Howard J. Heller

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.

Prevention of Stone Formation and Bone Loss In Absorptive Hypercalciuria by Combined Dietary and Pharmacological Interventions

PURPOSE We determined whether dietary restriction of calcium and oxalate, combined with thiazide and potassium citrate treatment, would prevent stone formation and avert bone loss in 18 men and 10 women with type I absorptive hypercalciuria. MATERIALS AND METHODS Patients were treated with thiazide (20) or indapamide (8) and potassium citrate (average dose 35 mEq. daily) for 1 to 11 years (mean 3.7) while maintained on low calcium oxalate diet. Serum and urinary chemistry studies and bone mineral density were measured at baseline and at the end of treatment. New stones formed were quantitated during 3 years before and during treatment. RESULTS During treatment urinary calcium significantly decreased (346 +/- 85 to 248 +/- 79 mg. daily, p <0.001) but urinary oxalate did not change. Urinary pH and citrate significantly increased, and urinary saturation of calcium oxalate significantly decreased by 46%. Stone formation rate decreased significantly from 2.94 to 0.05 per year (p <0.001). L2-L4 bone mineral density increased significantly by 5.7% compared to normal peak value, and by 7.1% compared with normal age and gender matched value. Femoral neck bone mineral density also increased significantly. CONCLUSIONS Dietary restriction of calcium and oxalate, combined with thiazide and potassium citrate, satisfactorily controlled hypercalciuria, prevented the secondary increase in urinary oxalate, reduced urinary saturation of calcium oxalate, virtually eliminated recurrent stone formation, and increased bone density of the spine and femoral neck. Thus, this dietary pharmacological program controlled stone formation as well as bone loss that often accompany type 1 absorptive hypercalciuria.

Etiological Role of Estrogen Status in Renal Stone Formation

PURPOSE Estrogen may protect against kidney stone formation since nephrolithiasis is more common in men than in women. Moreover, the incidence of stones rises after menopause in women. We examined the contribution of estrogen to kidney stone risk by comparing outpatient evaluations in the 2 genders, and in estrogen treated and untreated postmenopausal women. MATERIALS AND METHODS We reviewed the results of the initial evaluation of 1,454 adult calcium oxalate stone formers, including 1,050 men and 404 women. Of the postmenopausal women 39 and 50 were estrogen treated and untreated, respectively. Samples of urine and blood were collected 1 week after the imposition of a diet restricted moderately in sodium and calcium, and modestly in oxalate and animal protein. RESULTS Compared with men the daily excretion of urinary calcium, oxalate and uric acid was lower in women. Women had lower saturations of calcium oxalate and brushite as well as lower excretion of undissociated uric acid. Compared with men urinary calcium was lower in women until age 50 years, when it equaled that of men. Citrate was equal in the genders until the age 60 years, when it tended to decrease in women. Compared with nontreated postmenopausal women those treated with estrogen had lower mean 24-hour calcium plus or minus SD (155 +/- 62 versus 193 +/- 90 mg. per day, p <0.02), mean 2-hour fasting urine calcium (0.08 +/- 0.05 versus 0.12 +/- 0.09 mg./mg. creatinine, p <0.01) and mean calcium oxalate saturation (5.07 +/- 2.27 versus 6.48 +/- 3.44, p <0.05). CONCLUSIONS The lower risk of stone formation in women may be due to the lower urinary saturation of stone forming salts. Estrogen treatment may decrease the risk of stone recurrence in postmenopausal women by lowering urinary calcium and calcium oxalate saturation.

BISPHOSPHONATE-INDUCED HYPOCALCEMIA: REPORT OF 3 CASES AND REVIEW OF LITERATURE

OBJECTIVE To report 3 cases of bisphosphonate-induced hypocalcemia and review the relevant literature. METHODS We present the clinical and laboratory findings in 3 cases of bisphosphonate-induced hypocalcemia, and discuss the pathophysiologic mechanisms and the pertinent literature. RESULTS In our first patient (case 1), symptomatic hypocalcemia developed after intravenous administration of pamidronate for management of multiple myeloma. He had vitamin D insufficiency and impaired renal function at the time of pamidronate therapy. Our second patient (case 2) presented with symptomatic hypocalcemia 12 weeks after initiation of alendronate therapy for osteoporosis. Her serum 25-hydroxyvitamin D level was low (3 ng/mL), attributable to a combination of poor vitamin D intake, limited exposure to sunlight, use of phenytoin, and previous intestinal resections. In our third patient (case 3), hypocalcemia developed on 2 different occasions, each episode occurring after intravenous administration of pamidronate for hypercalcemia of malignancy. All 3 patients had underlying conditions that impaired the homeostatic response to bisphosphonates and contributed to the severe hypocalcemia. Review of published reports on symptomatic bisphosphonate-induced hypocalcemia disclosed that hypocalcemia develops in patients with unrecognized hypoparathyroidism, impaired renal function, or vitamin D deficiency. Overall, the rate of the development of hypocalcemia was related to the potency of the bisphosphonate administered. CONCLUSION The increasing use of bisphosphonates and the introduction of more potent agents impose a considerable risk for bisphosphonate-induced hypocalcemia in a substantial number of patients. Greater awareness of this complication, a better understanding of the underlying mechanisms, and proper assessment of patients in whom bisphosphonate therapy is contemplated should reduce the frequency of occurrence of this potentially life-threatening complication.

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 (ΔAUC) 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, ΔAUC 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.

Effect of Dietary Calcium on Stone Forming Propensity

PURPOSE Epidemiological studies have reported that high calcium diet protects against kidney stone formation in normal subjects. This metabolic study was designed to elucidate the physiological and physicochemical effects conferring this apparent protection. MATERIALS AND METHODS A total of 21 normal volunteers underwent 2 phases of study in a crossover, randomized design, wherein they consumed constant metabolic diets that matched the estimated highest and lowest quintiles of calcium intake from published epidemiological studies. RESULTS Urinary calcium was significantly greater on the high calcium diet (148 +/- 55 versus 118 +/- 43 mg. daily, p <0.01, p <0.01) but urinary oxalate did not differ between diets. There was no difference in relative saturation ratio of calcium oxalate between the 2 diets. The high calcium diet significantly increased saturation of brushite and decreased that of uric acid. Due to the other differences between the diets (more fluid, potassium, magnesium and phosphate in the high calcium diet), the high calcium diet also increased 24-hour urinary volume, potassium, phosphorus, pH and citrate. After adjustment of these confounding variables, the high calcium diet significantly increased relative saturation ratio of calcium oxalate by 24%. CONCLUSIONS High calcium diet from published epidemiological studies does not alter the propensity for calcium oxalate crystallization in normal subjects despite increased urinary calcium and unaltered urinary oxalate because of the greater amounts of ingested fluid, potassium and phosphate. However, high calcium intake alone, without concomitant changes in the diet, poses a modest risk for calcium stone formation.

The Role of Calcium in the Prevention of Kidney Stones

Nephrolithiasis is a common and important condition. Several lines of evidence suggest that increased urinary calcium increases the risk of kidney stones. Since dietary calcium raises urinary calcium, it has been common practice to reduce calcium intake in stone-formers who hyperabsorb calcium from the intestine, although no trial has yet been designed to directly demonstrate the effectiveness of calcium restriction. In contrast, some have suggested that calcium restriction may be harmful due to resultant hyperoxaluria and risk of bone loss. In fact, two powerful prospective observational studies have suggested that increased dietary calcium reduces the risk of the first kidney stone. However, calcium was not the only variable, since those with the highest quintile of calcium intake also ingested more fluid, potassium, magnesium and phosphate. Moreover, the otherwise thorough analysis was not adjusted for alkali intake, which may prevent stones, or oxalate intake, which may increase stone risk. Due to limitations in available data, future prospective studies should be designed to probe the effect of specific interventions with calcium, both dietary and supplemental, on urinary parameters and stone formation, particularly in hypercalciuric stone-formers, who may respond conversely. For now, dietary calcium should be gradually increased in stone-formers as guided by the urinary calcium, and hypocalciuric agents should be added as necessary.

Normal vitamin D receptor concentration and responsiveness to 1, 25-dihydroxyvitamin D3 in skin fibroblasts from patients with absorptive hypercalciuria.

To evaluate whether there is an increase in vitamin D receptor (VDR) concentration which could raise intestinal calcium absorption in absorptive hypercalciuric (AH) patients and promote hypercalciuria, we measured VDR concentration and VDR mRNA levels in skin fibroblasts from 16 patients with AH and 17 age-matched normal subjects before and following a 16-hour incubation in the presence of 10–8 M 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. There were no significant differences in VDR concentration between normal subjects and AH patients in the basal state (30 ± 11 vs. 30 ± 15 ng/mg protein, respectively) or following 1,25(OH)2D3-mediated upregulation (43 ± 18 vs. 42 ± 16 ng/mg protein) as measured by immunoblot methodology. Analysis of VDR mRNA/β-actin mRNA ratios demonstrated no significant differences between normal subjects and AH patients prior to (2.1 ± 1.7 vs. 1.8 ± 2.4) or following (2.7 ± 2.8 vs. 1.9 ± 1.8) 1,25(OH)2D3 exposure. As a measure of VDR bioactivity, we quantitated 1,25(OH)2D3-mediated induction of 25-hydroxyvitamin D3-24-hydroxylase. Again, no significant differences were observed between normal subjects and all patients (2.1 ± 1.6 vs. 1.9 ± 1.6 pmol/mg/30 min, respectively). These findings indicate that there is neither an increase in VDR concentration in skin fibroblasts, a recognized vitamin D responsive cell, nor increased sensitivity to upregulation of VDR numbers by 1,25(OH)2D3 in patients with AH. This suggests an alternative cause of intestinal hyperabsorption of calcium in AH other than alteration of the VDR number.

Angiographic Ablation of Mediastinal Parathyroid Adenomas: Local Experience and Review of the Literature

PURPOSE To evaluate local experience with a modified technique for angiographic ablation of mediastinal parathyroid adenomas. PATIENTS AND METHODS Three patients with likely mediastinal parathyroid adenomas that had single feeding arteries underwent attempted arteriographic ablation with a slow continuous infusion of contrast medium. Patients were closely monitored for symptoms and calcium dynamics immediately postprocedure and then on a long-term outpatient basis. RESULTS All three patients were cured (follow-up 22 to 68 months) with no long-term complications. CONCLUSION Percutaneous angiographic ablation with contrast medium is a reasonable alternative for patients with hyperparathyroidism due to a mediastinal adenoma who can be treated in centers with well-trained interventional radiologists.

Effect of High and Low Calcium Diets on Stone Forming Risk During Liberal Oxalate Intake

PURPOSE Recent studies suggest that a high calcium diet protects against calcium oxalate stone formation. We compared the effect of high and low calcium diets on urinary saturation of calcium oxalate during liberal oxalate intake. MATERIALS AND METHODS A total of 10 healthy subjects (5 male, 5 female) participated in a 2-phase, randomized, crossover study comparing high (1,000 mg daily) and low (400 mg daily) calcium intake on a liberal oxalate diet (200 mg daily). During each phase subjects adhered to an instructed diet for 3 days followed by a controlled, metabolic diet for 4 days. Blood and 24-hour urine specimens collected on the last 2 days of each phase were analyzed for serum biochemistry studies and stone risk factors, respectively. RESULTS Urinary calcium was higher (mean +/- SD 171 +/- 64 vs 124 +/- 49 mg daily, p = 0.002) and oxalate was lower (25 +/- 4.8 vs 27 +/- 4 mg daily, p = 0.02) on the high vs low calcium diet. Overall, the urinary relative saturation ratio of calcium oxalate was higher on the high compared with the low calcium diet (3.3 vs 2.5, p <0.0001) even after adjusting for confounding variables. CONCLUSIONS In normal subjects urinary saturation of calcium oxalate was higher on a high calcium diet than a low calcium diet during liberal oxalate intake because the decrease in urinary oxalate did not overcome the effect of increased calcium. A high calcium diet during liberal oxalate intake may pose an increased risk of calcium oxalate stone formation.