Neutralization of Western diet inhibits bone resorptionindependently of K intak - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-21 13:23 |只看该作者 |倒序浏览 |打印

作者：MarcMaurer, WalterRiesen, JuergenMuser, Henry N.Hulter,  RetoKrapf作者单位：1 Medizinische Universitätsklinik undZentrallabor, Kantonsspital Bruderholz, CH-4101 Bruderholz/Basel; Institut für klinische Chemie undHämatologie, Kantonsspital, CH-9007 St. Gallen,Switzerland; and Genentech,Incorporated, South San Francisco, California 94080-4990
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      【摘要】( `# V/ I* z/ r/ O# k! e9 S
   AWestern-type diet is associated with osteoporosis and calciumnephrolithiasis. On the basis of observations that calcium retentionand inhibition of bone resorption result from alkali administration, itis assumed that the acid load inherent in this diet is responsible forincreased bone resorption and calcium loss from bone. However, it isnot known whether the dietary acid load acts directly or indirectly(i.e., via endocrine changes) on bone metabolism. It is also unclearwhether alkali administration affects bone resorption/calcium balancedirectly or whether alkali-induced calcium retention is dependent onthe cation (i.e., potassium) supplied with administered base. Theeffects of neutralization of dietary acid load (equimolar amounts ofNaHCO 3 and KHCO 3 substituted for NaCl and KCl)in nine healthy subjects (6 men, 3 women) under metabolic balanceconditions on calcium balance, bone markers, and endocrine systemsrelevant to bone [glucocorticoid secretion, IGF-1, parathyroid hormone(PTH)/1,25(OH) 2 vitamin D and thyroid hormones] werestudied. Neutralization for 7 days induced a significant cumulativecalcium retention (10.7 ± 0.4 mmol) and significantly reduced theurinary excretion of deoxypyridinoline, pyridinoline, and n -telopeptide. Mean daily plasma cortisol decreased from264 ± 45 to 232 ± 43 nmol/l ( P = 0.032),and urinary excretion of tetrahydrocortisol (THF) decreased from2,410 ± 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 astate of cortisol excess, altered divalent ion metabolism, andincreased bone resorptive indices. Acidosis-induced increases incortisol secretion and plasma concentration may play a role in mildacidosis-induced alterations in bone metabolism and possibly inosteoporosis associated with an acidogenic Western diet. / T: z2 \; u; Q  s
      【关键词】 glucocorticoid acidbase potassium acidosis osteoporosis% V5 p# k$ ?7 }% k& F# ~2 R* ?
   INTRODUCTION

CHRONIC METABOLIC ACIDOSIS (CMA) is a frequentacid-base disturbance generated by extrarenal loss of base (e.g,diarrhea), increased acid production (e.g., organic acidosis such asketoacidosis), or impaired renal acid excretion (i.e., renal failureand inherited or acquired forms of renal tubular acidosis).
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CMA has a well-established potential for a catabolic effect on bone. Inaddition to renal phosphate wasting ( 28, 35, 36 ), experimentally induced CMA also results in hypercalciuria and negativecalcium balance, attributable to calcium efflux from bone ( 10, 34 ). CMA is associated with a poorly characterized metabolicbone disease ( 23 ), growth retardation ( 40 ),and calcium nephrolithiasis ( 7 ). In animal models, CMAresults in a decrease in bone calcium and gravimetrically determinedbone mass ( 2 ), decreased wet tissue femur density( 41 ), accelerated rates of cortical and trabecular boneresorption ( 2, 20, 29, 41 ), and diminished rates of boneformation ( 24 ), resulting in reduced trabecular bonevolume ( 29, 41 ).: x5 w0 J0 C9 h* t8 n  ]+ C# _9 I0 N' ~

In vitro studies have demonstrated that metabolic acidosis (imitated bythe use of media with low ambient pH and bicarbonate concentrations) isa potent stimulator of bone resorption and inhibitor of bone formation( 11, 32 ), suggesting that CMA acts directly at the tissuelevel to affect bone metabolism. However, CMA also might affect bonemetabolism indirectly, i.e., via numerous well-characterizedalterations 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 ), resultsin a mild form of hypothyroidism ( 9 ), and increases theserum 1,25(OH) 2 vitamin D [1,25(OH) 2 D]concentration (due to renal phosphate wasting) in humans, resulting ina decreased serum parathyroid hormone (PTH) concentration( 28 ).- ]! r' ~! f0 ]/ M1 c$ h
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In addition, a hyperglucocorticoid response to CMA has beendemonstrated in humans ( 39 ) and rats ( 48 ).The hyperglucocorticoid response has generated substantial interestbecause it might explain the negative nitrogen balance of CMA reportedin normal rats ( 39 ) and humans ( 1 ). Supportfor this possibility is that the catabolic muscle proteolytic effect ofCMA demonstrable in vitro in muscle from normal rats was not found inmuscle from adrenalectomized rats with CMA ( 39 ).: ^6 e' q" i* p
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The modern Western-type diet in humans, which is rich in animalprotein, has been implicated as a cause of lifelong mild CMA withsecondary bone catabolism caused by the induction by this diet of anobligatory daily acid load (endogenous acid production), due largely toendogenous oxidation of cationic and sulfur-containing amino acids( 46, 53 ). Although still within the broad range of normalvalues, plasma bicarbonate concentration decreases progressively whenendogenous acid production is increased by menu changes among normalfoodstuffs in normal subjects ( 33 ). In support of the hypothesis that ongoing metabolism of the Western diet can result innet bone catabolism, it was demonstrated that prolonged neutralization of endogenous acid production in postmenopausal women resulted incalcium and phosphate retention, reduced markers of bone resorption, and an increase in serum osteocalcin concentration, a marker of boneformation ( 46 ). Several uncontrolled observational studies have provided evidence that loss of bone mineral density (BMD) inelderly humans is less while they are ingesting a presumed alkali-richdiet 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 BMDprotection with high fruit/vegetable intake ( 51 ) alsoprovided seemingly contrary evidence that high animal protein (but not nonanimal protein) intake is protective for BMD loss, even after correction for multiple covariates ( 25 )." I. v* a: h5 A0 G6 A$ u, |* v

In addition, there is considerable debate on the issue of whether anincrease in potassium intake (typical of a vegetable-/fruit-rich diet)rather than the alkali per se is responsible for the salutary effectson bone. Indeed, studies that administered NaHCO 3 and sodium citrate have found little effect on urinary calcium excretion ( 34, 38, 45 ), whereas those in which KHCO 3 orpotassium citrate were administered have found large, significantreductions ( 34, 45, 46 ).
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The present study was designed to assess the possibility that even themildest CMA of the magnitude reported with the Western diet might besufficient to cause significant abnormalities in at least one of thereported bone-active endocrinopathies of CMA described above.Hyperglucorticoidism of very small magnitude was viewed as aparticularly likely candidate as an effector for diet-induced bonecatabolism because a recent retrospective cohort study found that evenvery low glucocorticoid doses within the physiological range (i.e., increased bothvertebral and nonvertebral fracture risk relative to age- andgender-matched controls ( 52 ).7 }5 H) P4 g" I
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METHODS- ?4 J9 S" ~; V
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The protocol was designed to measure the renal and systemicelectrolyte, acid-base, and endocrine response to neutralization ofendogenous acid production by oral ingestion of HCO 3 − in nine normal subjects. Nine nonsmoking subjects [6 men, 3 women, 22.1 ± 1.4 (SD) yr; body wt 70.6 ± 6.8 kg], who weretaking no concurrent medication, ate a constant whole-food metabolicdiet during all three consecutive study periods (control,neutralization of endogenous acid production, recovery). The diet wasadministered under metabolic ward conditions and provided the followingtotal content per kilogram of body weight per day, inclusive of the electrolyte supplements described below: 1.42 mmol Na (32.7 mg), 1.18 mmol K, 0.412 mmol Ca, 0.58 mmol PO 4, 16.1 mmol N, 0.24 mmol methionine, 36 kcal, and 47 ml H 2 O.5 C( a  o$ @8 @

All subjects ingested 1.10 mmol chloride salt supplement/kg bodywt 1 · day 1 during thecontrol (9 days) and the recovery periods (5 days). The daily chloridesupplement provided was equimolar (0.55 mmol/kg NaCl, 0.55 mmol/kgKCl). To experimentally neutralize endogenous acid production, a 7-dayneutralization period followed the control period wherein equimolarNaHCO 3 was substituted for the NaCl supplement andequimolar KHCO 3 was substituted for KCl. All salts wereadministered in gelatin capsules in six divided doses daily.( K3 b  d( t. O# ~9 E( }9 l/ z
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Fasting arterialized venous blood samples ( 22 ) wereobtained in a heparin-coated syringe from a heated hand or forearmvein. Blood samples were accepted only when P O 2 70 Torr (9.3 kPa) and were obtained at 8 AM unless otherwise specified.: ^  S4 X/ Z# A8 c/ ~
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All volunteers were paid for their participation and gave informedconsent. The study protocol was approved by the ethics committee of theKantonsspital, St. Gallen, Switzerland.
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Analytic procedures. All measurements were performed in duplicate. Acid-base parameters inblood and urine were determined as described elsewhere ( 27 ). Analysis of hormones and their metabolites wasperformed as described previously ( 8, 9, 28, 48 ).Biochemical bone markers were determined using ELISA assays fordeoxypyridinoline and pyridinoline ( 21 ) and n -telopeptide of type I collagen ( 24 ).

All steady-state values represent the mean of the last 2 days of thecorresponding 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 performedusing the general linear model procedure for two-way ANOVA withtreatment and subject effects (SAS Institute, Cary, NC).: {# D5 |& B) h2 G( p& l

RESULTS7 g# H% X* N8 l4 u# a

All volunteers tolerated the protocol well. There were nosignificant differences in body weights (Table 1 ) and blood pressure (not shown) duringany of the three study periods.

Table 1. Steady-state plasma acid-base and electrolyte composition duringcontrol, experimental, and recovery periods* A2 A% D+ @; H9 `, }

Administration of HCO 3 − resulted in a small butsignificant increase in the plasma HCO 3 − concentration(Table 1 ) from 24.8 ± 0.3 to 25.6 ± 0.3 mmol/l ( P decreased significantly from 83 ± 5 to 12 ± 3 mmol/24 h (Table 2, Fig. 1, P/ @% k, q& U0 ^
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Table 2. Urinary acid-base and electrolyte composition during control,experimental, and recovery periods
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Fig. 1. Effect of HCO 3 − administration on netacid excretion (NAE; mmol/24 h), urinary calcium (Ca 2  ),and urinary phosphate (PO 4 ) excretion., Excretion forcalcium and phosphate, daily changes in urinary excretion compared withthe previous steady-state periods;, cumulative change (sum ofthe daily difference for a given period) in urinary excretion rates.

As shown in Fig. 1 and Table 2, urinary calcium excretion decreasedimmediately, reversibly, and significantly duringHCO 3 − administration and remained decreased throughoutthe 7-day HCO 3 − period, resulting in significantcumulative calcium retention of 10.7 ± 0.4 mmol/7 days( P alsodecreased significantly and reversibly, resulting in a cumulative phosphate retention of 29.9 ± 1.2 mmol/7 days ( P in contrast to calcium excretion, phosphateexcretion values were decreased only transiently and returned to valuesnot different from control and recovery values by days 6 and 7 of HCO 3 − administration (Fig. 1, Table 2 ). Consistent with the unchanged cation intake during the protocol,the cumulative changes in sodium and potassium excretion averaged only 23 ± 17 and 18 ± 7 mmol, values that did not differsignificantly from zero.

As shown in Table 2, the fractional renal excretion of calcium,computed from the filtered load of ionized calcium, also decreasedsignificantly from 1.84 ± 0.09 (control) to 1.65 ± 0.08% during HCO 3 − administration and rose again to1.92 ± 0.09% in the recovery period ( P urinary phosphate clearance was not different among thesteady-state days of the three periods. Thus increased renal tubularreabsorption of calcium accounted, at least in part, for the observedHCO 3 − -induced urinary calcium retention.
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Figure 2 illustrates that markers of boneresorption (i.e., the urinary excretion of deoxypyridinoline,pyridinoline, and n -telopeptide of type I collagen)decreased significantly during HCO 3 − administration.The observed reduction in the excretion rates of bone resorptionmarkers and sustained calcium retention in young adult subjects thusgreatly extend the previous observation in postmenopausal women thatneutralization of endogenous acid production leads to inhibitionof bone resorption and positive calcium balance ( 46 ).

Fig. 2. Effect of HCO 3 − administration on 24-hurinary excretion rates of deoxypyridinoline ( A ),pyridinoline ( B ), and n -telopeptide( C ) of collagen type I. C, control; R, recovery.  A3 R+ y8 d$ r9 k) X! ?' y' Q" x
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As neutralization of endogenous acid production might inhibit boneresorption by direct local acidification (±paracrine/autocrine effectors) and/or indirectly via alterations in endocrine systems knownto be modulated by exogenous acid loads, i.e., the GH/IGF-1 axis,1,25(OH) 2 D and PTH, thyroid hormones, and glucocorticoid activity (see the beginning of this study), we assessed these endocrinesystems during steady states, i.e., the last 2 days of each study period.5 \) M; Z8 J, r4 {

As shown in Table 3, there were nosignificant differences in the serum concentrations of free IgF-1,1,25(OH) 2 D, and intact PTH among the three periods.Similarly, serum TSH, free T3, and free T4 concentrations were also notaffected significantly by HCO 3 − administration.Dynamic testing of any of these endocrine systems was not attemptedduring this study.* ~  N& o4 a) d) ~9 \9 m% w- S; n9 b

Table 3. Plasma hormone composition during control, experimental, and recoveryperiods
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Table 4 demonstrates the diurnal changesin plasma ACTH and plasma cortisol concentrations. No demonstrableeffect of alkali was noted on plasma ACTH levels throughout the day.However, plasma cortisol concentration at 7 AM was reducedsignificantly during the HCO 3 − period compared withcontrol (416 ± 23 vs. 483 ± 39 nmol/l, P = 0.046), and the difference remained significant over all four measureddiurnal values in the 24-h cycle (232 ± 43 vs. 264 ± 45 nmol/l, P = 0.032). Plots of the nine pairs of linearregression lines for plasma cortisol on time demonstrated a pattern ofparallel slopes for cortisol decay throughout the day, and this patternis also apparent in the homogeneity of individual slope values (seeTable 5 ). When tested by two-way ANOVA, the mean slope for cortisoldecay did not differ significantly during the HCO 3 − and Cl periods; however, the mean y -interceptcortisol value during the control/Cl period significantlyexceeded the corresponding mean value in the HCO 3 − period, providing for a shift in the elevation of plasma cortisol decaythroughout the day (Table 5 ).4 h7 Q9 O  P  w0 t( D

Table 4. Effect of HCO 3 − administration on diurnal plasma ACTHvalues and diurnal plasma cortisol concentrations
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Table 5. Linear regression analysis of diurnal plasma cortisol concentration:intercept and slope values during Cl andHCO 3 − bicarbonate periods

To further analyze the effect of neutralization of endogenous acidproduction on glucocorticoid activity/production, cortisol and cortisolmetabolites were determined in 24-h urine collections. As shown inTable 6, HCO 3 − administration decreased urinary free cortisol excretion significantly.Because tetrahydrocortisol (THF), cortisol's metabolite, is neithersecreted nor reabsorbed in the renal tubule, altered tubular handlingthat could occur in the case of cortisol cannot account for decreased THF excretion ( 19 ). Figure 3 thus concentrates on the excretion values for THF. As illustrated,HCO 3 − administration decreased 24-h THF excretion from2,410 ± 210 mg/24 h for control to 2,098 ± 190 mg/24 hduring HCO 3 − administration ( P ( P 3 − period, not significant vs.control period). There was no significant change in theTHF allo-THF/tetrahydrocortisone (THE) ratio during all study periods(Table 6 ).
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Table 6. Effect of neutralization of endogenous acid production on urinaryexcretion of glucocorticoid metabolites

Fig. 3. Effect of HCO 3 − administration on 24-hurinary excretion rates of tetrahydrocortisol (THF).& z9 K- g# O/ |

DISCUSSION5 d: |+ E# r( f& j* J
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These results furnish the first evidence that a very mild Westerndiet-induced CMA (a degree of acidosis that would not be recognized byapplying diagnostic acid-base criteria found in textbooks) results in astate of increased cortisol secretion and plasma concentration andprovides several novel findings in humans regarding the possiblecausality of the Western diet in the etiology of osteoporosis. Thepresent results demonstrate that ingestion of neutralizing alkali perse, as exchanged for chloride in the absence of other experimentalmaneuvers (e.g., concomitant potassium supplement), can result inurinary calcium retention and suppression of biochemical markers ofbone resorption. Finally, the present study demonstrates thatneutralizing alkali administered to very youthful male and femaleadults during the bone-anabolizing interval before achievement of peakbone mass can reproduce the bone metabolic effects of alkali pluspotassium reported in postmenopausal osteoporotic women( 46 ).
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This study establishes that the arithmetically trivial degree ofWestern diet-induced CMA is part of an endocrine-metabolic continuumthat includes the well-established hyperglucocorticoidism ofmoderate-to-severe CMA ( 39, 44, 48, 54 ). When even verymodest CMA, of the magnitude produced by a Western diet, can result inincreased cortisol secretion and plasma concentration, the intriguingpossibility arises that idiopathic osteoporosis and/or postmenopausalosteoporosis might be modulated, at least in part, by hypercortisolism.That mild hyperglucocorticoidism of long duration can lead toosteoporosis is supported by a recent retrospective cohort observationthat even very low glucocorticoid doses (i.e., both vertebral andnonvertebral fracture risk relative to age- and gender-matched controls( 52 ). Because the increased cortisol secretion andassociated increase in plasma concentration demonstrated in the presentstudy are probably of smaller magnitude than the net glucocorticoideffect achieved even by quite modest prednisone dosing, itscontribution to long-term putative bone loss incurred by the Westerndiet would presumably require many years of adrenal hypersecretion.Importantly, the pathophysiology of glucocorticoid-induced osteoporosisin humans shares with postmenopausal osteoporosis the twofundamental features found in experimentally induced CMA, namely,decreased trabecular bone formation/osteoblast recruitment rate and acomponent of early accelerated resorption ( 14, 49 ).0 S3 W3 t  r$ n7 s
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The finding that the urinary ratio [THF allo-THF]/THE is unchanged inthe prolonged transition from/to hypercortisolism of diet-induced CMAsuggests that 11 -hydroxysteroid dehydrogenase type 1 isoform(11 -HSD1) activity in liver and adipocytes and renal 11 -HSD2activity are grossly normal. However, the skeletal activity of eitheror both HSD isozymes is not known to be reflected in the excretionrates of urinary metabolites. 11 -HSD1 is strongly expressed innormal human bone in both osteoblasts and osteoclasts, whereas11 -HSD2 is weakly expressed and only in osteoblasts ( 16, 18 ). The glucocorticoid receptor may only be expressed inosteoblasts ( 5 ). The finding that administration ofcarbenoxolone, a potent inhibitor of both 11 -HSD isozymes, to normalsubjects resulted in a significant decrease in pyridinoline anddeoxypyridinoline excretion ( 18 ) suggests that variationin the activity of these isozymes in osteoblasts or osteoclasts or bothcan result in important alterations in glucocorticoid receptor-mediatedaction on bone metabolism. The recent in vitro findings that 11 -HSD1(cortisol-generating) activity in human osteoblasts is increased byincreasing ambient cortisol concentrations and that its osteoblasticactivity is increased as a function of a subject's age provideevidence that even very small increases in plasma cortisolconcentrations in humans may be subject to autocrine amplificationloops deleterious to skeletal function ( 17 ). Thus theeffects of CMA on these isozymes in bone remains an importantunanswered question.
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The present results provide the first evidence in any species that thealkali (as exchanged for chloride) vs. acid content of a diet per se,rather than the specific effect of a coadministered alkali-associatedcation (sodium or potassium), modulates bone resorption and theassociated alterations in calcium and phosphate homeostasis. Whetheralkali per se has a clear role has remained a question because studiesin which NaHCO 3 and sodium citrate were administered havefound little effect on calcium excretion ( 34, 38, 45 ),whereas those administering KHCO 3 or potassium citrate havefound significant reductions of large magnitude ( 38, 45, 46 ). The present study, by holding cation intake constant andexchanging equimolar HCO 3 − for chloride, haseliminated the argument that modest alkali treatment per se might beinsufficient to cause urinary calcium retention in the absence of aconcomitant increase in potassium intake. A specific role for thereduction in chloride intake in producing renal calcium and phosphateretention and decreased markers of bone resorption was not apparent inthe present study, but it was not rigorously excluded.+ i% f/ ~# e1 K( S
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Part of the confusion over the relative hypocalciuric roles of alkaliand coadministered cation has arisen because of the interpretation of astudy in adult male subjects ingesting a normal diet in whichsequential 4-day periods of KCl and then KHCO 3 administration were undertaken ( 37 ). Both the authors ofthat study and others ( 12 ) have interpreted those data asindicating that KCl as well as KHCO 3 administration topotassium-replete subjects resulted in decreased urinary calciumexcretion, yet the reported data for the 4 days of KCl administration(unlike the KHCO 3 results) showed no significant differencein calcium excretion relative to paired control values in the samesubjects despite a similar magnitude of potassium retention with bothpotassium salts ( 37 ). Furthermore, in contrast tosignificant hypercalciuria produced by prolonged NaCl loading, noeffect of prolonged KCl loading on calcium excretion was reported inhealthy young women ( 3 ). On the basis of the in vivoliterature to date, small alkali-independent effects of primaryalterations in potassium balance on calcium retention would bedifficult to detect in initially normokalemic animals or humans andhave not been reported. However, by the use of a very low extracellularfluid potassium concentration of 1.0 mM, cultured murine calvariaeexhibited an effect of low medium potassium concentration to increasecalcium efflux, to increase a bone resorption marker, and to decreasebone collagen synthesis ( 12 ) in the absence of detectableacid-base change. The applicability of the in vitro data in calvariaeto human potassium depletion is uncertain because the significanthypercalciuria reported in diet-induced potassium depletion in normalsubjects was accompanied by renal NaCl retention and weight gain,suggesting a role for extracellular fluid volume expansion in theetiology of hypercalciuria ( 26 ). Thus whether the bonecatabolism findings for a potassium-depleting environment in vitropredict an in vivo bone anabolic effect of potassium loading inpotassium-replete humans awaits future studies.

The present studies do not exclude cortisol-independent mechanisms formild CMA-induced reversible effects on bone metabolism. Localmechanisms in bone have been elucidated that might explain the effectof CMA in causing bone loss. In mature mouse osteoclasts in culture,acidified medium results in upregulation of both carbonic anhydrase IIand calcitonin receptor, the former being associated with increasedresorptive activity and the latter with suppressed osteoclasticactivity ( 12 ). In cultured murine calvariae, acidification of the medium results in calcium efflux accompanied by enhanced PGE 2 production ( 30 ), and calcium efflux isinhibited by both nonselective clyclooxygenase (COX) inhibitors andCOX-2-selective agents ( 31 ). Cultured osteoclasts alsoexhibit important morphological and functional changes to acidifiedmedia that include formation of the resorbing clear zone podosomes( 4 ) as well as augmentation of the final step inresorption, activity of the V-type plasma membraneH -ATPase ( 43 ). Thus CMA-induced bonecatabolism might conceivably be mediated within bone by a variety ofplausible mechanisms. We also cannot exclude the possibilitythat alkali-induced increases in distal HCO 3 − deliverymight have resulted in suppressed bone resorption as mediated bytubular calcium retention. We believe that this is an unlikelymechanism in the present study because we found no alkali-inducedsuppression of PTH levels nor ionized hypercalcemia, which arerecognized as the mediators of the small suppressive effects of calciumloading on bone resorption markers reported in young adults( 6 ).
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We did not find evidence for an effect of neutralization of acidogenicdiet on other endocrine axes [i.e., GH/IGF-1,PTH/1,25(OH) 2 D, and thyroid hormones], which are importantto bone integrity and are affected by acidosis (Table 3 ). However,subtle regulatory alterations cannot be excluded, i.e., alteredsensitivity of feedback loops and end-organ hormone (i.e., GH) sensitivities.) @6 R" k% c, I( P8 Z6 k8 r7 G

In summary, we have provided novel evidence that ingestion of anordinary acidogenic Western diet to normal young adult subjects resultsin a mild CMA in association with a state of increased cortisolsecretion and plasma concentration, altered divalent ion metabolism,and increased bone-resorptive indices. Because mildhyperglucocorticoidism is reported to result in an osteoporotic statethat shares numerous qualitative and quantitative histomorphometric features with postmenopausal osteoporosis and with experimental CMA inanimals, it is proposed that CMA-induced cortisol excess may play arole in mild CMA-induced alterations in bone metabolism in humans andpossibly in osteoporosis associated with the Western acidogenic diet.
      【参考文献】6 h/ B1 P; A' n: w# C) h& N4 i
1. Ballmer, PE,McNurlan MA,Hulter HN,Anderson SE,Garlick PE,andKrapf R. Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans. J Clin Invest 95:39-45,1995  .; q3 C  a4 ]7 g: v$ R

$ s  p( v' `; N% E: S
( d5 ]' o% `$ }6 f( K: g3 M; b
2. Barzel, US,andJowsey J. The effects of chronic acid and alkali administration on bone turnover in adult rats. Clin Sci (Colch) 36:517-524,1969  .$ K0 w( w5 Y% |) z% b+ d1 D/ V

* I0 l. R% @+ L; X* X1 d5 {/ j) x4 }

3. Bell, RR,Eldrid MM,andWatson FR. The influence of NaCl and KCl on urinary calcium excretion in healthy young women. Nutr Res 12:17-26,1992.
# c( `( ?- V3 O4 n$ T4 g

4. Biskobing, DM,andFan D. Acid pH increases carbonic anhydrase II and calcitonin receptor in mature osteoclasts. Calcif Tissue Int 67:178-183,2000  .* {6 _9 F! ^3 I6 E' K$ Z8 c

2 _* G) p+ M# q* m3 F! A
, J% _9 _# A: ^/ u
5. Bland, R,Worker CA,Noble BS,Eyre LJ,Bujalska U,Sheppard MC,Stewart PM,andHewison M. Characterization of 11 beta-hydroxysteroid dehydrogenase activity and corticosteroid receptor expression in human osteosarcoma cell lines. J Endocrinol 161:455-464,1994.$ k' A; y* G( O) Z$ }" W

6. Blumsohn, A,Herrington K,Hannon RA,Shao P,Eyre DR,andEastell R. The effect of calcium supplementation on the circadian rhythm of bone resorption. J Clin Endocrinol Metab 79:730-735,1994 .! t! T  b' W* F4 P
2 |+ V9 ?( H8 G" X, @, I' x' B
1 h; Y* U2 ^+ {. A- B3 B2 u7 @) @

7. Brenner, RJ,Spring DB,Sebastian A,McSherry EM,Genant HK,Palubinskas AJ,andMorris 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 .

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8. Brüngger, M,Hulter HN,andKrapf R. Effect of chronic metabolic acidosis on thyroid hormone homeostasis in humans. Am J Physiol Renal Physiol 272:F648-F653,1997 .
8 s6 g- G+ a: C0 Q' X
1 }" [: ]! {7 \% V. `4 w
* ]+ x# M  n- Y5 j6 J" a3 U% g
9. Brüngger, M,Hulter HN,andKrapf 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  .1 v4 H$ T7 L6 D& S) @; ^
# C, H" R  h/ g# m* K1 {: S
: m. X2 s5 n7 ?/ K! C6 X7 l0 r

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 .1 ^& d# ^  J7 r* c; X9 [

- \( u( H% |! A7 F( k
  k$ d! w1 L- r. ?
11. Bushinsky, DA. Stimulated osteoclastic and suppressed osteoblastic activity in metabolic but not respiratory acidosis. Am J Physiol Cell Physiol 268:C80-C88,1995 .1 ]0 n' ~, e9 J0 d

" L$ b; {" M, a; O+ C% }3 R

12. Bushinsky, DA,Riordan DR,Chan JS,andKrieger NS. Decreased potassium stimulates bone resorption. Am J Physiol Renal Physiol 272:F774-F780,1997 .. |: J1 D* P( J/ k% L; h- y
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& u, u5 |9 `7 M
+ O. h6 Z+ |0 Q( y1 d
14. Carbonare, LD,Arlot ME,Chavassieux PM,Roux JP,Portero NR,andMeunier PJ. Comparison of trabecular bone microarchitecture and remodeling in glucocorticoid-induced and postmenopausal osteoporosis. J Bone Min Res 16:97-103,2001  .

* f9 q. l# Q2 I, n* ^; X! `' q) j
) J0 e- E0 B. n6 }: K3 C5 |* n
15. Challa, A,Chan W,Krieg RJ,Thabet MA,Liu F,Hintz RL,andChan JCM Effect of metabolic acidosis on the expression of insulin-like growth factor and growth hormone receptor. Kidney Int 44:1224-1227,1993  ., J# K8 d# X2 F! d2 C/ E. Q
- R7 l: O8 H4 {% h0 s

16. Cooper, MS,Bujalska I,Rabbitt E,Walke EA,Bland R,Sheppard MC,Hewison M,andStewart 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  .% f7 J& @% n$ b' u  E

# j: o7 v6 ^4 L# E" I1 Y/ s- z
1 b& X" M  D7 Q# U
17. Cooper, MS,Rabbitt EH,Goddard PE,Bartlett WA,Hewison M,andStewart 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,andStewart PM. Expression and functional consequences of 11 -hydroxysteroid dehydrogenase activity in human bone. Bone 27:375-381,2000 .2 U' i) `0 _& m+ H% D$ \

19. Cope, CL. Adrenal Steroids and Disease. Philadelphia, PA: Lippincott, 1964, p. 85-112.
9 i( _. Z/ [  \( D6 j

+ ]# g2 V" O9 E/ [# l
20. Delling, G,andDonath K. Morphometrische, electronenmikroskopische und physikalisch-chemische untersuchungen uber die experimentelle osteoporose bei chronischer acidose. Virchows Arch 358:321-330,1973.3 @( u# t' F9 k% ~5 b" s

0 ]4 p. I# D6 F- J9 ]2 \/ L- j

21. Eyre, D. Collagen cross-linking amino acids. Methods Enzymol 144:115-139,1987  .
! P4 n4 B- I5 q
2 ~+ p* `8 t* R5 z

22. Forster, HV,Dempsey JA,Thomson J,Vidruk E,anddo Pico GA. Estimation of P O 2, P CO 2, pH, and lactate from arterialized venous blood. J Appl Physiol 32:134-137,1972 .- Z7 \; l1 u0 v! T. {& |, \( W* }( @

+ F" I+ I- q5 z0 ?6 T! z/ @! x0 h

23. Green, J,andKleeman CR. Role of bone in regulation of systemic acid-base balance. Kidney Int 39:9-26,1991  .7 p, j7 G! V% O3 F3 G3 n, L+ m7 ?5 N
" }  d  ?1 x0 C! J8 k7 P* Q
+ }5 f; ~+ m! e7 [/ Z. W4 ^; a
$ |/ \, B$ i: X& n. `% n" Y: m
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  .* S% K# o" W9 k2 j" A' G9 s

25. Hannan, MT,Tucker KL,Dawson-Hughes B,Cuples LA,Felson DT,andKiel 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  .8 r/ x# \2 o9 Q# z# m
; |) h! E: B; i
9 Z9 M3 z$ v$ g9 x: H/ {0 l' d/ Y

26. Jones, JW,Sebastian A,Hulter HN,Schambelan M,Sutton JM,andBiglieri EG. Systemic and renal acid-base effects of chronic dietary potassium depletion in humans. Kidney Int 21:402-410,1982  .
/ U5 S; y4 r, b7 o7 ]5 q
5 n) H5 V, e( G3 {" b! J

27. Krapf, R,Beeler I,Hertner D,andHulter HN. Chronic respiratory alkalosis. The effect of sustained hyperventilation on renal regulation of acid-base equilibrium. New Engl J Med 324:1394-1401,1991 .% Q/ H5 j+ o7 F/ e
5 M6 i0 r9 Y8 c) V1 m$ J
$ z2 _1 K0 h9 e. t0 ?
( @( y& [( W6 \/ w; [$ _0 g9 x
28. Krapf, R,Vetsch R,Vetsch W,andHulter 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  .
, s7 i0 Z+ G* h4 e: }. K. n9 \
9 M4 w0 _! H8 [" z% L$ V  w9 {
# z4 s1 V, ]0 f: C, _5 A
29. Kraut, JA,Mishler DR,Singer FR,andGoodman WG. The effects of metabolic acidosis on bone formation and resorption in the rat. Kidney Int 30:694-700,1986  .  L& l9 ~  m* y3 I
% Y" r* e; B( X0 D

' ^% C& c$ J  x- M
30. Krieger, NS,Parker WR,Alexander KM,andBushinsky DA. Prostaglandins regulate acid-induced cell-mediated bone resorption. Am J Physiol Renal Physiol 279:F1077-F1082,2000 .
  ?+ y8 f8 N! r
; ?! I! \; E/ \& e* a0 M

31. Krieger, NS,Parker WR,Smith SB,andBushinsky DA. Inhibition of cyclooxygenase 2 prevents acid-induced calcium efflux from bone (Abstract). J Am Soc Nephrol 12:744A,2001.: s" C1 b! c4 ^4 V9 Z

, r( q* f) `6 n8 d4 X1 s6 e6 Q$ ]
' o$ ^* |5 W4 P0 q2 b" G, N; S
32. Krieger, NS,Sessler NE,andBushinsky DA. Acidosis inhibits osteoblastic and stimulates osteoclastic activity in vitro. Am J Physiol Renal Fluid Electrolyte Physiol 262:F442-F448,1992 .- \" H' e6 d- z0 R
8 ]# y& ^, G( N1 S, u. `

33. Kurtz, I,Maher T,Hulter HN,Schambelan M,andSebastian A. Effect of diet on plasma acid base composition in normal humans. Kidney Int 24:670-680,1983  .

34. Lemann, J, Jr,Gray RW,andPleuss JA. Potassium bicarbonate, but not sodium bicarbonate, reduces urinary calcium excretion and improves calcium balance in healthy men. Kidney Int 35:688-695,1989  .

' F$ u' {7 y2 |6 ^# N

35. Lemann, J,Litzow JR,andLennon 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  .

- w0 R1 d/ t- \$ Y2 C

36. Lemann, J,Litzow JR,andLennon EJ. Studies on the mechanism by which chronic metabolic acidosis augments urinary calcium excretion in man. J Clin Invest 46:1318-1328,1967 .

; A' {, w& g2 `9 _9 E5 v. t  K

37. Lemann, J, Jr,Pleuss JA,Gray RW,andHoffman RG. Potassium administration reduces and potassium deprivation increases urinary calcium excretion in healthy adults. Kidney Int 39:973-983,1991  . [Corrigenda. Kidney Int 40: May 1991, p. 388.]

  ^0 |& t% d$ s3 e0 L1 s* n

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 .
* K8 e7 H2 u& |+ I

" Y9 C2 ~7 p, _
39. May, RC,Kelly RA,andMitch WE. Metabolic acidosis stimulates protein degradation in rat muscle by glucocorticoid-dependent mechanism. J Clin Invest 77:614-621,1986  .) b9 G( I7 p! r; Y8 @3 v% E

* `, d1 u, @- [( I1 a3 X

40. McSherry, EM,andMorris 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  .

, ~, e" d3 t5 b, l) y( B% X2 P
2 S+ ?& R# n, z' L- `5 N9 o: t
41. Myburgh, KH,Noakes TD,Roodt M,andHough FS. Effect of exercise on the development of osteoporosis in adult rats. J Appl Physiol 66:14-19,1989 .- H% V, K% V# }0 s

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.

# x4 r, D$ {2 f" z

43. Nordstrom, T,Shrode LD,Rotstein OD,Romanek R,Goto T,Heersche JN,Manoloson MF,Bisseau GF,andGrinstein S. Chronic extracellular acidosis induces plasmalemmal vacuolar type H ATPase activity in osteoclasts. J Biol Chem 272:6354-6360,1997 .
% \% ^: S' i1 ~! }( k. A* S

5 Y/ p( y- [* m+ R) s: C& i, S
44. Perez, GO,Oster JR,Katz FH,andVaamonde CA. The effect of acute metabolic acidosis on plasma cortisol, renin activity and aldosterone. Hormone Res 11:12-21,1979  .
: Z' J6 j: B% n5 b+ r; j/ _( j
4 _) X/ |$ t: _# a- [
, }: P, l1 Y6 U( I3 \
45. Sakhaee, K,Nicar M,Hill K,andPak 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  .
9 d: s5 T% d( `, K7 d2 [' E
! k3 A& e' \6 T+ P
' o# Y& r# k9 X% c( d% h
46. Sebastian, A,Harris ST,Ottaway JH,Todd KM,andMorris RC, Jr. Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate. N Engl J Med 330:1776-1781,1994 .1 @  q2 f# D& T% ]
8 |2 P2 V5 r0 v2 @8 Q- q

47. Sellmeyer, DE,Stone KL,Sebastian A,andCummings 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 .* |& K) h- H, w8 q9 |9 R

! i' }" h0 R) Y; B! b. x1 Z
48. Sicuro, A,Mahlbacher K,Hulter HN,andKrapf R. Effect of growth hormone on renal and systemic acid-base homeostasis in humans. Am J Physiol Renal Physiol 274:F650-F657,1998 .
" U* X  K8 y" m. I0 Q% ?

49. Stellon, AJ,Webb A,andCompston JE. Bone histomorphometry and structure in corticosteroid treated chronic active hepatitis. Gut 29:378-384,1988 .! E9 X, r  G3 T% g7 e1 w+ K( C4 p
1 ^+ J# j  D7 c+ V% m1 o
# N* @( h7 `9 W) F) G# E3 m; q

50. Teti, A,Blair HC,Schlesinger P,Grano M,Zambonin-Zallone A,Kahn AJ,Teitelbaum SL,andHruska KA. Extracellular protons acidify osteoclasts, reduce cytosolic calcium and promote expression of sell matrix attachment structures. J Clin Invest 84:773-780,1989  .4 E; w' g3 V8 z% m

51. Tucker, KL,Hannan MT,Chen H,Cupples LA,Wilson PWF,andKiel 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 ." N2 y1 h6 `: N' o

# X5 K2 C" m# v" ?" m- ]! d$ [' k
52. Van Staa, TP,Leufkens HGM,Abenhaim L,andCooper C. Use of oral corticosteroids and risk of fracture. J Bone Miner Res 15:993-1000,2000  .

53. Wachman, A,andBernstein DS. Diet and osteoporosis. Lancet 1:958-959,1968  .6 @4 ~* K2 D) {) Q$ r) l: w
- s5 t( _9 f9 W. |

- q  S3 U! J( V: t) r+ T0 u
54. Welbourne, TC. Acidosis activation of the pituitary-adrenal-glutaminase I axis. Endocrinology 99:1071-1079,1976 .

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