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Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients

L Darryl Quarles, MD
Michael Berkoben, MD
Section Editor
Stanley Goldfarb, MD
Deputy Editor
Alice M Sheridan, MD


The treatment of secondary hyperparathyroidism in chronic kidney disease (CKD) is based upon our understanding of the pathogenesis and clinical features of this disorder and the recognition that abnormal calcium and phosphate homeostasis may increase morbidity and mortality and on our understanding of mineral homeostasis among CKD patients.

Because of the interdependence of calcium, phosphate, vitamin D, and parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), it is difficult to elucidate the primary and proximate causes of parathyroid gland dysfunction in patients with CKD. In addition, no single pharmacologic intervention is usually completely sufficient to restore disordered calcium and phosphate homeostasis.

From a molecular standpoint, there are four major possible targets that regulate parathyroid gland function. These are:

G-protein-coupled calcium-sensing receptor (CaSR)

Vitamin D receptor (VDR)


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Literature review current through: Jan 2017. | This topic last updated: Thu Feb 02 00:00:00 GMT+00:00 2017.
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  1. Alvarez-Ude F, Feest TG, Ward MK, et al. Hemodialysis bone disease: correlation between clinical, histologic, and other findings. Kidney Int 1978; 14:68.
  2. Malluche HH, Mawad HW, Monier-Faugere MC. Renal osteodystrophy in the first decade of the new millennium: analysis of 630 bone biopsies in black and white patients. J Bone Miner Res 2011; 26:1368.
  3. Powe CE, Evans MK, Wenger J, et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med 2013; 369:1991.
  4. Wetmore JB, Quarles LD. Calcimimetics or vitamin D analogs for suppressing parathyroid hormone in end-stage renal disease: time for a paradigm shift? Nat Clin Pract Nephrol 2009; 5:24.
  5. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003; 42:S1.
  6. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2009; :S1.
  7. Gallieni M, Brancaccio D, Padovese P, et al. Low-dose intravenous calcitriol treatment of secondary hyperparathyroidism in hemodialysis patients. Italian Group for the Study of Intravenous Calcitriol. Kidney Int 1992; 42:1191.
  8. Moore C, Yee J, Malluche H, et al. Relationship between bone histology and markers of bone and mineral metabolism in African-American hemodialysis patients. Clin J Am Soc Nephrol 2009; 4:1484.
  9. Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int 2007; 72:1004.
  10. Massart A, Debelle FD, Racapé J, et al. Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial. Am J Kidney Dis 2014; 64:696.
  11. Saab G, Young DO, Gincherman Y, et al. Prevalence of vitamin D deficiency and the safety and effectiveness of monthly ergocalciferol in hemodialysis patients. Nephron Clin Pract 2007; 105:c132.
  12. Delanaye P, Weekers L, Warling X, et al. Cholecalciferol in haemodialysis patients: a randomized, double-blind, proof-of-concept and safety study. Nephrol Dial Transplant 2013; 28:1779.
  13. Stubbs JR, Idiculla A, Slusser J, et al. Cholecalciferol supplementation alters calcitriol-responsive monocyte proteins and decreases inflammatory cytokines in ESRD. J Am Soc Nephrol 2010; 21:353.
  14. Bhan I, Dobens D, Tamez H, et al. Nutritional vitamin D supplementation in dialysis: a randomized trial. Clin J Am Soc Nephrol 2015; 10:611.
  15. Coyne DW, Goldberg S, Faber M, et al. A randomized multicenter trial of paricalcitol versus calcitriol for secondary hyperparathyroidism in stages 3-4 CKD. Clin J Am Soc Nephrol 2014; 9:1620.
  16. Ma Y, Khalifa B, Yee YK, et al. Identification and characterization of noncalcemic, tissue-selective, nonsecosteroidal vitamin D receptor modulators. J Clin Invest 2006; 116:892.
  17. Teng M, Wolf M, Ofsthun MN, et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol 2005; 16:1115.
  18. Teng M, Wolf M, Lowrie E, et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 2003; 349:446.
  19. Shoji T, Shinohara K, Kimoto E, et al. Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population. Nephrol Dial Transplant 2004; 19:179.
  20. Palmer SC, McGregor DO, Macaskill P, et al. Meta-analysis: vitamin D compounds in chronic kidney disease. Ann Intern Med 2007; 147:840.
  21. Tonelli M. Vitamin D in patients with chronic kidney disease: nothing new under the sun. Ann Intern Med 2007; 147:880.
  22. Indridason OS, Quarles LD. Comparison of treatments for mild secondary hyperparathyroidism in hemodialysis patients. Durham Renal Osteodystrophy Study Group. Kidney Int 2000; 57:282.
  23. Slatopolsky E, Berkoben M, Kelber J, et al. Effects of calcitriol and non-calcemic vitamin D analogs on secondary hyperparathyroidism. Kidney Int Suppl 1992; 38:S43.
  24. Finch JL, Brown AJ, Kubodera N, et al. Differential effects of 1,25-(OH)2D3 and 22-oxacalcitriol on phosphate and calcium metabolism. Kidney Int 1993; 43:561.
  25. 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.
  26. Monier-Faugere MC, Geng Z, Friedler RM, et al. 22-oxacalcitriol suppresses secondary hyperparathyroidism without inducing low bone turnover in dogs with renal failure. Kidney Int 1999; 55:821.
  27. Slatopolsky E, Cozzolino M, Finch JL. Differential effects of 19-nor-1,25-(OH)(2)D(2) and 1alpha-hydroxyvitamin D(2) on calcium and phosphorus in normal and uremic rats. Kidney Int 2002; 62:1277.
  28. Slatopolsky E, Finch J, Brown A. New vitamin D analogs. Kidney Int Suppl 2003; :S83.
  29. Frazão JM, Elangovan L, Maung HM, et al. Intermittent doxercalciferol (1alpha-hydroxyvitamin D(2)) therapy for secondary hyperparathyroidism. Am J Kidney Dis 2000; 36:550.
  30. Slatopolsky E, Weerts C, Thielan J, et al. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxy-cholecalciferol in uremic patients. J Clin Invest 1984; 74:2136.
  31. Delmez JA, Tindira C, Grooms P, et al. Parathyroid hormone suppression by intravenous 1,25-dihydroxyvitamin D. A role for increased sensitivity to calcium. J Clin Invest 1989; 83:1349.
  32. Andress DL, Norris KC, Coburn JW, et al. Intravenous calcitriol in the treatment of refractory osteitis fibrosa of chronic renal failure. N Engl J Med 1989; 321:274.
  33. Quarles LD, Yohay DA, Carroll BA, et al. Prospective trial of pulse oral versus intravenous calcitriol treatment of hyperparathyroidism in ESRD. Kidney Int 1994; 45:1710.
  34. Levine BS, Song M. Pharmacokinetics and efficacy of pulse oral versus intravenous calcitriol in hemodialysis patients. J Am Soc Nephrol 1996; 7:488.
  35. Mazess RB, Elangovan L. A review of intravenous versus oral vitamin D hormone therapy in hemodialysis patients. Clin Nephrol 2003; 59:319.
  36. Moe SM, Kraus MA, Gassensmith CM, et al. Safety and efficacy of pulse and daily calcitriol in patients on CAPD: a randomized trial. Nephrol Dial Transplant 1998; 13:1234.
  37. 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.
  38. Coburn JW, Maung HM, Elangovan L, et al. Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4. Am J Kidney Dis 2004; 43:877.
  39. Sprague SM, Llach F, Amdahl M, et al. Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int 2003; 63:1483.
  40. Maung HM, Elangovan L, Frazão JM, et al. Efficacy and side effects of intermittent intravenous and oral doxercalciferol (1alpha-hydroxyvitamin D(2)) in dialysis patients with secondary hyperparathyroidism: a sequential comparison. Am J Kidney Dis 2001; 37:532.
  41. Gadallah MF, Arora N, Torres C, et al. Pulse oral versus pulse intraperitoneal calcitriol: a comparison of efficacy in the treatment of hyperparathyroidism and renal osteodystrophy in peritoneal dialysis patients. Adv Perit Dial 2000; 16:303.
  42. Tentori F, Hunt WC, Stidley CA, et al. Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int 2006; 70:1858.
  43. Ljunghall S, Althoff P, Fellström B, et al. Effects on serum parathyroid hormone of intravenous treatment with alphacalcidol in patients on chronic hemodialysis. Nephron 1990; 55:380.
  44. Matuszkiewicz-Rowińska J, Niemczyk S, Pacocha E, et al. [Long-term treatment with large doses of alphacalicidol in secondary hyperparathyroidism of patients dialyzed for end stage renal failure]. Pol Arch Med Wewn 1996; 96:15.
  45. Ritzerfeld M, Klasser M, Mann H. Alfacalcidol in the therapy of renal bone disease. Int J Clin Pharmacol Ther 2001; 39:546.
  46. Kurokawa K, Akizawa T, Suzuki M, et al. Effect of 22-oxacalcitriol on hyperparathyroidism of dialysis patients: results of a preliminary study. Nephrol Dial Transplant 1996; 11 Suppl 3:121.
  47. Tsukamoto Y, Hanaoka M, Matsuo T, et al. Effect of 22-oxacalcitriol on bone histology of hemodialyzed patients with severe secondary hyperparathyroidism. Am J Kidney Dis 2000; 35:458.
  48. Tamura S, Ueki K, Mashimo K, et al. Comparison of the efficacy of an oral calcitriol pulse or intravenous 22-oxacalcitriol therapies in chronic hemodialysis patients. Clin Exp Nephrol 2005; 9:238.
  49. Mochizuki T, Naganuma S, Tanaka Y, et al. Prospective comparison of the effects of maxacalcitol and calcitriol in chronic hemodialysis patients with secondary hyperparathyroidism: a multicenter, randomized crossover study. Clin Nephrol 2007; 67:12.
  50. Chertow GM, Blumenthal S, Turner S, et al. Cinacalcet hydrochloride (Sensipar) in hemodialysis patients on active vitamin D derivatives with controlled PTH and elevated calcium x phosphate. Clin J Am Soc Nephrol 2006; 1:305.
  51. Hsu CH, Patel SR, Young EW, Vanholder R. The biological action of calcitriol in renal failure. Kidney Int 1994; 46:605.
  52. Quarles LD, Davidai GA, Schwab SJ, et al. Oral calcitriol and calcium: efficient therapy for uremic hyperparathyroidism. Kidney Int 1988; 34:840.
  53. Sheikh MS, Maguire JA, Emmett M, et al. Reduction of dietary phosphorus absorption by phosphorus binders. A theoretical, in vitro, and in vivo study. J Clin Invest 1989; 83:66.
  54. Goodman WG, Ramirez JA, Belin TR, et al. Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy. Kidney Int 1994; 46:1160.
  55. Malberti F, Corradi B, Cosci P, et al. Long-term effects of intravenous calcitriol therapy on the control of secondary hyperparathyroidism. Am J Kidney Dis 1996; 28:704.
  56. Katoh N, Nakayama M, Shigematsu T, et al. Presence of sonographically detectable parathyroid glands can predict resistance to oral pulsed-dose calcitriol treatment of secondary hyperparathyroidism. Am J Kidney Dis 2000; 35:465.
  57. Fukuda N, Tanaka H, Tominaga Y, et al. Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 1993; 92:1436.
  58. Arnold A, Brown MF, Ureña P, et al. Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest 1995; 95:2047.
  59. Nemeth EF, Bennett SA. Tricking the parathyroid gland with novel calcimimetic agents. Nephrol Dial Transplant 1998; 13:1923.
  60. Antonsen JE, Sherrard DJ, Andress DL. A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure. Rapid communication. Kidney Int 1998; 53:223.
  61. Goodman WG, Frazao JM, Goodkin DA, et al. A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Kidney Int 2000; 58:436.
  62. Goodman WG, Hladik GA, Turner SA, et al. The Calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism. J Am Soc Nephrol 2002; 13:1017.
  63. Lindberg JS, Moe SM, Goodman WG, et al. The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism. Kidney Int 2003; 63:248.
  64. Quarles LD, Sherrard DJ, Adler S, et al. The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 2003; 14:575.
  65. Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 2004; 350:1516.
  66. Harris RZ, Padhi D, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and safety of cinacalcet hydrochloride in hemodialysis patients at doses up to 200 mg once daily. Am J Kidney Dis 2004; 44:1070.
  67. Moe SM, Chertow GM, Coburn JW, et al. Achieving NKF-K/DOQI bone metabolism and disease treatment goals with cinacalcet HCl. Kidney Int 2005; 67:760.
  68. Lindberg JS, Culleton B, Wong G, et al. Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: a randomized, double-blind, multicenter study. J Am Soc Nephrol 2005; 16:800.
  69. Szczech LA. The impact of calcimimetic agents on the use of different classes of phosphate binders: results of recent clinical trials. Kidney Int Suppl 2004; :S46.
  70. Sterrett JR, Strom J, Stummvoll HK, et al. Cinacalcet HCI (Sensipar/Mimpara) is an effective chronic therapy for hemodialysis patients with secondary hyperparathyroidism. Clin Nephrol 2007; 68:10.
  71. Messa P, Macário F, Yaqoob M, et al. The OPTIMA study: assessing a new cinacalcet (Sensipar/Mimpara) treatment algorithm for secondary hyperparathyroidism. Clin J Am Soc Nephrol 2008; 3:36.
  72. Sprague SM, Evenepoel P, Curzi MP, et al. Simultaneous control of PTH and CaxP Is sustained over three years of treatment with cinacalcet HCl. Clin J Am Soc Nephrol 2009; 4:1465.
  73. Arenas MD, Alvarez-Ude F, Gil MT, et al. Implementation of 'K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease' after the introduction of cinacalcet in a population of patients on chronic haemodialysis. Nephrol Dial Transplant 2007; 22:1639.
  74. Fishbane S, Shapiro WB, Corry DB, et al. Cinacalcet HCl and concurrent low-dose vitamin D improves treatment of secondary hyperparathyroidism in dialysis patients compared with vitamin D alone: the ACHIEVE study results. Clin J Am Soc Nephrol 2008; 3:1718.
  75. Palmer SC, Nistor I, Craig JC, et al. Cinacalcet in patients with chronic kidney disease: a cumulative meta-analysis of randomized controlled trials. PLoS Med 2013; 10:e1001436.
  76. Amgen Sensipar clears FDA: Phosphate binders are a competitive target. FDC Rep Drugs Cosmet 2004; 66:23.
  77. Wetmore JB, Gurevich K, Sprague S, et al. A Randomized Trial of Cinacalcet versus Vitamin D Analogs as Monotherapy in Secondary Hyperparathyroidism (PARADIGM). Clin J Am Soc Nephrol 2015; 10:1031.
  78. EVOLVE Trial Investigators, Chertow GM, Block GA, et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012; 367:2482.
  79. Block GA, Zaun D, Smits G, et al. Cinacalcet hydrochloride treatment significantly improves all-cause and cardiovascular survival in a large cohort of hemodialysis patients. Kidney Int 2010; 78:578.
  80. Parfrey PS, Drüeke TB, Block GA, et al. The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Clin J Am Soc Nephrol 2015; 10:791.
  81. Moe SM, Abdalla S, Chertow GM, et al. Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis: The EVOLVE Trial. J Am Soc Nephrol 2015; 26:1466.
  82. Block GA, Bushinsky DA, Cunningham J, et al. Effect of Etelcalcetide vs Placebo on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: Two Randomized Clinical Trials. JAMA 2017; 317:146.
  83. Block GA, Bushinsky DA, Cheng S, et al. Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial. JAMA 2017; 317:156.
  84. Middleton JP, Wolf M. Second Chances to Improve ESRD Outcomes With a Second-Generation Calcimimetic. JAMA 2017; 317:139.
  85. Amgen Sensipar label prepares for off-label use in pre-dialysis population. Pharmaceutical Approvals Monthly 2004; 9:28.