Clinical Reviews in Bone and Mineral Metabolism

, Volume 12, Issue 3, pp 142–164 | Cite as

The Role of PTHrP in Regulating Mineral Metabolism During Pregnancy, Lactation, and Fetal/Neonatal Development

Original Paper

Abstract

Parathyroid hormone-related protein (PTHrP) was originally identified as the cause of humoral hypercalcemia of malignancy (HHM), a condition that resembles primary hyperparathyroidism and the effects of excess parathyroid hormone (PTH). But HHM is an unusual situation because PTHrP is normally undetectable in the circulation of the child or adult. Instead, most of PTHrP’s actions are now understood to be paracrine or autocrine, and not humoral. However, PTHrP is present in the circulation at measurable levels during fetal development, pregnancy, and lactation. During these time periods, PTHrP has humoral actions that regulate mineral and bone homeostasis independently of PTH. In fact, the existence of PTHrP was also predicted by the characteristic pattern of serum chemistries and PTH in cord blood of normal newborns, and by the normalization of calcium metabolism that temporarily occurs in hypoparathyroid women who breast-feed. This article reviews our present understanding about PTHrP’s role to control mineral and bone metabolism during pregnancy, lactation, and fetal development. Excess PTHrP can also be produced by the placenta or the breasts during pregnancy, or by the breasts during lactation, and in both situations it can lead to hypercalcemia and other clinical features that are indistinguishable from HHM. The highest concentrations of PTHrP are found in milk, and recent evidence indicates that milk-based PTHrP may reduce mineral accretion by the newborn skeleton, but whether it does this through local actions in the neonatal gut or after absorption into the neonatal circulation is unknown.

Keywords

Pregnancy Lactation Fetus Neonate Placenta Mammary tissue 

Notes

Acknowledgments

Author has received grant support form Canadian Institutes of Health Research (No. 84253).

Disclosures

Conflicts of interest

Christopher S. Kovacs has no conflicts of interest or disclosures to make with respect to this work.

Animal/Human Studies

This article does not include any studies with human or animal subjects performed by the author.

References

  1. 1.
    Riggs BL, Arnaud CD, Reynolds JC, Smith LH. Immunologic differentiation of primary hyperparathyroidism from hyperparathyroidism due to nonparathyroid cancer. J Clin Invest. 1971;50(10):2079–83.PubMedCentralPubMedGoogle Scholar
  2. 2.
    Powell D, Singer FR, Murray TM, Minkin C, Potts JT Jr. Nonparathyroid humoral hypercalcemia in patients with neoplastic diseases. N Engl J Med. 1973;289(4):176–81.PubMedGoogle Scholar
  3. 3.
    Ponthier RL Jr, Rice BF. Hypercalcaemia of neoplasia, parathyroid hormone and vitamin D: studies in parabiosis. Acta Endocrinol (Copenh). 1974;77(3):527–39.Google Scholar
  4. 4.
    Mangin M, Webb AC, Dreyer BE, Posillico JT, Ikeda K, Weir EC, Stewart AF, Bander NH, Milstone L, Barton DE, Francke U, Broadus AE. Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy. Proc Natl Acad Sci USA. 1988;85:597–601.PubMedCentralPubMedGoogle Scholar
  5. 5.
    Suva LJ, Winslow GA, Wettenhall RE, Hammonds RG, Moseley JM, Diefenbach-Jagger H, Rodda CP, Kemp BE, Rodriguez H, Chen EY, Hudson PJ, Martin TJ, Wood WI. A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science. 1987;237:893–6.PubMedGoogle Scholar
  6. 6.
    Strewler GJ, Stern PH, Jacobs JW, Eveloff J, Klein RF, Leung SC, Rosenblatt M, Nissenson RA. Parathyroid hormonelike protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone. J Clin Invest. 1987;80(6):1803–7.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Grill V, Ho P, Body JJ, Johanson N, Lee SC, Kukreja SC, Moseley JM, Martin TJ. Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer. J Clin Endocrinol Metab. 1991;73:1309–15.PubMedGoogle Scholar
  8. 8.
    Kovacs CS, Kronenberg HM. Maternal-fetal calcium and bone metabolism during pregnancy, puerperium and lactation. Endocr Rev. 1997;18:832–72.PubMedGoogle Scholar
  9. 9.
    Kovacs CS. Control of skeletal homeostasis during pregnancy and lactation—lessons from physiological models. In: Thakker RV, Whyte MP, Eisman JA, Igarashi T, editors. Genetics of bone biology and skeletal disease. San Diego: Academic Press/Elsevier; 2012. p. 221–40.Google Scholar
  10. 10.
    Kovacs CS. Fetal control of calcium and phosphate homeostasis—lessons from mouse models. In: Thakker RV, Whyte MP, Eisman JA, Igarashi T, editors. Genetics of bone biology and skeletal disease. San Diego: Academic Press/Elsevier; 2012. p. 205–20.Google Scholar
  11. 11.
    Kovacs CS. The role of vitamin D in pregnancy and lactation: insights from animal models and clinical studies. Ann Rev Nutr. 2012;32:9.1–27.Google Scholar
  12. 12.
    Simmonds CS, Karsenty G, Karaplis AC, Kovacs CS. Parathyroid hormone regulates fetal-placental mineral homeostasis. J Bone Miner Res. 2010;25(3):594–605.PubMedGoogle Scholar
  13. 13.
    Kovacs CS. Fetal mineral homeostasis. In: Glorieux FH, Pettifor JM, Jüppner H, editors. Pediatric bone: biology and diseases. 2nd ed. San Diego: Elsevier/Academic Press; 2011. p. 247–75.Google Scholar
  14. 14.
    Kovacs CS, Chafe LL, Fudge NJ, Friel JK, Manley NR. PTH regulates fetal blood calcium and skeletal mineralization independently of PTHrP. Endocrinology. 2001;142(11):4983–93.PubMedGoogle Scholar
  15. 15.
    Kovacs CS, Manley NR, Moseley JM, Martin TJ, Kronenberg HM. Fetal parathyroids are not required to maintain placental calcium transport. J Clin Invest. 2001;107(8):1007–15.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Suzuki Y, Kovacs CS, Takanaga H, Peng JB, Landowski CP, Hediger MA. Calcium TRPV6 is involved in murine maternal-fetal calcium transport. J Bone Miner Res. 2008;23(8):1249–56.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Loughead JL, Mimouni F, Tsang RC. Serum ionized calcium concentrations in normal neonates. Am J Dis Child. 1988;142:516–8.PubMedGoogle Scholar
  18. 18.
    David L, Anast CS. Calcium metabolism in newborn infants. The interrelationship of parathyroid function and calcium, magnesium, and phosphorus metabolism in normal, sick, and hypocalcemic newborns. J Clin Invest. 1974;54:287–96.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Schauberger CW, Pitkin RM. Maternal-perinatal calcium relationships. Obstet Gynecol. 1979;53:74–6.PubMedGoogle Scholar
  20. 20.
    Garel JM, Barlet JP. Calcium metabolism in newborn animals: the interrelationship of calcium, magnesium, and inorganic phosphorus in newborn rats, foals, lambs, and calves. Pediatr Res. 1976;10:749–54.PubMedGoogle Scholar
  21. 21.
    Krukowski M, Smith JJ. pH and the level of calcium in the blood of fetal and neonatal albino rats. Biol Neonate. 1976;29:148–61.PubMedGoogle Scholar
  22. 22.
    Miao D, He B, Karaplis AC, Goltzman D. Parathyroid hormone is essential for normal fetal bone formation. J Clin Invest. 2002;109(9):1173–82.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Haddad JG Jr, Boisseau V, Avioli LV. Placental transfer of vitamin D3 and 25-hydroxycholecalciferol in the rat. J Lab Clin Med. 1971;77:908–15.PubMedGoogle Scholar
  24. 24.
    Noff D, Edelstein S. Vitamin D and its hydroxylated metabolites in the rat. Placental and lacteal transport, subsequent metabolic pathways and tissue distribution. Horm Res. 1978;9:292–300.Google Scholar
  25. 25.
    Hillman LS, Haddad JG. Human perinatal vitamin D metabolism. I. 25-Hydroxyvitamin D in maternal and cord blood. J Pediatr. 1974;84:742–9.PubMedGoogle Scholar
  26. 26.
    Wieland P, Fischer JA, Trechsel U, Roth HR, Vetter K, Schneider H, Huch A. Perinatal parathyroid hormone, vitamin D metabolites, and calcitonin in man. Am J Physiol. 1980;239:E385–90.PubMedGoogle Scholar
  27. 27.
    Fleischman AR, Rosen JF, Cole J, Smith CM, DeLuca HF. Maternal and fetal serum 1,25-dihydroxyvitamin D levels at term. J Pediatr. 1980;97:640–2.PubMedGoogle Scholar
  28. 28.
    Seki K, Furuya K, Makimura N, Mitsui C, Hirata J, Nagata I. Cord blood levels of calcium-regulating hormones and osteocalcin in premature infants. J Perinat Med. 1994;22:189–94.PubMedGoogle Scholar
  29. 29.
    Hollis BW, Pittard WB. Evaluation of the total fetomaternal vitamin D relationships at term: evidence for racial differences. J Clin Endocrinol Metab. 1984;59:652–7.PubMedGoogle Scholar
  30. 30.
    Viljakainen HT, Saarnio E, Hytinantti T, Miettinen M, Surcel H, Makitie O, Andersson S, Laitinen K, Lamberg-Allardt C. Maternal vitamin D status determines bone variables in the newborn. J Clin Endocrinol Metab. 2010;95(4):1749–57.PubMedGoogle Scholar
  31. 31.
    Kovacs CS. Fetus, Neonate and Infant. In: Feldman D, Pike WJ, Adams JS, editors. Vitamin D. 3rd ed. New York: Academic Press; 2011. p. 625–46.Google Scholar
  32. 32.
    McDonald KR, Fudge NJ, Woodrow JP, Friel JK, Hoff AO, Gagel RF, Kovacs CS. Ablation of calcitonin/calcitonin gene related peptide-a impairs fetal magnesium but not calcium homeostasis. Am J Physiol Endocrinol Metab. 2004;287(2):E218–26.PubMedGoogle Scholar
  33. 33.
    Ma Y, Samaraweera M, Cooke-Hubley S, Kirby BJ, Karaplis AC, Lanske B, Kovacs CS. Neither absence nor excess of FGF23 disturbs murine fetal-placental phosphorus homeostasis or prenatal skeletal development and mineralization. Endocrinology. 2014 (submitted).Google Scholar
  34. 34.
    Kirby BJ, Ma Y, Martin HM, Buckle Favaro KL, Karaplis AC, Kovacs CS. Upregulation of calcitriol during pregnancy and skeletal recovery after lactation do not require parathyroid hormone. J Bone Miner Res. 2013;28(9):1987–2000.PubMedGoogle Scholar
  35. 35.
    Takaiwa M, Aya K, Miyai T, Hasegawa K, Yokoyama M, Kondo Y, Kodani N, Seino Y, Tanaka H, Morishima T. Fibroblast growth factor 23 concentrations in healthy term infants during the early postpartum period. Bone. 2010;47(2):256–62.Google Scholar
  36. 36.
    Ohata Y, Arahori H, Namba N, Kitaoka T, Hirai H, Wada K, Nakayama M, Michigami T, Imura A, Nabeshima Y, Yamazaki Y, Ozono K. Circulating levels of soluble alpha-Klotho are markedly elevated in human umbilical cord blood. J Clin Endocrinol Metab. 2011;96(6):E943–7.PubMedGoogle Scholar
  37. 37.
    Simmonds CS, Kovacs CS. Role of parathyroid hormone (PTH) and PTH-related protein (PTHrP) in regulating mineral homeostasis during fetal development. Crit Rev Eukaryot Gene Expr. 2010;20(3):235–73.PubMedGoogle Scholar
  38. 38.
    Abbas SK, Pickard DW, Rodda CP, Heath JA, Hammonds RG, Wood WI, Caple IW, Martin TJ, Care AD. Stimulation of ovine placental calcium transport by purified natural and recombinant parathyroid hormone-related protein (PTHrP) preparations. Q J Exp Physiol. 1989;74:549–52.PubMedGoogle Scholar
  39. 39.
    Care AD, Abbas SK, Pickard DW, Barri M, Drinkhill M, Findlay JB, White IR, Caple IW. Stimulation of ovine placental transport of calcium and magnesium by mid-molecule fragments of human parathyroid hormone-related protein. Exp Physiol. 1990;75:605–8.PubMedGoogle Scholar
  40. 40.
    Care AD, Caple IW, Abbas SK, Pickard DW. The effect of fetal thyroparathyroidectomy on the transport of calcium across the ovine placenta to the fetus. Placenta. 1986;7:417–24.PubMedGoogle Scholar
  41. 41.
    MacIsaac RJ, Heath JA, Rodda CP, Moseley JM, Care AD, Martin TJ, Caple IW. Role of the fetal parathyroid glands and parathyroid hormone-related protein in the regulation of placental transport of calcium, magnesium and inorganic phosphate. Reprod Fertil Dev. 1991;3:447–57.PubMedGoogle Scholar
  42. 42.
    Barri M, Abbas SK, Pickard DW, Hammonds RG, Wood WI, Caple IW, Martin TJ, Care AD. Fetal magnesium homeostasis in the sheep. Exp Physiol. 1990;75:681–8.PubMedGoogle Scholar
  43. 43.
    Barlet JP, Davicco MJ, Rouffet J, Coxam V, Lefaivre J. Short communication: parathyroid hormone-related peptide does not stimulate phosphate placental transport. Placenta. 1994;15:441–4.PubMedGoogle Scholar
  44. 44.
    Stulc J, Stulcova B. Placental transfer of phosphate in anaesthetized rats. Placenta. 1996;17:487–93.PubMedGoogle Scholar
  45. 45.
    Kovacs CS, Ho-Pao CL, Hunzelman JL, Lanske B, Fox J, Seidman JG, Seidman CE, Kronenberg HM. Regulation of murine fetal-placental calcium metabolism by the calcium-sensing receptor. J Clin Invest. 1998;101:2812–20.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Chattopadhyay N, Baum N, Bai M, Riccardi D, Hebert SC, Harris EW, Brown EM. Ontogeny of the extracellular calcium-sensing receptor in rat kidney. Am J Physiol. 1996;271:F736–43.PubMedGoogle Scholar
  47. 47.
    Lee K, Deeds JD, Segre GV. Expression of parathyroid hormone-related peptide and its receptor messenger ribonucleic acids during fetal development of rats. Endocrinology. 1995;136:453–63.PubMedGoogle Scholar
  48. 48.
    Karmali R, Schiffmann SN, Vanderwinden JM, Hendy GN, Nys-DeWolf N, Corvilain J, Bergmann P, Vanderhaeghen JJ. Expression of mRNA of parathyroid hormone-related peptide in fetal bones of the rat. Cell Tissue Res. 1992;270:597–600.PubMedGoogle Scholar
  49. 49.
    Burton DW, Brandt DW, Deftos LJ. Parathyroid hormone-related protein in the cardiovascular system. Endocrinology. 1994;135(1):253–61.PubMedGoogle Scholar
  50. 50.
    Abbas SK, Pickard DW, Illingworth D, Storer J, Purdie DW, Moniz C, Dixit M, Caple IW, Ebeling PR, Rodda CP. Measurement of parathyroid hormone-related protein in extracts of fetal parathyroid glands and placental membranes. J Endocrinol. 1990;124:319–25.PubMedGoogle Scholar
  51. 51.
    Senior PV, Heath DA, Beck F. Expression of parathyroid hormone-related protein mRNA in the rat before birth: demonstration by hybridization histochemistry. J Mol Endocrinol. 1991;6:281–90.PubMedGoogle Scholar
  52. 52.
    Bowden SJ, Emly JF, Hughes SV, Powell G, Ahmed A, Whittle MJ, Ratcliffe JG, Ratcliffe WA. Parathyroid hormone-related protein in human term placenta and membranes. J Endocrinol. 1994;142:217–24.PubMedGoogle Scholar
  53. 53.
    Bruns ME, Ferguson JE II, Bruns DE, Burton DW, Brandt DW, Juppner H, Segre GV, Deftos LJ. Expression of parathyroid hormone-related peptide and its receptor messenger ribonucleic acid in human amnion and chorion-decidua: implications for secretion and function. Am J Obstet Gynecol. 1995;173(3 Pt 1):739–46.PubMedGoogle Scholar
  54. 54.
    Ferguson JE, Gorman JV, Bruns DE, Weir EC, Burtis WJ, Martin TJ, Bruns ME. Abundant expression of parathyroid hormone-related protein in human amnion and its association with labor. Proc Natl Acad Sci USA. 1992;89:8384–8.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Ferguson JE, Seaner R, Bruns DE, Redick JA, Mills SE, Jüppner H, Segre GV, Bruns ME. Expression of parathyroid hormone-related protein and its receptor in human umbilical cord: evidence for a paracrine system involving umbilical vessels. Am J Obstet Gynecol. 1994;170:1018–24.PubMedGoogle Scholar
  56. 56.
    Broadus AE, Macica C, Chen X. The PTHrP functional domain is at the gates of endochondral bones. Ann N Y Acad Sci. 2007;1116:65–81.PubMedGoogle Scholar
  57. 57.
    Chen X, Macica CM, Dreyer BE, Hammond VE, Hens JR, Philbrick WM, Broadus AE. Initial characterization of PTH-related protein gene-driven lacZ expression in the mouse. J Bone Miner Res. 2006;21(1):113–23.PubMedGoogle Scholar
  58. 58.
    Karaplis AC, Luz A, Glowacki J, Bronson RT, Tybulewicz VL, Kronenberg HM, Mulligan RC. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev. 1994;8:277–89.PubMedGoogle Scholar
  59. 59.
    Wysolmerski JJ, Philbrick WM, Dunbar ME, Lanske B, Kronenberg H, Broadus AE. Rescue of the parathyroid hormone-related protein knockout mouse demonstrates that parathyroid hormone-related protein is essential for mammary gland development. Development. 1998;125(7):1285–94.PubMedGoogle Scholar
  60. 60.
    Rubin LP, Kovacs CS, De Paepe ME, Tsai SW, Torday JS, Kronenberg HM. Arrested pulmonary alveolar cytodifferentiation and defective surfactant synthesis in mice missing the gene for parathyroid hormone-related protein. Dev Dyn. 2004;230(2):278–89.PubMedGoogle Scholar
  61. 61.
    MacIsaac RJ, Caple IW, Danks JA, Diefenbach-Jagger H, Grill V, Moseley JM, Southby J, Martin TJ. Ontogeny of parathyroid hormone-related protein in the ovine parathyroid gland. Endocrinology. 1991;129:757–64.PubMedGoogle Scholar
  62. 62.
    Tucci J, Russell A, Senior PV, Fernley R, Ferraro T, Beck F. The expression of parathyroid hormone and parathyroid hormone-related protein in developing rat parathyroid glands. J Mol Endocrinol. 1996;17:149–57.PubMedGoogle Scholar
  63. 63.
    Docherty HM, Ratcliffe WA, Heath DA, Docherty K. Expression of parathyroid hormone-related protein in abnormal human parathyroids. J Endocrinol. 1991;129(3):431–8.PubMedGoogle Scholar
  64. 64.
    Asa SL, Henderson J, Goltzman D, Drucker DJ. Parathyroid hormone-like peptide in normal and neoplastic human endocrine tissues. J Clin Endocrinol Metab. 1990;71(5):1112–8.PubMedGoogle Scholar
  65. 65.
    Danks JA, Ebeling PR, Hayman JA, Diefenbach-Jagger H, Collier FM, Grill V, Southby J, Moseley JM, Chou ST, Martin TJ. Immunohistochemical localization of parathyroid hormone-related protein in parathyroid adenoma and hyperplasia. J Pathol. 1990;161(1):27–33.PubMedGoogle Scholar
  66. 66.
    Ikeda K, Weir EC, Mangin M, Dannies PS, Kinder B, Deftos LJ, Brown EM, Broadus AE. Expression of messenger ribonucleic acids encoding a parathyroid hormone-like peptide in normal human and animal tissues with abnormal expression in human parathyroid adenomas. Mol Endocrinol. 1988;2:1230–6.PubMedGoogle Scholar
  67. 67.
    Matsushita H, Hara M, Honda K, Kuroda M, Usui M, Nakazawa H, Hara S, Shishiba Y. Inhibition of parathyroid hormone-related protein release by extracellular calcium in dispersed cells from human parathyroid hyperplasia secondary to chronic renal failure and adenoma. Am J Pathol. 1995;146(6):1521–8.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Allgrove J, Manning RM, Adami S, Chayen J, O’Riordan JL. Biologically active parathyroid hormone in foetal and maternal plasma [abstract]. Clin Sci. 1981;60:11P.Google Scholar
  69. 69.
    Allgrove J, Adami S, Manning RM, O’Riordan JL. Cytochemical bioassay of parathyroid hormone in maternal and cord blood. Arch Dis Child. 1985;60:110–5.PubMedCentralPubMedGoogle Scholar
  70. 70.
    Rubin LP, Posillico JT, Anast CS, Brown EM. Circulating levels of biologically active and immunoreactive intact parathyroid hormone in human newborns. Pediatr Res. 1991;29:201–7.PubMedGoogle Scholar
  71. 71.
    Abbas SK, Ratcliffe WA, Moniz C, Dixit M, Caple IW, Silver M, Fowden A, Care AD. The role of parathyroid hormone-related protein in calcium homeostasis in the fetal pig. Exp Physiol. 1994;79:527–36.PubMedGoogle Scholar
  72. 72.
    Care AD. Development of endocrine pathways in the regulation of calcium homeostasis. Baillieres Clin Endocrinol Metab. 1989;3:671–88.PubMedGoogle Scholar
  73. 73.
    Kovacs CS, Lanske B, Hunzelman JL, Guo J, Karaplis AC, Kronenberg HM. Parathyroid hormone-related peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor. Proc Natl Acad Sci USA. 1996;93:15233–8.PubMedCentralPubMedGoogle Scholar
  74. 74.
    Kovacs CS. Bone development in the fetus and neonate: role of the calciotropic hormones. Curr Osteoporos Rep. 2011;9(4):274–83.PubMedGoogle Scholar
  75. 75.
    Weatherley AJ, Ross R, Pickard DW, Care AD. The transfer of calcium during perfusion of the placenta and intact and thyroparathyroidectomized sheep. Placenta. 1983;4:271–7.PubMedGoogle Scholar
  76. 76.
    Rodda CP, Kubota M, Heath JA, Ebeling PR, Moseley JM, Care AD, Caple IW, Martin TJ. Evidence for a novel parathyroid hormone-related protein in fetal lamb parathyroid glands and sheep placenta: comparisons with a similar protein implicated in humoral hypercalcaemia of malignancy. J Endocrinol. 1988;117:261–71.PubMedGoogle Scholar
  77. 77.
    Wu TL, Vasavada RC, Yang K, Massfelder T, Ganz M, Abbas SK, Care AD, Stewart AF. Structural and physiologic characterization of the mid-region secretory species of parathyroid hormone-related protein. J Biol Chem. 1996;271:24371–81.PubMedGoogle Scholar
  78. 78.
    Kovacs CS, Chafe LL, Woodland ML, McDonald KR, Fudge NJ, Wookey PJ. Calcitropic gene expression suggests a role for intraplacental yolk sac in maternal-fetal calcium exchange. Am J Physiol Endocrinol Metab. 2002;282(3):E721–32.PubMedGoogle Scholar
  79. 79.
    Bond H, Baker B, Boyd RD, Cowley E, Glazier JD, Jones CJ, Sibley CP, Ward BS, Husain SM. Artificial perfusion of the fetal circulation of the in situ mouse placenta: methodology and validation. Placenta. 2006;27(Suppl A):S69–75.Google Scholar
  80. 80.
    Bond H, Dilworth MR, Baker B, Cowley E, Requena Jimenez A, Boyd RD, Husain SM, Ward BS, Sibley CP, Glazier JD. Increased maternofetal calcium flux in parathyroid hormone-related protein-null mice. J Physiol. 2008;586(7):2015–25.PubMedCentralPubMedGoogle Scholar
  81. 81.
    Philbrick WM, Wysolmerski JJ, Galbraith S, Holt E, Orloff JJ, Yang KH, Vasavada RC, Weir EC, Broadus AE, Stewart AF. Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev. 1996;76:127–73.PubMedGoogle Scholar
  82. 82.
    Riddle RC, Macica CM, Clemens TL. Vascular, cardiovascular, and neurologic actions of parathyroid-related protein. In: Bilezikian JP, Raisz LG, Martin TJ, editors. Principles of bone biology. 3rd ed. New York, NY: Academic Press; 2008. p. 733–48.Google Scholar
  83. 83.
    Lanske B, Karaplis AC, Lee K, Luz A, Vortkamp A, Pirro A, Karperien M, Defize L, Ho C, Abou-Samra AB, Jüppner H, Segre GV, Kronenberg HM. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science. 1996;273:663–6.PubMedGoogle Scholar
  84. 84.
    Givens MH, Macy IC. The chemical composition of the human fetus. J Biol Chem. 1933;102:7–17.Google Scholar
  85. 85.
    Trotter M, Hixon BB. Sequential changes in weight, density, and percentage ash weight of human skeletons from an early fetal period through old age. Anat Rec. 1974;179:1–18.PubMedGoogle Scholar
  86. 86.
    Widdowson EM, Dickerson JW. Chemical composition of the body. In: Comar CL, Bronner F, editors. Mineral metabolism: an advanced treatise, volume II, the elements, part A. New York: Academic Press; 1964. p. 1–247.Google Scholar
  87. 87.
    Dahlman T, Sjoberg HE, Bucht E. Calcium homeostasis in normal pregnancy and puerperium. A longitudinal study. Acta Obstet Gynecol Scand. 1994;73:393–8.PubMedGoogle Scholar
  88. 88.
    Gallacher SJ, Fraser WD, Owens OJ, Dryburgh FJ, Logue FC, Jenkins A, Kennedy J, Boyle IT. Changes in calciotropic hormones and biochemical markers of bone turnover in normal human pregnancy. Eur J Endocrinol. 1994;131:369–74.PubMedGoogle Scholar
  89. 89.
    Cross NA, Hillman LS, Allen SH, Krause GF, Vieira NE. Calcium homeostasis and bone metabolism during pregnancy, lactation, and postweaning: a longitudinal study. Am J Clin Nutr. 1995;61:514–23.PubMedGoogle Scholar
  90. 90.
    Rasmussen N, Frolich A, Hornnes PJ, Hegedus L. Serum ionized calcium and intact parathyroid hormone levels during pregnancy and postpartum. Br J Obstet Gynaecol. 1990;97:857–9.PubMedGoogle Scholar
  91. 91.
    Seki K, Makimura N, Mitsui C, Hirata J, Nagata I. Calcium-regulating hormones and osteocalcin levels during pregnancy: a longitudinal study. Am J Obstet Gynecol. 1991;164:1248–52.PubMedGoogle Scholar
  92. 92.
    Ardawi MS, Nasrat HA. HS BAA. Calcium-regulating hormones and parathyroid hormone-related peptide in normal human pregnancy and postpartum: a longitudinal study. Eur J Endocrinol. 1997;137(4):402–9.PubMedGoogle Scholar
  93. 93.
    Singh HJ, Mohammad NH, Nila A. Serum calcium and parathormone during normal pregnancy in Malay women. J Matern Fetal Med. 1999;8(3):95–100.PubMedGoogle Scholar
  94. 94.
    Bikle DD, Gee E, Halloran B, Haddad JG. Free 1,25-dihydroxyvitamin D levels in serum from normal subjects, pregnant subjects, and subjects with liver disease. J Clin Invest. 1984;74:1966–71.PubMedCentralPubMedGoogle Scholar
  95. 95.
    Tamma R, Colaianni G, Zhu LL, DiBenedetto A, Greco G, Montemurro G, Patano N, Strippoli M, Vergari R, Mancini L, Colucci S, Grano M, Faccio R, Liu X, Li J, Usmani S, Bachar M, Bab I, Nishimori K, Young LJ, Buettner C, Iqbal J, Sun L, Zaidi M, Zallone A. Oxytocin is an anabolic bone hormone. Proc Natl Acad Sci USA. 2009;106(17):7149–54.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Holt E. Calcium physiology during pregnancy. In: Lockwood CJ, Drezner MK, Basow DS, editors. UpToDate 214. Waltham, MA: UpToDate; 2013.Google Scholar
  97. 97.
    Turner M, Barre PE, Benjamin A, Goltzman D, Gascon-Barre M. Does the maternal kidney contribute to the increased circulating 1,25-dihydroxyvitamin D concentrations during pregnancy? Miner Electrolyte Metab. 1988;14:246–52.PubMedGoogle Scholar
  98. 98.
    Heaney RP, Skillman TG. Calcium metabolism in normal human pregnancy. J Clin Endocrinol Metab. 1971;33:661–70.PubMedGoogle Scholar
  99. 99.
    Halloran BP, DeLuca HF. Calcium transport in small intestine during pregnancy and lactation. Am J Physiol. 1980;239:E64–8.PubMedGoogle Scholar
  100. 100.
    Brommage R, Baxter DC, Gierke LW. Vitamin D-independent intestinal calcium and phosphorus absorption during reproduction. Am J Physiol. 1990;259:G631–8.PubMedGoogle Scholar
  101. 101.
    Fudge NJ, Kovacs CS. Pregnancy up-regulates intestinal calcium absorption and skeletal mineralization independently of the vitamin D receptor. Endocrinology. 2010;151(3):886–95.PubMedGoogle Scholar
  102. 102.
    Pahuja DN, DeLuca HF. Stimulation of intestinal calcium transport and bone calcium mobilization by prolactin in vitamin D-deficient rats. Science. 1981;214:1038–9.PubMedGoogle Scholar
  103. 103.
    Mainoya JR. Effects of bovine growth hormone, human placental lactogen and ovine prolactin on intestinal fluid and ion transport in the rat. Endocrinology. 1975;96:1165–70.PubMedGoogle Scholar
  104. 104.
    Takeuchi K, Morikawa H, Ueda Y, Mochizuki M. Studies on the effects of placental lactogen on calcium metabolism during pregnancy. Nippon Naibunpi Gakkai Zasshi. 1988;64:1175–86.PubMedGoogle Scholar
  105. 105.
    Wasserman RH, Comar CL, Nold MM, Lengemann FW. Placental transfer of calcium and strontium in the rat and rabbit. Am J Physiol. 1957;189:91–7.PubMedGoogle Scholar
  106. 106.
    Purdie DW, Aaron JE, Selby PL. Bone histology and mineral homeostasis in human pregnancy. Br J Obstet Gynaecol. 1988;95(9):849–54.PubMedGoogle Scholar
  107. 107.
    Kovacs CS. Calcium and bone metabolism in pregnancy and lactation. J Clin Endocrinol Metab. 2001;86(6):2344–8.PubMedGoogle Scholar
  108. 108.
    Naylor KE, Iqbal P, Fledelius C, Fraser RB, Eastell R. The effect of pregnancy on bone density and bone turnover. J Bone Miner Res. 2000;15(1):129–37.PubMedGoogle Scholar
  109. 109.
    Black AJ, Topping J, Durham B, Farquharson RG, Fraser WD. A detailed assessment of alterations in bone turnover, calcium homeostasis, and bone density in normal pregnancy. J Bone Miner Res. 2000;15(3):557–63.PubMedGoogle Scholar
  110. 110.
    Ritchie LD, Fung EB, Halloran BP, Turnlund JR, Van Loan MD, Cann CE, King JC. A longitudinal study of calcium homeostasis during human pregnancy and lactation and after resumption of menses. Am J Clin Nutr. 1998;67(4):693–701.PubMedGoogle Scholar
  111. 111.
    Ulrich U, Miller PB, Eyre DR, Chesnut CHR, Schlebusch H, Soules MR. Bone remodeling and bone mineral density during pregnancy. Arch Gynecol Obstet. 2003;268(4):309–16.PubMedGoogle Scholar
  112. 112.
    Kaur M, Pearson D, Godber I, Lawson N, Baker P, Hosking D. Longitudinal changes in bone mineral density during normal pregnancy. Bone. 2003;32(4):449–54.PubMedGoogle Scholar
  113. 113.
    Gambacciani M, Spinetti A, Gallo R, Cappagli B, Teti GC, Facchini V. Ultrasonographic bone characteristics during normal pregnancy: longitudinal and cross-sectional evaluation. Am J Obstet Gynecol. 1995;173:890–3.PubMedGoogle Scholar
  114. 114.
    Pearson D, Kaur M, San P, Lawson N, Baker P, Hosking D. Recovery of pregnancy mediated bone loss during lactation. Bone. 2004;34(3):570–8.PubMedGoogle Scholar
  115. 115.
    To WW, Wong MW, Leung TW. Relationship between bone mineral density changes in pregnancy and maternal and pregnancy characteristics: a longitudinal study. Acta Obstet Gynecol Scand. 2003;82(9):820–7.PubMedGoogle Scholar
  116. 116.
    Woodrow JP, Sharpe CJ, Fudge NJ, Hoff AO, Gagel RF, Kovacs CS. Calcitonin plays a critical role in regulating skeletal mineral metabolism during lactation. Endocrinology. 2006;147:4010–21.PubMedGoogle Scholar
  117. 117.
    Kirby BJ, Ardeshirpour L, Woodrow JP, Wysolmerski JJ, Sims NA, Karaplis AC, Kovacs CS. Skeletal recovery after weaning does not require PTHrP. J Bone Miner Res. 2011;26(6):1242–51.PubMedCentralPubMedGoogle Scholar
  118. 118.
    Sowers M. Pregnancy and lactation as risk factors for subsequent bone loss and osteoporosis. J Bone Miner Res. 1996;11:1052–60.PubMedGoogle Scholar
  119. 119.
    Paton LM, Alexander JL, Nowson CA, Margerison C, Frame MG, Kaymakci B, Wark JD. Pregnancy and lactation have no long-term deleterious effect on measures of bone mineral in healthy women: a twin study. Am J Clin Nutr. 2003;77(3):707–14.PubMedGoogle Scholar
  120. 120.
    Orloff JJ, Reddy D, de Papp AE, Yang KH, Soifer NE, Stewart AF. Parathyroid hormone-related protein as a prohormone: posttranslational processing and receptor interactions. Endocr Rev. 1994;15:40–60.PubMedGoogle Scholar
  121. 121.
    Khosla S, van Heerden JA, Gharib H, Jackson IT, Danks J, Hayman JA, Martin TJ. Parathyroid hormone-related protein and hypercalcemia secondary to massive mammary hyperplasia [letter]. N Engl J Med. 1990;322:1157.PubMedGoogle Scholar
  122. 122.
    Jackson IT, Saleh J, van Heerden JA. Gigantic mammary hyperplasia in pregnancy associated with pseudohyperparathyroidism. Plast Reconstr Surg. 1989;84(5):806–10.PubMedGoogle Scholar
  123. 123.
    Eller-Vainicher C, Ossola MW, Beck-Peccoz P, Chiodini I. PTHrP-associated hypercalcemia of pregnancy resolved after delivery: a case report. Eur J Endocrinol. 2012;166(4):753–6.PubMedGoogle Scholar
  124. 124.
    Sweeney LL, Malabanan AO, Rosen H. Decreased calcitriol requirement during pregnancy and lactation with a window of increased requirement immediately post partum. Endocr Pract. 2010;16(3):459–62.PubMedGoogle Scholar
  125. 125.
    Farrugia W, Ho PW, Rice GE, Moseley JM, Permezel M, Wlodek ME. Parathyroid hormone-related protein(1–34) in gestational fluids and release from human gestational tissues. J Endocrinol. 2000;165(3):657–62.PubMedGoogle Scholar
  126. 126.
    Curtis NE, Ho PW, King RG, Farrugia W, Moses EK, Gillespie MT, Moseley JM, Rice GE, Wlodek ME. The expression of parathyroid hormone-related protein mRNA and immunoreactive protein in human amnion and choriodecidua is increased at term compared with preterm gestation. J Endocrinol. 1997;154(1):103–12.PubMedGoogle Scholar
  127. 127.
    Callies F, Arlt W, Scholz HJ, Reincke M, Allolio B. Management of hypoparathyroidism during pregnancy–report of twelve cases. Eur J Endocrinol. 1998;139(3):284–9.PubMedGoogle Scholar
  128. 128.
    Grant DK. Papilloedema and fits in hypoparathyroidism. Q J Med. 1953;22:243–59.PubMedGoogle Scholar
  129. 129.
    Krysiak R, Kobielusz-Gembala I, Okopien B. Hypoparathyroidism in pregnancy. Gynecol Endocrinol. 2011;27(8):529–32.PubMedGoogle Scholar
  130. 130.
    Horwitz MJ, Tedesco MB, Sereika SM, Hollis BW, Garcia-Ocana A, Stewart AF. Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1–36). J Clin Endocrinol Metab. 2003;88(4):1603–9.PubMedGoogle Scholar
  131. 131.
    Horwitz MJ, Tedesco MB, Sereika SM, Syed MA, Garcia-Ocana A, Bisello A, Hollis BW, Rosen CJ, Wysolmerski JJ, Dann P, Gundberg C, Stewart AF. Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)2 vitamin D. J Bone Miner Res. 2005;20(10):1792–803.PubMedGoogle Scholar
  132. 132.
    Sato K. Hypercalcemia during pregnancy, puerperium, and lactation: review and a case report of hypercalcemic crisis after delivery due to excessive production of PTH-related protein (PTHrP) without malignancy (humoral hypercalcemia of pregnancy). Endocr J. 2008;55(6):959–66.PubMedGoogle Scholar
  133. 133.
    Marx SJ, Zusman RM, Umiker WO. Benign breast dysplasia causing hypercalcemia. J Clin Endocrinol Metab. 1977;45(5):1049–52.PubMedGoogle Scholar
  134. 134.
    Cornish J, Callon KE, Nicholson GC, Reid IR. Parathyroid hormone-related protein-(107–139) inhibits bone resorption in vivo. Endocrinology. 1997;138:1299–304.PubMedGoogle Scholar
  135. 135.
    Fenton AJ, Kemp BE, Hammonds RG Jr, Mitchelhill K, Moseley JM, Martin TJ, Nicholson GC. A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein; PTHrP[107–111]. Endocrinology. 1991;129:3424–6.PubMedGoogle Scholar
  136. 136.
    Fenton AJ, Kemp BE, Kent GN, Moseley JM, Zheng MH, Rowe DJ, Britto JM, Martin TJ, Nicholson GC. A carboxyl-terminal peptide from the parathyroid hormone-related protein inhibits bone resorption by osteoclasts. Endocrinology. 1991;129:1762–8.PubMedGoogle Scholar
  137. 137.
    Mitchell JA, Ting TC, Wong S, Mitchell BF, Lye SJ. Parathyroid hormone-related protein treatment of pregnant rats delays the increase in connexin 43 and oxytocin receptor expression in the myometrium. Biol Reprod. 2003;69(2):556–62.PubMedGoogle Scholar
  138. 138.
    Bucht E, Telenius-Berg M, Lundell G, Sjoberg HE. Immunoextracted calcitonin in milk and plasma from totally thyroidectomized women. Evidence of monomeric calcitonin in plasma during pregnancy and lactation. Acta Endocrinol (Copenh). 1986;113:529–35.Google Scholar
  139. 139.
    Balabanova S, Kruse B, Wolf AS. Calcitonin secretion by human placental tissue. Acta Obstet Gynecol Scand. 1987;66(4):323–6.PubMedGoogle Scholar
  140. 140.
    Ren Y, Chien J, Sun YP, Shah GV. Calcitonin is expressed in gonadotropes of the anterior pituitary gland: its possible role in paracrine regulation of lactotrope function. J Endocrinol. 2001;171(2):217–28.PubMedGoogle Scholar
  141. 141.
    Hurley DL, Tiegs RD, Wahner HW, Heath H. Axial and appendicular bone mineral density in patients with long-term deficiency or excess of calcitonin. N Engl J Med. 1987;317(9):537–41.PubMedGoogle Scholar
  142. 142.
    Gonzalez DC, Mautalen CA, Correa PH, el Tamer E, el Tamer S. Bone mass in totally thyroidectomized patients. Role of calcitonin deficiency and exogenous thyroid treatment. Acta Endocrinol (Copenh). 1991;124(5):521–5.Google Scholar
  143. 143.
    Giannini S, Nobile M, Sartori L, Binotto P, Ciuffreda M, Gemo G, Pelizzo MR, D’Angelo A, Crepaldi G. Bone density and mineral metabolism in thyroidectomized patients treated with long-term L-thyroxine. Clin Sci (Lond). 1994;87(5):593–7.Google Scholar
  144. 144.
    Nguyen TT, Heath H III, Bryant SC, O’Fallon WM, Melton LJ 3rd. Fractures after thyroidectomy in men: a population-based cohort study. J Bone Miner Res. 1997;12(7):1092–9.PubMedGoogle Scholar
  145. 145.
    Mirzaei S, Krotla G, Knoll P, Koriska K, Kohn H. Possible effect of calcitonin deficiency on bone mass after subtotal thyroidectomy. Acta Med Austriaca. 1999;26(1):29–31.PubMedGoogle Scholar
  146. 146.
    Cross NA, Hillman LS, Allen SH, Krause GF. Changes in bone mineral density and markers of bone remodeling during lactation and postweaning in women consuming high amounts of calcium. J Bone Miner Res. 1995;10:1312–20.PubMedGoogle Scholar
  147. 147.
    Kalkwarf HJ, Specker BL, Bianchi DC, Ranz J, Ho M. The effect of calcium supplementation on bone density during lactation and after weaning. N Engl J Med. 1997;337(8):523–8.PubMedGoogle Scholar
  148. 148.
    Polatti F, Capuzzo E, Viazzo F, Colleoni R, Klersy C. Bone mineral changes during and after lactation. Obstet Gynecol. 1999;94(1):52–6.PubMedGoogle Scholar
  149. 149.
    Kolthoff N, Eiken P, Kristensen B, Nielsen SP. Bone mineral changes during pregnancy and lactation: a longitudinal cohort study. Clin Sci (Colch). 1998;94(4):405–12.Google Scholar
  150. 150.
    Wagner CL, Hulsey TC, Fanning D, Ebeling M, Hollis BW. High-dose vitamin D3 supplementation in a cohort of breastfeeding mothers and their infants: a 6-month follow-up pilot study. Breastfeed Med. 2006;1(2):59–70.PubMedGoogle Scholar
  151. 151.
    Hollis BW, Wagner CL. Vitamin D requirements during lactation: high-dose maternal supplementation as therapy to prevent hypovitaminosis D for both the mother and the nursing infant. Am J Clin Nutr. 2004;80(6 Suppl):1752S–8S.PubMedGoogle Scholar
  152. 152.
    Basile LA, Taylor SN, Wagner CL, Horst RL, Hollis BW. The effect of high-dose vitamin D supplementation on serum vitamin D levels and milk calcium concentration in lactating women and their infants. Breastfeed Med. 2006;1(1):27–35.PubMedGoogle Scholar
  153. 153.
    Laskey MA, Prentice A. Effect of pregnancy on recovery of lactational bone loss [letter]. Lancet. 1997;349:1518–9.PubMedGoogle Scholar
  154. 154.
    Prentice A. Calcium in pregnancy and lactation. Annu Rev Nutr. 2000;20:249–72.PubMedGoogle Scholar
  155. 155.
    Prentice A, Jarjou LM, Cole TJ, Stirling DM, Dibba B, Fairweather-Tait S. Calcium requirements of lactating Gambian mothers: effects of a calcium supplement on breast-milk calcium concentration, maternal bone mineral content, and urinary calcium excretion. Am J Clin Nutr. 1995;62:58–67.PubMedGoogle Scholar
  156. 156.
    Prentice A, Jarjou LM, Stirling DM, Buffenstein R, Fairweather-Tait S. Biochemical markers of calcium and bone metabolism during 18 months of lactation in Gambian women accustomed to a low calcium intake and in those consuming a calcium supplement. J Clin Endocrinol Metab. 1998;83(4):1059–66.PubMedGoogle Scholar
  157. 157.
    Prentice A, Yan L, Jarjou LM, Dibba B, Laskey MA, Stirling DM, Fairweather-Tait S. Vitamin D status does not influence the breast-milk calcium concentration of lactating mothers accustomed to a low calcium intake. Acta Paediatr. 1997;86(9):1006–8.PubMedGoogle Scholar
  158. 158.
    Laskey MA, Prentice A, Hanratty LA, Jarjou LM, Dibba B, Beavan SR, Cole TJ. Bone changes after 3 mo of lactation: influence of calcium intake, breast-milk output, and vitamin D-receptor genotype. Am J Clin Nutr. 1998;67(4):685–92.PubMedGoogle Scholar
  159. 159.
    Giske LE, Hall G, Rud T, Landgren BM. The effect of 17beta-estradiol at doses of 0.5, 1 and 2 mg compared with placebo on early postmenopausal bone loss in hysterectomized women. Osteoporos Int. 2002;13(4):309–16.PubMedGoogle Scholar
  160. 160.
    Reid IR. Menopause. In: Favus MJ, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism. 5th ed. Washington, DC: ASBMR Press; 2003. p. 86–9.Google Scholar
  161. 161.
    Gallagher JC. Effect of estrogen on bone. In: Favus MJ, editor. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. Washington, DC: ASBMR Press; 2003. p. 327–30.Google Scholar
  162. 162.
    Ardeshirpour L, Dann P, Adams DJ, Nelson T, VanHouten J, Horowitz MC, Wysolmerski JJ. Weaning triggers a decrease in receptor activator of nuclear factor-kappaB ligand expression, widespread osteoclast apoptosis, and rapid recovery of bone mass after lactation in mice. Endocrinology. 2007;148(8):3875–86.PubMedGoogle Scholar
  163. 163.
    Miller SC, Bowman BM. Rapid inactivation and apoptosis of osteoclasts in the maternal skeleton during the bone remodeling reversal at the end of lactation. Anat Rec (Hoboken). 2007;290(1):65–73.Google Scholar
  164. 164.
    Collins JN, Kirby BJ, Woodrow JP, Gagel RF, Rosen CJ, Sims NA, Kovacs CS. Lactating Ctcgrp nulls lose twice the normal bone mineral content due to fewer osteoblasts and more osteoclasts, whereas bone mass is fully restored after weaning in association with up-regulation of Wnt signaling and other novel genes. Endocrinology. 2013;154(4):1400–13.PubMedCentralPubMedGoogle Scholar
  165. 165.
    Teti A, Zallone A. Do osteocytes contribute to bone mineral homeostasis? Osteocytic osteolysis revisited. Bone. 2009;44(1):11–6.PubMedGoogle Scholar
  166. 166.
    Qing H, Ardeshirpour L, Pajevic PD, Dusevich V, Jahn K, Kato S, Wysolmerski J, Bonewald LF. Demonstration of osteocytic perilacunar/canalicular remodeling in mice during lactation. J Bone Miner Res. 2012;27(5):1018–29.PubMedCentralPubMedGoogle Scholar
  167. 167.
    Liu XS, Ardeshirpour L, VanHouten JN, Shane E, Wysolmerski JJ. Site-specific changes in bone microarchitecture, mineralization, and stiffness during lactation and after weaning in mice. J Bone Miner Res. 2012;27(4):865–75.PubMedGoogle Scholar
  168. 168.
    Bjørnerem A, Ghasem-Zadeh A, Vu T, Seeman E. Bone microstructure during and after lactation [abstract]. J Bone Miner Res. 2010;25(Suppl 1). http://www.asbmr.org/Meetings/AnnualMeeting/AbstractDetail.aspx?aid=c00378e6-4402-4617-bebb-0ef5da447d4f.
  169. 169.
    Wiklund PK, Xu L, Wang Q, Mikkola T, Lyytikainen A, Volgyi E, Munukka E, Cheng SM, Alen M, Keinanen-Kiukaanniemi S, Cheng S. Lactation is associated with greater maternal bone size and bone strength later in life. Osteoporos Int. 2012;23(7):1939–45.PubMedGoogle Scholar
  170. 170.
    Bowman BM, Miller SC. Skeletal adaptations during mammalian reproduction. J Musculoskelet Neuronal Interact. 2001;1(4):347–55.PubMedGoogle Scholar
  171. 171.
    Vajda EG, Bowman BM, Miller SC. Cancellous and cortical bone mechanical properties and tissue dynamics during pregnancy, lactation, and postlactation in the rat. Biol Reprod. 2001;65(3):689–95.PubMedGoogle Scholar
  172. 172.
    Sowers M, Randolph J, Shapiro B, Jannausch M. A prospective study of bone density and pregnancy after an extended period of lactation with bone loss. Obstet Gynecol. 1995;85:285–9.PubMedGoogle Scholar
  173. 173.
    Henderson PH III, Sowers M, Kutzko KE, Jannausch ML. Bone mineral density in grand multiparous women with extended lactation. Am J Obstet Gynecol. 2000;182(6):1371–7.PubMedGoogle Scholar
  174. 174.
    Sowers M, Corton G, Shapiro B, Jannausch ML, Crutchfield M, Smith ML, Randolph JF, Hollis B. Changes in bone density with lactation. J Am Med Assoc. 1993;269:3130–5.Google Scholar
  175. 175.
    Dobnig H, Kainer F, Stepan V, Winter R, Lipp R, Schaffer M, Kahr A, Nocnik S, Patterer G, Leb G. Elevated parathyroid hormone-related peptide levels after human gestation: relationship to changes in bone and mineral metabolism. J Clin Endocrinol Metab. 1995;80:3699–707.PubMedGoogle Scholar
  176. 176.
    Yamamoto M, Duong LT, Fisher JE, Thiede MA, Caulfield MP, Rosenblatt M. Suckling-mediated increases in urinary phosphate and 3′,5′-cyclic adenosine monophosphate excretion in lactating rats: possible systemic effects of parathyroid hormone-related protein. Endocrinology. 1991;129:2614–22.PubMedGoogle Scholar
  177. 177.
    van Heerden JA, Gharib H, Jackson IT. Pseudohyperparathyroidism secondary to gigantic mammary hypertrophy. Arch Surg. 1988;123:80–2.PubMedGoogle Scholar
  178. 178.
    Ratcliffe WA, Thompson GE, Care AD, Peaker M. Production of parathyroid hormone-related protein by the mammary gland of the goat. J Endocrinol. 1992;133:87–93.PubMedGoogle Scholar
  179. 179.
    VanHouten JN, Dann P, Stewart AF, Watson CJ, Pollak M, Karaplis AC, Wysolmerski JJ. Mammary-specific deletion of parathyroid hormone-related protein preserves bone mass during lactation. J Clin Invest. 2003;112(9):1429–36.PubMedCentralPubMedGoogle Scholar
  180. 180.
    Ardeshirpour L, Dann P, Pollak M, Wysolmerski J, VanHouten J. The calcium-sensing receptor regulates PTHrP production and calcium transport in the lactating mammary gland. Bone. 2006;38(6):787–93.PubMedGoogle Scholar
  181. 181.
    VanHouten J, Dann P, McGeoch G, Brown EM, Krapcho K, Neville M, Wysolmerski JJ. The calcium-sensing receptor regulates mammary gland parathyroid hormone-related protein production and calcium transport. J Clin Invest. 2004;113(4):598–608.PubMedCentralPubMedGoogle Scholar
  182. 182.
    Yamamoto M, Fisher JE, Thiede MA, Caulfield MP, Rosenblatt M, Duong LT. Concentrations of parathyroid hormone-related protein in rat milk change with duration of lactation and interval from previous suckling, but not with milk calcium. Endocrinology. 1992;130:741–7.PubMedGoogle Scholar
  183. 183.
    Mamillapalli R, VanHouten J, Dann P, Bikle D, Chang W, Brown E, Wysolmerski J. Mammary-specific ablation of the calcium-sensing receptor during lactation alters maternal calcium metabolism, milk calcium transport, and neonatal calcium accrual. Endocrinology. 2013;154(9):3031–42.PubMedGoogle Scholar
  184. 184.
    Thompson GE, Ratcliffe WA, Hughes S, Abbas SK, Care AD. Local control of parathyroid hormone-related protein secretion by the mammary gland of the goat. Comp Biochem Physiol A. 1994;108:485–90.Google Scholar
  185. 185.
    Kovacs CS, Chik CL. Hyperprolactinemia caused by lactation and pituitary adenomas is associated with altered serum calcium, phosphate, parathyroid hormone (PTH), and PTH-related peptide levels. J Clin Endocrinol Metab. 1995;80:3036–42.PubMedGoogle Scholar
  186. 186.
    Stiegler C, Leb G, Kleinert R, Warnkross H, Ramschak-Schwarzer S, Lipp R, Clarici G, Krejs GJ, Dobnig H. Plasma levels of parathyroid hormone-related peptide are elevated in hyperprolactinemia and correlated to bone density status. J Bone Miner Res. 1995;10:751–9.PubMedGoogle Scholar
  187. 187.
    Thiede MA. Parathyroid hormone-related protein: a regulated calcium-mobilizing product of the mammary gland. J Dairy Sci. 1994;77:1952–63.PubMedGoogle Scholar
  188. 188.
    Dvir R, Golander A, Jaccard N, Yedwab G, Otremski I, Spirer Z, Weisman Y. Amniotic fluid and plasma levels of parathyroid hormone-related protein and hormonal modulation of its secretion by amniotic fluid cells. Eur J Endocrinol. 1995;133:277–82.PubMedGoogle Scholar
  189. 189.
    Thiede MA. The mRNA encoding a parathyroid hormone-like peptide is produced in mammary tissue in response to elevations in serum prolactin. Mol Endocrinol. 1989;3:1443–7.PubMedGoogle Scholar
  190. 190.
    Seki K, Kato T, Sekiya S, Makimura N, Kudoh K, Furuya K, Nagata I. Parathyroid-hormone-related protein in human milk and its relation to milk calcium. Gynecol Obstet Invest. 1997;44(2):102–6.PubMedGoogle Scholar
  191. 191.
    Uemura H, Yasui T, Yoneda N, Irahara M, Aono T. Measurement of N- and C-terminal-region fragments of parathyroid hormone-related peptide in milk from lactating women and investigation of the relationship of their concentrations to calcium in milk. J Endocrinol. 1997;153:445–51.PubMedGoogle Scholar
  192. 192.
    Kocabagli N, Riond JL, Spichiger UE, Wanner M. Parathyroid hormone-related protein and calcium homeostasis during the periparturient period of dairy cows. Am J Vet Res. 1995;56:380–5.PubMedGoogle Scholar
  193. 193.
    Lean IJ, DeGaris PJ, McNeil DM, Block E. Hypocalcemia in dairy cows: meta-analysis and dietary cation anion difference theory revisited. J Dairy Sci. 2006;89(2):669–84.PubMedGoogle Scholar
  194. 194.
    Horst RL, Goff JP, Reinhardt TA. Adapting to the transition between gestation and lactation: differences between rat, human and dairy cow. J Mammary Gland Biol Neoplasia. 2005;10(2):141–56.PubMedGoogle Scholar
  195. 195.
    Sowers MF, Hollis BW, Shapiro B, Randolph J, Janney CA, Zhang D, Schork A, Crutchfield M, Stanczyk F, Russell-Aulet M. Elevated parathyroid hormone-related peptide associated with lactation and bone density loss. J Am Med Assoc. 1996;276:549–54.Google Scholar
  196. 196.
    VanHouten JN, Wysolmerski JJ. Low estrogen and high parathyroid hormone-related peptide levels contribute to accelerated bone resorption and bone loss in lactating mice. Endocrinology. 2003;144(12):5521–9.PubMedGoogle Scholar
  197. 197.
    Duque G, Huang DC, Dion N, Macoritto M, Rivas D, Li W, Yang XF, Li J, Lian J, Marino FT, Barralet J, Lascau V, Deschenes C, Ste-Marie LG, Kremer R. Interferon-gamma plays a role in bone formation in vivo and rescues osteoporosis in ovariectomized mice. J Bone Miner Res. 2011;26(7):1472–83.PubMedGoogle Scholar
  198. 198.
    Alles N, Soysa NS, Hayashi J, Khan M, Shimoda A, Shimokawa H, Ritzeler O, Akiyoshi K, Aoki K, Ohya K. Suppression of NF-kappaB increases bone formation and ameliorates osteopenia in ovariectomized mice. Endocrinology. 2010;151(10):4626–34.PubMedGoogle Scholar
  199. 199.
    Salle BL, Berthezene F, Glorieux FH, Delvin EE, Berland M, David L, Varenne JP, Putet G. Hypoparathyroidism during pregnancy: treatment with calcitriol. J Clin Endocrinol Metab. 1981;52:810–3.PubMedGoogle Scholar
  200. 200.
    Sadeghi-Nejad A, Wolfsdorf JI, Senior B. Hypoparathyroidism and pregnancy. Treatment with calcitriol. J Am Med Assoc. 1980;243:254–5.Google Scholar
  201. 201.
    Cathebras P, Cartry O, Sassolas G. Rousset H [Hypercalcemia induced by lactation in 2 patients with treated hypoparathyroidism]. Rev Med Interne. 1996;17:675–6.PubMedGoogle Scholar
  202. 202.
    Shomali ME, Ross DS. Hypercalcemia in a woman with hypoparathyroidism associated with increased parathyroid hormone-related protein during lactation. Endocr Pract. 1999;5(4):198–200.PubMedGoogle Scholar
  203. 203.
    Caplan RH, Beguin EA. Hypercalcemia in a calcitriol-treated hypoparathyroid woman during lactation. Obstet Gynecol. 1990;76:485–9.PubMedGoogle Scholar
  204. 204.
    Mather KJ, Chik CL, Corenblum B. Maintenance of serum calcium by parathyroid hormone-related peptide during lactation in a hypoparathyroid patient. J Clin Endocrinol Metab. 1999;84(2):424–7.PubMedGoogle Scholar
  205. 205.
    Anai T, Tomiyasu T, Takai N, Miyakawa I. Remission of idiopathic hypoparathyroidism during lactation: a case report. J Obstet Gynaecol Res. 1999;25(4):271–3.PubMedGoogle Scholar
  206. 206.
    Segal E, Hochberg I, Weisman Y, Ish-Shalom S. Severe postpartum osteoporosis with increased PTHrP during lactation in a patient after total thyroidectomy and parathyroidectomy. Osteoporos Int. 2011;22:2907–11.Google Scholar
  207. 207.
    Giles MM, Fenton MH, Shaw B, Elton RA, Clarke M, Lang M, Hume R. Sequential calcium and phosphorus balance studies in preterm infants. J Pediatr. 1987;110:591–8.PubMedGoogle Scholar
  208. 208.
    Barltrop D, Oppe TE. Calcium and fat absorption by low birthweight infants from a calcium-supplemented milk formula. Arch Dis Child. 1973;48:580–2.PubMedCentralPubMedGoogle Scholar
  209. 209.
    Kobayashi A, Kawai S, Obe Y, Nagashima Y. Effects of dietary lactose and lactase preparation on the intestinal absorption of calcium and magnesium in normal infants. Am J Clin Nutr. 1975;28:681–3.PubMedGoogle Scholar
  210. 210.
    Kocian J, Skala I, Bakos K. Calcium absorption from milk and lactose-free milk in healthy subjects and patients with lactose intolerance. Digestion. 1973;9:317–24.PubMedGoogle Scholar
  211. 211.
    Shaw JC. Evidence for defective skeletal mineralization in low-birthweight infants: the absorption of calcium and fat. Pediatrics. 1976;57:16–25.PubMedGoogle Scholar
  212. 212.
    Senterre J, Salle B. Calcium and phosphorus economy of the preterm infant and its interaction with vitamin D and its metabolites. Acta Paediatr Scand Suppl. 1982;296:85–92.PubMedGoogle Scholar
  213. 213.
    Buchowski MS, Miller DD. Lactose, calcium source and age affect calcium bioavailability in rats. J Nutr. 1991;121:1746–54.PubMedGoogle Scholar
  214. 214.
    Cross NA, Hillman LS, Forte LR. The effects of calcium supplementation, duration of lactation, and time of day on concentrations of parathyroid hormone-related protein in human milk: a pilot study. J Hum Lact. 1998;14(2):111–7.PubMedGoogle Scholar
  215. 215.
    Tov AB, Mandel D, Weissman Y, Dollberg S, Taxir T, Lubetzky R. Changes in serum parathyroid hormone-related protein in breastfed preterm infants. Breastfeed Med. 2012;7(1):50–3.PubMedGoogle Scholar
  216. 216.
    Rong H, Hydbring E, Olsson K, Burtis WJ, Rankin W, Grill V, Bucht E. Parathyroid hormone-related protein in neonatal and reproductive goats determined by a sensitive time-resolved immunofluorometric assay. Eur J Endocrinol. 1997;136:546–51.PubMedGoogle Scholar
  217. 217.
    Kukreja SC, D’Anza JJ, Melton ME, Wimbiscus SA, Grill V, Martin TJ. Lack of effects of neutralization of parathyroid hormone-related protein on calcium homeostasis in neonatal mice. J Bone Miner Res. 1991;6:1197–201.PubMedGoogle Scholar
  218. 218.
    Davey RA, Turner AG, McManus JF, Chiu WS, Tjahyono F, Moore AJ, Atkins GJ, Anderson PH, Ma C, Glatt V, MacLean HE, Vincent C, Bouxsein M, Morris HA, Findlay DM, Zajac JD. Calcitonin receptor plays a physiological role to protect against hypercalcemia in mice. J Bone Miner Res. 2008;23(8):1182–93.PubMedCentralPubMedGoogle Scholar
  219. 219.
    Kovacs CS. Calcium and bone metabolism during pregnancy and lactation. J Mammary Gland Biol Neoplasia. 2005;10(2):105–18.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Faculty of Medicine, Endocrinology, Health Sciences CentreMemorial University of NewfoundlandSt. John’sCanada

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