Page 787 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 42 Agents That Affect Bone Mineral Homeostasis 773

Ca, P because it must be further metabolized to gain biologic activity
(Figure 42–3). Vitamin D is produced in the skin under ultra-
3
violet B (UVB) radiation (eg, in sunlight) from its precursor,
7-dehydrocholesterol. The initial product, pre-vitamin D , under-
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goes a temperature-sensitive isomerization to vitamin D . The
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D(+) Serum D(+), PTH (+) precursor of vitamin D is ergosterol, found in plants and fungi
2
Gut Bone
Ca, P (mushrooms). It undergoes a similar transformation to vitamin D
D(+), PTH (+) 2
CT(–) with UVB radiation. Vitamin D thus comes only from the diet,
2
whereas vitamin D comes from the skin or the diet, or both.
3
The subsequent metabolism of these two forms of vitamin D is
Ca, P essentially the same and follows the illustration for vitamin D
Kidney 3
metabolism in Figure 42–3. The first step is the 25-hydroxylation
of vitamin D to 25-hydroxyvitamin D (25[OH]D). A number of
D(–)
D(–) enzymes in the liver and other tissues perform this function,
PTH(–) PTH(+) of which CYP2R1 is the most important. 25(OH)D is then
CT(+)
CT(+)
FGF23(+) metabolized to the active hormone 1,25-dihydroxyvitamin D
Ca P (1,25[OH] D) in the kidney and elsewhere. PTH stimulates the
2
production of 1,25(OH) D in the kidney, whereas FGF23 is
2
FIGURE 42–1 Mechanisms contributing to bone mineral inhibitory. Elevated levels of blood phosphate and calcium also
homeostasis. Serum calcium (Ca) and phosphorus (P) concentrations inhibit 1,25(OH) D production in part by their effects on FGF23
2
are controlled principally by three hormones, 1,25-dihydroxyvitamin (high phosphate stimulates FGF23 production) and PTH (high
D (D), fibroblast growth factor 23 (FGF23), and parathyroid hormone
2
(PTH), through their action on absorption from the gut and from calcium inhibits PTH production). 1,25(OH) D regulates its
bone and on renal excretion. PTH and 1,25(OH) 2 D increase the input own levels by stimulating the enzyme 24-hydroxyase (CYP24A1),
of calcium and phosphorus from bone into the serum and stimulate which begins the catabolism of 1,25(OH) D, suppressing PTH
2
bone formation. 1,25(OH) 2 D also increases calcium and phosphate production, and stimulating FGF23 production, all of which
absorption from the gut. In the kidney, 1,25(OH) 2 D decreases excre- combine to reduce 1,25(OH) D levels. Other tissues also produce
2
tion of both calcium and phosphorus, whereas PTH reduces calcium 1,25(OH) D; the control of this production differs from that
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but increases phosphorus excretion. FGF23 stimulates renal excretion in the kidney, as will be discussed subsequently. The complex
of phosphate. Calcitonin (CT) is a less critical regulator of calcium interplay among PTH, FGF23, and 1,25(OH) D is discussed in
homeostasis, but in pharmacologic concentrations can reduce serum detail later. 2
calcium and phosphorus by inhibiting bone resorption and stimulat- To summarize: 1,25(OH) D suppresses the production of PTH,
2
ing their renal excretion. Feedback may alter the effects shown; for as does calcium, but stimulates the production of FGF23. Phos-
example, 1,25(OH) 2 D increases urinary calcium excretion indirectly
through increased calcium absorption from the gut and inhibition phate stimulates both PTH and FGF23 secretion. In turn PTH
of PTH secretion and may increase urinary phosphate excretion stimulates 1,25(OH) D production, whereas FGF23 is inhibitory.
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because of increased phosphate absorption from the gut and stimu- 1,25(OH) D stimulates the intestinal absorption of calcium and
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lation of FGF23 production. phosphate. 1,25(OH) D and PTH promote both bone formation
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and resorption in part by stimulating the proliferation and differen-
tiation of osteoblasts and osteoclasts. Both PTH and 1,25(OH) D
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filtered phosphate are reabsorbed by the kidney. The movement enhance renal retention of calcium, but PTH promotes renal phos-
of calcium and phosphate across the intestinal and renal epithelia phate excretion, as does FGF23, whereas 1,25(OH) D promotes
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is closely regulated. Dysfunction of the intestine (eg, nontropi- renal reabsorption of phosphate.
cal sprue) or kidney (eg, chronic renal failure) can disrupt bone Other hormones—calcitonin, prolactin, growth hormone,
mineral homeostasis. insulin, insulin-like growth factors, thyroid hormone, glucocorti-
Three hormones serve as the principal regulators of calcium coids, and sex steroids—influence calcium and phosphate homeo-
and phosphate homeostasis: parathyroid hormone (PTH), stasis under certain physiologic circumstances and can be considered
fibroblast growth factor 23 (FGF23), and vitamin D via its secondary regulators. Deficiency or excess of these secondary regula-
active metabolite 1,25-dihydroxyvitamin D (1,25[OH] D) tors within a physiologic range does not produce the disturbance of
2
(Figure 42–2). The role of calcitonin (CT) is less critical dur- calcium and phosphate homeostasis that is observed in situations
ing adult life but may play a greater role during pregnancy and of deficiency or excess of PTH, FGF23, and vitamin D. However,
lactation. The term vitamin D, when used without a subscript, certain of these secondary regulators—especially calcitonin, gluco-
refers to both vitamin D (ergocalciferol) and vitamin D (cho- corticoids, and estrogens—are useful therapeutically and discussed
2
3
lecalciferol). This applies also to the metabolites of vitamin D in subsequent sections.
2
and D . Vitamin D and its metabolites differ from vitamin D In addition to these hormonal regulators, calcium and phos-
3
3
2
and its metabolites only in the side chain where they con- phate themselves, other ions such as sodium and fluoride, and a
tain a double bond between C-22–23 and a methyl group at variety of drugs (bisphosphonates, anticonvulsants, and diuretics)
C-24 (Figure 42–3). Vitamin D is considered a prohormone also alter calcium and phosphate homeostasis.