Inadequate exposure to sunlight predisposes to vitamin Dvitamin D (dependency).
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, various renal tubular disorders, familial , chronic metabolic acidosis, hyperparathyroidism, hypoparathyroidism, inadequate dietary calcium, and disorders or medications that impair the mineralization of bone matrix.
Vitamin D deficiency causes hypocalcemia, which stimulates production of parathyroid hormone (PTH), causing hyperparathyroidism. 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:
D2 (ergocalciferol)
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 Sources, Functions, and Effects of Vitaminsvitamin 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. It 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, hypoparathyroidism, and renal osteodystrophy. Its usefulness in reducing all-cause mortality or 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). Vitamin D supplementation does not effectively treat or prevent depression or cardiovascular disease (4, 5) and has minimal effects on preventing acute respiratory infections (67) in patients who are vitamin D deficient, especially those who are institutionalized; however, large doses of vitamin D may increase fracture risk (8, 9). Because the causes of falls are multifactorial, other studies have not found that vitamin D supplements alone reduce falls and fractures in older adults (10, 11).
(See also Overview of Vitamins.)
Actions of Vitamin D and Its Metabolites
Organ | Actions |
|---|---|
Bone | Promotes bone formation by maintaining appropriate calcium and phosphate concentrations |
Immune system | Stimulates immunogenic and antitumor activity Decreases risk of autoimmune disorders |
Intestine | Enhances calcium and phosphate transport (absorption) |
Kidneys | Enhances calcium reabsorption by the tubules |
Parathyroid glands | Inhibits parathyroid hormone secretion |
Pancreas | Stimulates insulin production |
Physiology references
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. Neale RE, Baxter C, Romero BD, et al. The D-Health Trial: a randomised controlled trial of the effect of vitamin D on mortality [published correction appears in Lancet Diabetes Endocrinol. 2022 Apr;10(4):e7. doi: 10.1016/S2213-8587(22)00083-3]. Lancet Diabetes Endocrinol. 2022;10(2):120-128. doi:10.1016/S2213-8587(21)00345-4
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. Jolliffe DA, Camargo CA Jr, Sluyter JD, et al. Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials. Lancet Diabetes Endocrinol. 2021;9(5):276-292. doi:10.1016/S2213-8587(21)00051-6
7. 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
8. 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. 2019;2(12):e1917789. Published 2019 Dec 2. doi:10.1001/jamanetworkopen.2019.17789
9. Zhao JG, Zeng XT, Wang J, Liu L. Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis. JAMA. 2017;318(24):2466-2482. doi:10.1001/jama.2017.19344
10. 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
11. LeBoff MS, Chou SH, Ratliff KA, et al. Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults. N Engl J Med. 2022;387(4):299-309. doi:10.1056/NEJMoa2202106
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 adults (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 adults, 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.
Reduced absorption
Malabsorption can deprive the body of dietary vitamin D; only a small amount of 25(OH)D is recirculated enterohepatically.
Abnormal metabolism
Vitamin D deficiency may result from defects in the production of 25(OH)D or 1,25-dihydroxyvitamin D. People with chronic kidney disease 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.
vitamin D metabolism.
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 adults, 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 radiographs
Radiographs 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.
Radiographs
Bone changes, seen on radiographs, 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 radiographs; the fibrous lamellae can also be seen, and incomplete ribbonlike areas of demineralization (pseudofractures, Looser lines, Milkman syndrome) appear in the cortex.
Laboratory tests
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 by measuring
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
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 international units [IU]) 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 third week, enough calcium and phosphate are deposited in bones to be visible on radiographs. After about 1 month, the dose can usually be reduced gradually to the usual maintenance level of 15 mcg (600 IU) once/day.
If tetany is present, vitamin D should be supplemented with IV calcium salts for up to 1 week (see Hypocalcemia).
Some older adult patients need vitamin D3 25 to > 50 mcg (1000 to ≥ 2000 IU) daily to maintain a 25(OH)D level > 20 ng/mL (> 50 nmol/L); this dose is higher than the recommended dietary allowance for people < 70 years (600 IU) or > 70 years (800 IU). The current upper limit for vitamin D is 4000 IU/day. Higher doses of vitamin D2 (eg, 25,000 to 50,000 IU every week or every month) are sometimes prescribed; however, 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
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 for people in communities who are at risk of vitamin D deficiency.
The benefits of sunlight exposure for vitamin D status must be weighed against the increased skin damage and skin cancer risks.
Screening
The US Preventive Services Task force has concluded that there is insufficient evidence to assess the benefits and harms of screening for vitamin D deficiency in asymptomatic adults (1). Endocrine societies in the United States, Europe, and other countries have published a clinical practice guideline for people without other indications for vitamin D supplementation or testing. This guideline recommends against empiric vitamin D supplementation or 25(OH)D screening in peoples between 18 and 74 years of age, including adults with obesity or with dark skin pigmentation. The recommended dietary allowance of vitamin D3 supplements may benefit people over age 75, people who are at high risk of prediabetes, and pregnant women, but routine 25(OH)D testing is not needed (2).
Screening references
1. US Preventive Services Task Force, Krist AH, Davidson KW, et al. Screening for Vitamin D Deficiency in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2021;325(14):1436-1442. doi:10.1001/jama.2021.3069
2. Demay MB, Pittas AG, Bikle DD, et al. Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. Published online June 3, 2024. doi:10.1210/clinem/dgae290
Key Points
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 radiographs.
To confirm the diagnosis, measure the level of 25(OH)D (D2 + D3).
To treat vitamin D
