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Vitamin A and Bone Health: The Balancing Act
Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health, vol. 16, no. 4, 414e419, 2013 Ó Copyright 2013 by The International Society for Clinical Densitometry 1094-6950/16:414e419/$36.00 http://dx.doi.org/10.1016/j.jocd.2013.08.016
Special Section on Bone and Nutrition
Vitamin A and Bone Health: The Balancing Act Sherry A. Tanumihardjo* Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA
Abstract The role of vitamin A status as it relates to bone health is historical yet controversial. Population-based studies have linked high dietary intake of preformed vitamin A, which is obtained from animal-source foods, fortified foods, and some supplements, to greater risk of osteoporosis and hip fracture. In contrast, carotenoids, some of which are vitamin A precursors from plants, are associated with improved bone health. Carotenoids may be a biomarker that reflects a generally healthy lifestyle, which includes fruit and vegetable consumption. Current dietary recommendations to increase fruit and vegetable intake in the Dietary Guidelines for Americans will result in greater intakes of provitamin A carotenoids if consumers comply. This could lead to artificially high intakes of vitamin A in dietary analyses. However, multiple factors affect the bioconversion of provitamin A carotenoids to the active form of vitamin A. The human body will strive to maintain vitamin A balance by down-regulating provitamin A carotenoid bioconversion. If high preformed vitamin A intake is associated with poor bone health and provitamin A carotenoids are protective, future studies are needed to clarify the associations between total body stores of vitamin A, dietary intake of the pre- and pro-forms, and bone health throughout the life cycle. Key Words: Bioconversion; fruit; provitamin A carotenoids; retinol; vegetables.
embryogenesis will cause improper skeletal formation (4). In this work we review vitamin A nutrition with the primary interest of educating the reader on total body vitamin A balance from the diet (Fig. 1).
Introduction Osteoporosis is characterized by low bone mass and deterioration of bone, which leads to an increased risk of fragility fracture. Bone fractures confounded by osteoporosis reduce quality and often duration of life. Upwards of 40% of postmenopausal women and 25% of elderly men will sustain osteoporosis-related bone fractures in their lifetime (1). Given that the global population continues to age, the number of fractures will likely increase in the future. Nutrient deficiency and excess are related to poor bone health (2). Determining optimal nutrition status for healthy bones is important for global public health. In particular, excess vitamin A in the diet has been linked to a greater incidence of hip fracture (1e3). However, vitamin A is also necessary for proper bone development, and thus deficiency of the vitamin during
Functions of Vitamin A Vitamin A (Fig. 2) is a fat-soluble, essential nutrient that is involved in multiple metabolic functions in the body. Vitamin A as the aldehyde form (i.e., retinal) is essential for night vision. Vitamin A deficiency may cause complete blindness if night blindness or Bitot’s spots (also known as xerophthalmia) are not treated with vitamin A (5). Vitamin A as the hormone form (i.e., retinoic acid) is essential for growth, reproduction, and cellular differentiation. High intake levels of preformed vitamin A as retinol or retinyl esters from animal-source foods, fortified foods, or daily supplements can be toxic (2); therefore, the body stores the vitamin in the liver as retinol esterified to fatty acids (retinyl esters) and shuttles it around the body in plasma as retinol bound to retinol binding protein (5). Serum retinol concentrations are a common measure in population survey studies, but they do not necessarily reflect total body stores of vitamin
Accepted 06/12/13. *Address correspondence to: Sherry A. Tanumihardjo, PhD, Department of Nutritional Sciences, University of WisconsinMadison, 1415 Linden Drive, Madison, WI 53706. E-mail: [email protected]
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Fig. 1. Bone health is a balance between optimal nutrition status, physical activity, and genetics. Vitamin A is needed for proper bone development, but excess preformed vitamin A has negative bone consequences. In contrast, provitamin A carotenoids, such as b-cryptoxanthin and b-carotene, seem to be protective. Carotenoids are phytochemicals found in fruit and vegetables and high concentrations may act as a biomarker of a healthy lifestyle.
A unless liver vitamin A stores as retinyl esters are dangerously low (5). Fasting plasma retinyl palmitate concentrations may be used to qualitatively assess vitamin A excess, but it is unknown at what liver concentration of vitamin A that retinyl palmitate begins to circulate at an increased level (5). This critical concentration should be determined by the use of more-sensitive methodology, such as stable isotope techniques that quantitatively determine total body stores of vitamin A (5). A ‘‘healthy’’ liver storage range has not been defined, but typically levels !0.1 mmol retinol equivalents/ g liver elicit a biological response to circulate more retinol and above this concentration, liver retinyl ester formation enzymes are up-regulated (5). At 0.4 mmol/g liver, provitamin A carotenoid bioconversion to retinol slows as demonstrated in an animal model (6). Further, values O1 mmol/g have been called hypervitaminotic, but the manifestations of having a liver store concentration around this value are currently unknown (5).
Dietary Sources of Vitamin A Dietary vitamin A (Fig. 2) is found as the preform in dairy, liver, and fortified foods, such as breakfast cereal. The most common form is retinyl palmitate, although other esters are also naturally occurring. Retinyl palmitate is added to lowfat milk, and retinyl acetate is sometimes added to yogurt; both synthetic forms may be used in dietary supplements and can be found on the Supplement Facts panel as such. The provitamin A forms are plant-derived and are known as carotenoids (6). Although more than 700 carotenoids have been identified in nature, only approximately 50 can be cleaved to biosynthesize retinol. The most common provitamin A
415 carotenoids found in food are a-carotene, b-carotene, and b-cryptoxanthin (Fig. 2). Carotenoids give some fruits and vegetables their yellow and orange colors. For example, orange carrots are orange because of high amounts of a- and b-carotene, and oranges and tangerines are orange because of high amounts of b-cryptoxanthin (6). Some literature suggests that carotenoids are important in bone remodeling regulation. Carotenoids might reduce fracture risk by reducing bone resorption or by enhancing bone formation (1). Vitamin A enzymology is complex (2). Because of their fat-soluble nature, vitamin A and carotenoids must be dispersed in mixed micelles with lipid for absorption. After absorption, retinol is re-esterified to fatty acids; some of the provitamin A carotenoids are cleaved to retinal, reduced to retinol, and esterified; and the remaining provitamin A carotenoids escape cleavage. The newly synthesized retinyl esters and the intact carotenoids are packaged into lipid-containing chylomicra, which are circulated to distribute their components throughout the body. The remaining retinyl esters and carotenoids in the chylomicron remnant are cleared by the liver. Here, vitamin A and carotenoids can be stored or recirculated. Retinol will circulate bound to its carrier protein or be stored as retinyl esters (5), and carotenoids will circulate in lipoproteins (2).
Bioconversion Factors for Provitamin A Carotenoids The Institute of Medicine (IOM) is responsible for reviewing historical and current literature to recommend appropriate nutrient intake levels for healthy people (7). Current Recommended Dietary Allowances (RDAs) are 700 retinol activity equivalents (RAEs) for women and 900 RAE for men (7). The RAE is a calculation that includes both preformed retinol and provitamin A carotenoids from foods. The equivalency, however, is not straightforward and is based on mass. For retinol, the equivalency is 1 mg retinol equals 1 RAE. For the provitamin A carotenoids, it is complicated by the fact that many factors influence the bioavailability of the carotenoids from the food matrix and bioconversion to retinol (6,8). Bioavailability is the amount of carotenoid that is absorbed from the process of digestion and available for physiological function. Factors that affect provitamin A carotenoid bioavailability are an active area of research (8). Nonetheless, IOM has assigned values of 12 mg b-carotene to 1 RAE and 24 mg a-carotene or b-cryptoxanthin to 1 RAE from a mixed diet. Thus, if a person ate a snack of 1 cup orange carrot sticks and 1 cup 2% reduced-fat milk, they would ingest 1150 RAE, which is greater than the RDAs. However, because most of this RAE (w90%) is derived from the provitamin A carotenoid in the carrot, the person may not actually convert this much of the provitamin A to retinol if their vitamin A status is in balance. Vitamin A status is one of the driving factors in the bioconversion of provitamin A carotenoids to retinol (6,8). However, if a person has a deficient vitamin A status, they may convert more of the provitamin A carotenoid to retinol than the IOM predictions (6e8).
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Fig. 2. Preformed vitamin A includes retinol and the retinyl esters. Retinyl acetate and palmitate are the forms commonly used in dietary supplements. Retinyl palmitate is the major storage form in human liver and may be found in circulation during hypervitaminosis A. The most common provitamin A carotenoids in the human diet are a-carotene, b-carotene, and b-cryptoxanthin. Clinicians need to be informed about the regulatory mechanisms that control provitamin A carotenoid bioconversion to retinol, the active form of vitamin A. These mechanisms are down-regulated when vitamin A status is adequate. If patients are consuming the recommended amounts of fruit and vegetables and they include variety, some days they will seemingly consume greater amounts than the tolerable upper intake level (UL) for vitamin A, which is 3000 mg preformed vitamin A. The UL is the greatest level thought to pose no risk of adverse health effects in the general population (7), and for vitamin A, it is based on the preformed vitamin from animalsource foods, fortified foods, and supplements, not the provitamin A carotenoid forms from fruit and vegetables. For
example, one cup of carrot strips has 1020 RAE, and a half-cup cooked spinach has w500 RAE. Combined, this is twice the current RDA for women, that is, 700 RAE. Add 1 cup of cooked pumpkin at 1900 RAE and the UL is easily surpassed, but it is as RAE from plants and not preformed retinol from animals or supplements. As provitamin A carotenoid RAE, the body would only make enough vitamin A from these foods to meet vitamin A requirements because of the mechanisms that regulate bioconversion (6). If a person is eating most of their vitamin A as fruit and vegetables, their skin would likely turn yellow as the result of provitamin A carotenoid storage in the adipose long before they would develop hypervitaminosis A from plant food. Concerns
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Vitamin A and Bone Health should be dismissed in regard to seemingly ‘‘high’’ dietary vitamin A intakes associated with healthy diets at recommended fruit and vegetable intakes (4e6 cups for 1800e2400 kcal daily intake). Plant foods also contain other nutrients and phytochemicals, which may explain improved bone health. Eating whole fruits and vegetables promotes optimal health rather than any one single component. Investigators of studies that include whole foods must realize the complexity of diet and bone interactions rather than assuming that the studied nutrient is causally related to the observed outcome (1).
Hypervitaminosis A and Osteoporosis Provitamin A carotenoids are converted to vitamin A predominantly in the intestinal wall by an enzyme known as bcarotene 15, 150 -monooxygenase; however, this process is highly regulated by vitamin A status (8). Considering current fruit and vegetable intakes and bioconversion regulation, it is unlikely that hypervitaminosis A can occur from provitamin A carotenoid intake. However, as stated above, dietary recommendations of fruit and vegetable intake may lead to calculated vitamin A intakes that are high for healthy eating plans. This may cause concern to consumers if they do not understand the subtleties. Unless a person has a very active enzymatic system, it is unlikely that large amounts of vitamin A would be biosynthesized from high intakes of provitamin A carotenoids due to the many factors that affect carotenoid bioavailability and bioconversion (8). However, considering the widespread use of preformed vitamin A sources, the topic of excessive dietary vitamin A and bone health will be discussed. Excessive preformed vitamin A intakes from animalsource foods, supplements, and fortified foods will lead to hypervitaminosis A (2) and this is associated with low bone mass, osteoporosis, and fragility fractures (1). Historically, hypervitaminosis A has been associated with bone alterations in human remains, Arctic people who are known to eat animal liver, and in children with excessive vitamin A intakes from liver or supplements (2). Observational studies conducted in developed countries, where osteoporosis incidence is high, found associations between retinol intakes at only two-times the current RDA (1500 mg retinol equivalents) and hip fracture or osteoporosis (1). The UL for preformed vitamin A is 3000 mg retinol equivalents, which is twice the amount associated with poor bone health (7). Most people in developed countries get more vitamin A than recommended. Studies that link vitamin A intakes with poor bone health are observational and epidemiologic in nature, and not all studies have demonstrated a link between high vitamin A intake and bone fractures (9). Therefore, questions are currently unanswered in regard to the association of preformed vitamin A intake, vitamin A total body stores, and bone health. Actual vitamin A status needs to be measured by total body vitamin A stores in people who have low bone mass and fracture incidence with sensitive biomarkers of liver stores, such as stable isotope methods, to uncover the true relationship (5). Correlation studies suggest that high dietary intake of
417 preformed vitamin A may have adverse bone consequences, and from a public health standpoint, this needs to be investigated. However, this is not the case for the dietary provitamin A carotenoids from plants, which supports continued promotion of high intakes of fruit and vegetables for optimal health. General symptoms of hypervitaminosis A include nausea, headache, fatigue, anorexia, dizziness, and dry skin (2,3). The mechanisms by which excess preformed vitamin A cause poor bone health are not entirely known but are likely related to increased osteoclastic bone resorption and decreased osteoblastic bone formation (3). Studies in animals have further demonstrated calcification of cartilage during vitamin A treatment (3). In humans, increased bone resorption, increased alkaline phosphatase activity, and hypercalcemia have been documented with excess vitamin A ingestion (3).
Potential Mechanisms of Carotenoids in Optimizing Bone Health Most of the evidence for beneficial effects of carotenoids on bone health has been associated with the hydrocarbon carotenes and the oxygen-containing b-cryptoxanthin (Fig. 2) Carotenoids may produce a bone benefit through their antioxidant properties. Oxidative stress caused by reactive oxygen species may be involved in bone resorption and adversely modulate osteoblastic differentiation (1). These processes negatively impact bone balance and decrease bone mass. Carotenoids acting as antioxidants can quench singlet oxygen and trap peroxyl radicals, reducing oxidative stress, thus potentially reducing bone resorption (1). In epidemiologic studies, high antioxidant intake, such as carotenoids from fruit and vegetables, was associated with lower risk of fracture. Lower serum/plasma levels of provitamin A carotenoids and vitamin A have been observed in groups of women with osteoporosis (1). These results are somewhat counterintuitive because, as noted previously, supplementation or fortification with preformed vitamin A is associated with greater agerelated bone loss (2). Plant sources of vitamin A are likely protective to bone or the carotenoids are acting as biomarkers for other nutrients and phytochemicals in fruits and vegetables that protect bone (1). In addition to the human studies noted above, in vitro and animal studies have found beneficial effects of carotenoids on bone. In tissue culture experiments, b-cryptoxanthin had a direct stimulatory effect on osteoblastic bone formation, an inhibitory effect on bone resorption, and enhanced mineralization (10). Indeed, increased calcium content was observed in bone tissue cultures exposed to b-cryptoxanthin (10). Limited in vivo animal work supports these in vitro studies. b-Cryptoxanthin increased bone calcium content and reduced bone loss induced by ovariectomy in rats (10). Consistent with these in vitro and animal data, adults receiving juice fortified with b-cryptoxanthin had increased markers of bone formation and reduced bone resorption markers (1,10). Supporting a role of this carotenoid in bone metabolism, b-cryptoxanthin was lower in menopausal women with osteoporosis than those without (1). However, existing human
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418 data are limited, and more targeted studies are needed. These observations have clinical relevance given the projected increase in osteoporotic fractures attributable to global aging. Further investigations are needed to elucidate the action of b-cryptoxanthin on bone health. Dietary sources of b-cryptoxanthin are few but include citrus fruits such as oranges and tangerines, which are found worldwide. Osteoarthritis, with its frequently observed formation of bone spurs, is a common occurrence with advancing age. Greater circulating concentrations of b-cryptoxanthin and fruit intake by food frequency questionnaire have been associated with lower risk of knee osteoarthritis (1). Although greater serum concentrations for many carotenoids were associated with a lower incidence of lumbar spine osteophytes, only lower serum b-carotene was associated with a greater incidence of bone spurs after multivariate analysis. Because osteoarthritis is common in older adults, randomized controlled trials are needed to determine whether dietary modification or provitamin A carotenoid supplementation may reduce the overall risk of developing bone spurs (1). This relationship requires further evaluation because benefits may not result from a single carotenoid but the combination of the fruit matrix.
Tanumihardjo
Vitamin A as a Drug This article would not be complete without a short discussion of the use of vitamin A derivatives as drugs. For many years in the United States, isotretinoin (Accutane; HoffmanLaRoche, Basel, Switzerland) was sold as an acne treatment. Isotretinoin is 13-cis-retinoic acid and is highly teratogenic (Fig. 3). In fact, one-third of all pregnancies exposed to isotretinoin will end in spontaneous abortion, and those fetuses whom are not aborted will likely have serious birth defects (13). Other derived vitamin A medications are etretinate and acitretin, which are used for psoriasis, and tretinoin, which is used as a topical acne treatment. Etretinate has a very long half-life (120 days) and should not be used in women of reproductive age who may want to get pregnant because of this long storage time (13). Tretinoin is the alltrans-form of retinoic acid and because it is only prescribed topically, does not result in teratogenicity. Skeletal toxicity may also occur with systemic retinoid treatments (1).
Vitamin A Supplements In general, multivitamins, which include vitamin A, have not been found to be overly beneficial. In fact, a metaanalysis of randomized controlled trials found no effect on the risk of mortality (11). The form of vitamin A in supplements affects it toxicity potential (12). Water-miscible forms seem to be more toxic than oil-based supplements. This likely is related to the way that vitamin A is processed during digestion. Other studies have not linked high vitamin A intake to osteoporosis (9,12). When prescribing or recommending supplements, the safest advice is to recommend a multivitamin that has the vitamin A predominantly in the form of b-carotene. If it is as the preformed retinyl acetate or retinyl palmitate, it will be highly available, and absorption will not be as regulated as when the vitamin is in the provitamin A form. Furthermore, supplement labels follow the Daily Value, which is based on the 1968 recommended dietary allowance of 1500 mg retinol equivalents (5000 IU). Considering that the UL for vitamin A is set at 3000 mg, a healthy diet with fortified foods and a daily supplement that contain retinyl ester could easily meet this preformed amount. Consumers also need to be aware of which supplements contain vitamin A that is not written on the label. This predominantly occurs in supplements that are liver extracts from fish. Although some fish liver oils are purified, some of them are not and those that are not will contain preformed vitamin A. Cod liver oil, on the other hand, often states the amount of preformed vitamin A written on the label. This is totally in the preform and therefore care must be taken not to consume too much cod liver oil or to use it in combination with other preformed vitamin A-containing supplements.
Fig. 3. A variety of vitamin A derivatives have been used as drugs. They are all similar in structure to all-trans-retinoic acid, which is not only used in topical creams but made by the human body to accomplish many metabolic processes.
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Vitamin A and Bone Health
Key Points Vitamin A is an essential nutrient involved in vision and many metabolic processes in the body. Excess vitamin A is associated with poor bone health. Provitamin A carotenoids, such as b-carotene and b-cryptoxanthin, seem to protect bone. The body regulates bioconversion of provitamin A carotenoids to retinol to mitigate excess vitamin A.
In conclusions, vitamin A is necessary for bone growth (4), yet an excess of the preformed vitamin A is associated with suboptimal bone health (1e3). Therefore, balance is important for human vitamin A status. The beneficial associations reported between carotenoids and bone health could be an indicator for the intake of other antioxidants, nutrients, or minerals, or reflect a healthy lifestyle that is more common in people with high dietary intakes of carotenoids (i.e., fruits and vegetables). Reported associations may simply reflect carotenoids acting as a biomarker for other components in fruit and vegetables that support optimal skeletal status. Vegetables are an important source of dietary minerals including calcium and potassium, which are associated with greater bone density (1). Further research is essential to clarify whether the observed associations are causally related to bone health and to assess vitamin A status across the life cycle to better define total body stores of vitamin A using isotopic methods and bone status (5). If beneficial bone effects are confirmed with a diet high in carotenoids, but not preformed vitamin A, such dietary approaches could potentially offer safe, inexpensive ways to reduce bone loss with advancing age. Dietary interventions that could slow or halt bone loss are obviously appealing in that low cost, population-based preventive approaches would be feasible (1). Moreover, such a dietbased approach would likely be embraced by people who prefer not to use prescription drugs or supplements to maintain their health. This would lead to a reduction in fractures, which would lead to major personal and societal benefits. Conversely, the potential negative impact of preformed vitamin A on bone needs to be further investigated to determine if vitamin A status per se or other synergistic nutritional or non-nutritional interactions negatively impact bone health (1). Randomized controlled trials of retinol supplementation and/or retinoid treatment are necessary to further evaluate the effect on bone health. Considering that (1) many people take supplements; (2) vitamin A is safest in the provitamin A form (6); and (3) b-cryptoxanthin seems to protect bone health (10); a dietary supplement marketed to postmenopausal women, the group at greatest risk for osteoporotic fractures, that is formulated with b-cryptoxanthin as the vitamin A source may not
419 only meet vitamin A needs but also assist in maintaining bone density during aging. Perhaps including b-cryptoxanthin in a supplement with calcium and vitamin D may enhance bone formation and inhibit resorption in osteoporotic patients. Eating a diet high in fruits and vegetables is essential throughout the life cycle and may help youth reach optimal bone mass in preparation for their adult years.
Acknowledgments S.A.T. declares no competing financial interest in relation to this educational article. S.A.T. wrote the article from the 13 listed references and originally prepared the illustrations. The references used are predominantly review articles, and the readers are encouraged to seek the primary references if interested, which are cited in these review articles. Support for this article came from an endowment to S.A.T. entitled ‘‘Friday Chair for Vegetable Processing Research.’’
References 1. Tanumihardjo SA, Binkley N. 2013 Carotenoids and bone health. In: Carotenoids and Human Health. Tanumihardjo S, ed. New York: Springer Science and Business Media. 2. Penniston KL, Tanumihardjo SA. 2006 The acute and chronic toxic effects of vitamin A. Am J Clin Nutr 83:191e201. 3. Binkley N, Krueger D. 2000 Hypervitaminosis A and bone. Nutr Rev 58:138e144. 4. See AW-M, Kaiser ME, White JC, Clagett-Dame M. 2008 A nutritional model of late embryonic vitamin A deficiency produces defects in organogenesis at a high penetrance and reveals new roles for the vitamin in skeletal development. Dev Biol 316: 171e190. 5. Tanumihardjo SA. 2011 Vitamin A: biomarkers of nutrition for development. Am J Clin Nutr 94:658Se665S. 6. Tanumihardjo SA. 2008 Food-based approaches for ensuring adequate vitamin A nutrition. Comp Rev Food Sci Food Safety 7:373e381. 7. Institute of Medicine, Food and Nutrition Board. 2001 Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press:65e126. 8. Tanumihardjo SA, Palacios N, Pixley KV. 2010 Provitamin A carotenoid bioavailability: what really matters? Int J Vitam Nutr Res 80:336e350. 9. Caire-Juvera G, Ritenbaugh C, Wactawski-Wende J, et al. 2009 Vitamin A and retinol intakes and the risk of fractures among participants of the Women’s Health Initiative Observational Study. Am J Clin Nutr 89:323e330. 10. Yamaguchi M. 2008 b-Cryptoxanthin and bone metabolism: the preventive role in osteoporosis. J Health Sci 54:356e369. 11. Macpherson H, Pipingas A, Pase MP. 2013 Multivitaminmultimineral supplementation and mortality: a meta-analysis of randomized controlled trials. Am J Clin Nutr 97:437e444. 12. Myhre AM, Carlsen MH, Bohn SK, et al. 2003 Watermiscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations. Am J Clin Nutr 78:1152e1159. 13. Duerbeck NB, Dowling DD. 2012 Vitamin A: too much of a good thing? Obstet Gynecol Surv 67:122e128.
Journal of Clinical Densitometry: Assessment & Management of Musculoskeletal Health
Volume 16, 2013
Special Section on Bone and Nutrition
Vitamin A and Bone Health: The Balancing Act Sherry A. Tanumihardjo* Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA
Abstract The role of vitamin A status as it relates to bone health is historical yet controversial. Population-based studies have linked high dietary intake of preformed vitamin A, which is obtained from animal-source foods, fortified foods, and some supplements, to greater risk of osteoporosis and hip fracture. In contrast, carotenoids, some of which are vitamin A precursors from plants, are associated with improved bone health. Carotenoids may be a biomarker that reflects a generally healthy lifestyle, which includes fruit and vegetable consumption. Current dietary recommendations to increase fruit and vegetable intake in the Dietary Guidelines for Americans will result in greater intakes of provitamin A carotenoids if consumers comply. This could lead to artificially high intakes of vitamin A in dietary analyses. However, multiple factors affect the bioconversion of provitamin A carotenoids to the active form of vitamin A. The human body will strive to maintain vitamin A balance by down-regulating provitamin A carotenoid bioconversion. If high preformed vitamin A intake is associated with poor bone health and provitamin A carotenoids are protective, future studies are needed to clarify the associations between total body stores of vitamin A, dietary intake of the pre- and pro-forms, and bone health throughout the life cycle. Key Words: Bioconversion; fruit; provitamin A carotenoids; retinol; vegetables.
embryogenesis will cause improper skeletal formation (4). In this work we review vitamin A nutrition with the primary interest of educating the reader on total body vitamin A balance from the diet (Fig. 1).
Introduction Osteoporosis is characterized by low bone mass and deterioration of bone, which leads to an increased risk of fragility fracture. Bone fractures confounded by osteoporosis reduce quality and often duration of life. Upwards of 40% of postmenopausal women and 25% of elderly men will sustain osteoporosis-related bone fractures in their lifetime (1). Given that the global population continues to age, the number of fractures will likely increase in the future. Nutrient deficiency and excess are related to poor bone health (2). Determining optimal nutrition status for healthy bones is important for global public health. In particular, excess vitamin A in the diet has been linked to a greater incidence of hip fracture (1e3). However, vitamin A is also necessary for proper bone development, and thus deficiency of the vitamin during
Functions of Vitamin A Vitamin A (Fig. 2) is a fat-soluble, essential nutrient that is involved in multiple metabolic functions in the body. Vitamin A as the aldehyde form (i.e., retinal) is essential for night vision. Vitamin A deficiency may cause complete blindness if night blindness or Bitot’s spots (also known as xerophthalmia) are not treated with vitamin A (5). Vitamin A as the hormone form (i.e., retinoic acid) is essential for growth, reproduction, and cellular differentiation. High intake levels of preformed vitamin A as retinol or retinyl esters from animal-source foods, fortified foods, or daily supplements can be toxic (2); therefore, the body stores the vitamin in the liver as retinol esterified to fatty acids (retinyl esters) and shuttles it around the body in plasma as retinol bound to retinol binding protein (5). Serum retinol concentrations are a common measure in population survey studies, but they do not necessarily reflect total body stores of vitamin
Accepted 06/12/13. *Address correspondence to: Sherry A. Tanumihardjo, PhD, Department of Nutritional Sciences, University of WisconsinMadison, 1415 Linden Drive, Madison, WI 53706. E-mail: [email protected]
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Fig. 1. Bone health is a balance between optimal nutrition status, physical activity, and genetics. Vitamin A is needed for proper bone development, but excess preformed vitamin A has negative bone consequences. In contrast, provitamin A carotenoids, such as b-cryptoxanthin and b-carotene, seem to be protective. Carotenoids are phytochemicals found in fruit and vegetables and high concentrations may act as a biomarker of a healthy lifestyle.
A unless liver vitamin A stores as retinyl esters are dangerously low (5). Fasting plasma retinyl palmitate concentrations may be used to qualitatively assess vitamin A excess, but it is unknown at what liver concentration of vitamin A that retinyl palmitate begins to circulate at an increased level (5). This critical concentration should be determined by the use of more-sensitive methodology, such as stable isotope techniques that quantitatively determine total body stores of vitamin A (5). A ‘‘healthy’’ liver storage range has not been defined, but typically levels !0.1 mmol retinol equivalents/ g liver elicit a biological response to circulate more retinol and above this concentration, liver retinyl ester formation enzymes are up-regulated (5). At 0.4 mmol/g liver, provitamin A carotenoid bioconversion to retinol slows as demonstrated in an animal model (6). Further, values O1 mmol/g have been called hypervitaminotic, but the manifestations of having a liver store concentration around this value are currently unknown (5).
Dietary Sources of Vitamin A Dietary vitamin A (Fig. 2) is found as the preform in dairy, liver, and fortified foods, such as breakfast cereal. The most common form is retinyl palmitate, although other esters are also naturally occurring. Retinyl palmitate is added to lowfat milk, and retinyl acetate is sometimes added to yogurt; both synthetic forms may be used in dietary supplements and can be found on the Supplement Facts panel as such. The provitamin A forms are plant-derived and are known as carotenoids (6). Although more than 700 carotenoids have been identified in nature, only approximately 50 can be cleaved to biosynthesize retinol. The most common provitamin A
415 carotenoids found in food are a-carotene, b-carotene, and b-cryptoxanthin (Fig. 2). Carotenoids give some fruits and vegetables their yellow and orange colors. For example, orange carrots are orange because of high amounts of a- and b-carotene, and oranges and tangerines are orange because of high amounts of b-cryptoxanthin (6). Some literature suggests that carotenoids are important in bone remodeling regulation. Carotenoids might reduce fracture risk by reducing bone resorption or by enhancing bone formation (1). Vitamin A enzymology is complex (2). Because of their fat-soluble nature, vitamin A and carotenoids must be dispersed in mixed micelles with lipid for absorption. After absorption, retinol is re-esterified to fatty acids; some of the provitamin A carotenoids are cleaved to retinal, reduced to retinol, and esterified; and the remaining provitamin A carotenoids escape cleavage. The newly synthesized retinyl esters and the intact carotenoids are packaged into lipid-containing chylomicra, which are circulated to distribute their components throughout the body. The remaining retinyl esters and carotenoids in the chylomicron remnant are cleared by the liver. Here, vitamin A and carotenoids can be stored or recirculated. Retinol will circulate bound to its carrier protein or be stored as retinyl esters (5), and carotenoids will circulate in lipoproteins (2).
Bioconversion Factors for Provitamin A Carotenoids The Institute of Medicine (IOM) is responsible for reviewing historical and current literature to recommend appropriate nutrient intake levels for healthy people (7). Current Recommended Dietary Allowances (RDAs) are 700 retinol activity equivalents (RAEs) for women and 900 RAE for men (7). The RAE is a calculation that includes both preformed retinol and provitamin A carotenoids from foods. The equivalency, however, is not straightforward and is based on mass. For retinol, the equivalency is 1 mg retinol equals 1 RAE. For the provitamin A carotenoids, it is complicated by the fact that many factors influence the bioavailability of the carotenoids from the food matrix and bioconversion to retinol (6,8). Bioavailability is the amount of carotenoid that is absorbed from the process of digestion and available for physiological function. Factors that affect provitamin A carotenoid bioavailability are an active area of research (8). Nonetheless, IOM has assigned values of 12 mg b-carotene to 1 RAE and 24 mg a-carotene or b-cryptoxanthin to 1 RAE from a mixed diet. Thus, if a person ate a snack of 1 cup orange carrot sticks and 1 cup 2% reduced-fat milk, they would ingest 1150 RAE, which is greater than the RDAs. However, because most of this RAE (w90%) is derived from the provitamin A carotenoid in the carrot, the person may not actually convert this much of the provitamin A to retinol if their vitamin A status is in balance. Vitamin A status is one of the driving factors in the bioconversion of provitamin A carotenoids to retinol (6,8). However, if a person has a deficient vitamin A status, they may convert more of the provitamin A carotenoid to retinol than the IOM predictions (6e8).
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Fig. 2. Preformed vitamin A includes retinol and the retinyl esters. Retinyl acetate and palmitate are the forms commonly used in dietary supplements. Retinyl palmitate is the major storage form in human liver and may be found in circulation during hypervitaminosis A. The most common provitamin A carotenoids in the human diet are a-carotene, b-carotene, and b-cryptoxanthin. Clinicians need to be informed about the regulatory mechanisms that control provitamin A carotenoid bioconversion to retinol, the active form of vitamin A. These mechanisms are down-regulated when vitamin A status is adequate. If patients are consuming the recommended amounts of fruit and vegetables and they include variety, some days they will seemingly consume greater amounts than the tolerable upper intake level (UL) for vitamin A, which is 3000 mg preformed vitamin A. The UL is the greatest level thought to pose no risk of adverse health effects in the general population (7), and for vitamin A, it is based on the preformed vitamin from animalsource foods, fortified foods, and supplements, not the provitamin A carotenoid forms from fruit and vegetables. For
example, one cup of carrot strips has 1020 RAE, and a half-cup cooked spinach has w500 RAE. Combined, this is twice the current RDA for women, that is, 700 RAE. Add 1 cup of cooked pumpkin at 1900 RAE and the UL is easily surpassed, but it is as RAE from plants and not preformed retinol from animals or supplements. As provitamin A carotenoid RAE, the body would only make enough vitamin A from these foods to meet vitamin A requirements because of the mechanisms that regulate bioconversion (6). If a person is eating most of their vitamin A as fruit and vegetables, their skin would likely turn yellow as the result of provitamin A carotenoid storage in the adipose long before they would develop hypervitaminosis A from plant food. Concerns
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Vitamin A and Bone Health should be dismissed in regard to seemingly ‘‘high’’ dietary vitamin A intakes associated with healthy diets at recommended fruit and vegetable intakes (4e6 cups for 1800e2400 kcal daily intake). Plant foods also contain other nutrients and phytochemicals, which may explain improved bone health. Eating whole fruits and vegetables promotes optimal health rather than any one single component. Investigators of studies that include whole foods must realize the complexity of diet and bone interactions rather than assuming that the studied nutrient is causally related to the observed outcome (1).
Hypervitaminosis A and Osteoporosis Provitamin A carotenoids are converted to vitamin A predominantly in the intestinal wall by an enzyme known as bcarotene 15, 150 -monooxygenase; however, this process is highly regulated by vitamin A status (8). Considering current fruit and vegetable intakes and bioconversion regulation, it is unlikely that hypervitaminosis A can occur from provitamin A carotenoid intake. However, as stated above, dietary recommendations of fruit and vegetable intake may lead to calculated vitamin A intakes that are high for healthy eating plans. This may cause concern to consumers if they do not understand the subtleties. Unless a person has a very active enzymatic system, it is unlikely that large amounts of vitamin A would be biosynthesized from high intakes of provitamin A carotenoids due to the many factors that affect carotenoid bioavailability and bioconversion (8). However, considering the widespread use of preformed vitamin A sources, the topic of excessive dietary vitamin A and bone health will be discussed. Excessive preformed vitamin A intakes from animalsource foods, supplements, and fortified foods will lead to hypervitaminosis A (2) and this is associated with low bone mass, osteoporosis, and fragility fractures (1). Historically, hypervitaminosis A has been associated with bone alterations in human remains, Arctic people who are known to eat animal liver, and in children with excessive vitamin A intakes from liver or supplements (2). Observational studies conducted in developed countries, where osteoporosis incidence is high, found associations between retinol intakes at only two-times the current RDA (1500 mg retinol equivalents) and hip fracture or osteoporosis (1). The UL for preformed vitamin A is 3000 mg retinol equivalents, which is twice the amount associated with poor bone health (7). Most people in developed countries get more vitamin A than recommended. Studies that link vitamin A intakes with poor bone health are observational and epidemiologic in nature, and not all studies have demonstrated a link between high vitamin A intake and bone fractures (9). Therefore, questions are currently unanswered in regard to the association of preformed vitamin A intake, vitamin A total body stores, and bone health. Actual vitamin A status needs to be measured by total body vitamin A stores in people who have low bone mass and fracture incidence with sensitive biomarkers of liver stores, such as stable isotope methods, to uncover the true relationship (5). Correlation studies suggest that high dietary intake of
417 preformed vitamin A may have adverse bone consequences, and from a public health standpoint, this needs to be investigated. However, this is not the case for the dietary provitamin A carotenoids from plants, which supports continued promotion of high intakes of fruit and vegetables for optimal health. General symptoms of hypervitaminosis A include nausea, headache, fatigue, anorexia, dizziness, and dry skin (2,3). The mechanisms by which excess preformed vitamin A cause poor bone health are not entirely known but are likely related to increased osteoclastic bone resorption and decreased osteoblastic bone formation (3). Studies in animals have further demonstrated calcification of cartilage during vitamin A treatment (3). In humans, increased bone resorption, increased alkaline phosphatase activity, and hypercalcemia have been documented with excess vitamin A ingestion (3).
Potential Mechanisms of Carotenoids in Optimizing Bone Health Most of the evidence for beneficial effects of carotenoids on bone health has been associated with the hydrocarbon carotenes and the oxygen-containing b-cryptoxanthin (Fig. 2) Carotenoids may produce a bone benefit through their antioxidant properties. Oxidative stress caused by reactive oxygen species may be involved in bone resorption and adversely modulate osteoblastic differentiation (1). These processes negatively impact bone balance and decrease bone mass. Carotenoids acting as antioxidants can quench singlet oxygen and trap peroxyl radicals, reducing oxidative stress, thus potentially reducing bone resorption (1). In epidemiologic studies, high antioxidant intake, such as carotenoids from fruit and vegetables, was associated with lower risk of fracture. Lower serum/plasma levels of provitamin A carotenoids and vitamin A have been observed in groups of women with osteoporosis (1). These results are somewhat counterintuitive because, as noted previously, supplementation or fortification with preformed vitamin A is associated with greater agerelated bone loss (2). Plant sources of vitamin A are likely protective to bone or the carotenoids are acting as biomarkers for other nutrients and phytochemicals in fruits and vegetables that protect bone (1). In addition to the human studies noted above, in vitro and animal studies have found beneficial effects of carotenoids on bone. In tissue culture experiments, b-cryptoxanthin had a direct stimulatory effect on osteoblastic bone formation, an inhibitory effect on bone resorption, and enhanced mineralization (10). Indeed, increased calcium content was observed in bone tissue cultures exposed to b-cryptoxanthin (10). Limited in vivo animal work supports these in vitro studies. b-Cryptoxanthin increased bone calcium content and reduced bone loss induced by ovariectomy in rats (10). Consistent with these in vitro and animal data, adults receiving juice fortified with b-cryptoxanthin had increased markers of bone formation and reduced bone resorption markers (1,10). Supporting a role of this carotenoid in bone metabolism, b-cryptoxanthin was lower in menopausal women with osteoporosis than those without (1). However, existing human
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418 data are limited, and more targeted studies are needed. These observations have clinical relevance given the projected increase in osteoporotic fractures attributable to global aging. Further investigations are needed to elucidate the action of b-cryptoxanthin on bone health. Dietary sources of b-cryptoxanthin are few but include citrus fruits such as oranges and tangerines, which are found worldwide. Osteoarthritis, with its frequently observed formation of bone spurs, is a common occurrence with advancing age. Greater circulating concentrations of b-cryptoxanthin and fruit intake by food frequency questionnaire have been associated with lower risk of knee osteoarthritis (1). Although greater serum concentrations for many carotenoids were associated with a lower incidence of lumbar spine osteophytes, only lower serum b-carotene was associated with a greater incidence of bone spurs after multivariate analysis. Because osteoarthritis is common in older adults, randomized controlled trials are needed to determine whether dietary modification or provitamin A carotenoid supplementation may reduce the overall risk of developing bone spurs (1). This relationship requires further evaluation because benefits may not result from a single carotenoid but the combination of the fruit matrix.
Tanumihardjo
Vitamin A as a Drug This article would not be complete without a short discussion of the use of vitamin A derivatives as drugs. For many years in the United States, isotretinoin (Accutane; HoffmanLaRoche, Basel, Switzerland) was sold as an acne treatment. Isotretinoin is 13-cis-retinoic acid and is highly teratogenic (Fig. 3). In fact, one-third of all pregnancies exposed to isotretinoin will end in spontaneous abortion, and those fetuses whom are not aborted will likely have serious birth defects (13). Other derived vitamin A medications are etretinate and acitretin, which are used for psoriasis, and tretinoin, which is used as a topical acne treatment. Etretinate has a very long half-life (120 days) and should not be used in women of reproductive age who may want to get pregnant because of this long storage time (13). Tretinoin is the alltrans-form of retinoic acid and because it is only prescribed topically, does not result in teratogenicity. Skeletal toxicity may also occur with systemic retinoid treatments (1).
Vitamin A Supplements In general, multivitamins, which include vitamin A, have not been found to be overly beneficial. In fact, a metaanalysis of randomized controlled trials found no effect on the risk of mortality (11). The form of vitamin A in supplements affects it toxicity potential (12). Water-miscible forms seem to be more toxic than oil-based supplements. This likely is related to the way that vitamin A is processed during digestion. Other studies have not linked high vitamin A intake to osteoporosis (9,12). When prescribing or recommending supplements, the safest advice is to recommend a multivitamin that has the vitamin A predominantly in the form of b-carotene. If it is as the preformed retinyl acetate or retinyl palmitate, it will be highly available, and absorption will not be as regulated as when the vitamin is in the provitamin A form. Furthermore, supplement labels follow the Daily Value, which is based on the 1968 recommended dietary allowance of 1500 mg retinol equivalents (5000 IU). Considering that the UL for vitamin A is set at 3000 mg, a healthy diet with fortified foods and a daily supplement that contain retinyl ester could easily meet this preformed amount. Consumers also need to be aware of which supplements contain vitamin A that is not written on the label. This predominantly occurs in supplements that are liver extracts from fish. Although some fish liver oils are purified, some of them are not and those that are not will contain preformed vitamin A. Cod liver oil, on the other hand, often states the amount of preformed vitamin A written on the label. This is totally in the preform and therefore care must be taken not to consume too much cod liver oil or to use it in combination with other preformed vitamin A-containing supplements.
Fig. 3. A variety of vitamin A derivatives have been used as drugs. They are all similar in structure to all-trans-retinoic acid, which is not only used in topical creams but made by the human body to accomplish many metabolic processes.
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Vitamin A and Bone Health
Key Points Vitamin A is an essential nutrient involved in vision and many metabolic processes in the body. Excess vitamin A is associated with poor bone health. Provitamin A carotenoids, such as b-carotene and b-cryptoxanthin, seem to protect bone. The body regulates bioconversion of provitamin A carotenoids to retinol to mitigate excess vitamin A.
In conclusions, vitamin A is necessary for bone growth (4), yet an excess of the preformed vitamin A is associated with suboptimal bone health (1e3). Therefore, balance is important for human vitamin A status. The beneficial associations reported between carotenoids and bone health could be an indicator for the intake of other antioxidants, nutrients, or minerals, or reflect a healthy lifestyle that is more common in people with high dietary intakes of carotenoids (i.e., fruits and vegetables). Reported associations may simply reflect carotenoids acting as a biomarker for other components in fruit and vegetables that support optimal skeletal status. Vegetables are an important source of dietary minerals including calcium and potassium, which are associated with greater bone density (1). Further research is essential to clarify whether the observed associations are causally related to bone health and to assess vitamin A status across the life cycle to better define total body stores of vitamin A using isotopic methods and bone status (5). If beneficial bone effects are confirmed with a diet high in carotenoids, but not preformed vitamin A, such dietary approaches could potentially offer safe, inexpensive ways to reduce bone loss with advancing age. Dietary interventions that could slow or halt bone loss are obviously appealing in that low cost, population-based preventive approaches would be feasible (1). Moreover, such a dietbased approach would likely be embraced by people who prefer not to use prescription drugs or supplements to maintain their health. This would lead to a reduction in fractures, which would lead to major personal and societal benefits. Conversely, the potential negative impact of preformed vitamin A on bone needs to be further investigated to determine if vitamin A status per se or other synergistic nutritional or non-nutritional interactions negatively impact bone health (1). Randomized controlled trials of retinol supplementation and/or retinoid treatment are necessary to further evaluate the effect on bone health. Considering that (1) many people take supplements; (2) vitamin A is safest in the provitamin A form (6); and (3) b-cryptoxanthin seems to protect bone health (10); a dietary supplement marketed to postmenopausal women, the group at greatest risk for osteoporotic fractures, that is formulated with b-cryptoxanthin as the vitamin A source may not
419 only meet vitamin A needs but also assist in maintaining bone density during aging. Perhaps including b-cryptoxanthin in a supplement with calcium and vitamin D may enhance bone formation and inhibit resorption in osteoporotic patients. Eating a diet high in fruits and vegetables is essential throughout the life cycle and may help youth reach optimal bone mass in preparation for their adult years.
Acknowledgments S.A.T. declares no competing financial interest in relation to this educational article. S.A.T. wrote the article from the 13 listed references and originally prepared the illustrations. The references used are predominantly review articles, and the readers are encouraged to seek the primary references if interested, which are cited in these review articles. Support for this article came from an endowment to S.A.T. entitled ‘‘Friday Chair for Vegetable Processing Research.’’
References 1. Tanumihardjo SA, Binkley N. 2013 Carotenoids and bone health. In: Carotenoids and Human Health. Tanumihardjo S, ed. New York: Springer Science and Business Media. 2. Penniston KL, Tanumihardjo SA. 2006 The acute and chronic toxic effects of vitamin A. Am J Clin Nutr 83:191e201. 3. Binkley N, Krueger D. 2000 Hypervitaminosis A and bone. Nutr Rev 58:138e144. 4. See AW-M, Kaiser ME, White JC, Clagett-Dame M. 2008 A nutritional model of late embryonic vitamin A deficiency produces defects in organogenesis at a high penetrance and reveals new roles for the vitamin in skeletal development. Dev Biol 316: 171e190. 5. Tanumihardjo SA. 2011 Vitamin A: biomarkers of nutrition for development. Am J Clin Nutr 94:658Se665S. 6. Tanumihardjo SA. 2008 Food-based approaches for ensuring adequate vitamin A nutrition. Comp Rev Food Sci Food Safety 7:373e381. 7. Institute of Medicine, Food and Nutrition Board. 2001 Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press:65e126. 8. Tanumihardjo SA, Palacios N, Pixley KV. 2010 Provitamin A carotenoid bioavailability: what really matters? Int J Vitam Nutr Res 80:336e350. 9. Caire-Juvera G, Ritenbaugh C, Wactawski-Wende J, et al. 2009 Vitamin A and retinol intakes and the risk of fractures among participants of the Women’s Health Initiative Observational Study. Am J Clin Nutr 89:323e330. 10. Yamaguchi M. 2008 b-Cryptoxanthin and bone metabolism: the preventive role in osteoporosis. J Health Sci 54:356e369. 11. Macpherson H, Pipingas A, Pase MP. 2013 Multivitaminmultimineral supplementation and mortality: a meta-analysis of randomized controlled trials. Am J Clin Nutr 97:437e444. 12. Myhre AM, Carlsen MH, Bohn SK, et al. 2003 Watermiscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations. Am J Clin Nutr 78:1152e1159. 13. Duerbeck NB, Dowling DD. 2012 Vitamin A: too much of a good thing? Obstet Gynecol Surv 67:122e128.
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