Volume 8, Issue 1 , Pages 67-72, January 2012
Biochemical control of bone loss and stone-forming propensity by potassium-calcium citrate after bariatric surgery
Article Outline
Abstract
Background
Patients undergoing Roux-en-Y gastric bypass (RYGB) surgery are prone to developing bone loss and kidney stones. The goal of the present study was to test the hypothesis that an effervescent formulation of potassium calcium citrate (PCC) would avert metabolic complications by providing bioavailable calcium and alkali.
Methods
A total of 24 patients with RYGB underwent a 2-phase crossover randomized trial comparing PCC and placebo. During the last 2 days of each 2-week phase, the serum and 24-hour urine samples were analyzed for calcium and bone turnover markers, acid base status, and urinary stone risk factors.
Results
Compared with placebo, PCC marginally reduced the serum parathyroid hormone level and significantly decreased urinary deoxypyridinoline by 12% (P <.001) and serum type 1 collagen C-telopeptide by 22% (P <.01). PCC significantly increased the net gastrointestinal alkali absorption, citrate, and pH and significantly lowered the urinary net acid excretion (P <.001). The urinary saturation of uric acid decreased significantly (P <.001). The supersaturation of calcium oxalate and brushite did not change despite an increase in calcium and pH. In untreated urine samples with citrate concentrations altered to mimic those of placebo and PCC, calcium oxalate agglomeration was significantly inhibited by PCC.
Conclusion
In RYGB patients, PCC supplementation inhibited bone resorption by providing bioavailable calcium, reduced the urinary saturation of uric acid, and increased the inhibitor activity against calcium oxalate agglomeration by providing alkali that increased urinary pH and citrate.
Keywords: Bariatric surgery , Nephrolithiasis , Osteoporosis , Obesity , Potassium calcium citrate
Obesity is a major health concern and a high economic burden. With the escalating prevalence of morbid obesity in the United States [1], bariatric surgery has become increasingly popular [2]. Roux-en-Y gastric bypass (RYGB) is now 1 of the most common interventions for the treatment of this condition [3]. This approach has been shown to sustain weight loss without undue morbidity [4]. However, metabolic bone disease [5], [6] and nephrolithiasis [7], [8], [9] have emerged as major potential complications of RYGB, just as in earlier intestinal bypass procedures [10], [11].
The pathophysiologic mechanisms for the development of bone disease and nephrolithiasis in RYGB are diverse. A major cause of bone loss is impaired intestinal calcium absorption, which leads to stimulation of parathyroid hormone (PTH) and bone resorption [6], [12], [13], [14]. Nephrolithiasis has been attributed to hyperoxaluria and hypocitraturia (from intestinal fat malabsorption and alkali loss) [9], [15], [16].
Specific guidelines for the prevention of bone loss and stone formation in RYGB are lacking. Supplementation with calcium (usually as a tablet preparation) and vitamin D are recommended for the prevention of bone loss [17]. In many patients after RYGB, tablet formulations of calcium supplements might be poorly bioavailable owing to limited exposure to gastric acid. We have previously reported that patients with RYGB absorb calcium poorly from common commercial calcium citrate and calcium carbonate tablets [18]. In patients with adequate bioavailability, the ensuing increase in urinary calcium might increase the stone risk. To date, alkali therapy has not been used with RYGB, despite its known value in controlling nephrolithiasis [19].
Therefore, a product is needed that provides optimally bioavailable calcium and alkali load. The present study was undertaken to test the hypothesis that potassium calcium citrate (PCC) confers bioavailable calcium to suppress PTH and bone resorption and alkali load to increase the urinary pH and citrate to reduce uric acid and calcium oxalate crystallization.
Methods
Patient data
A total of 24 patients with RYGB participated in the trial after giving written informed consent. They included 7 men and 17 women (21 whites and 3 blacks, mean age 51 yr, range 40–65). They were evaluated at a mean of 4.7 years (range 1.0–14.5) after RYGB. They had stable weight with <10 lb of change during the preceding 3 months. All had undergone open or laparoscopic RYGB with a 50–150-cm Roux limb. The mean preoperative body weight was 166 kg, and the average postoperative weight loss was 52.7 kg. Excluded from the study were those who were pregnant, and those with a creatinine clearance of <70 mL/min, hyperkalemia, hypercalcemia, and receiving treatment with calcium-sparing diuretics, glucocorticoids, bisphosphonates, or teriparatide. The patients were allowed to maintain their customary calcium supplements and vitamin D. The estimated mean dietary calcium was 630 mg/d and the mean supplemental calcium was 640 mg/d. Vitamin D was taken by 14 patients at an average dose of 600 U/d.
Methods
PCC and placebo were prepared by a well-known compounding pharmacy under aseptic conditions using United States Pharmacopeia compounds, following the strict guidelines of the Clinical Trials Pharmacy of the University of Texas Southwestern Medical Center. Each packet of PCC contained 20 mEq potassium, 10 mmol (400 mg) calcium, and 50 mEq citrate. In water, the contents dissolved rapidly with effervescence. The placebo packets contained inert microcrystalline cellulose equivalent in volume to PCC.
Study protocol
The Institutional Review Board of the University of Texas Southwestern Medical Center approved the study protocol. All patients participated in a 2-phase crossover study, assigned at random by an independent statistician. Each phase was 2 weeks in duration with a washout period of 1 week between phases. During the PCC phase, 1 packet of PCC was dissolved in 250 mL of water and drunk at breakfast and dinner to provide 20 mmol (800 mg) calcium and 40 mEq potassium daily. During the placebo phase, microcrystalline cellulose was administered in the same fashion.
In each study phase, the patients received PCC or placebo for 13 days. Compliance, determined by the packet count at the end of each phase, was 99%. All patients were instructed to adhere to their customary diet and to keep the same total fluid intake during the 2 phases. A total of 24 subjects completed both phases of the present study.
On the morning of day 14, a fasting venous blood sample was taken for serum chemistry test, 25-hydroxyvitamin D (25-OHD), PTH, cross-linked carboxy-terminal c-telopeptide of type 1 collagen (CTX), and bone-specific alkaline phosphatase. Two 24-hour urine samples were collected on days 12 and 13 for the measurement of the total volume, calcium, pH, citrate, oxalate, ammonium, creatinine, sodium, potassium, magnesium, phosphorus, chloride, and deoxypyridinoline. Titratable acidity was obtained from the urine sample collected on day 13 for the calculation of the net acid excretion (NAE).
Crystal agglomeration of calcium oxalate
Calcium oxalate agglomeration inhibition was obtained using a modified method from Kok et al. [20]. In 8 fresh urine samples collected from patients without PCC treatment, the concentrations of calcium, citrate, and pH were brought to the same levels as from the group mean values of the 24 patients during the PCC and placebo phases using appropriate dilution and/or addition of calcium and citrate and titration of pH. Thus, for each sample, 1 aliquot contained 49 mg/L calcium and 194 mg/L citrate, with pH 5.92, to represent the placebo phase. The other aliquot contained 59.6 mg/L calcium and 339 mg/L citrate, with pH 6.38, to represent the PCC phase.
For each aliquot of urine, the test solution was prepared by diluting 1 part of the urine aliquot with 4 parts of synthetic stock solution metastably supersaturated with calcium oxalate. After seeding 20 mL of test solution with 2.8 mg of pure mature crystals of calcium oxalate dihydrate, the filtrate concentration of calcium was determined frequently. From the decrement in the filtrate concentration of calcium plotted over time, the interval in minutes required to reach one half of the maximal decline was obtained to yield the crystal agglomeration inhibition. A greater value for crystal agglomeration inhibition meant a lower degree of calcium oxalate agglomeration.
Analytical procedures and calculations
The serum electrolytes, calcium, phosphorus, alkaline phosphatase, and creatinine were analyzed as a part of a systematic multichannel analysis. Serum 25-OHD was measured using a immunodiagnostic assay. Serum PTH was quantitated using enzyme-linked immunosorbent assay (Biomerica, Irvine, CA) and serum CTX, bone-specific alkaline phosphatase, and urinary deoxypyridinoline using an enzyme-linked immunosorbent assay from Quidel (San Diego, CA). Urinary calcium and magnesium were determined using atomic absorption spectroscopy, oxalate using a chromatography system with a carbonate-bicarbonate eluent and an anion column, and phosphorus using ammonium molybdate-based reagents. Urinary uric acid was analyzed using the urate oxidase method with an alkalinized aliquot to prevent precipitation, citrate using a citrate lyase assay, and pH by electrode. Urinary sodium and potassium were analyzed using flame emission photometry, chloride using a Labconco Buchler chloridometer (Labconco Corporation; Kansas City, MO), ammonium using a glutamate dihydrogenase method, and creatinine using the picric acid method.
From these urinary measures, urinary saturation with respect to calcium oxalate, brushite (CaHPO4
·2H20), and undissociated uric acid was calculated as the solubility index (SI) using the Joint Expert Speciation System program [21]. The SI value of 1 indicates saturation; >1, supersaturation; and <1, undersaturation. The NAE was calculated as (ammonium + titratable acidity) − (citrate + bicarbonate). The net gastrointestinal alkali absorption was calculated by a formula using key urinary cations and anions.
Statistical analysis
The results are presented as the mean ± standard deviation. Paired t tests were used to assess significant differences between the placebo and PCC phases. Repeated measures analysis of variance models were used to assess the effect of the order of the phases. Statistical analysis was performed using SAS, version 9.1 (SAS Institute, Cary, NC).
Results
Effect on calcium metabolism and bone turnover
The mean serum PTH level was greater than the upper normal limit during both phases (Table 1 and Fig. 1A). It was marginally lower with PCC than with placebo (P = .12). Although serum CTX decreased significantly with PCC (P <.01), it remained above the upper normal range during both phases. Urinary deoxypyridinoline was within normal limits in both phases (Fig. 1B) but was significantly lower with PCC than with placebo (P <.001). The serum 25-OHD level was low normal and showed no difference between the 2 phases. The serum calcium, phosphorus, magnesium, alkaline phosphatase, and bone-specific alkaline phosphatase levels were normal and did not differ between the phases.
Table 1. Serum and urinary biochemical profile
| Profile | Phase | P value | |
|---|---|---|---|
| Placebo | PCC | ||
| Calcium metabolism and bone turnover | |||
| Serum | |||
| Calcium (mg/dL) | 9.1±.4 | 9.1±.6 | .81 |
| Phosphorus (mg/dL) | 3.7±.4 | 3.8±.6 | .17 |
| Magnesium (mg/dL) | 2.1±.2 | 2.1±.2 | .86 |
| Alkaline phosphatase (IU/L) | 79±21 | 82±21 | .22 |
| PTH (pg/mL) | 75±33 | 67±31 | .12 |
| 25-OHD (ng/mL) | 21.2±8.3 | 21.2±7.7 | .98 |
| CTX (ng/mL) | .84±.30 | .65±.30 | <.001 |
| Bone specific alkaline phosphatase (U/L) | 27.9±8.6 | 27.0±6.9 | .32 |
| Urine | |||
| Deoxypyridinoline (nmol/mmol creatinine) | 6.89±2.12 | 6.02±2.08 | .009 |
| Electrolyte and acid base status | |||
| Serum | |||
| Sodium (mEq/L) | 139±2 | 139±2 | .25 |
| Potassium (mEq/L) | 4.1±.3 | 4.4±.4 | .001 |
| Chloride (mEq/L) | 106±3 | 105±2 | .18 |
| Carbon dioxide (mEq/L) | 24±3 | 25±3 | .06 |
| Urine | |||
| Net acid excretion (mEq/d) | 54±32 | 17±22 | <.001 |
| Net gastrointestinal alkali absorption (mEq/d) | 23±40 | 66±40 | <.001 |
| Potassium (mEq/d) | 51±24 | 75±30 | <.001 |
| Sodium (mEq/d) | 169±90 | 172±93 | .87 |
| Chloride (mEq/d) | 162±80 | 158±78 | .82 |
| Stone risk factors | |||
| Urine | |||
| Calcium (mg/d) | 100±65 | 122±75 | .12 |
| Oxalate (mg/d) | 42.5±19.4 | 39.3±18.2 | .34 |
| Phosphorus (mg/d) | 834±361 | 659±308 | .001 |
| Uric acid (mg/d) | 502±236 | 460±155 | .24 |
| pH | 5.92±.42 | 6.38±.48 | <.001 |
| Citrate (mg/d) | 396±340 | 739±423 | <.001 |
| Creatinine (mg/d) | 1269±444 | 1249±371 | .66 |
| Total volume (L/d) | 2.04±.88 | 2.18±.87 | .30 |
| SI | |||
| Calcium oxalate | 3.31±1.69 | 3.04±1.72 | .51 |
| Brushite | .66±.49 | .74±.45 | .37 |
| Uric acid | 1.19±.76 | .50±.49 | <.001 |
| Agglomeration inhibition of calcium oxalate (s) | 23.4±14.5 | 38.4±15.8 | .009 |
Fig. 1.
(A) Effect of PCC and placebo on serum calcium (Ca) and PTH. Vertical bars indicate mean ± standard deviation. Dashed horizontal line represents upper normal limit of serum PTH. (B) Effect of PCC and placebo on serum CTX and urinary deoxypyridinoline (DPD). Dashed horizontal lines represent upper normal limits. **P <.01, †P <.001 between 2 phases.
Effect on acid base status
Serum electrolytes did not differ significantly between the 2 phases (Table 1). NAE was significantly lower with PCC than with placebo. The net gastrointestinal alkali absorption was significantly greater with PCC than with placebo (Table 1). Urinary potassium was significantly greater in the PCC phase than in the placebo phase. Urinary sodium and chloride did not differ significantly between the 2 phases.
Effect on urinary crystallization of stone-forming salts
Urinary calcium was modestly greater during the PCC than the placebo phase (Table 1). The urinary oxalate level was high normal and did not differ between the 2 phases. The urinary phosphorus level was significantly lower with PCC than with placebo. The urinary uric acid level did not differ significantly between the 2 phases. The urinary pH and citrate levels were significantly greater with PCC than with placebo.
The urinary solubility index (SI) of calcium oxalate and brushite did not differ significantly between the 2 phases (Table 1 and Fig. 2A). The SI of uric acid was significantly lower with PCC than with placebo. Crystal agglomeration of calcium oxalate was significantly greater in the urine samples with added citrate (Fig. 2B).
Fig. 2.
(A) Effect of PCC and placebo on SI of calcium oxalate (Ca oxalate), brushite, and uric acid. Dashed horizontal line indicates saturation value. (B) Effect of PCC and placebo on agglomeration inhibition of calcium oxalate. Data individually depicted for 8 urine samples, in which concentrations of citrate and calcium and pH were altered to mimic those of PCC and placebo phases.
Discussion
The present study was undertaken to determine the value of a new effervescent formulation, PCC, in averting 2 potential complications of RYGB, bone loss and stone formation, by providing an optimally bioavailable calcium and alkali load.
Bone loss resulting in osteoporosis is emerging as a potential complication of RYGB [22]. Although other factors might be involved [23], a major cause for bone loss is secondary hyperparathyroidism from impaired intestinal calcium absorption, specifically resulting from the duodenal bypass (limiting the exposure of food to gastric acid, which impairs the solubility of the calcium salts), fast intestinal transit, and vitamin D deficiency [12], [13]. The complication of nephrolithiasis is attributed to hyperoxaluria (potentially from fat malabsorption and bile salts) [8], [9], [15], [24] and hypocitraturia (from intestinal alkali loss) [16], [25], [26]. In our previous study [16], patients with RYGB presented with significantly greater urinary oxalate and lower urinary citrate levels than did the obese control subjects. However, the urinary calcium level was also lower in RYGB patients, suggesting that this impairment might protect against nephrolithiasis by opposing the effects of hyperoxaluria and hypocitraturia.
Currently, calcium and vitamin D supplements are considered the standard of care after RYGB. However, calcium supplements are generally available in tablet formulation, which might be poorly absorbed owing to their low solubility (without adequate exposure to gastric acid) and rapid passage. We recently compared the single-dose bioavailability of 2 common calcium supplements (tablet formulation) among RYGB patients. Both calcium citrate (Citracal, Mission Pharmacal, San Antonio, TX) and calcium carbonate (OsCal, SmithKline Beecham Consumer Healthcare, Pittsburgh, PA) were poorly absorbed [18]. Although Citracal was slightly better absorbed, its bioavailability in RYGB patients was considerably less than that of healthy subjects [18]. Another problem with calcium supplementation is that it could aggravate stone formation by increasing the urinary calcium level. Thus, a preparation that would not only offer bioavailable calcium but also reduce the stone risk is needed.
To meet that objective, we formulated PCC, a new effervescent preparation containing calcium citrate and potassium citrate. The dissolution of calcium citrate before ingestion overcomes the poor solubility of the calcium tablets and rapid transit experienced by RYGB patients. In healthy subjects, we showed that effervescent calcium citrate was superior to solid calcium citrate [27]. The alkali load provided by potassium citrate corrected the acid accumulation and restored the normal urinary citrate level. In the present study, serum PTH was high during the placebo phase, even though the average calcium intake was about 1200 mg/d. The serum PTH level declined marginally with PCC treatment, although it remained elevated. The serum calcium level did not change, and the urinary calcium level increased only slightly, likely owing to the increased calcium accretion in the bone from “bone hunger” or the hypocalciuric action of alkali [28]. Urinary deoxypyridinoline and serum CTX significantly decreased during PCC treatment, indicating inhibited bone resorption. The most likely explanation is suppression of PTH. However, we acknowledge that other factors could play a role [23], including the skeletal effect of alkali. To determine the effect of the serum 25-OHD levels on the response to PCC treatment, serum PTH and CTX were evaluated in subjects with 25-OHD ≥20 ng/mL and <20 ng/mL. Serum CTX diminished significantly, regardless of the initial serum 25-OHD level. However, the serum PTH declined significantly in those with 25-OHD levels ≥20 ng/mL.
Calcium citrate alone provides only a slight alkali load [28]. A larger alkali load was delivered by PCC, because urinary NAE decreased by 37 mEq/d and the net gastrointestinal alkali absorption increased by 42 mEq/d. Similarly, urinary pH increased by .46 U and citrate by 343 mg/d. Urinary alkalinization reduced the propensity to uric acid crystallization by reducing uric acid saturation. Hypercitraturia accentuated inhibitor activity against calcium oxalate crystallization by inhibition of calcium oxalate agglomeration.
Urinary oxalate did not change significantly during PCC treatment, although it was expected to decline from oxalate binding by calcium. Therefore, other mechanisms, such as increased oxalate permeability owing to unabsorbed bile salts [24] might drive hyperoxaluria after RYGB. The expected increase in urinary saturation of calcium oxalate from increased urinary calcium did not occur, probably because of increased formation of oxalate complexes (from an increase in pH) and calcium complexes (from an increase in citrate) [29]. Despite the increase in urinary pH, urinary saturation of brushite did not increase during PCC treatment, owing to a decline in urinary phosphorus and increased complexation of calcium at a higher pH [30]. In an additional data analysis, it was found that 6 patients appeared to be “poor responders” to PCC, indicated by a lack of urinary alkalinization and citraturic. In contrast, urinary pH and citrate increased significantly, and the urinary SI of calcium oxalate and uric acid decreased significantly in the remaining 18 “responder” subjects.
The results of the present report are consistent with a previous study of healthy postmenopausal women treated with potassium citrate and calcium citrate tablets [28]. A trend was seen toward continued reduction in bone resorption markers [28]. The urinary saturation of neither calcium oxalate nor brushite changed significantly during combined treatment with potassium citrate and calcium citrate, despite an increase in urinary calcium. The urinary saturation of uric acid declined, and inhibitor activity against calcium oxalate agglomeration probably increased because of the increased urinary citrate.
Conclusion
PCC is a superior option for reducing the risk of bone disease and nephrolithiasis after RYGB. As an effervescent preparation, PCC offers solubilized calcium, suppressing PTH and bone resorption. It also provides an alkali load to protect against nephrolithiasis.
Disclosures
The authors have no commercial associations that might be a conflict of interest in relation to this article.
Acknowledgment
The authors would like to acknowledge Eve Guth, M.D., and Edward Livingston, M.D., for their assistance with patient recruitment, Prasanthi Tondapu, M.D., for the recruitment and instruction of patients, John Poindexter for data management, and Hadley Palmer for her editorial assistance in the preparation of our report.
References
- . Morbidity of severe obesity . Surg Clin North Am . 2001;81:1039–1061
- . Trends in bariatric surgical procedures . JAMA . 2005;294:1909–1917
- . Bariatric surgery worldwide 2003 . Obes Surg . 2004;14:1157–1164
- Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery . N Engl J Med . 2004;351:2683–2693
- . Effect of Roux-en-Y gastric bypass on bone metabolism in patients with morbid obesity: Mansoura experiences . Obes Surg . 2008;18:1526–1531
- . Metabolic bone disease after gastric bypass surgery for obesity . Am J Med Sci . 2005;329:57–61
- . Effect of gastric bypass surgery on kidney stone disease . J Urol . 2009;181:2573–2577
- . Hyperoxaluria in kidney stone formers treated with modern bariatric surgery . J Urol . 2007;177:565–569
- Hyperoxaluric nephrolithiasis is a complication of Roux-en-Y gastric bypass surgery . Kidney Int . 2007;72:100–107
- Long-term morbidity following jejunoileal bypass: the continuing potential need for surgical reversal . Arch Surg . 1995;130:318–325
- . A prospective comparison of gastric and jejunoileal bypass procedures for morbid obesity . Ann Surg . 1977;186:500–509
- Risk of secondary hyperparathyroidism after laparoscopic gastric bypass surgery in obese women . Surg Endosc . 2007;21:1393–1396
- Increase of bone resorption and the parathyroid hormone in postmenopausal women in the long-term after Roux-en-Y gastric bypass . Obes Surg . 2009;19:1132–1138
- . True fractional calcium absorption is decreased after Roux-en-Y gastric bypass surgery . Obesity (Silver Spring) . 2006;14:1940–1948
- . Enteric hyperoxaluria, nephrolithiasis, and oxalate nephropathy: potentially serious and unappreciated complications of Roux-en-Y gastric bypass . Surg Obes Relat Dis . 2005;1:481–485
- . Hypocitraturia and hyperoxaluria after Roux-en-Y gastric bypass surgery . J Urol . 2010;183:1026–1030
- American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic and Bariatric Surgery Medical Guidelines for Clinical Practice for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient . Surg Obes Relat Dis . 2008;4(5 Suppl):S109–S184
- Comparison of the absorption of calcium carbonate and calcium citrate after Roux-en-Y gastric bypass . Obes Surg . 2009;19:1256–1261
- . Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis . J Urol . 1993;150:1761–1764
- . Excessive crystal agglomeration with low citrate excretion in recurrent stone-formers . Lancet . 1986;1:1056–1058
- . Therapeutic action of citrate in urolithiasis explained by chemical speciation: increase in pH is the determinant factor . Nephrol Dial Transplant . 2006;21:361–369
- The decline in hip bone density after gastric bypass surgery is associated with extent of weight loss . J Clin Endocrinol Metab . 2008;93:3735–3740
- Changes in bone mineral density, body composition and adiponectin levels in morbidly obese patients after bariatric surgery . Obes Surg . 2009;19:41–46
- . Effect of bile salts and fatty acids on the colonic absorption of oxalate . Gastroenterology . 1976;70:1096–1100
- . Gastric band placement for obesity is not associated with increased urinary risk of urolithiasis compared to bypass . J Urol . 2009;182:2340–2346
- . A prospective study of risk factors for nephrolithiasis after Roux-en-Y gastric bypass surgery . J Urol . 2009;182:2334–2339
- . Pharmacokinetic and pharmacodynamic comparison of two calcium supplements in postmenopausal women . J Clin Pharmacol . 2000;40:1237–1244
- . Effects of potassium alkali and calcium supplementation on bone turnover in postmenopausal women . J Clin Endocrinol Metab . 2005;90:3528–3533
- . Comparison of semi-empirical and computer derived methods for estimating urinary saturation of calcium oxalate . J Urol . 2009;182:2951–2956
- . Comparison of semi-empirical and computer derived methods for estimating urinary saturation of brushite . J Urol . 2009;181:1423–1428
PII: S1550-7289(11)00471-0
doi:10.1016/j.soard.2011.05.001
© 2012 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.
Volume 8, Issue 1 , Pages 67-72, January 2012
