chronic kidney disease, various renal tubular disorders, familial , chronic metabolic acidosis, hyperparathyroidism, hypoparathyroidism, inadequate dietary calcium, and disorders or drugs that impair the mineralization of bone matrix.
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.
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 Vitamins
calcitriolparathyroid hormone (PTH), and serum concentrations of calcium and phosphate.
), but mainly it increases calcium and phosphate absorption from the intestine and promotes normal bone formation and mineralization.
psoriasis, hypoparathyroidism, and renal osteodystrophy1–34, 56, 7) and falls (89).
(See also Overview of Vitamins.)
Physiology references
1. Autier P, Mullie P, Macacu A, et alLancet Diabetes Endocrinol 5 (12):986–1004, 2017. doi: 10.1016/S2213-8587(17)30357-1
2. Manson JE, Cook NR, Lee IM, et alN Engl J Med 380(1):33-44, 2019. doi: 10.1056/NEJMoa1809944
3. Cianferotti L, Bertoldo F, Bischoff-Ferrari HA, et alEndocrine 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 alJAMA 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 alJAMA Netw Open 2(12):e1917789, 2019. doi:10.1001/jamanetworkopen.2019.17789
7. Kong SH, Jang HN, Kim JH, et alEndocrinol Metab 37:344-358, 2022. doi:10.3803/EnM.2021.1374
8. Ling Y, Xu F, Xia X, et alClin Nutr 40:5531-5537, 2021. doi:10.1016/j.clnu.2021.09.031
9. Appel LJ, Michos ED, Mitchell CM, et alAnn Intern Med 174:145-156, 2021. doi:10.7326/M20-3812
Inadequate exposure to sunlight
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)
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
Abnormal metabolism
Resistance to effects of vitamin D
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.
Osteomalacia predisposes to fractures. In older people, hip fractures may result from only minimal trauma.
Levels of 25(OH)D (D2 + D3)
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
Tetany due to infantile rickets may be clinically indistinguishable from seizures due to other causes. Blood tests and clinical history may help distinguish them.
X-rays
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.
Laboratory tests
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.
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 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.
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 (>
Key Points
The deficiency can cause muscle aches and weakness, bone pain, and osteomalacia.
To confirm the diagnosis, measure the level of 25(OH)D (D2+D3).
