are not readily broken down except with extensive weathering. Thus natural levels of soluble (available) silica are low. Chemical and biological (plants, algae and lichens) weathering, however, releases silicon from these stable minerals, increasing its bioavailability. Dissolution of Si, from soil minerals in water results in the formation, by hydrolysis, of soluble silica species. Below pH 9, and at a total Si concentration below 2 mM, silicon is present predominately as Si(OH)4 the most stable specie at low Si concentration. This monomeric form of silica, ‘monomeric silica’, is water soluble and a weak acid (pKa of 9.6), thus also referred to as ‘monosilicic acid’ or ‘orthosilicic acid’ (22). At neutral pH, this tetrahedral, uncharged (i.e. neutral) species is relatively inert, but does undergo condensation reactions (polymerisation) to form larger silica (polysilicic acid) species, especially at Si concentrations > 2-3 mM. Indeed, only in very dilute solutions, it is suggested, that the monomer will be found in its pure form, as often the dimer [(HO)3Si-O-Si(OH)3] is also present (but never > 2%), even in solutions greatly below 2 mM Si (22, 22). Above 2 mM Si, Si(OH)4 undergoes polymerization to form small oligomers (linear and cyclic trimers and tetramers or cyclic decamers) and, at concentration much above 2 mM, small colloidal species will also be present, which upon aggregation will eventually results in the formation of an amorphous precipitate, which at neutral pH (pH 6-7) is a gel (20, 22-24). Thus polymerisation of Si(OH)4 reduces its solubility and hence bioavailability.
Silicon also exists as ‘organo-silicon’ compounds or silicones, but these synthetic (man-made) compounds are rarely found in the diet and in nature in general. Silicon as Si(OH)4 is inert and until recently was suggested not to take part in any chemical or biological interactions, even though it is known to be actively taken up and transported by some primitive organisms and plants to form elaborate silica exoskeletons and biogenic silica, respectively, and the formation of which is assisted and controlled by proteins and polysaccharides (25-27). Recently Kinrade et al (28, 29) reported that Si(OH)4 interacts readily with alkyl diols of sugars to form five and six-coordinate Si complexes suggesting that interactions with bio-molecules is possible.
Human exposure to silicon
Human are exposed to numerous sources of silica/silicon including dust, pharmaceuticals, cosmetics and medical implants and devices (see Table 1), but the major and most important source of exposure for the majority of the population is the diet.
Human exposure to silicon
Dietary intake of Si is between 20-50 mg Si/day for most Western populations (30-33); ≥ 2-fold higher than typical intake of iron and zinc. Higher intakes (140-204 mg/day) have been reported in China and India where plant-based foods may form a more predominant part of the diet (34, 35). The intake within different age groups is not well documented (33). It appears to be similar for children (27 mg/day) and adults (29 mg/day) in Finland, although their major sources of intake are different (32). In children the major source is from cereals (68% of total dietary intake), whereas the major source in adult males is from beer ingestion (44%) (30, 32). Intake in females is lower than in males, which is due to the higher intake of beer in males (30, 32, 36). Beer is a highly bioavailable natural source of silicon (see below). Intake also decreases significantly with age in adults (0.1 mg for every additional year) (30, 33).
Silicon in drinking water is derived from the weathering of rocks and soil minerals and since different types of minerals weather at different rates, the concentration of Si in water is dependent upon the surrounding geology. In the UK for example, Si concentrations are low (0.2-2.5 mg/L) in the north and west of Britain (‘highland’ Britain), where the rocks are ‘old’ and well-weathered (37-39), and the water is naturally soft (37). In contrast, Si levels are much higher (2.8-14 mg/L) in the south and east of Britain (‘lowland’ Britain) from the weathering of ‘young rocks’; the water is naturally hard as it is high in dissolved solids and is also alkaline (37, 38, 40, 41). The Si concentration of European mineral waters is within a similar range (4-16 mg/L) to lowland drinking waters and their pH is typically around neutral, or slightly above. Recently, however, higher levels (30-40 mg/L) have been reported in Spritzer and Fiji mineral waters, from natural sources in Malaysia and Fiji respectively.
Drinking water and other fluids provides the most readily bioavailable source of Si in the diet, since silicon is principally present as Si(OH)4, and fluid ingestion can account for ≥ 20% of the total dietary intake of Si (42).
Silica in food is derived from natural sources, including adherent soil particles on surfaces of vegetables and from its addition as additives (see below). Natural levels of Si in food are much higher in plant derived foods than meat or dairy products (Table 2). Plants take up and accumulate Si from soil and soil solutions that becomes incorporated as a structural component conferring strength and rigidity to stalks, for example, in grasses and cereals and also in some plants such as horsetail (Equisetum arvensa) where Si is essential (41, 43). Such plants, termed ‘Si accumulators’, are generally the monocotyledons, which include the cereals, grasses (e.g. rice) and some herbaceous plants. These accumulate some 10-20 times more Si than the dicotyledons (e.g. legumes). Indeed, some monocotyledons, such as rice, actively take up and transport Si and silicon-related genes have been recently identified. Plants produce biogenic (phytolithic) silica which is often associated with the polysaccharide/carbohydrate components of the cell wall.
Food sources of silicon
High levels of Si are found in unrefined (‘whole’) grains such as barley, oats, rice bran and wheat bran (32, 44-46). Upto 50%, of the Si is present in the hulls and husks. Rice hulls, for example, contain 110 mg Si/g, and during manufacturing/industrial treatment these are removed which reduces Si in the refined foods. However, grain products such as breakfast cereals, flour and bread, biscuit, rice, pasta, cake and pastry etc., are still high dietary sources of Si (32, 44, 45) (see Table 2). Barley and hops are used in making beer and the mashing process breaks down their phytolythic silica, into soluble forms, so this beverage is high in Si (32, 44, 47, 42) (Table 3). In comparison wines and liquor/spirits have lower levels of Si (44) (Table 3). Sugar cane also actively takes up Si and refined and unrefined sugars are also high in Si (32, 44).
Silicon in beverages
High natural levels of Si are also present in some vegetables, namely beans (green, Kenyan, French), spinach and root vegetables and some herbs (32, 44). Fruits contain low levels of Si except for bananas and dried fruits and nuts. However, very little Si is digested in the gut and made available from bananas (<2%) (30).
Seafood is also high in Si with mussels having the highest levels (32). Animal and dairy products are low in Si (44) (Table 2), higher levels are found in offal and the less popular food-parts, such as the brain, heart, liver, lung and kidney (32). High levels of Si are also present in arteries, where it maintains the integrity of the lining of the aortic tissue (termed the tunica intima) (48).
As noted above, Si is also added to manufactured and processed foods as additives, increasing the Si content of these foods. Commonly, this is in the form of silicates such as calcium silicate, sodium aluminosilicate, magnesium hydrogen metasilicate (talc), magnesium trisilicate, calcium aluminium silicate, bentonite and kaolin (49, 50). These silicates are either extracted from their naturally occurring minerals or produced synthetically with tailored properties, namely a high surface area with hygroscopic properties (37). Silicates are thought to be inert and not absorbed in the gastrointestinal tract (37, 49), and, under UK regulations governing silicate additives, are added at less than 2% of the weight of the food (37). Silicates are used as anticaking agents for better flow and storage properties, as thickeners and stabilizers, as clarifying agents in beer and wine, as glazing, polishing and release agents in sweets, as dusting powder in chewing gum and as coating agents in rice (32, 50-52). Silicate additives are thought to be inert and not readily absorbed from the gastrointestinal tract.
Silicon is also available as a food supplement in tablet and solution forms. These show varying bioavailability (<1 to >50%) and most show negligible-low bioavailability. Biosil® or choline-stabilised orthosilicic acid (BioMineral NV, Destelbergen, Belgium), is a concentrated solution of orthosilicic acid (2% solution) in a choline (47%) and glycerol (33%) matrix. This is promoted as ‘biologically active silicon’ and studies in man have suggested that it is a readily bioavailable source of Si (53) and biologically active (54-56). Silica+® (Pharmafood, Belgium) is made from the dry extract of horsetail and contains 12 mg Si per tablet, of which 85% is suggested to be bioavailable. However, studies conducted in man have shown it to be significantly less bioavailable than Biosil® (57). Other supplements available over the counter include Silicea (silicon dioxide; Weleda, UK), Silicol (colloidal silica gel; Saguna, Germany), Silica (silicon dioxide; New Era, UK), Horsetail (horsetail extract; Good n'Natural, UK) and G5 (monomethyl trisilanol in solution; LLR-G5, Ireland).
Data from The Third National Health and Nutrition Examination Survey (NHANES III, 1984-1988) estimated the median intake of Si from supplements to be 2 mg/d (33). The main users of Si supplements were adults (19 y +).
Silicon is present in some pharmaceuticals. Silicic acid and sodium silicates were administered, orally or intramuscularly, as possible treatments for pulmonary tuberculosis and atherosclerosis in Germany in the early part of this century (37). Later, a silica found in bamboo, was also used as a possible treatment for asthma and tuberculosis (22). In modern pharmaceuticals Si is present mainly in antidiarrhoeals, antacids and in proprietary analgesics such as aspirin. In analgesics, silicates (magnesium silicate and magnesium trisilicates) are present as excipients, which are inert ingredients that hold the other ingredients together, or as desiccants, if the active ingredient is hygroscopic (37, 52, 58). The levels of silicates in these drugs, however, are not well documented and bioavailability is suggested to be negligible. Abusive use, however, can cause inflammation of the kidneys termed ‘analgesic nephropathy’, but it is unclear if this is related to the active ingredient or the excipient (37).
Silicon is also present in cosmetics and toiletries as a viscosity control agents and as an excipient (52, 59). Silica and silicates (e.g. hydrated silica and magnesium aluminium silicate) are present in toothpaste, creams, lipstick and coloured cosmetics (52, 60). Silicates are also likely to be present, as an excipient, in powdered cosmetics, while in talcum powder the main ingredient is magnesium hydrogen silicate. Phytolithic silica may be present, as a contaminant, in facial scrub and shampoos as often these are plant based, while silicones may be present in some hand and nail creams and in nail varnish.
Dermal absorption of silica/silicates is not well documented and it is thought to be negligible as these compounds are not lipid soluble. In contrast, silicones, in hand and nail creams, for example, are suggested to be readily absorbed.
The main route of entry of silicon in to the body is from the gastrointestinal tract. Indeed, urinary excretion of Si, a good marker of absorbed Si, correlates with dietary intake of Si (30, 61-63). However, the gastrointestinal absorption, metabolism and excretion of silicon is still poorly understood. There are only a few studies investigating the gastrointestinal bioavailability of Si from food, beverages or pharmaceuticals (30, 46, 47, 53, 57, 62-68).
The absorption of silicon, however, is strongly influenced by the form of silica ingested and this is related to the rate of production of soluble and absorbable species of silica in the gastrointestinal tract (30, 53, 64, 69). Biogenic/phytolithic silica is present in plant derived foods, and since these are largely insoluble forms of Si, they were thought to be relatively unavailable (32, 42, 53, 57, 70) until recently (30, 61, 62). However, a mean 41% of ingested Si is absorbed from solid foods and generally the Si content of the food is a marker of its uptake (30), suggesting phytolithic silica is broken down and absorbed. Absorption however requires their breakdown to much smaller soluble species such as orthosilicic acid (30, 61, 62).
Orthosilicic acid is the major silica species present in drinking water and other fluids/beverages, including beer, so these provide the most available source of silicon to man. It is readily absorbed and excreted; at least 50% of intake (30, 33, 42, 47, 62, 67).
Silicate additives are also present in foods and beverages. As with pharmaceuticals these are added as inert additives or excipients and are thought not to be absorbed. A number of studies, in man and animals, however, have reported marked increases in serum Si concentration or excretion of Si in urine (5-56%) following ingestion of silicates (zeolite A (an aluminosilicate), sodium aluminosilicate, or magnesium trisilicate) suggesting that these are partly solubilised to orthosilicic acid in the gastrointestinal tract and absorbed (63, 65, 68).
The mechanism of gastrointestinal uptake of silica is not known, but the silica species in the gastrointestinal tract influences its absorption (64), as noted above. Simple uncharged species such as orthosilicic acid will interact very weakly, or not at all, with the mucosally-bound mucus layer, thus will be readily mobile and will permeate easily across the mucus layer. Indeed, orthosilicic acid is readily and rapidly absorbed and excreted in urine, and uptake occurs predominately in the proximal small intestine (62, 64). This is likely to be by the paracellular pathway or small-pore transcellular pathway and is unlikely to be energy dependent. In contrast, charged polymeric silica species will either interact more strongly with the mucus layer, through cation bridges, and thus be less mobile, and/or will be too large to permeate through the mucus layer. Thus, polymeric/colloidal species of silica that are not readily broken down in the gastrointestinal tract will not be significantly absorbed and will be excreted in faeces (64). Other factors that may affect the absorption of silica are discussed below.
Kelsay et al. (46), demonstrated that a high fibre diet (fruit and vegetables) reduces the gastrointestinal uptake of minerals, including Si. Urinary excretion of Si was 35% compared with 58% from a low fibre diet; while faecal excretion was 97% and 67% respectively. Both diets, however, produced a negative Si balance, although, this was more negative with the high fibre diet (−14.6 mg/day compared with −3.5 mg/day).
Carlisle (68), found the silica supplementation to be more effective when rats were fed a low calcium diet, and Nielsen (15), suggested that low dietary calcium enhances the uptake of silica. These results, suggest that, either calcium and silica compete for the same absorption pathway, or that calcium forms insoluble, luminal calcium silicate that reduces silica bioavailability. Magnesium could similarly reduce the bioavailability of silica by forming insoluble silicates, since magnesium orthosilicate is considered the predominant form of silica in urine and possibly in plasma (71). Charnot and Pérès (72), suggested that silica controls the metabolism of calcium and magnesium.
Reduced gastric acid output, as occurs with ageing, is suggested to reduce the ability to metabolise dietary silica. Thus, the gastrointestinal absorption of Si may decrease with ageing (49). Gut permeability, however, increases with ageing, but this is unlikely to significantly enhance Si absorption which is already high. In addition Si intake also seems to decrease with ageing (30, 33). We recently, however, found no marked significant differences in the absorption of Si between young (<40 y old) and elderly (>60 y old) men and women (Sripanyakorn et al., unpublished data).
Charnot and Pérès (72) suggested that Si metabolism is controlled by steroid and thyroid hormones and that inadequate or reduced hormone or thyroid activity, as occurs with ageing, decreases silica absorption.
Silicon absorbed across the intestinal mucosa reaches the blood circulation, but it is not known whether any absorbed silica is retained by the mucosal cells, as occurs with some metal cations, although this is likely to be small. In blood, Si elutes with the non-protein bound fraction suggesting that silica does not associate with plasma proteins or that it forms a weak, easily disassociated interaction (73). Silica will be present as the neutral orthosilicic acid species which readily diffuses into erythrocytes and other tissues (74), but may also be present as silicates (73) such as magnesium orthosilicate (71).
The main route of excretion of absorbed silica is via the kidneys into urine. Indeed, renal function appears to be an important determinant of plasma Si concentration and with impaired renal function, as seen in uraemic patients for example, plasma Si concentration is significantly elevated compared with normal healthy subjects (3.8 ± 1.74 mg/l vs 0.16 ± 0.04 mg/l in healthy subjects) (40, 41, 70, 73, 75). Both plasma and urinary Si levels correlate with creatinine clearance (61, 62, 76, 77). Berlyne et al. (76) also found that urinary Si correlates with calcium and magnesium levels in urine, again, suggesting that Si may be present as calcium and magnesium silicates. High levels of Si are present in the liver following intracardiac injection of silica in rats, so absorbed silica could also be excreted in bile, and subsequently eliminated in faeces (74). However, this is unlikely to be significant as absorption of Si into serum (area under the curve) correlates significantly with its excretion in urine (61, 62). Furthermore, silicic acid is water soluble and bile is an excretory pathway of lipid soluble molecules. Finally, renal and not biliary or gall bladder stones occur with long-term excessive Si intake.
As silicon is not associated with plasma proteins, it is readily filtered by the renal glomerulus (73, 74), and is eliminated with little tubular re-absorption (71). Much of the absorbed silica is eliminated within 4-8 hr following its ingestion (30,47,61,62,64). Indeed, the renal clearance of Si, is high (82-96 ml/min) (61,62). However, absorbed silica is also likely to be taken up by tissues which may delay its total elimination from the body. Thus, studies in rats, with the 31Si isotope injected intracardially, have demonstrated that most of the Si is readily eliminated from plasma into urine (77% of ingested dose by 4 hr), but some is also distributed between a number of organs, including bone, skin, muscle and testes, but not the brain (78,79). Highest levels of 31Si were found in the kidneys, liver and lungs (78); these were six fold higher compared to the concentration in plasma collected at the same time period. The one study in man, using the 32Si radioisotope, showed that 36% of the oral dose was absorbed and eliminated in urine and although there was no evidence of retention, this was not a balance study as faecal excretion was not measured (65). The possibility, therefore, that some silicon was retained can not be excluded. The only documented balance study in man, investigating Si (46), found a negative Si balance, indicating the difficulty of undertaking such studies. Schwarz and Milne (16) suggested that in healthy, non-silicon deficient animals it is unlikely for Si to be accumulated. However, Si appears to be present in all tissues, including the brain (12-27 μg/g), and the total body burden is several grams, suggesting that at least some ingested Si is accumulated (68,70,73,75,80,81).
As noted above, some absorbed silicon is retained by the body as Si is present in all tissues. In addition fasting serum Si concentration is increased with Si supplementation in rats and humans and in the rat bone Si level correlates with dietary Si intake (Jugdaohsingh et al., unpublished data). Tissue levels however vary. In the rat highest levels are found in bone and other connective tissues such as, skin, nail, hair, trachea, tendons and aorta and very much less (10-20 fold less) in soft tissues (19; Jugdaohsingh et al., unpublished data). A similar tissue Si distribution is expected in humans, although this has not been investigated. Silicon is suggested to be integrally bound to connective tissues and their components and to have an important structural role (82) as silicon deprivation studies have reported detrimental effects on these tissues (16,17) as is also speculated to occur with normal ageing with the decline in tissue Si levels. Vice versa, silicon supplementation has been reported to have beneficial effects on these tissues especially bone where much of current work has concentrated (36,48,54-56, 83-86). The potential importance of Si to bone health is discussed below.
Circumstantial evidence for the essentiality of silicon in animals (see below) and the presence of silica in most cells and in primitive organisms such as bacteria, viruses and fungi suggests that it may have a desirable or even an essential biological role in all organisms (16, 22). For some primitive organisms, such as diatoms, other algae, and sponges silicon is essential for survival and replication and so is actively taken-up and transported from the low levels in their environment (natural waters) (22, 26, 87-90). Similarly, silicon is also essential in some plants, namely rice, oats, barley, maize, cucumber, tobacco and tomatoes, as silicon deficiency reduces their growth and vice versa, addition of silicon improves growth and guards against attack by pathogens (22, 91).
Silicon deprivation experiments in the 1970's, in growing chicks (17) and rats (16), suggested that silica may also be essential for normal growth and development in higher animals, including humans, primarily in the formation of bone and connective tissues. However, these results have not been subsequently replicated, at least to the same magnitude and thus the essentiality of Si in higher animals remains questionable. It is however the most ubiquitous of all trace elements (92) and is present in blood at concentrations similar to physiologically important elements such as iron, copper and zinc (93) and is excreted in urine in similar orders of magnitude to calcium, one of the most important cell signalling molecules and major bone mineral, prompting suggestions that Si may have an important if not essential (biological) role.
Silicon and bone health
There is perhaps no question that silicon appears to have a beneficial role in bone formation and in bone health. Since the findings of Carlisle (17) and Schwarz & Milne (16) of a potential role of silicon in bone and connective tissues, there have been numerous studies over the past 30 years investigating this potential role of dietary silicon. A brief summary of the accumulated evidence is given below; see also Tables Tables44--66.
Effect of dietary silicon on bone health; human studies
Effect of dietary silicon on bone health: tissue and osteoblast cell culture studies
Dietary silicon intake and BMD
As mentioned above, the main and most important source of exposure to silicon is from the diet and recently two cross-sectional epidemiological studies from our group have reported that dietary silicon intake is associated with higher bone mineral density (BMD). In the Framingham Offspring cohort we reported that higher intake of dietary silicon was significantly positively associated with BMD at the hip sites of men and pre-menopausal women, but not in post-menopausal women (36). This study was repeated using the APOSS (Aberdeen Prospective Osteoporosis Screening Study) cohort, a women only cohort, and it similarly showed that dietary silicon intake was significantly positively associated with BMD at the hip and spine of pre-menopausal women. We also showed a similar correlation in post-menopausal women but only in those currently on hormone replacement therapy (HRT) (94). A weaker (non-significant) correlation was found in past-HRT users and no correlation in those who had never taken HRT. These two studies suggest that higher silicon intake is associated with higher BMD, a marker of bone strength, and also, a potential interaction between silicon and oestrogen status.
No silicon deprivation studies have been conducted in humans, but, as described above, in laboratory animals Si deprivation resulted in skeletal abnormalities and defects. In chicks, legs and beaks were paler, thinner, more flexible and thus easily fractured (17). In rats, defects to the skull including the eye sockets was reported as was disturbances and impairment to incisor enamel pigmentation (16). More recent studies by Seaborn and Nielsen (95-100) (see Table 5) and others have not been able to reproduce these dramatic effects but have reported decreases in BMD, mineral content and collagen synthesis, and increases in collagen breakdown, thus confirming Si deprivation has a negative impact on bone.
Effect of dietary silicon on bone health; studies in laboratory animals
In osteoporotic subjects silicon supplementation with monomethyl trisilanol resulted in increased bone volume (83) and increases in femoral and lumbar spine BMD (84) (Table 4). In the latter study, silicon was shown to be more effective than Etidronate (a bisphosphonate) and sodium fluoride. A more recent study by Spector et al (56) in osteopenic and osteoporotic subjects, using choline-stabilised orthosilicic acid (ch-OSA), reported a trend for increased bone formation markers in serum, especially PINP (pro-collagen type I N-terminal propeptide) a marker type I collagen synthesis, with increasing dose of ch-OSA. A slight significant increase in femoral BMD was observed with the mid ch-OSA dose (6 mg Si/d).
Similarly in ovariectomised rats, supplementation with silicon or ch-OSA reduced bone resorption and bone loss and increased bone formation and bone mineral content or BMD (54,101,102) (Table 5). Results in chickens showed increased BMD and mechanical strength and in horses (mares) reduced bone-related injuries with silicon supplementation (103-108).
In vitro cell culture studies
Numerous cell and tissue culture studies have also been conducted to determine the mechanisms of silicon's effect on bone (Table 6) (109-119). Studies by Carlisle in the early 80's using chondrocytes and tibial epiphyses from chick embryos reported that silicon increased bone matrix synthesis (non-collagenous matrix polysaccharides and collagen) and that Si dose dependently increased prolyl hydroxylase activity, the enzyme involved in collagen synthesis (109-114). Recent studies with human osteoblast cells and zeolite A, an acid labile aluminosilicate, reported increased osteoblast proliferation, extracellular matrix synthesis, alkaline phosphatase (ALP) activity and osteocalcin synthesis (115-117). More recent studies using orthosilicic acid have also reported increases in type I collagen synthesis and cellular differentiation (118) and in addition increases in the mRNA of these proteins, suggesting potential involvement of Si in gene transcription (118, 119).
Thus tissue and cell culture studies have also suggested that silicon is involved in bone formation by increasing matrix synthesis and differentiation of osteoblast cells. Effects of silicon on bone resorption and osteoclast cell activity has not been well studied. Schutze et al (120) reported that zeolite A, but not separately its individual components (Si and Al), inhibited osteoclast activity (pit number and cathepsin B enzyme activity).
Bone implants and cements
Additional evidence of the involvement of silicon in bone is provided by in vivo and in vitro studies with silicon-containing implants and ceramics such as Si-substituted hydroxyapatites and Bioglass™. Such materials have been shown to bond much better to bone than their non-silicon-containing counterparts due to the spontaneous formation of a biologically active apatite-like layer on their surface (121). Silica on these materials is said to undergo partial dissolution to form an amorphous Si layer and the dissolved Si has been implicated for the in vivo efficacy of these implants as it has been shown to be involved in gene upregulation, osteoblast proliferation and differentiation, type I collagen synthesis and apatite formation. One recent paper reported more ordered collagen fibrils and mature bone formation with Si-substituted hydroxyapatite (122).
Mechanisms are not clear but it has been suggested, based on the evidence above, that silicon is involved in bone formation through the synthesis and/or stabilization of collagen. Collagen has an important structural role in animals contributing to the architecture and resilience of bone and connective tissue. It is the most abundant protein in bone matrix conferring flexibility and, with elastin, is a major component of connective tissues which is found in skin, cartilage, tendons and arteries, for example. High levels of Si were found to be strongly bound to connective tissues and its components, namely glycoaminoglycans, polysaccharides and mucopolysaccharides (82) implying an integral role for Si. Quite how Si may be involved in collagen synthesis and or its stabilisation is still not established. It has been implicated in gene transcription of type I collagen gene, a cofactor for prolyl hydroxylase the enzyme involved in collagen synthesis, in the utilisation (i.e. gastrointestinal uptake and metabolism) of essential elements that are required for bone and collagen synthesis, such as copper (123), calcium and magnesium and in the scavenging and detoxifying toxic aluminium. Silicon has also been found at the mineralisation front of growing bone (18) suggesting also an involvement in early calcification/mineralization of bone matrix.
The toxicity associated with the inhalation of particulate crystalline silica and silicates, such as quartz, and man-made fibrous silicates (e.g. asbestos) has been extensively studied as long-term exposure causes scarring of the lung, that may lead to reduced lung capacity, lung cancer, and the increased risk of tuberculosis and heart complications. These crystalline silicates are phagocytosed by macrophages that then release cytokines that attract and stimulate other immune cells including fibroblasts, which are responsible for the excessive production of collagen (fibrotic tissue) that is characteristic of silicosis (22).
Oral ingestion of crystalline or amorphous silica/silicates in the diet may also cause toxicity. The inflorescences of Steria italica (millet) promotes oesophageal cancer, while the seeds of the Phalaris family of grass (e.g. canary grass, Phalaris canariensis) promote skin tumours (42, 124, 125). Finely ground silicate minerals from eroded acid granite in drinking water has been linked to ‘Endemic or Balkan Nephropathy’, which is inflammation of the kidneys (interstitial nephritis), found in confine parts of the Balkans (Yugoslavia, Bulgaria and Romania) (63). Long-term use of high doses of silicate containing drugs, such as analgesics and antacids (magnesium trisilicates) could cause damage to the renal kidney tubules and lead to chronic interstitial nephritis (63). As noted previously, the high levels of silica in these drugs can lead to the formation of renal stones/calculi which are responsible for kidney damage. Formation of silica stones/calculi (urolithiasis) is also a common problem in cattle and sheep who ingest large quantities of silica daily, since grass consists of 2% silica by weight, and drink very little water (22, 37). However, ingestion of amorphous silica is not associated with toxicity in the rat (33).
Chronic haemodialysis patients are potentially at risk from the accumulation of silicon (73, 75, 81). The high silicon levels of these patients have been associated with nephropathy, neuropathy, chest disease, bone diseases and liver disease (73, 75, 81).
However for much of the population with normal renal function the normal intake of dietary silicon from foods and water has not been associated with any known toxicity (33). There are no known symptoms or diseases of silicon excess or deficiency in humans.
Silicon is a major (naturally occurring) trace element in the human body derived predominantly from the diet. The intake and metabolism of which has only recently been determined. We ingest between 20-50 mg/day in the Western world, greater than two-fold our intake of iron and zinc and it is excreted in similar magnitude to calcium, suggesting more than a role as a ‘ubiquitous contaminant’. Indeed accumulated evidence over the last 30 years suggests an important role in bone formation and bone and connective tissue health. Mechanisms are unclear but evidence exists of its involvement in collagen synthesis and/or its stabilization and in matrix mineralization. However much still remains to be understood on this potential biological role of silicon. Whether silicon has an essential role in man, as it has in lower animals also remains to be established. Establishment of a biological role for this element will have important implication for nutrition as a preventative measure, or Si containing supplements as a treatment, for bone and connective tissue diseases.
The Frances and Augustus Newman Foundation and the charitable foundation of the Institute of Brewing and Distilling for their support.
1. Osteoporosis: clinical guidelines for prevention and treatment. Royal College of Physicians of London; 1999.
2. Sambrook P, Cooper C. Osteoporosis (Seminar) The Lancet. 2006;367:2010–2018. [PubMed]
3. Ralston SH. Osteoporosis. British Medical Journal. 1997;315:469–315. [PMC free article] [PubMed]
4. Rutherford OM. Bone density and physical activity. Proceedings of the Nutrition Society. 1997;56:967–975. [PubMed]
5. Eisman JA. Genetics, calcium intake and osteoporosis. Proceedings of the Nutrition Society. 1997;57:187–193. [PubMed]
6. Saltman PD, Strause LG. The role of trace minerals in osteoporosis. Journal of the American College of Nutrition. 1993;12(4):384–389. [PubMed]
7. Reid DM, New SA. Nutritional influences on bone mass. Proceedings of the Nutrition Society. 1997;56:977–987. [PubMed]
8. Dawson-Hughes B. (Editorial) Osteoporosis treatment and calcium requirement. American Journal of Clinical Nutrition. 1998;67:5–6. [PubMed]
9. Chapuy MC, Meunier PJ. (Review) Prevention and treatment of osteoporosis. Aging. 1995;7(4):164–173. [PubMed]
10. Nieves JW, Komar L, Cosman F, Lindsay R. (Review Article) Calcium potentiates the effects of estrogen and calcitonin on bone mass: review and analysis. Journal of Clinical Nutrition. 1998;67:18–24. [PubMed]
11. Francis RM, Anderson FH, Patel S, Sahota O, Van Staa TP. Calcium and vitamin D in the prevention of osteoporotic fractures. (Review) Q J Med. 2006;99:355–363. [PubMed]
12. Robins SP, New SA. Markers of bone turnover in relation to bone health (symposium on ‘Nutritional aspects of bone’) Proceedings of the Nutrition Society. 1997;56:903–914. [PubMed]
13. Relea P, Revilla M, Ripoll E, Arribas I. Zinc, biochemical markers of nutrition, and type 1 osteoporosis. Age and ageing. 1995;24:303–307. [PubMed]
14. Marie PJ, Hott M. Short-term effects of fluoride and strontium on bone formation and resorption in the mouse. Metabolism: Clinical and Experimental. 1986;35(6):547–551. [PubMed]
15. Nielsen FH. Nutritional requirements for boron, silicon, vanadium, nickel, and arsenic: current knowledge and speculation. The FASEB Journal. 1991;5:2661–2667. [PubMed]
16. Schwarz K, Milne DB. Growth promoting effects of silicon in rats. Nature. 1972;239:333–334. [PubMed]
17. Carlisle EM. Silicon: an essential element for the chick. Science. 1972;178:619. [PubMed]
18. Carlisle EM. Silicon as an essential trace element in animal nutrition. In: Evered D, O'Connor M, editors. Silicon Biochemistry Ciba Foundation Symposium 121. John Wiley and Sons Ltd.; Chichester: 1986. pp. 123–139. [PubMed]
19. Exley C. Silicon in life: a bioinorganic solution to bioorganic essentiality. Journal of Inorganic Biochemistry. 1998;69:139–144.
20. Sjöberg S. Silica in aqueous environments. Journal of Non-Crystalline Solids. 1996;196:51–57.
21. Klein C. Rocks, minerals, and a dusty world. In: Guthrie GD Jr, Mossman BT, editors. Reviews in Mineralogy Vol. 28. Health effects of mineral dust, Mineralogical Society of America. Bookcrafters Inc.; Washington DC: 1993. p. 8.
22. Iler RK. Solubility, polymerisation, colloid and surface properties, and biochemistry. John Wiley & Sons; New York: 1979. The chemistry of silica.
23. Glasser LSD, Lachowski EE. Silicate species in solution. Part 1. Experimental observations. Journal of the Chemical Society, Dalton Transaction. 1980:393–398.
24. Glasser LSD. Sodium silicates. Chemistry in Britain. 1982:36–40.
25. Kröger N, Deutzmann R, Sumper M. Polycationic peptides from diatom biosilica that direct silica nanosphere formation. Science. 1999;286:1129–1132. [PubMed]
26. Cha JN, Shimizu K, Zhou Y, Christiansen SC, Chmelka BF, Stucky GD, Morse DE. Silicatein filaments and subunits from a marine sponge direct the polymerization of silica and silicones in vitro. Proceedings of the National Academy of Sciences USA. 1999;96:361–365. [PMC free article] [PubMed]
27. Perry CC, Keeling-Tucker T. Biosilification: the role of the organic matrix in structure control. J Biol Inorg Chem. 2000;5:537–550. [PubMed]
28. Kinrade SD, Balec RJ, Schach AS, et al. The structure of aqueous pentaoxo silicon complexes with cis-1,2-dihydroxycyclopentane and furanoidic vicinal cis-diols. Dalton Transactions. 2004;21(20):3241–3. [PubMed]
29. Kinrade SD, Del Nin JW, Schach AS. Stable five- and six-coordinated silicate anions in aqueous solution. Science. 1999;285:1542–1545. [PubMed]
30. Jugdaohsingh R, Anderson SH, Tucker KL, Elliott H, Kiel DP, Thompson RPH, Powell JJ. Dietary silicon intake and absorption. American Journal of Clinical Nutrition. 2002;75:887–893. [PubMed]
31. McNaughton SA, Bolton-Smith C, Mishra GD, Jugdaohsingh R, Powell JJ. Dietary silicon intake in post-menopausal women. Br J Nutr. 2005;94(5):813–7. [PubMed]
32. Pennington JAT. Silicon in foods and diets. Food Additives and Contaminants. 1991;8:97–118. [PubMed]
33. National Academy of sciences. National Academy Press; Washington DC, USA: 2001. Dietary reference intakes for vitamin A, vitamin K, boron, chromium, copper, iodine, iron, manganese, nickel, silicon, vanadium and zinc. [PubMed]
34. Chen F, Cole P, Wen L, et al. Estimates of trace element intakes in Chinese farmers. Community and International Nutrition. 1994;124:196–201. [PubMed]
35. Anasuya A, Bapurao S, Paranjape PK. Fluoride and silicon intake in normal and endemic fluorotic areas. Journal of Trace Elements in Medicine and Biology. 1996;10:149–155. [PubMed]
36. Jugdaohsingh R, Tucker KL, Qiao N, Cupples LA, Kiel DP, Powell JJ. Silicon intake is a major dietary determinant of bone mineral density in men and pre-menopausal women of the Framingham Offspring Cohort. Journal Bone and Mineral Research. 2004;19:297–307. [PubMed]
37. Dobbie JW, Smith MJB. Silicate nephrotoxicity in the experimental animal: the missing factor in analgesic nephropathy. Scottish Medical Journal. 1982;27:10–16. [PubMed]
38. Birchall JD, Chappell JS. Aluminium, water chemistry, and Alzheimer's disease. The Lancet. 1989:953. [PubMed]
39. Taylor GA, Newens AJ, Edwardson JA, Kay DWK, Forster DP. Alzheimer's disease and the relationship between silicon and aluminium in water supplies in northen England. Journal of Epidemiology and Community Health. 1995;49:323–328. [PMC free article] [PubMed]
40. Parry R, Plowman D, Delves HT, Roberts NB, Birchall JD, Bellia JP, Davenport A, Ahmad R, Fahal I, Altman P. Silicon and aluminium interactions in haemodialysis patients. Nephrology Dialysis Transplantation. 1998;13:1759–1762. [PubMed]
41. Roberts NB, Williams P. Silicon measurement in serum and urine by direct current plasma emission spectrometry. Clinical Chemistry. 1990;36:1460–1465. [PubMed]
42. Bellia JP, Birchall JD, Roberts NB. Beer: a dietary source of silicon. The Lancet. 1994;343:235. [PubMed]
43. Sangster AG, Hodson MJ. Silica in higher plants. In: Evered D, O'Connor M, editors. Silicon Biochemistry, Ciba Foundation Symposium 121. John Wiley and Sons Ltd.; Chichester: 1986. pp. 90–111.
44. Powell JJ, McNaughton SA, Jugdaohsingh R, Anderson S, Dear J, Khot F, Mowatt L, Gleason KL, Sykes M, Thompson RPH, Bolton-Smith C, Hodson MJ. A provisional database for the silicon content of foods in the United Kingdom. British Journal of Nutrition. 2005;94:804–812. [PubMed]
45. Schwarz K. Silicon, fibre, and atherosclerosis. The Lancet. 1977:454–457. [PubMed]
46. Kelsay JL, Behall KM, Prather ES. Effect of fiber from fruits and vegetables on metabolic responses of human subjects. II. Calcium, magnesium, iron, and silicon balances. The American Journal of Clinical Nutrition. 1979;32:1876–1880. [PubMed]
47. Sripanyakorn S, Jugdaohsingh R, Elliott H, Walker C, Mehta P, Shoukru S, Thompson RP, Powell JJ. The silicon content of beer and its bioavailability in healthy volunteers. British Journal of Nutrition. 2004;91:403–409. [PubMed]
48. Loeper J, Goy-Loeper J, Rozensztajn L, Fragny M. The antiatheromatous action of silicon. Atherosclerosis. 1979;33:397–408. [PubMed]
49. Toxicological evaluation of some food additives including anticaking agents, antimicrobials, antioxidants, emulsifiers and thickening agents. World Health Organisation; Geneva: 1974. Anonymous. Anticaking agents. Silicon dioxide and certain silicates; pp. 21–30. [PubMed]
50. Hanssen M, Marsden J. E for Additives. HarperCollins Publishers; Glasgow: 1987.
51. Oelmüller R, Grinschgl B. Better storage and improved flow of powdered food products. Food Technology International. :13–14.
52. Villota R, Hawkes JG. Food applications and the toxicological and nutritional implications of amorphous silicon dioxide. Critical Reviews in Food Science and Nutrition. 1986;23:289–321. [PubMed]
53. Calomme MR, Cos P, D'Haese PC, Vingerhoets R, Lamberts LV, De Broe ME, Van Hoorebeke C, Vanden Berghe DA. Absorption of silicon in healthy subjects. In: Collery P, Brätter P, Negretti de Brätter V, Khassanova L, Etienne J-C, editors. Metal Ions in Biology and Medicine. Vol. 5. John Libbey Eurotext; Paris: 1998. pp. 228–232.
54. Calomme M, Geusens P, Demeester N, Behets GJ, D'Haese P, Sindambiwe JB, Van Hoof V, Vanden Berghe D. Partial prevention of long-term femoral bone loss in aged ovariectomized rats supplemented with choline-stabilized orthosilicic acid. Calcif Tissue Int. 2006;78(4):227–32. [PubMed]
55. Barel A, Calomme M, Timchenko A, De Paepe K, Demeester N, Rogiers V, Clarys P, Vanden Berghe D. Effect of oral intake of choline-stabilized orthosilicic acid on skin, nails and hair in women with photodamaged skin. Arch Dermatol Res. 2005;297(4):147–53. [PubMed]
56. Spector TD, Calomme MR, Anderson S, Swaminathan R, Jugdaohsingh R, Vanden-Berge DA, Powell JJ. Effect of bone turnover and BMD of low dose oral silicon as an adjunct to calcium/vitamin D3 in a randomized placebo-controlled trial. Journal of Bone Mineral Research. 2005;20:S172.
57. Van Dyck K, Van Cauwenbergh R, Robberecht H, Deelstra H. Bioavailability of silicon from food and food supplements. Fresenius Journal of Analytical Chemistry. 1999;363:541–544.
58. Gore AY, Banker GS. Surface chemistry of colloidal silica and a possible application to stabilize aspirin in solid matrixes. Journal of Pharmaceutical Sciences. 1979;68:197–202. [PubMed]
59. Bradley SG, Munson AE, McCay JA, Brown RD, Musgrove DL, Wilson S, Stern M, Luster MI, White KL., Jr. Subchronic 10 day immunotoxicity of polydimethylsiloxane (silicone) fluid, gel and elastomer and polyurethane disks in female B6C3F1 mice. Drug and Chemical Toxicology. 1994;17:175–220. [PubMed]
60. Ligthelm AJ, Butow KW, Weber A. Silica granuloma of a lymph node. International Journal of Oral and Maxillofacial Surgery. 1988;17:352–353. [PubMed]
61. Jugdaohsingh R. Soluble silica and aluminium bioavailability. University of London; 1999. PhD thesis.
62. Reffitt DM, Jugdoahsingh R, Thompson RPH, Powell JJ. Silicic acid: its gastrointestinal uptake and urinary excretion in man and effects on aluminium excretion. Journal of Inorganic Biochemistry. 1999;76:141–147. [PubMed]
63. Dobbie JW, Smith MJB. Urinary and serum silicon in normal and uraemic individuals. In: Evered D, O'Connor M, editors. Silicon Biochemistry, Ciba Foundation Symposium 121. John Wiley and Sons Ltd.; Chichester: 1986. pp. 194–208.
64. Jugdaohsingh R, Reffitt DM, Oldham C, Day JP, Fifield LK, Thompson RP, Powell JJ. Oligomeric but not monomeric silica prevents aluminum absorption in humans. Am J Clin Nutr. 2000;71(4):944–9. [PubMed]
65. Cefali EA, Nolan JC, McConnell WR, Walters DL. Pharmacokinetic study of Zeolite A, sodium aluminosilicate, magnesium silicate and aluminum hydroxide in dogs. Pharmaceutical Research. 1995;12:270–274. [PubMed]
66. Popplewell JF, King SJ, Day JP, Ackrill P, Fifield LK, Cresswell RG, Tada di- ML, Lui K. Kinetics of uptake and elimination of silicic acid by a human subject: A novel application of 32Si and accelerator mass spectrometry. Journal of Inorganic Biochemistry. 1998;69:177–180. [PubMed]
67. Bellia JP, Birchall JD, Roberts NB. The role of silicic acid in the renal excretion of aluminium. Annals of Clinical and Laboratory Science. 1996;26:227–233. [PubMed]
68. Carlisle EM. Silicon overdose in man. Nutrition Reviews. 1982;40:208–209. [PubMed]
69. Nielsen FH. Possible future implication of nickel, arsenic, silicon, vanadium, and other ultratrace elements in human nutrition. In: Prasad AS, editor. Current Topics in Nutrition and Disease, Vol. 6, Clinical, Biochemical, and Nutritional aspects of Trace Elements. Alan R. Liss, Inc.; New York: 1982. pp. 380–397.
70. Sanz-Medel A, Fairman B, Wróbel K. Aluminium and silicon speciation in biological materials of clinical relevance. In: Caroli S, editor. Element Speciation in Bioinorganic Chemistry, Chemical Analysis Series. Vol. 135. John Wiley and Sons Ltd.; Chichester: 1996. pp. 223–254.
71. Berlyne GM, Adler AJ, Ferran N, Bennett S, Holt J. Silicon metabolism I: some aspects of renal silicon handling in normal man. Nephron. 1986;43:5–9. [PubMed]
72. Charnot Y, Pérès G. Modification de l'absorption et du métabolisme tissulaire du silicium en relation âvec l'age, le sehe et diverses glandes endocrines. Lyon Medicine. 1971;13:85. [PubMed]
73. D'Haese PC, Shaheen FA, Huraid SO, Djukanovic L, Polenakovic MH, Spasovski G, Shikole A, Schurgers ML, Daneels RF, Lamberts LV, Van Landeghem GF, De Broe ME. Increased silicon levels in dialysis patients due to high silicon content in the drinking water, inadequate water treatment procedures, and concentrate contamination: a multicentre study. Nephrology Dialysis Transplantation. 1995;10:1838–1844. [PubMed]
74. Adler AJ, Berlyne GM. Silicon metabolism II. Renal handling in chronic renal failure patients. Nephron. 1986;44:36–39. [PubMed]
75. Hosokawa S, Yoshida O. Silicon transfer during haemodialysis. International Urology and Nephrology. 1990;22:373–378. [PubMed]
76. Berlyne G, Dudek E, Adler AJ, Rubin RE, Seidmen M. Silicon metabolism: the basic facts in renal failure. Kidney International. 1985;28:S175–S177. [PubMed]
77. Gitelman HJ, Alderman F, Perry SJ. Renal handling of silicon in normals and patients with renal insufficiency. Kidney International. 1992;42:957–959. [PubMed]
78. Adler AJ, Etzion Z, Berlyne GM. Uptake, distribution, and excretion of 31silicon in normal rats. American Journal of Physiology. 1986;251:E670–E673. [PubMed]
79. Berlyne GM, Shainkin-Kestenbaum R, Yagil R, Alfassi Z, Kushelevsky A, Etzion Z. Distribution of 31silicon-labeled silicic acid in the rat. Biological Trace Element Research. 1986;10:159–162.
80. Le Vier RR. Distribution of silicon in the adult rat and rhesus monkey. Bioinorganic Chemistry. 1975;4:109–115. [PubMed]
81. Hosokawa S, Oyamaguchi A, Yoshida O. Trace elements and complications in patients undergoing chronic hemodialysis. Nephron. 1990;55:375–379. [PubMed]
82. Schwarz K. A bound form of silicon in glycosaminoglycans and polyuronides. Proceedings of the National Academy of Sciences USA. 1973;70:1608–1612. [PMC free article] [PubMed]
83. Schiano A, Eisinger F, Detolle P, Laponche AM, Brisou B, Eisinger J. Silicium, tissu osseux et immunité Revue du Rhumatisme. 1979;46:483–486. [PubMed]
84. Eisinger J, Clairet D. Effects of silicon, fluoride, etidronate and magnesium on bone mineral density: a retrospective study. Magnesium Research. 1993;6:247–249. [PubMed]
85. Lassus A. Colloidal silicic acid for oral and topical treatment of aged skin, fragile hair and brittle nails in females. Journal of International Medical Research. 1993;21(4):209–215. [PubMed]
86. Lassus A. Colloidal silicic acid for the treatment of psoriatic skin lesions, arthropathy and onychopathy. A pilot study. Journal of International Medical Research. 1997;25(4):206–209. [PubMed]
87. Hildebrand M, Volcani BE, Gassman W, Schroeder JI. A gene family of silicon transporters. Nature. 1997;385:688–689. [PubMed]
88. Uriz MJ, Turon X, Becerro MA. Silica deposition in Demosponges: spiculogenesis in Crambe crambe. Cell and Tissue Research. 2000;301(2):299–309. [PubMed]
89. Sullivan CW. Silicification by diatoms. In: Evered D, O'Connor M, editors. Silicon Biochemistry, Ciba Foundation Symposium 121. John Wiley and Sons Ltd.; Chichester: 1986. pp. 59–86. 1986.
90. Werner D. Silicate metabolism. In: Werner D, editor. The Biology of Diatoms. Blackwell Scientific Publications; Oxford: 1977. pp. 140–141.
91. Epstein E. Silicon. Annu. Rev. Plant Physiol. Plant Mol. Biol. 1999;50:641–664. [PubMed]
92. Dobbie JW, Smith MJB. Silicon: its role in medicine and biology. Scottish Medical Journal. 1982;27:1–2. [PubMed]
93. Dobbie JW, Smith MJB. The silicon content of body fluids. Scottish Medical Journal. 1982;27:17–19. [PubMed]
94. Macdonald HM, Hardcastle AE, Jugdaohsingh R, Reid DM, Powell JJ. Dietary silicon intake is associated with bone mineral density in premenopasual women and postmenopausal women taking HRT. Journal of Bone Mineral Research. 2005;20:S393.
95. Seaborn CD, Nielsen FH. Dietary silicon affects acid and alkaline phosphatase and 45Ca uptake in bone of rats. The Journal of Trace Elements in Experimental Medicine. 1994;7:1–11.
96. Seaborn CD, Nielsen FH. Effect of germanium and silicon on bone mineralisation. Biological Trace Element Research. 1994;42:151–164. [PubMed]
97. Seaborn CD, Nielsen FH. Effects of germanium and silicon on bone mineralisation. Biological Trace Element Research. 1994;42:151–163. [PubMed]
98. Seaborn CD, Nielsen FH. Silicon deprivation decreases collagen formation in wounds and bone, and ornithine transaminase enzyme activity in liver. Biological Trace Element Research. 2002;89:251–261. [PubMed]
99. Seaborn CD, Nielsen FH. Dietary silicon and arginine affect mineral element composition of rat femur and vertebra. Biological Trace Element Research. 2002;89:239–250. [PubMed]
100. Nielsen FH, Poellot R. Dietary silicon affects bone turnover differently in ovariectomised and sham-operated growing rats. The Journal of Trace Elements in Experimental Medicine. 2004;17(3):137–149.
101. Hott M, de Pollak C, Modrowski D, Marie PJ. Short-term effects of organic silicon on trabecular bone in mature overietomized rats. Caclified Tissue International. 1993;53:174–179. [PubMed]
102. Rico H, Gallego-Largo JL, Hernández ER, Villa LF, Sanchez-Atrio A, Seco C, Gérvas JJ. Effect of silicon supplement on osteopenia induced by ovariectomy in rats. Calcified Tissue International. 2000;66:53–55. [PubMed]
103. Merkley JW, Miller ER. The effects of sodium-fluoride and sodium-silicate on growth and bone strength of broilers. Poultry Science. 1983;62:798–804. [PubMed]
104. Roland DA. Further studies of effects of sodium aluminosilicate on egg-shell quality. Poultry Science. 1988;67:577–584. [PubMed]
105. Calomme MR, Wijnen P, Sindambiwe JB, Cos P, Mertens J, Geusens P, Vanden Berghe DA. Effect of choline stabilised orthosilicic acid on bone density in chicks. Calcif Tissue Int. 2002;70:292.
106. Nielsen BD, Potter GD, Morris EL, Odom TW, Senor DM, Reynolds JA, Smith WB, Martin MT, Bird EH. Training distance to failure in young racing quarter horses fed sodium zeolite A. J. Equine Vet Sci. 1993;13:562–567.
107. Lang KJ, Nielsen BD, Waite KL, Hill GM, Orth MW. Supplemental silicon increases plasma and milk silicon concentrations in horses. J Animal Sci. 2001;79:2627–2633. [PubMed]
108. Calomme MR, Vanden Berghe DA. Supplementation of calves with stabilised orthosilicic acid. Biological Trace Element Research. 1997;56:153–164. [PubMed]
109. Carlisle EM, Alpenfels WF. A requirement for silicon for bone growth in culture. Federation Proceedings. 1978;37:1123.
110. Carlisle EM, Alpenfels WF. A silicon requirement for normal growth for cartilage in culture. Federation Proceedings. 1980:39–787.
111. Carlisle EM, Garvey DL. The effect of silicon on formation of extracellular matrix components by chondrocytes in culture. Federation Proceedings. 1982;41:461.
112. Carlisle EM, Suchil C. Silicon and ascorbate interaction in cartilage formation in culture. Federation Proceedings. 1983;42:398.
113. Carlisle EM, Alpenfels WF. The role of silicon in proline synthesis. Federation Proceedings. 1984;43:680.
114. Carlisle EM, Berger JW, Alpenfels WF. A silicon requirement for prolyl hydroxylase activity. Federation Proceedings. 1981;40:886.
115. Brady MC, Dobson PRM, Thavarajah M, Kanis JA. Zeolite A stimulates proliferation and protein synthesis in human osteoblast –like cells and osteosarcoma cell line MG-63. Journal of Bone and Mineral Research. 1991:S139.
116. Mills BG, Frausto A, Wiegand KE. Mitogenis effect of N-0974 on human bone cells. Journal of Dental Research. 1989:68. Abstract No. 1363.
117. Keeting PE, Oursler MJ, Wiegand KE, Bonde SK, Spelsberg TC, Riggs BL. Zeolite A increases proliferation, differentiation, and transforming growth factor b production in normal adult human osteoblast-like cells in vitro. J Bone Miner Res. 1992;7:1281–1289. [PubMed]
118. Reffitt DM, Ogston N, Jugdaohsingh R, et al. Orthosilicic acid stimulates collagen type I synthesis and osteoblastic differentiation in human osteoblast-like cells in vitro. Bone. 2003;32:127–135. [PubMed]
119. Arumugam MQ, Ireland DC, Brooks RA, Rushton N, Bonfield W. The effect orthosilicic acid on collagen type I, alkaline phosphatase and osteocalcin mRNA expression in human bone-derived osteoblasts in vitro. Bioceramics 18, Pts 1 &2 Key Engineering Materials. 2006;309-311:121–124.
120. Schutze N, Oursler MJ, Nolan J, Riggs BL, Spelberg TC. Zeolite A inhibits osteoclast-mediated bone resorption in vitro. J Cell Biochem. 1995;58:39–46. [PubMed]
121. Hench LL, Xynos ID, Polak JM. Bioactive glasses for in situ tissue regeneration. Journal of Biomaterials Science Polymer Edition. 2004;15(4):543–62. [PubMed]
122. Porter AE, Patel N, Skepper JN, Best SM, Bonfield W. Effect of sintered silicate-substituted hydroxyapatite on remodelling processes at the bone-implant interface. Biomaterials. 2004;25:3303–3314. [PubMed]
123. Birchall JD. The essentiality of silicon in biology. Chemical Society Reviews. 1995:351–357.
124. O'Neill C, Jordan P, Bhatt T, Newman R. Silica and oesophageal cancer. In: Evered D, O'Connor M, editors. Silicon Biochemistry, Ciba Foundation Symposium 121. John Wiley and Sons Ltd.; Chichester: 1986. pp. 214–225.
125. Newman R. Association of biogenic silica with disease. Nutrition and Cancer. 1986;8:217–221. [PubMed]
What is vanadium? What do we need it?
Vanadium is a trace element that is absorbed in the intestines and stored in the liver and bones. It helps to normalize blood sugar imbalances and increases the metabolism and conversion of glucose into lipids. Although it has yet to be recognized as an essential nutrient for humans, vanadium is believed to play an important role in the formation of bones and teeth.
Some experts believe vanadium reduces blood pressure and aids in the increase of muscle tissue. A form of vanadium, vanadyl sulfate, may improve the utilization of glucose in individuals with type-II diabetes. However, other studies have refuted this research; furthermore, many studies have shown that it does not help people with type-I diabetes.
How much vanadium should I take?
At present, there are no recommended daily allowances or requirements for vanadium. Some experts believe 10 micrograms is an adequate daily amount; the average Western diet provides 15-30 micrograms of vanadium per day.
What are some good sources of vanadium? What forms are available?
While there is no one significant source of vanadium, it can be found in very small amounts in a variety of foods, including cereals, mushrooms, parsley, corn, soy products, gelatin, and some forms of seafood. Vanadium supplements are also available, either in powder or capsule form.
What can happen if I don't get enough vanadium? What can happen if I take too much? Are there any side-effects I should be aware of?
Animal studies have shown that vanadium deficiency can have a number of adverse effects, including impaired growth, bone deformities and infertility; these results have not been duplicated in human subjects. Anecdotal reports of health care and government workers exposed to large amounts of vanadium have demonstrated a possible link to manic depression and other mental disorders, but the meaning of these conditions has yet to be effectively determined.
Chromium and vanadium may interfere with the absorption of one another. In addition, tobacco smoke may decrease the absorption of vanadium. As of this writing, there are no known drug interactions with vanadium.
Aharon Y, Mevorach M, Shamoon H. Vanadyl sulfate does not enhance insulin action in patients with type 1 diabetes. Diabetes Care 1998;21:2194.
Boden G, Chen X, Ruiz J, et al. Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non-insulin-dependent diabetes mellitus. Metab Clin Exp 1996;45(9):1130—5.
Chakraborty A, Ghosh R, Roy K, et al. Vanadium: A modifier of drug metabolizing enzyme patterns and its critical role in cellular proliferation in transplantable murine lymphoma. Oncology 1995;52:310—4.
Domingo JL, Schuhmacher M, Agramunt MC, Muller L, Neugebauer F. Levels of metals and organic substances in blood and urine of workers at a new hazardous waste incinerator. Int Arch Occup Environ Health 2001 May;74(4):263-9.
Wang J, Yuen VG, McNeill JH. Effect of vanadium on insulin sensitivity and appetite. Metabolism 2001 Jun;50(6):667-73.