Vitamin D is a fat-soluble vitamin that is either produced in the skin with ultraviolet (UV) light exposure, or absorbed from the intestine in chylomicrons. Dietary vitamin D is available in two forms: D2 (ergocalciferol, derived from plants or yeast) or D3 (cholecalciferol, derived from animals or produced in human skin exposed to sunlight). D3 is the more physiologic and potent form, but D2 is historically the predominant form found in vitamin D supplements and fortified foods. Vitamin D is hydroxylated to 25-hydroxycalciferol (25-OH-D) in the liver, and hydroxylated again to calcitriol, or 1, 25-(OH)2-D in the kidney. The 25-OH-D form is measured in blood to assess vitamin D stores, and it has a half-life of about 2 weeks. The 1,25-(OH)2-D form is the most biologically active. Vitamin D is measured in international units (IU), where 1 IU is defined as 0.025 μg D3, which is 65 pmol D3. Units of other forms of vitamin D, (25-OH-D and 1,25-(OH)2-D) are defined as molar equivalents to D3 (i.e., 65 pmol = 1 IU).

The 1,25-(OH)2-D form is a hormone acting via a nuclear receptor (VDR), which in the presence of vitamin D binds the retinoic acid receptor (RXR). The RXR-VRD-vitamin D complex binds so-called vitamin D responsive elements in nuclear DNA and alters gene expression. In both renal tubular cells and in the intestinal epithelium, vitamin D increases absorption of calcium and phosphate. In bone, it stimulates both osteoblastic and osteoclastic activity. Recall that parathyroid hormone (PTH) is predominantly regulated by the plasma calcium level. PTH stimulates osteoclast activity and bone resorption, stimulates calcium resorption and phosphate loss in the renal tubule, and promotes hydroxylation of 25-OH-D to 1,25-(OH)2-D by the kidney. In vitamin D deficiency, poor calcium absorption stimulates PTH release, and renal calcium absorption and osteoclast activity are increased. Increased renal hydroxylation of 25-OH-D can often compensate
for decreased levels of precursor to maintain normal or high levels of 1,25-(OH)-D with low levels of 25-OH-D. Decreased renal absorption results in low phosphate levels. Alkaline phosphatase is high, reflecting increased bone turnover.

Vitamin D deficiency is usually diagnosed by a serum vitamin D level <20 ng/mL, and levels <15 ng/mL represent severe deficiency. In children with growing bones, severe chronic vitamin D deficiency results in rickets, a disorder of bone development characterized by poor mineralization throughout the skeleton. This results in a tendency of the long bones to bend under the stress of walking (or muscle contraction in perambulatory children), and can produce varus or valgus deformities of the legs. The skull may be affected, with palpable softening (rachitic craniotabes), delayed closure of the fontanelles, frontal bossing, and exaggerated positional flattening of the occiput. Hypertrophy of the costochondral junctions produces the “rachitic rosary,” which can progress to a Harrison groove when the ribs begin to contract. Epiphyses of the long bones widen, producing a characteristic appearance on x-ray. Tooth development is also delayed. Muscle weakness and hypotonia are common, and the hypocalcemia can be so severe as to cause tetany, seizures, laryngospasm, and dilated cardiomyopathy. Hypochromic anemia can be a feature of rickets. In older patients, vitamin D deficiency results in osteomalacia without the other characteristic skeletal changes of rickets.