Reduced bone formation and relatively increased bone resorption in absorptive hypercalciuria.

Absorptive hypercalciuria (AH), a common stone-forming condition characterized biochemically by intestinal hyperabsorption of calcium and hypercalciuria may be associated with bone loss. In AH type I (AH-1), hypercalciuria persists despite restriction in dietary calcium intake. We therefore hypothesized that the skeleton may contribute to the hypercalciuria in this subgroup of patients. Histomorphometric analysis of iliac crest biopsies were performed on nine stone-formers with AH-1 and on nine matched normal subjects. After stabilization on a stone-prevention diet, calcium homeostasis in the stone formers was then evaluated on inpatient constant metabolic diet before and after short-term blockade of bone resorption by alendronate (10 mg daily, 17 days total). Compared with controls, the stone-formers had lower indices of bone formation (osteoblast surface/bone surface 1.8+/-2.1 vs 3.0+/-1.5%, P=0.04; wall thickness 35.8+/-6.9 vs 47.2+/-7.6%, P=0.001) and relatively higher bone resorption (osteoclast surface/bone surface 0.4+/-0.2 vs 0.2+/-0.2%, P=0.05). In the stone-formers, a short-term course of alendronate treatment corrected fasting urinary calcium (0.14+/-0.06 to 0.06+/-0.04 mg Ca/mg Cr, P=0.001) and marginally reduced 24-h urinary calcium by 48 mg/day (P=0.06). Increased intestinal calcium absorption and hypercalciuria persisted, but estimated calcium balance improved (P=0.007). Our results suggest that the hypercalciuria of AH-1 originates primarily from intestinal hyperabsorption of calcium, but bone resorption in excess of bone formation may contribute.

Sustained-release sodium fluoride in the treatment of the elderly with established osteoporosis.

BACKGROUND: We ascertained the safety and efficacy of fluoride in augmenting spinal bone mass and reducing spinal fractures in older women with established osteoporosis. We compared a combination of sustained-release sodium fluoride, calcium citrate, and cholecalciferol (SR-NaF group) with calcium and cholecalciferol alone (control group). METHODS: Eighty-five ambulatory women aged 65 years or older with 1 or more nontraumatic vertebral compression fractures were enrolled in a 42-month randomized, double-blind, placebo-controlled trial. Primary outcome measures were vertebral fracture rate, bone mass, and safety. RESULTS: The vertebral fracture rate determined by means of computer assistance in the SR-NaF group was significantly lower than that in the control group (relative risk [RR], 0.32; 95% confidence interval [CI], 0.14-0.73; P =.007). Results of visual adjudicated inspection also confirmed a significant reduction in fracture rate (RR, 0.40; 95% CI, 0.17-0.95; P =.04). Bone mineral density in L2 through L4 increased significantly from baseline in the SR-NaF group by 5.4% (95% CI, 2.7%-8.2%; P<.001), and by 3.2% in the control group (95% CI, 0.8%-5.6%; P =.01). The between-group differences in bone mineral density were not significant. The femoral neck and total hip bone mineral density remained stable in the SR-NaF group and was not significantly different from that of the control group. There were no significant differences in adverse effects between groups. CONCLUSION: The SR-NaF group significantly decreased the risk for vertebral fractures and increased spinal bone mass without reducing bone mass at the femoral neck and total hip.

Biochemical profile of idiopathic uric acid nephrolithiasis.

BACKGROUND: The objective of this study was to elucidate a biochemical profile of patients with idiopathic uric acid nephrolithiasis, without secondary causes (such as dehydration or diarrhea). Study subjects comprised 56 patients with idiopathic uric acid nephrolithiasis (UA stone group) who underwent a full outpatient evaluation. The control group was composed of 54 with absorptive hypercalciuria and 2 normal subjects, matched with the UA stone group according to age, body mass index, and gender. METHODS: Urinary pH and ammonium and serum and urinary uric acid were measured. The fractional excretion of urate was calculated. RESULTS: Compared with the control group, the UA stone group had a significantly higher serum uric acid and significantly lower urinary uric acid, pH (5.34 +/- 0.23 vs. 6.17 +/- 0.36, P < 0.001), and fractional excretion of urate (0.052 +/- 0.028 vs. 0.080 +/- 0.029, P < 0.001), but individual values overlapped considerably between the two groups. Discriminant analysis of the relationship between urinary pH and fractional excretion of urate yielded a "discriminant score," which provided a much better separation between the two groups, with a correct classification in 95.5% of subjects. In contrast, urinary ammonium, citrate, sulfate, and potassium did not differ between two groups. CONCLUSIONS: In idiopathic uric acid nephrolithiasis, urinary pH and fractional excretion of urate are significantly lower than in control subjects, suggestive of defects in urinary acidification and urate excretion. Since these impairments are believed to be associated with primary gout, the underlying disturbance in idiopathic uric acid nephrolithiasis may be primary gout.

Adequacy of a single stone risk analysis in the medical evaluation of urolithiasis.

PURPOSE: We tested the hypothesis that a single 24-hour urine sample for stone risk analysis would be sufficient for the simplified medical evaluation of urolithiasis. MATERIALS AND METHODS: We retrospectively analyzed stone risk profile data on 24-hour urine samples obtained during random and restricted diets in 225 patients with recurrent urolithiasis. RESULTS: In 2 random samples we noted no significant difference in urinary calcium, oxalate, uric acid, citrate, pH, total volume, sodium, potassium, sulfate or phosphorus. For these risk factors there was a highly significant positive correlation in the 2 random samples (r > or = 0.68, p <0.0003) and the value of each was abnormal or normal in at least 81% of patients. Urinary magnesium and ammonium were significantly lower in random sample 2 than 1, the former by 4%. After calcium, sodium and oxalate dietary restriction mean urinary calcium and sodium plus or minus standard deviation decreased significantly by 25% from 251 +/- 125 to 187 +/- 98 mg. daily and by 38% from 183 +/- 87 to 113 +/- 57 mEq. daily, respectively. Other risk factors had a slight or no significant change. Correcting random urinary calcium for the excessive urinary excretion of sodium brought urinary calcium to 210 +/- 108 mg. daily, similar to the value on the restricted diet. CONCLUSIONS: The reproducibility of urinary stone risk factors is satisfactory in repeat urine samples. A single stone risk analysis is sufficient for the simplified medical evaluation of urolithiasis.

Pharmacokinetic and pharmacodynamic comparison of two calcium supplements in postmenopausal women.

This randomized crossover study compared the single-dose bioavailability and effects on parathyroid function of two commercially formulated calcium supplements containing 500 mg of elemental calcium. Twenty-five postmenopausal women underwent three phases of study wherein they each took a single dose of calcium citrate with a standard breakfast (as Citracal 250 mg + D), calcium carbonate (as Os-Cal 500 mg + D), or placebo at 8 a.m. Blood samples were drawn at baseline and hourly for 4 or 6 hours after each dose. Fasting and postload urine samples were also collected. Compared with calcium carbonate, calcium citrate provided a 46% greater peak-basal variation and 94% higher change in area under the curve for serum calcium and a 41% greater increment in urinary calcium. Moreover, the decrement in serum parathyroid hormone concentration from baseline was greater after calcium citrate. In conclusion, calcium citrate is more bioavailable than calcium carbonate when given with a meal.

Correction of thiazide-induced hypomagnesemia by potassium-magnesium citrate from review of prior trials.

PURPOSE: To ascertain whether hypomagnesemia develops during short-term thiazide treatment in normal subjects and if it can be corrected by potassium-magnesium citrate (Relyte) supplementation. METHODS: Serum magnesium data were retrieved from 242 normal subjects from prior 4 trials. After 1-3 weeks of treatment with hydrochlorothiazide 50 mg/day, subjects received supplementation with Relyte or a related compound while continuing on thiazide for 3 weeks. RESULTS: Hypomagnesemia (< or =1.8 mg/dl) was disclosed in 19.4% of 242 subjects on thiazide alone. In such patients, Relyte treatment significantly increased serum magnesium concentration to the normal range, whereas supplementation with potassium citrate or potassium chloride did not. In the Relyte group comprised of 131 subjects, the frequency of hypomagnesemia decreased from 22.9% on thiazide alone to 4.6% after 4 weeks of Relyte supplementation. In contrast, the frequency of hypomagnesemia displayed a non-significant increase from 15.7% on thiazide alone to 20-24% on potassium citrate or potassium chloride. CONCLUSION: Mild hypomagnesemia develops in about one fifth of normal subjects during short-term thiazide treatment. Relyte can readily correct it.

Medical therapy and new approaches to management of urolithiasis.

A simple, step-by-step approach to diagnosis and medical treatment of stone disease is described. It uses urinary stone risk profile obtained before and after dietary modification, history, and minimum diagnostic tests. For each abnormal stone risk factor, potential causes are discussed and treatment options are presented. The article concludes with diagnosis and treatment of combined disturbances.

A comparison of fluoride bioavailability from a sustained-release NaF preparation (Neosten) and other fluoride preparations.

Twelve normal subjects completed a crossover study with sustained-release sodium fluoride (Neosten, 11.3 mg F), monofluorophosphate (MFP, 10 mg F), and plain sodium fluoride (P-NaF, 11.3 mg F). After each preparation was given with 400 mg calcium, serum fluoride (Fser) was measured for 24 hours, and pharmacokinetic data were calculated. Fluoride absorption in the Neosten group, as measured by change in the area under the curve (delta AUC) of Fser, was less than 33% of that in the MFP and P-NaF treated groups. Both peak Fser (Cmax) and peak-basal variation in the Neosten group were 25% that found in the other groups. t1/2 was nearly twofold greater after Neosten. MFP and P-NaF showed greater bioavailability than Neosten and much higher Cmax that exceeded the toxic threshold of Fser (190 ng/ml). These findings could explain the ineffectiveness of MFP and P-NaF observed in recent clinical trials.

Potassium-magnesium citrate versus potassium chloride in thiazide-induced hypokalemia.

BACKGROUND: The purpose of this study was to compare the value of potassium-magnesium citrate (KMgCit) with potassium chloride in overcoming thiazide-induced hypokalemia. METHODS: Sixty normal subjects first took hydrochlorothiazide (HCTZ; 50 mg/day). After three weeks of treatment (or earlier if hypokalemia developed), they were randomized to take KMgCit (42 mEq K, 21 mEq Mg, and 63 mEq citrate/day) or potassium chloride (42 mEq/day) for three weeks while continuing on HCTZ. RESULTS: KMgCit significantly increased the serum potassium concentration from 3.42 +/- 0.30 mEq/L on HCTZ alone to about 3.8 mEq/L (P < 0.001). Potassium chloride produced a similar increase in serum potassium concentration from 3.45 +/- 0.44 mEq/L to about 3.8 mEq/L (P < 0. 001). KMgCit significantly increased the serum magnesium concentration by 0.11 to 0.12 mEq/L (P < 0.01), whereas potassium chloride produced a marginal decline or no significant change. KMgCit was less effective than potassium chloride in correcting HCTZ-induced hypochloridemia and hyperbicarbonatemia. KMgCit, but not potassium chloride, significantly increased urinary pH (by about 0.6 unit), citrate (by about 260 mg/day), and urinary magnesium. CONCLUSIONS: KMgCit is equally effective as potassium chloride in correcting thiazide-induced hypokalemia. In addition, KMgCit, but not potassium chloride, produces a small but significant increase in serum magnesium concentration by delivering a magnesium load, and it confers alkalinizing and citraturic actions.

Meta-analysis of randomized trials for medical prevention of calcium oxalate nephrolithiasis.

OBJECTIVES: To determine the efficacy of commonly used medications in comparison with placebo or no treatment for the prevention of renal stone recurrence (metaphylaxis) as documented in the literature. METHODS: A MEDLINE search identified 14 randomized, controlled trials comprising 20 treatment arms and 6 different drug therapies for the prevention of stone recurrence. The active treatment arms from each of the trials were combined, and the results were compared with those of the control or no treatment arms overall and for each category of drug therapy (thiazide diuretics, allopurinol, phosphate, magnesium, and alkali citrate). A meta-analysis was performed of the combined treatment and control arms for all trials from which sufficient data were provided, both for overall medical therapy and for thiazide treatment. RESULTS: A statistically significant benefit of drug therapy for stone metaphylaxis was identified (P = 0.04), largely because of the benefit of thiazides compared with placebo or no treatment (P = 0.02). Allopurinol conferred no overall benefit, although the only trial evaluating therapy in hyperuricosuric patients showed a statistically significant benefit. CONCLUSION: Medical therapy for calcium stone disease reduces the incidence of recurrence. Although only thiazide diuretics among the drug therapies were shown to significantly reduce stone recurrence, variability in study design and study population precluded adequate analysis of other drug therapies such as alkali citrate. Standardization of study design and reporting should improve the evaluation of the efficacy of new drug treatments.

Pharmacokinetics of calcium absorption from two commercial calcium supplements.

This study was conducted to compare pharmacokinetic indices of calcium absorption after a single oral (500 mg calcium) load of Citracal (calcium citrate) and Os-Cal (calcium carbonate). In 18 postmenopausal normal women, venous blood samples were obtained for the measurement of calcium before and hourly for 6 hours after an oral ingestion of Citracal, Os-Cal, or placebo with a breakfast meal. The change in area under the curve (delta AUC) in serum calcium from preload was 2.5-fold greater for Citracal than Os-Cal, and the peak-basal variation in serum calcium was 76% higher for Citracal than Os-Cal. The increment in serum calcium from preload after Citracal administration was significantly higher than that obtained after placebo load during most time periods and significantly higher than that of Os-Cal at 1, 4, and 5 hours after load. In contrast, delta AUC and peak basal variation of Os-Cal did not differ significantly from placebo and increment in serum calcium was significantly increased from placebo only at 6 hours. In conclusion, Citracal is much more bioavailable than Os-Cal.

Mapping a gene defect in absorptive hypercalciuria to chromosome 1q23.3-q24.

Absorptive hypercalciuria (AH), a common cause of kidney stones, is due to intestinal hyperabsorption of calcium. The presence of a family history of nephrolithiasis, in about half of the affected individuals studied indicates that an inherited genetic defect is one likely cause of AH. Although it is known that intestinal calcium absorption is regulated by a number of factors, the molecular biological basis for the increased calcium absorption in AH is unknown. This study was designed to determine the chromosomal locus of the gene defect linked to the AH phenotype in three families with a severe form of AH. Three kindreds were evaluated in a systematic autosomal genome-wide linkage analysis study. The AH phenotype, characterized by hyperabsorption of calcium and hypercalciuria, was linked to only one chromosomal locus, 1q23.3-q24. A 2-point logarithm of odds score of 3.3 was obtained with markers D1S318 and D1S196 at a recombination frequency of theta = 0. Nonparametric multipoint linkage analysis yielded a peak nonparametric linkage Z(all)-score of 12.7, P = 6 x 10(-6) Analysis of key recombinants within the families studied localized the gene to a 4.3-megabase region between markers D1S2681 (centromere) and D1S2815. A trait associated with intestinal hyperabsorption of calcium in a severe form of absorptive hypercalciuria has been mapped to chromosome 1q23.3-q24.

Effect of varying doses of potassium-magnesium citrate on thiazide-induced hypokalemia and magnesium loss.

The purpose of this study was to compare the efficacy of three dosages of potassium-magnesium citrate in overcoming thiazide-induced hypokalemia and magnesium loss and increasing urinary pH and citrate. Sixty-one normal subjects first took hydrochlorothiazide at 50 mg/d. After 3 weeks of thiazide treatment or earlier if hypokalemia developed, the subjects were randomized to take one of three dosages of potassium-magnesium citrate (K ( 4 ) MgCit ( 2 ) ) for 3 weeks while continuing on the thiazide: 4 tablets per day (24 mEq potassium, 12 mEq magnesium, and 36 mEq citrate per day), 7 tablets per day (49 mEq potassium, 24.5 mEq magnesium, and 73.5 mEq citrate per day), or 10 tablets per day (70 mEq potassium, 35 mEq magnesium, and 105 mEq citrate per day). Outcome measures were changes in serum potassium and magnesium and urinary potassium, magnesium, pH, and citrate. All three dosages of potassium-magnesium citrate significantly increased serum potassium concentration, with >80% of subjects regaining normal values despite continued thiazide therapy. The two higher dosages, but not the lowest dosage, caused a small but significant increase in serum magnesium concentration, while substantially increasing urinary magnesium. All three dosages significantly increased urinary pH and citrate in a dose-dependent manner. The lowest dosage produced increases sufficient to prevent stone recurrence. Side effects of thiazide therapy were ameliorated by the highest dosage but not by the two lower dosages. Potassium-magnesium citrate at a dosage of 4 tablets per day is adequate to correct thiazide-induced hypokalemia and to increase urinary pH and citrate sufficiently for stone prevention. Higher dosages are probably required for the prevention of magnesium loss and adverse symptoms of thiazide therapy.

Effect of potassium magnesium citrate on thiazide-induced hypokalemia and magnesium loss.

The study was performed to ascertain the value of potassium magnesium citrate, magnesium citrate, and potassium citrate in overcoming thiazide-induced hypokalemia and magnesium loss. Sixty-two healthy subjects were first administered hydrochlorothiazide, 50 mg/d. After 3 weeks of thiazide treatment (or earlier for potassium level

Medical prevention of renal stone disease.

Medical treatment designed to prevent stone formation is important in idiopathic calcium oxalate nephrolithiasis, because of the high rate of stone recurrence. Several randomized trials have established the values of conservative and drug treatments. A high fluid intake alone has been reported to inhibit the recurrence of stone formation in single stone formers. In patients with recurrent disease, a significant reduction in stone formation rate from pretreatment was found in the placebo group maintained on a conservative program, underscoring the importance of increased fluid intake and dietary modification. In patients with active recurrent stone disease, treatment with drugs along with a conservative program is necessary. Allopurinol, thiazide, potassium citrate and potassium-magnesium citrate have been shown to inhibit stone formation compared with placebo. It has not been clearly established that a selective treatment is more effective than a more randomly chosen drug treatment. Another advantage of medical approach is its ability to correct nonrenal complications of stone disease, such as bone loss that sometimes accompanies stone disease.

The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.

This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.

Converting enzyme inhibition causes hypocitraturia independent of acidosis or hypokalemia.

BACKGROUND: Angiotensin II stimulates the proximal tubular Na/H antiporter and increases proximal tubular cell pH. Because intracellular pH may affect urinary citrate excretion and enzymes responsible for renal citrate metabolism, the present studies examined the effect of enalapril, an angiotensin converting enzyme inhibitor, on the activity of renal cortical ATP citrate lyase and urinary citrate excretion. METHODS: Enalapril was given to rats (15 mg/kg/day) for seven days and to humans (10 mg twice daily) for 10 days. Blood and 24-hour urine samples were obtained in both groups. Renal cortical tissue from rats was analyzed for enzyme activity. RESULTS: In rats, enalapril decreased urinary citrate excretion by 88%. The change in urinary citrate was not associated with a difference in plasma pH, bicarbonate nor potassium concentration. However, similar to metabolic acidosis and hypokalemia, enalapril caused a 42% increase in renal cortical ATP citrate lyase activity. When given to humans, enalapril significantly decreased urinary citrate excretion and urine citrate concentration by 12% and 16%, respectively, without affecting plasma pH or electrolytes. CONCLUSIONS: Enalapril decreases urinary citrate in rats and humans. This is due, at least in part, to increases in cytosolic citrate metabolism through ATP citrate lyase in rats similar to that seen with chronic metabolic acidosis and hypokalemia. The effects of enalapril on urinary citrate and renal cortical ATP citrate lyase occur independently of acidosis or hypokalemia but may be due to intracellular acidosis that is common to all three conditions.

The effect of varying molar ratios of potassium-magnesium citrate on thiazide-induced hypokalemia and magnesium loss.

This study was conducted to compare the value of an older formulation of potassium-magnesium citrate (K4MgCit2) with newer formulations (K3MgHCit2 and K5MgCit2Cl) with respect to the correction of thiazide-induced hypokalemia and magnesium loss, alkalinizing effect, and citraturic action. Sixty-two healthy volunteers first took hydrochlorothiazide 50 mg/day. After 3 weeks of thiazide treatment (or earlier if hypokalemia developed), they were randomized to take one of three drugs for 3 weeks while continuing thiazide: K4MgCit2 (49 mEq K, 25 mEq Mg, and 74 mEq citrate/day), K3MgHCit2 (49 mEq K, 33 mEq Mg, and 98 mEq citrate/day), and K5MgCit2Cl (49 mEq K, 20 mEq Mg, 10 mEq Cl and 59 mEq citrate/day). Outcome measures were changes in serum potassium and magnesium, and urinary potassium, magnesium, pH, and citrate. The three drugs were equally effective in correcting thiazide-induced hypokalemia. K3MgHCit2 and K4MgCit2 produced a small but significant increase in serum magnesium concentration, whereas K5MgCit2Cl did not. Although all three supplements significantly increased urinary pH and citrate, these effects were more marked with K3MgHCit2 and K4MgCit2 than with K5MgCit2. All three supplements were generally well tolerated, with the lowest side effect profile obtained with K4MgCit2. The new formulation of K3MgHCit2 exerts similar correction of thiazide-induced hypokalemia and magnesium loss, and enhancement of urinary pH and citrate, compared with the older K4MgCit2. However, it is less well tolerated. The new formulation of K5MgCit2Cl does not avert magnesium loss, and has less prominent alkalinizing and citraturic effects than the older preparation.