Intestinal calcium absorption from different calcium preparations: Influence of anion and solubility

Not only is the calcium content of a preparation significant for providing adequate calcium supplementation for the prophylaxis and therapy of osteoporosis, but also its bioavailablity is of essential importance. In the present study, the bioavailability of calcium citrate and calcium lactogluconate/carbonate from a therapeutic dose (= 500 mg Ca²⁺) was compared in men aged between 45 and 60 years on an intra-individual basis. Calcium citrate was administered both as a solution and as a suspension to 18 healthy volunteers. Using a double-isotope method, the intestinal absorption from the three preparations was determined in randomized order at intervals of 2–4 weeks. The stable isotope⁴⁴Ca (20 mg), in highly enriched form, was added in each case to the ready-to-drink solutions and, at the same time, a sterile and pyrogen-free solution containing 5 mg of the stable isotope⁴²Ca was injected intravenously. The intestinal calcium absorption was then determined after 24 h on the basis of the ratio of the two isotopes in the plasma. There was a significantly higher absorption of 29% from the citrate solution than from the lactogluconate/carbonate solution (25%). Absorption from the citrate suspension was similar to that from the lactogluconate/carbonate solution. While no correlation was found between the measured values for calcium absorption from the three preparations and the plasma concentration of 1,25-dihydroxycholecalciferol, significant inverse correlations with the basal parathyroid hormone concentration were observed for the citrate and lactogluconate/carbonate solution. The results of this study show that quantitative data on intestinal calcium absorption can be obtained without employing radioactive isotopes in humans. Moreover, they show that calcium absorption is not determined only by the solubility and the degree of ionization of the calcium salt administered, but rather that it is of a complex nature.     

Influence of age on effects of endogenous 1,25-dihydroxyvitamin D on calcium absorption in normal women

Recent reports of increases in serum 1,25-dihydroxyvitamin D [1,25(OH₂)D] concentration with aging despite no changes or decreases in calcium absorption suggest that elderly women have intestinal resistance to vitamin D action. Thus, in 15 young adult (30±1 year) and 15 elderly (74±1 year) women (mean±SE), we assessed the responsiveness of intestinal calcium absorption to increases in circulating 1,25(OH)₂D induced by 4 days of an experimental diet (150 mg calcium and 1600 mg phosphorus daily). True fractional calcium absorption (FCA) (⁴⁴Ca mixed with food and ⁴²Ca given intravenously, then their ratio in urine measured by mass spectrometry) was determined. Baseline serum intact parathyroid hormone (PTH) concentration was higher in the older women (P=0.01) whereas serum 1,25(OH)₂D concentration and true FCA were similar. In both groups, serum 1,25(OH)₂D concentrations increased (P<0.002) on the experimental diet. After 4 days on the diet, serum 1,25(OH)₂D increased over baseline by 30.5 and 35.6% and, despite these increases, true FCA was 40±3 versus 40±4%/24 hours (NS between groups) in the young and elderly women, respectively. These data suggest that either elderly women have normal intestinal responsiveness to vitamin D or that the resistance to it is too mild to be detected by these methods.     

Influence of glucocorticoids on calcium absorption in different segments of the rat intestine

Summary Glucocorticoids enhance the movement of fluid and sodium in the duodenum, thereby resulting in an increase in the passive transport of calcium. Since passive transport of calcium predominates in the distal intestinal segments, the influence of glucocorticoids on calcium and fluid transport in the duodenum, mid-jejunum, ileum, and colon of the rat was studied. Calcium transport and fluid absorption was determiend by thein vivo ligated loop technique. One segment was ligated in each animal. Under either normal osmolarity or hypertonic conditions, administration of cortisone stimulated intestinal fluid absorption in each segment of the small intestine, but not in the colon. Since the final fluid sodium concentration was not altered, cortisone enhanced net sodium absorption in proportion to the increase in fluid transport. Glucocorticoids inhibited the active transport of calcium in the proximal regions of the small intestine by bidirectional changes in calcium flux. However, the inhibitory effect was not apparent under the conditions where passive transport predominates. The stimulation of passive transport in the mid-jejunum overcomes the inhibition of active transport. In the ileal region, glucocorticoids increased active transport of calcium by 165%, whereas the enhancement of calcium transport under conditions where passive transport predominated reached 217%. This result indicates that both active and passive transport of calcium were enhanced by glucocorticoid treatment. In the colon, glucocorticoids increased active transport by 170%. However, the magnitude of the increase in calcium transport was less under conditions where passive transport predominates (129%), indicating that glucocorticoids stimulate the active transport of calcium in the colon with no appreciable stimulation of passive transport.     

Use of stable48Ca in the clinical measurement of intestinal calcium absorption

Summary Measurements of intestinal-calcium-absorption efficiency are fundamental for understanding calcium homeostasis in health and disease. Stable calcium isotopes are attractive tracers for such measurements, to avoid excessive radiation exposure to the subject and permit serial studies at short intervals. To realize this, we found it necessary to improve the sensitivity and precision of existing thermal neutron activation analyses for⁴⁸Ca. This report describes the details, sensitivity, precision, and accuracy of the improved method, and gives the results of studies in which intravenous⁴⁸Ca was used in conjunction with oral⁴⁷Ca to measure intestinal-calcium-absorption efficiency in patients.     

Effects of a cation exchange resin on intestinal calcium absorption and urinary calcium in calcium stone formers

Summary The effect on the urinary excretion of calcium of an oral cation exchange resin with-out phosphorus was studied in healthy control subjects and patients with recurrent calcium lithiasis under out-patient conditions. An immediate reduction of intestinal calcium absorption and urinary calcium excretion was found in five control subjects and in one patient after ingestion of resin, whereas calcium excretion remained unchanged in all other patients during long-term treatment. In addition, signs of mild transitory hyperparathyroidism together with an increase in intestinal calcium transport were observed during treatment. It is suggested that intraluminal binding of calcium ions to the resin leads to substantial changes in calcium metabolism with the result that urinary calcium excretion returns to pretreatment values.     

Influence of calcium-binding protein in bovine milk on intestinal calcium absorption

In order to confirm the effect of calcium-binding protein in bovine milk (mCaBP) on intestinal calcium absorption, calcium transport was measured in the presence and the absence of exogenous mCaBP using the everted gut sac method and ligated-loop method. Exogenous mCaBP significantly stimulated the absorption of calcium in the lower ileum, but not in the duodenum in both vitamin D-deficient and normal rats only as determined by the ligated-loop method. These observations suggest that the stimulating mechanism of exogenous mCaBP for calcium transport is clearly different from that of vitamin D-dependent CaBP in intestinal epithelial cells, and that calcium transport in the lower intestine is effectively stimulated in the presence of both exogenous mCaBP and vitamin D-dependent CaBP. These results are tempting to suggest that mCaBP and vitamin D-dependent CaBP participate at the outside and the inside of epithelial cell, respectively, to stimulate intestinal calcium absorption, and both CaBPs interact each other in calcium transport system. The mechanism of mCaBP action in the intestine is still unclear.     

Time course of calcium absorption in humans: Evidence for a colonic component

Summary We examined the time course of calcium absorption (CaAbs) in 155 studies, using a double isotope technique. The subjects were 118 healthy peri-menopausal women (mean age 53.3 years), studied as impatients under metabolic balance conditions. We measured the ratio of radiolabeled calcium (oral:IV) in serum and urine for 144 hours after the oral dose, and generated a composite CaAbs curve for all 155 studies using normalized data. Although CaAbs was 80.9% complete at 3 hours, it was still only 95.8% complete at 7 hours; the remaining 4.2% was absorbed in a slower late component, and did not reach completion until about 26 hours. The rapid initial component probably represents mainly small intestinal absorption and the late component, colonic. At the dietary intakes of our subjects, we estimate the size of the late component at about 6.8 mg/day. For fully accurate measurements of CaAbs, it is necessary to allow for this small late component.     

Gastrointestinal calcium absorption and dietary calcium load: Relationships with bone remodelling in vertebral osteoporosis

Patients with vertebral osteoporosis have a wide range of bone loss rates, bone remodelling rates and capacities for gastrointestinal (GI) calcium absorption. To test the hypothesis that variations in GI absorptive capacity determine rates of bone loss or remodelling, we have sought relationships betwen calcium absorption or vitamin D metabolite levels on the one hand and rates of cancellous and cortical bone loss (measured by serial quantiative computed tomography in the radius;n=25) or indices of bone remodelling in tetracycline-prelabelled transiliac biopsies (n=41) on the other, in a sequential untreated group. Calcium absorption (net and true) was measured in 18-day balances and by a two-isotope deconvolution method (fractional absorption and maximum absorption rate, MAR). There was no significant seasonal effect on any of these four measures of calcium absorption (variance ratio,F=0.52–1.61,p>0.1) or on 1,25-dihydroxyvitamin D levels (F=0.13,p>0.1; range 11–69 pg/ml), notwithstanding the expected seasonal effect on 25-hydroxyvitamin D levels (mean 18.7 ng/ml, zenith mid July, semi-amplitude 7.5 ng/ml;F=6.82,p<0.01). Neither this metabolite nor 1,25-dihydroxyvitamin D correlated with any index of calcium absorption (p>0.1). No measure of calcium absorption (or intake) had a significant relationship with radial cortical or cancellous bone loss (p all >0.1) but cancellous bone loss was associated with the rate of endogenous calcium excretion (r=0.50,p<0.05). A positive relationship between 25-hydroxyvitamin D and unlabelled osteoid surface (a marker of reduced blast vigour) persisted after adjustment for season (Student'st=2.70,p<0.01) but did not reflect 1,25-dihydroxyvitamin D levels. This study did not address the question of whether reduced GI calcium absorption has a uniform effect on bone remodelling in osteoporosis. However, variations in capacity for calcium absorption are unlikely to be responsible for the heterogeneity in bone loss and remodelling rates seen in vertebral osteoporosis.     

Adult-type hypolactasia and calcium availability: decreased calcium intake or impaired calcium absorption?

Summary Adult-type hypolactasia, as mediated by a widespread genetic predisposition, not only reduces calcium intake but also calcium absorption in the presence of high amounts of lactose and may, therefore, promote osteoporosis. A lactose-reduced diet and lactose-free calcium supplements may reverse this imbalance. Introduction and hypothesis Adult-type hypolactasia (HL) defined by the LCT_(−13910) polymorphism may reduce calcium intake by reducing dairy consumption and, therefore, promote osteoporosis. This study aimed to evaluate whether lactose also decreases intestinal calcium absorption in subjects with HL and whether lactose-reduced diet and lactose-free calcium supplementation as recommended could maintain bone mineral density (BMD). Methods Based on LCT genotyping, 73 postmenopausal women with and without HL underwent a conventional H₂ breath test with a concomitant oral strontium absorption test lasting 150 minutes, which closely reflects intestinal calcium absorption. In addition, we compared bone-specific laboratory parameters, lumbar and femoral BMD, and spinal radiographs to a similar bone assessment 5 years earlier. Results LCT genotyping and functional lactose malabsorption tests were highly correlated. Dairy product consumption was reduced by 80% in HL individuals. During concomitant lactose application, mean strontium absorption was blunted by 54% in HL subjects after 150 minutes (1272 ± 629 μg/L vs. 2020 ± 1130 μg/L in lactose tolerant subjects, p = 0.001). Nevertheless, BMD in HL subjects remained stable with lactose-free calcium supplements during the observation period. Conclusion Both decreased calcium intake as well as lactose-associated impaired calcium absorption may predispose subjects with HL to osteoporosis. Lactose-free calcium supplementation may help to maintain BMD in HL subjects.     

The effect of an oral calcium load on plasma ionized calcium and parathyroid hormone concentrations in osteoporotic postmenopausal women

Summary Plasma ionized calcium (IC) and parathyroid hormone (PTH) concentrations were measured in 31 osteoporotic postmenopausal women at hourly intervals for 5 hours after a 1 g oral calcium load. Fifteen subjects had normal radiocalcium absorption and 16 subjects were malabsorbers of calcium. IC rose and PTH fell after the calcium load in both groups with a plateau at 3–4 hours, and the rise in IC was greater (P<0.01) in the normal absorbers. There was a nonsignificant trend for the fall in PTH to be greater in the normal absorbers. In the group as a whole the mean increase in IC (above baseline) at 4 hours was directly related to calcium absorption (P<0.025) and the mean change in PTH was inversely related to calcium absorption (P<0.05). These results demonstrate that in subjects with postmenopausal osteoporosis the responses of IC and PTH to an oral calcium load are a function of calcium absorptive status.     

The absorption of tricalcium phosphate and its acute metabolic effects

Summary The use of calcium (Ca) supplements by postmenopausal women is growing rapidly. A commercial preparation of tricalcium phosphate (TCP) is available in the USA. Depending on the relative absorption of Ca versus phosphate, a rise in serum phosphorus (P) could stimulate parathyroid hormone (iPTH) secretion. We therefore compared Ca absorption and the metabolic responses following TCP to that of Ca carbonate (CC) on separate occasions in each of 10 women, aged 22–40 years. The subjects were fasted overnight for 12 hours while good hydration was maintained. Following a 2-hour baseline-urine collection, 1200 mg calcium (as CC or TCP) was ingested and two 2-hour postload urine collections were made. Blood was drawn at 1, 2, and 4 hours after the Ca load. Serum (S) and urine (U) Ca, P, and creatinine, and U cyclic AMP (cAMP) were determined. iPTH levels following TCP were also measured. Ca absorption was determined by the postload rise in Uca above baseline. Uca excretion increased significantly and was accompanied by significant rises in Sca after both preparations. Following TCP, S and U phosphorus increased. Urinary cAMP did not change after either preparation, and iPTH levels fell after oral TCP. We conclude that Ca taken as TCP is absorbed adequately and, thus, despite a rise in the S phosphorus level does not stimulate parathyroid activity.     

The assessment of intestinal calcium absorption using stable strontium

Summary The availability of currently used methods of measuring. intestinal calcium absorption is limited by their expense and complexity. Since this measurement may be important in selecting appropriate therapies for patients with osteoporosis, a simpler procedure is required. This paper describes a test which measures the intestinal absorption of stable strontium. A comparison of this test with the single-isotope radio-calcium absorption test in the same group of patients showed a close correlation between the fractional absorption rates of the two elements (r=0.93,P<0.001). Subjects were correctly categorized as having normal or low absorption in 12 out of 13 cases (92%) and the value in the misclassified subject was at the borderline between normal and low calcium absorption. The convenience, low cost, and freedom from radioactivity of stable strontium make it suitable for routine clinical use and, if necessary, repeated testing. If these early results are confirmed, this test will make the assessment of calcium absorption much more widely available.     

Comparison between the fractional isotopic calcium absorption and an oral calcium tolerance test

Summary In 27 subjects with several disorders of calcium metabolism, the fractional intestinal absorption of⁴⁷CaCl₂ was rather poorly correlated with the urinary output of calcium or with the maximal increase of serum calcium after an oral calcium load. Conversely, a good correlation was observed with the product of these parameters. We propose that this product be used as an estimate of intestinal calcium absorption when a radioisotopic method is not available.     

Classification of idiopathic hypercalciuric patients by isotopic calcium absorption: A comparison with oral calcium tolerance test

Summary To test the accuracy of calcium tolerance test in estimating calcium absorption, we have measured the radioactive calcium absorption (expressed as Fx) in 27 patients with IH and renal calcium stones. The results of this test were compared with those of a standard oral calcium tolerance test. Although only seven of nine AH patients displayed normal fasting calcium excretion, they all displayed Fx values above normal and a normal parathyroid activity. Conversely, only 5 of our 18 RH patients demonstrated a hyperabsorption of radioactive calcium and an elevation in iPTH and cAMP above normal limits, yet all of them showed an increased calciuric response to an oral calcium challenge. Calcium absorption was inversely related to iPTH (r=−082;P<0.001) and cAMP (r=−064P<0.05) in AH, but directly proportional to these parameters (r=0.62P<0.001 andr=0.46P<0.05, respectively) in RH patients. In view of these results, two ratios, iPTH/Fx and cAMP/Fx were used to discriminate between the two groups of patients. Both ratios were over normal limits in all RH patients and within normal range in all but one AH patient. Furthermore, no overlap was found between the two groups. Conversely, we were unable to completely separate AH from RH subjects on the basis of the oral calcium tolerance test, since in both groups the fasting and the absolute (or percentage) changes in urinary calcium, cAMP and blood iPTH levels following oral calcium loading, overlapped in each instance. The result of this study indicates that two indices, iPTH/Fx and cAMP/Fx, may prove particularly useful in differentiating AH from RH patients. Furthermore, since only a subgroup of patients with an abnormal calciuric response to an oral calcium load manifest an increase in calcium absorption, it is concluded that the calcium tolerance test overestimates calcium absorption in IH. Supported in part by Grant No. 5T32 AM0703310     

Experimental studies on intestinal absorption following Martin's operation

Experimental studies were done on rats on compensatory absorptive capacity following Martin's operation for extensive aganglionosis. Experimental aganglionosis was produced in the descending colon of rats by serosal application of 0.1% benzalkonium chloride solution. Wide side-toside anastomosis was performed between the aganglionic colon and the distal ileum, removing the remaining colon. As to absorptive capacity of water and electrolytes, this experimental intestine was compared, with other intestines, especially control intestine, in which similar side-to-side anastomosis was done between the normal colon and the normal ileum. “Experimental” as well as control intestine showed higher absorptive capacities of water, Na and Cl per unit length than did summed up values of the ileum and the colon per unit length. Postoperative body weight curves showed fairly good increases and appearance of feces showed a fair improvement in the experimental group. Autopsy of experimental intestine revealed marked dilatation of the anastomosed ileum and mucosal hypertrophy of the anastomosed colon. These results suggested a favorable compensatory absorptive capacity following Martin's operation.     

A simplified technique for the measurement of intestinal absorption of calcium in the dog: Effects of PO4 depletion and 25(OH)D3 in uremia

Summary A simplified method is described for the measurement of calcium absorption in the dog. This method uses⁴⁵Ca and takes less than 8 h to perform. Calcium absorption was measured in normal and uremic dogs on different intakes of calcium and phosphorus and compared to the results obtained in the same animal maintained on the same diet by another method using⁴⁷Ca and a double dilution procedure. The correlation coefficient between the two methods was 0.99 (P<0.001). The advantages of the simplified method are discussed.     

Interrelation of cortisone and 1,25 dihydroxycholecalciferol on intestinal calcium and phosphate absorption

Summary The interrelation of glucocorticoids and 1,25 dihydroxycholecalciferol (1,25(OH)₂D₃) on intestinal calcium and phosphate absorption was investigated. The active and passive transport of calcium and phosphate was evaluated by thein situ intestinal loop technique. Administration of cortisone resulted in a decrease of the luminal fluid and an increase of the luminal calcium and phosphate concentration. Under active transport conditions, administration of cortisone resulted in a decrease of net calcium absorption through two mechanisms: (1) depressed vitamin D-dependent calcium absorption, (2) increased vitamin D-independent calcium backflux. The enhancement of bidirectional phosphate flux by cortisone was independent of 1,25(OH)₂D₃. An enhancement of water movement by cortisone resulted in an increase of luminal calcium and phosphate concentration which favors the passive diffusion of these ions. Enhanced calcium diffusion by cortisone compensates for the inhibitory effect of cortisone on vitamin D-dependent calcium transport. However, enhanced phosphate diffusion by cortisone is additive to the effect of 1,25(OH)₂D₃.     

Calcium absorption in normal and osteoporotic postmenopausal women

Summary Hourly fractional absorption of radiocalcium (alpha), serum calcitriol, and a number of other variables were measured in 152 normal and 148 osteoporotic postmenopausal women. Alpha, body weight, and serum albumin were all significantly lower in the osteoporotic than in the normal women, and plasma alkaline phosphatase, fasting urinary calcium, sodium, and hydroxyproline were all significantly higher in the osteoporotic than in the normal group. The most significant determinant of alpha in each group was the serum calcitriol concentration, but calcium absorption relative to serum calcitriol was significantly lower in the osteoporotic than in the normal women. The serum calcitriol level was slightly but not significantly lower in the osteoporotic than in the normal group and accounted for only 20% of the difference in alpha between them. The implied “resistance” to calcitriol in the osteoporotic group was significantly related to serum albumin and body weight but independent of age. Urinary hydroxyproline was an inverse function of alpha and a positive function of fasting urinary calcium in the osteoporotic group.     

A comparison of the effects of alfacalcidol treatment and vitamin D2 supplementation on calcium absorption in elderly women with vertebral fractures

Although vitamin D supplementation in the frail elderly improves calcium absorption, suppresses parathyroid hormone, decreases bone loss and reduces the risk of fractures, such treatment may be ineffective in patients with vertebral osteoporosis, because of impaired vitamin D metabolism or resistance to the action of vitamin D metabolites on the bowel. We have therefore performed a randomized, single masked study comparing the effects of alfacalcidol treatment (0.25 µg twice daily) and vitamin D₂ supplementation (500-1000 units daily) on calcium absorption and bone turnover in 46 elderly women (median age 69 years, range 64–79 years) with radiological evidence of vertebral fractures. Serum 25-hydroxyvitamin D increased significantly after 3 and 6 months of treatment with vitamin D₂ (p<0.001), but was unchanged in the group receiving alfacalcidol. Serum 1,25-dihydroxyvitamin D did not change significantly in either group over the study period. Fractional⁴⁵Ca absorption increased after 3 months of treatment with alfacalcidol (p<0.05), but was unchanged with vitamin D₂. There was also a reduction in plasma intact parathyroid hormone and serum alkaline phosphatase after 6 months of treatment with alfacalcidol (p<0.05) which was not seen in the group receiving vitamin D₂. Our study shows that vitamin D₂ supplementation is ineffective in stimulating calcium absorption in elderly women with vertebral osteoporosis. By increasing calcium absorption in such patients, alfacalcidol may prove more effective than vitamin D in the management of vertebral osteoporosis.     

Gastrointestinal oxalic acid absorption in calcium-treated rats

We studied whether urinary oxalate excretion after an acute oral load of oxalic acid is influenced by concomitant administration of calcium in rats. Male Wistar rats weighing approximately 180 g were divided into six groups of five animals each. After inducing anesthesia, the animals were orally (via a gastrostomy) given 110 μmol of oxalic acid along with 0, 27.5, 55, 110, or 220 μmol of calcium (0, 27.5, 55, 110, or 220 μmol Ca group, respectively). Saline was given to the control group instead of oxalic acid. Urine specimens were collected before administration and then at hourly intervals up to 5 h afterward. Urinary oxalate and citrate levels were measured by capillary electrophoresis, while urinary calcium, magnesium, and phosphorus levels were measured by ICP spectrophotometry. Urinary oxalate excretion peaked at 1 h after administration and was higher in the 0, 27.5, and 55 μmol Ca groups than in the control group. The urinary recovery of oxalate in these groups was 10–15%, while the recovery rate was less than 3% in other groups. Urinary Ca excretion showed no significant changes, either over time or between groups. Free oxalic acid is absorbed more readily from the gastrointestinal tract than calcium oxalate, while simultaneous administration of calcium appears to block intestinal oxalic acid absorption in a dose-dependent manner.