Rickets and Osteomalacia

Osteomalacia and rickets have been reported with long-term anticonvulsant therapy additional risk factors for these conditions (e.g., poor sunlight exposure) increases risk... 

Acute symptomatic hypocalcemia may be seen in hospitalized patients for various reasons. Rapid remineralization of bone after surgery for primary hyperparathyroidism (hungry bone syndrome), treatment for hyperthyroidism, or treatment for hematological malignancy may result in hypocalcemia. Acute hemorrhagic or edematous pancreatitis is frequently complicated by hypocalcemia. Vitamin D deficiency may also be associated with hypocalcemia because of impaired intestinal absorption of calcium and skeletal resistance to PTH. Osteomalacia and rickets are discussed in a later section of this chapter. 

Metabolic bone diseases result from a partial uncoupling or imbalance between bone resorption and formation. Decreased bone mass, or osteopenia, is more common than abnormal increases of bone mass. The most prevalent metabolic bone diseases are osteoporosis, osteomalacia and rickets, and renal osteodystrophy. Osteoporosis, the most prevalent metabolic bone disease in developed countries, is characterized by loss of bone mass, microarchitectural deterioration of bone tissue, and increased risk of fracture. Rickets and osteomalacia, which are more common in the less-developed countries, are characterized by defective mineralization of bone matrix. Renal osteodystrophy is a complex condition that develops in response to abnormalities of the endocrine and excretory functions of the kidneys. These three metabolic bone diseases and Paget s disease, a localized bone disease, are discussed below followed by laboratory markers of bone metabolism. 

Osteomalacia and rickets are caused by a mineralization defect during bone formation, resulting in an increase in osteoid, the unmineralized organic matrix of bone. Defective mineralization produces rickets in children and osteomalacia in adults. Osteomalacia or rickets is usually due to either vitamin D deficiency or phosphate depletion. 

Osteomalacia and rickets may also occur because of phosphate depletion. The most common cause of rickets in the United States is hypophosphatemic osteomalacia (also known as hypophosphatemic vitamin D-resistant rickets and vitamin D-resistant rickets).This disorder is an X-linked dominant inherited trait characterized by renal phosphate wasting. Tubular phosphate wasting can also occur sporadically in adults and as part of Fanconi syndrome. Certain rare mesenchymal tumors may also produce a phosphaturic factor (phosphatonin or FGF-23), resultmg in renal phosphate wasting and osteomalacia. 

Low-turnover bone diseases include osteomalacia and adynamic (also known as aplastic) bone diseases. Osteomalacia and adynamic bone disease are distinguished by the extent of unmineralized bone matrix or osteoid osteoid is increased in osteomalacia and normal or low in adynamic bone disease. Osteomalacia in chronic renal failure may reflect vitamin D deficiency because of the decreased renal synthesis of l,25(OH)2D (see Osteomalacia and Rickets) or aluminum-related disease. In the 1970s and 1980s, aluminum intoxication was a significant contributing factor to the development of osteomalacia and adynamic bone... 

BAP is increased in metabolic bone diseases, including osteoporosis, osteomalacia and rickets, hyperparathyroidism, renal osteodystrophy, and thyrotoxicosis, and in individuals with acromegaly, bony metastases, glucocorticoid excess, Paget s disease, and other disorders with increased bone formation." ... 

Dresner M. Osteomalacia and rickets. In Goldman L, Bennett JC, ed. Cecil Textbook of Medicine. Philadelphia, WB Saunders, 2000 1391—... 

The combination of hypophosphatemia, vitamin D resistance, osteomalacia, and rickets is seen in a number of syndromes (W24). These include (a) familial hypophosphatemic vitamin D-resistant rickets, a sex-linked, dominant disorder (P3), (b) familial vitamin D dependency, an autosomal recessive disorder due to la-hydroxylase deficiency (F19), and (c) nonfamilial hypophosphatemic osteomalacia (D9), considered by some workers (P3) to be a separate disease entity because of its late onset, its severity, and its lack of response to therapy. In addition, there are many inherited and acquired disorders which are associated with impairment of renal tubular reabsorption of phosphate, and these may be accompanied by hypophosphatemia, rickets, and relative vitamin D resistance. Serum alkaline phosphatase values in these disorders correlate poorly with the severity of the disease (A14) and with the response to therapy (E4, MclO, P7, S50). 

Some drugs, for example anticonvulsants phenytoin, phenobarbital and corticosteroids can lead to osteomalacia and rickets by depressing vitamin D dependent calcium uptake in the intestine. 

Vitamin D contributes to the calcemic action of the parathyroid hormone (C2, N14). Deficiency of vitamin D therefore results in a fall in ionic calcium concentration which stimulates the parathyroids. Parathyroid hypertrophy is seen in vitamin D-deficient animals (C3, H7, S7) and man (PI) and can be prevented by exposure to ultraviolet light (H7). A low plasma phosphorus concentration and high Cp/Ca are characteristic of osteomalacia and rickets, and the FEl is of the same order as that in parathyroid tumor (Nil) (Fig. 10). However, this high phosphate clearance, unlike that of parathyroid tumor, can be reduced to a normal or subnormal value by intravenous infusion of calcium (N5). 

The bony features of osteomalacia and rickets are also shared by other bone diseases (see later). 

In addition to the classical environmental or nutritional cause of these diseases, both osteomalacia and rickets can have a pharmacological origin via chronic treatment with anticonvulsants (phenobarbital and phenytoin) or glucocorticoids. These agents interfere with intestinal absorption of calcium and, thereby, cause pseudohyperparathyroidism. As a result, an increase in bone turnover and a decrease in the formation of appropriately mineralized bone is observed. In these patients, treatment with vitamin D improves calcium absorption, ultimately enhancing mineralization of the bone. 

Severe osteomalacia and rickets have been seen in a few patients taking phenytoin, phenobarbital, or primidone with acetazola-mide. A marked reduction in serum primidone levels with a loss in seizure controi, rises in serum carbamazepine levels with toxicity, and rises in phenytoin levels have also been described in a veiy small number of patients given acetazolamide. 

Provitamin and vitamin D are liposoluble compounds, and their absorption in the intestine depends on lipid absorption. Intestinal diseases accompanied by pronounced steatorrhea result in vitamin D deficiency with osteomalacia and rickets. Although vitamin D was one of the first vitamins to be identified, it is only recently that its role in metabolism has been clarified. The mechanism of action of vitamin D raises problems at the histological and the molecular level Which tissues are the target of vitamin D What are the intricacies of the molecular reaction involving vitamin D in calcification ... 

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