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Vitamin D and the Skeleton
By Brinda N. Kalro, MD, DABMA, CCD. Dr. Kalro is Assistant Professor, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Hospital, Pittsburgh, PA; she reports no financial relationship to this field of study.
Vitamin D, aptly referred to as the "sunshine vitamin" and the "D-lightful hormone," is a vital nutrient for the formation and maintenance of healthy bones, both in children and adults. Vitamin D has long been regarded as an antirachitic vitamin since its deficiency in children results in rickets. In actual fact, it is a steroid hormone because its nuclear receptor has the ability to upregulate cellular gene expression.1 Vitamin D receptors (VDRs) are present in osteoblasts and various other cell types in the body. Vitamin D deficiency causes rickets in children, and osteoporosis and osteomalacia in adults. Vitamin D deficiency is a problem worldwide and is largely unrecognized and under-treated.
In the mid-1600s, it was noted that children living in industrialized cities of Northern Europe had bony deformities consistent with severe rickets. In 1822, Sniadecki made a similar observation of children living in Warsaw due to lack of sun exposure, but not in the rural areas outside Warsaw.2 In 1890, Palm, an English physician, arrived at the same conclusion based on his correspondence with physicians from India and Asia.3 Folklore has it that in the 1800s on the coasts of Great Britain, the use of cod liver oil to prevent rickets was common.4 Cod liver oil was also effective in preventing rickets in dogs.5 In 1924, Bills evaluated fish for their vitamin D content and found vitamin D in their flesh and oils. Interestingly, not all fish when exposed to sunlight were able to synthesize vitamin D in their skin.6,7 Fish liver oils contain only vitamin D3 and the reason for this is unclear.
Biosynthesis of Vitamin D
There are two forms of vitamin D, which are very similar molecules and essentially have the same biologic potency in humans. Vitamin D2 (ergocalciferol) is a plant-derived sterol and vitamin D3 (cholecalciferol) is fish-derived (flesh and cod liver oil) and synthesized in skin in humans. Both forms are pro-hormones and require activation first by the liver and then the kidneys to become biologically active. Although vitamins D2 and D3 are structurally different, vitamin D2 is just as potent in performing biological functions as D3.8 Vitamin D2 is also as effective as vitamin D3 in maintaining serum 25(OH)-vitamin D levels.9
Vitamin D is acquired via diet, sunlight, or supplements. Dietary sources of vitamin D2 include plants and yeast, and sources of vitamin D3 include oily fish and fish liver oils (salmon, mackerel, and cod liver oil). Other dietary sources of vitamin D include fortified milk, cereals, and breads.
In most vertebrates and in humans, exposure to ultraviolet light (wavelength 290-315 nm) induces cutaneous synthesis of vitamin D3. 7-dehydrocholesterol (7-DHC) in the skin absorbs UVB radiation and is converted to pre-vitamin D3. Factors that interfere with the absorption of UVB radiation by the skin can decrease or block vitamin D synthesis. Topical sunscreens used to prevent skin cancer can block both UVB and UVA radiation and decrease vitamin D production significantly (SPF 15 by 99.9%).10 Melanin in the skin of African and Asian individuals is extremely effective in absorbing UVB radiation. 7-DHC content of the skin also decreases with aging.11 In addition, time of day, season, latitude (away from the equator), and clothing influence cutaneous vitamin D production significantly.
Metabolism of Vitamin D
Vitamin D3 can synthesized in the skin. Vitamin D2 and D3 are ingested in dietary form. Both D2 and D3 (ingested and cutaneous) are hydroxylated in the liver to 25-hydroxyvitamin D2 and D3, respectively. 25-hydroxyvitamin D (both D2 and D3) is the major circulating form of vitamin D and its levels are used to assess the vitamin D status of an individual. The enzyme D-1a hydroxylase in renal cells further converts 25-hydroxy-vitamin D2 or D3 to 1,25-dihydroxyvitamin D2 or D3, respectively. 1,25 dihydroxyvitamin D interacts with its specific VDR in the small intestine and affects intestinal absorption and transport of calcium and phosphate. Only 10-15% of dietary calcium is absorbed in a vitamin D-deficient state, but approximately 30% of dietary calcium is absorbed in a vitamin D-replete state. When there is an increased demand for calcium by the body, free and total circulating concentrations of 1,25 dihydroxyvitamin D increase and intestinal calcium absorption increases by as much as 20-50%.12
RDA of Vitamin D
Since higher intakes of vitamin D can reduce bone resorption and subsequent bone loss, the recommended daily allowance (RDA) of vitamin D has been revised recently. Current guidelines recommend a daily intake of 800-1,000 IU of vitamin D2 or D3 daily in adults.13 Daily intake of vitamin D of up to 1,400 IU daily in the winter months has been reported to be safe.1 The safe upper limit for vitamin D intake for the general adult population was set in 1997 at 2,000 IU per day.14 Serum 25-hydroxyvitamin D levels are a good reflection of the body's vitamin D stores, and the desired adult level is 30 ng/mL (75 nmol/L) or higher.13
Side effects from vitamin D intake are minimal. However, excess supplementation can cause fatigue, lassitude, headache, somnolence, anorexia, nausea, vomiting, constipation, and weight loss. With continued excess intake, polyuria, polydipsia and nocturia, hypercalcemia, and its associated side effects can develop.
For adequate vitamin D from sunlight, a common practical recommendation is 5-15 minutes of sun exposure between the hours of 10 am and 3 pm to the face, arms, hands, and back twice per week in the spring, summer, and autumn. This is usually sufficient to maintain adequate vitamin D levels. Vitamin D intoxication has not been reported from excess chronic sun exposure. However, intoxication can occur with daily dietary intake exceeding 10,000 IU per day.15
In the United States, it is estimated that about 90% of individuals between the ages of 50 and 71 years do not get adequate amounts of vitamin D from their diet.16 In 1989, a national study revealed that the average American spends 93% of their 24-hour day indoors.17 Since then, even less time is spent outside given the increasing availability of air conditioned indoor environments, computers, video games, and extensive television programs.
A survey of women of childbearing age in the United States found that 41% of African-American women and 4% of Caucasian women were vitamin D-deficient at the end of winter and summer, respectively.18 Obese individuals are more likely to be vitamin D-deficient. Circulating vitamin D levels are only 33% of levels in normal-weight individuals.19
Vitamin D in Pregnancy and Lactation
The antirachitic activity of human milk depends on the vitamin D status of the mother, which, apart from maternal vitamin D intake, is affected by race and season. The incidence of rickets in infants who are solely breast-fed is increasing, more so in the winter months and Northern latitudes. Dietary maternal vitamin D supplementation and UV light exposure influences the vitamin D content of human milk.20-22 Circulating 25-hydroxyvitamin D levels in breast-fed infants are directly related to the vitamin D content of breast milk.23
Hypovitaminosis D in the mother and the breast-fed infant is a severe and growing problem even in sun-rich environments.24 Maternal supplementation with high doses of vitamin D (2,000, 4,000, or 6,400 IU per day) appeared to be safe and resulted in increased maternal 25-hydroxyvitamin D levels and improved antirachitic activity of human milk.25,26 Given that breast-fed infants are at increased risk for vitamin D deficiency, the American Academy of Pediatrics in 2003 recommended that all breast-fed children receive 200 IU of supplemental vitamin D daily.27
Vitamin D and Bone Health
Vitamin D is one of the key components of bone health and is also important for muscle health and strength. Increased fracture risk can result from inadequate absorption of calcium, increased rate of bone loss, impaired muscle strength, and increased susceptibility to falling.
Vitamin D deficiency decreases intestinal absorption of calcium. This results in an increase in the synthesis and serum levels of parathyroid hormone (PTH). PTH ramps up the renal production of 1,25-dihydroxyvitamin D levels with a consequent increase in intestinal absorption of calcium. PTH also stimulates bone resorption by osteoclasts to increase serum calcium levels resulting in loss of bone mineralization and consequent increased risk of osteoporosis. This compensatory hyperparathyroidism also increases renal phosphate excretion and hypophosphatemia. This combination of low calcium and phosphate levels results in inadequate mineralization of bone. 1,25-dihydroxyvitamin D and PTH work synergistically to maintain normal levels of calcium in the blood through enhanced intestinal absorption of calcium, decreased urinary calcium loss, or release of calcium from the bones. Serum 25-hydroxyvitamin D levels of less than 20 ng/mL leads to secondary hyperparathyroidism and increased bone turnover states. Calcitonin, a hormone produced by the C cells of the thyroid gland, has a high affinity for bone osteoclasts and acts in opposition to PTH by inhibiting bone resorption by osteoclasts.
Chronic vitamin D deficiency in infants and young children (when growth plates are open) interferes with chondrocyte maturation and inhibits calcification of cartilage. Vascular invasion of the growth plate is suppressed and hypertrophy of the cartilaginous layer occurs in the growth plate causing disorganization of chondrocytes and widening of epiphyseal plates resulting in rickets. Secondary hyperparathyroidism maintains serum calcium levels but there is increased loss of phosphate from the kidneys.
A similar process occurs in adults, but the outcome is different since the epiphyseal plates are closed. In adults both osteomalacia and osteoporosis can result from vitamin D deficiency. In osteomalacia, newly formed bone matrix cannot be adequately mineralized resulting in increased risk of fractures. Osteomalacia can be associated with bone pain, back pain, myalgias, muscle weakness, and radiographic evidence of pseudofractures.
While osteomalacia is often symptomatic with bone pain, osteoporosis is a "silent disease" in the absence of fractures. Osteoporosis is characterized by bone fragility with an increased propensity for fractures of the hip, spine, and forearm, although any bone can be affected. As the bone tissue deteriorates, bone architecture is disrupted causing the bone to become fragile and fracture (or collapse as is the case with vertebrae) from relatively minor falls or trauma.
Individuals of all ethnic backgrounds are susceptible to osteoporosis and the incidence is greater in women than in men. A woman's risk of a hip fracture equals her combined risk of breast, uterine, and ovarian cancer. It is estimated that about 26% of women older than age 65 years in the United States has osteoporosis, and approximately 10 million individuals older than age 50 years have osteoporosis.28 An additional 34 million people have osteopenia or low bone mass. Half of the women with osteoporosis will sustain an osteoporosis-related fracture in their lifetime; 10% of patients with a hip fracture will sustain a further osteoporotic fracture within a year.
Approximately 1.5 million fractures in men and women are reported annually in the United States. Approximately 500,000 hospitalizations, 800,000 emergency department visits, and 180,000 nursing home placements secondary to osteoporosis and its complications occur each year. Fragility fractures are associated with considerable mortality and morbidity requiring long-term care,29 resulting in an enormous economic and social burden on health care and society.30 It therefore becomes important to identify patients at risk for osteoporosis and its complications, and employ timely strategies to prevent and effectively treat the condition.
Vitamin D deficiency can lead to decreased bone mineral density (BMD) per se31 and increased hip fracture risk.32 Adequate vitamin D intake in elderly women was associated with a lower risk of osteoporotic fractures.32 More than half (52%) of postmenopausal women receiving therapy to prevent or treat osteoporosis in North America were found to be vitamin D-deficient when their 25(OH)-vitamin D levels were measured.33
VDRs mediate the hormone's complex effects in many cell types, including osteoblasts and osteoclasts. Polymorphisms in the VDR may account for genetic variations in skeletal metabolism.
All osteoblasts have VDRs. VDR knockout mice helped clarify specific effects of vitamin D on bone. Most mutant mice died young with hypocalcemia. However, maintenance of these mutant mice on a rescue calcium and phosphorus-rich diet completely corrected bone formation and mineralization, but alopecia persisted. This interesting observation suggests that vitamin D may not be necessary for bone matrix formation and mineralization in the presence of normal calcium homeostasis.
Human muscle contains VDRs that are vital to maintenance of muscle strength and stability. Vitamin D deficiency has been associated with lower muscle strength and performance, and increased fall frequency. In the National Health and Nutrition Examination Survey III (NHANES), women aged 60 years and older with low vitamin D levels walked more slowly and rose more slowly from a sitting to standing position than those with normal levels.34 One of the major risk factors for falls in the elderly is muscle weakness. A recent meta-analysis suggests that vitamin D reduces the risk of falling in the elderly by 22%.35
Several randomized, controlled prospective trials have demonstrated decreased fracture risks (hip and vertebral) with vitamin D, both with and without calcium supplementation.36-41 Vitamin D deficiency can also be the cause for continued bone loss in menopausal patients despite estrogen therapy and bisphosphonates. Individuals with unexplained low bone density should have their vitamin D levels assessed. Vitamin D deficiency can also result in delayed healing of fractures in elderly individuals. Hence assessing the vitamin D status of these patients is important.
Patients with celiac disease and those having undergone bariatric surgery can have vitamin D and calcium malabsorption without apparent gastrointestinal symptoms. Other conditions associated with vitamin D deficiency secondary to malabsorption include Crohn's disease, pancreatitis, cystic fibrosis, and resection of the small intestine. Vitamin D deficiency has also been observed in patients following liver and bone marrow transplants and in those with severe burns.42
Vitamin D is an important nutrient in the maintenance of healthy bones and muscles. The primary role of vitamin D is to facilitate intestinal calcium absorption and to maintain serum calcium levels by stimulating bone resorption. Vitamin D deficiency is a common, global problem and is largely undiagnosed. Sun exposure has an important role in providing daily vitamin D requirement in individuals of all ages. Several commercial assays are available to determine serum 25-hydroxyvitamin D levels, which reflect the vitamin D status of an individual. Intake of the RDA of vitamin D is vital in maintaining serum vitamin D, calcium, and phosphorus homeostasis, and musculoskeletal health. Vitamin D-replete states prevent metabolic bone disorders in infants, children, and adults, and decrease the morbidity and mortality associated with these disorders.
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