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Calcimimetics or vitamin D analogs for suppressing parathyroid hormone in end-stage renal disease: time for a paradigm shift?

Nature Clinical Practice Nephrology volume 5, pages 24–33 (2009)Cite this article

Abstract

Considerable advances have been made in the understanding of the pathogenesis and treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). These include the discovery that the calcium-sensing receptor has an important role in the regulation of parathyroid gland function, the development of calcimimetics to target this receptor, the recognition that vitamin D receptor activation has important functions beyond the regulation of mineral metabolism, the identification of the phosphaturic factor fibroblast growth factor 23 and the contribution of this hormone to disordered phosphate and vitamin D metabolism in CKD. However, despite the availability of calcimimetics, phosphate binders, and vitamin D analogs, control of SHPT remains suboptimal in many patients with advanced kidney disease. In this Review, we explore several unresolved issues regarding the pathogenesis and treatment of SHPT. Specifically, we examine the significance of elevated circulating fibroblast growth factor 23 levels in CKD, question the proposition that calcitriol deficiency is truly a pathological state, explore the relative importance of the vitamin D receptor and the calcium-sensing receptor in parathyroid gland function and evaluate the evidence to support the treatment of SHPT with calcimimetics and vitamin D analogs. Finally, we propose a novel treatment framework in which calcimimetics are the primary therapy for suppressing parathyroid hormone production in patients with end-stage renal disease.

Key Points

  • Calcitriol (1,25[OH]2D) deficiency in advanced kidney disease might be an adaptive response mediated by an increase in fibroblast growth factor 23 (FGF23) production

  • Increases in circulating FGF23 levels seem to occur earlier than increases in serum PTH levels in patients with kidney disease, and FGF23 exerts the opposite effect to PTH on the CYP27B1 and CYP24A1 enzyme systems that are responsible for the synthesis and metabolism of calcitriol

  • Both the calcium-sensing receptor and the vitamin D receptor are important in the development of secondary hyperparathyroidism (SHPT), but the former seems more important and, as such, a more promising target for therapy

  • Calcimimetics have consistently been shown to provide superior control of mineral metabolic parameters when added to vitamin D analog therapy and, increasingly, when tested against high-dose vitamin D therapy; these agents should, therefore, be considered first-line therapy (after phosphorus control) in most patients with SHPT

  • Randomized controlled trials of calcimimetics plus low-dose vitamin D analogs versus escalating doses of vitamin D analogs should be undertaken to determine the relative survival benefits of each regimen

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Figure 1: Alternative paradigms for the pathogenesis of SHPT in chronic kidney disease.

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References

  1. Al-Badr W and Martin KJ (2008) Vitamin D and kidney disease. Clin J Am Soc Nephrol 3: 1555–1560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Brown AJ and Slatopolsky E (2007) Drug Insight: vitamin D analogs in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Nat Clin Pract Endocrinol Metab 3: 134–144

    Article  CAS  PubMed  Google Scholar 

  3. Mehrotra R et al. (2008) Hypovitaminosis D in chronic kidney disease. Clin J Am Soc Nephrol 3: 1144–1151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zehnder D et al. (2007) Cross-sectional analysis of abnormalities of mineral homeostasis, vitamin D and parathyroid hormone in a cohort of pre-dialysis patients. The chronic renal impairment in Birmingham (CRIB) study. Nephron Clin Pract 107: c109–c116

    Article  CAS  PubMed  Google Scholar 

  5. Slatopolsky E et al. (2001) Role of phosphorus in the pathogenesis of secondary hyperparathyroidism. Am J Kidney Dis 37: S54–S57

    Article  CAS  PubMed  Google Scholar 

  6. Rowe PS (2004) The wrickkened pathways of FGF23, MEPE and PHEX. Crit Rev Oral Biol Med 15: 264–281

    Article  PubMed  PubMed Central  Google Scholar 

  7. Saito H et al. (2003) Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and 1alpha,25-dihydroxyvitamin D3 production. J Biol Chem 278: 2206–2211

    Article  CAS  PubMed  Google Scholar 

  8. Liu S et al. (2006) Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 17: 1305–1315

    Article  CAS  PubMed  Google Scholar 

  9. Krajisnik T et al. (2007) Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol 195: 125–131

    Article  CAS  PubMed  Google Scholar 

  10. Shimada T et al. (2004) FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19: 429–435

    Article  CAS  PubMed  Google Scholar 

  11. Perwad F et al. (2007) Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro. Am J Physiol Renal Physiol 293: F1577–F1583

    Article  CAS  PubMed  Google Scholar 

  12. Larsson T et al. (2003) Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int 64: 2272–2279

    Article  CAS  PubMed  Google Scholar 

  13. Gutierrez O et al. (2005) Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 16: 2205–2215

    Article  CAS  PubMed  Google Scholar 

  14. Shigematsu T et al. (2004) Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis 44: 250–256

    Article  CAS  PubMed  Google Scholar 

  15. Gutierrez OM et al. (2008) Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 359: 584–592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Isakova T et al. (2008) Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. J Am Soc Nephrol 19: 615–623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Urakawa I et al. (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444: 770–774

    Article  CAS  PubMed  Google Scholar 

  18. Koh N et al. (2001) Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 280: 1015–1020

    Article  CAS  PubMed  Google Scholar 

  19. Tokumoto M et al. (2005) Parathyroid cell growth in patients with advanced secondary hyperparathyroidism: vitamin D receptor, calcium sensing receptor, and cell cycle regulating factors. Ther Apher Dial 9 (Suppl 1): S27–S34

    Article  CAS  PubMed  Google Scholar 

  20. Portale AA et al. (1987) Dietary intake of phosphorus modulates the circadian rhythm in serum concentration of phosphorus. Implications for the renal production of 1,25-dihydroxyvitamin D. J Clin Invest 80: 1147–1154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Coburn JW et al. (2004) Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4. Am J Kidney Dis 43: 877–890

    Article  CAS  PubMed  Google Scholar 

  22. Tentori F et al. (2006) Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int 70: 1858–1865

    Article  CAS  PubMed  Google Scholar 

  23. Messa P et al. (2008) The OPTIMA study: assessing a new cinacalcet (Sensipar/Mimpara) treatment algorithm for secondary hyperparathyroidism. Clin J Am Soc Nephrol 3: 36–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Block GA et al. (2004) Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 350: 1516–1525

    Article  CAS  PubMed  Google Scholar 

  25. Brown EM and MacLeod RJ (2001) Extracellular calcium sensing and extracellular calcium signaling. Physiol Rev 81: 239–297

    Article  CAS  PubMed  Google Scholar 

  26. Brown EM (2007) Clinical lessons from the calcium-sensing receptor. Nat Clin Pract Endocrinol Metab 3: 122–133

    Article  CAS  PubMed  Google Scholar 

  27. Silver J and Levi R (2005) Regulation of PTH synthesis and secretion relevant to the management of secondary hyperparathyroidism in chronic kidney disease. Kidney Int Suppl 95: S8–S12

    Article  CAS  Google Scholar 

  28. Pollak MR et al. (1993) Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75: 1297–1303

    Article  CAS  PubMed  Google Scholar 

  29. Ho C et al. (1995) A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet 11: 389–394

    Article  CAS  PubMed  Google Scholar 

  30. Li YC et al. (1998) Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice. Endocrinology 139: 4391–4396

    Article  CAS  PubMed  Google Scholar 

  31. Drueke T et al. (2007) Can calcimimetics inhibit parathyroid hyperplasia? Evidence from preclinical studies. Nephrol Dial Transplant 22: 1828–1839

    Article  CAS  PubMed  Google Scholar 

  32. Goodman WG (2005) Calcimimetics: a remedy for all problems of excess parathyroid hormone activity in chronic kidney disease? Curr Opin Nephrol Hypertens 14: 355–360

    Article  CAS  PubMed  Google Scholar 

  33. Kos CH et al. (2003) The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone. J Clin Invest 111: 1021–1028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tu Q et al. (2003) Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background. J Clin Invest 111: 1029–1037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Colloton M et al. (2005) Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism? Kidney Int 67: 467–476

    Article  CAS  PubMed  Google Scholar 

  36. Chin J et al. (2000) Activation of the calcium receptor by a calcimimetic compound halts the progression of secondary hyperparathyroidism in uremic rats. J Am Soc Nephrol 11: 903–911

    CAS  PubMed  Google Scholar 

  37. de Francisco AL et al. (2008) Calcium-mediated parathyroid hormone release changes in patients treated with the calcimimetic agent cinacalcet. Nephrol Dial Transplant 23: 2895–2901

    Article  CAS  PubMed  Google Scholar 

  38. Lomonte C et al. (2008) Does vitamin D receptor and calcium receptor activation therapy play a role in the histopathologic alterations of parathyroid glands in refractory uremic hyperparathyroidism. Clin J Am Soc Nephrol 3: 794–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Matsushita H et al. (1999) Proliferation of parathyroid cells negatively correlates with expression of parathyroid hormone-related protein in secondary parathyroid hyperplasia. Kidney Int 55: 130–138

    Article  CAS  PubMed  Google Scholar 

  40. Gogusev J et al. (1997) Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int 51: 328–336

    Article  CAS  PubMed  Google Scholar 

  41. Kifor O et al. (1996) Reduced immunostaining for the extracellular Ca2-sensing receptor in primary and uremic secondary hyperparathyroidism. J Clin Endocrinol Metab 81: 1598–1606

    CAS  PubMed  Google Scholar 

  42. Brown AJ et al. (1999) Decreased calcium-sensing receptor expression in hyperplastic parathyroid glands of uremic rats: role of dietary phosphate. Kidney Int 55: 1284–1292

    Article  CAS  PubMed  Google Scholar 

  43. Ritter CS et al. (2001) Parathyroid hyperplasia in uremic rats precedes down-regulation of the calcium receptor. Kidney Int 60: 1737–1744

    Article  CAS  PubMed  Google Scholar 

  44. Martin LN et al. (1998) Parathyroid glands in uraemic patients with refractory hyperparathyroidism: histopathology and p53 protein expression analysis. Histopathology 33: 46–51

    CAS  PubMed  Google Scholar 

  45. Fukuda N et al. (1993) Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 92: 1436–1443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang X et al. (2001) Vitamin D receptor and PCNA expression in severe parathyroid hyperplasia of uremic patients. Chin Med J (Engl) 114: 410–414

    CAS  Google Scholar 

  47. Tokumoto M et al. (2002) Reduced p21, p27 and vitamin D receptor in the nodular hyperplasia in patients with advanced secondary hyperparathyroidism. Kidney Int 62: 1196–1207

    Article  CAS  PubMed  Google Scholar 

  48. Yano S et al. (2003) Decrease in vitamin D receptor and calcium-sensing receptor in highly proliferative parathyroid adenomas. Eur J Endocrinol 148: 403–411

    Article  CAS  PubMed  Google Scholar 

  49. Maiti A and Beckman MJ (2007) Extracellular calcium is a direct effecter of VDR levels in proximal tubule epithelial cells that counter-balances effects of PTH on renal Vitamin D metabolism. J Steroid Biochem Mol Biol 103: 504–508

    Article  CAS  PubMed  Google Scholar 

  50. Brown AJ et al. (1996) Rat calcium-sensing receptor is regulated by vitamin D but not by calcium. Am J Physiol 270: F454–F460

    CAS  PubMed  Google Scholar 

  51. Canaff L and Hendy GN (2002) 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 277: 30337–30350

    Article  CAS  PubMed  Google Scholar 

  52. Fishbane S et al.: Cinacalcet HCl with low-dose vitamin D improves treatment of secondary hyperparathyroidism in dialysis patients versus vitamin D alone—the ACHIEVE study. Clin J Am Soc Nephrol, in press

  53. Quarles LD et al. (2003) The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 14: 575–583

    Article  CAS  PubMed  Google Scholar 

  54. Lindberg JS et al. (2003) The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism. Kidney Int 63: 248–254

    Article  CAS  PubMed  Google Scholar 

  55. Strippoli GF et al. (2006) Meta-analysis of biochemical and patient-level effects of calcimimetic therapy. Am J Kidney Dis 47: 715–726

    Article  CAS  PubMed  Google Scholar 

  56. Fukagawa M et al. (2008) Cinacalcet (KRN1493) effectively decreases the serum intact PTH level with favorable control of the serum phosphorus and calcium levels in Japanese dialysis patients. Nephrol Dial Transplant 23: 328–335

    Article  CAS  PubMed  Google Scholar 

  57. Block GA et al. (2008) Combined therapy with cinacalcet and low doses of vitamin D sterols in patients with moderate to severe secondary hyperparathyroidism. Nephrol Dial Transplant 23: 2311–2318

    Article  CAS  PubMed  Google Scholar 

  58. Chertow GM et al. (2006) Cinacalcet hydrochloride (Sensipar) in hemodialysis patients on active vitamin D derivatives with controlled PTH and elevated calcium x phosphate. Clin J Am Soc Nephrol 1: 305–312

    Article  CAS  PubMed  Google Scholar 

  59. Martin KJ et al. (1998) 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 9: 1427–1432

    CAS  PubMed  Google Scholar 

  60. Delmez JA et al. (2000) A controlled trial of the early treatment of secondary hyperparathyroidism with calcitriol in hemodialysis patients. Clin Nephrol 54: 301–308

    CAS  PubMed  Google Scholar 

  61. Coyne DW et al. (2002) Differential effects of acute administration of 19-Nor-1,25-dihydroxy-vitamin D2 and 1,25-dihydroxy-vitamin D3 on serum calcium and phosphorus in hemodialysis patients. Am J Kidney Dis 40: 1283–1288

    Article  CAS  PubMed  Google Scholar 

  62. Joist HE et al. (2006) Differential effects of very high doses of doxercalciferol and paricalcitol on serum phosphorus in hemodialysis patients. Clin Nephrol 65: 335–341

    Article  CAS  PubMed  Google Scholar 

  63. Sprague SM et al. (2003) Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int 63: 1483–1490

    Article  CAS  PubMed  Google Scholar 

  64. Brandi L et al. (1992) Long-term suppression of secondary hyperparathyroidism by intravenous 1 alpha-hydroxyvitamin D3 in patients on chronic hemodialysis. Am J Nephrol 12: 311–318

    Article  CAS  PubMed  Google Scholar 

  65. Lindberg J et al. (2001) A long-term, multicenter study of the efficacy and safety of paricalcitol in end-stage renal disease. Clin Nephrol 56: 315–323

    CAS  PubMed  Google Scholar 

  66. Akizawa T et al. (2002) Long-term effect of 1,25-dihydroxy-22-oxavitamin D(3) on secondary hyperparathyroidism in haemodialysis patients: one-year administration study. Nephrol Dial Transplant 17 (Suppl 10): S28–S36

    Article  Google Scholar 

  67. Teng M et al. (2003) Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 349: 446–456

    Article  CAS  PubMed  Google Scholar 

  68. Teng M et al. (2005) Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol 16: 1115–1125

    Article  CAS  PubMed  Google Scholar 

  69. Kalantar-Zadeh K et al. (2006) Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int 70: 771–780

    Article  CAS  PubMed  Google Scholar 

  70. Sprague SM et al. (2001) Suppression of parathyroid hormone secretion in hemodialysis patients: comparison of paricalcitol with calcitriol. Am J Kidney Dis 38: S51–S56

    Article  CAS  PubMed  Google Scholar 

  71. Block GA (1998) Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 31: 607–617

    Article  CAS  PubMed  Google Scholar 

  72. Liu PT et al. (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311: 1770–1773

    Article  CAS  PubMed  Google Scholar 

  73. Bikle DD (2007) What is new in vitamin D: 2006–2007. Curr Opin Rheumatol 19: 383–388

    Article  CAS  PubMed  Google Scholar 

  74. Peterlik M and Cross HS (2005) Vitamin D and calcium deficits predispose for multiple chronic diseases. Eur J Clin Invest 35: 290–304

    Article  CAS  PubMed  Google Scholar 

  75. Andress D (2007) Nonclassical aspects of differential vitamin D receptor activation: implications for survival in patients with chronic kidney disease. Drugs 67: 1999–2012

    Article  CAS  PubMed  Google Scholar 

  76. Chertow GM et al. (2002) Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 62: 245–252

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. JB Wetmore is an Assistant Professor of Medicine in the Division of Nephrology and Hypertension at the University of Kansas Medical Center and Director of Inpatient Dialysis at the University of Kansas Hospital, Director of the Division of Nephrology and Hypertension and Director of the Kidney Institute at the University of Kansas Medical Center, and LD Quarles is Summerfield Endowed Professor of Medicine, Kansas City, KS, USA.,

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Correspondence to L Darryl Quarles.

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James B Wetmore serves as a consultant for and receives research support and speaker's bureau honoraria from Amgen. L Darryl Quarles serves as a consultant for, holds stock in and also receives research support and speaker's bureau honoraria from Amgen.

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Wetmore, J., Quarles, L. Calcimimetics or vitamin D analogs for suppressing parathyroid hormone in end-stage renal disease: time for a paradigm shift?. Nat Rev Nephrol 5, 24–33 (2009). https://doi.org/10.1038/ncpneph0977

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