Skip to main content
SpringerLink
Log in

Acid–Base Balance and Bone Health

  • Chapter
  • First Online:
Nutrition and Bone Health

Part of the book series: Nutrition and Health ((NH))

  • 3056 Accesses

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  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. Bushinsky DA. Acid-base imbalance and the skeleton. Eur J Nutrition. 2001;40:238–44.

    CAS  Google Scholar 

  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. Bushinsky DA, Frick KK. The effects of acid on bone. Curr Opin Nephrol Hypertens. 2000;9:369–79.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. 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. Bushinsky DA. The contribution of acidosis to renal osteodystrophy. Kidney Int. 1995;47:1816–32.

    CAS  PubMed  Google Scholar 

  9. Krieger NS, Frick KK, Bushinsky DA. Mechanism of acid-induced bone resorption. Curr Opin Nephrol Hypertens. 2004;13:423–36.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Swan RC, Pitts RF. Neutralization of infused acid by nephrectomized dogs. J Clin Invest. 1955;34:205–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. Bushinsky DA. Acidosis and bone. Miner Electrol Metab. 1994;20:40–52.

    CAS  Google Scholar 

  20. Bushinsky DA, Ori Y. Effects of metabolic and respiratory acidosis on bone. Curr Opin Nephrol Hypertens. 1993;2(4):588–96.

    CAS  PubMed  Google Scholar 

  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. Bushinsky DA. Net proton influx into bone during metabolic, but not respiratory, acidosis. Am J Physiol. 1988;254:F306–10.

    CAS  PubMed  Google Scholar 

  23. Bushinsky DA, Lechleider RJ. Mechanism of proton-induced bone calcium release: calcium carbonate-dissolution. Am J Physiol. 1987;253:F998–1005.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  27. Bergstrom WH, Ruva FD. Changes in bone sodium during acute acidosis in the rat. Am J Physiol. 1960;198:1126–8.

    CAS  PubMed  Google Scholar 

  28. Bettice JA, Gamble Jr JL. Skeletal buffering of acute metabolic acidosis. Am J Physiol. 1975;229:1618–24.

    CAS  PubMed  Google Scholar 

  29. Burnell JM. Changes in bone sodium and carbonate in metabolic acidosis and alkalosis in the dog. J Clin Invest. 1971;50:327–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  33. Bettice JA. Skeletal carbon dioxide stores during metabolic acidosis. Am J Physiol. 1984;247:F326–30.

    CAS  PubMed  Google Scholar 

  34. Kraut JA, Mishler DR, Kurokawa K. Effect of colchicine and calcitonin on calcemic response to metabolic acidosis. Kidney Int. 1984;25:608–12.

    CAS  PubMed  Google Scholar 

  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. Widdowson EM, McCance RA, Spray CM. The chemical composition of the human body. Clin Sci. 1951;10:113–25.

    CAS  PubMed  Google Scholar 

  37. Coe FL, Bushinsky DA. Pathophysiology of hypercalciuria. Am J Physiol. 1984;247:F1–13.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  39. Lemann Jr J, Adams ND, Gray RW. Urinary calcium excretion in human beings. N Engl J Med. 1979;301:535–41.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  43. Green J, Kleeman CR. Role of bone in regulation of systemic acid-base balance. Kidney Int. 1991;39:9–26.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. McSherry E. Acidosis and growth in nonuremic renal disease. Kidney Int. 1978;14:349–54.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  50. Fletcher RF, Jones JH, Morgan DB. Bone disease in chronic renal failure. Q J Med. 1963;32:321–39.

    CAS  PubMed  Google Scholar 

  51. Bishop MC, Ledingham JG. Alkali treatment of renal osteodystrophy. Br Med J. 1972;4:529.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Pellegrino ED, Blitz RM. The composition of human bone in uremia. Medicine. 1965;44:397–418.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Barzel US. Osteoporosis II: an overview. In: Barzel US, editor. Osteoporosis II, vol 1. New York: Grune and Stratton; 1976.

    Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  67. Neuman WF, Neuman MW. The chemical dynamics of bone mineral. Chicago: University Chicago Press; 1958.

    Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  70. Bushinsky DA. Net calcium efflux from live bone during chronic metabolic, but not respiratory, acidosis. Am J Physiol. 1989;256:F836–42.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  72. Krieger NS, Sessler NE, Bushinsky DA. Acidosis inhibits osteoblastic and stimulates osteoclastic activity in vitro. Am J Physiol. 1992;262:F442–8.

    CAS  PubMed  Google Scholar 

  73. Bushinsky DA, Sessler NE. Critical role of bicarbonate in calcium release from bone. Am J Physiol. 1992;263:F510–5.

    CAS  PubMed  Google Scholar 

  74. Bushinsky DA. Stimulated osteoclastic and suppressed osteoblastic activity in metabolic but not respiratory acidosis. Am J Physiol. 1995;268:C80–8.

    CAS  PubMed  Google Scholar 

  75. Krieger NS, Parker WR, Alexander KM, Bushinsky DA. Prostaglandins regulate acid-induced cell-mediated bone resorption. Am J Physiol. 2000;279:F1077–82.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  77. Krieger NS, Frick KK, Bushinsky DA. Cortisol inhibits acid-induced bone resorption in vitro. J Am Soc Nephrol. 2002;13:2534–9.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  79. Feldman RS, Krieger NS, Tashjian JAH. Effects of parathyroid hormone and calcitonin on osteoclast formation in vitro. Endocrinology. 1980;107:1137–43.

    CAS  PubMed  Google Scholar 

  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. 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.

    CAS  PubMed  Google Scholar 

  82. Ellies LG, Nelson DGA, Featherstone JDB. Crystallographic structure and surface morphology of sintered carbonated apatites. J Biomed Mater Res. 1988;22:541–53.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  85. Nelson DGA, Featherstone JDB. Preparation, analysis and characterization of carbonated apatites. Calcif Tissue Intl. 1982;34:S69–81.

    Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  95. Bushinsky DA. Metabolic alkalosis decreases bone calcium efflux by suppressing osteoclasts and stimulating osteoblasts. Am J Physiol. 1996;271:F216–22.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  101. Sprague SM, Krieger NS, Bushinsky DA. Aluminum inhibits bone nodule formation and calcification in vitro. Am J Physiol. 1993;264:F882–90.

    CAS  PubMed  Google Scholar 

  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. 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. Bushinsky DA, Nilsson EL. Additive effects of acidosis and parathyroid hormone on mouse osteoblastic and osteoclastic function. Am J Physiol. 1995;269:C1364–70.

    CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  107. Frick KK, Bushinsky DA. Chronic metabolic acidosis reversibly inhibits extracellular matrix gene expression in mouse osteoblasts. Am J Physiol. 1998;275:F840–7.

    CAS  PubMed  Google Scholar 

  108. Davies JE. In vitro modeling of the bone/implant interface. Anat Rec. 1996;245:426–45.

    CAS  PubMed  Google Scholar 

  109. Rodan GA. Osteopontin overview. Ann N Y Acad Sci. 1995;760:1–5.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  112. Smith WL. Prostanoid biosynthesis and mechanisms of action. Am J Physiol. 1992;263:F181–91.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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. Krieger NS, Bushinsky DA. Pharmacologic inhibition of intracellular calcium release blocks acid-induced bone resorption. Am J Physiol Renal Physiol. 2011;300:F91–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. Martin A, David V, Quarles LD. Regulation and function of the FGF23/Klotho endocrine pathways. Physiol Rev. 2012;92(1):131–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Razzaque MS. The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol. 2009;5(11):611–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Gutierrez OM. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359:584–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  129. Quarles LD. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest. 2008;118:3820–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  141. Arnett TR, Dempster DW. Effect of pH on bone resorption by rat osteoclasts in vitro. Endocrinology. 1986;119:119–24.

    CAS  PubMed  Google Scholar 

  142. Goldhaber P, Rabadjija L. H+ stimulation of cell-mediated bone resorption in tissue culture. Am J Physiol. 1987;253:E90–8.

    CAS  PubMed  Google Scholar 

  143. Glimcher MJ. The nature of the mineral component of bone and the mechanism of calcification. Instr Course Lect. 1987;36:49–69.

    CAS  PubMed  Google Scholar 

  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 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Nephrology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 675, Rochester, NY, 14642, USA

    David A. Bushinsky M.D. & Nancy S. Krieger Ph.D.

Authors
  1. David A. Bushinsky M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nancy S. Krieger Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David A. Bushinsky M.D. .

Editor information

Editors and Affiliations

  1. Department of Medicine, Physiology, and Biophysics, Boston University Medical Center, Boston, Massachusetts, USA

    Michael F. Holick

  2. Helen Hayes Hospital and Department of Epidemiology, Mailman School of Public Health Institute of Human Nutrition, Columbia University, New York, New York, USA

    Jeri W. Nieves

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this chapter

Cite this chapter

Bushinsky, D.A., Krieger, N.S. (2015). Acid–Base Balance and Bone Health. In: Holick, M., Nieves, J. (eds) Nutrition and Bone Health. Nutrition and Health. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2001-3_22

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-2001-3_22

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-2000-6

  • Online ISBN: 978-1-4939-2001-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation