Hostname: page-component-7d8f8d645b-2q4x6 Total loading time: 0 Render date: 2023-05-27T11:17:29.022Z Has data issue: false Feature Flags: { "useRatesEcommerce": true } hasContentIssue false

Regulation of bone cell function by acid–base balance

Published online by Cambridge University Press:  05 March 2007

Tim Arnett*
Department of Anatomy and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK
Corresponding author: Dr Timothy R. Arnett, fax +44 20 7679 7349,
Rights & Permissions[Opens in a new window]


HTML view is not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Bone growth and turnover results from the coordinated activities of two key cell types. Bone matrix is deposited and mineralised by osteoblasts and it is resorbed by osteoclasts, multinucleate cells that excavate pits on bone surfaces. It has been known since the early 20th century that systemic acidosis causes depletion of the skeleton, an effect assumed to result from physico-chemical dissolution of bone mineral. However, our own work has shown that resorption pit formation by cultured osteoclasts was absolutely dependent on extracellular acidification; these cells are inactive at pH levels above about 7·3 and show maximum stimulation at a pH of about 6·9. Bone resorption is most sensitive to changes in H+ concentration at a pH of about 7·1 (which may be close to the interstitial pH in bone). In this region pH shifts of <0·05 units can cause a doubling or halving of pit formation. In whole-bone cultures, chronic HCO3- acidosis results in similar stimulations of osteoclast-mediated Ca2+ release, with a negligible physico-chemical component. In vivo, severe systemic acidosis (pH change of about –0·05 to –0·20) often results from renal disease; milder chronic acidosis (pH change of about –0·02 to –0·05) can be caused by excessive protein intake, acid feeding, prolonged exercise, ageing, airway diseases or the menopause. Acidosis can also occur locally as a result of inflammation, infection, wounds, tumours or diabetic ischaemia. Cell function, including that of osteoblasts, is normally impaired by acid; the unusual stimulatory effect of acid on osteoclasts may represent a primitive ‘fail-safe’ that evolved with terrestrial vertebrates to correct systemic acidosis by ensuring release of alkaline bone mineral when the lungs and kidneys are unable to remove sufficient H+ equivalent. The present results suggest that even subtle chronic acidosis could be sufficient to cause appreciable bone loss over time.

Macronutrient Group Symposium on ‘Protein intake and chronic disease’
Copyright © The Nutrition Society 2003


Albright, F & Reifenstein, EC (1948) The Parathyroid Glands and Metabolic Bone Disease, p. 242, Baltimore, MD: Williams and Wilkins.Google Scholar
Arnett, TR & Dempster, DW (1986) Effect of pH on bone resorption by rat osteoclasts in vitro. Endocrinology 119, 119124.CrossRefGoogle Scholar
Arnett, TR & Dempster, DW (1987) A comparative study of disaggregated chick and rat osteoclasts in vitro: effects of calcitonin and prostaglandins. Endocrinology 120, 602608.CrossRefGoogle ScholarPubMed
Arnett, TR & Dempster, DW (1990) Perspectives: protons and osteoclasts. Journal of Bone and Mineral Research 5, 10991103.CrossRefGoogle Scholar
Arnett, TR & Spowage, M (1996) Modulation of the resorptive activity of rat osteoclasts by small changes in extracellular pH near the physiological range. Bone 18, 277279.CrossRefGoogle ScholarPubMed
Avioli, LV (1978) Renal osteodystrophy. In Metabolic Bone Disease, vol. II 149215 [Avioli, LV and Krane, SM, editor]. New York: Academic Press.CrossRefGoogle Scholar
Ball, D & Maughan, RJ (1997) Blood and urine acid-base status of premenopausal omnivorous and vegetarian women. British Journal of Nutrition 78, 683693.CrossRefGoogle ScholarPubMed
Barrett, MG, Belinsky, GS, Tashjian, AH Jr (1997) A new action of parathyroid hormone: receptor-mediated stimulation of extracellular acidification in human osteoblast-like SaOS-2 cells. Journal of Biological Chemistry 272, 2634626353.CrossRefGoogle ScholarPubMed
Barzel, US (1995) The skeleton as an ion-exchange system–implications for the role of acid-base imbalance in the genesis of osteoporosis. Journal of Bone and Mineral Research 10, 14311436.CrossRefGoogle Scholar
Barzel, US & Jowsey, J (1969) The effects of chronic acid and alkali administration on bone turnover in adult rats. Clinical Science 36, 517524.Google Scholar
Belinsky, G, Tashjian, AH Jr (2000) Direct measurement of hormone-induced acidification in intact bone. Journal of Bone and Mineral Research 15, 550556.CrossRefGoogle ScholarPubMed
Biskobing, DM & Fan, D (2000) Acid pH increases carbonic anhydrase II and calcitonin receptor mRNA expression in mature osteoclasts. Calcified Tissue International 67, 178183.CrossRefGoogle ScholarPubMed
Bridgeman, G & Brookes, M (1996) Blood supply to the human femoral diaphysis in youth and senescence. Journal of Anatomy 188, 611621.Google ScholarPubMed
Buclin, T, Cosma, M, Appenzeller, M, Jacquet, AF, Decosterd, LA, Biollaz, J & Burckhardt, P (2001) Diet acids and alkalis influence calcium retention in bone. Osteoporosis International 12, 493499.CrossRefGoogle ScholarPubMed
Bushinsky, DA (1989) Net calcium efflux from live bone during chronic metabolic, but not respiratory, acidosis. American Journal of Physiology 256, F836F842.Google Scholar
Bushinsky, DA (1995) Stimulated osteoclastic and suppressed osteoblastic activity in metabolic but not respiratory acidosis. American Journal of Physiology 268, C80C88.CrossRefGoogle Scholar
Bushinsky, DA, Goldring, JM & Coe, FL (1985) Cellular contribution to pH-mediated calcium flux in neonatal mouse calvariae. American Journal of Physiology 248, F785F789.Google ScholarPubMed
Bushinsky, DA, Krieger, NS, Geisser, DI, Grossman, EB & Coe, FL (1983) Effects of pH on bone calcium and proton fluxes in vitro. American Journal of Physiology 245, F204F209.Google Scholar
Bushinsky, DA & Lechleider, RJ (1987) Mechanism of protoninduced bone calcium release: calcium carbonate-dissolution. American Journal of Physiology 253, F998F1005.Google Scholar
Bushinsky, DA, Sessler, NE & Krieger, NS (1992) Greater unidirectional calcium efflux from bone during metabolic, compared with respiratory, acidosis. American Journal of Physiology 262, F425F431.Google ScholarPubMed
Chan, YL, Savdie, E, Mason, RS & Posen, S (1985) The effect of metabolic acidosis on vitamin D metabolites and bone histology in uremic rats. Calcified Tissue International 37, 158164.CrossRefGoogle ScholarPubMed
Cooke, AM (1955a) Osteoporosis. Lancet i, 878882.Google Scholar
Cooke, AM (1955b) Osteoporosis. Lancet i, 929937.Google Scholar
Cunningham, J, Fraher, LJ, Clemens, TL, Revell, PA & Papapoulos, SE (1982) Chronic acidosis with metabolic bone disease. Effect of alkali on bone morphology and vitamin D metabolism. American Journal of Medicine 73, 199204.CrossRefGoogle Scholar
Dawson-Hughes, B, Dallal, GE, Krall, EA, Sadowski, L, Sahyoun, N & Tannenbaum, S (1990) A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women. New England Journal of Medicine 323, 878883.CrossRefGoogle Scholar
Frassetto, LA, Morris, RC, Sebastian, A Jr (1996) Effect of age on blood acid-base composition in adult humans: role of age-related renal functional decline. American Journal of Physiology 271, F1114F1122.Google ScholarPubMed
Frassetto, L & Sebastian, A (1996) Age and systemic acid-base equilibrium: analysis of published data. Journal of Gerontology 51, B91B99.Google ScholarPubMed
Frick, KK & Bushinsky, DA (1998) Chronic metabolic acidosis reversibly inhibits extracellular matrix gene expression in mouse osteoblasts. American Journal of Physiology 275, F840F847.Google ScholarPubMed
Gibbons, DC, Meghji, S, Hoebertz, A, Rosendaal, M & Arnett, TR (2001) Hypoxia is a powerful stimulator of bone resorption. Journal of Bone and Mineral Research 16 1175.Google Scholar
Ginty, F, Flynn, A & Cashman, KD (1998) The effect of short-term calcium supplementation on biochemical markers of bone metabolism in healthy young adults. British Journal of Nutrition 80, 437443.Google ScholarPubMed
Goldhaber, P & Rabadjija, L (1987) H + stimulation of cell-mediated bone resorption in tissue culture. American Journal of Physiology 253, E90E98.Google ScholarPubMed
Goto, K (1918) Mineral metabolism in experimental acidosis. Journal of Biological Chemistry 36, 355376.Google Scholar
Green, J & Kleeman, CR (1991) Role of bone in regulation of systemic acid-base balance. Kidney International 39, 926.CrossRefGoogle ScholarPubMed
Heaney, RP (2001) Protein intake and bone health: the influence of belief systems on the conduct of nutritional science. American Journal of Clinical Nutrition 73, 56.CrossRefGoogle ScholarPubMed
Hoebertz, A, Meghji, S, Burnstock, G & Arnett, TR (2001) Extracellular ADP is a powerful osteolytic agent: evidence for signaling through the P2Y 1 receptor on bone cells. FASEB Journal 15, 11391148.CrossRefGoogle ScholarPubMed
Jaffe, HL, Bodansky, A & Chandler, JP (1932) Ammonium chloride decalcification as modified by calcium intake: the relationship between generalized osteoporosis and ostitis fibrosa. Journal of Experimental Medicine 56, 823834.CrossRefGoogle Scholar
Kraut, JA, Mishler, DR & Kurokawa, K (1984) Effect of colchicine and calcitonin on calcemic response to metabolic acidosis. Kidney International 25, 608612.CrossRefGoogle ScholarPubMed
Lacey, DL, Timms, E, Tan, HL, Kelley, MJ, Dunstan, CR, Burgess, T, Elliott, R, Colombero, A, Elliott, G, Scully, S, Hsu, H, Sullivan, J, Hawkins, N, Davy, E, Capparelli, C, Eli, A, Qian, YX, Kaufman, S, Sarosi, I, Shalhoub, V, Senaldi, G, Guo, J, Delaney, J & Boyle, WJ (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165176.CrossRefGoogle ScholarPubMed
Lemann, J, Jr, Litzow, JR, Lennon EJ (1966) The effects of chronic acid loads in normal man: further evidence for the participation of bone mineral in the defense against chronic metabolic acidosis. Journal of Clinical Investigation 45, 16081614.CrossRefGoogle ScholarPubMed
Martin, GR & Jain, RK (1994) Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy. Cancer Research 54, 56705674.Google ScholarPubMed
Meghji, S, Henderson, B, Morrison, MS & Arnett, TR (2001) pH dependence of bone resorption: mouse calvarial osteoclasts are activated by acidosis. American Journal of Physiology 280, E112E119.Google ScholarPubMed
Morrison, MS & Arnett, TR (1998) pH effects on osteoclast formation and activation. Bone 22 30S.Google Scholar
Morrison, M, Turin, L, King, BF, Burnstock, G & Arnett, TR (1998) ATP is a potent stimulator of the activation and formation of rodent osteoclasts. Journal of Physiology 511, 495500.CrossRefGoogle ScholarPubMed
Murrills, RJ, Stein, LS & Dempster, DW (1993) Stimulation of bone resorption and osteoclast clear zone formation by low pH: a time-course study. Journal of Cellular Physiology 154, 511518.CrossRefGoogle Scholar
New, SA (2002) The role of the skeleton in acid–base homeostasis. Proceedings of the Nutrition Society 61, 151164.CrossRefGoogle ScholarPubMed
New, SA, Robins, SP, Campbell, MK, Martin, JC, Garton, MJ, Bolton-Smith, C, Grubb, DA, Lee, SJ & Reid, DM (2000) Dietary influences on bone mass and bone metabolism: further evidence of a positive link between fruit and vegetable consumption and bone health?. American Journal of Clinical Nutrition 71, 142151.CrossRefGoogle Scholar
Nordström, T, Shrode, LD, Rotstein, OD, Romanek, R, Goto, T, Heersche, JN, Manolson, MF, Brisseau, GF & Grinstein, S (1997) Chronic extracellular acidosis induces plasmalemmal vacuolar type H + ATPase activity in osteoclasts. Journal of Biological Chemistry 272, 63546360.CrossRefGoogle ScholarPubMed
Orr-Walker, BJ, Home, AM, Evans, MC, Grey, AB, Murray, MAF, McNeil, AR & Reid, IR (1999) Hormone replacement therapy causes a respiratory alkalosis in normal postmenopausal women. Journal of Clinical Endocrinology and Metabolism 84, 19972001.Google ScholarPubMed
Rabadjija, L, Brown, EM, Swartz, SL, Chen, CJ & Goldhaber, P (1990) H + -stimulated release of prostaglandin E 2 and cyclic adenosine 3', 5'-monophosphoric acid and their relationship to bone resorption in neonatal mouse calvaria cultures. Bone and Mineral 11, 295304.CrossRefGoogle Scholar
Reid, IR, Ames, RW, Evans, MC, Gamble, GD & Sharpe, SJ (1995) Long-term effects of calcium supplementation on bone loss and fractures in postmenopausal women: a randomized controlled trial. American Journal of Medicine 98, 331335.CrossRefGoogle Scholar
Relman, AS (1968) The acidosis of renal disease. American Journal of Medicine 44, 706713.CrossRefGoogle ScholarPubMed
Santhanagopal, A & Dixon, SJ (1999) Insulin-like growth factor I rapidly enhances acid efflux from osteoblastic cells. American Journal of Physiology 277, E423E432.Google ScholarPubMed
Scopacasa, F, Need, AG, Horowitz, M, Wishart, JM, Morris, HA & Nordin, BE (2000) Inhibition of bone resorption by divided-dose calcium supplementation in early postmenopausal women. Calcified Tissue International 67, 440442.CrossRefGoogle ScholarPubMed
Sebastian, A, Harris, ST, Ottaway, JH, Todd, KM, Morris, RC Jr (1994) Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate. New England Journal of Medicine 330, 17761781.CrossRefGoogle ScholarPubMed
Straub, B, Muller, M, Schrader, M, Heicappell, R & Miller, K (2001) Osteoporosis and mild metabolic acidosis in the rat after orchiectomy and their prevention: should prophylactic therapy be administered to patients with androgen deprivation?. Journal of Urology 165, 17831789.CrossRefGoogle ScholarPubMed
Trilok, G & Draper, HH (1989a) Sources of protein-induced endogenous acid production and excretion by human adults. Calcified Tissue International 44, 335338.CrossRefGoogle ScholarPubMed
Trilok, G & Draper, HH (1989b) Effect of a high protein intake on acid-base balance in adult rats. Calcified Tissue International 44, 339342.CrossRefGoogle ScholarPubMed
Waldmann, R, Champigny, G, Lingueglia, E, De, Weille, JR, Heurteaux, C, Lazdunski M (1999) H + -gated cation channels. Annals of the New York Academy of Sciences 868, 6776.CrossRefGoogle ScholarPubMed
Yates, AJ, Oreffo, RO, Mayor, K & Mundy, GR (1991) Inhibition of bone resorption by inorganic phosphate is mediated by both reduced osteoclast formation and decreased activity of mature osteoclasts. Journal of Bone and Mineral Research 6, 473478.CrossRefGoogle ScholarPubMed