Osteomalacia secondary causes

The secondary causes of rickets and osteomalacia that result from vitamin D deficiency are illustrated in Figure 1. For example, in liver disease, serum concentrations of 25(OH)D3 are invariably too low, and in renal disease too little of the hormonal form of vitamin D, l,25(OH)2D3, is produced. Other causes relate to reduced cell receptor responsiveness to the hormone because of genetic mutations and, hence, inappropriate adaptations that normally contribute to conservation of calcium and/or phosphate ions. 

Long-term anticonvulsive therapy with diphenylhydantoin or phenobarbital is known to cause osteomalacia by influencing calcium metabolism (24,25). Alteration in the metabolism of vitamin D, presumably secondary to induction of hepatic microsomal enzymes, leads to the calcium and bone abnormalities (26). Patients on anticonvulsive therapy with phenytoin exhibit a decrease in serum 25-hydroxyvitamin D (27). Adequate dietary amounts of vitamin precursors or microsomal enzyme stimulators might prevent these effects of long-term therapy. 

Osteomalacia is due to prrimary or secondary vitamin D deficiency. In secondary cases, e.g. malabsorption or renal disease, high doses of vitamin D are sometimes needed. Long-term therapy with some antiepilepsy drugs may cause osteomalacia see Vitamin D). 

The clinical manifestations of serum phosphate depletion depend on the length and degree of the deficiency. Moderate hypophosphatemia of 1.5 to 2,4 mg/dL (0.48 to 0.77 mmol/L) is usually not associated with clinical signs and symptoms (unless chronic, when osteomalacia or rickets develops). Plasma concentrations less than 1.5 mg/dL (0.48 mmol/L) may produce clinical manifestations. Because phosphate is necessary for the formation of ATP, glycolysis and cellular function are impaired by low intracellular phosphate concentrations. Muscle wealmess, acute respiratory failure, and decreased cardiac output may occur in phosphate depletion. At very low serum phosphate (<1 mg/dL or <0.32 mmol/L), rhabdomyolysis may occur. Phosphate depletion in erythrocytes decreases erythrocyte 2,3-diphosphoglycerate, which causes tissue hypoxia because of increased affinity of hemoglobin for oxygen. Severe hypophosphatemia (serum phosphate concentration <0.5 mg/dL [<0.16 mmol/L]) may result in hemolysis of the red blood cells. Mental confusion and frank coma also may be secondary to the low ATP and tissue hypoxia. If hypophosphatemia is chronic, impaired mineralization of bone produces rickets in children and osteomalacia in adults. 

Laboratory findings in rickets and osteomalacia include an increased serum ALP, with other alterations in bone and mineral metabolism dependent on the cause and severity of the disorder. ALP is usually increased because of the increased osteoblastic activity associated with producing unmineralized osteoid. Calcium may be low-normal or low in vitamin D deficiency depending on the severity of the disease. Phosphate may be normal or low, but falls with the development of secondary hyperparathyroidism. The serum calcium and PTH concentrations are usually normal in renal tubular defects of phosphate transport. Vitamin D nutrition may be assessed by the determination of serum 25(OH)D. Renal phosphate defects can be best assessed by determination of the renal phosphate threshold. 

Vitamin D and its metabolites play an important role in the maintenance of extracellular calcium concentrations and in normal skeletal structure and mineralization. Vitamin D is necessary for the optimal absorption of calcium and phosphorus. On a worldwide basis, the most common cause of hypocalcemia is nutritional vitamin D deficiency. In malnourished populations, manifestations include rickets and osteomalacia. Nutritional vitamin D deficiency is uncommon in Western societies because of the fortification of miUc with ergocalciferol. " The most common cause of vitamin D deficiency in Western societies is gastrointestinal disease. Gastric surgery, chronic pancreatitis, small-bowel disease, intestinal resection, and bypass surgery are associated with decreased concentrations of vitamin D and its metabolites. Vitamin D replacement therapy may need to be administered by the intravenous route if poor oral bioavailability is noted. Decreased production of 1,25-dihydroxyvitamin D3 may occur as a result of a hereditary defect resulting in vitamin D-dependent rickets. It also can occur secondary to chronic renal insufficiency if there is insufficient production of the 1 -a -hydroxylase enzyme for the... 

Other chronic disorders cause osteomalacia. " " Phosphate depletion from low dietary intake, phosphate-binding antacids, and oncogenic osteomalacia (potentially phosphaturic effect) can cause osteomalacia. Hypophosphatasia is an inborn error of metabolism in which deficient activity of alkaline phosphatase causes impaired mineralization of bone matrix. Acidosis from renal dysfunction, distal renal tubular acidosis, hypergammaglobulinemic states (e.g., multiple myeloma), and drugs (e.g., chemotherapy) compromises bone mineralization. Renal tubular disorders secondary to Fanconi s syndrome, hereditary diseases (e.g., Wilson s disease, a defect in copper metabolism), acquired disease (e.g., myeloma), and toxins (e.g., lead) cause osteomalacia to varying degrees. Chronic wastage of phosphorus and/or calcium limits mineralization, which may be further compromised by acidosis and secondary hyperparathyroidism. 

It is obvious that a variety of disorders would result from a disturbance of the vitamin D endocrine system. Fat malabsorption would result in a deficiency of vitamin D giving rise ultimately to osteomalacia or rickets or secondary hyperparathyroidism. A hepatic disorder such as severe cirrhosis, or biliary atresia, may result in malabsorption of vitamin D and defective vitamin D-25-hydroxylation. Dilantin and phenobarbital cause low plasma 25-OH-D levels resulting in rickets and osteomala-cia246) Qf parathyroid glands would cause a severe hypocalcemia and tetany. 

Once the epiphyseal plates are closed later in adolescence, vitamin D deficiency can no longer cause bone deformities. Instead, there is an inability to mineralize newly deposited bone matrix leading to wide osteoid seams within the trabecular and cortical bone causing the bone disease commonly known as osteomalacia. In addition, the secondary hyperparathyroidism that results from vitamin D deficiency results in the mobilization of precious calcium stores from the bone thereby exacerbating bone loss and causing osteoporosis. This can increase a person s risk for fracture. 

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