Acid-Alkaline Balance: general research articles of human health

The resources listed below represent a collection of scientific articles discussing research on the overall effects of chronic, low-grade, metabolic acidosis on health. These sources provide a useful collection of observations for those interested in expanding their understanding of the health impacts of pH imbalance and the importance of acid-alkaline balance.

Alonso, A., de la Fuente, C., et al. (2004). Fruit and vegetable consumption is inversely associated with blood pressure in a Mediterranean population with a high vegetable-fat intake: the Seguimiento Universidad de Navarra (SUN) Study. Br J Nutr 92(2): 311-9. PMID: 15333163

Alpern, R.J., Sakhaee, K. (1997). The clinical spectrum of chronic metabolic acidosis: homeostatic mechanisms produce significant morbidity. Am J Kidney Dis 29(2): 291-302. PMID: 9016905

Berardi, J. M., A. C. Logan, and A. V. Rao. (2008). Plant based dietary supplement increases urinary pH. J Int Soc Sports Nutr 5:20.

Brüngger, M., H. N. Hulter, and R. Krapf. (1997). Effect of chronic metabolic acidosis on the growth hormone/IGF-1 endocrine axis: New cause of growth hormone insensitivity in humans. Kidney Int 51(1):216-21.

Bushinsky, D.A. (2002). Recurrent hypercalciuric nephrolithiasis—does diet help? N Engl J Med 346(2): 124-5. PMID: 11784880

Ceglia, L., S. Harris, S. Abrams, et al. (2009). Potassium bicarbonate attenuates the urinary nitrogen excretion that accompanies an increase in dietary protein and may promote calcium absorption. J Clin Endocrinol Metab 94(2): 645-653.

Coppoolse, R., T. J. Barstow, W.W. Stringer, et al. (1997). Effect of acute bicarbonate administration on exercise responses of COPD patients. Med Sci Sports Exerc 29: 725-732.

Cordain, L., S. B. Eaton, et al. (2005). Origins and evolution of the Western diet: Health implications for the 21st century. Am J Clin Nutr 81:341-54.

Cordain, L., Miller, J.B., et al. (2000). Plant-animal subsistence ratios and macronutrient energy estimations in worldwide hunter-gatherer diets. Am J Clin Nutr 71(3): 682-92. PMID: 10702160

De Brito-Ashurst, I., M. Varagunam, et al. (2009). Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol 20(9):2075-84.

Demigné, C. (2006). Could minor cations and anions or other constituents such as fibers, contribute to the alkalinising properties of plant foods? 2nd International Acid-Base Symposium, Munich, 8 – 9 September.

Eaton, S. B. and M. Konner. 1985. Paleolithic nutrition—A consideration of its nature and current implications. New Engl. J Med 312:283–289.

Demigne, C. Could minor cations and anions or other constituents such as fibers, contribute to the alkalinising properties of plant foods? 2nd International Acid-Base Symposium: Nutrition - Health - Disease, Welhenstephan, Germany.

Eaton, S.B., Eaton, S.B., 3rd (2000). Paleolithic vs. modern diets—selected pathophysiological implications. Eur J Nutr 39(2): 67-70. PMID: 10918987

Farr, M., Garvey, K., et al. (1985). Significance of the hydrogen ion concentration in synovial fluid in rheumatoid arthritis. Clin Exp Rheumatol 3(2): 99-104. PMID: 4017318

Feely, R. A., Sabine, C.L., et al. (2004). Impact of anthropogenic CO2 on the CaCO3 system in the oceans. Science 305(5682): 362-6. PMID: 15256664

Frangiosa, A., L.S. DeSanto, P. Anastasio, et al. (2006). Acid-base balance in heart failure. J Nephrol 19(9 Suppl): S115-S120.

Frassetto, L. A., R.C. Morris, Jr., and A. Sebastian. (2007). Dietary sodium chloride intake independently predicts the degree of hyperchloremic metabolic acidosis in healthy humans consuming a net acid-producing diet. Am J Physiol Renal Physiol 93: 521-525.

Frassetto, L. A., M. Schloetter, et al. (2009). Metabolic and psysiologic improvements from consuming a paleolithic, hunter-gatherer type diet. Eur J Clin Nutr 63(8):947-55.

Frassetto, L., Morris, R.C. Jr., et al. (2001). Diet, evolution and aging. The pathophysiologic effects of the post-agricultural inversion of the potassium-to-sodium and base-to-chloride ratios in the human diet. Eur J Nutr 40(5): 200-13.

Gonick, H. C., Goldberg, G., et al. (1968). Reexamination of the acid-ash content of several diets. Am J Clin Nutr 21(9): 898-903. PMID: 5675852

Guyton, A. C. 1961 Textbook of medical physiology. Philadelphia: Saunders.

Hosch, M., Muser, J., Hulter, H.N., Krapf, R. (2004). Ureagenesis: evidence for a lack of hepatic regulation of acid-base equilibrium in humans. Am J Physiol Renal Physiol (286): F94-9. PMID: 14656759

Hunt, J. R., L. K. Johnson, and Z. K. Fariba Roughead. (2009). Dietary protein and calcium interact to influence calcium retention: A controlled feeding study. Am J Clin Nutr 89:1357-65.

Jaffe, R. (2000). Autoimmunity and cofactor replacement. Int J Integr Med 2(2).

Kiwull-Schone, H., Kalhoff, H., et al. (2001). Minimal-invasive approach to study pulmonary, metabolic and renal responses to alimentary acid-base changes in conscious rabbits. Eur J Nutr 40(5): 255-9.

Lemann, Jr., J., R.W. Gray, and J.A. Pleuss. (1989). Potassium bicarbonate, but not sodium bicarbonate, reduces urinary calcium excretion and improves calcium balance in healthy men. Kidney Int 35: 688-695.

Lofberg, E., A. Gutierrez, B. Anderstam, et al. (2006). Effect of bicarbonate on muscle protein in patients receiving hemodialysis. Am J Kidney Dis 48: 419-429.

Lukaski, H.C. (2005). Low dietary zinc decreases erythrocyte carbonic anhydrase activities and impairs cardiorespiratory function in men during exercise. Am J Clin Nutr 81(5): 1045-51. PMID: 15883427

Maalouf, N.M., M.A. Cameron, O.W. Moe, et al. (2007). Low urine pH: A novel feature of the metabolic syndrome. Clin J Am Soc Nephrol 2: 883-888.

Manz, F., Remer, T., et al. (1995). Effects of a high protein intake on renal acid excretion in bodybuilders. Z Ernahrungswiss 34(1): 10-5. PMID: 7785291

Martin, H.E., Wertman, M. (1947). Serum potassium, magnesium, and calcium levels in diabetic acidosis. J Clin Invest 26(2): 217-28. PMID: 16695408

McCarty, M. (2005). Acid-base balance may influence risk for insulin resistance syndrome by modulating cortisol output. Med Hypotheses 64: 380-384. PMID: 15607573

Mitch, W.E., R. Medina, S. Grieber, et al. (1994). Metabolic acidosis stimulates muscle protein degradation by activating the adenosine triphosphate-dependent pathway involving ubiquitin and proteasomes. J Clin Invest 93: 2127-2133.

Morris, R.C., Jr., Sebastian, A. (2002). Alkali therapy in renal tubular acidosis: who needs it? J Am Soc Nephrol 13(8): 2186-8. PMID: 12138154

Pizzorno, J., L. A. Frassetto, and J. Katzinger. (2010). Diet-induced acidosis: Is it real and clinically relevant? Br J Nutr 103(8):1185-94.

Queen, S. (1994). Free radical therapy: part IV: acidemia and free calcium excess. Health Realities Journal.

Relman, A.S., Lennon, E.J., et al. (1961). Endogenous production of fixed acid and the measurement of the net balance of acid in normal subjects. J Clin Invest 40: 1621-30. PMID: 13740723

Remer, T., Manz, F. (2003). Paleolithic diet, sweet potato eaters, and potential renal acid load. Am J Clin Nutr 78(4): 802-3; author reply 803-4. PMID: 14522740

Robergs, R.A., Ghiasvand, F., et al. (2004). Biochemistry of exercise-induced metabolic acidosis. Am J Physiol Regul Integr Comp Physiol 287(3): R502-16. PMID: 15308499

Sabine, C.L., Feely, R.A., et al. (2004). The oceanic sink for anthropogenic CO2. Science 305(5682): 367-71. PMID: 15256665

Spiller, G.A., Bruce, B. (1998). Vegan diets and cardiovascular health [editorial; comment]. J Am Coll Nutr 17(5): 407-8. PMID: 9791835

Stratton-Phelps, M., House, J.K. (2004). Effect of a commercial anion dietary supplement on acid-base balance, urine volume, and urinary ion excretion in male goats fed oat or grass hay diets. Am J Vet Res 65(10): 1391-7. PMID: 15524326

Ströhle, A., A. Hahn, and A. Sebastian. (2010). Latitude, local ecology, and hunter-gatherer dietary acid load: Implications from evolutionary ecology. Am J Clin Nutr 92(4):940-5.

Vormann, J., Worlitschek, M., et al. (2001). Supplementation with alkaline minerals reduces symptoms in patients with chronic low back pain. J Trace Elem Med Biol 15(2-3): 179-83. PMID: 11787986

Weisinger, J.R., Favus, M.J., et al. (1989). Regulation of 1,25-dihydroxyvitamin D3 by calcium in the parathyroidectomized, parathyroid hormone-replete rat. J Bone Miner Res 4(6): 929-35. PMID: 2610024

Wenzel, U. E. A. (2000). Membrane transport proteins and their role in acid base homeostasis. Acid-Base Metabolism: Nutrition - Health - Disease, Welhenstephan, Germany.

Whiting, S.J. and J.A. Muirhead. (2005). Measurement of net acid excretion by use of paper strips. Nutrition 21: 961-963.

Wiederkehr, M. R., J. Kalogiros; and R. Krapf. (2004). Correction of metabolic acidosis improves thyroid and growth hormone axes in haemodialysis patients. Nephrology Dialysis Transplantation 19(5): 1190-97.

Wiederseiner, J. M., J. Muser, T. Lutz, H. N. Hulter, and R. Krapf. (2004). Acute metabolic acidosis: Characterization and diagnosis of the disorder and the plasma potassium response. J Am Soc Nephrol 15: 1589-1596.


Acid-alkaline balance and bone health: research articles of special interest
by Dr. Susan E. Brown, PhD
The resources listed below represent a collection of scientific articles discussing research on the effects of chronic, low-grade metabolic acidosis on bone, including studies relating acidbase balance to osteopenia and osteoporosis. These sources represent an expanding database of observations that support pH balance as a necessary component of full bone health.
Abelow, B. J. et al. 1992 Cross-cultural association between dietary animal protein and hip fracture: A hypothesis. Calcif Tiss Int 50:14–18. 
Alexy, U., T. Remer, et al. (2005). Long-term protein intake and dietary potential renal acid load are associated with bone modeling and remodeling at the proximal radius in healthy children. Am J Clin Nutr 82:1107-14.
Amanzadeh, J., Gitomer, W.L., et al. (2003). Effect of high protein diet on stone-forming propensity and bone loss in rats. Kidney Int 64(6): 2142-9. PMID: 14633136
Arnett, T. R. and D. W. Dempster. 1986. Effect of pH on bone resorption by rat osteoclasts in vitro. Endocrin 119:119–124.
Arnett, T. (2003). Regulation of bone cell function by acid-base balance. Proc Nutr Soc 62(2): 511-20. PMID: 14506899
Arnett, T. R., Spowage, M. (1996). Modulation of the resorptive activity of rat osteoclasts by small changes in extracellular pH near the physiological range. Bone 18(3): 277-9. PMID: 8703584
Bäckman, T. (1999). Acid-base balance, dentinogenesis, and dental caries. Faculty of  Medicine, University of Oulu, Finland.
Ballard, T. L., Clapper, J.A., et al. (2005). Effect of protein supplementation during a 6-mo strength and conditioning program on insulin-like growth factor I and markers of bone turnover in young adults. Am J Clin Nutr 81(6): 1442-8. PMID: 15941900
Barzel, U.S., Jowsey, J. (1969). The effects of chronic acid and alkali administration on bone turnover in adult rats. Clin Sci 36(3): 517-24. PMID: 5795240
Barzel, U.S., Massey, L.K. (1998). Excess dietary protein can adversely affect bone. J Nutr 128(6): 1051-3. PMID: 9614169
Brandao-Burch, A., J.C. Utting, I.R. Orriss, et al. (2005). Acidosis inhibits bone formation by osteoblasts in vitro by preventing mineralization. Calcif Tissue Int 77: 167-174.
Breslau, N.A., Brinkley, L., et al. (1988). Relationship of animal protein-rich diet to kidney stone formation and calcium metabolism. J Clin Endocrinol Metab 66(1): 140-6. PMID:  2826524
Buclin, T., Cosma, M., et al. (2001). Diet acids and alkalis influence calcium retention in bone. Osteoporos Int 12(6): 493-9. PMID: 11446566
Budde, R.A., Crenshaw, T.D. (2003). Chronic metabolic acid load induced by changes in dietary electrolyte balance increased chloride retention but did not compromise bone in growing swine. J Anim Sci 81(1): 197-208. PMID: 12597391
Burket, J. C., J. MacLeay, et al. (2010). Variations in cancellous bone tissue composition and mechanical properties with a model of osteoporosis and treatment in sheep. Presentation number SU0048, ASBMR Conference, Toronto, Canada.
Bushinsky, D.A. (1987). Effects of parathyroid hormone on net proton flux from neonatal  mouse calvariae. Am J Physiol 252(4 Pt 2): F585-9. PMID: 3031997
Bushinsky, D.A. (1989). Internal exchanges of hydrogen ions: bone. In: Seldein D.W., 
Giebisch, G., eds. The regulation of acid-base balance. New York: Raven Press, pp. 69-88.
Bushinsky, D.A. (1995). Stimulated osteoclastic and suppressed osteoblastic activity in metabolic but not respiratory acidosis. Am J Physiol 268(1 Pt 1): C80-8. PMID: 7840163 
Bushinsky, D.A. (1996). Metabolic alkalosis decreases bone calcium efflux by suppressing osteoclasts and stimulating osteoblasts. Am J Physiol 271(1 Pt 2): F216-22. PMID: 8760264
Bushinsky, D.A. (2001). Acid-base imbalance and the skeleton. Eur J Nutr 40(5): 238-44.
Bushinsky, D.A., Coe, F.L. (1985). Hyperkalemia during acute ammonium chloride acidosis in man. Nephron 40(1): 38-40. PMID: 3923378
Bushinsky, D.A., Gavrilov, K., et al. (1997). Effect of metabolic acidosis on the potassium  content of bone. J Bone Miner Res 12(10): 1664-71. PMID: 9333127
Bushinsky, D.A., Gavrilov, K., et al. (1996). Effects of osteoclastic resorption on bone surface ion composition. Am J Physiol 271(4 Pt 1): C1025-31. PMID: 8897806
Bushinsky, D.A., Krieger, N.S., et al. (1983). Effects of pH on bone calcium and proton fluxes in vitro. Am J Physiol 245(2): F204-9. PMID: 6881337
Bushinsky, D.A., Lechleider, R.J. (1987). Mechanism of proton-induced bone calcium release: calcium carbonate-dissolution. Am J Physiol 253(5 Pt 2): F998-1005. PMID: 2825542
Bushinsky, D.A., Levi-Setti, R., et al. (1986). Ion microprobe determination of bone surface elements: effects of reduced medium pH. Am J Physiol 250(6 Pt 2): F1090-7. PMID: 3717349
Bushinsky, D.A., Nilsson, E.L. (1995). Additive effects of acidosis and parathyroid hormone on mouse osteoblastic and osteoclastic function. Am J Physiol 269(6 Pt 1): C1364-70. PMID:8572164
Bushinsky, D.A., Sessler, N.E. (1992). Critical role of bicarbonate in calcium release from bone. Am J Physiol 263(3 Pt 2): F510-5. PMID: 1415579
Bushinsky, D.A., Sessler, N.E., et al. (1994). Proton-induced physicochemical calcium release from ceramic apatite disks. J Bone Miner Res 9(2): 213-20. PMID: 8140934
Bushinsky, D.A., Sessler, N.E., et al. (1992). Greater unidirectional calcium efflux from bone during metabolic, compared with respiratory, acidosis. Am J Physiol 262(3 Pt 2): F425-31.PMID: 1558159
Bushinsky, D.A., Smith, S.B., et al. (2002). Acute acidosis-induced alteration in bone bicarbonate and phosphate. Am J Physiol Renal Physiol 283(5): F1091-7. PMID: 12372785
Bushinsky, D.A., Smith, S.B., et al. (2003). Chronic acidosis-induced alteration in bone bicarbonate and phosphate. Am J Physiol Renal Physiol 285(3): F532-9. PMID: 12759230
Canas, F., Terepka, A.R., et al. (1969). Potassium and milieu interieur of bone. Am J Physiol 217(1): 117-20. PMID: 5785866
Carter, J.D., Vasey, F.B., et al. (2006). The effect of a low-carbohydrate diet on bone turnover. Osteoporos Int 17(9): 1398-403. PMID: 16718399
Cochran, M., Wilkinson, R. (1975). Effect of correction of metabolic acidosis on bone mineralisation rates in patients with renal osteomalacia. Nephron 15: 98-110.
Dargent-Molina, P., S. Sabia, et al. (2008). Proteins, dietary acid load, and calcium and risk of post-menopausal fractures in the E3N French Women Prospective Study. J Bone Miner Res 23(12):1915-22.
Dawson-Hughes, B., S.S. Harris, N.J. Palermo, et al. (2009). Treatment with potassium bicarbonate lowers calcium excretion and bone resorption in older men and women. J Clin Endocrinol Metab 94: 96-102.
Dawson-Hughes, B., Harris, S.S., et al. (2008). Alkaline diets favor lean tissue mass in older adults. Am J Clin Nutr 87(3): 662-5. PMID: 18326605
Dawson-Hughes, B., Harris, S.S., et al. (2004). Effect of dietary protein supplements on calcium excretion in healthy older men and women. J Clin Endocrinol Metab 89(3): 1169-73.PMID: 15001604
Dawson-Hughes, B., Harris, S.S. (2002). Calcium intake influences the association of protein intake with rates of bone loss in elderly men and women. Am J Clin Nutr 75(4): 773-779. ID: 11916767
Devine, A., Prince, R.L., et al. (1996). Nutritional effect of calcium supplementation by skim milk powder or calcium tablets on total nutrient intake in postmenopausal women. Am J Clin Nutr 64(5): 731-7. PMID: 8901793
Domrongkitchaiporn, S., Pongsakul, C., et al. (2001). Bone mineral density and histology in distal renal tubular acidosis. Kidney Int 59(3): 1086-93. PMID: 11231364
Domrongkitchaiporn, S., Pongsakul, C., et al. (2002). Bone histology and bone mineral density after correction of acidosis in distal renal tubular acidosis. Kidney Int 62(6): 2160-6.PMID: 12427141
Duff, T.L., Whiting, S.J. (1998). Calciuric effects of short-term dietary loading of protein, sodium chloride and potassium citrate in prepubescent girls. J Am Coll Nutr 17(2): 148-54. PMID: 9550458
Fenton, T.R., A.W. Lyon, M. Eliaziw, et al. (2009). Meta-analysis of the effect of the acid-ash hypothesis of osteoporosis on calcium balance. J Bone Miner Res 24: 1835-1840.
Fenton, T. R., A. W. Lyon, M. Eliasziw, et al. (2009). Phosphate decreases urine calcium and increases calcium balance: A meta-analysis of the osteoporosis acid-ash diet hypothesis.Nutr J 8:41.
Fenton, T. R., M. Eliasziw, et al. (2010). Bone fractures or the loss of bone mineral density: A prospective cohort study. BMC Musculo Dis 11:88.
Frassetto, L., R.C. Morris Jr., and A. Sebastian. (1997). Potassium bicarbonate reduces urinary nitrogen excretion in postmenopausal women. J Clin Endocrinol Metab 82: 254-259.
Frassetto, L., R.C. Morris, Jr. and A. Sebastian. (2004). Diet acid load and bone health. In Nutritional Aspects of Osteoporosis, 2nd ed. Ed. P. Burckhardt, B. Dawson-Hughes and R.P. Heaney. San Diego, CA: Elsevier Academic Press.
Frassetto, L., Morris, R.C. Jr., et al. (1997). Potassium bicarbonate reduces urinary nitrogen 
excretion in postmenopausal women. J Clin Endocrinol Metab 82(1): 254-9.
Frassetto, L., Morris, R.C. Jr., et al. (2005). Long-term persistence of the urine calciumlowering effect of potassium bicarbonate in postmenopausal women. J Clin Endocrinol Metab
90(2): 831-4. PMID: 15572425
Frassetto, L., Sebastian, A. (1996). Age and systemic acid-base equilibrium: analysis of 
published data. J Gerontol A Biol Sci Med Sci 51(1): B91-9. PMID: 8548506
Frassetto, L.A., Morris, R.C. Jr., et al. (1996). Effect of age on blood acid-base composition 
in adult humans: role of age-related renal functional decline. Am J Physiol 271(6 Pt 2): 
Frassetto, L.A., Nash, E., et al. (2000). Comparative effects of potassium chloride and 
bicarbonate on thiazide-induced reduction in urinary calcium excretion. Kidney Int 58(2): 
748-52. PMID: 10916098
Frassetto, L.A., Todd, K.M., et al. (1998). Estimation of net endogenous noncarbonic acid 
production in humans from diet potassium and protein contents. Am J Clin Nutr 68(3): 576-
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Frassetto, L.A., Todd, K.M., et al. (2000). Worldwide incidence of hip fracture in elderly 
women: relation to consumption of animal and vegetable foods. J Gerontol Biol Sci Med Sci 
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Frick, K.K., Bushinsky, D.A. (1998). Chronic metabolic acidosis reversibly inhibits 
extracellular matrix gene expression in mouse osteoblasts. Am J Physiol 275(5 Pt 2): F840-
7. PMID: 9815143
Frick, K.K., Bushinsky, D.A. (2003). Metabolic acidosis stimulates RANKL RNA expression in 
bone through a cyclo-oxygenase-dependent mechanism. J Bone Miner Res 18(7): 1317-25. 
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Hardcastle, A. C., L. Aucott, et al. (2011). Dietary patterns, bone resorption and bone 
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