FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 330:1776-1781 June 23, 1994 Number 25 Next

Abstract Letters Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background In normal subjects, a low level of metabolic acidosis and positive acid balance (the production of more acid than is excreted) are typically present and correlate in degree with the amount of endogenous acid produced by the metabolism of foods in ordinary diets abundant in protein. Over a lifetime, the counteraction of retained endogenous acid by base mobilized from the skeleton may contribute to the decrease in bone mass that occurs normally with aging.

Methods To test that possibility, we administered potassium bicarbonate to 18 postmenopausal women who were given a constant diet (652 mg [16 mmol] of calcium and 96 g of protein per 60 kg of body weight). The potassium bicarbonate was given orally for 18 days in doses (60 to 120 mmol per day) that nearly completely neutralized the endogenous acid.

Results During the administration of potassium bicarbonate, the calcium and phosphorus balance became less negative or more positive -- that is, less was excreted in comparision with the amount ingested (mean [±SD] change in calcium balance, +56 ±76 mg [1.4 ±1.9 mmol] per day per 60 kg; P = 0.009; change in phosphorus balance, +47 ±64 mg [1.5 ±2.1 mmol] per day per 60 kg; P = 0.007) because of reductions in urinary calcium and phosphorus excretion. The changes in calcium and phosphorus balance were positively correlated (P<0.001). Serum osteocalcin concentrations increased from 5.5 ±2.8 to 6.1 ±2.8 ng per milliliter (P<0.001), and urinary hydroxyproline excretion decreased from 28.9 ±12.3 to 26.7 ±10.8 mg per day (220 ±94 to 204 ±82 µmol per day; P = 0.05). Net renal acid excretion decreased from 70.9 ±10.1 to 12.8 ±21.8 mmol per day, indicating nearly complete neutralization of endogenous acid.

Conclusions In postmenopausal women, the oral administration of potassium bicarbonate at a dose sufficient to neutralize endogenous acid improves calcium and phosphorus balance, reduces bone resorption, and increases the rate of bone formation.

Two conditions must be present for the normal dietary acid load to contribute to the age-related decline in bone mass: a diet-dependent signal for mobilization of the skeletal-base reserve must be continually present, and a fraction of the daily load of endogenous acid must neutralize base from bone and therefore not appear as acid excreted in the urine. Both conditions have been confirmed experimentally. Regarding the first, in subjects eating ordinary diets, blood pH and plasma bicarbonate concentrations are reduced progressively as endogenous acid production is increased within the normal range^2,3. Reductions in extracellular pH and plasma bicarbonate concentrations are potent and independent signals for the stimulation of bone resorption and inhibition of bone formation^4,5,6,7. With respect to the second, in healthy subjects eating ordinary diets in whom the plasma acid-base composition is stable, net renal acid excretion does not fully account for endogenous acid production^2,8.

We investigated whether the long-term reduction in the net production of endogenous acid that results from the oral administration of alkali can reduce bone loss. Before initiating long-term studies, we studied postmenopausal women to determine whether reducing the net production of endogenous acid by means of the short-term administration of a particular alkali (potassium bicarbonate for a few weeks) improved calcium and phosphorus balance and reduced bone resorption or increased bone formation.

Methods

We carried out studies of calcium and phosphorus balance in 18 women who were hospitalized in the General Clinical Research Center of Moffitt-Long Hospitals, San Francisco. The committee on human research approved the protocol, and each woman gave informed consent. The women were white and ranged in age from 51 to 77 years, in weight from 53 to 76 kg, in height from 153 to 175 cm, and in body-mass index (the weight in kilograms divided by the square of the height in meters) from 21 to 28. All had undergone menopause at least five years earlier, were physically active, were taking no medications or hormones, and had normal blood pressure; one was a vegetarian. All were within the expected weight range for their height and frame size according to the method of Weigley⁹ and Metropolitan Life Insurance tables for 1983. The bone density of the lumbar spine, measured by computed tomography in 16 women, averaged 94.6 mg per cubic centimeter (range, 47.1 to 144.1). The women's z scores, defined as the number of standard deviations from the average value in a larger group of normal women of the same age studied in the same laboratory, averaged -0.27 (range, -1.6 to +2.1). The bone density of the spine, measured by dual-energy x-ray absorptiometry in nine women, averaged 0.78 mg per square centimeter (range, 0.58 to 0.89), which yielded z scores averaging -1.1 (range, -2.7 to +0.2). Four women had evidence of vertebral compression fractures on radiography.

The women were given a constant daily diet containing the following mean (±SD) amounts of nutrients per 60 kg of body weight: calcium, 652 ±180 mg (16 ±5 mmol); phosphorus, 871 ±51 mg (28 ±2 mmol); potassium, 59 ±3 mmol; sodium, 119 ±3 mmol; protein, 96 ±1 g; and energy, 1995 ±17 kcal. To facilitate adaptation to the diet, each woman's customary calcium intake was taken into consideration in determining her calcium intake (adjusted with calcium carbonate) for the study, and each woman followed the diet for 20 to 22 days before a 6-day control period. After the control period, potassium bicarbonate (60 to 120 mmol per day per 60 kg in aqueous solution) was provided as an alkali supplement for 18 days, then discontinued for a 12-day recovery period, during which dietary intake was otherwise kept constant. We chose potassium rather than sodium bicarbonate because potassium citrate, but not sodium citrate, induced a reduction in urinary calcium concentrations in men with uric acid nephrolithiasis¹⁰. We hypothesized that in postmenopausal women, the administration of potassium bicarbonate would improve the external mineral balance.

The control periods were six days in length, with pooled stool samples marked with brilliant blue dye. The amount of potassium bicarbonate in stool was determined from the recovery of an ingested nonabsorbable marker (polyethylene glycol).

Sample Collection

Arterialized venous blood samples were collected between 3:30 p.m. and 4:30 p.m., at least three hours after the noon meal, without stasis or exposure to air, from a vein on the back of the hand, which was warmed in a water bath at 44 °C for five minutes. The frequency of sampling during each of the three study periods (the control, supplementation, and recovery periods) varied, depending on the variable. We analyzed the specimens for blood pH and carbon dioxide tension; plasma total carbon dioxide, sodium, potassium, and chloride levels; and serum creatinine, total calcium, ionized calcium, magnesium, and inorganic phosphorus levels (measured 4 times during the control period, 10 times during the supplementation period, and 7 times during the recovery period); serum 25-hydroxyvitamin D levels (measured once during each period); and serum 1,25-dihydroxyvitamin D, parathyroid hormone, and osteocalcin levels (measured 4, 6, and 3 times).

Each voided urine specimen was divided in half; one half was preserved in acid for measurement of calcium, and the other half was maintained under a thin layer of mineral oil, preserved with thymol, and pooled in 24-hour collections for the determination of pH and carbon dioxide content. In addition, we measured the total volume and the concentrations of ammonium, titratable acid, sodium, potassium, chloride, inorganic phosphorus, magnesium, and creatinine in the 24-hour samples. Hydroxyproline was measured in three, six, and four 24-hour samples from the three periods, respectively.

Because the composition of the diet and the amounts of nutrients ingested by each woman were constant throughout the study, urinary hydroxyproline excretion was not affected by variations in collagen intake; therefore, changes in hydroxyproline excretion were interpreted as indicating changes in the rate of bone resorption^11,12,13,14. Changes in the serum osteocalcin concentration were considered to indicate changes in the rate of bone formation^{13,15,16,17,18}.

Dietary intake was determined from analyses of duplicate diets.

Laboratory Methods

The methods used for measuring the acid-base, mineral, and electrolyte analytes have been described previously^2,19. Ionized calcium was measured in heparinized whole blood with a Nova 8 ionized calcium-pH analyzer (Nova Biomedical, Newton, Mass.). Serum osteocalcin and parathyroid hormone were measured by radioimmunoassay and calcitriol by radioreceptor assay, with assay kits obtained from Nichols Institute (San Juan Capistrano, Calif.).

Statistical Analysis

The results were analyzed by repeated-measures analysis of variance of the average values for the three study periods for each woman and post hoc paired comparisons by the Student-Newman-Keuls test, with SAS software. The results are presented as means ±SD.

Results

The calcium balance was negative -- that is, more calcium was excreted than ingested -- throughout the study, but it was significantly less negative during the period of supplementation with potassium bicarbonate than during the control period (P = 0.009) (Table 1). After the discontinuation of potassium bicarbonate supplementation, calcium balance returned toward the more negative values during the control period. The net intestinal absorption of calcium was not significantly influenced by the ingestion of potassium bicarbonate. Rather, the potassium bicarbonate-induced improvement in calcium balance was accounted for by a reduction in urinary calcium excretion (Table 1 and Figure 1).

View this table: [in this window] [in a new window]   Table 1. Mineral Balance in 18 Postmenopausal Women before, during, and after the Administration of Potassium Bicarbonate (KHCO).

 

View larger version (25K): [in this window] [in a new window]   Figure 1. Effect of Potassium Bicarbonate Supplementation on Calcium and Phosphorus Excretion in Urine, External Calcium and Phosphorus Balance, and Calcium and Phosphorus Excretion in Stool in 18 Postmenopausal Women. The values shown at the bottom of the figure are the average (±SD) potassium bicarbonate-induced changes from the control period (before supplementation). To convert calcium values to millimoles per day per 60 kg, divide by 40; to convert phosphorus values to millimoles per day per 60 kg, divide by 31. NS denotes not significant. The P values are for the comparisons between the control period and the supplementation period.

 
The findings with respect to the balance of inorganic phosphorus were qualitatively similar to those for calcium (Table 1 and Figure 1). The net intestinal absorption of phosphorus was not significantly influenced by potassium bicarbonate supplementation. On a molar basis, the potassium bicarbonate-induced changes in calcium and phosphorus were positively correlated (r = 0.88, P<0.001).

Potassium balance was nearly zero (neutral) during the control period, became positive during the period of potassium bicarbonate supplementation, and returned to control-period levels after potassium bicarbonate was discontinued (Table 1). The sodium balance was slightly positive throughout the study (Table 1).

Statistically significant and reversible increases in plasma potassium and bicarbonate concentrations and blood pH occurred during the administration of potassium bicarbonate (Table 2). Neither the plasma ionized calcium concentration nor the total inorganic phosphorus concentration changed significantly. The serum 1,25-dihydroxyvitamin D concentration did not change during the period of potassium bicarbonate supplementation, but it increased significantly after supplementation was discontinued (P<0.001). Serum parathyroid hormone concentrations increased slightly but significantly (P = 0.019) during supplementation; this increase persisted after potassium bicarbonate was discontinued.

View this table: [in this window] [in a new window]   Table 2. Results of Blood Assays in 18 Postmenopausal Women before, during, and after the Administration of Potassium Bicarbonate (KHCO).

 
The mean serum osteocalcin concentration increased from 5.5 ±2.8 to 6.1 ±2.8 ng per milliliter (P<0.001) (Table 2), and urinary hydroxyproline excretion decreased from 28.9 ±12.3 to 26.7 ±10.8 mg per day (220 ±94 to 204 ±82 µmol per day; P = 0.05) during potassium bicarbonate administration.

Net renal acid excretion decreased promptly toward zero after the initiation of potassium bicarbonate supplementation (from 70.9 ±10.1 mmol per day per 60 kg of body weight in the control period to 12.8 ±21.8 mmol per day per 60 kg during the supplementation period), indicating that endogenous acid was almost completely neutralized during treatment (Figure 2). After potassium bicarbonate was discontinued, net acid excretion returned promptly to control-period levels (73.2 ±9.9 meq per day per 60 kg) (Figure 2).

View larger version (25K): [in this window] [in a new window]   Figure 2. Effect of Potassium Bicarbonate Supplementation on Net Renal Acid Excretion. The narrow vertical lines above the bars represent 1 SE.

 
Discussion

Bone mineral base is released into the systemic circulation when exogenous acid is administered^3,4,20,21,22. When acid loading is continued for several weeks or months, excretion of acid in urine -- quantitatively the principal component of the homeostatic response to an exogenous acid load -- fails to keep pace with the increased load^20,21. Mobilization of bone alkali continues, bone mineral content and bone mass progressively decline,^{23,24,25,26,27} and osteoporosis occurs^{23,24,26,27,28,29}. In bone studied in vitro, extracellular acidification increases the activity of osteoclasts, the cells that mediate bone resorption,^7,30,31,32 and inhibits the activity of osteoblasts, the cells that mediate bone formation⁷.

Lifelong ingestion of ordinary diets constitutes a less intense, more prolonged variant of the short-term experimental administration of large exogenous acid loads. Typical American diets are acid-producing in that renal excretion of acid exceeds excretion of base, and when measured directly, the net balance of endogenous acid (production less excretion) is positive^3,8. The rate of endogenous acid production is low, however, compared with that induced experimentally with exogenous acid loads. On average, in healthy subjects eating ordinary diets, net renal acid excretion very nearly equals systemic net acid production, hence on average there is no apparent retention of acid that might require, or induce, mobilization of bone mineral base^3,8. But even with an average value of zero for net acid balance, it is possible that some people have a positive acid balance. Published data indicate that a subgroup of healthy subjects do indeed retain acid in the steady state². Acid balance correlates directly with endogenous acid production². A person will have a positive acid balance if his or her rate of acid production is in the upper half of the normal range, and the balance will more often be positive than negative when acid production is in the mid-normal range².

Thus, even with average rates of endogenous acid production, the kidney fails to keep pace with acid production, with the result that acid is continually retained in the body. Indeed, in normal subjects eating diets that yield rates of endogenous acid production spanning the normal range (0 to 150 mmol per day), we found that steady-state blood acidity was higher and plasma bicarbonate concentrations were lower in direct relation to the steady-state rate of endogenous acid production².

Clearly then, within its normal range, diet-dependent production of endogenous acid can impose an acid load on the body, resulting in both steady-state increases in blood acidity and retention of acid². Although blood pH stabilizes at a progressively lower level with each increasing level of acid production within the normal range, the fact that stability occurs at each level implies a continuing supply of base from an internal reservoir, presumably the skeleton.

If typical acid-producing diets result in a continuing drain on bone mineral base, supplementing the diets with exogenous base might neutralize the acid produced and thereby eliminate the drain on bone. In that case, calcium and phosphorus balance should improve and the rate of bone resorption should decrease. To test that possibility, we measured external calcium and phosphorus balance and urinary hydroxyproline excretion in postmenopausal women who received potassium bicarbonate (60 to 120 mmol per day per 60 kg) as a dietary supplement. The women ate a typical whole-food diet and had a rate of production of endogenous acid, estimated on the basis of their net acid excretion (50 to 90 mmol per day per 60 kg), that predictably produced a positive acid balance. The administration of potassium bicarbonate induced a significant increase in both the calcium and the phosphorus balance, resulting predominantly from the reduced urinary excretion of these minerals. The improvement in phosphorus balance correlated with an improvement in calcium balance; on a molar basis, the slope of the relation was 1.0, suggesting that one mole of phosphorus was retained per mole of calcium retained. Since the phosphorus:calcium ratio in hydroxyapatite is less than 1.0 (6:10), adequate phosphorus was retained to permit calcium retention as hydroxyapatite. Supplementation with potassium bicarbonate also reduced urinary excretion of hydroxyproline, in association with an increase in the serum osteocalcin concentration. Thus, the administration of potassium bicarbonate appeared to reduce the rate of bone resorption and increase the rate of bone formation.

Taken together, these results suggest that countering the normal diet-related production of endogenous acid with orally administered potassium bicarbonate can attenuate or reverse the loss of bone mass that occurs over the long term in postmenopausal women. Our findings extend those of Lutz³³ that the oral administration of alkali (by means of substitution of sodium bicarbonate for dietary sodium chloride) can improve calcium balance in postmenopausal women, those of Lemann et al.³⁴. that orally administered potassium bicarbonate (but not sodium bicarbonate) can improve calcium and phosphorus balance in young men, and those of Barzel³⁵ that orally administered potassium bicarbonate and sodium bicarbonate in combination can attenuate the negative calcium balance induced by immobilization.

Increased plasma acidity or decreased plasma bicarbonate concentrations might stimulate bone resorption directly by favoring the physicochemical process of mineral dissolution and indirectly by reducing the pH and bicarbonate concentration within osteoclasts, thus promoting the adhesion of those cells to their bone-resorptive sites and the secretion of hydrogen ions into the subapical bone-resorbing fluid compartment^{4,5,6,7,26,30,31,32}. Acidosis also inhibits osteoblast function,⁷ potentially inhibiting bone formation.

Our findings suggest that in postmenopausal women, dietary supplementation with oral potassium bicarbonate in doses sufficient to reduce the net production of endogenous acid reduces the rate of bone resorption, increases the rate of bone formation, and attenuates or reverses the loss of bone in defense of systemic acid-base homeostasis. These findings are consistent with current knowledge of the acid-base responses of osteoclasts and osteoblasts studied in vitro; they suggest that the age-related reduction in bone mass may result at least in part from the cumulative effect of skeletal buffering of diet-dependent endogenous acid production. The long-term administration of potassium bicarbonate may therefore be effective in preventing and treating postmenopausal osteoporosis.

Supported by grants from the Public Health Service (P01DK 39964, R01 DK32631, and M01 00079) and the University of California, San Francisco, Research Evaluation and Allocation Committee (MSC-22) and Academic Senate, and by gifts from Church and Dwight Company and the Emil Mosbacher, Jr., Foundation.

We are indebted to the staff of the General Clinical Research Center, in particular the nursing staff under the direction of DeAnna Sheeley, R.N., and the late Maureen Ford, R.N., and the laboratory and dietary staff; to Ms. Patricia Douglass for her administrative contributions at all phases of the project; to Claude D. Arnaud, M.D., for counsel, encouragement, and support; to Vicki McKee, F.N.P., for help in recruiting subjects and implementing the protocol; to Anthony A. Portale, M.D., for advice on laboratory methods and other helpful discussions; to Mr. B. Muiz Brinkerhoff for data management; and to Renee Merriam, R.N., for organizational support.

Source Information

From the Department of Medicine and the General Clinical Research Center, Moffitt-Long Hospitals, University of California, San Francisco.

Address reprint requests to Dr. Sebastian at Box 0126, University of California, San Francisco, CA 94143.

References

1. Wachman A, Bernstein DS. Diet and osteoporosis. Lancet 1968;1:958-959. [Medline]
2. Kurtz I, Maher T, Hulter HN, Schambelan M, Sebastian A. Effect of diet on plasma acid-base composition in normal humans. Kidney Int 1983;24:670-680. [Medline]
3. Kleinman JG, Lemann J Jr. Acid production. In: Maxwell MH, Kleeman CR, Narins RG, eds. Clinical disorders of fluid and electrolyte metabolism. 4th ed. New York: McGraw-Hill, 1987:159-73.
4. Bushinsky DA. Internal exchanges of hydrogen ions: bone. In: Seldin DW, Giebisch G, eds. The regulation of acid-base balance. New York: Raven Press, 1989:69-88.
5. Bushinsky DA, Sessler NE, Krieger NS. Greater unidirectional calcium efflux from bone during metabolic, compared with respiratory, acidosis. Am J Physiol 1992;262:F425-F431. [Free Full Text]
6. Bushinsky DA, Sessler NE. Critical role of bicarbonate in calcium release from bone. Am J Physiol 1992;263:F510-F515. [Free Full Text]
7. Krieger NS, Sessler NE, Bushinsky DA. Acidosis inhibits osteoblastic and stimulates osteoclastic activity in vitro. Am J Physiol 1992;262:F442-F448. [Free Full Text]
8. Lennon EJ, Lemann J Jr, Litzow JR. The effects of diet and stool composition on the net external acid balance of normal subjects. J Clin Invest 1966;45:1601-1607.
9. Weigley ES. Average? Ideal? Desirable? A brief overview of height-weight tables in the United States. J Am Diet Assoc 1984;84:417-423. [Medline]
10. Sakhaee K, Nicar M, Hill K, Pak CYC. Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts. Kidney Int 1983;24:348-352. [Medline]
11. Epstein S. Serum and urinary markers of bone remodeling: assessment of bone turnover. Endocr Rev 1988;9:437-449. [Free Full Text]
12. Deacon AC, Hulme P, Hesp R, Green JR, Tellez M, Reeve J. Estimation of whole body bone resorption rate: a comparison of urinary total hydroxyproline excretion with two radioisotopic tracer methods in osteoporosis. Clin Chim Acta 1987;166:297-306. [CrossRef][Medline]
13. Charles P, Poser JW, Mosekilde L, Jensen FT. Estimation of bone turnover evaluated by ⁴⁷Ca-kinetics: efficiency of serum bone gamma-carboxyglutamic acid-containing protein, serum alkaline phosphatase, and urinary hydroxyproline excretion. J Clin Invest 1985;76:2254-2258.
14. Klein L, Lafferty FW, Pearson OH, Curtiss PH Jr. Correlation of urinary hydroxyproline, serum alkaline phosphatase and skeletal calcium turnover. Metabolism 1964;13:272-284. [CrossRef][Medline]
15. Hyldstrup L, Clemmensen I, Jensen BA, Transbol I. Non-invasive evaluation of bone formation: measurements of serum alkaline phosphatase, whole body retention of diphosphonate and serum osteocalcin in metabolic bone disorders and thyroid disease. Scand J Clin Lab Invest 1988;48:611-619. [CrossRef][Medline]
16. Johansen JS, Giwercman A, Hartwell D, et al. Serum bone Gla-protein as a marker of bone growth in children and adolescents: correlation with age, height, serum insulin-like growth factor I, and serum testosterone. J Clin Endocrinol Metab 1988;67:273-278. [Free Full Text]
17. Worsfold M, Sharp CA, Davie MWJ. Serum osteocalcin and other indices of bone formation: an 8-decade population study in healthy men and women. Clin Chim Acta 1988;178:225-235. [CrossRef][Medline]
18. Brown JP, Delmas PD, Malaval L, Edouard C, Chapuy MC, Meunier PJ. Serum bone Gla-protein: a specific marker for bone formation in postmenopausal osteoporosis. Lancet 1984;1:1091-1093. [Medline]
19. Jones JW, Sebastian A, Hulter HN, Schambelan M, Sutton JM, Biglieri EG. Systemic and renal acid-base effects of chronic dietary potassium depletion in humans. Kidney Int 1982;21:402-410. [Medline]
20. Lemann J Jr, 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;45:1608-1614.
21. Lemann J Jr, Lennon EJ, Goodman AD, Litzow JR, Relman AS. The net balance of acid in subjects given large loads of acid or alkali. J Clin Invest 1965;44:507-517.
22. Lemann J Jr, Litzow JR, Lennon EJ. Studies of the mechanism by which chronic metabolic acidosis augments urinary calcium excretion in man. J Clin Invest 1967;46:1318-1328. [Medline]
23. Barzel US, Jowsey J. The effects of chronic acid and alkali administration on bone turnover in adult rats. Clin Sci 1969;36:517-524. [Medline]
24. Barzel US. The effect of excessive acid feeding on bone. Calcif Tissue Res 1969;4:94-100. [CrossRef][Medline]
25. Burnell JM. Changes in bone sodium and carbonate in metabolic acidosis and alkalosis in the dog. J Clin Invest 1971;50:327-331.
26. Delling G, Donath K. Morphometrische, elektronenmikroskopische und physikalisch-chemische Untersuchungen uber die experimentelle Osteoporose bei chronischer Acidose. Virchows Arch [A] Pathol Anat 1973;358:321-30.
27. Barzel US. Acid-induced osteoporosis: an experimental model of human osteoporosis. Calcif Tissue Res 1976;21:Suppl:417-422.
28. Jaffe HL, Bodansky A, Chandler JP. Ammonium chloride decalcification, as modified by calcium intake: the relation between generalized osteoporosis and ostitis fibrosa. J Exp Med 1932;56:823-834. [Abstract]
29. Bernstein DS, Wachman A, Hattner RS. Acid base balance in metabolic bone disease. In: Barzel US, ed. Osteoporosis. New York: Grune & Stratton, 1970:207-16.
30. Arnett TR, Dempster DW. Effect of pH on bone resorption by rat osteoclasts in vitro. Endocrinology 1986;119:119-124. [Free Full Text]
31. Goldhaber P, Rabadjija L. H+ stimulation of cell-mediated bone resorption in tissue culture. Am J Physiol 1987;253:E90-E98. [Free Full Text]
32. Teti A, Blair HC, Schlesinger P, et al. Extracellular protons acidify osteoclasts, reduce cytosolic calcium, and promote expression of cell-matrix attachment structures. J Clin Invest 1989;84:773-780.
33. Lutz J. Calcium balance and acid-base status of women as affected by increased protein intake and by sodium bicarbonate ingestion. Am J Clin Nutr 1984;39:281-288. [Free Full Text]
34. Lemann J Jr, Gray RW, Pleuss JA. Potassium bicarbonate, but not sodium bicarbonate, reduces urinary calcium excretion and improves calcium balance in healthy men. Kidney Int 1989;35:688-695. [Medline]
35. Barzel US. Alkali therapy in immobilization osteoporosis. Israel J Med Sci 1971;7:499.

Abstract Letters Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

Related Letters:

Mineral Balance in Postmenopausal Women Treated With Potassium Bicarbonate
Wood R. J., Sebastian A., Morris R. C.
Extract | Full Text  
N Engl J Med 1994; 331:1312-1313, Nov 10, 1994. Correspondence

Clinical Problem-Solving: Necrotizing Fasciitis
Kaufman J. L., Korzets A., Cohen E., Zahavi I., Thibault G. E.
Extract | Full Text  
N Engl J Med 1994; 331:279-280, Jul 28, 1994. Correspondence

This article has been cited by other articles:

• Kerstetter, J. E (2009). Dietary protein and bone: a new approach to an old question. Am. J. Clin. Nutr. 90: 1451-1452 [Full Text]  
• Ceglia, L., Harris, S. S., Abrams, S. A., Rasmussen, H. M., Dallal, G. E., Dawson-Hughes, B. (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: 645-653 [Abstract] [Full Text]  
• Fenton, T. R, Eliasziw, M., Lyon, A. W, Tough, S. C, Hanley, D. A (2008). Meta-analysis of the quantity of calcium excretion associated with the net acid excretion of the modern diet under the acid-ash diet hypothesis. Am. J. Clin. Nutr. 88: 1159-1166 [Abstract] [Full Text]  
• Macdonald, H. M, Black, A. J, Aucott, L., Duthie, G., Duthie, S., Sandison, R., Hardcastle, A. C, Lanham New, S. A, Fraser, W. D, Reid, D. M (2008). Effect of potassium citrate supplementation or increased fruit and vegetable intake on bone metabolism in healthy postmenopausal women: a randomized controlled trial. Am. J. Clin. Nutr. 88: 465-474 [Abstract] [Full Text]  
• Bonny, O., Rubin, A., Huang, C.-L., Frawley, W. H., Pak, C. Y.C., Moe, O. W. (2008). Mechanism of Urinary Calcium Regulation by Urinary Magnesium and pH. J. Am. Soc. Nephrol. 19: 1530-1537 [Abstract] [Full Text]  
• Burckhardt, P. (2008). The Effect of the Alkali Load of Mineral Water on Bone Metabolism: Interventional Studies. J. Nutr. 138: 435S-437S [Abstract] [Full Text]  
• Thorpe, M., Mojtahedi, M. C., Chapman-Novakofski, K., McAuley, E., Evans, E. M. (2008). A Positive Association of Lumbar Spine Bone Mineral Density with Dietary Protein Is Suppressed by a Negative Association with Protein Sulfur. J. Nutr. 138: 80-85 [Abstract] [Full Text]  
• Rafferty, K., Heaney, R. P. (2008). Nutrient Effects on the Calcium Economy: Emphasizing the Potassium Controversy. J. Nutr. 138: 166S-171S [Abstract] [Full Text]  
• Lanham-New, S. A. (2008). The Balance of Bone Health: Tipping the Scales in Favor of Potassium-Rich, Bicarbonate-Rich Foods. J. Nutr. 138: 172S-177S [Abstract] [Full Text]  
• Vatanparast, H., Bailey, D. A., Baxter-Jones, A. D. G., Whiting, S. J. (2007). The Effects of Dietary Protein on Bone Mineral Mass in Young Adults May Be Modulated by Adolescent Calcium Intake. J. Nutr. 137: 2674-2679 [Abstract] [Full Text]  
• Sharma, A. P., Sharma, R. K., Kapoor, R., Kornecki, A., Sural, S., Filler, G. (2007). Incomplete distal renal tubular acidosis affects growth in children. Nephrol Dial Transplant 22: 2879-2885 [Abstract] [Full Text]  
• Frassetto, L. A., Morris, R. C. Jr., Sebastian, A. (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. 293: F521-F525 [Abstract] [Full Text]  
• Welch, A. A, Bingham, S. A, Reeve, J., Khaw, K. (2007). More acidic dietary acid-base load is associated with reduced calcaneal broadband ultrasound attenuation in women but not in men: results from the EPIC-Norfolk cohort study. Am. J. Clin. Nutr. 85: 1134-1141 [Abstract] [Full Text]  
• Jehle, S., Zanetti, A., Muser, J., Hulter, H. N., Krapf, R. (2006). Partial Neutralization of the Acidogenic Western Diet with Potassium Citrate Increases Bone Mass in Postmenopausal Women with Osteopenia. J. Am. Soc. Nephrol. 17: 3213-3222 [Abstract] [Full Text]  
• Heaney, R. P (2006). Absorbability and utility of calcium in mineral waters.. Am. J. Clin. Nutr. 84: 371-374 [Abstract] [Full Text]  
• Felsenfeld, A. J., Levine, B. S. (2006). Milk Alkali Syndrome and the Dynamics of Calcium Homeostasis. CJASN 1: 641-654 [Full Text]  
• Lanham-New, S. A (2006). Fruit and vegetables: the unexpected natural answer to the question of osteoporosis prevention?. Am. J. Clin. Nutr. 83: 1254-1255 [Full Text]  
• Morris, R. C. Jr., Schmidlin, O., Frassetto, L. A., Sebastian, A. (2006). Relationship and Interaction between Sodium and Potassium.. J. Am. Coll. Nutr. 25: 262S-270S [Abstract] [Full Text]  
• Heaney, R. P. (2006). Role of dietary sodium in osteoporosis.. J. Am. Coll. Nutr. 25: 271S-276S [Abstract] [Full Text]  
• Bonjour, J.-P. (2005). Dietary Protein: An Essential Nutrient For Bone Health. J. Am. Coll. Nutr. 24: 526S-536S [Abstract] [Full Text]  
• Sebastian, A. (2005). Dietary protein content and the diet's net acid load: opposing effects on bone health. Am. J. Clin. Nutr. 82: 921-922 [Full Text]  
• Remer, T., Berkemeyer, S. (2005). Letter re: Persistent Hypocalciuric Effect of Potassium Bicarbonate in Postmenopausal Women. J. Clin. Endocrinol. Metab. 90: 4980-4981 [Full Text]  
• Sebastian, A., Frassetto, L., Morris, R. C. Jr. (2005). Authors' Response: Long-Term Persistence of the Urine Calcium-Lowering Effect of Potassium Bicarbonate in Postmenopausal Women. J. Clin. Endocrinol. Metab. 90: 4417-4418 [Full Text]  
• Sakhaee, K., Maalouf, N. M., Abrams, S. A., Pak, C. Y. C. (2005). Effects of Potassium Alkali and Calcium Supplementation on Bone Turnover in Postmenopausal Women. J. Clin. Endocrinol. Metab. 90: 3528-3533 [Abstract] [Full Text]  
• Macdonald, H. M, New, S. A, Fraser, W. D, Campbell, M. K, Reid, D. M (2005). Low dietary potassium intakes and high dietary estimates of net endogenous acid production are associated with low bone mineral density in premenopausal women and increased markers of bone resorption in postmenopausal women. Am. J. Clin. Nutr. 81: 923-933 [Abstract] [Full Text]  
• Rafferty, K., Davies, K. M., Heaney, R. P. (2005). Potassium Intake and the Calcium Economy. J. Am. Coll. Nutr. 24: 99-106 [Abstract] [Full Text]  
• He, F. J., Markandu, N. D., Coltart, R., Barron, J., MacGregor, G. A. (2005). Effect of Short-Term Supplementation of Potassium Chloride and Potassium Citrate on Blood Pressure in Hypertensives. Hypertension 45: 571-574 [Abstract] [Full Text]  
• Cordain, L., Eaton, S B., Sebastian, A., Mann, N., Lindeberg, S., Watkins, B. A, O'Keefe, J. H, Brand-Miller, J. (2005). Origins and evolution of the Western diet: health implications for the 21st century. Am. J. Clin. Nutr. 81: 341-354 [Abstract] [Full Text]  
• Frassetto, L., Morris, R. C. Jr., Sebastian, A. (2005). Long-Term Persistence of the Urine Calcium-Lowering Effect of Potassium Bicarbonate in Postmenopausal Women. J. Clin. Endocrinol. Metab. 90: 831-834 [Abstract] [Full Text]  
• Kerstetter, J. E., O'Brien, K. O., Caseria, D. M., Wall, D. E., Insogna, K. L. (2005). The Impact of Dietary Protein on Calcium Absorption and Kinetic Measures of Bone Turnover in Women. J. Clin. Endocrinol. Metab. 90: 26-31 [Abstract] [Full Text]  
• Ince, B. A., Anderson, E. J., Neer, R. M. (2004). Lowering Dietary Protein to U.S. Recommended Dietary Allowance Levels Reduces Urinary Calcium Excretion and Bone Resorption in Young Women. J. Clin. Endocrinol. Metab. 89: 3801-3807 [Abstract] [Full Text]  
• Tylavsky, F. A, Holliday, K., Danish, R., Womack, C., Norwood, J., Carbone, L. (2004). Fruit and vegetable intakes are an independent predictor of bone size in early pubertal children. Am. J. Clin. Nutr. 79: 311-317 [Abstract] [Full Text]  
• New, S. A, MacDonald, H. M, Campbell, M. K, Martin, J. C, Garton, M. J, Robins, S. P, Reid, D. M (2004). Lower estimates of net endogenous noncarbonic acid production are positively associated with indexes of bone health in premenopausal and perimenopausal women. Am. J. Clin. Nutr. 79: 131-138 [Abstract] [Full Text]  
• Macdonald, H. M, New, S. A, Golden, M. H., Campbell, M. K, Reid, D. M (2004). Nutritional associations with bone loss during the menopausal transition: evidence of a beneficial effect of calcium, alcohol, and fruit and vegetable nutrients and of a detrimental effect of fatty acids. Am. J. Clin. Nutr. 79: 155-165 [Abstract] [Full Text]  
• Lemann, J. Jr., Bushinsky, D. A., Hamm, L. L. (2003). Bone buffering of acid and base in humans. Am. J. Physiol. Renal Physiol. 285: F811-F832 [Abstract] [Full Text]  
• Lin, P.-H., Ginty, F., Appel, L. J., Aickin, M., Bohannon, A., Garnero, P., Barclay, D., Svetkey, L. P. (2003). The DASH Diet and Sodium Reduction Improve Markers of Bone Turnover and Calcium Metabolism in Adults. J. Nutr. 133: 3130-3136 [Abstract] [Full Text]  
• Kerstetter, J. E, O'Brien, K. O, Insogna, K. L (2003). Dietary protein, calcium metabolism, and skeletal homeostasis revisited. Am. J. Clin. Nutr. 78: 584S-592 [Abstract] [Full Text]  
• Jenkins, D. J., Kendall, C. W., Marchie, A., Jenkins, A. L, Augustin, L. S., Ludwig, D. S, Barnard, N. D, Anderson, J. W (2003). Type 2 diabetes and the vegetarian diet. Am. J. Clin. Nutr. 78: 610S-616 [Abstract] [Full Text]  
• Rapuri, P. B, Gallagher, J C., Haynatzka, V. (2003). Protein intake: effects on bone mineral density and the rate of bone loss in elderly women. Am. J. Clin. Nutr. 77: 1517-1525 [Abstract] [Full Text]  
• Remer, T., Dimitriou, T., Manz, F. (2003). Dietary potential renal acid load and renal net acid excretion in healthy, free-living children and adolescents. Am. J. Clin. Nutr. 77: 1255-1260 [Abstract] [Full Text]  
• Kerstetter, J. E., O'Brien, K. O., Insogna, K. L. (2003). Low Protein Intake: The Impact on Calcium and Bone Homeostasis in Humans. J. Nutr. 133: 855S-861 [Abstract] [Full Text]  
• Maurer, M., Riesen, W., Muser, J., Hulter, H. N., Krapf, R. (2003). Neutralization of Western diet inhibits bone resorption independently of K intake and reduces cortisol secretion in humans. Am. J. Physiol. Renal Physiol. 284: F32-F40 [Abstract] [Full Text]  
• Sebastian, A., Frassetto, L. A, Sellmeyer, D. E, Merriam, R. L, Morris, R C. Jr (2002). Estimation of the net acid load of the diet of ancestral preagricultural Homo sapiens and their hominid ancestors. Am. J. Clin. Nutr. 76: 1308-1316 [Abstract] [Full Text]  
• Morris, R. C. Jr., Sebastian, A. (2002). Alkali Therapy In Renal Tubular Acidosis: Who Needs It?. J. Am. Soc. Nephrol. 13: 2186-2188 [Full Text]  
• Sellmeyer, D. E., Schloetter, M., Sebastian, A. (2002). Potassium Citrate Prevents Increased Urine Calcium Excretion and Bone Resorption Induced by a High Sodium Chloride Diet. J. Clin. Endocrinol. Metab. 87: 2008-2012 [Abstract] [Full Text]  
• 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: 773-779 [Abstract] [Full Text]  
• Remer, T., Manz, F. (2001). Don't Forget the Acid Base Status When Studying Metabolic and Clinical Effects of Dietary Potassium Depletion. J. Clin. Endocrinol. Metab. 86: 5996-5996 [Full Text]  
• He, F. J, MacGregor, G. A (2001). Fortnightly review: Beneficial effects of potassium. BMJ 323: 497-501 [Full Text]  
• Heaney, R. P. (2001). Calcium Needs of the Elderly to Reduce Fracture Risk. J. Am. Coll. Nutr. 20: 192S-197 [Abstract] [Full Text]  
• Sellmeyer, D. E, Stone, K. L, Sebastian, A., Cummings, S. R (2001). A high ratio of dietary animal to vegetable protein increases the rate of bone loss and the risk of fracture in postmenopausal women. Am. J. Clin. Nutr. 73: 118-122 [Abstract] [Full Text]  
• Frassetto, L. A., Todd, K. M., Morris, R. C. Jr., Sebastian, A. (2000). Worldwide Incidence of Hip Fracture in Elderly Women: Relation to Consumption of Animal and Vegetable Foods. Journals of Gerontology Series A: Biological Sciences and Medical Sciences 55: 585M-592 [Abstract] [Full Text]  
• Weinsier, R. L, Krumdieck, C. L (2000). Dairy foods and bone health: examination of the evidence. Am. J. Clin. Nutr. 72: 681-689 [Abstract] [Full Text]  
• Weger, W., Kotanko, P., Weger, M., Deutschmann, H., Skrabal, F. (2000). Prevalence and characterization of renal tubular acidosis in patients with osteopenia and osteoporosis and in non-porotic controls. Nephrol Dial Transplant 15: 975-980 [Abstract] [Full Text]  
• Ilich, J. Z., Kerstetter, J. E. (2000). Nutrition in Bone Health Revisited: A Story Beyond Calcium. J. Am. Coll. Nutr. 19: 715-737 [Abstract] [Full Text]  
• Gueguen, L., Pointillart, A. (2000). The Bioavailability of Dietary Calcium. J. Am. Coll. Nutr. 19: 119S-136 [Abstract] [Full Text]  
• New, S. A, Robins, S. P, Campbell, M. K, Martin, J. C, Garton, M. J, Bolton-Smith, C., Grubb, D. A, Lee, S. J, Reid, D. M (2000). Dietary influences on bone mass and bone metabolism: further evidence of a positive link between fruit and vegetable consumption and bone health?1. Am. J. Clin. Nutr. 71: 142-151 [Abstract] [Full Text]  
• Frick, K. K., Bushinsky, D. A. (1999). In vitro metabolic and respiratory acidosis selectively inhibit osteoblastic matrix gene expression. Am. J. Physiol. Renal Physiol. 277: F750-F755 [Abstract] [Full Text]  
• Heller, H. J. (1999). The Role of Calcium in the Prevention of Kidney Stones. J. Am. Coll. Nutr. 18: 373S-378 [Abstract] [Full Text]  
• Weaver, C. M, Proulx, W. R, Heaney, R. (1999). Choices for achieving adequate dietary calcium with a vegetarian diet. Am. J. Clin. Nutr. 70: 543S-548 [Abstract] [Full Text]  
• Orr-Walker, B. J., Horne, A. M., Evans, M. C., Grey, A. B., Murray, M. A. F., McNeil, A. R., Reid, I. R. (1999). Hormone Replacement Therapy Causes a Respiratory Alkalosis in Normal Postmenopausal Women. J. Clin. Endocrinol. Metab. 84: 1997-2001 [Abstract] [Full Text]  
• Tucker, K. L, Hannan, M. T, Chen, H., Cupples, L A., Wilson, P. W., Kiel, D. P (1999). Potassium, magnesium, and fruit and vegetable intakes are associated with greater bone mineral density in elderly men and women. Am. J. Clin. Nutr. 69: 727-736 [Abstract] [Full Text]  
• Kerstetter, J. E., Mitnick, M. E., Gundberg, C. M., Caseria, D. M., Ellison, A. F., Carpenter, T. O., Insogna, K. L. (1999). Changes in Bone Turnover in Young Women Consuming Different Levels of Dietary Protein. J. Clin. Endocrinol. Metab. 84: 1052-1055 [Abstract] [Full Text]  
• Munger, R. G, Cerhan, J. R, Chiu, B. C-H (1999). Prospective study of dietary protein intake and risk of hip fracture in postmenopausal women. Am. J. Clin. Nutr. 69: 147-152 [Abstract] [Full Text]  
• Morris, R. C. Jr, Sebastian, A., Forman, A., Tanaka, M., Schmidlin, O. (1999). Normotensive Salt Sensitivity : Effects of Race and Dietary Potassium. Hypertension 33: 18-23 [Abstract] [Full Text]  
• Frick, K. K., Bushinsky, D. A. (1998). Chronic metabolic acidosis reversibly inhibits extracellular matrix gene expression in mouse osteoblasts. Am. J. Physiol. Renal Physiol. 275: F840-F847 [Abstract] [Full Text]  
• Massey, L. K. (1998). Does Excess Dietary Protein Adversely Affect Bone? Symposium Overview. J. Nutr. 128: 1048-1050 [Full Text]  
• Barzel, U. S., Massey, L. K. (1998). Excess Dietary Protein Can Adversely Affect Bone. J. Nutr. 128: 1051-1053 [Abstract] [Full Text]  
• 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: 148-154 [Abstract] [Full Text]  
• McCarron, D. A., Barzel, U. S., Sharma, A. M., Schorr, U., Appel, L. J., Moore, T. J., Obarzanek, E., The DASH Collaborative Research Group, (1997). Dietary Patterns and Blood Pressure. NEJM 337: 636-638 [Full Text]  
• Frassetto, L., Morris, R. C. Jr., Sebastian, A. (1997). Potassium Bicarbonate Reduces Urinary Nitrogen Excretion in Postmenopausal Women. J. Clin. Endocrinol. Metab. 82: 254-259 [Abstract] [Full Text]  
• Wood, R. J., Sebastian, A., Morris, R. C. (1994). Mineral Balance in Postmenopausal Women Treated With Potassium Bicarbonate. NEJM 331: 1312-1313 [Full Text]  
• Sebastian, A., Morris, R. C. (1994). Improved Mineral Balance and Skeletal Metabolism in Postmenopausal Women Treated with Potassium Bicarbonate. NEJM 331: 279-279 [Full Text]  
• Kraut, J. A., Coburn, J. W. (1994). Bone, Acid, and Osteoporosis. NEJM 330: 1821-1822 [Full Text]  
• Bushinsky, D. A., Parker, W. R., Alexander, K. M., Krieger, N. S. (2001). Metabolic, but not respiratory, acidosis increases bone PGE2 levels and calcium release. Am. J. Physiol. Renal Physiol. 281: F1058-F1066 [Abstract] [Full Text]