Resurrection of vitamin D deficiency and rickets

Abstract

The epidemic scourge of rickets in the 19th century was caused by vitamin D deficiency due to inadequate sun exposure and resulted in growth retardation, muscle weakness, skeletal deformities, hypocalcemia, tetany, and seizures. The encouragement of sensible sun exposure and the fortification of milk with vitamin D resulted in almost complete eradication of the disease. Vitamin D (where D represents D2 or D3) is biologically inert and metabolized in the liver to 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D that is used to determine vitamin D status. 25(OH)D is activated in the kidneys to 1,25-dihydroxyvitamin D [1,25(OH)2D], which regulates calcium, phosphorus, and bone metabolism. Vitamin D deficiency has again become an epidemic in children, and rickets has become a global health issue. In addition to vitamin D deficiency, calcium deficiency and acquired and inherited disorders of vitamin D, calcium, and phosphorus metabolism cause rickets. This review summarizes the role of vitamin D in the prevention of rickets and its importance in the overall health and welfare of infants and children.

Figure 1. Skeletal deformities observed in rickets.

(A) Photograph from the 1930s of a sister (left) and brother (right), aged 10 months and 2.5 years, respectively, showing enlargement of the ends of the bones at the wrist, carpopedal spasm, and a typical “Taylorwise” posture of rickets. (B) The same brother and sister 4 years later, with classic knock-knees and bow legs, growth retardation, and other skeletal deformities. Reproduced from ref. .

Figure 2. UV radiation therapy for rickets.

(A) Photograph from the 1920s of a child with rickets being exposed to UV radiation. (B) Radiographs demonstrating florid rickets of the hand and wrist (left) and the same wrist and hand taken after treatment with 1 hour UV radiation 2 times a week for 8 weeks. Note mineralization of the carpal bones and epiphyseal plates (right). Reproduced from ref. .

Figure 3. The photoproduction and metabolism of vitamin D and the various biologic effects of 1,25(OH)₂ D on calcium, phosphorus, and bone metabolism.

Vitamin D is either produced in the skin by exposure to UVB radiation or is ingested in the diet. Vitamin D (D represents vitamin D₂ or vitamin D₃) is converted by the vitamin D-25-hydroxylase (25-OHase) in the liver to 25(OH)D. 25(OH)D is converted in the kidneys by 1-OHase to 1,25(OH)₂D. Once formed, 1,25(OH)₂D enhances intestinal calcium and phosphorus absorption and stimulates the expression of RANKL on the osteoblasts to interact with its receptor RANK on preosteoclasts to induce mature osteoclastic activity, which releases calcium and phosphorus (HPO₄^2–). In addition, 1,25(OH)₂D inhibits the renal 1-OHase and stimulates the expression of the renal 25(OH)D-24-hydroxylase (24-OHase). The induction of the 24-OHase results in the destruction of 1,25(OH)₂D into a water-soluble inactive metabolite calcitroic acid. PreD₃, previtamin D.

Figure 4. Biochemical changes in calcium and phosphorus metabolism due to vitamin D or calcium deficiency, vitamin D–resistant syndromes, or hypophosphatemic syndromes that cause rickets or osteomalacia.

Vitamin D and/or calcium deficiency leads to a decrease in the level of ionized calcium (Ca²⁺), resulting in an increase in PTH. PTH increases tubular reabsorption of calcium to correct the serum calcium into the normal range. However, in severe calcium and vitamin D deficiency, the serum calcium is below normal. In addition, PTH causes phosphorus loss via the urine, resulting in a decrease in serum HPO₄^2–. An inadequate calcium-phosphorus product (Ca⁺² × HPO₄^2–) leads to a defect in bone mineralization that causes rickets in children and osteomalacia in adults. There are various inherited and acquired disorders that can disrupt calcium and phosphorus metabolism that can also result in defective mineralization of the skeleton. There are 3 inherited syndromes that cause vitamin D resistance. Vitamin D–dependent rickets type 1 (DDR-1) is due to a mutation of the 1-OHase. A mutation of the VDR gene results in an ineffective recognition of 1,25(OH)₂D, causing DDR-2. A genetic defect that results in the overproduction of hormone response element–binding protein (HRBP) eliminates the interaction of 1,25(OH)₂D with its VDR, resulting in DDR-3. There are also inherited and acquired disorders that cause severe hypophosphatemia and decrease renal production of 1,25(OH)₂D. The acquired disorders X-linked hypophosphatemic rickets (XLH) and autosomal dominant hypophosphatemic rickets (ADHR) are caused by the increased production or decreased destruction, respectively, of phosphatonins that include FGF23. Tumor-induced osteomalacia (TIO) is caused by the tumor’s production of FGF23, which results in phosphaturia and a decrease in the renal production of 1,25(OH)₂D.

Figure 5. Noncalcemic functions of 1,25(OH)₂ D.

Vitamin D coming from the photoproduction of previtamin D or coming from the diet is converted in the liver to 25(OH)D by the vitamin 25-OHase. 25(OH)D is converted in the kidneys by 1-OHase. 1,25(OH)₂D not only regulates calcium and phosphorus metabolism but can stimulate the pancreas to produce insulin and to downregulate the renal production of renin. 1,25(OH)₂D also interacts with its nuclear receptor (VDR) in a wide variety of tissues and cells and helps maintain normal cell proliferation and differentiation. 25(OH)D can also be converted to 1,25(OH)₂D in a wide variety of cells, including colon, prostate, and breast, for the autocrine production of 1,25(OH)₂D. It is believed that the autocrine production of 1,25(OH)₂D is important for regulating cell growth and maturation, which decreases risk of the cell becoming malignant. 25(OH)D also is metabolized in macrophages by the 1-OHase to produce 1,25(OH)₂D. The expression of the VDR and 1-OHase is upregulated when TLR2/1 is stimulated by LPS. This results in an increase in the expression of the VDR and the 1-OHase. The increase production of 1,25(OH)₂D increases the nuclear expression of cathelicidin (CD) in the macrophage, which is a cationic peptide that causes the destruction of infective agents including M. tuberculosis.