Excerpt from Disorders of Bone Mineralization

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Several diseases can result in defective mineralization of bone in children, including the following:

• Rickets
• • Nutritional rickets
  • Congenital rickets
  • Rickets of prematurity
  • Genetic rickets
  • Neoplastic rickets
  • Hypophosphatemic rickets
  • Drug-induced rickets
• Renal causes - Renal osteodystrophy, Fanconi syndrome
• Tumor-induced osteomalacia
• Other causes
• • Hypophosphatasia
  • McCune-Albright syndrome
  • Osteogenesis imperfecta with mineralization defect (syndrome resembling osteogenesis imperfecta)

The disorders listed above may result in failure of osteoid calcification (rickets) in children because of a disruption in the pathway of either vitamin D or phosphate metabolism. Defective mineralization in bone causes osteomalacia, which can occur in both children and adults. Rickets, once thought defeated, is reappearing and remains a major health problem in many developing and developed countries.

The primary absorption site for vitamin D is the jejunum. The two main sources of vitamin D in humans are vitamin D-3 (cholecalciferol), produced by the skin after UV radiation (290-320 nm), and vitamin D-2 (ergosterol), provided by vegetable sources. Both have identical biological actions and are concentrated in the liver, where a microsomal and mitochondrial enzyme hydroxylates them in position 25. This generates 25(OH) vitamin D-3, which is hydroxylated again in the kidneys. Hydroxylation in position 1 in the mitochondria yields 1,25-dihydroxyvitamin D (1,25(OH)2 vitamin D-3), or calcitriol, the most active form of vitamin D.

Of note, the kidney generates at least 30 other metabolites, but their biological significance is not clear. The pathophysiology of rickets is not completely understood, nor is the role of the many vitamin D metabolites. Calcitriol levels may be normal in patients with rickets, suggesting that it is not the only active form of the vitamin.

Causes of rickets related to phosphate deficiency are discussed in the article Hypophosphatemic Rickets, and those related to Osteogenesis Imperfecta are discussed in the specific article.

Pathophysiology

Calcification of osteoid depends on adequate levels of ionized calcium and phosphate in the extracellular fluid. Vitamin D influences these levels after its dihydroxylation into calcitriol (at the 25 position in the liver and the 1 position in the kidney). If the enzyme controlling either of these steps is deficient because of mutation, vitamin D function is less than normal. In addition, a renal tubular defect that reduces reabsorption may alter phosphate metabolism. Finally, a genetic absence of the receptor for calcitriol results in deficient calcification.

Clinical and laboratory findings

Clinical results and laboratory examination findings vary with each disorder. Low phosphate and high alkaline phosphatase levels characterize most of the disorders. Exceptions are noted in the discussion of each disorder.

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