Acid–Base Balance and Bone Health

  • David A. BushinskyEmail author
  • Nancy S. Krieger
Part of the Nutrition and Health book series (NH)


On a typical Western diet, humans generate metabolic acids which must be excreted, through renal mechanisms, to maintain a stable physiologic systemic pH. Any impairment of kidney function will lead to a fall in systemic pH which is termed metabolic acidosis. During metabolic acidosis, the bone buffers acid (protons) and also releases calcium, a response that has been observed both in vivo and in vitro. Using an in vitro model system of cultured neonatal mouse calvariae we have studied the effect of metabolic acidosis on bone. Acutely there is direct proton-mediated physicochemical release of calcium from bone. There is also sodium and potassium release from the mineral surface in exchange for the hydrogen ions. With metabolic acidosis of longer duration (>24 h), release of bone calcium occurs by a cell-mediated stimulation of bone resorption and inhibition of bone formation. The cell-mediated response to metabolic acidosis involves changes in specific gene expression and is primarily due to a stimulation of endogenous osteoblastic prostaglandin E2 production, leading to production of RANKL and subsequent activation of osteoclastic bone resorption. The initial signaling event in the osteoblast appears to be activation of a specific proton receptor, OGR1. In addition to a net increase in bone resorption, metabolic acidosis has also recently been shown to stimulate production of osteoblastic FGF23. In contrast to metabolic acidosis, respiratory acidosis, due to an increase in the partial pressure of CO2, does not alter proton or calcium flux in bone. As renal function decreases with age, kidneys cannot excrete the daily acid load and this mild metabolic acidosis can lead to a significant decrease in bone mineralization potentially contributing to osteoporosis and fracture.


Metabolic acidosis Bone resorption Calcium Osteoblasts Bone formation Prostaglandins FGF23 



This work was supported in part by grants AR 46289, DK 57716, and DK 56788 from the National Institutes of Health.

The authors thank Kevin K. Frick, Ph.D. and Riccardo Levi-Setti, Ph.D. for years of fruitful collaboration.


  1. 1.
    Bushinsky DA. Acid-base imbalance and the skeleton. In: Burckhardt P, Dawson-Hughes B, Heaney RP, editors. Nutritional aspects of osteoporosis. Norwell, MA: Serono Symposia USA; 1998. p. 208–17.Google Scholar
  2. 2.
    Bushinsky DA. Acid-base imbalance and the skeleton. Eur J Nutrition. 2001;40:238–44.Google Scholar
  3. 3.
    Bushinsky DA. Acidosis and bone. In: Burckhardt P, Dawson-Hughes B, Weaver CM, editors. Nutritional influences on bone health, vol. 1. London: Springer-Verlag; 2010. p. 161–7.Google Scholar
  4. 4.
    Bushinsky DA, Frick KK. The effects of acid on bone. Curr Opin Nephrol Hypertens. 2000;9:369–79.PubMedGoogle Scholar
  5. 5.
    Kurtz I, Maher T, Hulter HN, Schambelan M, Sebastian A. Effect of diet on plasma acid-base composition in normal humans. Kidney Int. 1983;24:670–80.PubMedGoogle Scholar
  6. 6.
    Bushinsky DA. Metabolic acidosis. In: Jacobson HR, Striker GE, Klahr S, editors. The principles and practice of nephrology. St. Louis, MO: Mosby; 1995. p. 924–32.Google Scholar
  7. 7.
    Bushinsky DA. Internal exchanges of hydrogen ions: bone. In: Seldin DW, Giebisch G, editors. The regulation of acid-base balance. New York: Raven Press; 1989. p. 69–88.Google Scholar
  8. 8.
    Bushinsky DA. The contribution of acidosis to renal osteodystrophy. Kidney Int. 1995;47:1816–32.PubMedGoogle Scholar
  9. 9.
    Krieger NS, Frick KK, Bushinsky DA. Mechanism of acid-induced bone resorption. Curr Opin Nephrol Hypertens. 2004;13:423–36.PubMedGoogle Scholar
  10. 10.
    Barzel US. The skeleton as an ion exchange system: implications for the role of acid-base imbalance in the genesis of osteoporosis. J Bone Miner Res. 1995;10:1431–6.PubMedGoogle Scholar
  11. 11.
    Lemann Jr J, Bushinsky DA, Hamm LL. Bone buffering of acid and base in humans. Am J Physiol Renal Physiol. 2003;285:F811–32.PubMedGoogle Scholar
  12. 12.
    Lemann Jr J, Litzow JR, Lennon EJ. The effects of chronic acid loads in normal man: further evidence for the participation of bone mineral in the defense against chronic metabolic acidosis. J Clin Invest. 1966;45:1608–14.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Lemann Jr J, Litzow JR, Lennon EJ. Studies of the mechanism by which chronic metabolic acidosis augments urinary calcium excretion in man. J Clin Invest. 1967;46:1318–28.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Swan RC, Pitts RF. Neutralization of infused acid by nephrectomized dogs. J Clin Invest. 1955;34:205–12.PubMedCentralPubMedGoogle Scholar
  15. 15.
    Levitt MF, Turner LB, Sweet AY, Pandiri D. The response of bone, connective tissue, and muscle to acute acidosis. J Clin Invest. 1956;35:98–105.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Adler S, Roy A, Relman AS. Intracellular acid-base regulation. I. The response of muscle cells to changes in CO2 tension or extra-cellular bicarbonate concentration. J Clin Invest. 1965;44:8–20.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Poole-Wilson PA, Cameron IR. Intracellular pH and K+ of cardiac and skeletal muscle in acidosis and alkalosis. Am J Physiol. 1975;229:1305–10.PubMedGoogle Scholar
  18. 18.
    Bushinsky DA, Krieger NS. Regulation of bone formation and dissolution. In: Coe F, Favus M, Pak C, Parks J, Preminger G, editors. Kidney stones: medical and surgical management. New York: Raven Press; 1996. p. 239–58.Google Scholar
  19. 19.
    Bushinsky DA. Acidosis and bone. Miner Electrol Metab. 1994;20:40–52.Google Scholar
  20. 20.
    Bushinsky DA, Ori Y. Effects of metabolic and respiratory acidosis on bone. Curr Opin Nephrol Hypertens. 1993;2(4):588–96.PubMedGoogle Scholar
  21. 21.
    Bushinsky DA, Krieger NS. Role of the skeleton in calcium homeostasis. In: Seldin DW, Giebisch G, editors. The kidney: physiology and pathophysiology. New York: Raven Press; 1992. p. 2395–430.Google Scholar
  22. 22.
    Bushinsky DA. Net proton influx into bone during metabolic, but not respiratory, acidosis. Am J Physiol. 1988;254:F306–10.PubMedGoogle Scholar
  23. 23.
    Bushinsky DA, Lechleider RJ. Mechanism of proton-induced bone calcium release: calcium carbonate-dissolution. Am J Physiol. 1987;253:F998–1005.PubMedGoogle Scholar
  24. 24.
    Bushinsky DA, Krieger NS, Geisser DI, Grossman EB, Coe FL. Effects of pH on bone calcium and proton fluxes in vitro. Am J Physiol. 1983;245:F204–9.PubMedGoogle Scholar
  25. 25.
    Bushinsky DA, Levi-Setti R, Coe FL. Ion microprobe determination of bone surface elements: effects of reduced medium pH. Am J Physiol. 1986;250:F1090–7.PubMedGoogle Scholar
  26. 26.
    Bushinsky DA, Wolbach W, Sessler NE, Mogilevsky R, Levi-Setti R. Physicochemical effects of acidosis on bone calcium flux and surface ion composition. J Bone Miner Res. 1993;8(1):93–102.PubMedGoogle Scholar
  27. 27.
    Bergstrom WH, Ruva FD. Changes in bone sodium during acute acidosis in the rat. Am J Physiol. 1960;198:1126–8.PubMedGoogle Scholar
  28. 28.
    Bettice JA, Gamble Jr JL. Skeletal buffering of acute metabolic acidosis. Am J Physiol. 1975;229:1618–24.PubMedGoogle Scholar
  29. 29.
    Burnell JM. Changes in bone sodium and carbonate in metabolic acidosis and alkalosis in the dog. J Clin Invest. 1971;50:327–31.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Bushinsky DA, Gavrilov K, Stathopoulos VM, Krieger NS, Chabala JM, Levi-Setti R. Effects of osteoclastic resorption on bone surface ion composition. Am J Physiol. 1996;271:C1025–31.PubMedGoogle Scholar
  31. 31.
    Bushinsky DA, Gavrilov K, Chabala JM, Featherstone JDB, Levi-Setti R. Effect of metabolic acidosis on the potassium content of bone. J Bone Min Res. 1997;12:1664–71.Google Scholar
  32. 32.
    Bushinsky DA, Lam BC, Nespeca R, Sessler NE, Grynpas MD. Decreased bone carbonate content in response to metabolic, but not respiratory, acidosis. Am J Physiol. 1993;265:F530–6.PubMedGoogle Scholar
  33. 33.
    Bettice JA. Skeletal carbon dioxide stores during metabolic acidosis. Am J Physiol. 1984;247:F326–30.PubMedGoogle Scholar
  34. 34.
    Kraut JA, Mishler DR, Kurokawa K. Effect of colchicine and calcitonin on calcemic response to metabolic acidosis. Kidney Int. 1984;25:608–12.PubMedGoogle Scholar
  35. 35.
    Widdowson EM, Dickerson JWT. Chemical composition of the body. In: Comar CL, Bronner F, editors. Mineral metabolism. New York: Academic Press; 1964. p. 1–247.Google Scholar
  36. 36.
    Widdowson EM, McCance RA, Spray CM. The chemical composition of the human body. Clin Sci. 1951;10:113–25.PubMedGoogle Scholar
  37. 37.
    Coe FL, Bushinsky DA. Pathophysiology of hypercalciuria. Am J Physiol. 1984;247:F1–13.PubMedGoogle Scholar
  38. 38.
    Bushinsky DA, Riera GS, Favus MJ, Coe FL. Response of serum 1,25(OH)2D3 to variation of ionized calcium during chronic acidosis. Am J Physiol. 1985;249:F361–5.PubMedGoogle Scholar
  39. 39.
    Lemann Jr J, Adams ND, Gray RW. Urinary calcium excretion in human beings. N Engl J Med. 1979;301:535–41.PubMedGoogle Scholar
  40. 40.
    Adams ND, Gray RW, Lemann Jr J. The calciuria of increased fixed acid production in humans: evidence against a role for parathyroid hormone and 1,25(OH)2-vitamin D. Calcif Tissue Int. 1979;28:233–8.PubMedGoogle Scholar
  41. 41.
    Weber HP, Gray RW, Dominguez JH, Lemann Jr J. The lack of effect of chronic metabolic acidosis on 25-OH vitamin D metabolism and serum parathyroid hormone in humans. J Clin Endocrinol Metab. 1976;43:1047–55.PubMedGoogle Scholar
  42. 42.
    Bushinsky DA, Favus MJ, Schneider AB, Sen PK, Sherwood LM, Coe FL. Effects of metabolic acidosis on PTH and 1,25(OH)2D3 response to low calcium diet. Am J Physiol. 1982;243:F570–5.PubMedGoogle Scholar
  43. 43.
    Green J, Kleeman CR. Role of bone in regulation of systemic acid-base balance. Kidney Int. 1991;39:9–26.PubMedGoogle Scholar
  44. 44.
    McSherry E, Morris RC. Attainment and maintenance of normal stature with alkali therapy in infants and children with classic renal tubular acidosis. J Clin Invest. 1978;61:509–27.PubMedCentralPubMedGoogle Scholar
  45. 45.
    McSherry E. Acidosis and growth in nonuremic renal disease. Kidney Int. 1978;14:349–54.PubMedGoogle Scholar
  46. 46.
    Challa A, Krieg Jr RJ, Thabet MA, Veldhuis JD, Chan JC. Metabolic acidosis inhibits growth hormone secretion in rats: mechanism of growth retardation. Am J Physiol. 1993;265:E547–53.PubMedGoogle Scholar
  47. 47.
    Goodman AD, Lemann Jr J, Lennon EJ, Relman AS. Production, excretion, and net balance of fixed acid in patients with renal acidosis. J Clin Invest. 1965;44:495–506.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Litzow JR, Lemann Jr J, Lennon EJ. The effect of treatment of acidosis on calcium balance in patients with chronic azotemic renal disease. J Clin Invest. 1967;46:280–6.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Mora Palma FJ, Ellis HA, Cook DB, Dewar JH, Ward MK, Wilkinson R, Kerr DNS. Osteomalacia in patients with chronic renal failure before dialysis or transplantation. Q J Med. 1983;52:332–48.PubMedGoogle Scholar
  50. 50.
    Fletcher RF, Jones JH, Morgan DB. Bone disease in chronic renal failure. Q J Med. 1963;32:321–39.PubMedGoogle Scholar
  51. 51.
    Bishop MC, Ledingham JG. Alkali treatment of renal osteodystrophy. Br Med J. 1972;4:529.PubMedCentralPubMedGoogle Scholar
  52. 52.
    Cochran M, Wilkinson R. Effect of correction of metabolic acidosis on bone mineralization rates in patients with renal osteomalacia. Nephron. 1975;15:98–110.PubMedGoogle Scholar
  53. 53.
    Lefebvre A, de Vernejoul MC, Gueris J, Goldfarb B, Graulet AM, Morieux C. Optimal correction of acidosis changes progression of dialysis osteodystrophy. Kidney Int. 1989;36:1112–8.PubMedGoogle Scholar
  54. 54.
    Pellegrino ED, Blitz RM, Letteri JM. Inter-relationships of carbonate, phosphate, monohydrogen phosphate, calcium, magnesium, and sodium in uraemic bone: comparison of dialyzed and non-dialyzed patients. Clin Sci Mol Med. 1977;53:307–16.PubMedGoogle Scholar
  55. 55.
    Kaye M, Frueth AJ, Silverman M. A study of vertebral bone powder from patients with chronic renal failure. J Clin Invest. 1970;49:442–53.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Pellegrino ED, Blitz RM. The composition of human bone in uremia. Medicine. 1965;44:397–418.PubMedGoogle Scholar
  57. 57.
    Brenner RJ, Spring DB, Sebastian A, McSherry EM, Genant HK, Palubinskas AJ, Morris JRC. Incidence of radiographically evident bone disease, nephrocalcinosis, and nephrolithiasis in various types of renal tubular acidosis. N Engl J Med. 1982;307:217–21.PubMedGoogle Scholar
  58. 58.
    Domrongkitchaiporn S, Pongsakul C, Stitchantrakul W, Sirikulchayanonta V, Ongphiphadhanakul B, Radinahamed P, Karnsombut P, Kunkitti N, Ruang-raksa C, Rajatanavin R. Bone mineral density and histology in distal renal tubular acidosis. Kidney Int. 2001;59:1086–93.PubMedGoogle Scholar
  59. 59.
    Domrongkitchaiporn S, Pongskul C, Sirikulchayanonta V, Stitchantrakul W, Leeprasert V, Ongphiphadhanakul B, Radinahamed P, Rajatanavin R. Bone histology and bone mineral density after correction of acidosis in distal renal tubular acidosis. Kidney Int. 2002;62:2160–6.PubMedGoogle Scholar
  60. 60.
    Lennon EJ, Lemann Jr J, Litzow JR. The effects of diet and stool composition on the net external acid balance of normal subjects. J Clin Invest. 1966;45:1601–7.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Barzel US. Osteoporosis II: an overview. In: Barzel US, editor. Osteoporosis II, vol 1. New York: Grune and Stratton; 1976.Google Scholar
  62. 62.
    Frassetto LA, Morris Jr RC, Sebastian A. Effect of age on blood acid-base composition in adult humans: role of age-related renal functional decline. Am J Physiol. 1996;271:F1114–22.PubMedGoogle Scholar
  63. 63.
    Frassetto L, Sebastian A. Age and systemic acid-base equilibrium: analysis of published data. J Gerontol A Biol Sci Med Sci. 1996;51:B91–9.PubMedGoogle Scholar
  64. 64.
    Sakhaee K, Nicar M, Hill K, Pak CY. Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts. Kidney Int. 1983;24:348–52.PubMedGoogle Scholar
  65. 65.
    Lemann Jr J, Gray RW, Pleuss JA. Potassium bicarbonate, but not sodium bicarbonate, reduces urinary calcium excretion and improves calcium balance in healthy men. Kidney Int. 1989;35:688–95.PubMedGoogle Scholar
  66. 66.
    Sebastian A, Harris ST, Ottaway JH, Todd KM, Morris Jr RC. Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate. N Engl J Med. 1994;330:1776–81.PubMedGoogle Scholar
  67. 67.
    Neuman WF, Neuman MW. The chemical dynamics of bone mineral. Chicago: University Chicago Press; 1958.Google Scholar
  68. 68.
    Dominguez JH, Raisz LG. Effects of changing hydrogen ion, carbonic acid, and bicarbonate concentrations on bone resorption in vitro. Calcif Tissue Int. 1979;29:7–13.PubMedGoogle Scholar
  69. 69.
    Bushinsky DA, Goldring JM, Coe FL. Cellular contribution to pH-mediated calcium flux in neonatal mouse calvariae. Am J Physiol. 1985;248:F785–9.PubMedGoogle Scholar
  70. 70.
    Bushinsky DA. Net calcium efflux from live bone during chronic metabolic, but not respiratory, acidosis. Am J Physiol. 1989;256:F836–42.PubMedGoogle Scholar
  71. 71.
    Bushinsky DA, Sessler NE, Krieger NS. Greater unidirectional calcium efflux from bone during metabolic, compared with respiratory, acidosis. Am J Physiol. 1992;262:F425–31.PubMedGoogle Scholar
  72. 72.
    Krieger NS, Sessler NE, Bushinsky DA. Acidosis inhibits osteoblastic and stimulates osteoclastic activity in vitro. Am J Physiol. 1992;262:F442–8.PubMedGoogle Scholar
  73. 73.
    Bushinsky DA, Sessler NE. Critical role of bicarbonate in calcium release from bone. Am J Physiol. 1992;263:F510–5.PubMedGoogle Scholar
  74. 74.
    Bushinsky DA. Stimulated osteoclastic and suppressed osteoblastic activity in metabolic but not respiratory acidosis. Am J Physiol. 1995;268:C80–8.PubMedGoogle Scholar
  75. 75.
    Krieger NS, Parker WR, Alexander KM, Bushinsky DA. Prostaglandins regulate acid-induced cell-mediated bone resorption. Am J Physiol. 2000;279:F1077–82.Google Scholar
  76. 76.
    Bushinsky DA, Parker WR, Alexander KM, Krieger NS. Metabolic, but not respiratory, acidosis increases bone PGE2 levels and calcium release. Am J Physiol. 2001;281:F1058–66.Google Scholar
  77. 77.
    Krieger NS, Frick KK, Bushinsky DA. Cortisol inhibits acid-induced bone resorption in vitro. J Am Soc Nephrol. 2002;13:2534–9.PubMedGoogle Scholar
  78. 78.
    Schelling SH, Wolfe HJ, Tashjian JAH. Role of the osteoclast in prostaglandin E2 -stimulated bone resorption. A correlative morphometric and biochemical analysis. Lab Invest. 1980;42:290–5.PubMedGoogle Scholar
  79. 79.
    Feldman RS, Krieger NS, Tashjian JAH. Effects of parathyroid hormone and calcitonin on osteoclast formation in vitro. Endocrinology. 1980;107:1137–43.PubMedGoogle Scholar
  80. 80.
    Stern PH, Raisz LG. Organ culture of bone. In: Simmons DJ, Kunin AS, editors. Skeletal research. New York: Academic Press; 1979. p. 21–59.Google Scholar
  81. 81.
    Bushinsky DA, Sessler NE, Glena RE, Featherstone JDB. Proton-induced physicochemical calcium release from ceramic apatite disks. J Bone Miner Res. 1994;9:213–20.PubMedGoogle Scholar
  82. 82.
    Ellies LG, Nelson DGA, Featherstone JDB. Crystallographic structure and surface morphology of sintered carbonated apatites. J Biomed Mater Res. 1988;22:541–53.PubMedGoogle Scholar
  83. 83.
    Ellies LG, Carter JM, Natiella JR, Featherstone JDB, Nelson DGA. Quantitative analysis of early in vivo tissue response to synthetic apatite implants. J Biomed Mater Res. 1988;22:137–48.PubMedGoogle Scholar
  84. 84.
    Nelson DGA, Featherstone JDB, Duncan JF, Cutress TW. Effect of carbonate and fluoride on the dissolution behavior of synthetic apatites. Caries Res. 1983;17:200–11.PubMedGoogle Scholar
  85. 85.
    Nelson DGA, Featherstone JDB. Preparation, analysis and characterization of carbonated apatites. Calcif Tissue Intl. 1982;34:S69–81.Google Scholar
  86. 86.
    Nelson DGA, Barry JC, Shields CP, Glena R, Featherstone JDB. Crystal morphology, composition, and dissolution behavior of carbonated apatites prepared at controlled pH and temperature. J Colloid Interface Sci. 1989;130:467–79.Google Scholar
  87. 87.
    Boskey AL, Posner AS. Conversion of amorphous calcium phosphate to microcrystalline hydroxyapatite-pH-dependent, solution mediated, solid-solid conversion. J Phys Chem. 1973;77:2313–7.Google Scholar
  88. 88.
    Grynpas MD, Bonar LC, Glimcher MJ. Failure to detect an amorphous calcium-phosphate solid phase in bone mineral. A radial distribution function study. Calcif Tissue Int. 1984;36:291–301.PubMedGoogle Scholar
  89. 89.
    Chabala JM, Levi-Setti R, Bushinsky DA. Alteration in surface ion composition of cultured bone during metabolic, but not respiratory, acidosis. Am J Physiol. 1991;261:F76–84.PubMedGoogle Scholar
  90. 90.
    Bushinsky DA, Chabala JM, Levi-Setti R. Ion microprobe analysis of bone surface elements: effects of 1,25(OH)2D3. Am J Physiol. 1989;257:E815–22.PubMedGoogle Scholar
  91. 91.
    Bushinsky DA, Chabala JM, Levi-Setti R. Ion microprobe analysis of mouse calvariae in vitro: evidence for a "bone membrane". Am J Physiol. 1989;256:E152–8.PubMedGoogle Scholar
  92. 92.
    Bushinsky DA, Chabala JM, Levi-Setti R. Comparison of in vitro and in vivo 44 Ca labeling of bone by scanning ion microprobe. Am J Physiol. 1990;259:E586–92.PubMedGoogle Scholar
  93. 93.
    Pasquale SM, Messier AA, Shea ML, Schaefer KE. Bone CO2 -titration curves in acute hypercapnia obtained with a modified titration technique. J Appl Physiol. 1980;48:197–201.PubMedGoogle Scholar
  94. 94.
    Sprague SM, Krieger NS, Bushinsky DA. Greater inhibition of in vitro bone mineralization with metabolic than respiratory acidosis. Kidney Int. 1994;46:1199–206.PubMedGoogle Scholar
  95. 95.
    Bushinsky DA. Metabolic alkalosis decreases bone calcium efflux by suppressing osteoclasts and stimulating osteoblasts. Am J Physiol. 1996;271:F216–22.PubMedGoogle Scholar
  96. 96.
    Frick KK, Jiang L, Bushinsky DA. Acute metabolic acidosis inhibits the induction of osteoblastic egr-1 and type 1 collagen. Am J Physiol. 1997;272:C1450–6.PubMedGoogle Scholar
  97. 97.
    Kraut JA, Mishler DR, Singer FR, Goodman WG. The effects of metabolic acidosis on bone formation and bone resorption in the rat. Kidney Int. 1986;30:694–700.PubMedGoogle Scholar
  98. 98.
    Bhargava U, Bar-Lev M, Bellows CG, Aubin JE. Ultrastructural analysis of bone nodules formed in vitro by isolated fetal rat calvaria cells. Bone. 1988;9:155–63.PubMedGoogle Scholar
  99. 99.
    Ecarot-Charrier B, Glorieux FH, Van Der Rest M, Pereira G. Osteoblasts isolated from mouse calvaria initiate matrix mineralization in culture. J Cell Biol. 1983;96:639–43.PubMedGoogle Scholar
  100. 100.
    Sudo H, Kodama HA, Amagai Y, Yamamoto S, Kasai S. In vitro differentiation and calcification in a new clonal osteogenic cell line derived from newborn mouse calvaria. J Cell Biol. 1983;96:191–8.PubMedGoogle Scholar
  101. 101.
    Sprague SM, Krieger NS, Bushinsky DA. Aluminum inhibits bone nodule formation and calcification in vitro. Am J Physiol. 1993;264:F882–90.PubMedGoogle Scholar
  102. 102.
    Goodman WG, Coburn JW, Slatopolsky E, Salusky IB. Renal osteodystrophy in adults and children. In: Favus MJ, editor. Primer on the metabolic bone diseases and disorders of mineral metabolism, vol. 4. Philadelphia: Lippincott-Raven; 1999. p. 347–63.Google Scholar
  103. 103.
    Slatopolsky E, Delmez J. Bone disease in chronic renal failure and after renal transplantation. In: Coe F, Favus M, editors. Disorders of bone and mineral metabolism. New York, NY: Raven Press; 1992. p. 905–34.Google Scholar
  104. 104.
    Bushinsky DA, Nilsson EL. Additive effects of acidosis and parathyroid hormone on mouse osteoblastic and osteoclastic function. Am J Physiol. 1995;269:C1364–70.PubMedGoogle Scholar
  105. 105.
    Krieger NS, Hefley TJ. Differential effects of parathyroid hormone on protein phosphorylation in two osteoblast-like cell populations isolated from neonatal mouse calvaria. Calc Tiss Int. 1989;44:192–9.Google Scholar
  106. 106.
    Stein GS, Lian JB, Stein JL, van Wijnen AJ, Montecino M. Transcriptional control of osteoblast growth and differentiation (Review). Physiol Rev. 1996;76:593–629.PubMedGoogle Scholar
  107. 107.
    Frick KK, Bushinsky DA. Chronic metabolic acidosis reversibly inhibits extracellular matrix gene expression in mouse osteoblasts. Am J Physiol. 1998;275:F840–7.PubMedGoogle Scholar
  108. 108.
    Davies JE. In vitro modeling of the bone/implant interface. Anat Rec. 1996;245:426–45.PubMedGoogle Scholar
  109. 109.
    Rodan GA. Osteopontin overview. Ann N Y Acad Sci. 1995;760:1–5.PubMedGoogle Scholar
  110. 110.
    Hauschka PV, Lian JB, Cole DE, Gundberg CM. Osteocalcin and matrix gla protein: vitamin K-dependent proteins in bone. Physiol Rev. 1989;69:990–1047.PubMedGoogle Scholar
  111. 111.
    O'Neill GP, Kennedy BP, Mancini JA, Kargman S, Ouellet M, Yergey J, Falgueyret JP, Cromlish WA. Selective inhibitors of COX-2. Agents Actions Suppl. 1995;46:159–68.PubMedGoogle Scholar
  112. 112.
    Smith WL. Prostanoid biosynthesis and mechanisms of action. Am J Physiol. 1992;263:F181–91.PubMedGoogle Scholar
  113. 113.
    Krieger NS, Frick KK, LaPlante Strutz K, Michalenka A, Bushinsky DA. Regulation of COX-2 mediates acid-induced bone calcium efflux in vitro. J Bone Miner Res. 2007;22(6):907–17.PubMedGoogle Scholar
  114. 114.
    Frick KK, Bushinsky DA. Metabolic acidosis stimulates RANK ligand RNA expression in bone through a cyclooxygenase dependent mechanism. J Bone Miner Res. 2003;18:1317–25.PubMedGoogle Scholar
  115. 115.
    Frick KK, Krieger NS, Nehrke K, Bushinsky DA. Metabolic acidosis increases intracellular calcium in bone cells through activation of the proton receptor OGR1. J Bone Miner Res. 2009;24(2):305–13.PubMedCentralPubMedGoogle Scholar
  116. 116.
    Frick KK, Bushinsky DA. Effect of metabolic and respiratory acidosis on intracellular calcium in osteoblasts. Am J Physiol. 2010;299:418–25.Google Scholar
  117. 117.
    Krieger NS, Bushinsky DA. Pharmacologic inhibition of intracellular calcium release blocks acid-induced bone resorption. Am J Physiol Renal Physiol. 2011;300:F91–7.PubMedCentralPubMedGoogle Scholar
  118. 118.
    Seuwen K, Ludwig MG, Wolf RM. Receptors for protons or lipid messengers or both? J Recept Sig Transd. 2006;26(5–6):599–610.Google Scholar
  119. 119.
    Ludwig MG, Vanek M, Gueirine D, Gasser JA, Jones CE, Junker U, Hofstetter H, Wolf RM, Seuwen K. Proton-sensing G-protein-coupled receptors. Nature. 2003;425:93–8.PubMedGoogle Scholar
  120. 120.
    Iwai K, Koike M, Ohshima S, Miyatake K, Uchiyama Y, Saeki Y, Ishii M. RGS18 acts as a negative regulator of osteoclastogenesis by modulating the acid-sensing OGR1/NFAT signaling pathway. J Bone Miner Res. 2007;22(10):1612–20.PubMedGoogle Scholar
  121. 121.
    Pereverzev A, Komarova SV, Korcok J, Armstrong S, Tremblay GB, Dixon SJ, Sims SM. Extracellular acidification enhances osteoclast survival through an NFAT-independent, protein kinase C-dependent pathway. Bone. 2008;42(1):150–61.PubMedGoogle Scholar
  122. 122.
    Pande S, Ritter CS, Rothstein M, Wiesen K, Vassiliadis J, Kumar R, Schiavi SC, Slatopolsky E, Brown AJ. FGF-23 and sFRP-4 in chronic kidney disease and post-renal transplantation. Nephron Phys. 2006;104:23–32.Google Scholar
  123. 123.
    Martin A, David V, Quarles LD. Regulation and function of the FGF23/Klotho endocrine pathways. Physiol Rev. 2012;92(1):131–55.PubMedCentralPubMedGoogle Scholar
  124. 124.
    Razzaque MS. The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol. 2009;5(11):611–9.PubMedCentralPubMedGoogle Scholar
  125. 125.
    Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutierrez OM, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121:4393–408.PubMedCentralPubMedGoogle Scholar
  126. 126.
    Kendrick J, Cheung AK, Kaufman JS, Greene T, Roberts WL, Smits G, Chonchol M. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis. J Am Soc Nephrol. 2011;22(10):1913–22.PubMedCentralPubMedGoogle Scholar
  127. 127.
    Gutierrez OM. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359:584–92.PubMedCentralPubMedGoogle Scholar
  128. 128.
    Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, Quarles LD. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol. 2006;17(5):1305–15.PubMedGoogle Scholar
  129. 129.
    Quarles LD. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest. 2008;118:3820–8.PubMedCentralPubMedGoogle Scholar
  130. 130.
    Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh-Many T. PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol. 2010;299(4):F882–9.Google Scholar
  131. 131.
    Krieger NS, Culbertson CD, Kyker-Snowman K, Bushinsky DA. Metabolic acidosis increases fibroblast growth factor 23 in neonatal mouse bone. Am J Physiol. 2012;303:F431–6.Google Scholar
  132. 132.
    Bushinsky DA, Smith SB, Gavrilov KL, Gavrilov LF, Li J, Levi-Setti R. Acute acidosis-induced alteration in bone bicarbonate and phosphate. Am J Physiol Renal Physiol. 2002;283:F1091–7.PubMedGoogle Scholar
  133. 133.
    Bushinsky DA, Sprague SM, Hallegot P, Girod C, Chabala JM, Levi-Setti R. Effects of aluminum on bone surface ion composition. J Bone Min Res. 1995;10:1988–97.Google Scholar
  134. 134.
    Bushinsky DA, Chabala JM, Gavrilov KL, Levi-Setti R. Effects of in vivo metabolic acidosis on midcortical bone ion composition. Am J Physiol. 1999;277:F813–9.PubMedGoogle Scholar
  135. 135.
    Canzanello VJ, Bodvarsson M, Kraut JA, Johns CA, Slatopolsky E, Madias NE. Effect of chronic respiratory acidosis on urinary calcium excretion in the dog. Kidney Int. 1990;38:409–16.PubMedGoogle Scholar
  136. 136.
    Lau K, Rodriquez Nichols F, Tannen RL. Renal excretion of divalent ions in response to chronic acidosis: evidence that systemic pH is not the controlling variable. J Lab Clin Med. 1987;109:27–33.PubMedGoogle Scholar
  137. 137.
    Schaefer KE, Pasquale S, Messier AA, Shea M. Phasic changes in bone CO2 fractions, calcium, and phosphorus during chronic hypercapnia. J Appl Physiol. 1980;48:802–11.PubMedGoogle Scholar
  138. 138.
    Schaefer KE, Nichols Jr G, Carey CR. Calcium phosphorus metabolism in man during acclimatization to carbon dioxide. J Appl Physiol. 1963;18:1079–84.PubMedGoogle Scholar
  139. 139.
    Ori Y, Lee SG, Krieger NS, Bushinsky DA. Osteoblastic intracellular pH and calcium in metabolic and respiratory acidosis. Kidney Int. 1995;47:1790–6.PubMedGoogle Scholar
  140. 140.
    Arnett TR, Dempster DW. A comparative study of disaggregated chick and rat osteoclasts in vitro: effects of calcitonin and prostaglandins. Endocrinology. 1987;120:602–8.PubMedGoogle Scholar
  141. 141.
    Arnett TR, Dempster DW. Effect of pH on bone resorption by rat osteoclasts in vitro. Endocrinology. 1986;119:119–24.PubMedGoogle Scholar
  142. 142.
    Goldhaber P, Rabadjija L. H+ stimulation of cell-mediated bone resorption in tissue culture. Am J Physiol. 1987;253:E90–8.PubMedGoogle Scholar
  143. 143.
    Glimcher MJ. The nature of the mineral component of bone and the mechanism of calcification. Instr Course Lect. 1987;36:49–69.PubMedGoogle Scholar
  144. 144.
    Glimcher MJ. Composition, structure and organization of bone and other mineralized tissues, and the mechanism of calcification. In: Greep RO, Astwood EB, Aurbach GD, editors. Handbook of physiology, endocrinology. Washington: American Physiology Society; 1976. p. 25–116.Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Medicine, Division of NephrologyUniversity of Rochester School of Medicine and DentistryRochesterUSA

Personalised recommendations