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Chapter 42: Agents That Affect Bone Mineral Homeostasis

INTRODUCTION

Calcium and phosphorus, the 2 major elements of bone, are crucial not only for the mechanical strength of the skeleton but also for the normal function of many other cells in the body. Three hormones are the main regulators of calcium and phosphate homeostasis, parathyroid hormone (PTH), vitamin D, and fibroblast growth factor 23 (FGF23) (Figure 42–1). Calcitonin, glucocorticoids, and estrogens play secondary roles. These hormones, or drugs that mimic or suppress their actions, are used in the treatment of bone mineral disorders (eg, osteoporosis, rickets, osteomalacia, Paget’s disease), as are several nonhormonal agents.

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FIGURE 42–1

Effects of active metabolites of vitamin D (D), parathyroid hormone (PTH), calcitonin (CT), and fibroblast growth factor 23 (FGF23) on calcium and phosphorus homeostasis. Active metabolites of vitamin D increase absorption of calcium from both gut and bone, whereas PTH increases reabsorption from bone. Vitamin D metabolites and PTH both reduce urinary excretion of calcium. In animals with vitamin D deficiency, active metabolites of vitamin D produce a net increase in bone mineralization by increasing the availability of serum calcium and phosphate. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 42–1.)

An illustration shows the effect on calcium and phosphorus homeostasis caused by active metabolites of vitamin D, parathyroid hormone, calcitonin, and fibroblast growth factor 23.
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An illustration shows the effect on calcium and phosphorus homeostasis caused by active metabolites of vitamin D, parathyroid hormone, calcitonin, and fibroblast growth factor 23.

HORMONAL REGULATORS OF BONE MINERAL HOMEOSTASIS

A. Parathyroid Hormone

Parathyroid hormone (PTH), an 84-amino-acid peptide, increases serum calcium and lowers serum phosphate. It acts on membrane G protein-coupled receptors to increase cyclic adenosine monophosphate (cAMP) in bone and renal tubular cells. In the kidney, PTH inhibits calcium excretion, promotes phosphate excretion, and stimulates the production of active vitamin D metabolites (Figure 42–1, Table 42–1). In bone, PTH promotes bone turnover by increasing the activity of both osteoblasts and osteoclasts (Figure 42–2B). Osteoclast activation is not a direct effect and instead results from PTH stimulation of osteoblast formation of RANK ligand (RANKL), a member of the tumor necrosis factor (TNF) cytokine family that stimulates the activity of mature osteoclasts and the differentiation of osteoclast precursors.

TABLE 42–1Actions of PTH and active vitamin D metabolites on intestine, kidney, and bone.
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TABLE 42–1 Actions of PTH and active vitamin D metabolites on intestine, kidney, and bone.
Organ PTH Active Vitamin D Metabolites
Intestine Indirectly increases calcium and phosphate absorption by increasing vitamin D metabolites Increased calcium and phosphate absorption
Kidney Decreased calcium excretion, increased phosphate excretion Increased resorption of calcium and phosphate but usually net increase in urinary calcium due to effects in GI tract and bone
Bone Calcium and phosphate resorption increased by continuous high concentrations. Low intermittent doses increase bone formation Direct effect is increased calcium and phosphate resorption; indirect effect is promoting mineralization by increasing the availability of calcium and phosphate
Net effect on serum ...

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