Parathyroid hormone (PTH), an 84-amino-acid peptide, 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. ||Download (.pdf) 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 levels ||Serum calcium increased, serum phosphate decreased ||Serum calcium and phosphate both increased |
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 and modified, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 42–2.)
At the continuous high concentrations seen in hyperparathyroidism, the net effect of elevated PTH is increased bone resorption, hypercalcemia, and hyperphosphatemia. However, low intermittent doses of PTH produce a net increase in bone formation; this is the basis of the use of teriparatide, a recombinant truncated form of PTH, for parenteral treatment of osteoporosis.
High-Yield Terms to Learn
|Hyperparathyroidism ||A condition of PTH excess characterized by hypercalcemia, bone pain, cognitive abnormalities, and renal stones. Primary disease results from parathyroid gland dysfunction. Secondary disease most commonly results from chronic kidney disease |
|Osteoblast ||Bone cell that promotes bone formation |
|Osteoclast ||Bone cell that promotes bone resorption |
|Osteomalacia ||A condition of abnormal mineralization of adult bone secondary to nutritional deficiency of vitamin D or inherited defects in the formation or action of active vitamin D metabolites |
|Osteoporosis ||Abnormal loss of bone with increased risk of fractures, spinal deformities, and loss of stature; remaining bone is histologically normal |
|Paget’s disease ||A bone disorder, of unknown origin, characterized by excessive bone destruction and disorganized repair. Complications include skeletal deformity, musculoskeletal pain, kidney stones, and organ dysfunction secondary to pressure from bony overgrowth |
|Rickets ||The same as osteomalacia, but occurs in the growing skeleton |
|RANK ligand ||An osteoblast-derived growth factor that stimulates osteoclast activity and osteoclast precursor differentiation |
The synthesis and secretion of PTH is primarily regulated by the serum concentration of free ionized calcium; a drop in free ionized calcium stimulates PTH release. Active metabolites of vitamin D play a secondary role in regulating PTH secretion by inhibiting PTH synthesis (Figure 42–2A).
Vitamin D, a fat-soluble vitamin (Figure 42–3), can be synthesized in the skin from 7-dehydrocholesterol under the influence of ultraviolet light or absorbed from the diet in the natural form (vitamin D3, cholecalciferol) or the plant form (vitamin D2, ergocalciferol). Active metabolites are formed in the liver (25-hydroxyvitamin D or calcifediol) and kidney (1,25-dihydroxyvitamin D or calcitriol plus other metabolites). Renal synthesis of active vitamin D metabolites is stimulated by PTH. Synthesis of 1,25-dihydroxyvitamin D2 is inhibited by phosphate, fibroblast growth factor 23 (FGF23), and vitamin D metabolites (Figure 41–2). The action of vitamin D metabolites is mediated by activation of 1 or possibly a family of nuclear receptors that regulate gene expression.
Conversion of 7-dehydrocholesterol to vitamin D3 and metabolism of vitamin D3 to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and to 24,25-dihydroxyvitamin D3 (24,25(OH)2D3). The inset shows the side chain for ergosterol. Ergosterol undergoes similar transformation to vitamin D2 (ergocalciferol), which, in turn is metabolized to 1,25-dihydroxyvitamin D2 and 24,25-dihydroxyvitamin D2. In humans, corresponding D2 and D3 have equivalent effects and potency. They are therefore referred to in the text without a subscript. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 42–3.)
Active vitamin D metabolites cause a net increase in serum concentrations of calcium and phosphate by increasing intestinal absorption and bone resorption and decreasing renal excretion (Figure 42–1, Table 42–1). Because their effect in the gastrointestinal (GI) tract and bone is greater than their effect in the kidney, they also increase urinary calcium. Active vitamin D metabolites are required for normal mineralization of bone; deficiencies cause rickets in growing children and adolescents and osteomalacia in adults. Vitamin D metabolites inhibit PTH secretion directly and indirectly, by increasing serum calcium.
Vitamin D, vitamin D metabolites, and synthetic derivatives are used to treat deficiency states, including nutritional deficiency, intestinal osteodystrophy, chronic kidney or liver disease, hypoparathyroidism, and nephrotic syndrome. They are also used, in combination with calcium supplementation, to prevent and treat osteoporosis in older women and men. Topical formulations are used in psoriasis, a hyperproliferative skin disorder. The 2 forms of vitamin D—cholecalciferol and ergocalciferol—are available as oral supplements and are commonly added to dairy products and other foods. In patients with conditions that impair vitamin D activation (chronic kidney disease, liver disease, hypoparathyroidism), an active form of vitamin D such as calcitriol is required. In the treatment of secondary hyperparathyroidism associated with chronic kidney disease, calcitriol reduces PTH levels, corrects hypocalcemia, and improves bone disease, but it can also result in hypercalcemia and hypercalciuria through direct effects on intestinal, bone, and renal handling of calcium and phosphate. Several forms of active vitamin D that selectively inhibit PTH formation while posing less risk of hypercalcemia have been developed. 1α-Hydroxyvitamin D2 (doxercalciferol) is a prodrug that is converted in the liver to 1,25-dihydroxyvitamin D, whereas 19-nor-1,25-dihydroxyvitamin D2 (paricalcitol) and calcipotriene (calcipotriol) are analogs of calcitriol. All cause less hypercalcemia and, in patients with normal renal function, less hypercalciuria than calcitriol. Oral and parenteral doxercalciferol and oral paricalcitol are approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Calcipotriene (calcipotriol) is approved for topical treatment of psoriasis. These and other analogs are being investigated for use in various malignancies and inflammatory disorders.
The primary toxicity caused by chronic overdose with vitamin D or its active metabolites is hypercalcemia, hyperphosphatemia, and hypercalciuria.
C. Fibroblast growth factor 23 (FGF23)
FGF23 is secreted by osteocytes in bone and inhibits 1,25(OH)2D production and phosphate reabsorption in the kidney. It is not used as a drug.
Calcitonin, a peptide hormone secreted by the thyroid gland, decreases serum calcium and phosphate by inhibiting bone resorption and inhibiting renal excretion of these minerals (Figure 42–1). Bone formation is not impaired initially, but ultimately both formation and resorption are reduced. The hormone has been used in conditions in which an acute reduction of serum calcium is needed (eg, Paget’s disease and hypercalcemia). Calcitonin is approved for treatment of osteoporosis and has been shown to increase bone mass and to reduce spine fractures. However, it is not as effective as teriparatide or bisphosphonates. Although human calcitonin is available, salmon calcitonin is most often selected for clinical use because of its longer half-life and greater potency. Calcitonin is administered by injection or as a nasal spray.
Estrogens and selective estrogen receptor modulators (SERMs; eg, raloxifene) can prevent or delay bone loss in postmenopausal women (see Chapter 40). Their action involves the inhibition of PTH-stimulated bone resorption (Figure 42–2B).
The glucocorticoids (Chapter 39) inhibit bone mineral maintenance. As a result, chronic systemic use of these drugs is a common cause of osteoporosis in adults. However, these hormones are useful in the intermediate-term treatment of hypercalcemia.