To summarize: 1,25(OH)2D suppresses the production of PTH, as does calcium, but stimulates the production of FGF23. Phosphate stimulates both PTH and FGF23 secretion. In turn PTH stimulates 1,25(OH)2D production, whereas FGF23 is inhibitory. 1,25(OH)2D stimulates the intestinal absorption of calcium and phosphate. 1,25(OH)2D and PTH promote both bone formation and resorption 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, as does FGF23, whereas 1,25(OH)2D promotes renal reabsorption of phosphate.
Other hormones—calcitonin, prolactin, growth hormone, insulin, insulin-like growth factors, thyroid hormone, glucocorticoids, and sex steroids—influence calcium and phosphate homeostasis under certain physiologic circumstances 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 phosphate themselves, other ions such as sodium and fluoride, and a variety of drugs (bisphosphonates, anticonvulsants, and diuretics) also alter calcium and phosphate homeostasis.
A 1,25(OH)2D in blood 1,25(OH) D
PTH +– FGF23Thyroid 1,25(OH)2D 1,25(OH)2D
FIGURE 42–2 The hormonal interactions controlling bone mineral homeostasis. In the body (A), 1,25-dihydroxyvitamin D (1,25[OH]2D) 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)2D in turn inhibits the production of PTH by the parathyroid glands and stimulates FGF23 release from bone. 1,25(OH)2D is the principal regulator of intestinal calcium and phosphate absorption. At the level of the bone (B), both PTH and 1,25(OH)2D 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)2D 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)2D. FGF23 in excess leads to osteomalacia indirectly by inhibiting 1,25(OH)2D production and lowering phosphate levels. MCSF, macrophage colony-stimulating factor; OPG, osteoprotegerin; RANKL, ligand for receptor for activation of nuclear factor-κB.