Potassium bicarbonate reduces high protein-induced hypercalciuria in adult men

Nutrition Research, Vol. 14, No. 7, pp. 991-1002, 1994 Copyright 9 1994 Elsevie~ Science Ltd Printed in the USA. All rights reserved 0271-5317/94 $6.00 + .00

Pergamon

0271-5317(94)E00029-8

POTASSIUM

BICARBONATE REDUCES HIGH PROTEIN-INDUCED H Y P E R C A L C I U R I A IN A D U L T M E N

T i m o t h y J. Green, MSc and S u s a n J. Whiting, PhD I D i v i s i o n of N u t r i t i o n and Dietetics, C o l l e g e of Pharmacy, U n i v e r s i t y of S a s k a t c h e w a n , Saskatoon, S a s k a t c h e w a n , S7N OWO Canada ABSTRACT The effect of adding s o d i u m b i c a r b o n a t e (NaHCO)) and p o t a s s i u m b i c a r b o n a t e (KHCO3) on high p r o t e i n - l n d u c e d h y p e r c a l c i u r i a was e v a l u a t e d in eight h e a l t h y m a l e subjects. S u b j e c t s w e r e a c c l i m a t e d to h i g h p r o t e i n and then r e c e i v e d in r a n d o m order, each of the f o l l o w i n g s u p p l e m e n t s for f o u r - d a y periods: 60 g p r o t e i n (HP), 60 g p r o t e i n + 90 mmol N a H C O 3 (HP+Na), and 60 g p r o t e i n + 90 mmol KHCO 3 (HP+K). S u b j e c t s w e r e then g i v e n a m o d e r a t e p r o t e i n (MP) diet. S u b j e c t s p r o v i d e d a 24h o u r u r i n e sample on Day 3 and Day 4, and a f a s t i n g u r i n e and b l o o d sample on Day 5, of each period. Day 3 and Day 4 c a l c i u m e x c r e t i o n s w e r e i n c r e a s e d d u r i n g the H P t r e a t m e n t as c o m p a r e d w i t h the M P treatment. During the H P + K treatment, Day 3 and Day 4 c a l c i u m e x c r e t i o n s w e r e g r e a t l y r e d u c e d r e l a t i v e to the HP treatment. In contrast, d u r i n g the HP+Na treatment, c a l c i u m e x c r e t i o n was r e d u c e d r e l a t i v e to the HP t r e a t m e n t on Day 3, but not on Day 4. S e r u m c a l c i u m was s i g n i f i c a n t l y i n c r e a s e d d u r i n g the H P + K r e l a t i v e to the M P treatment. This study suggests that K H C O ~ but not NaHCO3, c o n s i s t e n t l y reduces high p r o t e i n - i n d u c e d h y p e r c a l c i u r i a to levels seen d u r i n g i n g e s t i o n of a m o d e r a t e p r o t e i n diet. KEY WORDS: Potassium

Calcium,

Protein,

Sodium,

Bicarbonate,

INTRODUCTION M a n y factors i n f l u e n c e the m e t a b o l i s m of its r e t e n t i o n by the body. Factors m e d i a t i n g c a l c i u m m e t a b o l i s m t h r o u g h the kidney include (i) and s o d i u m (2). Both factors p r o m o t e the i A u t h o r to w h o m c o r r e s p o n d e n c e

calcium, a l t e r i n g t h e i r e f f e c t on animal p r o t e i n loss of u r i n a r y

should be addressed.

991

992

T.J. GREEN and S.J. WHITING calcium, which may result in bone loss. While dietary sodium has been implicated as a hypercalciuretic factor, only sodium provided as NaCl has been shown to increase urinary calcium excretion (3). Sodium provided as NaHCO~ was reported to reduce the hypercalciuria induced by a hlgh protein diet in a study of post-menopausal women (4). Studies of subjects consuming a moderate protein diet, however, did not show that NaHCO 3 reduced urinary calcium excretion (5,6). The effect of dietary potassium on urinary calcium excretion has recently been studied, and KHCO. was hypocalciuric in subjects consuming a moderate protein die~ (5,6). Due to the contradictory findings on the effects of NaHC03 on urinary calcium excretion, an objective of the present study was to clarify the effect of NaHCO~ on high protein-induced hypercalciuria. Another objective was to establish the effect of KHCO 3 on high proteininduced hypercalciuria. MATERIALS AND METHODS Subjects Male volunteer subjects, aged 20-31 y (25.4 • 4 y), were recruited for this study. All subjects described themselves as healthy and none were using oral medications. A daily calcium intake of between 500 and 1800 mg, as determined from 24 hour recall, was necessary for inclusion in the study. Subjects were of normal body weight, 76.8 • 8.1 kg. Initially nine subjects began the study, but data from one subject was removed because he did not correctly receive all experimental treatments. Written informed consent was received from each participant. All procedures were approved by the University of Saskatchewan Committee On Ethics In Human Experimentation. Experimental Design The total duration of the study was 33 days. The study was divided into five study weeks: stabilization, high protein (HP), moderate protein (MP), high protein + KHCO 3 (HP+K), and high protein + NaHCO 3 (HP+Na) (Fig. i). Each Week began on Monday (Day i) and ended on Sunday (Day 7) with the exception of Week 5 which ended on Friday (Day 5). During Week 1 (acclimation to high protein) subjects adapted to the high protein diet by consuming 79.2 g Promod R (Ross Laboratories, Montreal, Quebec) daily, which provided 60 g of protein as well as 7.8 mmol calcium, 7.5 mmol phosphorus, 9 mmol sodium, and 12 mmol potassium. During Week i, subjects consumed their normal diet but on one day subjects were given the experimental diet, and individualized experimental diets were designed based on satiety and food preferences. During the next four weeks subjects were given the experimental diet from breakfast of Day 1 until the evening of Day 4. Experimental diets remained isoenergetic as protein was

POTASSIUM AND URINARY CALCIUM

993

s w i t c h e d w i t h carbohydrate. During W e e k s 2 t h r o u g h 4, s u b j e c t s r e c e i v e d daily, in a r a n d o m c r o s s o v e r manner, one of the f o l l o w i n g supplements: 60 g protein, 60 g p r o t e i n + 90 m m o l KHCO 3 (Wiler Fine Chemicals, London, Ontario) or 60 g p r o t e i n + 90 mmol N a H C O 3 (Wiler Fine Chemicals, London, Ontario). During W e e k 5 all s u b j e c t s received, in p l a c e of the p r o t e i n supplement, i s o c a l o r i c c a r b o h y d r a t e as 90 g of P o l y c o s e R (Ross Laboratories, Montreal, Quebec). In o r d e r to m a t c h the p h o s p h a t e and c a l c i u m in the p r o t e i n supplement, 13.2 mmol of c a l c i u m p h o s p h a t e d i b a s i c USP (Wiler Fine Chemicals, Ltd, London, Ontario) was added to the c a r b o h y d r a t e supplement. S u p p l e m e n t s w e r e d i v i d e d into t h r e e equal doses. T w e n t y - f o u r h o u r u r i n e was c o l l e c t e d on Day 3 and Day 4 of each e x p e r i m e n t a l week. S e r u m and u r i n e samples w e r e c o l l e c t e d on the m o r n i n g of Day 5 from s u b j e c t s w h i l e fasting (a single Day 5 u r i n e was m i s s e d from one subject). After providing samples on Day 5, s u b j e c t s w e r e free to c o n s u m e t h e i r normal diet until Day 1 of the next week. From Day 5 to Day 7, d u r i n g Weeks 2 and 3, s u b j e c t s c o n t i n u e d to c o n s u m e the p r o t e i n supplement. Experimental

Diet

S u b j e c t s w e r e g i v e n t h e i r own e x p e r i m e n t a l diets so that they c o n s u m e d the same foods on days 1 t h r o u g h 4 of each e x p e r i m e n t a l week. A typical e x p e r i m e n t a l diet c o n s i s t e d of the f o l l o w i n g food items: 3 cans liquid meal r e p l a c e m e n t (Ensure R, Ross Laboratories, Montreal, Quebec), 3 p u d d i n g s (Ensure P u d d i n g R, Ross Laboratories, Montreal, Quebec), 3 fibre cookies (Fibermed R w i t h Fruit supplements, Purdue Frederick, Inc., Toronto), 2 frozen d i n n e r s (Le M e n u R beef sirloin tips and s e a s o n e d b r e a s t of c h i c k e n parmigiana, C a m p b e l l Foods Ltd., Toronto), and 7 U P R or Diet 7 U P R (Pepsi Cola Ltd., Saskatoon). E n e r g y d i f f e r e n c e s b e t w e e n s u b j e c t s w e r e a c c o u n t e d for by a d d i n g or r e m o v i n g puddings, cookies, and dinners. Distilled, d e i o n i z e d w a t e r was also provided. Caffeine containing b e v e r a g e s and alcohol w e r e not p e r m i t t e d d u r i n g c o n t r o l l e d phases of the study. The n u t r i e n t c o n t e n t of the e x p e r i m e n t a l diet is p r e s e n t e d in T a b l e i. On Days 5-7 of W e e k s 2 and 3, and t h r o u g h o u t W e e k i, w h e n subjects were not c o n s u m i n g the e x p e r i m e n t a l diet, each dose of p r o t e i n s u p p l e m e n t was g i v e n with 30 grams of Lipton R O r a n g e F l a v o u r C r y s t a l s (Thomas J. Lipton, Inc., Edmonton, Alberta) m i x e d in water. On days w h e n subjects w e r e c o n s u m i n g the c o n t r o l l e d diet the p r o t e i n s u p p l e m e n t was m i x e d w i t h the liquid meal replacement. Sample C o l l e c t i o n s

and A n a l y t i c a l

Methods

The total u r i n e v o l u m e of each c o l l e c t i o n was recorded. A l i q u o t s of u r i n e w e r e then r e m o v e d from each c o l l e c t i o n and stored at -20~ until analysis. Ten m L of HCI (6 mol/L) was then added to each of the 24-hour c o l l e c t i o n s as a preservative. Similarly, i0 m L of HCl (I mol/L) was added to

994

T.J. GREEN and S.J. WHITING Table Nutrient

i.

content

of the e x p e r i m e n t a l

Nutrient

Typical

Daily

Energy Protein Calcium Potassium Sodium phosphate

11.7 MJ 103 g 36 m m o l 83 m m o l 177 m m o l 54 m m o l

diet

Intake

I Range reflects differences between c o n s u m e d the same a m o u n t each week.

Range I

I0.0 93 29 77 159 48 subjects,

-

14.1 MJ 120 g 43 m m o l 92 m m o l 207 m m o l 61 mmol

as e a c h

subject

the f a s t i n g samples. A l i q u o t s of a c i d i f i e d u r i n e w e r e r e m o v e d and s t o r e d at 4~ until analysis. A c i d i f i e d u r i n e was a n a l y z e d for total calcium, by the c r e s o l p t h a l e i n m e t h o d (Calcium R e a g e n t Kit, 1250 -125, DMA, Inc., Arlington, Texas); creatinine, by a m o d i f i e d J a f f 4 m e t h o d (7); m a g n e s i u m , by atomic absorption spectrophotometry; phosphate, by the m e t h o d of Fiske and S u b b a r o w (7); s o d i u m and potassium, by flame p h o t o m e t r y (Corning Flame P h o t o m e t e r 410, C o r n i n g M e d i c a l and Scientific, Corning, NY); and sulphate, by ion e x c h a n g e chromatography (Dionex Qic Analyzer, Dionex, Sunnyvale, CA). U n a c i d i f i e d u r i n e was a n a l y z e d for c h l o r i d e by the m e r c u r i c t h i o c y a n a t e m e t h o d (Chloride R e a g e n t Kit, G i l f o r d Systems, Oberlin, Ohio); and net acid e x c r e t i o n (NAE) by s u m m i n g t i t r a t a b l e a c i d i t y and u r i n a r y a m m o n i u m (8). F o l l o w i n g c o l l e c t i o n b l o o d samples w e r e p e r m i t t e d to clot and the s e r u m was r e m o v e d and s t o r e d at - 80~ until analysis. S e r u m c a l c i u m and c r e a t i n i n e w e r e a n a l y z e d u s i n g a K o d a k E k t a c h e m 700 A n a l y z e r (clinical P r o d u c t s Division, E a s t m a n Kodak, Rochester, NY). During the HP t r e a t m e n t one s u b j e c t had a s e r u m c a l c i u m c o n c e n t r a t i o n (1.73 mmol/L) well b e l o w the normal range for serum c a l c i u m (2.1-2.6 mmol/L); this v a l u e was o m i t t e d from analysis. S e r u m samples w e r e a n a l y z e d for sodium, potassium, phosphate, and m a g n e s i u m u s i n g m e t h o d s s i m i l a r to those o u t l i n e d for urine. C a l c i t r i o l was m e a s u r e d in serum s a m p l e s u s i n g a 3H r a d i o - r e c e p t o r assay kit ( l , 2 5 - d i h y d r o x y v i t a m i n D-3H R R A kit #60065, I N C S T A R Corp., Stillwater, MN). Statistical

Analysis

R e s u l t s w e r e a n a l y z e d by a r e p e a t e d - m e a s u r e s A N O V A (9) and are p r e s e n t e d in t a b l e s as m e a n s • s t a n d a r d e r r o r of the m e a n (SEM). The S t u d e n t - N e u m a n - K e u l s test was u s e d to d e t e r m i n e d i f f e r e n c e s b e t w e e n m e a n s (9). Differences between means were c o n s i d e r e d to be s i g n i f i c a n t at P S 0.05.

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T.J. GREEN and S.J. WHITING RESULTS

Serum Values S e r u m v a l u e s are g i v e n in T a b l e 2. Day 5 s e r u m c a l c i u m was s i g n i f i c a n t l y h i g h e r d u r i n g the h i g h p r o t e i n + K H C O 3 (HP+K) t r e a t m e n t t h a n d u r i n g the h i g h p r o t e i n (HP) treatment. Serum s o d i u m w a s l o w e s t d u r i n g the HP t r e a t m e n t c o m p a r e d to all other treatments. S e r u m p o t a s s i u m was lower d u r i n g the H P + N a t r e a t m e n t t h a n d u r i n g the HP treatment. S e r u m c r e a t i n i n e was h i g h e r d u r i n g the HP t r e a t m e n t as c o m p a r e d to the M P and H P + K treatments. T h e r e w e r e no s i g n i f i c a n t c h a n g e s in s e r u m phosphate, magnesium, or c a l c i t r i o l levels w i t h t r e a t m e n t (data not shown). Fasting

Urine

Values

As shown in T a b l e 2, Day 5 fasting c a l c i u m e x c r e t i o n rose w i t h HP t r e a t m e n t r e l a t i v e to all other t r e a t m e n t s . Fasting p h o s p h a t e e x c r e t i o n showed no s i g n i f i c a n t c h a n g e s in r e s p o n s e to any of the treatments. Fasting sodium excretion was higher d u r i n g the H P + N a t r e a t m e n t r e l a t i v e to the o t h e r t h r e e treatments. F a s t i n g p o t a s s i u m e x c r e t i o n was i n c r e a s e d d u r i n g the H P + K t r e a t m e n t r e l a t i v e to the HP+Na and H P t r e a t m e n t s but not the M P treatment. Twenty-Four

Hour Urine Values

Day 3 and 4 u r i n e v a l u e s are g i v e n in T a b l e 3. As expected, u r i n a r y c a l c i u m e x c r e t i o n w a s s i g n i f i c a n t l y i n c r e a s e d w i t h the H P t r e a t m e n t r e l a t i v e to the MP t r e a t m e n t on b o t h Day 3 and 4. W i t h the a d d i t i o n of KHCO 3 (HP+K), Day 3 and 4 c a l c i u m e x c r e t i o n s w e r e g r e a t l y r e d u c e d r e l a t i v e to the HP treatment. In contrast, w i t h the f u r t h e r a d d i t i o n of N a H C O 3 (HP+Na), c a l c i u m e x c r e t i o n was r e d u c e d r e l a t i v e to the HP t r e a t m e n t o n l y on Day 3. This h y p o c a l c i u r i c e f f e c t of N a H C O 3 d i s a p p e a r e d by Day 4. Urinary phosphate excretion was s i g n i f i c a n t l y l o w e r d u r i n g the H P + K t r e a t m e n t as c o m p a r e d to all o t h e r t r e a t m e n t s on Day 4 but not on Day 3. Magnesium e x c r e t i o n r o s e d u r i n g the HP t r e a t m e n t r e l a t i v e to the M P and HP+Na t r e a t m e n t s on Day 3, but these e f f e c t s w e r e not e v i d e n t on Day 4. Net a c i d e x c r e t i o n (NAE) was s i g n i f i c a n t l y h i g h e r d u r i n g the HP t r e a t m e n t t h a n d u r i n g the M P t r e a t m e n t on b o t h Day 3 and 4. The a d d i t i o n of b i c a r b o n a t e (HP+Na and HP+K) l o w e r e d NAE to levels s i g n i f i c a n t l y b e l o w the M P t r e a t m e n t on Days 3 and 4. An u n e x p e c t e d f i n d i n g was t h a t NAE on Day 3 w a s s i g n i f i c a n t l y lower d u r i n g the H P + N a t r e a t m e n t than d u r i n g the H P + K t r e a t m e n t d e s p i t e the a d m i n i s t r a t i o n of equal a m o u n t s of b i c a r b o n a t e . T r e a t m e n t had no s i g n i f i c a n t e f f e c t on u r i n a r y c r e a t i n i n e excretion. Sodium

excretion

was

increased

during

the H P + N a

treatment

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POTASSIUM AND URINARY CALCIUM

999

and potassium excretion was increased during the HP+K treatment relative to the other treatments on Days 3 and 4. Urinary sulphate excretion was significantly higher during the three high protein treatments than during the MP treatment (only Day 4 samples were analyzed). Treatment had no significant effect on urinary chloride. Renal Handlinq of Calcium Glomerular filtration rate (GFR), measured as endogenous creatinine clearance, was calculated by dividing urinary creatinine excretion (Day 4) by fasting serum creatinine. Fractional excretion of calcium (FE-Ca) was calculated by dividing the product of Day 4 urinary calcium (mmol/day) and fasting serum creatinine (mmol/L) by the product of fasting serum calcium (mmol/L) and Day 4 urinary creatinine (mmol/day), and multiplying by 100 %. The effects of dietary treatment on GFR and FE-Ca are shown in Table 3. Dietary treatment had no significant effect on GFR. The fractional excretion of calcium was significantly lower during the MP and HP+K treatments than during the HP and HP+Na treatments. DISCUSSION Dietary factors promoting urinary calcium loss or retention may be important determinants for the subsequent development of osteoporosis. When hypercalciuria is induced by a diet high in animal protein, for example, there is evidence of bone loss (I). A recent study has shown a positive relationship between hip fracture incidence and animal protein intake (i0). In the present study the addition of 60 g protein to a moderate protein diet of approximately I00 g, increased urinary calcium excretion by approximately 40 %. This finding agrees with the results of other investigators who have shown similar increases in urinary calcium excretion with dietary protein administration (ii). It is well known that high protein feeding increases net acid excretion (NAE) (4,12-14), and much of the increase in NAE is due to the oxidation of the sulphur amino acids, methionine and cysteine. We observed a rise in urinary sulphate excretion during the three high protein treatments as compared to the moderate protein treatment. The addition of alkali to the high protein diet, as either KHCO 3 or NaHCO3, reduced NAE relative to both the high protein and moderate protein treatments. On Day 3 only, NAE was significantly lower during NaHCO 3 administration than during KHCO~ administration, and adding NaHCO 3 and KHCO 3 lowered urinary calclum to the same extent. On Day 4, however, both NaHCO 3 and KHCO 3 reduced NAE excretion by the same amount; yet adding KHCO 3 but not NaHCO 3 lowered urinary calcium excretion. Data in the literature support a transient hypocalciuric effect of NaHCO 3. While Lemann and coworkers (5) found no significant

1000

T.J. GREEN and S.J. WHITING

hypocalciuric effect, averaged over 12 days, of 60 mmol/day N a H C O 3 in subjects fed a moderate level of dietary protein, they later reported (6) that NaHCO 3 treatment was hypocalciuric on days 1 and 2 but not on days 3 and 4 of administration. Our data suggests that during this initial adaptation period to NaHCO 3 there is a significant decrease in net acid excretion which would act to decrease urinary calcium more than expected (15). We speculate that NaHCO 3 does not sustain hypocalciuria as the hypocalciuric action of the bicarbonate is eventually opposed by the hypercalciuric effect of the sodium cation. Lutz (4) had reported that 70 mmol/day NaHCO~ overcame high protein-induced hypercalciuria; however, although not readily apparent, her study involved removing an equal amount of N a C l when NaHCO. was added. While she attributed the fall in urinary calcium excretion to the addition of NaHCO3, in actuality NaCl was removed from the diet. Removing NaCl would be expected to decrease calcium excretion as adding NaCl has been shown to increase it (2). In contrast to NaHCO3, the addition of KHCO 3 to the high protein diet was effective in reducing urinary calcium excretion by approximately 40 %, thus reducing high proteininduced calcium excretion to a level seen with moderate protein diets. Our results showing a hypocalciuric effect of alkaline potassium agree with those of other studies, which tested alkaline potassium salts added to moderate protein diets (5,6,16,17). The addition of 60 mmol KHCO3, for example, resulted in a 26% decrease in urinary calclum excretion averaged over 12 days in a study of i0 male subjects (5); Kcitrate reduced urinary calcium excretion by 50% in a six-day study of eight men and women (17). In these studies, and our study, it appears that the hypocalciuric action of the alkali (bicarbonate or citrate) is not opposed by the presence of the potassium. It has been proposed, however, that potassium itself may be hypocalciuric (20). The exact mechanism by which potassium, especially when present in the diet as an alkaline salt, could act to decrease urinary calcium, is yet undetermined. Lemann and colleagues (20) have suggested two possible actions: extracellular volume contraction or phosphate retention causing suppression of calcitriol synthesis. Our data are somewhat supportive of the latter as we found evidence of phosphate retention on Day 4 but no change in calcitriol levels. It might be expected that the mechanism could be determined from animal studies. In the rat, however, alkaline potassium salts do not reduce urinary calcium excretion (21,22). In summary, the retention of both calcium and phosphate with alkaline potassium treatment suggests a beneficial effect on bone, and this regimen may prove useful in the prevention and treatment of osteoporosis. Longer term studies of groups at risk for bone loss, such as post-menopausal women with low calcium intakes, should be conducted to show if there is a

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beneficial effect on bone density. Our finding of a positive effect of alkaline potassium on calcium excretion gives further impetus to dietary recommendations promoting an increase in fruit and vegetable consumption. ACKNOWLEDGMENTS We thank Tracy Duff and Lisa Fugleburg for their technical assistance and Ross Laboratories (Montreal, Canada) for donating Ensure R, Promod R, and Polycose R. This work was supported by the Natural Sciences and Engineering Research Council of Canada. REFERENCES I.

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Sakhaee K, Alpern R, Jacobson HR, Pak CYC. Contrasting effects of various potassium salts on renal citrate excretion. J Clin Endocrinol Metab 1991;72:396-400.

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Lemann JJr, Pluess JA, Gray RW. Potassium causes calcium retention in healthy adults. J Nutr 1993;123:1623-1626.

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Greger JL, Kaup SM, Behling AR. Calcium, magnesium and phosphorus utilization by rats fed sodium and potassium salts of various inorganic anions. J Nutr 1991;121: 1382-1388.

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Accepted for publication February 16, 1994.