Vitamin D Deficiency Rickets And Osteomalacia

Vitamin D Deficiency Rickets And Osteomalacia

Vitamin D deficiency is the most common cause of rickets. Vitamin D deficiency prevents the efficient absorption of dietary calcium and phosphorus. In a vitamin D–deficient state, only 10–15% of dietary calcium and 50–60% of dietary phosphorus are absorbed. The poor absorption of calcium causes a decrease in serum-ionized calcium levels. This is immediately recognized by the calcium sensor in the parathyroid glands, resulting in an increase in the expression, synthesis, and secretion of parathyroid hormone (PTH) (1, 20, 22, 27). PTH conserves calcium by increasing tubular reabsorption of calcium in both the proximal and distal convoluted tubules. PTH, like 1,25(OH)₂D, enhances the expression of RANKL on osteoblasts to increase the production of mature osteoclasts to mobilize calcium stores from the skeleton. PTH also decreases phosphorus reabsorption in the kidney, causing loss of phosphorus into the urine (Figure 4). The serum calcium level is usually normal in a vitamin D–deficient infant or child. However, the serum phosphorus level is low, and thus there is inadequate calcium-phosphorus product, which is necessary to mineralize the osteoid laid down by osteoblasts ( 1, 20, 22, 24, 28) (Figure 4). Thus, typically, infants with vitamin D–deficiency rickets have a normal serum calcium level, low normal or low fasting serum phosphorus levels, elevated alkaline phosphatase levels, and low 25(OH)D levels (<15 ng/ml) ( 23, 28–31) (Table 2). The secondary hyperparathyroidism stimulates the kidneys to produce 1,25(OH)₂D, and thus, 1,25(OH)₂D levels are normal or often elevated, which is why the measurement of 1,25(OH)₂D is of no value in determining a state of vitamin D deficiency (24). Only when the calcium stores in the skeleton are totally depleted will the infant or child become hypocalcemic.

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.

Table 2

Vitamin D status and associated biochemistries: serum levels of 25(OH)D, 1,25(OH)₂D, Ca, HPO₄ ^2–, alkaline phosphatase (Alk. phos.), PTH, and FGF23

Vitamin D deficiency causes global poor mineralization of the skeleton. Clinical and radiological bone manifestations predominate in areas of rapid bone growth, including the long bone epiphyses and the costochondral junctions (5, 6, 12– 14, 30– 32). This is why rickets is mostly observed before 18 months of age, with maximum frequency between the ages of 4 and 12 months. Skeletal deformities are usually a result of long-standing rickets. Hypertrophy of the costochondral junctions leads to beading and the classic rachitic rosary that progresses with involution of the ribs and protrusion of the sternum (pigeon chest) and recession of the costochondral junctions and traverse depressions causing Harrison's groove. Once the child begins to stand, gravity pushing on the lower limbs results in either inward (genu valgum) or outward (genu varum) tibial and femoral bowing. Muscle pull can also cause bone deformities in both upper and lower limbs even before the infant begins to walk. Muscle traction on the softened ribcage is responsible for the chest deformation, leading to pectus carinatum, thoracic asymmetry, and widening of the thoracic base. Softening of the occipital area (rachitic craniotabes), enlarged sutures and fontanelles, delayed closing of fontanelles, and occipital or parietal flattening can be observed ( 5, 6, 12, 13, 30– 32) (Figure 1). Tooth development is impaired, with delayed eruption, enamel hypoplasia, and early dental caries ( 12– 14). The pelvic bone structure is flattened in rachitic children. Because of the high incidence of infant and maternal morbidity and mortality in rachitic women, children were often delivered by Caesarian section ( 1, 2).

Extraskeletal manifestations associated with hypocalcemia lead to tetany, seizures, laryngospasm, and hypocalcemic myocardiopathy and death (6, 12– 14, 32). Often there is delayed motor development with hypotonia in the absence of hypocalcemia. Weakness of the thoracic muscles together with softening of the ribcage results in defective ventilation with respiratory obstruction and infection. In older children and adolescents, symptoms similar to those observed in adult osteomalacia, including bone pain, waddling gait, and fatigue, may be present ( 12– 14, 24, 30– 32). Hematologic disorders are often observed in common rickets, including hypochromic anemia and the rare Von Jacksch–Luzet syndrome. This syndrome is associated with severe anemia and a profile of chronic myeloid leukemia with erythroblastosis, leukocytosis, myelocytosis, and possible myeloblastosis. The spleen and liver can be enlarged as a result of extramedullary hematopoiesis. The bone marrow is hypoplastic. This syndrome is often cured with simple vitamin D therapy ( 31).

Severe calcium deficiency can lead to rickets in much the same way as vitamin D deficiency (32– 35). Very low dietary calcium intake leads to decreased ionized calcium and secondary hyperparathyroidism. This causes a mineralization defect in the skeleton that results in growth retardation and many of the skeletal manifestations seen in vitamin D deficiency, but these are of greater severity due to the hypocalcemia ( 31– 35) (Figure 4).

Inadequate calcium intake during the 3rd trimester of pregnancy can cause a serious calcium deficit in the fetal skeleton that is rapidly being mineralized during the last 7 weeks in utero. Typically at 28 weeks, 100 mg/d of calcium is being deposited in the skeleton, whereas at 35 weeks 350 mg/d is being deposited (30, 31, 36). Therefore, mother's milk containing 240–340 mg/l of calcium is unable to meet the demands of postnatal accretion rates of a preterm infant ( 30, 31).

Young children and adolescents, especially non-white individuals, on a strict vegetarian diet or a diet that is high in phytate, which binds calcium, can also be calcium deficient, which leads to rickets (33– 35). This, in combination with vitamin D deficiency, is often the precipitating cause of rickets in children of Middle Eastern descent living in Great Britain and African American children in the United States ( 32– 35).

The calcium deficiency and associated secondary hyperparathyroidism increase the requirement for vitamin D, since the vitamin D is rapidly metabolized to 1,25(OH)₂D. The combination of calcium deficiency and vitamin D deficiency accelerates and makes more severe the skeletal abnormalities and hypocalcemia.

Vitamin D Deficiency Rickets And Osteomalacia

Source: https://www.jci.org/articles/view/29449