1 Medizinische Universitätsklinik und Zentrallabor, Kantonsspital Bruderholz, CH-4101 Bruderholz/Basel; 2 Institut für klinische Chemie und Hämatologie, Kantonsspital, CH-9007 St. Gallen, Switzerland; and 3 Genentech, Incorporated, South San Francisco, California 94080-4990
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A Western-type diet is associated with osteoporosis and calcium nephrolithiasis. On the basis of observations that calcium retention and inhibition of bone resorption result from alkali administration, it is assumed that the acid load inherent in this diet is responsible for increased bone resorption and calcium loss from bone. However, it is not known whether the dietary acid load acts directly or indirectly (i.e., via endocrine changes) on bone metabolism. It is also unclear whether alkali administration affects bone resorption/calcium balance directly or whether alkali-induced calcium retention is dependent on the cation (i.e., potassium) supplied with administered base. The effects of neutralization of dietary acid load (equimolar amounts of NaHCO3 and KHCO3 substituted for NaCl and KCl) in nine healthy subjects (6 men, 3 women) under metabolic balance conditions on calcium balance, bone markers, and endocrine systems relevant to bone [glucocorticoid secretion, IGF-1, parathyroid hormone (PTH)/1,25(OH)2 vitamin D and thyroid hormones] were studied. Neutralization for 7 days induced a significant cumulative calcium retention (10.7 ± 0.4 mmol) and significantly reduced the urinary excretion of deoxypyridinoline, pyridinoline, and n-telopeptide. Mean daily plasma cortisol decreased from 264 ± 45 to 232 ± 43 nmol/l (P = 0.032), and urinary excretion of tetrahydrocortisol (THF) decreased from 2,410 ± 210 to 2,098 ± 190 µg/24 h (P = 0.027). No significant effect was found on free IGF-1, PTH/1,25(OH)2 vitamin D, or thyroid hormones. An acidogenic Western diet results in mild metabolic acidosis in association with a state of cortisol excess, altered divalent ion metabolism, and increased bone resorptive indices. Acidosis-induced increases in cortisol secretion and plasma concentration may play a role in mild acidosis-induced alterations in bone metabolism and possibly in osteoporosis associated with an acidogenic Western diet.
glucocorticoid; acid-base; potassium; acidosis; osteoporosis
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
CHRONIC METABOLIC ACIDOSIS (CMA) is a frequent acid-base disturbance generated by extrarenal loss of base (e.g, diarrhea), increased acid production (e.g., organic acidosis such as ketoacidosis), or impaired renal acid excretion (i.e., renal failure and inherited or acquired forms of renal tubular acidosis).
CMA has a well-established potential for a catabolic effect on bone. In addition to renal phosphate wasting (28, 35, 36), experimentally induced CMA also results in hypercalciuria and negative calcium balance, attributable to calcium efflux from bone (10, 34). CMA is associated with a poorly characterized metabolic bone disease (23), growth retardation (40), and calcium nephrolithiasis (7). In animal models, CMA results in a decrease in bone calcium and gravimetrically determined bone mass (2), decreased wet tissue femur density (41), accelerated rates of cortical and trabecular bone resorption (2, 20, 29, 41), and diminished rates of bone formation (24), resulting in reduced trabecular bone volume (29, 41).
In vitro studies have demonstrated that metabolic acidosis (imitated by the use of media with low ambient pH and bicarbonate concentrations) is a potent stimulator of bone resorption and inhibitor of bone formation (11, 32), suggesting that CMA acts directly at the tissue level to affect bone metabolism. However, CMA also might affect bone metabolism indirectly, i.e., via numerous well-characterized alterations in endocrine function that include parathyroid, thyroid, adrenal and growth hormone (GH)/IGF-1 dysfunction.
CMA decreases free serum IGF-1 levels during CMA in rats and humans (8, 15) due to GH insensitivity (8), results in a mild form of hypothyroidism (9), and increases the serum 1,25(OH)2 vitamin D [1,25(OH)2D] concentration (due to renal phosphate wasting) in humans, resulting in a decreased serum parathyroid hormone (PTH) concentration (28).
In addition, a hyperglucocorticoid response to CMA has been demonstrated in humans (39) and rats (48). The hyperglucocorticoid response has generated substantial interest because it might explain the negative nitrogen balance of CMA reported in normal rats (39) and humans (1). Support for this possibility is that the catabolic muscle proteolytic effect of CMA demonstrable in vitro in muscle from normal rats was not found in muscle from adrenalectomized rats with CMA (39).
The modern Western-type diet in humans, which is rich in animal protein, has been implicated as a cause of lifelong mild CMA with secondary bone catabolism caused by the induction by this diet of an obligatory daily acid load (endogenous acid production), due largely to endogenous oxidation of cationic and sulfur-containing amino acids (46, 53). Although still within the broad range of normal values, plasma bicarbonate concentration decreases progressively when endogenous acid production is increased by menu changes among normal foodstuffs in normal subjects (33). In support of the hypothesis that ongoing metabolism of the Western diet can result in net bone catabolism, it was demonstrated that prolonged neutralization of endogenous acid production in postmenopausal women resulted in calcium and phosphate retention, reduced markers of bone resorption, and an increase in serum osteocalcin concentration, a marker of bone formation (46). Several uncontrolled observational studies have provided evidence that loss of bone mineral density (BMD) in elderly humans is less while they are ingesting a presumed alkali-rich diet with higher levels of estimated fruit and vegetable intake (42, 47, 51). These observational studies are intriguing but not compelling, however, both because acid excretion was not measured and because the Framingham database examined over the identical time interval that suggested both static and dynamic BMD protection with high fruit/vegetable intake (51) also provided seemingly contrary evidence that high animal protein (but not nonanimal protein) intake is protective for BMD loss, even after correction for multiple covariates (25).
In addition, there is considerable debate on the issue of whether an increase in potassium intake (typical of a vegetable-/fruit-rich diet) rather than the alkali per se is responsible for the salutary effects on bone. Indeed, studies that administered NaHCO3 and sodium citrate have found little effect on urinary calcium excretion (34, 38, 45), whereas those in which KHCO3 or potassium citrate were administered have found large, significant reductions (34, 45, 46).
The present study was designed to assess the possibility that even the mildest CMA of the magnitude reported with the Western diet might be sufficient to cause significant abnormalities in at least one of the reported bone-active endocrinopathies of CMA described above. Hyperglucorticoidism of very small magnitude was viewed as a particularly likely candidate as an effector for diet-induced bone catabolism because a recent retrospective cohort study found that even very low glucocorticoid doses within the physiological range (i.e., <2.5 mg oral prednisolone daily) significantly increased both vertebral and nonvertebral fracture risk relative to age- and gender-matched controls (52).
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The protocol was designed to measure the renal and systemic
electrolyte, acid-base, and endocrine response to neutralization of
endogenous acid production by oral ingestion of HCO
All subjects ingested 1.10 mmol chloride salt supplement/kg body
wt1 · day
1 during the
control (9 days) and the recovery periods (5 days). The daily chloride
supplement provided was equimolar (0.55 mmol/kg NaCl, 0.55 mmol/kg
KCl). To experimentally neutralize endogenous acid production, a 7-day
neutralization period followed the control period wherein equimolar
NaHCO3 was substituted for the NaCl supplement and
equimolar KHCO3 was substituted for KCl. All salts were
administered in gelatin capsules in six divided doses daily.
Fasting arterialized venous blood samples (22) were obtained in a heparin-coated syringe from a heated hand or forearm vein. Blood samples were accepted only when PO2 was >70 Torr (9.3 kPa) and were obtained at 8 AM unless otherwise specified.
All volunteers were paid for their participation and gave informed consent. The study protocol was approved by the ethics committee of the Kantonsspital, St. Gallen, Switzerland.
Analytic procedures. All measurements were performed in duplicate. Acid-base parameters in blood and urine were determined as described elsewhere (27). Analysis of hormones and their metabolites was performed as described previously (8, 9, 28, 48). Biochemical bone markers were determined using ELISA assays for deoxypyridinoline and pyridinoline (21) and n-telopeptide of type I collagen (24).
All steady-state values represent the mean of the last 2 days of the corresponding study period. Results are reported as means ± SE. Statistical analysis was performed by ANOVA for repeated measurements. Slope and intercept testing for plasma cortisol on time was performed using the general linear model procedure for two-way ANOVA with treatment and subject effects (SAS Institute, Cary, NC). ![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
All volunteers tolerated the protocol well. There were no
significant differences in body weights (Table
1) and blood pressure (not shown) during
any of the three study periods.
|
Administration of HCO
|
|
As shown in Fig. 1 and Table 2, urinary calcium excretion decreased
immediately, reversibly, and significantly during
HCO18 ± 7 mmol, values that did not differ
significantly from zero.
As shown in Table 2, the fractional renal excretion of calcium,
computed from the filtered load of ionized calcium, also decreased
significantly from 1.84 ± 0.09 (control) to 1.65 ± 0.08% during HCO
Figure 2 illustrates that markers of bone
resorption (i.e., the urinary excretion of deoxypyridinoline,
pyridinoline, and n-telopeptide of type I collagen)
decreased significantly during HCO
|
As neutralization of endogenous acid production might inhibit bone resorption by direct local acidification (±paracrine/autocrine effectors) and/or indirectly via alterations in endocrine systems known to be modulated by exogenous acid loads, i.e., the GH/IGF-1 axis, 1,25(OH)2D and PTH, thyroid hormones, and glucocorticoid activity (see the beginning of this study), we assessed these endocrine systems during steady states, i.e., the last 2 days of each study period.
As shown in Table 3, there were no
significant differences in the serum concentrations of free IgF-1,
1,25(OH)2D, and intact PTH among the three periods.
Similarly, serum TSH, free T3, and free T4 concentrations were also not
affected significantly by HCO
|
Table 4 demonstrates the diurnal changes
in plasma ACTH and plasma cortisol concentrations. No demonstrable
effect of alkali was noted on plasma ACTH levels throughout the day.
However, plasma cortisol concentration at 7 AM was reduced
significantly during the HCO periods; however, the mean y-intercept
cortisol value during the control/Cl
period significantly
exceeded the corresponding mean value in the HCO
|
|
To further analyze the effect of neutralization of endogenous acid
production on glucocorticoid activity/production, cortisol and cortisol
metabolites were determined in 24-h urine collections. As shown in
Table 6, HCO
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
These results furnish the first evidence that a very mild Western diet-induced CMA (a degree of acidosis that would not be recognized by applying diagnostic acid-base criteria found in textbooks) results in a state of increased cortisol secretion and plasma concentration and provides several novel findings in humans regarding the possible causality of the Western diet in the etiology of osteoporosis. The present results demonstrate that ingestion of neutralizing alkali per se, as exchanged for chloride in the absence of other experimental maneuvers (e.g., concomitant potassium supplement), can result in urinary calcium retention and suppression of biochemical markers of bone resorption. Finally, the present study demonstrates that neutralizing alkali administered to very youthful male and female adults during the bone-anabolizing interval before achievement of peak bone mass can reproduce the bone metabolic effects of alkali plus potassium reported in postmenopausal osteoporotic women (46).
This study establishes that the arithmetically trivial degree of Western diet-induced CMA is part of an endocrine-metabolic continuum that includes the well-established hyperglucocorticoidism of moderate-to-severe CMA (39, 44, 48, 54). When even very modest CMA, of the magnitude produced by a Western diet, can result in increased cortisol secretion and plasma concentration, the intriguing possibility arises that idiopathic osteoporosis and/or postmenopausal osteoporosis might be modulated, at least in part, by hypercortisolism. That mild hyperglucocorticoidism of long duration can lead to osteoporosis is supported by a recent retrospective cohort observation that even very low glucocorticoid doses (i.e., <2.5 mg oral prednisolone daily) significantly increased both vertebral and nonvertebral fracture risk relative to age- and gender-matched controls (52). Because the increased cortisol secretion and associated increase in plasma concentration demonstrated in the present study are probably of smaller magnitude than the net glucocorticoid effect achieved even by quite modest prednisone dosing, its contribution to long-term putative bone loss incurred by the Western diet would presumably require many years of adrenal hypersecretion. Importantly, the pathophysiology of glucocorticoid-induced osteoporosis in humans shares with postmenopausal osteoporosis the two fundamental features found in experimentally induced CMA, namely, decreased trabecular bone formation/osteoblast recruitment rate and a component of early accelerated resorption (14, 49).
The finding that the urinary ratio [THF+allo-THF]/THE is unchanged in
the prolonged transition from/to hypercortisolism of diet-induced CMA
suggests that 11-hydroxysteroid dehydrogenase type 1 isoform
(11
-HSD1) activity in liver and adipocytes and renal 11
-HSD2
activity are grossly normal. However, the skeletal activity of either
or both HSD isozymes is not known to be reflected in the excretion
rates of urinary metabolites. 11
-HSD1 is strongly expressed in
normal human bone in both osteoblasts and osteoclasts, whereas
11
-HSD2 is weakly expressed and only in osteoblasts (16, 18). The glucocorticoid receptor may only be expressed in
osteoblasts (5). The finding that administration of
carbenoxolone, a potent inhibitor of both 11
-HSD isozymes, to normal
subjects resulted in a significant decrease in pyridinoline and
deoxypyridinoline excretion (18) suggests that variation
in the activity of these isozymes in osteoblasts or osteoclasts or both
can result in important alterations in glucocorticoid receptor-mediated
action on bone metabolism. The recent in vitro findings that 11
-HSD1
(cortisol-generating) activity in human osteoblasts is increased by
increasing ambient cortisol concentrations and that its osteoblastic
activity is increased as a function of a subject's age provide
evidence that even very small increases in plasma cortisol
concentrations in humans may be subject to autocrine amplification
loops deleterious to skeletal function (17). Thus the
effects of CMA on these isozymes in bone remains an important
unanswered question.
The present results provide the first evidence in any species that the
alkali (as exchanged for chloride) vs. acid content of a diet per se,
rather than the specific effect of a coadministered alkali-associated
cation (sodium or potassium), modulates bone resorption and the
associated alterations in calcium and phosphate homeostasis. Whether
alkali per se has a clear role has remained a question because studies
in which NaHCO3 and sodium citrate were administered have
found little effect on calcium excretion (34, 38, 45),
whereas those administering KHCO3 or potassium citrate have
found significant reductions of large magnitude (38, 45,
46). The present study, by holding cation intake constant and
exchanging equimolar HCO
Part of the confusion over the relative hypocalciuric roles of alkali and coadministered cation has arisen because of the interpretation of a study in adult male subjects ingesting a normal diet in which sequential 4-day periods of KCl and then KHCO3 administration were undertaken (37). Both the authors of that study and others (12) have interpreted those data as indicating that KCl as well as KHCO3 administration to potassium-replete subjects resulted in decreased urinary calcium excretion, yet the reported data for the 4 days of KCl administration (unlike the KHCO3 results) showed no significant difference in calcium excretion relative to paired control values in the same subjects despite a similar magnitude of potassium retention with both potassium salts (37). Furthermore, in contrast to significant hypercalciuria produced by prolonged NaCl loading, no effect of prolonged KCl loading on calcium excretion was reported in healthy young women (3). On the basis of the in vivo literature to date, small alkali-independent effects of primary alterations in potassium balance on calcium retention would be difficult to detect in initially normokalemic animals or humans and have not been reported. However, by the use of a very low extracellular fluid potassium concentration of 1.0 mM, cultured murine calvariae exhibited an effect of low medium potassium concentration to increase calcium efflux, to increase a bone resorption marker, and to decrease bone collagen synthesis (12) in the absence of detectable acid-base change. The applicability of the in vitro data in calvariae to human potassium depletion is uncertain because the significant hypercalciuria reported in diet-induced potassium depletion in normal subjects was accompanied by renal NaCl retention and weight gain, suggesting a role for extracellular fluid volume expansion in the etiology of hypercalciuria (26). Thus whether the bone catabolism findings for a potassium-depleting environment in vitro predict an in vivo bone anabolic effect of potassium loading in potassium-replete humans awaits future studies.
The present studies do not exclude cortisol-independent mechanisms for
mild CMA-induced reversible effects on bone metabolism. Local
mechanisms in bone have been elucidated that might explain the effect
of CMA in causing bone loss. In mature mouse osteoclasts in culture,
acidified medium results in upregulation of both carbonic anhydrase II
and calcitonin receptor, the former being associated with increased
resorptive activity and the latter with suppressed osteoclastic
activity (12). In cultured murine calvariae, acidification of the medium results in calcium efflux accompanied by enhanced PGE2 production (30), and calcium efflux is
inhibited by both nonselective clyclooxygenase (COX) inhibitors and
COX-2-selective agents (31). Cultured osteoclasts also
exhibit important morphological and functional changes to acidified
media that include formation of the resorbing clear zone podosomes
(4) as well as augmentation of the final step in
resorption, activity of the V-type plasma membrane
H+-ATPase (43). Thus CMA-induced bone
catabolism might conceivably be mediated within bone by a variety of
plausible mechanisms. We also cannot exclude the possibility
that alkali-induced increases in distal HCO
We did not find evidence for an effect of neutralization of acidogenic diet on other endocrine axes [i.e., GH/IGF-1, PTH/1,25(OH)2D, and thyroid hormones], which are important to bone integrity and are affected by acidosis (Table 3). However, subtle regulatory alterations cannot be excluded, i.e., altered sensitivity of feedback loops and end-organ hormone (i.e., GH) sensitivities.
In summary, we have provided novel evidence that ingestion of an ordinary acidogenic Western diet to normal young adult subjects results in a mild CMA in association with a state of increased cortisol secretion and plasma concentration, altered divalent ion metabolism, and increased bone-resorptive indices. Because mild hyperglucocorticoidism is reported to result in an osteoporotic state that shares numerous qualitative and quantitative histomorphometric features with postmenopausal osteoporosis and with experimental CMA in animals, it is proposed that CMA-induced cortisol excess may play a role in mild CMA-induced alterations in bone metabolism in humans and possibly in osteoporosis associated with the Western acidogenic diet.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: R. Krapf, Medizinische Universitätsklinik, Kantonsspital Bruderholz, CH-4101 Bruderholz/Basel, Switzerland (E-mail: reto.krapf{at}ksbh.ch).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
September 24, 2002;10.1152/ajprenal.00212.2002
Received 5 June 2002; accepted in final form 8 August 2002.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Ballmer, PE,
McNurlan MA,
Hulter HN,
Anderson SE,
Garlick PE,
and
Krapf R.
Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans.
J Clin Invest
95:
39-45,
1995[ISI][Medline].
2.
Barzel, US,
and
Jowsey J.
The effects of chronic acid and alkali administration on bone turnover in adult rats.
Clin Sci (Colch)
36:
517-524,
1969[ISI][Medline].
3.
Bell, RR,
Eldrid MM,
and
Watson FR.
The influence of NaCl and KCl on urinary calcium excretion in healthy young women.
Nutr Res
12:
17-26,
1992[ISI].
4.
Biskobing, DM,
and
Fan D.
Acid pH increases carbonic anhydrase II and calcitonin receptor in mature osteoclasts.
Calcif Tissue Int
67:
178-183,
2000[ISI][Medline].
5.
Bland, R,
Worker CA,
Noble BS,
Eyre LJ,
Bujalska U,
Sheppard MC,
Stewart PM,
and
Hewison M.
Characterization of 11 beta-hydroxysteroid dehydrogenase activity and corticosteroid receptor expression in human osteosarcoma cell lines.
J Endocrinol
161:
455-464,
1994.
6.
Blumsohn, A,
Herrington K,
Hannon RA,
Shao P,
Eyre DR,
and
Eastell R.
The effect of calcium supplementation on the circadian rhythm of bone resorption.
J Clin Endocrinol Metab
79:
730-735,
1994[Abstract].
7.
Brenner, RJ,
Spring DB,
Sebastian A,
McSherry EM,
Genant HK,
Palubinskas AJ,
and
Morris RC, Jr.
Incidence of radiographically evident bone disease, nephrocalcinosis and nephrolithiasis in various types of renal tubular acidosis.
N Engl J Med
307:
217-221,
1982[Abstract].
8.
Brüngger, M,
Hulter HN,
and
Krapf R.
Effect of chronic metabolic acidosis on thyroid hormone homeostasis in humans.
Am J Physiol Renal Physiol
272:
F648-F653,
1997
9.
Brüngger, M,
Hulter HN,
and
Krapf R.
Effect of chronic metabolic acidosis on the growth hormone/UGF-1 endocrine axis: new cause of growth hormone insensitivity in humans.
Kidney Int
51:
216-221,
1997[ISI][Medline].
10.
Bushinsky, DA.
Net calcium efflux from live bone during chronic metabolic, but not respiratory, acidosis.
Am J Physiol Renal Fluid Electrolyte Physiol
256:
F836-F842,
1989
11.
Bushinsky, DA.
Stimulated osteoclastic and suppressed osteoblastic activity in metabolic but not respiratory acidosis.
Am J Physiol Cell Physiol
268:
C80-C88,
1995
12.
Bushinsky, DA,
Riordan DR,
Chan JS,
and
Krieger NS.
Decreased potassium stimulates bone resorption.
Am J Physiol Renal Physiol
272:
F774-F780,
1997
14.
Carbonare, LD,
Arlot ME,
Chavassieux PM,
Roux JP,
Portero NR,
and
Meunier PJ.
Comparison of trabecular bone microarchitecture and remodeling in glucocorticoid-induced and postmenopausal osteoporosis.
J Bone Min Res
16:
97-103,
2001[ISI][Medline].
15.
Challa, A,
Chan W,
Krieg RJ,
Thabet MA,
Liu F,
Hintz RL,
and
Chan JCM
Effect of metabolic acidosis on the expression of insulin-like growth factor and growth hormone receptor.
Kidney Int
44:
1224-1227,
1993[ISI][Medline].
16.
Cooper, MS,
Bujalska I,
Rabbitt E,
Walke EA,
Bland R,
Sheppard MC,
Hewison M,
and
Stewart PM.
Modulation of 11 b-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation.
J Bone Min Res
16:
1037-1044,
2001[ISI][Medline].
17.
Cooper, MS,
Rabbitt EH,
Goddard PE,
Bartlett WA,
Hewison M,
and
Stewart PM.
Osteoblastic 11-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure.
J Bone Min Res
17:
979-986,
2000.
18.
Cooper, MS,
Walker EA,
Bland R,
Fraser WD,
Hewison M,
and
Stewart PM.
Expression and functional consequences of 11-hydroxysteroid dehydrogenase activity in human bone.
Bone
27:
375-381,
2000[ISI][Medline].
19.
Cope, CL.
Adrenal Steroids and Disease. Philadelphia, PA: Lippincott, 1964, p. 85-112.
20.
Delling, G,
and
Donath K.
Morphometrische, electronenmikroskopische und physikalisch-chemische untersuchungen uber die experimentelle osteoporose bei chronischer acidose.
Virchows Arch
358:
321-330,
1973.
21.
Eyre, D.
Collagen cross-linking amino acids.
Methods Enzymol
144:
115-139,
1987[ISI][Medline].
22.
Forster, HV,
Dempsey JA,
Thomson J,
Vidruk E,
and
do Pico GA.
Estimation of PO2, PCO2, pH, and lactate from arterialized venous blood.
J Appl Physiol
32:
134-137,
1972
23.
Green, J,
and
Kleeman CR.
Role of bone in regulation of systemic acid-base balance.
Kidney Int
39:
9-26,
1991[ISI][Medline].
24.
Hannan, DA.
A specific immunoassay for monitoring human bone resorption: quantitation of type I collagen cross-linked N-telopeptides in urine.
J Bone Miner Res
7:
1251-1258,
1992[ISI][Medline].
25.
Hannan, MT,
Tucker KL,
Dawson-Hughes B,
Cuples LA,
Felson DT,
and
Kiel DP.
Effect of dietary protein on bone loss in elderly men and women: the Framingham Osteoporosis Study.
J Bone Min Res
15:
2504-2512,
2000[ISI][Medline].
26.
Jones, JW,
Sebastian A,
Hulter HN,
Schambelan M,
Sutton JM,
and
Biglieri EG.
Systemic and renal acid-base effects of chronic dietary potassium depletion in humans.
Kidney Int
21:
402-410,
1982[ISI][Medline].
27.
Krapf, R,
Beeler I,
Hertner D,
and
Hulter HN.
Chronic respiratory alkalosis. The effect of sustained hyperventilation on renal regulation of acid-base equilibrium.
New Engl J Med
324:
1394-1401,
1991[Abstract].
28.
Krapf, R,
Vetsch R,
Vetsch W,
and
Hulter HN.
Chronic metabolic acidosis increases the serum concentration of 1,25-dihydroxyvitamin D in humans by stimulating its production rate.
J Clin Invest
90:
2456-2463,
1992[ISI][Medline].
29.
Kraut, JA,
Mishler DR,
Singer FR,
and
Goodman WG.
The effects of metabolic acidosis on bone formation and resorption in the rat.
Kidney Int
30:
694-700,
1986[ISI][Medline].
30.
Krieger, NS,
Parker WR,
Alexander KM,
and
Bushinsky DA.
Prostaglandins regulate acid-induced cell-mediated bone resorption.
Am J Physiol Renal Physiol
279:
F1077-F1082,
2000
31.
Krieger, NS,
Parker WR,
Smith SB,
and
Bushinsky DA.
Inhibition of cyclooxygenase 2 prevents acid-induced calcium efflux from bone (Abstract).
J Am Soc Nephrol
12:
744A,
2001.
32.
Krieger, NS,
Sessler NE,
and
Bushinsky DA.
Acidosis inhibits osteoblastic and stimulates osteoclastic activity in vitro.
Am J Physiol Renal Fluid Electrolyte Physiol
262:
F442-F448,
1992
33.
Kurtz, I,
Maher T,
Hulter HN,
Schambelan M,
and
Sebastian A.
Effect of diet on plasma acid base composition in normal humans.
Kidney Int
24:
670-680,
1983[ISI][Medline].
34.
Lemann, J, Jr,
Gray RW,
and
Pleuss JA.
Potassium bicarbonate, but not sodium bicarbonate, reduces urinary calcium excretion and improves calcium balance in healthy men.
Kidney Int
35:
688-695,
1989[ISI][Medline].
35.
Lemann, J,
Litzow JR,
and
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
45:
1608-1614,
1966[ISI][Medline].
36.
Lemann, J,
Litzow JR,
and
Lennon EJ.
Studies on the mechanism by which chronic metabolic acidosis augments urinary calcium excretion in man.
J Clin Invest
46:
1318-1328,
1967[ISI].
37.
Lemann, J, Jr,
Pleuss JA,
Gray RW,
and
Hoffman RG.
Potassium administration reduces and potassium deprivation increases urinary calcium excretion in healthy adults.
Kidney Int
39:
973-983,
1991[ISI][Medline]. [Corrigenda. Kidney Int 40: May 1991, p. 388.]
38.
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
39:
281-288,
1984[Abstract].
39.
May, RC,
Kelly RA,
and
Mitch WE.
Metabolic acidosis stimulates protein degradation in rat muscle by glucocorticoid-dependent mechanism.
J Clin Invest
77:
614-621,
1986[ISI][Medline].
40.
McSherry, EM,
and
Morris RC, Jr.
Attainment and maintenance of normal stature with alkali therapy in infants and children with classic renal tubular acidosis.
J Clin Invest
61:
509-527,
1978[ISI][Medline].
41.
Myburgh, KH,
Noakes TD,
Roodt M,
and
Hough FS.
Effect of exercise on the development of osteoporosis in adult rats.
J Appl Physiol
66:
14-19,
1989
42.
New, SA.
Impact of food clusters on bone.
In: Nutritional Aspects of Osteoporosis, edited by Burckhardt P,
Dawson-Hughes B,
and Hearney RP.. New York: Academic, 2001, p. 379-397.
43.
Nordstrom, T,
Shrode LD,
Rotstein OD,
Romanek R,
Goto T,
Heersche JN,
Manoloson MF,
Bisseau GF,
and
Grinstein S.
Chronic extracellular acidosis induces plasmalemmal vacuolar type H+ ATPase activity in osteoclasts.
J Biol Chem
272:
6354-6360,
1997
44.
Perez, GO,
Oster JR,
Katz FH,
and
Vaamonde CA.
The effect of acute metabolic acidosis on plasma cortisol, renin activity and aldosterone.
Hormone Res
11:
12-21,
1979[ISI][Medline].
45.
Sakhaee, K,
Nicar M,
Hill K,
and
Pak CYC
Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts.
Kidney Int
24:
348-352,
1983[ISI][Medline].
46.
Sebastian, A,
Harris ST,
Ottaway JH,
Todd KM,
and
Morris RC, Jr.
Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate.
N Engl J Med
330:
1776-1781,
1994
47.
Sellmeyer, DE,
Stone KL,
Sebastian A,
and
Cummings SR.
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,
2001
48.
Sicuro, A,
Mahlbacher K,
Hulter HN,
and
Krapf R.
Effect of growth hormone on renal and systemic acid-base homeostasis in humans.
Am J Physiol Renal Physiol
274:
F650-F657,
1998
49.
Stellon, AJ,
Webb A,
and
Compston JE.
Bone histomorphometry and structure in corticosteroid treated chronic active hepatitis.
Gut
29:
378-384,
1988[Abstract].
50.
Teti, A,
Blair HC,
Schlesinger P,
Grano M,
Zambonin-Zallone A,
Kahn AJ,
Teitelbaum SL,
and
Hruska KA.
Extracellular protons acidify osteoclasts, reduce cytosolic calcium and promote expression of sell matrix attachment structures.
J Clin Invest
84:
773-780,
1989[ISI][Medline].
51.
Tucker, KL,
Hannan MT,
Chen H,
Cupples LA,
Wilson PWF,
and
Kiel DP.
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,
1999
52.
Van Staa, TP,
Leufkens HGM,
Abenhaim L,
and
Cooper C.
Use of oral corticosteroids and risk of fracture.
J Bone Miner Res
15:
993-1000,
2000[ISI][Medline].
53.
Wachman, A,
and
Bernstein DS.
Diet and osteoporosis.
Lancet
1:
958-959,
1968[Medline].
54.
Welbourne, TC.
Acidosis activation of the pituitary-adrenal-glutaminase I axis.
Endocrinology
99:
1071-1079,
1976[Abstract].