FGF23, a peptide hormone produced by osteocytes, has been discovered to regulate Pi metabolism in hypophosphatemic disorders. It binds to a receptor complex in proximal tubule cells and inhibits NPT2, similar to PTH, to promote Pi excretion. Excess production of FGF23 is associated with several diseases, such as rickets in children and osteomalacia in adults due to hypophosphatemia. Autosomal dominant hypophosphatemic rickets (ADHR) occurs when a mutation in FGF23 prevents its cleavage and inactivation. X-linked hypophosphatemic rickets (XLHR) is caused by a mutation in the PHEX gene, leading to overproduction of FGF23. Additionally, ectopic production of FGF23 by slow-growing occult mesenchymal tumors can cause a hypophosphatemic paraneoplastic syndrome. FGF23 not only inhibits Pi reabsorption but also inhibits the expression of 1α-hydroxylase, which hinders the production of 1,25-dihydroxyvitamin D and worsens hypophosphatemia. The exact mechanism and location of Pi level sensing are not completely understood. Recent evidence suggests that long-term elevation of Pi increases FGF23 production, indicating a potential negative feedback loop. Osteocytes decrease the production of FGF23 in response to 1,25-dihydroxyvitamin D. Gonadal and adrenal steroid hormones have significant effects on bone. Estrogen, specifically 17β-Estradiol (E2), has anabolic effects on bone and regulates osteoblast and osteoclast function. It promotes osteoblast survival and osteoclast apoptosis, favoring bone formation over resorption. Androgens also have bone anabolic effects, partly due to local conversion of testosterone to E2 in men. The combined effects of testosterone and E2 contribute to higher peak bone mass in men. In postmenopausal women, estrogen deficiency leads to rapid bone loss for approximately 5 years, followed by slower age-related bone loss similar to both sexes. Therefore, women are vulnerable to postmenopausal osteoporosis. High therapeutic doses of glucocorticoids stimulate bone resorption and inhibit intestinal calcium absorption. The most critical adverse effect is the inhibition of osteoblast differentiation, impairing bone formation. Patients receiving high levels of glucocorticoids as anti-inflammatory or immunosuppressive drugs are at risk for glucocorticoid-induced osteoporosis and require careful monitoring. The integrated response of PTH and 1,25-dihydroxyvitamin D to a hypocalcemic challenge is depicted in Fig. 40.10, illustrating the physiological regulation of Ca++/Pi metabolism.
Study of hypophosphatemic disorders has led to the discovery that FGF23, a peptide hormone produced by osteocytes, is a regulator of Pi metabolism. FGF23 binds to a receptor complex in proximal tubule cells and, like PTH, inhibits NPT2 to promote Pi excretion. Several diseases are associated with excess production of FGF23, including rickets in children and osteomalacia secondary to hypophosphatemia in adults. In autosomal dominant hypophosphatemic rickets (ADHR), a mutation in FGF23 prevents its cleavage and inactivation. X-linked hypophosphatemic rickets (XLHR) is caused by a mutation of the PHEX gene (protein with homology to endopeptidases on the X chromosome), which also causes overproduction of FGF23. Finally, FGF23 is sometimes ectopically produced by slow-growing occult mesenchymal tumors, causing a hypophosphatemic paraneoplastic syndrome. In addition to inhibition of Pi reabsorption, FGF23 also inhibits expression of 1α-hydroxylase in the proximal tubule, thereby inhibiting production of 1,25-dihydroxyvitamin D and exacerbating hypophosphatemia. The physiological role of this pathway is not completely understood, and many questions remain, °GI °1,25(OH)2D3 absorption •Fig. 40.10 IntegratedhormoneresponsestoperturbationsofCa++ (A),Pi(B),andvitaminD(C).
including how and where Pi levels are sensed. Pi is not as tightly regulated as calcium, either temporally or with respect to concentration range, but recent evidence suggest that long-term elevation of Pi is associated with increased production of FGF23. In what appears to be an emerging negative feedback loop, 1,25-dihydroxyvitamin D decreases production of FGF23 by osteocytes.
Gonadal and adrenal steroid hormones have profound effects on bone. 17β-Estradiol (E2; see has important anabolic effects on bone and is a potent regulator of osteoblast and osteoclast function. Estrogen promotes survival of osteoblasts and apoptosis of osteoclasts, thereby favoring bone formation over resorption. Androgens also have bone anabolic effects, although some of these effects are due to local conversion of testosterone to E2 in men (see ). The combined effects of testosterone and E2 account for the higher peak bone mass observed in men. In postmenopausal women, estrogen deficiency results in an initial phase of rapid bone loss that lasts about 5 years, followed by a second phase of slower age-related bone loss that is similar in both sexes. For this reason, women are susceptible to postmenopausal osteoporosis.
Glucocorticoids at high therapeutic doses promote bone resorption and inhibit intestinal Ca absorption. However, the most critical adverse effect is inhibition of osteoblast differentiation, which impairs bone formation. Therefore patients treated with high levels of a glucocorticoid as an antiinflammatory or immunosuppressive drug are at risk for glucocorticoid-induced osteoporosis and should be monitored carefully.
Integrated Physiological Regulation of Ca++/Pi Metabolism
The integrated response of PTH and 1,25-dihydroxyvitamin D to a hypocalcemic challenge is shown in