Page 799 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 42 Agents That Affect Bone Mineral Homeostasis 785

of hypoparathyroidism and reduces the need for large doses of from the parathyroid gland response to lowered serum ionized
calcium and calcitriol with less risk of hypercalciuria. calcium and low 1,25(OH) D. FGF23 levels rise early in this dis-
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order for unclear reasons and this can further reduce 1,25(OH) D
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production by the kidney. Moreover, the increase in FGF23 is
NUTRITIONAL VITAMIN D DEFICIENCY associated with increased morbidity and mortality in CKD in
OR INSUFFICIENCY part due to its impact on the heart. Although still investigational,
antibodies to FGF23 in the early stages of renal failure result in
The level of vitamin D thought to be necessary for good health normalization of 1,25(OH) D levels, and may prove useful in
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is being reexamined with the appreciation that vitamin D acts on CKD treatment. However, inhibition of FGF23 may further the
a large number of cell types beyond those responsible for bone rise in serum phosphate with the potential for increased vascular
and mineral metabolism. A level of 25(OH)D above 10 ng/mL calcification, a major issue in CKD. With impaired 1,25(OH) D
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is necessary for preventing rickets or osteomalacia. However, production, less calcium is absorbed from the intestine, and less
substantial epidemiologic and some prospective trial data indicate bone is resorbed under the influence of PTH. As a result hypocal-
that a higher level, such as 20–30 ng/mL, is required to optimize cemia usually develops, furthering the development of secondary
intestinal calcium absorption, optimize the accrual and mainte- hyperparathyroidism. The bones show a mixture of osteomalacia
nance of bone mass, reduce falls and fractures, and prevent a wide and osteitis fibrosa.
variety of diseases including diabetes mellitus, hyperparathyroid- In contrast to the hypocalcemia that is more often associated
ism, autoimmune diseases, and cancer. An expert panel for the with chronic kidney disease, some patients may become hyper-
Institute of Medicine (IOM) has recommended that a level of calcemic from overzealous treatment with calcium. However,
20 ng/mL (50 nM) was sufficient, although up to 50 ng/mL the most common cause of hypercalcemia is the development of
(125 nM) was considered safe. For individuals between the ages severe secondary (sometimes referred to as tertiary) hyperpara-
of 1 and 70 years, 600 IU/d vitamin D was thought to be suffi- thyroidism. In such cases, the PTH level in blood is very high.
cient to meet these goals, although up to 4000 IU was considered Serum alkaline phosphatase levels also tend to be high. Treatment
safe. These recommendations are based primarily on data from often requires parathyroidectomy. A less common circumstance
randomized placebo-controlled clinical trials (RCTs) that evalu- leading to hypercalcemia is development of a form of bone disease
ated falls and fractures; data supporting the nonskeletal effects of characterized by a profound decrease in bone cell activity and loss
vitamin D were considered too preliminary to be used in their of the calcium buffering action of bone (adynamic bone disease).
recommendations because of lack of RCTs for these other actions. In the absence of kidney function, any calcium absorbed from the
The lower end of these recommendations has been considered too intestine accumulates in the blood. Such patients are very sensitive
low and the upper end too restrictive by a number of vitamin D to the hypercalcemic action of 1,25(OH) D. These individuals
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experts, and the Endocrine Society has published a different set of generally have a high serum calcium but nearly normal alkaline
recommendations suggesting that 30 ng/mL was a more appropri- phosphatase and PTH levels. The bone in such patients may have
ate lower limit. Nevertheless, the call for better clinical data from a high aluminum content, especially in the mineralization front,
RCTs, especially for the nonskeletal actions, is appropriate. The which blocks normal bone mineralization. These patients do not
IOM guidelines—at least with respect to the lower recommended respond favorably to parathyroidectomy. Deferoxamine, an agent
levels of vitamin D supplementation—are unlikely to correct used to chelate iron (see Chapter 57), also binds aluminum and
vitamin D deficiency in individuals with obesity, dark complex- is being used to treat this disorder. However, with the reduction
ions, limited capacity for sunlight exposure, or malabsorption. in use of aluminum-containing phosphate binders, most cases of
Vitamin D deficiency or insufficiency can be treated by higher adynamic bone disease are not associated with aluminum deposi-
dosages (either D or D , 1000–4000 IU/d or 50,000 IU/week tion but are attributed in some cases to overzealous suppression of
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for several weeks). No other vitamin D metabolite is indicated. PTH secretion.
Because the half-life of vitamin D metabolites in blood is greater
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than that of vitamin D , there are advantages to using vitamin D Vitamin D Preparations
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rather than vitamin D supplements, although when administered
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on a daily or weekly schedule these differences may be moot. The The choice of vitamin D preparation to be used in the setting of
diet should also contain adequate amounts of calcium as several chronic kidney disease depends on the type and extent of bone
studies indicate a synergism between calcium and vitamin D with disease and hyperparathyroidism. Individuals with vitamin D
respect to a number of their actions. deficiency or insufficiency should first have their 25(OH)D levels
restored to normal (20–30 ng/mL) with vitamin D. Calcifediol
or 1,25(OH) D (calcitriol) rapidly corrects hypocalcemia and at
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CHRONIC KIDNEY DISEASE least partially reverses secondary hyperparathyroidism and osteitis
fibrosa. Many patients with muscle weakness and bone pain gain
The major sequelae of chronic kidney disease (CKD) that impact an improved sense of well-being.
bone mineral homeostasis are deficient 1,25(OH) D production, Two analogs of calcitriol—doxercalciferol and paricalcitol—
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retention of phosphate with an associated reduction in ionized are approved in the United States for the treatment of second-
calcium levels, and the secondary hyperparathyroidism that results ary hyperparathyroidism of chronic kidney disease. (In Japan,