Vitamin D deficiency is common worldwide. It is a common cause of rickets and osteomalacia, but these disorders may also result from other conditions, such as chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more , various renal tubular disorders, familial hypophosphatemic (vitamin D–resistant) rickets Hypophosphatemic Rickets Hypophosphatemic rickets is a genetic disorder characterized by hypophosphatemia, defective intestinal absorption of calcium, and rickets or osteomalacia unresponsive to vitamin D. It is usually... read more , chronic metabolic acidosis Metabolic Acidosis Metabolic acidosis is primary reduction in bicarbonate (HCO3−), typically with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low or slightly... read more , hyperparathyroidism Metabolic Acidosis Metabolic acidosis is primary reduction in bicarbonate (HCO3−), typically with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low or slightly... read more , hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is a deficiency of parathyroid hormone often caused by an autoimmune disorder or by iatrogenic damage or removal of the glands during thyroidectomy or parathyroidectomy. Symptoms... read more , inadequate dietary calcium, and disorders or drugs that impair the mineralization of bone matrix.
Vitamin D deficiency causes hypocalcemia Hypocalcemia Hypocalcemia is a total serum calcium concentration < 8.8 mg/dL (< 2.20 mmol/L) in the presence of normal plasma protein concentrations or a serum ionized calcium concentration < 4... read more , which stimulates production of parathyroid hormone (PTH), causing hyperparathyroidism Hyperparathyroidism Hyperparathyroidism occurs when one or more of the parathyroid glands become overactive, causing elevated serum levels of parathyroid hormone and leading to hypercalcemia. Patients may be asymptomatic... read more . Hyperparathyroidism increases absorption, bone mobilization, and renal conservation of calcium but increases excretion of phosphate. As a result, the serum level of calcium may be normal, but because of hypophosphatemia, bone mineralization is impaired.
Physiology of Vitamin D Deficiency and Dependency
Vitamin D has 2 main forms:
D3 (cholecalciferol): The naturally occurring form and the form used for low-dose supplementation
Vitamin D3 is synthesized in skin by exposure to direct sunlight (ultraviolet B radiation) and obtained in the diet chiefly in fish liver oils and salt water fish (see table ). In some countries, milk and other foods are fortified with vitamin D. Human breast milk is low in vitamin D, containing an average of only 10% of the amount in fortified cow’s milk.
Vitamin D levels may decrease with age because skin synthesis declines. Sunscreen use and dark skin pigmentation also reduce skin synthesis of vitamin D.
Vitamin D is a prohormone with several active metabolites that act as hormones. Vitamin D is metabolized by the liver to 25(OH)D (calcifediol, calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D), which is then converted by the kidneys to 1,25-dihydroxyvitamin D (1,25-dihydroxycholecalciferol, calcitriol, or active vitamin D hormone). 25(OH)D, the major circulating form, has some metabolic activity, but 1,25-dihydroxyvitamin D is the most metabolically active. The conversion to 1,25-dihydroxyvitamin D is regulated by its own concentration, parathyroid hormone (PTH), and serum concentrations of calcium and phosphate.
Vitamin D affects many organ systems (see table ), but mainly it increases calcium and phosphate absorption from the intestine and promotes normal bone formation and mineralization.
Vitamin D and related analogs may be used to treat psoriasis Psoriasis Psoriasis is an inflammatory disease that manifests most commonly as well-circumscribed, erythematous papules and plaques covered with silvery scales. Multiple factors contribute, including... read more , hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is a deficiency of parathyroid hormone often caused by an autoimmune disorder or by iatrogenic damage or removal of the glands during thyroidectomy or parathyroidectomy. Symptoms... read more , and renal osteodystrophy Calcium and phosphate . Vitamin D's usefulness in preventing leukemia and breast, prostate, colon, or other cancers has not been proved, nor has its efficacy in treating various other nonskeletal disorders in adults (1–3 Physiology references Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more ). Vitamin D supplementation does not effectively treat or prevent depression or cardiovascular disease (4, 5 Physiology references Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more ). Some evidence suggests that taking the combined recommended daily allowance of both vitamin D and calcium reduces the risk of fractures (6, 7 Physiology references Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more ) and falls (8 Physiology references Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more ), but primarily in patients who are vitamin D deficient. Because the causes of falls are multifactorial, other studies have not found that vitamin D supplements alone reduce falls in older adults (9 Physiology references Inadequate exposure to sunlight predisposes to vitamin D deficiency. Deficiency impairs bone mineralization, causing rickets in children and osteomalacia in adults and possibly contributing... read more ).
(See also Overview of Vitamins Overview of Vitamins Vitamins may be Fat soluble (vitamins A, D, E, and K) Water soluble (B vitamins and vitamin C) The B vitamins include biotin, folate, niacin, pantothenic acid, riboflavin (B2), thiamin (B1)... read more .)
1. Autier P, Mullie P, Macacu A, et al: Effect of vitamin D supplementation on non-skeletal disorders: A systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol 5 (12):986–1004, 2017. doi: 10.1016/S2213-8587(17)30357-1
2. Manson JE, Cook NR, Lee IM, et al: Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med 380(1):33-44, 2019. doi: 10.1056/NEJMoa1809944
3. Cianferotti L, Bertoldo F, Bischoff-Ferrari HA, et al: Vitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: research for evidence and a scientific statement from the European Society for Clinical and Economic aspects of Osteoporosis and Osteoarthritis (ESCEO). Endocrine 56:245-261, 2017. doi:10.1007/s12020-017-1290-9
4. Okereke OI, Reynolds CF 3rd, Mischoulon D, et al: Effect of long-term vitamin D3 supplementation vs placebo on risk of depression or clinically relevant depressive symptoms and on change in mood scores: A randomized clinical trial. JAMA 324(5):471-480, 2020. doi: 10.1001/jama.2020.10224
5. Barbarawi M, Kheiri B, Zayed Y, et al: Vitamin D supplementation and cardiovascular disease risks in more than 83,000 individuals in 21 randomized clinical trials: A meta-analysis [published correction appears in JAMA Cardiol 2019 Nov 6]. JAMA Cardiol 4(8):765-776, 2019. doi: 10.1001/jamacardio.2019.1870
6. Yao P, Bennett D, Mafham M, et al: Vitamin D and calcium for the prevention of fracture: A systematic review and meta-analysis. JAMA Netw Open 2(12):e1917789, 2019. doi:10.1001/jamanetworkopen.2019.17789
7. Kong SH, Jang HN, Kim JH, et al: Effect of vitamin D supplementation on risk of fractures and falls according to dosage and interval: a meta-analysis. Endocrinol Metab 37:344-358, 2022. doi:10.3803/EnM.2021.1374
8. Ling Y, Xu F, Xia X, et al: Vitamin D supplementation reduces the risk of fall in the vitamin D deficient elderly: an updated meta-analysis. Clin Nutr 40:5531-5537, 2021. doi:10.1016/j.clnu.2021.09.031
9. Appel LJ, Michos ED, Mitchell CM, et al: The effects of four doses of vitamin D supplements on falls in older adults: a response-adaptive, randomized clinical trial. Ann Intern Med 174:145-156, 2021. doi:10.7326/M20-3812
Etiology of Vitamin D Deficiency and Dependency
Vitamin D deficiency may result from the following:
Inadequate exposure to sunlight
Inadequate intake of vitamin D
Reduced absorption of vitamin D
Abnormal metabolism of vitamin D
Resistance to the effects of vitamin D
Inadequate exposure or intake
Inadequate direct sunlight exposure or sunscreen use and inadequate intake usually occur simultaneously to result in clinical deficiency. Susceptible people include
Older people (who are often undernourished and are not exposed to enough sunlight)
Certain communities (eg, women and children who are confined to the home or who wear clothing that covers the entire body and face)
Inadequate vitamin D stores are common among older people, particularly those who are housebound, institutionalized, or hospitalized or who have had a hip fracture.
Recommended direct sunlight exposure is 5 to 15 minutes (suberythemal dose) to the arms and legs or to the face, arms, and hands, at least 3 times a week. However, many dermatologists do not recommend increased sunlight exposure because risk of skin cancer is increased.
Malabsorption Overview of Malabsorption Malabsorption is inadequate assimilation of dietary substances due to defects in digestion, absorption, or transport. Malabsorption can affect macronutrients (eg, proteins, carbohydrates, fats)... read more can deprive the body of dietary vitamin D; only a small amount of 25(OH)D is recirculated enterohepatically.
Vitamin D deficiency may result from defects in the production of 25(OH)D or 1,25-dihydroxyvitamin D. People with chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more may develop rickets or osteomalacia because renal production of 1,25-dihydroxyvitamin D is decreased and phosphate levels are elevated. Hepatic dysfunction can also interfere with production of active vitamin D metabolites.
Type I hereditary vitamin D–dependent rickets is an autosomal recessive disorder characterized by absent or defective conversion of 25(OH)D to 1,25-dihydroxyvitamin D in the kidneys. In X-linked familial hypophosphatemia, decreased reabsorption of phosphate from the glomerular filtrate in the kidney with low or inappropriately normal levels of 1,25-dihydroxyvitamin D leads to bone deformities.
Many antiseizure drugs and use of glucocorticoids increase the need for vitamin D supplementation.
Resistance to effects of vitamin D
Type II hereditary vitamin D–dependent rickets has several forms and is due to mutations in the 1,25-dihydroxyvitamin D receptor. This receptor affects the metabolism of 1,25-dihydroxyvitamin D in the gut, kidney, bone, and other cells. In this disorder, 1,25-dihydroxyvitamin D is abundant but ineffective because the receptor is not functional.
Symptoms and Signs of Vitamin D Deficiency and Dependency
Vitamin D deficiency can cause muscle aches, muscle weakness, and bone pain at any age.
Vitamin D deficiency in a pregnant woman causes deficiency in the fetus. Occasionally, deficiency severe enough to cause maternal osteomalacia results in rickets with metaphyseal lesions in neonates.
In young infants, rickets causes softening of the entire skull (craniotabes). When palpated, the occiput and posterior parietal bones may indent easily.
In older infants with rickets, sitting and crawling are delayed, as is fontanelle closure; there is bossing of the skull and costochondral thickening. Costochondral thickening can look like beadlike prominences along the lateral chest wall (rachitic rosary).
In children 1 to 4 years, epiphyseal cartilage at the lower ends of the radius, ulna, tibia, and fibula enlarge; kyphoscoliosis develops, and walking is delayed.
In older children and adolescents, walking is painful; in extreme cases, deformities such as bowlegs and knock-knees develop. The pelvic bones may flatten, narrowing the birth canal in adolescent girls.
Tetany is caused by hypocalcemia and may accompany infantile or adult vitamin D deficiency. Tetany may cause paresthesias of the lips, tongue, and fingers; carpopedal and facial spasm; and, if very severe, seizures. Maternal deficiency can cause tetany in neonates.
Osteomalacia predisposes to fractures. In older people, hip fractures may result from only minimal trauma.
Diagnosis of Vitamin D Deficiency and Dependency
Levels of 25(OH)D (D2 + D3)
Vitamin D deficiency may be suspected based on any of the following:
A history of inadequate sunlight exposure or dietary intake
Symptoms and signs of rickets, osteomalacia, or neonatal tetany
Characteristic bone changes seen on x-ray
X-rays of the radius and ulna plus serum levels of calcium, phosphate, alkaline phosphatase, parathyroid hormone (PTH), and 25(OH)D are needed to differentiate vitamin D deficiency from other causes of bone demineralization.
Assessment of vitamin D status and serologic tests for syphilis can be considered for infants with craniotabes based on the history and physical examination, but most cases of craniotabes resolve spontaneously. Rickets can be distinguished from chondrodystrophy because the latter is characterized by a large head, short extremities, thick bones, and normal serum calcium, phosphate, and alkaline phosphatase levels.
Tetany due to infantile rickets may be clinically indistinguishable from seizures due to other causes. Blood tests and clinical history may help distinguish them.
Bone changes, seen on x-rays, precede clinical signs. In rickets, changes are most evident at the lower ends of the radius and ulna. The diaphyseal ends lose their sharp, clear outline; they are cup-shaped and show a spotty or fringy rarefaction. Later, because the ends of the radius and ulna have become noncalcified and radiolucent, the distance between them and the metacarpal bones appears increased. The bone matrix elsewhere also becomes more radiolucent. Characteristic deformities result from the bones bending at the cartilage-shaft junction because the shaft is weak. As healing begins, a thin white line of calcification appears at the epiphysis, becoming denser and thicker as calcification proceeds. Later, the bone matrix becomes calcified and opacified at the subperiosteal level.
In adults, bone demineralization, particularly in the spine, pelvis, and lower extremities, can be seen on x-rays; the fibrous lamellae can also be seen, and incomplete ribbonlike areas of demineralization (pseudofractures, Looser lines, Milkman syndrome) appear in the cortex.
Because levels of serum 25(OH)D reflect body stores of vitamin D and correlate with symptoms and signs of vitamin D deficiency better than levels of other vitamin D metabolites, the best way to diagnose vitamin D deficiency is generally considered to be
25(OH)D (D2 + D3) levels
Target 25(OH)D levels are > 20 to 24 ng/mL (about 50 to 60 nmol/L) for maximal bone health; whether higher levels have other benefits remains uncertain, and higher absorption of calcium may increase risk of coronary artery disease.
If the diagnosis is unclear, serum levels of 1,25-dihydroxyvitamin D and urinary calcium concentration can be measured. In severe deficiency, serum 1,25-dihydroxyvitamin D is abnormally low, usually undetectable. Urinary calcium is low in all forms of the deficiency except those associated with acidosis.
In vitamin D deficiency, serum calcium may be low or, because of secondary hyperparathyroidism, may be normal. Serum phosphate usually decreases, and serum alkaline phosphatase usually increases. Serum PTH may be normal or elevated.
Type I hereditary vitamin D–dependent rickets results in normal serum 25(OH)D, low serum 1,25-dihydroxyvitamin D and calcium, and normal or low serum phosphate.
Treatment of Vitamin D Deficiency and Dependency
Correction of calcium and phosphate deficiencies
Supplemental vitamin D
Calcium deficiency (which is common) and phosphate deficiency should be corrected.
As long as calcium and phosphate intake is adequate, adults with osteomalacia and children with uncomplicated rickets can be cured by giving vitamin D3 40 mcg (1600 units) orally once a day. Serum 25(OH)D and 1,25-dihydroxyvitamin D begin to increase within 1 or 2 days. Serum calcium and phosphate increase and serum alkaline phosphatase decreases within about 10 days. During the 3rd week, enough calcium and phosphate are deposited in bones to be visible on x-rays. After about 1 month, the dose can usually be reduced gradually to the usual maintenance level of 15 mcg (600 units) once/day.
If tetany is present, vitamin D should be supplemented with IV calcium salts for up to 1 week (see Hypocalcemia Treatment Hypocalcemia is a total serum calcium concentration < 8.8 mg/dL (< 2.20 mmol/L) in the presence of normal plasma protein concentrations or a serum ionized calcium concentration < 4... read more ).
Some older patients need vitamin D3 25 to > 50 mcg (1000 to ≥ 2000 units) daily to maintain a 25(OH)D level > 20 ng/mL (> 50 nmol/L); this dose is higher than the recommended daily allowance for people < 70 years (600 units) or > 70 years (800 units). The current upper limit for vitamin D is 4000 units/day. Higher doses of vitamin D2 (eg, 25,000 to 50,000 units every week or every month) are sometimes prescribed; because vitamin D3 is more potent than vitamin D2, it is now preferred.
Because rickets and osteomalacia due to defective production of vitamin D metabolites are vitamin D–resistant, they do not respond to the doses usually effective for rickets due to inadequate intake. Endocrinologic evaluation is required because treatment depends on the specific defect. When 25(OH)D production is defective, vitamin D3 50 mcg (2000 units) once a day increases serum levels and results in clinical improvement. Patients with kidney disorders often need 1,25-dihydroxyvitamin D (calcitriol) supplementation.
Type I hereditary vitamin D–dependent rickets responds to 1,25-dihydroxyvitamin D 1 to 2 mcg orally once a day. Some patients with type II hereditary vitamin D–dependent rickets respond to very high doses (eg, 10 to 24 mcg/day) of 1,25-dihydroxyvitamin D; others require long-term infusions of calcium.
Prevention of Vitamin D Deficiency and Dependency
Dietary counseling is particularly important in communities whose members are at risk of vitamin D deficiency. Fortifying unleavened chapati flour with vitamin D (125 mcg/kg) has been effective among Indian immigrants in Britain. The benefits of sunlight exposure for vitamin D status must be weighed against the increased skin damage and skin cancer risks.
All breastfed infants should be given supplemental vitamin D 10 mcg (400 units) once a day from birth to 6 months; at 6 months, a more diversified diet is available. Any benefit of doses higher than the recommended daily allowance is unproved.
Vitamin D deficiency is common and results from inadequate exposure to sunlight and inadequate dietary intake (usually occurring together) and/or from chronic kidney disease.
The deficiency can cause muscle aches and weakness, bone pain, and osteomalacia.
Suspect vitamin D deficiency in patients who have little exposure to sunlight and a low dietary intake, typical symptoms and signs (eg, rickets, muscle aches, bone pain), or bone demineralization seen on x-rays.
To confirm the diagnosis, measure the level of 25(OH)D (D2+D3).
To treat vitamin D deficiency, correct deficiencies of calcium and phosphate and give supplemental vitamin D.
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