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Chapter: Basic & Clinical Pharmacology : Agents That Affect Bone Mineral Homeostasis

Basic Pharmacology

Calcium and phosphate, the major mineral constituents of bone, are also two of the most important minerals for general cellular function.

BASIC PHARMACOLOGY

 

Calcium and phosphate, the major mineral constituents of bone, are also two of the most important minerals for general cellular function. Accordingly, the body has evolved complex mechanisms to carefully maintain calcium and phosphate homeostasis (Figure 42–1). Approximately 98% of the 1–2 kg of calcium and 85% of the 1 kg of phosphorus in the human adult are found in bone, the principal reservoir for these minerals. This reservoir is dynamic, with con-stant remodeling of bone and ready exchange of bone mineral with that in the extracellular fluid. Bone also serves as the princi-pal structural support for the body and provides the space for hematopoiesis. This relationship is more than fortuitous as ele-ments of the bone marrow affect skeletal processes just as skeletal elements affect hematopoeitic processes. Abnormalities in bone mineral homeostasis can lead to a wide variety of cellular dysfunc-tions (eg, tetany, coma, muscle weakness), and to disturbances in structural support of the body (eg, osteoporosis with fractures) and loss of hematopoietic capacity (eg, infantile osteopetrosis).


Calcium and phosphate enter the body from the intestine. The average American diet provides 600–1000 mg of calcium per day, of which approximately 100–250 mg is absorbed. This amount represents net absorption, because both absorption (principally in the duodenum and upper jejunum) and secretion (principally in the ileum) occur. The quantity of phosphorus in the American diet is about the same as that of calcium. However, the efficiency of absorption (principally in the jejunum) is greater, ranging from 70% to 90%, depending on intake. In the steady state, renal excre-tion of calcium and phosphate balances intestinal absorption. In general, over 98% of filtered calcium and 85% of filtered phosphate is reabsorbed by the kidney. The movement of calcium and phos-phate across the intestinal and renal epithelia is closely regulated. Dysfunction of the intestine (eg, nontropical sprue) or kidney (eg, chronic renal failure) can disrupt bone mineral homeostasis. 


Three hormones serve as the principal regulators of calcium and phosphate homeostasis: parathyroid hormone (PTH),fibroblast growth factor 23 (FGF23), and vitamin D (Figure 42–2). Vitamin D is a prohormone rather than a true hormone, because it must be further metabolized to gain biologic activity. 

 

PTH stimulates the production of the active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25[OH]2D), in the kidney. Other tissues also produce 1,25(OH)2D; the control of this production differs from that in the kidney, as will be discussed subsequently. The complex interplay among PTH, FGF23, and 1,25(OH)2D is discussed in detail later. To summarize briefly: 1,25(OH)2D suppresses the production of PTH as does calcium, whereas phosphate stimulates PTH secretion. 1,25(OH)2D stim-ulates the intestinal absorption of calcium and phosphate. 1,25(OH)2D and PTH promote both bone formation and resorp-tion in part by stimulating the proliferation and differentiation of osteoblasts and osteoclasts. Both PTH and 1,25(OH)2D enhance renal retention of calcium, but PTH promotes renal phosphate excretion, whereas 1,25(OH)2D promotes renal reabsorption of phosphate. FGF23 is a recently discovered hormone produced primarily by bone that stimulates renal phosphate excretion and inhibits renal production of 1,25(OH)2D. 1,25(OH)2D and phosphate in turn stimulate the production of FGF23.

Other hormones—calcitonin, prolactin, growth hormone, insu-lin, thyroid hormone, glucocorticoids, and sex steroids—influence calcium and phosphate homeostasis under certain physiologic cir-cumstances and can be considered secondary regulators. Deficiency or excess of these secondary regulators within a physiologic range does not produce the disturbance of calcium and phosphate homeostasis that is observed in situations of deficiency or excess of PTH, FGF23, and vitamin D. However, certain of these secondary regulators—especially calcitonin, glucocorticoids, and estrogens— are useful therapeutically and discussed in subsequent sections.

In addition to these hormonal regulators, calcium and phos-phate themselves, other ions such as sodium and fluoride, and a variety of drugs (bisphosphonates, plicamycin, and diuretics) also alter calcium and phosphate homeostasis.


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