Page 788 - Basic _ Clinical Pharmacology ( PDFDrive )

774 SECTION VII Endocrine Drugs

A 1,25(OH) D Bone
2
Gut
+ +
Ca 2+
in blood

+ – 1,25(OH) D
2
Thyroid PTH + – FGF23
1,25(OH) D
2
–
Kidney
PTH

Calcitonin
Parathyroids 25(OH)D
B Monocyte
Stem cells

+ +
Preosteoclast PTH
1,25(OH) D Preosteoblasts
2
+ +

Osteoclast Osteoblasts
RANKL +
MCSF + Osteoid
OPG –
–
Calcified
Bisphosphonates bone
Calcitonin
Estrogen

FIGURE 42–2 The hormonal interactions controlling bone mineral homeostasis. In the body (A), 1,25-dihydroxyvitamin D (1,25[OH] 2 D)
is produced by the kidney under the control of parathyroid hormone (PTH), which stimulates its production, and fibroblast growth factor 23
(FGF23), which inhibits its production. 1,25(OH) 2 D in turn inhibits the production of PTH by the parathyroid glands and stimulates FGF23 release
from bone. 1,25(OH) 2 D is the principal regulator of intestinal calcium and phosphate absorption. At the level of the bone (B), both PTH and
1,25(OH) 2 D regulate bone formation and resorption, with each capable of stimulating both processes. This is accomplished by their stimulation
of preosteoblast proliferation and differentiation into osteoblasts, the bone-forming cell. PTH also stimulates osteoblast formation indirectly
by inhibiting the osteocyte’s production of sclerostin, a protein that blocks osteoblast proliferation by inhibiting the wnt pathway (not shown).
PTH and 1,25(OH) 2 D stimulate the expression of RANKL by the osteoblast, which, with MCSF, stimulates the differentiation and subsequent
activation of osteoclasts, the bone-resorbing cell. OPG blocks RANKL action, and may be inhibited by PTH and 1,25(OH) 2 D. FGF23 in excess leads
to osteomalacia indirectly by inhibiting 1,25(OH) 2 D production and lowering phosphate levels. MCSF, macrophage colony-stimulating factor;
OPG, osteoprotegerin; RANKL, ligand for receptor for activation of nuclear factor-κB.

PRINCIPAL HORMONAL Within the gland is a calcium-sensitive protease capable of cleav-
REGULATORS OF BONE MINERAL ing the intact hormone into fragments, thereby providing one
mechanism by which calcium limits the production of PTH. A
HOMEOSTASIS second mechanism involves the calcium-sensing receptor (CaSR)
which, when stimulated by calcium, reduces PTH production
PARATHYROID HORMONE and secretion. The parathyroid gland also contains the vitamin
D receptor (VDR) and the enzyme, CYP27B1, that produces
Parathyroid hormone (PTH) is a single-chain peptide hormone 1,25(OH) D, thus enabling circulating or endogenously pro-
2
composed of 84 amino acids. It is produced in the parathyroid duced 1,25(OH) D to suppress PTH production. 1,25(OH) D
2
2
gland in a precursor form of 115 amino acids, the excess 31 also induces the CaSR, making the parathyroid gland more sensi-
amino terminal amino acids being cleaved off before secretion. tive to suppression by calcium. Biologic activity resides in the