Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point-of-care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors and editors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

Choose from the list below to learn more about subscriptions for a:


Subscribers log in here


Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia

INTRODUCTION

The demonstration that the rare disorder, familial hypocalciuric hypercalcemia, was caused by inactivating mutations in the gene for the calcium-sensing receptor (CaSR, sometimes referred to as CaR) had two major consequences: it explained the phenotypic expression of the disease, and it initiated an ongoing effort to explain the normal physiologic functions of the receptor. This topic will briefly review our understanding of the function of the CaSR in the parathyroid glands and kidneys and then describe conditions caused by mutations in this gene, particularly familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia (table 1). There is also increasing evidence that abnormalities of the CaSR can be an acquired defect in hyperparathyroidism and hypoparathyroidism.

FUNCTIONS OF THE CALCIUM-SENSING RECEPTOR

The calcium-sensing receptor (CaSR) is expressed in multiple tissues, including the parathyroid glands, kidneys, bone marrow, osteoclasts and osteoblasts, breast, thyroid C-cells, gastrin-secreting cells in the stomach, intestine, some areas of the brain, and others [1-7]. One of its main functions is to regulate calcium balance [1,2,8]. The CaSR senses small changes in the serum ionized calcium concentration. In response to these changes, the CaSR brings about changes in the function of parathyroid glands and kidneys, which are directed at normalizing serum calcium concentration. This receptor is also activated by magnesium and by certain amino acids and therefore may have a role in the cellular response to changes in other constituents of the extracellular environment [9,10].

Parathyroid gland — The CaSR is highly expressed on the surface of the chief cells of the parathyroid glands [1,2]. It permits the parathyroid gland to sense variations in the serum calcium concentration, leading to the desired changes in parathyroid hormone (PTH) secretion. A fall in serum calcium concentration is a potent stimulus to the release of PTH (figure 1). This is an appropriate physiologic response since, via its effects to increase bone resorption, to increase the formation of calcitriol in the kidney and to reduce renal calcium excretion, PTH acts to raise the serum calcium concentration toward normal. Chronic hypocalcemia, acting via the CaSR, has other homeostatically appropriate effects on parathyroid function, including increasing PTH gene expression and stimulating parathyroid cellular proliferation. Conversely, when serum calcium concentration is high, synthesis and secretion of PTH are inhibited. (See "Parathyroid hormone secretion and action", section on 'Actions of PTH'.)

There are clearly PTH-independent roles for the CaSR in maintaining the normally exquisitely tight regulation of serum calcium concentration. Mice lacking both the PTH and CaSR genes develop marked hypercalcemia in response to oral calcium loads, while those lacking only PTH can mount an effective defense against hypercalcemia via the CaSR by upregulating renal calcium excretion and calcitonin secretion [11]. In addition, polymorphisms of the CaSR may underlie some of the variability observed in the serum calcium concentrations in normal subjects [12-14].

Kidney

Urine calcium excretion — The CaSR is an important regulator of urinary calcium excretion [15-19]. It explains why hypercalcemia reduces calcium and sodium transport in the loop of Henle, with an associated decrease in urinary concentrating ability. Receptors expressed on the basolateral membrane on the cells of the thick ascending limb of the loop of Henle appear to be the major site where this occurs [8,20,21].

                 

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jul 2014. | This topic last updated: Oct 17, 2013.
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 ©2014 UpToDate, Inc.
References
Top
  1. Brown EM, Hebert SC. Calcium-receptor-regulated parathyroid and renal function. Bone 1997; 20:303.
  2. Brown EM, Hebert SC. A cloned extracellular Ca(2+)-sensing receptor: molecular mediator of the actions of extracellular Ca2+ on parathyroid and kidney cells? Kidney Int 1996; 49:1042.
  3. Cheng I, Klingensmith ME, Chattopadhyay N, et al. Identification and localization of the extracellular calcium-sensing receptor in human breast. J Clin Endocrinol Metab 1998; 83:703.
  4. Ray JM, Squires PE, Curtis SB, et al. Expression of the calcium-sensing receptor on human antral gastrin cells in culture. J Clin Invest 1997; 99:2328.
  5. Kameda T, Mano H, Yamada Y, et al. Calcium-sensing receptor in mature osteoclasts, which are bone resorbing cells. Biochem Biophys Res Commun 1998; 245:419.
  6. Hebert SC, Cheng S, Geibel J. Functions and roles of the extracellular Ca2+-sensing receptor in the gastrointestinal tract. Cell Calcium 2004; 35:239.
  7. Geibel J, Sritharan K, Geibel R, et al. Calcium-sensing receptor abrogates secretagogue- induced increases in intestinal net fluid secretion by enhancing cyclic nucleotide destruction. Proc Natl Acad Sci U S A 2006; 103:9390.
  8. Hebert SC. Extracellular calcium-sensing receptor: implications for calcium and magnesium handling in the kidney. Kidney Int 1996; 50:2129.
  9. Tfelt-Hansen J, Brown EM. The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit Rev Clin Lab Sci 2005; 42:35.
  10. Hofer AM, Curci S, Doble MA, et al. Intercellular communication mediated by the extracellular calcium-sensing receptor. Nat Cell Biol 2000; 2:392.
  11. Kantham L, Quinn SJ, Egbuna OI, et al. The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion. Am J Physiol Endocrinol Metab 2009; 297:E915.
  12. Cole DE, Peltekova VD, Rubin LA, et al. A986S polymorphism of the calcium-sensing receptor and circulating calcium concentrations. Lancet 1999; 353:112.
  13. Cole DE, Vieth R, Trang HM, et al. Association between total serum calcium and the A986S polymorphism of the calcium-sensing receptor gene. Mol Genet Metab 2001; 72:168.
  14. Scillitani A, Guarnieri V, De Geronimo S, et al. Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor. J Clin Endocrinol Metab 2004; 89:5634.
  15. Kos CH, Karaplis AC, Peng JB, et al. The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone. J Clin Invest 2003; 111:1021.
  16. Tu Q, Pi M, Karsenty G, et al. Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background. J Clin Invest 2003; 111:1029.
  17. Houillier P, Paillard M. Calcium-sensing receptor and renal cation handling. Nephrol Dial Transplant 2003; 18:2467.
  18. Frick KK, Bushinsky DA. Molecular mechanisms of primary hypercalciuria. J Am Soc Nephrol 2003; 14:1082.
  19. Gambaro G, Vezzoli G, Casari G, et al. Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms. Am J Kidney Dis 2004; 44:963.
  20. Riccardi D, Lee WS, Lee K, et al. Localization of the extracellular Ca(2+)-sensing receptor and PTH/PTHrP receptor in rat kidney. Am J Physiol 1996; 271:F951.
  21. Hebert SC. Calcium and salinity sensing by the thick ascending limb: a journey from mammals to fish and back again. Kidney Int Suppl 2004; :S28.
  22. Haas M. The Na-K-Cl cotransporters. Am J Physiol 1994; 267:C869.
  23. Friedman PA, Gesek FA. Calcium transport in renal epithelial cells. Am J Physiol 1993; 264:F181.
  24. Amlal H, Legoff C, Vernimmen C, et al. Na(+)-K+(NH4+)-2Cl- cotransport in medullary thick ascending limb: control by PKA, PKC, and 20-HETE. Am J Physiol 1996; 271:C455.
  25. Wang WH, Lu M, Hebert SC. Cytochrome P-450 metabolites mediate extracellular Ca(2+)-induced inhibition of apical K+ channels in the TAL. Am J Physiol 1996; 271:C103.
  26. Schwartzman M, Ferreri NR, Carroll MA, et al. Renal cytochrome P450-related arachidonate metabolite inhibits (Na+ + K+)ATPase. Nature 1985; 314:620.
  27. de Jesus Ferreira MC, Héliès-Toussaint C, Imbert-Teboul M, et al. Co-expression of a Ca2+-inhibitable adenylyl cyclase and of a Ca2+-sensing receptor in the cortical thick ascending limb cell of the rat kidney. Inhibition of hormone-dependent cAMP accumulation by extracellular Ca2+. J Biol Chem 1998; 273:15192.
  28. Gong Y, Renigunta V, Himmerkus N, et al. Claudin-14 regulates renal Ca⁺⁺ transport in response to CaSR signalling via a novel microRNA pathway. EMBO J 2012; 31:1999.
  29. Sands JM, Naruse M, Baum M, et al. Apical extracellular calcium/polyvalent cation-sensing receptor regulates vasopressin-elicited water permeability in rat kidney inner medullary collecting duct. J Clin Invest 1997; 99:1399.
  30. Renkema KY, Velic A, Dijkman HB, et al. The calcium-sensing receptor promotes urinary acidification to prevent nephrolithiasis. J Am Soc Nephrol 2009; 20:1705.
  31. Yamaguchi T, Sugimoto T. [Impaired bone mineralization in calcium-sensing receptor (CaSR) knockout mice : the physiological action of CaSR in bone microenvironments]. Clin Calcium 2007; 17:1567.
  32. Brown EM, Lian JB. New insights in bone biology: unmasking skeletal effects of the extracellular calcium-sensing receptor. Sci Signal 2008; 1:pe40.
  33. Chang W, Tu C, Chen TH, et al. The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development. Sci Signal 2008; 1:ra1.
  34. 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.
  35. 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.
  36. Bai M, Janicic N, Trivedi S, et al. Markedly reduced activity of mutant calcium-sensing receptor with an inserted Alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. J Clin Invest 1997; 99:1917.
  37. Cole DE, Janicic N, Salisbury SR, Hendy GN. Neonatal severe hyperparathyroidism, secondary hyperparathyroidism, and familial hypocalciuric hypercalcemia: multiple different phenotypes associated with an inactivating Alu insertion mutation of the calcium-sensing receptor gene. Am J Med Genet 1997; 71:202.
  38. Pearce SH, Trump D, Wooding C, et al. Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism. J Clin Invest 1995; 96:2683.
  39. Ho C, Conner DA, Pollak MR, et al. A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet 1995; 11:389.
  40. Bai M, Pearce SH, Kifor O, et al. In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia. J Clin Invest 1997; 99:88.
  41. Lietman SA, Tenenbaum-Rakover Y, Jap TS, et al. A novel loss-of-function mutation, Gln459Arg, of the calcium-sensing receptor gene associated with apparent autosomal recessive inheritance of familial hypocalciuric hypercalcemia. J Clin Endocrinol Metab 2009; 94:4372.
  42. Marx SJ, Attie MF, Levine MA, et al. The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds. Medicine (Baltimore) 1981; 60:397.
  43. Law WM Jr, Heath H 3rd. Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families. Ann Intern Med 1985; 102:511.
  44. Heath H 3rd. Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am 1989; 18:723.
  45. Brown EM. Clinical lessons from the calcium-sensing receptor. Nat Clin Pract Endocrinol Metab 2007; 3:122.
  46. Heath H 3rd, Jackson CE, Otterud B, Leppert MF. Genetic linkage analysis in familial benign (hypocalciuric) hypercalcemia: evidence for locus heterogeneity. Am J Hum Genet 1993; 53:193.
  47. Lloyd SE, Pannett AA, Dixon PH, et al. Localization of familial benign hypercalcemia, Oklahoma variant (FBHOk), to chromosome 19q13. Am J Hum Genet 1999; 64:189.
  48. Nesbit MA, Hannan FM, Howles SA, et al. Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia. N Engl J Med 2013; 368:2476.
  49. Nesbit MA, Hannan FM, Howles SA, et al. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat Genet 2013; 45:93.
  50. CASRdb: Calcium-sensing receptor database. www.casrdb.mcgill.ca (Accessed on January 21, 2009).
  51. Pearce SH, Bai M, Quinn SJ, et al. Functional characterization of calcium-sensing receptor mutations expressed in human embryonic kidney cells. J Clin Invest 1996; 98:1860.
  52. Zajickova K, Vrbikova J, Canaff L, et al. Identification and functional characterization of a novel mutation in the calcium-sensing receptor gene in familial hypocalciuric hypercalcemia: modulation of clinical severity by vitamin D status. J Clin Endocrinol Metab 2007; 92:2616.
  53. Marx SJ, Stock JL, Attie MF, et al. Familial hypocalciuric hypercalcemia: recognition among patients referred after unsuccessful parathyroid exploration. Ann Intern Med 1980; 92:351.
  54. Heath H III. The familial benign hypocalciuric hypercalcemia syndromes. In: Principles of Bone Biology, Bilezikian JP, Raisz LG, Rodan GA (Eds), Academic Press, San Diego, CA 1996. p.769.
  55. Whitcomb DC. Genetic aspects of pancreatitis. Annu Rev Med 2010; 61:413.
  56. Silverberg SJ, Shane E, Jacobs TP, et al. Nephrolithiasis and bone involvement in primary hyperparathyroidism. Am J Med 1990; 89:327.
  57. Christensen SE, Nissen PH, Vestergaard P, et al. Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods. Clin Endocrinol (Oxf) 2008; 69:713.
  58. Pasieka JL, Andersen MA, Hanley DA. Familial benign hypercalcaemia: hypercalciuria and hypocalciuria in affected members of a small kindred. Clin Endocrinol (Oxf) 1990; 33:429.
  59. Warner J, Epstein M, Sweet A, et al. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J Med Genet 2004; 41:155.
  60. Simonds WF, James-Newton LA, Agarwal SK, et al. Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore) 2002; 81:1.
  61. Carling T, Szabo E, Bai M, et al. Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor. J Clin Endocrinol Metab 2000; 85:2042.
  62. Egbuna OI, Brown EM. Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations. Best Pract Res Clin Rheumatol 2008; 22:129.
  63. Kobayashi M, Tanaka H, Tsuzuki K, et al. Two novel missense mutations in calcium-sensing receptor gene associated with neonatal severe hyperparathyroidism. J Clin Endocrinol Metab 1997; 82:2716.
  64. Obermannova B, Banghova K, Sumník Z, et al. Unusually severe phenotype of neonatal primary hyperparathyroidism due to a heterozygous inactivating mutation in the CASR gene. Eur J Pediatr 2009; 168:569.
  65. Marx SJ, Lasker RD, Brown EM, et al. Secretory dysfunction in parathyroid cells from a neonate with severe primary hyperparathyroidism. J Clin Endocrinol Metab 1986; 62:445.
  66. Hendy GN, D'Souza-Li L, Yang B, et al. Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat 2000; 16:281.
  67. Waller S, Kurzawinski T, Spitz L, et al. Neonatal severe hyperparathyroidism: genotype/phenotype correlation and the use of pamidronate as rescue therapy. Eur J Pediatr 2004; 163:589.
  68. Wilhelm-Bals A, Parvex P, Magdelaine C, Girardin E. Successful use of bisphosphonate and calcimimetic in neonatal severe primary hyperparathyroidism. Pediatrics 2012; 129:e812.
  69. 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.
  70. D'Souza-Li L, Yang B, Canaff L, et al. Identification and functional characterization of novel calcium-sensing receptor mutations in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia. J Clin Endocrinol Metab 2002; 87:1309.
  71. Watanabe S, Fukumoto S, Chang H, et al. Association between activating mutations of calcium-sensing receptor and Bartter's syndrome. Lancet 2002; 360:692.
  72. Konrad M, Weber S. Recent advances in molecular genetics of hereditary magnesium-losing disorders. J Am Soc Nephrol 2003; 14:249.
  73. Watanabe T, Bai M, Lane CR, et al. Familial hypoparathyroidism: identification of a novel gain of function mutation in transmembrane domain 5 of the calcium-sensing receptor. J Clin Endocrinol Metab 1998; 83:2497.
  74. Conley YP, Finegold DN, Peters DG, et al. Three novel activating mutations in the calcium-sensing receptor responsible for autosomal dominant hypocalcemia. Mol Genet Metab 2000; 71:591.
  75. Tan YM, Cardinal J, Franks AH, et al. Autosomal dominant hypocalcemia: a novel activating mutation (E604K) in the cysteine-rich domain of the calcium-sensing receptor. J Clin Endocrinol Metab 2003; 88:605.
  76. Lienhardt A, Bai M, Lagarde JP, et al. Activating mutations of the calcium-sensing receptor: management of hypocalcemia. J Clin Endocrinol Metab 2001; 86:5313.
  77. Baron J, Winer KK, Yanovski JA, et al. Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism. Hum Mol Genet 1996; 5:601.
  78. De Luca F, Ray K, Mancilla EE, et al. Sporadic hypoparathyroidism caused by de Novo gain-of-function mutations of the Ca(2+)-sensing receptor. J Clin Endocrinol Metab 1997; 82:2710.
  79. Suzuki M, Aso T, Sato T, et al. A case of gain-of-function mutation in calcium-sensing receptor: supplemental hydration is required for renal protection. Clin Nephrol 2005; 63:481.
  80. Hough TA, Bogani D, Cheeseman MT, et al. Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification. Proc Natl Acad Sci U S A 2004; 101:13566.
  81. Pearce SH, Williamson C, Kifor O, et al. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N Engl J Med 1996; 335:1115.
  82. Burren CP, Curley A, Christie P, et al. A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges. J Pediatr Endocrinol Metab 2005; 18:689.
  83. Sato K, Hasegawa Y, Nakae J, et al. Hydrochlorothiazide effectively reduces urinary calcium excretion in two Japanese patients with gain-of-function mutations of the calcium-sensing receptor gene. J Clin Endocrinol Metab 2002; 87:3068.
  84. Winer KK, Ko CW, Reynolds JC, et al. Long-term treatment of hypoparathyroidism: a randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and calcium. J Clin Endocrinol Metab 2003; 88:4214.
  85. Kifor O, Moore FD Jr, Wang P, et al. Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism. J Clin Endocrinol Metab 1996; 81:1598.
  86. Gogusev J, Duchambon P, Hory B, et al. Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int 1997; 51:328.
  87. Pallais JC, Kifor O, Chen YB, et al. Acquired hypocalciuric hypercalcemia due to autoantibodies against the calcium-sensing receptor. N Engl J Med 2004; 351:362.
  88. Kifor O, Moore FD Jr, Delaney M, et al. A syndrome of hypocalciuric hypercalcemia caused by autoantibodies directed at the calcium-sensing receptor. J Clin Endocrinol Metab 2003; 88:60.
  89. Makita N, Sato J, Manaka K, et al. An acquired hypocalciuric hypercalcemia autoantibody induces allosteric transition among active human Ca-sensing receptor conformations. Proc Natl Acad Sci U S A 2007; 104:5443.
  90. Kifor O, McElduff A, LeBoff MS, et al. Activating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism. J Clin Endocrinol Metab 2004; 89:548.
  91. Li Y, Song YH, Rais N, et al. Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism. J Clin Invest 1996; 97:910.
  92. Gavalas NG, Kemp EH, Krohn KJ, et al. The calcium-sensing receptor is a target of autoantibodies in patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab 2007; 92:2107.
  93. Mayer A, Ploix C, Orgiazzi J, et al. Calcium-sensing receptor autoantibodies are relevant markers of acquired hypoparathyroidism. J Clin Endocrinol Metab 2004; 89:4484.
  94. Brown EM. Anti-parathyroid and anti-calcium sensing receptor antibodies in autoimmune hypoparathyroidism. Endocrinol Metab Clin North Am 2009; 38:437.
  95. Kemp EH, Gavalas NG, Krohn KJ, et al. Activating autoantibodies against the calcium-sensing receptor detected in two patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab 2009; 94:4749.
  96. Hu J. Allosteric modulators of the human calcium-sensing receptor: structures, sites of action, and therapeutic potentials. Endocr Metab Immune Disord Drug Targets 2008; 8:192.
  97. Nemeth EF. Pharmacological regulation of parathyroid hormone secretion. Curr Pharm Des 2002; 8:2077.
  98. Timmers HJ, Karperien M, Hamdy NA, et al. Normalization of serum calcium by cinacalcet in a patient with hypercalcaemia due to a de novo inactivating mutation of the calcium-sensing receptor. J Intern Med 2006; 260:177.
  99. Fitzpatrick LA, Dabrowski CE, Cicconetti G, et al. The effects of ronacaleret, a calcium-sensing receptor antagonist, on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mineral density. J Clin Endocrinol Metab 2011; 96:2441.
  100. Kumar S, Matheny CJ, Hoffman SJ, et al. An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation. Bone 2010; 46:534.