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Center for Mineral Metabolism and Clinical Research (K.S., N.M.M., C.Y.C.P.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-8885; and Department of Pediatrics (S.A.A.), Children’s Nutrition Research Center, Baylor College of Medicine, Houston, Texas 77030-2600
Address all correspondence and requests for reprints to: Khashayar Sakhaee, M.D., 5323 Harry Hines Boulevard, Dallas, Texas 75390-8885. E-mail: khashayar.sakhaee{at}email.swmed.edu.
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Abstract |
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Introduction |
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Because these agents have different effects on bone, we explored whether the combined use of calcium and alkali might exert an additional bone-protective action. The present placebo-controlled, crossover study was undertaken to compare the effects of potassium citrate, calcium citrate, and potassium citrate plus calcium citrate on calcium metabolism, acid-base status, and markers of bone turnover in postmenopausal women.
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Subjects and Methods |
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Eighteen healthy postmenopausal women participated in the study. Sixteen women were Caucasian, and two were Asian. The mean age was 58 yr (range, 48–76 yr). Other demographic information and bone mineral density data are shown in Table 1
. Two subjects had osteoporosis (defined by a T-score <–2.5 at either the femoral neck or the lumbar spine); the remaining women did not.
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Study protocol
This study was a crossover double-blind trial. Participants underwent four phases of study in a random order, using a 4 x 4 Latin square randomization scheme developed by a statistician. Each phase was 2 wk in duration, with a washout period of 2 wk between phases. During the placebo phase, subjects took two tablets of calcium citrate placebo and two tablets of potassium citrate placebo twice daily, providing neither calcium nor potassium citrate. During the potassium citrate phase, each subject took two tablets of potassium citrate [1080 mg (10 mEq) per tablet] and two tablets of calcium citrate placebo twice a day, to deliver a daily intake of 4.3 g (40 mmol) of potassium citrate. During the calcium citrate phase, subjects took two tablets of calcium citrate [200 mg (5 mmol) calcium per tablet] and two tablets of potassium citrate placebo twice daily, providing 800 mg (20 mmol) of calcium daily. During the combined potassium citrate-calcium citrate phase, subjects received two tablets of potassium citrate and two tablets of calcium citrate twice a day, providing 4.3 g (40 mmol) of potassium citrate and 800 mg (20 mmol) of calcium per day. Calcium citrate (Citracal), potassium citrate (Urocit-K), and corresponding placebo tablets were provided by the Mission Pharmacal Co. (San Antonio, TX).
In each study phase, subjects received study drug(s) for 14 d (d 1–14). Compliance with each of the study drugs was ascertained by pill count at the end of each phase. On d 8–11, subjects were instructed by a University of Texas Southwestern Medical Center General Clinical Research Center (GCRC) dietitian to rigidly follow a diet with a daily composition of approximately 60 g of protein, 400 mg (10 mmol) of calcium, 800 mg (26 mmol) of phosphorus, 2.3 g (100 mmol) of sodium, 2.3 g (60 mmol) of potassium, and 3 liters of fluids. This diet, called "basal diet," corresponded in composition to the diet usually consumed by many subjects who do not take calcium supplements. During the last 3 d of the study (d 12–14), subjects were admitted to the GCRC where they received a constant metabolic diet of the same composition.
On d 12–14, a fasting venous blood sample was obtained each day for the measurement of sodium, potassium, chloride, total carbon dioxide content, calcium, phosphorus, alkaline phosphatase, and creatinine. On d 13 and 14, a fasting venous blood sample was taken each day for the analysis of 25-hydroxyvitamin D (25-OHD), calcitriol [1,25-(OH)2D], PTH, serum cross-linked carboxy-terminal C-telopeptide of type I collagen (CTX), osteocalcin (GLA), and bone-specific alkaline phosphatase (BAP). Two 24-h urine samples were collected on d 13 and 14 for the measurement of calcium, pH, citrate, ammonium (NH4+), creatinine, sodium, potassium, calcium, magnesium, phosphorus, chloride, and markers of bone resorption, hydroxyproline (OHP), and cross-linked amino-terminal telopeptide of type I collagen (NTX). Fractional intestinal calcium absorption was determined by dual isotope technique using stable calcium isotopes: 2.5 mg of 42Ca (0.0625 mmol) was infused iv, and 1 mg of 46Ca (0.025 mmol) was given orally with 100 mg (2.5 mmol) of calcium in a synthetic meal replacing breakfast. Urine was collected over the ensuing 24 h. Urine samples were prepared for thermal ionization mass spectrometric analysis as previously described (10) by using an oxalate precipitation technique. Samples were analyzed for isotopic enrichment by using a Finnigan MAT 261 (Thermo Electron, Bremen, Germany) magnetic sector thermal ionization mass spectrometer. The fractional intestinal absorption of calcium was determined as the dose-corrected quotient of the oral to iv tracers in the 24-h urine (11). The precision of the estimate of fractional calcium absorption is 3–5% of the resulting measurement.
Analytical procedures and calculations
Serum electrolytes, calcium, phosphorus, alkaline phosphatase, and creatinine were analyzed as part of a systematic multichannel analysis (GCRC Core Laboratory using the SYNCHRON CX9 ALX system; Beckman Coulter, Inc., Fullerton, CA). Serum 25-OHD, 1,25-(OH)2D, PTH, and GLA were measured by respective ELISAs (ALPCO Diagnostics, Windham, NH). Serum CTX was quantitated by ELISA (CTX Serum CrossLaps, Nordic Bioscience Diagnostics A/S, Herlev, Denmark). Serum BAP was assessed by ELISA (Quidel Corp., San Diego, CA). Urinary OHP was determined colorimetrically (Hypronosticon kit, Organon Teknika, Durham, NC). Urinary NTX was assessed by ELISA (Osteomark NTx, OSTEX International, Inc., Seattle, WA). Urinary calcium was analyzed by using atomic absorption spectrophotometry. Urinary citrate was quantitated enzymatically by using reagents from Boehringer-Mannheim Biochemical (Indianapolis, IN). Urinary ammonium was determined by the glutamate dehydrogenase method. Absorbed calcium was calculated as the product of the fractional intestinal absorption of calcium and the total amount of calcium ingested (from diet and supplement). In each subject, mean values for various serum or urinary tests were taken in deriving the group mean.
Samples for bone markers, intact serum PTH (sPTH), and vitamin D metabolites were batched, and measurements were performed at the end of the study.
Statistical analysis
The four groups were compared by repeated-measures ANOVA. Significant differences among treatment phases were further analyzed by comparisons between pairs of treatment, by use of contrasts constructed from the ANOVA models. By employing the Bonferroni inequality to adjust for multiple testing, six pairwise comparisons were assessed: a) potassium citrate vs. placebo, b) calcium citrate vs. placebo, c) calcium citrate vs. potassium citrate, d) combined treatment (potassium citrate plus calcium citrate) vs. calcium citrate, e) combined treatment vs. potassium citrate, and f) combined treatment vs. placebo. The effects of alkali and calcium on a basal diet were obtained from a) and b), respectively. c) compared potassium citrate with calcium citrate on a basal diet. The effect of alkali on a high calcium intake was provided by d), whereas that of calcium on a high alkali intake was derived from e). f) yielded the effect of both alkali and calcium on a basal diet. In addition, we tested for the existence of trend in the change in the markers of bone resorption as the drug treatment changed from placebo to potassium citrate to calcium citrate to the combined treatment (12).
The level of significance was 0.05 for the overall (four group) and trend tests. Each pairwise comparison was made with a Bonferroni-adjusted type I error of 0.0083. Statistical analysis was performed with SAS version 9.0 (SAS Institute, Cary, NC) and with S-PLUS version 6.2 (Insightful Corp., Seattle, WA).
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Results |
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Mean compliance by pill count was 97.7% during each study phase. Serum electrolytes and creatinine and urinary volume, sodium, creatinine, and sulfate were not different among the four phases of the study (Table 2).
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Compared with placebo, potassium citrate significantly reduced urinary calcium [180 ± 86 (SD) to 145 ± 85 mg/d (4.50 ± 2.15 to 3.63 ± 2.13 mmol/d); P < 0.0001] without significantly changing sPTH, vitamin D metabolites, fractional intestinal calcium absorption, or total calcium absorbed (symbol a in Table 3). Moreover, potassium citrate significantly increased urinary pH (6.13 ± 0.33 to 6.63 ± 0.31; P < 0.001) and citrate and significantly decreased urinary ammonium (symbol a in Table 2
). Urinary and serum markers of bone resorption and bone formation were not significantly altered (Table 4 and Fig. 1).
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Compared with placebo, calcium citrate significantly increased urinary calcium [180 ± 86 to 239 ± 98 mg/d (4.50 ± 2.15 to 5.98 ± 2.45 mmol/d); P < 0.0001] and marginally reduced fasting sPTH (P = 0.09), without significantly altering vitamin D metabolites or fractional intestinal calcium absorption (symbol b in Table 3). However, the total amount of calcium absorbed increased significantly [182 ± 44 to 506 ± 116 mg/d (4.55 ± 1.10 to 12.65 ± 2.90 mmol/d); P < 0.0001]. Urinary pH marginally increased, urinary citrate significantly increased, and ammonium significantly decreased (symbol b in Table 2). Urinary OHP and serum CTX significantly decreased, but urinary NTX did not change significantly (symbol b in Table 4 and Fig. 1). Serum bone formation markers (GLA and BAP) were not significantly altered.
Compared with potassium citrate alone, calcium citrate resulted in a significantly higher urinary calcium and absorbed calcium [185 ± 36 to 506 ± 116 mg/d (4.63 ± 0.90 to 12.65 ± 2.90 mmol/d); P < 0.0001], and lower sPTH (34.3 ± 14.5 vs. 40.9 ± 19.3 pg/ml; P = 0.005) (symbol c in Table 3). Moreover, it yielded lower urinary pH and higher urinary ammonium (Table 2). Markers of bone turnover were not significantly different (Table 4).
Effect of combined potassium citrate and calcium citrate
The comparison of combined treatment (potassium citrate plus calcium citrate) vs. calcium citrate alone allowed assessment of the effect of potassium citrate during a high calcium intake (shown by symbol d in the Tables). Serum calcium, fasting PTH, and 1,25-(OH)2D and total calcium absorbed did not differ between the two phases (Table 3). During combined treatment, urinary calcium was numerically lower but not significantly different from calcium citrate alone. Urinary pH and citrate were significantly higher, and urinary ammonium was lower than with calcium citrate alone (Table 2). There were no significant differences in the markers of bone turnover (Table 4).
Comparison of combined treatment (potassium citrate plus calcium citrate) vs. potassium citrate yielded the effect of calcium citrate during a high alkali intake (shown by symbol e in the Tables). During combined treatment, serum calcium significantly increased [9.5 ± 0.5 to 9.7 ± 0.4 mg/dl (2.38 ± 0.13 to 2.43 ± 0.10 mmol/liter); P < 0.0001] and fasting sPTH significantly decreased (34.2 ± 14.9 vs. 40.9 ± 19.3 pg/ml; P = 0.005) (Table 3). Urinary calcium increased significantly [145 ± 85 to 228 ± 92 mg/d (3.63 ± 2.13 to 5.70 ± 2.30 mmol/d); P < 0.001]. Urinary citrate was significantly greater, urinary pH was numerically higher, and urinary ammonium was numerically lower than in potassium citrate alone (Table 2). Urinary NTX was significantly lower (by 18%; P = 0.007) on combined treatment (Fig. 1).
Comparison of combined treatment (potassium citrate plus calcium citrate) vs. placebo yielded the effect of alkali and calcium given together during a basal diet (shown by symbol f in the Tables). During combined treatment, serum and urinary calcium were significantly higher, and fasting sPTH was marginally lower (P = 0.08) than during the placebo phase (Table 3). However, serum 1,25-(OH)2D and fractional intestinal calcium absorption did not differ between the two phases. Nonetheless, the total amount of calcium absorbed was significantly increased [182 ± 44 to 498 ± 128 mg/d (4.55 ± 1.10 to 12.45 ± 3.20 mmol/d); P < 0.0001]. Urinary pH and citrate were significantly higher, and urinary ammonium was significantly lower than during placebo (Table 2). All three markers of bone resorption decreased significantly (OHP by 9.5%, NTX by 18.1%, and CTX by 20.4%), although markers of bone formation did not change (Table 4 and Fig. 1).
Tests of trend
A trend in the change in markers of bone resorption as the drug treatment changed from placebo to potassium citrate to calcium citrate to the combined treatment was noted (Fig. 2). Each of the trend tests was statistically significant. The observed significances were 0.003 for urinary NTX, less than 0.0001 for serum CTX (Fig. 2), and 0.01 for urinary OHP (data not shown).
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Discussion |
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The use of potassium citrate as a bone protective agent is based on prior studies showing beneficial effects of alkali on three target organs. In the kidneys, alkali provided as a potassium salt has been reported to reduce urinary calcium by enhancing renal tubular reabsorption of calcium (4, 7, 8) possibly through activation of the epithelial calcium channel (13). In the intestinal tract, potassium citrate treatment has been reported to enhance calcium absorption among patients with distal renal tubular acidosis (14). In the skeletal tissue, the osteoclastic resorption is inhibited (9) and osteoblastic formation is stimulated by alkali (4, 9).
In this study, potassium citrate delivered a moderate alkali load, commensurate with a significant rise in urinary pH and citrate and a decrease in ammonium (Table 2). Although the fasting serum bicarbonate did not change, it is likely that it rose transiently after each dose of potassium citrate, thus accounting for the significant increase in urinary pH. Moreover, urinary calcium declined by 35 mg/d (0.88 mmol/d) as reported earlier with potassium alkali but not with sodium alkali (7, 8). Fractional intestinal calcium absorption did not change, likely resulting in net calcium retention. However, no change in bone turnover markers occurred. Thus, the hypocalciuric action of potassium citrate was probably mainly renal in origin (15). The potentially retained calcium was probably insufficient to alter bone markers.
The above findings differ from previous studies in which potassium alkali was shown to significantly alter bone turnover markers in postmenopausal women (4, 5). Although in our study the dietary protein intake was equivalent to the recommended daily allowance (RDA) of 0.8 g protein/kg·d (Ref. 16 ; see http://books.nap.edu/catalog/10490.html), the subjects in the previous reports had a much higher intake of protein, which could have delivered more acid load (17). The resulting stimulated state of osteoclastic bone resorption may have been more amenable to correction by alkali. Another potential explanation is the lower dose of potassium alkali used in the present study (40 mEq/d, compared with 60–120 mEq/d used in previous studies).
In the present study, the fractional intestinal calcium absorption was unaffected by alkali. Earlier reports had disclosed that alkali therapy increases intestinal calcium absorption among patients with distal renal tubular acidosis (14) but does not alter it in normal subjects and postmenopausal women (4, 8). Thus, the action of alkali on intestinal handling of calcium may depend on the prevailing state of acid-base balance.
The classic physiological action of calcium supplementation on bone implicates parathyroid suppression from absorbed calcium, leading to inhibition of osteoclastic bone resorption (2, 3). In this study, urinary OHP and serum CTX significantly decreased during calcium supplementation, although urinary NTX did not change (Table 4). These results are consistent with the prior reports on the effect of calcium supplementation on bone turnover (3, 18, 19). However, the exact mechanism by which calcium citrate inhibits bone resorption is not clear. Although urinary calcium rose substantially (suggestive of increased absorbed calcium from the intestinal tract), fasting sPTH only marginally declined, and serum 1,25-(OH)2D and fractional intestinal calcium absorption did not change. One possibility is that the PTH suppression was missed because the rise in serum calcium and suppression in sPTH were transient. Therefore, it is conceivable that sPTH returned to baseline by the time it was measured, after an overnight fast. Alternatively, other factors beside parathyroid suppression may have contributed to suppressed bone resorption. One possible factor is alkali load delivered by calcium citrate. Although modest, there was a marginal increase in urinary pH, significantly higher urinary citrate, and lower urinary ammonium. Another potential explanation is that calcium itself might directly affect bone resorption, mediated via calcium sensor receptor protein regulating osteoclastic function (20).
Comparison of combined treatment (potassium citrate plus calcium citrate) with calcium citrate alone afforded an assessment of the action of potassium citrate on a high calcium intake. Compared with calcium citrate alone, combined treatment significantly increased urinary pH and citrate and significantly lowered urinary ammonium, thus indicating provision of alkali load by potassium citrate during high calcium intake. However, urinary calcium was numerically lower but not significantly different from the calcium citrate alone, suggesting that the hypocalciuric action of potassium alkali (7, 8) was largely lost during a high-calcium diet. The inhibition of PTH secretion by calcium citrate may have contributed to the attenuation of the hypocalciuric action of potassium citrate, although there are no direct studies to support this theory. As on a basal diet, potassium citrate did not change bone markers during high calcium intake, although a subtle effect on bone could not be excluded.
The effect of calcium citrate in the setting of high alkali intake was discerned by comparing combined treatment (potassium citrate plus calcium citrate) with potassium citrate alone. Compared with potassium citrate alone, combined treatment significantly increased serum and urinary calcium, and decreased fasting sPTH, indicating that calcium citrate suppresses parathyroid function by increasing absorbed calcium during high alkali intake. Moreover, urinary citrate was significantly greater, and urinary pH was numerically higher, compared with potassium citrate. Thus, the alkali load delivered by combined treatment was slightly greater than that delivered by potassium citrate alone, probably from the mild alkalinizing action of calcium citrate. Urinary NTX significantly declined, but the other two markers of bone resorption did not. Thus, calcium citrate on high alkali intake probably exerted a bone protective action by the same mechanism(s) as on a basal diet.
The most prominent effects of combined treatment were displayed when compared with placebo. Combined treatment significantly increased serum and urinary calcium and marginally reduced fasting sPTH, suggestive of suppression of parathyroid function by absorbed calcium from calcium citrate. Moreover, combined treatment significantly increased urinary pH and citrate and reduced urinary ammonium, indicative of alkali load from potassium citrate. All three markers of bone resorption decreased. Thus, on a basal diet (simulated by placebo), combined treatment conferred a bone protective action probably by the dual action of calcium citrate and potassium citrate.
A noteworthy finding here was that markers of bone formation were not altered by any treatment. The result probably reflects the short duration of treatment (2 wk), which is insufficient to elicit adequate osteoblastic response.
The results of this study may not be applied to use of other calcium salts. Calcium citrate alone was recently shown to be significantly more effective than calcium carbonate alone in reducing markers of bone resorption in postmenopausal women, without differing changes in sPTH (21).
In summary, potassium citrate alone conferred an alkali load, thereby reducing urinary calcium and potentially causing calcium retention. Calcium citrate alone probably suppressed parathyroid function, conferred a mild alkali load, and reduced bone resorption. Potassium citrate in a setting of a high calcium intake (with calcium citrate) conferred an alkali load but lacked hypocalciuric action. Calcium citrate in a setting of high alkali intake (with potassium citrate) suppressed parathyroid function and conferred a slightly greater alkali load. In a basal dietary setting (simulated by placebo), combined treatment reduced bone resorption by dual effects of alkali load from potassium citrate and of absorbed calcium from calcium citrate. Combined treatment may be considered among postmenopausal women with impaired intestinal calcium absorption or who are on a habitually high-animal-protein diet, although greater doses of potassium alkali may be needed. Future studies must be conducted to elucidate the long-term effects of the combined treatment on bone mineral density and fracture risk.
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Acknowledgments |
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Footnotes |
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C.Y.C.P. was the principal investigator for the new drug application of Urocit-K that was approved by the Federal Drug Administration for the prevention of uric acid stones and calcium stones associated with hypocitraturia. The University of Texas Southwestern Medical Center, the sponsor of Urocit-K and Citracal, has a licensing agreement with the Mission Pharmacal Company, which markets these drugs. The Mission Pharmacal Company kindly provided all study drugs for this study, including placebo medications, free of charge. It did not provide any funding or other support. None of the authors own equity in the Mission Pharmacal Company or serve as a consultant or member of its board.
First Published Online March 8, 2005
Abbreviations: BAP, Bone-specific alkaline phosphatase; CTX, C-terminal telopeptide of type I collagen; GLA, osteocalcin; 25-OHD, 25-hydroxy vitamin D; 1,25(OH)2D, calcitriol; OHP, hydroxyproline; NTX, N-terminal telopeptide of type I collagen; sPTH, serum PTH.
Received December 14, 2004.
Accepted February 24, 2005.
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