Page 802 - Basic _ Clinical Pharmacology ( PDFDrive )

788 SECTION VII Endocrine Drugs

and pathologic picture resembling vitamin D–dependent rickets develop bone disease. It is not yet clear what value vitamin D ther-
develops. However, affected children fail to respond to the standard apy has in such patients, because therapeutic trials with vitamin D
doses of vitamin D used in the treatment of nutritional rickets. A (or any vitamin D metabolite) have not yet been carried out.
defect in 1,25(OH) D production by the kidney contributes to Because the problem is not related to vitamin D metabolism, one
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the phenotype as 1,25(OH) D levels are low relative to the degree would not anticipate any advantage in using the more expensive
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of hypophosphatemia observed. This combination of low serum vitamin D metabolites in place of vitamin D.
phosphate and low or low-normal serum 1,25(OH) D provides
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the rationale for treating these patients with oral phosphate (1–3 g IDIOPATHIC HYPERCALCIURIA
daily) and calcitriol (0.25–2 mcg daily). Reports of such combina-
tion therapy are encouraging in this otherwise debilitating disease,
although prolonged treatment often leads to secondary hyperpara- Individuals with idiopathic hypercalciuria, characterized by hyper-
thyroidism. More recently the use of FGF23 antibodies for children calciuria and nephrolithiasis with normal serum calcium and PTH
with X-linked hypophosphatemic (XLH) rickets has shown promise levels, have been divided into three groups: (1) hyperabsorbers,
and may become the treatment of choice for these conditions. patients with increased intestinal absorption of calcium, resulting
in high-normal serum calcium, low-normal PTH, and a second-
ary increase in urine calcium; (2) renal calcium leakers, patients
PSEUDOVITAMIN D DEFICIENCY with a primary decrease in renal reabsorption of filtered calcium,
RICKETS & HEREDITARY VITAMIN D– leading to low-normal serum calcium and high-normal serum
PTH; and (3) renal phosphate leakers, patients with a primary
RESISTANT RICKETS decrease in renal reabsorption of phosphate, leading to increased
1,25(OH) D production, increased intestinal calcium absorption,
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These distinctly different autosomal recessive diseases present as child- increased ionized serum calcium, low-normal PTH levels, and a
hood rickets that do not respond to conventional doses of vitamin D. secondary increase in urine calcium. There is some disagreement
Pseudovitamin D–deficiency rickets is due to an isolated deficiency about this classification, and many patients are not readily catego-
of 1,25(OH) D production caused by mutations in 25(OH)-D- rized. Many such patients present with mild hypophosphatemia,
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1α-hydroxylase (CYP27B1). This condition is treated with cal- and oral phosphate has been used with some success in reduc-
citriol (0.25–0.5 mcg daily). Hereditary vitamin D–resistant rickets ing stone formation. However, a clear role for phosphate in the
(HVDRR) is caused by mutations in the gene for the vitamin D treatment of this disorder has not been established and is not
receptor. The serum levels of 1,25(OH) D are very high in HVDRR recommended.
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but inappropriately low for the level of calcium in pseudovitamin Therapy with hydrochlorothiazide, up to 50 mg twice daily, or
D–deficient rickets. Treatment with large doses of calcitriol has been chlorthalidone, 50–100 mg daily, is recommended. Loop diuret-
claimed to be effective in restoring normocalcemia in some HVDRR ics such as furosemide and ethacrynic acid should not be used
patients, presumably those with a partially functional vitamin D because they increase urinary calcium excretion. The major toxic-
receptor, although many patients are completely resistant to all forms ity of thiazide diuretics, besides hypokalemia, hypomagnesemia,
of vitamin D. Calcium and phosphate infusions have been shown and hyperglycemia, is hypercalcemia. This is seldom more than
to correct the rickets in some children, similar to studies in mice in a biochemical observation unless the patient has a disease such
which the VDR gene has been deleted. These diseases are rare. as hyperparathyroidism in which bone turnover is accelerated.
Accordingly, one should screen patients for such disorders before
IDIOPATHIC INFANTILE starting thiazide therapy and monitor serum and urine calcium
when therapy has begun.
HYPERCALCEMIA An alternative to thiazides is allopurinol. Some studies indicate
that hyperuricosuria is associated with idiopathic hypercalcemia
Mutations in CYP24A1, the enzyme catabolizing 25(OH)D and and that a small nidus of urate crystals could lead to the calcium
1,25(OH) D, have recently been found to account for a number of oxalate stone formation characteristic of idiopathic hypercalcemia.
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cases of idiopathic infantile hypercalcemia. However, these muta- Allopurinol, 100–300 mg daily, may reduce stone formation by
tions have also been described in adults with previously unexplained reducing uric acid excretion.
hypercalcemia and elevated 1,25(OH) D levels. At this point no
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definitive therapy has been established, but vitamin D supplemen- OTHER DISORDERS OF BONE
tation needs to be avoided. The diagnosis can be made by finding a
reduced ratio of 24,25(OH) D to 25(OH)D in the blood. MINERAL HOMEOSTASIS
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PAGET’S DISEASE OF BONE
NEPHROTIC SYNDROME
Paget’s disease is a localized bone disorder characterized by uncon-
Patients with nephrotic syndrome can lose vitamin D metabolites in trolled osteoclastic bone resorption with secondary increases in
the urine, presumably by loss of the vitamin D–binding protein. poorly organized bone formation. The cause of Paget’s disease is
Such patients may have very low 25(OH)D levels. Some of them obscure, although some studies suggest that a measles-related virus