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Calcium and phosphorus, the two 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 disease), as are several nonhormonal agents.



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, Vanderah TW: Basic & Clinical Pharmacology, 15th ed. New York, NY: McGraw Hill; 2021.)


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.


Hormonal interactions controlling bone mineral homeostasis. (A) The 1,25-dihydroxyvitamin D that is produced by the kidney under control of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) stimulates intestinal uptake of calcium and phosphate, and, in those with vitamin D deficiency, promotes bone formation. Calcitonin inhibits resorption from bone, whereas PTH stimulates bone resorption. Extracellular calcium and 1,25-dihydroxyvitamin D inhibit PTH production. (B) Both PTH and 1,25-dihydroxyvitamin D regulate bone formation and resorption. This is accomplished by their activation of precursor differentiation and by stimulation of osteoblast production of signaling factors, including RANK ligand (RANKL), macrophage colony-stimulating factor (MCSF), and osteoprotegerin (OPG). (Reproduced with permission from Katzung BG, Vanderah TW: Basic & Clinical Pharmacology, 15th ed. New York, NY: McGraw Hill; 2021.)

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