| Subject: Re: Vitamin A |
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ca
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Date Posted: 14:03:06 10/26/12 Fri
Author Host/IP: nat-8-165-91-11-225.tamulink.tamu.edu/165.91.11.225
In reply to:
Naqibullah jogezai
's message, "Vitamin A" on 00:10:33 10/20/06 Fri
>Vitamin A
>
>
>
>
>Vitamin A is a generic term for a large number of
>related compounds. Retinol (an alcohol) and retinal
>(an aldehyde) are often referred to as preformed
>vitamin A. Retinal can be converted by the body to
>retinoic acid, the form of vitamin A known to affect
>gene transcription. Retinol, retinal, retinoic acid,
>and related compounds are known as retinoids.
>Beta-carotene and other carotenoids that can be
>converted by the body into retinol are referred to as
>provitamin A carotenoids. Hundreds of different
>carotenoids are synthesized by plants, but only about
>10 % of them are provitamin A carotenoids[1]
>
>
>Discovery
>
>In 1913, Elmer McCollum, a biochemist at the
>University of Wisconsin, and colleague Marguerite
>Davis identified a fat-soluble nutrient in butterfat
>and cod liver oil. Their work confirmed that of Thomas
>Osborne and Lafayette Mendel, at Yale, which suggested
>a fat-soluble nutrient in butterfat, also in 1913 [1].
>Vitamin A was first synthesized in 1947.
>meow
>Structure
>Many different geometric isomers of retinol, retinal
>and retinoic acid are possible as a result of either a
>trans or cis configuration of the four double bonds
>found in the polyene chain. The cis isomers are less
>stable and can readily convert to the all-trans
>configuration. Nevertheless, some cis isomers are
>found naturally and carry out essential functions. For
>example, the 11-cis-retinal isomer is the chromophore
>of rhodopsin, the vertebrate photoreceptor molecule.
>Rhodopsin is comprised of the 11-cis-retinal
>covalently linked via a Schiff base to the opsin
>protein (either rod opsin or blue, red or green cone
>opsins). The process of vision relies on the
>light-induced isomerisation of the chromophore from
>11-cis to all-trans resulting in a change of the
>conformation and activation of the photoreceptor
>molecule.
>Vitamin A or retinol has a structure depicted to the
>right. Retinol is the immediate precursor to two
>important active metabolites: retinal, which plays a
>critical role in vision, and retinoic acid, which
>serves as an intracellular messenger that affects
>transcription of a number of genes. Vitamin A does not
>occur in plants, but many plates contain carotenoids
>such as beta-carotene that can be converted to vitamin
>A within the intestine and other tissues.
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>Sources
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>Different dietary sources of vitamin A have different
>potencies. For example, beta-carotene is less easily
>absorbed than retinol and must be converted to retinal
>and retinol by the body. The most recent international
>standard of measure for vitamin A is retinol activity
>equivalency (RAE), which represents vitamin A activity
>as retinol. Two micrograms (mcg) of beta-carotene in
>oil provided as a supplement can be converted by the
>body to 1 mcg of retinol giving it an RAE ratio of
>2:1. However, 12 mcg of beta-carotene from foods are
>required to provide the body with 1 mcg of retinol,
>giving dietary beta-carotene an RAE ratio of 12:1.
>Other provitamin A carotenoids in foods are less
>easily absorbed than beta-carotene, resulting in RAE
>ratios of 24:1. The RAE ratios for beta-carotene and
>other provitamin A carotenoids are shown in the table
>below. An older international standard, still commonly
>used, is the international unit (IU). One IU is
>equivalent to 0.3 mcg of retinol
>
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>Retinol activity equivalency (RAE) ratios for
>beta-carotene and other provitamin A carotenoids
>Quantity Consumed Quantity Bioconverted to Retinol
>RAE ratio
>1 mcg of dietary or supplemental vitamin A 1 mcg of
>retinol* 1:1
>2 mcg of supplemental beta-carotene 1 mcg of retinol
>2:1
>12 mcg of dietary beta-carotene 1 mcg of retinol
>12:1
>24 mcg of dietary alpha-carotene 1 mcg of retinol
>24:1
>24 mcg of dietary beta-cryptoxanthin 1 mcg of retinol
>24:1
>
>
>Food sources
>Free retinol is not generally found in foods. Retinyl
>palmitate, a precursor and storage form of retinol, is
>found in foods from animals. Plants contain
>carotenoids, some of which are precursors for vitamin
>A (e.g., alpha-carotene and beta-carotene). Yellow and
>orange vegetables contain significant quantities of
>carotenoids. Green vegetables also contain
>carotenoids, though the pigment is masked by the green
>pigment of chlorophyll (1). A number of good food
>sources of vitamin A are listed in the table below
>along with their vitamin A content in retinol activity
>equivalents (mcg RAE). In those foods where retinol
>activity comes mainly from provitamin A carotenoids,
>the carotenoid content and the retinol activity
>equivalents are presented. You may use the USDA food
>composition database to check foods for their content
>of several different carotenoids, including lycopene,
>lutein and zeaxanthin.
>
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>Food Serving Vitamin A, RAE Vitamin A, IU Retinol, mcg
>Retinol, IU
>Cod liver oil 1 teaspoon 1,350 mcg 4,500 IU 1,350
>mcg 4,500 IU
>Fortified breakfast cereals 1 serving 150-230 mcg
>500-767 IU 150-230 mcg 500-767 IU
>Egg 1 large 91 mcg 303 IU 89 mcg 296 IU
>Butter 1 tablespoon 97 mcg 323 IU 95 mcg 317 IU
>Whole milk 1 cup (8 fl ounces) 68 mcg 227 IU 68 mcg
>227 IU
>2% fat milk (vitamin A added) 1 cup (8 fl ounces) 134
>mcg 447 IU 134 mcg 447 IU
>Nonfat milk (vitamin A added) 1 cup (8 fl ounces) 149
>mcg 500 IU 149 mcg 500 IU
>Sweet potato 1/2 cup, mashed 959 mcg 3,196 IU 0 0
>Carrot (raw) 1/2 cup, chopped 385 mcg 1,283 IU 0 0
>Cantaloupe 1/2 medium melon 466 mcg 1,555 IU 0 0
>Spinach 1/2 cup, cooked 472 mcg 1,572 IU 0 0
>Squash, butternut 1/2 cup, cooked 572 mcg 1,906 IU
>0 0
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>Function
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>Vision
>
>The retina is located at the back of the eye. When
>light passes through the lens, it is sensed by the
>retina and converted to a nerve impulse for
>interpretation by the brain. Retinol is transported to
>the retina via the circulation, where it moves into
>retinal pigment epithelial cells (diagram)(2).
>
>The Visual Cycle
>
>
>Retinol is transported to the retina via the
>circulation, where it moves into retinal pigment
>epithelial cells. There, retinol is esterified to form
>a retinyl ester that can be stored. When needed,
>retinyl esters are broken apart (hydrolyzed) and
>isomerized to form 11-cis retinol, which can be
>oxidized to form 11-cis retinal. 11-cis Retinal can be
>shuttled to the rod cell, where it binds to a protein
>called opsin to form the visual pigment, rhodopsin
>(visual purple). Absorption of a photon of light
>catalyzes the isomerization of 11-cis retinal to
>all-trans retinal and results in its release. This
>isomerization triggers a cascade of events, leading to
>the generation of an electrical signal to the optic
>nerve. The nerve impulse generated by the optic nerve
>is conveyed to the brain where it can be interpreted
>as vision. Once released all-trans retinal is
>converted to all-trans retinol, which can be
>transported across the interphotoreceptor matrix to
>the retinal epithelial cell to complete the visual
>cycle.
> There, retinol is esterified to form a retinyl
>ester, which can be stored. When needed, retinyl
>esters are broken apart (hydrolyzed) and isomerized to
>form 11-cis retinol, which can be oxidized to form
>11-cis retinal. 11-cis Retinal can be shuttled across
>the interphotoreceptor matrix to the rod cell, where
>it binds to a protein called opsin to form the visual
>pigment, rhodopsin (visual purple). Rod cells with
>rhodopsin can detect very small amounts of light,
>making them important for night vision. Absorption of
>a photon of light catalyzes the isomerization of
>11-cis retinal to all-trans retinal and results in its
>release. This isomerization triggers a cascade of
>events, leading to the generation of an electrical
>signal to the optic nerve. The nerve impulse generated
>by the optic nerve is conveyed to the brain where it
>can be interpreted as vision. Once released all-trans
>retinal is converted to all-trans retinol, which can
>be transported across the interphotoreceptor matrix to
>the retinal epithelial cell to complete the visual
>cycle (2). Inadequate retinol available to the retina
>results in impaired dark adaptation, known as "night
>blindness."
>Regulation of gene expression
>Retinoic acid (RA) and its isomers act as hormones to
>affect gene expression and thereby influence numerous
>physiological processes. All-trans RA and 9-cis RA are
>transported to the nucleus of the cell bound to
>cytoplasmic retinoic acid-binding proteins (CRABP).
>Within the nucleus, RA binds to retinoic acid receptor
>proteins (diagram)
>
>. All-trans RA binds to retinoic acid receptors (RAR)
>and 9-cis RA binds to retinoid receptors (RXR). RAR
>and RXR form RAR/RXR heterodimers, which bind to
>regulatory regions of the chromosome called retinoic
>acid response elements (RARE). A dimer is a complex of
>two protein molecules. Heterodimers are complexes of
>two different proteins, while homodimers are complexes
>of two of the same protein. Binding of all-trans RA
>and 9-cis RA to RAR and RXR respectively allows the
>complex to regulate the rate of gene transcription,
>thereby influencing the synthesis of certain proteins
>used throughout the body. RXR may also form
>heterodimers with thyroid hormone receptors (THR) or
>vitamin D receptors (VDR). In this way, vitamin A,
>thyroid hormone, and vitamin D may interact to
>influence gene transcription (3). Through the
>stimulation and inhibition of transcription of
>specific genes, retinoic acid plays a major role in
>cellular differentiation, the specialization of cells
>for highly specific physiological roles. Most of the
>physiological effects attributed to vitamin A appear
>to result from its role in cellular differentiation
>Immunity
>Vitamin A is commonly known as the anti-infective
>vitamin, because it is required for normal functioning
>of the immune system (4). The skin and mucosal cells
>(cells that line the airways, digestive tract, and
>urinary tract) function as a barrier and form the
>body's first line of defense against infection.
>Retinol and its metabolites are required to maintain
>the integrity and function of these cells (5). Vitamin
>A and retinoic acid (RA) play a central role in the
>development and differentiation of white blood cells,
>such as lymphocytes that play critical roles in the
>immune response. Activation of T-lymphocytes, the
>major regulatory cells of the immune system, appears
>to require all-trans RA binding of RAR
>Growth and development
>Both vitamin A excess and deficiency are known to
>cause birth defects. Retinol and retinoic acid (RA)
>are essential for embryonic development (4). During
>fetal development, RA functions in limb development
>and formation of the heart, eyes, and ears (6).
>Additionally, RA has been found to regulate expression
>of the gene for growth hormone
>Red blood cell production
>Red blood cells, like all blood cells, are derived
>from precursor cells called stem cells. These stem
>cells are dependent on retinoids for normal
>differentiation into red blood cells. Additionally,
>vitamin A appears to facilitate the mobilization of
>iron from storage sites to the developing red blood
>cell for incorporation into hemoglobin, the oxygen
>carrier in red blood cells (2, 7).
>Disease Prevention
>Studies in cell culture and animal models have
>documented the capacity for natural and synthetic
>retinoids to reduce carcinogenesis significantly in
>skin, breast, liver, colon, prostate, and other sites
>(2). However, the results of human studies examining
>the relationship between the consumption of preformed
>vitamin A and cancer are less clear
>Breast cancer
>Retinol and its metabolites have been found to reduce
>the growth of breast cancer cells in the test tube,
>but observational studies of dietary retinol intake in
>humans have been less optimistic. The majority of
>epidemiological studies have failed to find
>significant associations between retinol intake and
>breast cancer risk in women (8-9), although one large
>prospective study found total vitamin A intake to be
>inversely associated with the risk of breast cancer in
>premenopausal women with a family history of breast
>cancer. Blood levels of retinol reflect the intake of
>both preformed vitamin A and provitamin A carotenoids
>like b-carotene. Although a recent case-control study
>found serum retinol levels and serum antioxidant
>levels to be inversely related to the risk of breast
>cancer, two recent prospective studies did not observe
>significant associations between blood retinol levels
>and the subsequent risk of developing breast cancer.
>Presently, there is little evidence in humans that
>increased intake of preformed vitamin A or retinol
>reduces breast cancer risk
>Diseases of the skin
>Both natural and synthetic retinoids have been used as
>pharmacologic agents to treat disorders of the skin.
>Etretinate and acitretin are retinoids that have been
>useful in the treatment of psoriasis, while tretinoin
>(Retin-A) and isotretinoin (Accutane) have been used
>successfully to treat severe acne. Retinoids most
>likely affect the transcription of skin growth factors
>and their receptors (10).
>Acute promyelotic leukemia
>Normal differentiation of myeloid stem cells in the
>bone marrow gives rise to platelets, red blood cells,
>and white blood cells, which are important for the
>immune response. Altered differentiation of those stem
>cells results in the proliferation of immature
>leukemic cells, giving rise to leukemia. A mutation of
>the retinoic acid receptor RAR has been discovered in
>patients with a specific type of leukemia called acute
>promyelotic leukemia (APL). Treatment with all-trans
>retinoic acid or high doses of all-trans retinyl
>palmitate restores normal differentiation, and leads
>to improvement in some APL patients(11)
>Deficiency
>Vitamin A deficiency among children in developing
>nations is the leading preventable cause of blindness
>(12). The earliest evidence of vitamin A deficiency is
>impaired dark adaptation or night blindness. Mild
>vitamin A deficiency may result in changes in the
>conjunctiva (corner of the eye) called Bitot's spots.
>Severe or prolonged vitamin A deficiency causes a
>condition called xeropthalmia (dry eye), characterized
>by changes in the cells of the cornea (clear covering
>of the eye) that ultimately result in corneal ulcers,
>scarring, and blindness. Vitamin A deficiency can be
>considered a nutritionally acquired immunodeficiency
>disease (13). Even children who are only mildly
>deficient in vitamin A have a higher incidence of
>respiratory disease and diarrhea, as well as a higher
>rate of mortality from infectious disease, than
>children who consume sufficient vitamin A (14).
>Supplementation of vitamin A has been found to
>decrease the severity of and deaths from diarrhea and
>measles in developing countries, where vitamin A
>deficiency is common (15). HIV-infected women who were
>vitamin A deficient were three to four times more
>likely to transmit HIV to their infants (16). The
>onset of infection reduces blood retinol levels very
>rapidly. This phenomenon is generally believed to be
>related to decreased synthesis of retinol binding
>protein (RBP) by the liver. In this manner, infection
>stimulates a vicious cycle, because inadequate vitamin
>A nutritional status is related to increased severity
>and likelihood of death from infectious disease (17).
>1-Keratomalacia
>A condition associated with vitamin A deficiency and
>protein-calorie malnutrition, characterized by a hazy,
>dry cornea that becomes denuded.Corneal ulceration
>with secondary infection is common. The lacrimal
>glands and conjunctiva are also affected. Lack of
>tears causes extreme dryness of the eyes, and foamy
>Bitot's spots appear on the bulbar conjunctiva. Night
>blindness may be associated.
>
>2-Nyctalopia,
>This also known as moon blink, was a temporary night
>blindness believed to be caused by sleeping in
>moonlight in the tropics. (Greek for "night
>blindness") is a condition making it difficult or
>impossible to see in the dark. It is a symptom of
>several eye diseases. Night blindness may exist from
>birth, or be caused by injury or malnutrition (for
>example, a lack of vitamin A).The most common cause of
>nyctalopia is retinitis pigmentosa, a disorder in
>which the rod cells in the retina gradually lose their
>ability to respond to the light. Patients suffering
>from this genetic condition have progressive
>nyctalopia and eventually their daytime vision may
>also be affected. In congenital stationary night
>blindness, the rods do not work / work very little
>from birth, but as the name implies, sufferers do not
>get worse.
>Another cause of night blindness is a deficiency of
>retinol, or vitamin A, found in fish oils, liver and
>dairy products. In the Second World War, pilots flying
>night missions were encouraged to eat plenty of
>carrots, which contain carotenoids and can be
>converted into retinol.The opposite problem, known as
>hemeralopia, is much rarer.
>The outer area of the retina is made up of more rods
>than cones. The rod cells are the cells that enable us
>to see in poor illumination. This is the reason why
>loss of side vision often results in night blindness.
>Individuals suffering from night blindness not only
>see poorly at night, but also require some time for
>their eyes to adjust from brightly lit areas to dim
>ones. Contrast vision may also be greatly reduced.
>
>Vitamin A excess
>1-Osteoporosis
>It is a disease of bone in which the bone mineral
>density (BMD) is reduced, bone microarchitecture is
>disrupted, and the amount and variety of
>non-collagenous proteins in bone is changed.
>Osteoporotic bones are more susceptible to fracture.
>Osteoporosis is defined by the World Health
>Organization (WHO) as either a bone mineral density
>2.5 standard deviations below peak bone mass
>(20-year-old person standard) as measured by DXA, or
>any fragility fracture. While treatment modalities are
>becoming available, prevention is still the most
>important way to reduce fracture. Due to its hormonal
>component, more women, particularly after menopause,
>suffer from osteoporosis than men.
>Osteoporosis can be thought of as analogous to
>"sarcopenia", which is the age-related loss of
>skeletal muscle. The combination of sarcopenia and
>osteporosis results in the significant frailty often
>seen in the elderly population
>Risk factors
>Risk factors for osteoporotic fracture can be split
>between modifiable and non-modifiable:
>Nonmodifiable: history of fracture as an adult, family
>history of fracture, female sex, advanced age,
>European or Asian ancestry, and dementia
>Potentially modifiable: prolonged intake of the
>prescription drug prednisone, tobacco smoking, intake
>of soft drinks (containing phosphoric acid), low body
>weight <58 kg (127 lb), estrogen deficiency, early
>menopause (<45 years) or bilateral oophorectomy,
>premature ovarian failure, prolonged premenstrual
>amenorrhea (>1 year), low calcium and vitamin D
>intake, alcoholism, impaired eyesight despite adequate
>correction, recurrent falls, inadequate physical
>activity (i.e. too little or also if done in excess),
>high risk of falls, poor health/frailty. Coeliac
>disease can lead those with an otherwise adequate
>calcium intake to develop osteoperosis due to the
>inability to absorb calcium. Osteoporotic fracture may
>indeed be the event that leads to diagnosis that
>coeliac disease (which affects around one in a hundred
>people in the West[1]) has affected the patient for
>many years.
>A strong association between cadmium, lead and
>osteoporosis has also been established. Low level
>exposure to cadmium is associated with an increased
>loss of bone mineral density readily in both genders,
>leading to osteoporosis and increased risk of
>fractures, especially in elderly and in females. [2]
>[3] [4]
>Diagnosis
>Dual energy X-ray absorptiometry (DXA, formerly DEXA)
>is considered the gold standard for diagnosis of
>osteoporosis. Diagnosis is made when the bone mineral
>density is less than or equal to 2.5 standard
>deviations below that of a young adult reference
>population. This is translated as a T-score. The World
>Health Organization has established diagnostic
>guidelines as T-score -1.0 or greater is "normal",
>T-score between -1.0 and -2.5 is "low bone mass" (or
>"osteopenia") and -2.5 or below as osteoporosis. A low
>trauma or osteoporotic fracture, defined as one that
>occurs as a result of a fall from a standing height,
>is also diagnostic of osteoporosis regardless of the
>T-score.
>In order to differentiate between "primary"
>(post-menopausal, regardless of age, or senile -
>related to age) and "secondary" osteoporosis, blood
>tests and X-rays are usually done to rule out cancer
>with metastasis to the bone, multiple myeloma,
>Cushing's disease and other causes mentioned above.
>Pathogenesis
>The underlying mechanism in all cases of osteoporosis
>is an imbalance between bone resorption and bone
>formation. Either bone resorption is excessive, and/or
>bone formation is diminished. Bone matrix is
>manufactured by the osteoblast cells, whereas bone
>resorption is accomplished by osteoclast cells. The
>mechanisms influencing the formation of the disease
>are complex. Most cases do not result from inadequate
>calcium intake, but include other factors affecting
>bone matrix formation and reabsorption. These include:
>(1) cigarette smoking, which inhibits the activity of
>osteoblasts; (2) sedentary lifestyle with little
>weight bearing exercise, such as walking; (3) a family
>history of osteoporosis; and being age 30 or older.
>Both men and women are at equal risk starting at age
>30. Trabecular bone is the sponge-like bone in the
>center of long bones and vertebrae. Cortical bone is
>the hard outer shell of bones. Because osteoblasts and
>osteoclasts inhabit the surface of bones, trabecular
>bone is more active, more subject to bone turnover, to
>remodeling. Long before any overt fractures occur, the
>small spicules of trabecular bone break and are
>reformed in the process known as remodeling. Bone will
>grow and change shape in response to physical stress.
>The bony prominences and attachments in runners are
>different in shape and size than those in
>weightlifters. It is an accumulation of fractures in
>trabecular bone that are incompletely repaired that
>leads to the manifestation of osteoporosis. Common
>osteoporotic fracture sites, the wrist, the hip and
>the spine, have a relatively high trabecular bone to
>cortical bone ratio. These areas rely on trabecular
>bone for strength.
>Low peak bone mass is important in the development of
>osteoporosis. Bone mass peaks in both men and women
>between the ages of 25 and 35, thereafter diminishing.
>Achieving a higher peak bone mass through exercise and
>proper nutrition during adolescence is important for
>the prevention of osteoporosis.
>Bone remodeling is heavily influenced by nutritional
>and hormonal factors. Calcium and vitamin D are
>nutrients required for normal bone growth. Parathyroid
>hormone regulates the mineral composition of bone,
>with higher levels causing resorption of calcium and
>bone. Glucocorticoid hormones cause osteoclast
>activity to increase, causing bone resorption.
>Calcitonin, estrogen and testosterone increase
>osteoblast activity, causing bone growth. The loss of
>estrogen following menopause causes a phase of rapid
>bone loss. Similarly, testosterone levels in men
>diminish with advancing age and are related to male
>osteoporosis. In addition to estrogen,
>follicle-stimulating hormone (FSH) affects BMD. In
>mice, lower levels of FSH mean less resorption by
>osteoclasts.[5]
>Physical activity causes bone remodeling. People who
>remain physically active throughout life have a lower
>risk of osteoporosis. Conversely, people who are
>bedridden are at a significantly increased risk.
>Physical activity has its greatest impact during
>adolescence, affecting peak bone mass most. In adults,
>physical activity helps maintain bone mass, and can
>increase it by 1 or 2%. However, excessive exercise
>can lead to constant damages to the bones which can
>cause exhaustion of the structures as described above.
>There are numerous examples of marathon runners who
>developed severe osteoporosis later in life.
>Lastly, osteoporosis on its own would not be a
>significant disease, were it not for the falls which
>precipitate fractures. Age-related sarcopenia, or loss
>of muscle mass, loss of balance and dementia
>contribute greatly to the increased fracture risk in
>patients with osteoporosis. Physical fitness in later
>life is associated more with a decreased risk of
>falling than with an increased bone mineral density.
>Treatment
>Patients at risk for osteoporosis (e.g. steroid use)
>are generally treated with vitamin D and calcium
>supplements. In renal disease, a different form of
>Vitamin D (1,25-dihydroxycholecalciferol or calcitriol
>which is the main biologically active form of vitamin
>D) is used, as the kidney cannot adequately generate
>calcitriol from calcidiol (25-hydroxycholecalciferol)
>which is the storage form of vitamin D.
>In osteoporosis (or a very high risk), bisphosphonate
>drugs are prescribed. The most often prescribed
>bisphosphonates are presently sodium alendronate
>(Fosamax®) 10 mg a day or 70 mg once a week,
>risedronate (Actonel®) 5mg a day or 35mg once a week
>or and ibandronate (Boniva® once a month).
>Other medicines prescribed for prevention of
>osteoporosis include raloxifene (Evista®), a selective
>estrogen receptor modulator (SERM). Estrogen
>replacement remains a good treatment for prevention of
>osteoporosis but, at this time, is not recommended
>unless there are other indications for its use as well.
>Recently, teriparatide (Forteo®, recombinant
>parathyroid hormone 1-34) has been shown to be
>effective in osteoporosis. It is used mostly for
>patients who have already fractured, have particularly
>low BMD or several risk factors for fracture or cannot
>tolerate the oral bisphosphonates. It is given as a
>daily injection with the use of a pen-type injection
>device. Teriparatide is only licensed for treatment if
>bisphosphonates have failed or are contraindicated
>(however, this differs by country).
>Oral Strontium ranelate (Protelos® - Servier) is the
>first in a new class of drugs called a Dual Action
>Bone Agents (DABA's), and has proven efficacy in the
>prevention of vertebral and non-vertebral fractures
>(including hip fracture). Strontium Ranelate works by
>stimulating the proliferation of osteoblast (bone
>building) cells, and inhibiting the proliferation of
>osteoclast (bone absorbing) cells. This means that
>strontium Ranelate increases BMD by forming new bone,
>rather than just preserving existing bone. In
>comparison to bisphosphonates which only act on one
>aspect of bone remodeling, strontium ranelate also
>preserves bone turnover, allowing the
>microarchitecture of the bone to be continuously
>repaired as it would in healthy bone. Strontium
>ranelate is taken as a 2g oral suspension daily, and
>is licenced for the treatment of osteoporosis to
>prevent vertebral and hip fracture (this may differ by
>country). Strontium ranelate has show significant
>efficacy at reducing both vertebral, and non-vertebral
>fractures in patients over the age of 80, who are the
>most at risk where osteoporosis is concerned. This is
>unique to strontium ranelate as bisphosphonates can
>only show efficacy in vertebral fracture reduction,
>not non-vertabral. Strontium ranelate has side effect
>benefits over the bisphosphonates, as it does not
>cause any form of upper GI side effect, which is the
>most common cause for medication withdrawal in
>osteoporosis.
>Changes to lifestyle factors and diet are also
>recommended; the "at-risk" patient should include
>1500mg of calcium daily either via dietary means (for
>instance, an 8 oz glass of milk contains approximately
>300 mg of calcium) or via supplementation. The body
>will absorb only about 500 mg of calcium at one time
>and so intake should be spread throughout the day.
>However, the benefit of supplementation of calcium
>alone remains, to a degree, controversial since
>several nations with high calcium intakes through
>milk-products (e.g. the USA, Sweden) have some of the
>highest rates of osteoporosis worldwide. A few studies
>even suggested an adverse effect of calcium excess on
>bone density and blamed the milk industry for
>misleading customers. Some nutrionists assert that
>excess consumption of dairy products causes
>acification, which leeches calcium from the system,
>and argue that vegetables and nuts are a better source
>of calcium and that in fact milk products should be
>avoided. In any case, thirty minutes of weight-bearing
>exercise such as walking or jogging, three times a
>week, has been shown to increase bone mineral density,
>and reduce the risk of falls by strengthening the
>major muscle groups in the legs and back.
>In a recent study that examined the relationship
>between calcium supplementation and clinical fracture
>risk in an elderly population, there was a significant
>decrease in fracture risk in patients that received
>calcium supplements versus those that received
>placebo. However, this benefit only applied to
>patients who were compliant to their treatment
>regimen. [6]
>Increasing vitamin D intake has been shown to reduce
>fractures up to twenty-five percent in older people,
>according to recent studies.
>There is some evidence to suggest bone density
>benefits from taking the following supplements (in
>addition to calcium and vitamin D): boron, magnesium,
>zinc, copper, manganese, silicon, strontium, folic
>acid, and vitamins B6, C, and K. [7] [8]
>2-Teratogenesis
>It is a medical term from the Greek, literally meaning
>monster-making, which derives from teratology, the
>study of the frequency, causation, and development of
>congenital malformations—misleadingly called birth
>defects. These include gross morphological
>abnormalities, such as cleft lip and/or palate,
>anencephaly, or ventricular septal defect, but may
>also include phenomena such as increased risk of
>cervical cancer or discoloration of tooth enamel.
>These malformations can arise from genetic
>abnormalities of the fetus, from adverse environmental
>circumstances (termed teratogens or tetragens), or a
>combination of these factors. Teratogenesis has gained
>a more specific usage for the development of abnormal
>cell masses during fetal growth (see pregnancy),
>causing physical defects in the fetus.
>
>
>
>Isotretinoin (13-cis-retinoic-acid)
> Often used to treat severe acne, is such a strong
>teratogen that just a single dose taken by a pregnant
>woman may result in serious birth defects. Because of
>this effect, most countries have systems in place to
>ensure that it is not given to pregnant women, and
>that the patient is aware of how important it is to
>prevent pregnancy during and at least one month after
>treatment. Medical guidelines also suggest that
>pregnant women should limit vitamin A intake to about
>700 μg/day, as it has teratogenic potential when
>consumed in excess.[3][
>
>
>
>Recommended Dietary Allowance (RDA) for Vitamin A as
>Preformed Vitamin A (Retinol)
>Life Stage Age Males: mcg/day (IU/day) Females:
>mcg/day (IU/day)
>Infants 0-6 months 400 (1333 IU) 400 (1333 IU)
>Infants 7-12 months 500 (1667 IU) 500 (1667 IU)
>Children 1-3 years 300 (1000 IU) 300 (1000 IU)
>Children 4-8 years 400 (1333 IU) 400 (1333 IU)
>Children 9-13 years 600 (2000 IU) 600 (2000 IU)
>Adolescents 14-18 years 900 (3000 IU) 700 (2333 IU)
>Adults 19 years and older 900 (3000 IU) 700 (2333
>IU)
>Pregnancy 18 years and younger - 750 (2500 IU)
>Pregnancy 19-years and older - 770 (2567 IU)
>Breastfeeding 18 years and younger - 1,200 (4000
>IU)
>Breastfeeding 19-years and older - 1,300 (4333 IU)
>
>
>Safety
>Safety in pregnancy
>Although normal fetal development requires sufficient
>vitamin A intake, consumption of excess preformed
>vitamin A (retinol) during pregnancy is known to cause
>birth defects. No increase in the risk of vitamin
>A-associated birth defects has been observed at doses
>of preformed vitamin A from supplements below 3,000
>mcg/day (10,000 IU/day) (18). Since a number of foods
>in the U.S. are fortified with preformed vitamin A,
>pregnant women should avoid multivitamin or prenatal
>supplements that contain more than 1,500 mcg (5,000
>IU) of vitamin A . Vitamin A from beta-carotene is not
>known to increase the risk of birth defects.
>Etretinate and isotretinoin (Accutane), synthetic
>derivatives of retinol, are known to cause birth
>defects and should not be taken during pregnancy or if
>there is a possibility of becoming pregnant. Tretinoin
>(Retin-A), another retinol derivative, is prescribed
>as a topical preparation that is applied to the skin.
>Because of the potential for systemic absorption of
>topical tretinoin, its use during pregnancy is not
>recommended
>Toxicity
>The condition caused by vitamin A toxicity is called
>hypervitaminosis A. It is caused by overconsumption of
>preformed vitamin A, not carotenoids. Preformed
>vitamin A is rapidly absorbed and slowly cleared from
>the body, so toxicity may result acutely from
>high-dose exposure over a short period of time, or
>chronically from much lower intake (2). Vitamin A
>toxicity is relatively rare. Symptoms include nausea,
>headache, fatigue, loss of appetite, dizziness, and
>dry skin. Signs of chronic toxicity include, dry itchy
>skin, loss of appetite, headache, and bone and joint
>pain. Severe cases of hypervitaminosis A may result in
>liver damage, hemorrhage, and coma. Generally, signs
>of toxicity are associated with long-term consumption
>of vitamin A in excess of 10 times the RDA (8,000 to
>10,000 mcg/day or 25,000 to 33,000 IU/day). However,
>there is evidence that some populations may be more
>susceptible to toxicity at lower doses, including the
>elderly, chronic alcohol users, and some people with a
>genetic predisposition to high cholesterol (9). In
>January 2001, the Food and Nutrition Board (FNB) of
>the Institute of Medicine set the tolerable upper
>level (UL) of vitamin A intake for adults at 3,000 mcg
>(10,000 IU)/day of preformed vitamin A (18)
>Chronic alcohol consumption results in depletion of
>liver stores of vitamin A, and may contribute to
>alcohol-induced liver damage. However, the liver
>toxicity of preformed vitamin A (retinol) is enhanced
>by chronic alcohol consumption, thus narrowing the
>therapeutic window for vitamin A supplementation in
>alcoholics . Oral contraceptives that contain estrogen
>and progestin increase retinol binding protein (RBP)
>synthesis by the liver, increasing the export of
>RBP-retinol complex in the blood. Whether this
>increases the dietary requirement of vitamin A is not
>known. Retinoids or retinoid analogs, including
>acitretin, all-trans-retinoic acid, bexarotene,
>etretinate and isotretinoin (Accutane), should not be
>used in combination with vitamin A supplements,
>because they may increase the risk of vitamin A
>toxicity
>Recommendation
>The RDA for vitamin A (2,300 IU/day for women and
>3,000 IU/day for men) is sufficient to support normal
>gene expression, immune function, and vision. However,
>following the Linus Pauling Institute’s recommendation
>to take a multivitamin/multimineral supplement daily
>could supply as much as 5,000 IU/day of vitamin A as
>retinol, the amount that has been associated with
>adverse effects on bone health in older adults. For
>this reason, we recommend taking a
>multivitamin/multimineral supplement that provides no
>more than 2,500 IU of vitamin A or a supplement that
>provides 5,000 IU of vitamin A, of which at least 50%
>comes from beta-carotene (see example supplement
>label). High potency vitamin A supplements should not
>be used without medical supervision due to the risk of
>toxicity.
>
>Tolerable Upper Level of Intake (UL) for Preformed
>Vitamin A (Retinol)
>Age Group UL in mcg/day (IU/day)
>Infants 0-12 months 600 (2,000 IU)
>Children 1-3 years 600 (2,000 IU)
>Children 4-8 years 900 (3,000 IU)
>Children 9-13 years 1,700 (5,667 IU)
>Adolescents 14-18 years 2,800 (9,333 IU)
>Adults 19 years and older 3,000 (10,000 IU
>Dietary Reference Intakes for Vitamin A
> Children (< 4 yrs): 300 μg
> Children (4+ yrs): 400 - 600 μg
> Women: 700 μg
> Men: 600 μg
> Lactation: 1200 μg
>References
>1 Barker ME, Blumsohn A. Is vitamin A consumption a
>risk factor for osteoporotic fracture?. Proc Nutr Soc.
>2003;62:845-850. [Medline].
>2 Bates CJ. Vitamin A. Lancet. Jan 7
>1995;345(8941):31-5. [Medline].
>3 Bhalla K, Ennis DM, Ennis ED. Hypercalcemia caused
>by iatrogenic hypervitaminosis A. J Am Diet Assoc.
>2005;105:119-121. [Medline].
>4 Genaro Pde S, Martini LA. Vitamin A supplementation
>and risk of skeletal fracture. Nutr Rev. Feb
>2004;62(2):65-7. [Medline].
>5 Hathcock JN, Hattan DG, Jenkins MY, et al.
>Evaluation of vitamin A toxicity. Am J Clin Nutr. Aug
>1990;52(2):183-202. [Medline].
>6 Hathcock JN. Vitamins and minerals: efficacy and
>safety. Am J Clin Nutr. Aug 1997;66(2):427-37.
>[Medline].
>7 Michaelsson K, Lithell H, Vessby B, et al. Serum
>retinol levels and the risk of fracture. N Engl J Med.
>2003;348:287-294. [Medline].
>8 Miksad R, Ledinghen V, McDougall C, et al. Hepatic
>hydrothorax associated with vitamin A toxicity. J Clin
>Gastroenterol. 2002;34:275-279. [Medline].
>9 Nagai K, Hosaka H, Kubo S, et al. Vitamin A toxicity
>secondary to excessive intake of yellow-green
>vegetables, liver and laver. J Hepatol. Jul
>1999;31(1):142-8. [Medline].
>10 O'Donnell J. Polar hysteria: an expression of
>hypervitaminosis A. Am J Ther. 2004;11:507-516.
>[Medline].
>11 Olson JA. Adverse effects of large doses of vitamin
>A and retinoids. Semin Oncol. Sep 1983;10(3):290-3.
>[Medline].
>12 Perrotta S, Nobili B, Rossi F, et al. Infant
>hypervitaminosis A causes severe anemia and
>thrombocytopenia: evidence of a retinol-dependent bone
>marrow cell growth inhibition. Blood.
>2002;99:2017-2022. [Medline].
>13 Sharieff GQ, Hanten K. Pseudotumor cerebri and
>hypercalcemia resulting from vitamin A toxicity. Ann
>Emerg Med. Apr 1996;27(4):518-21. [Medline].
>14 Browne, M. B. 1993. Label Facts for Healthful
>Eating. Mazer Corporation, Dayton, OH.
>15 Federation of American Societies for Experimental
>Biology, Life Sciences Research Office. Prepared for
>the Interagency Board for Nutrition Monitoring and
>Related Research, 1995. Third Report on Nutrition
>Monitoring in the United States: Volumes 1 and 2. U.S.
>Government Printing Office, Washington, DC.
>16 Subcommittee on the 10th Edition of the RDAs, Food
>and Nutrition Board, Commission on Life Sciences,
>National Research Council. 1987. Recommended Dietary
>Allowances, 10th ed. Academy Press, Washington, DC.
>17 U.S. Department of Agriculture, U.S. Department of
>Health and Human Services. Your Health: Dietary
>Guidelines for Americans, 4th ed. Home and Garden
>Bulletin No. 232. U.S. Government Printing Office,
>Washington, DC
>18 ^ Research Suggests 1 in 100 Brits at Risk for
>Coeliac Disease. Coeliac UK (2006).
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