UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Parathyroid hormone secretion and action

Authors
Ghada El-Hajj Fuleihan, MD, MPH
Edward M Brown, MD
Section Editor
Clifford J Rosen, MD
Deputy Editor
Jean E Mulder, MD

INTRODUCTION

Parathyroid hormone (PTH) is one of three key hormones modulating calcium and phosphate homeostasis; the other two are calcitriol (1,25-dihydroxyvitamin D) and fibroblast growth factor 23 (FGF23) [1]. The minute-to-minute control of serum ionized calcium concentration is exclusively mediated by PTH, maintaining the concentration of this divalent cation within a narrow range through stimulation of renal tubular calcium reabsorption and bone resorption [2,3].

On a more chronic basis, PTH also stimulates the conversion of calcidiol (25-hydroxyvitamin D) to calcitriol in renal tubular cells, thereby stimulating intestinal calcium absorption as well as bone turnover. Calcitriol feeds back to inhibit PTH secretion indirectly through its calcemic action, as well as by exerting a direct inhibitory action on PTH biosynthesis and parathyroid cell proliferation [4].

This topic will review PTH secretion and action. Clinical disorders related to PTH excess or insufficiency, as well as the use of PTH for the treatment of osteoporosis, are reviewed separately.

(See "Primary hyperparathyroidism: Clinical manifestations".)

(See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

                    
To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Sep 2017. | This topic last updated: Jul 20, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. Potts JT, Juppner H. Parathyroid hormone: Molecular biology and regulation. In: Principles of Bone Biology, Bilezikian JP, Raisz LG, Rodan GA (Eds), Academic Press, San Diego 1996. p.325.
  2. Brown EM. Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab 1983; 56:572.
  3. Diaz R, El-Hajj Fuleihan G, Brown EM. Regulation of parathyroid function. In: Handbook of Physiology, Section 7: The Endocrine System, Fray GGS (Ed), Oxford University Press, New York 1999.
  4. Kumar R, Thompson JR. The regulation of parathyroid hormone secretion and synthesis. J Am Soc Nephrol 2011; 22:216.
  5. Habener JF, Kemper BW, Rich A, Potts JT Jr. Biosynthesis of parathyroid hormone. Recent Prog Horm Res 1976; 33:249.
  6. Murray TM, Rao LG, Divieti P, Bringhurst FR. Parathyroid hormone secretion and action: evidence for discrete receptors for the carboxyl-terminal region and related biological actions of carboxyl- terminal ligands. Endocr Rev 2005; 26:78.
  7. D'Amour P, Räkel A, Brossard JH, et al. Acute regulation of circulating parathyroid hormone (PTH) molecular forms by calcium: utility of PTH fragments/PTH(1-84) ratios derived from three generations of PTH assays. J Clin Endocrinol Metab 2006; 91:283.
  8. Haden ST, Brown EM, Hurwitz S, et al. The effects of age and gender on parathyroid hormone dynamics. Clin Endocrinol (Oxf) 2000; 52:329.
  9. Brown EM, Pollak M, Seidman CE, et al. Calcium-ion-sensing cell-surface receptors. N Engl J Med 1995; 333:234.
  10. Naveh-Many T, Friedlaender MM, Mayer H, Silver J. Calcium regulates parathyroid hormone messenger ribonucleic acid (mRNA), but not calcitonin mRNA in vivo in the rat. Dominant role of 1,25-dihydroxyvitamin D. Endocrinology 1989; 125:275.
  11. Naveh-Many T, Rahamimov R, Livni N, Silver J. Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D. J Clin Invest 1995; 96:1786.
  12. Slatopolsky E, Finch J, Denda M, et al. Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 1996; 97:2534.
  13. Fine A, Cox D, Fontaine B. Elevation of serum phosphate affects parathyroid hormone levels in only 50% of hemodialysis patients, which is unrelated to changes in serum calcium. J Am Soc Nephrol 1993; 3:1947.
  14. Adler AJ, Ferran N, Berlyne GM. Effect of inorganic phosphate on serum ionized calcium concentration in vitro: a reassessment of the "trade-off hypothesis". Kidney Int 1985; 28:932.
  15. Canaff L, Hendy GN. Human calcium-sensing receptor gene. Vitamin D response elements in promoters P1 and P2 confer transcriptional responsiveness to 1,25-dihydroxyvitamin D. J Biol Chem 2002; 277:30337.
  16. Silver J, Naveh-Many T. FGF23 and the parathyroid glands. Pediatr Nephrol 2010; 25:2241.
  17. Berndt T, Kumar R. Phosphatonins and the regulation of phosphate homeostasis. Annu Rev Physiol 2007; 69:341.
  18. Cole DE, Peltekova VD, Rubin LA, et al. A986S polymorphism of the calcium-sensing receptor and circulating calcium concentrations. Lancet 1999; 353:112.
  19. Pollak MR, Brown EM, Chou YH, et al. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993; 75:1297.
  20. Pollak MR, Chou YH, Marx SJ, et al. Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype. J Clin Invest 1994; 93:1108.
  21. Pollak MR, Brown EM, Estep HL, et al. Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation. Nat Genet 1994; 8:303.
  22. El-Hajj Fuleihan G, Brown EM, Heath H III. Familial benign hypocalciuric hypercalcemia and neonatal primary hyperparathyroidism. In: Principles of Bone Biology, Bilezikian JP, Raisz LG, Rodan GA (Eds), Academic Press, San Diego 2002. p.1031.
  23. Costa-Guda J, Arnold A. Genetic and epigenetic changes in sporadic endocrine tumors: parathyroid tumors. Mol Cell Endocrinol 2014; 386:46.
  24. Yano S, Sugimoto T, Tsukamoto T, et al. Association of decreased calcium-sensing receptor expression with proliferation of parathyroid cells in secondary hyperparathyroidism. Kidney Int 2000; 58:1980.
  25. Cañadillas S, Canalejo A, Santamaría R, et al. Calcium-sensing receptor expression and parathyroid hormone secretion in hyperplastic parathyroid glands from humans. J Am Soc Nephrol 2005; 16:2190.
  26. Al-Ali H, Fuleihan GE. Nutritional osteomalacia: substantial clinical improvement and gain in bone density posttherapy. J Clin Densitom 2000; 3:97.
  27. Brown EM. Lithium induces abnormal calcium-regulated PTH release in dispersed bovine parathyroid cells. J Clin Endocrinol Metab 1981; 52:1046.
  28. Haden ST, Stoll AL, McCormick S, et al. Alterations in parathyroid dynamics in lithium-treated subjects. J Clin Endocrinol Metab 1997; 82:2844.
  29. Kallner G, Petterson U. Renal, thyroid and parathyroid function during lithium treatment: laboratory tests in 207 people treated for 1-30 years. Acta Psychiatr Scand 1995; 91:48.
  30. Martin KJ, González EA, Gellens M, et al. 19-Nor-1-alpha-25-dihydroxyvitamin D2 (Paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol 1998; 9:1427.
  31. Tan AU Jr, Levine BS, Mazess RB, et al. Effective suppression of parathyroid hormone by 1 alpha-hydroxy-vitamin D2 in hemodialysis patients with moderate to severe secondary hyperparathyroidism. Kidney Int 1997; 51:317.
  32. Jüppner H, Abou-Samra AB, Freeman M, et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 1991; 254:1024.
  33. Gardella TJ, Jüppner H. Molecular properties of the PTH/PTHrP receptor. Trends Endocrinol Metab 2001; 12:210.
  34. Dobolyi A, Palkovits M, Usdin TB. The TIP39-PTH2 receptor system: unique peptidergic cell groups in the brainstem and their interactions with central regulatory mechanisms. Prog Neurobiol 2010; 90:29.
  35. D'Amour P. Acute and chronic regulation of circulating PTH: significance in health and in disease. Clin Biochem 2012; 45:964.
  36. Dunlay R, Hruska K. PTH receptor coupling to phospholipase C is an alternate pathway of signal transduction in bone and kidney. Am J Physiol 1990; 258:F223.
  37. Hruska KA, Moskowitz D, Esbrit P, et al. Stimulation of inositol trisphosphate and diacylglycerol production in renal tubular cells by parathyroid hormone. J Clin Invest 1987; 79:230.
  38. Abou-Samra AB, Jueppner H, Westerberg D, et al. Parathyroid hormone causes translocation of protein kinase-C from cytosol to membranes in rat osteosarcoma cells. Endocrinology 1989; 124:1107.
  39. Murrills RJ, Matteo JJ, Samuel RL, et al. In vitro and in vivo activities of C-terminally truncated PTH peptides reveal a disconnect between cAMP signaling and functional activity. Bone 2004; 35:1263.
  40. Jüppner H, Potts JT Jr. Immunoassays for the detection of parathyroid hormone. J Bone Miner Res 2002; 17 Suppl 2:N81.
  41. Talmage RV, Mobley HT. Calcium homeostasis: reassessment of the actions of parathyroid hormone. Gen Comp Endocrinol 2008; 156:1.
  42. Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003; 349:1207.
  43. Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 1998; 95:3597.
  44. Lee SK, Lorenzo JA. Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation. Endocrinology 1999; 140:3552.
  45. Hodsman AB, Bauer DC, Dempster DW, et al. Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev 2005; 26:688.
  46. Mohan S, Kutilek S, Zhang C, et al. Comparison of bone formation responses to parathyroid hormone(1-34), (1-31), and (2-34) in mice. Bone 2000; 27:471.
  47. Friedman PA, Gesek FA. Calcium transport in renal epithelial cells. Am J Physiol 1993; 264:F181.
  48. van Abel M, Hoenderop JG, van der Kemp AW, et al. Coordinated control of renal Ca(2+) transport proteins by parathyroid hormone. Kidney Int 2005; 68:1708.
  49. Gesek FA, Friedman PA. On the mechanism of parathyroid hormone stimulation of calcium uptake by mouse distal convoluted tubule cells. J Clin Invest 1992; 90:749.
  50. Hebert SC. Extracellular calcium-sensing receptor: implications for calcium and magnesium handling in the kidney. Kidney Int 1996; 50:2129.
  51. el-Hajj Fuleihan G, Seifter J, Scott J, Brown EM. Calcium-regulated renal calcium handling in healthy men: relationship to sodium handling. J Clin Endocrinol Metab 1998; 83:2366.
  52. Murer H, Lötscher M, Kaissling B, et al. Renal brush border membrane Na/Pi-cotransport: molecular aspects in PTH-dependent and dietary regulation. Kidney Int 1996; 49:1769.
  53. Pfister MF, Lederer E, Forgo J, et al. Parathyroid hormone-dependent degradation of type II Na+/Pi cotransporters. J Biol Chem 1997; 272:20125.
  54. Broadus AE, Horst RL, Lang R, et al. The importance of circulating 1,25-dihydroxyvitamin D in the pathogenesis of hypercalciuria and renal-stone formation in primary hyperparathyroidism. N Engl J Med 1980; 302:421.
  55. Neves KR, Graciolli FG, dos Reis LM, et al. Vascular calcification: contribution of parathyroid hormone in renal failure. Kidney Int 2007; 71:1262.
  56. Rostand SG, Drüeke TB. Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure. Kidney Int 1999; 56:383.
  57. Lindsay R, Nieves J, Formica C, et al. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet 1997; 350:550.
  58. Finkelstein JS, Klibanski A, Schaefer EH, et al. Parathyroid hormone for the prevention of bone loss induced by estrogen deficiency. N Engl J Med 1994; 331:1618.
  59. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344:1434.
  60. Hattersley G, Dean T, Corbin BA, et al. Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling. Endocrinology 2016; 157:141.
  61. Cheloha RW, Gellman SH, Vilardaga JP, Gardella TJ. PTH receptor-1 signalling-mechanistic insights and therapeutic prospects. Nat Rev Endocrinol 2015; 11:712.
  62. Gesty-Palmer D, Flannery P, Yuan L, et al. A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation. Sci Transl Med 2009; 1:1ra1.
  63. Shimizu M, Joyashiki E, Noda H, et al. Pharmacodynamic Actions of a Long-Acting PTH Analog (LA-PTH) in Thyroparathyroidectomized (TPTX) Rats and Normal Monkeys. J Bone Miner Res 2016; 31:1405.
  64. Santa Maria C, Cheng Z, Li A, et al. Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism. Semin Cell Dev Biol 2016; 49:11.