EFFECT OF TETRACYCLINE ON RETENTION OF CALCIUM AND STRONTIUM IN RODENTS.
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Calcium is important for bone health. It has been customary to focus on dietary calcium intake, but of central importance for the body needs in the individual patient is the actual calcium absorption. This absorption consists of an active vitamin D-mediated component and a passive diffusional component. A number of different methods are available for the evaluation of calcium absorption. At present the calcium absorption tests using calcium isotopes (radioactive or stable) appear to be the most reproducible way of determining calcium absorption. The major nutrient sources for calcium are milk and milk products, whereas some of the green vegetables have a low bioavailability of calcium. When deciding whether an increased calcium intake is advisable, the following questions must be answered. What is the calcium absorptive status of the patient? How should the calcium supplement be dispensed? What calcium salt should be used? When should calcium supplements be taken? What is the compliance of the patient? When should the treatment be evaluated? The calcium supplement might be taken as milk (or milk products) or, in patients with lactose intolerance, as calcium supplements. Quite a number of calcium supplements are available on the market, and many of them are marketed without proper knowledge of the bioavailability of the actual preparation. For the benefit of our patients it is now reasonable to demand such investigations before marketing calcium supplements.
Increasing dietary protein results in an increase in urinary calcium. Despite over 80 y of research, the source of the additional urinary calcium remains unclear. Because most calcium balance studies found little effect of dietary protein on intestinal calcium absorption, it was assumed that the skeleton was the source of the calcium. The hypothesis was that the high endogenous acid load generated by a protein-rich diet would increase bone resorption and skeletal fracture. However, there are no definitive nutrition intervention studies that show a detrimental effect of a high protein diet on the skeleton and the hypothesis remains unproven. Recent studies from our laboratory demonstrate that dietary protein affects intestinal calcium absorption. We conducted a series of short-term nutrition intervention trials in healthy adults where dietary protein was adjusted to either low, medium or high. The highest protein diet resulted in hypercalciuria with no change in serum parathyroid hormone. Surprisingly, within 4 d, the low protein diet induced secondary hyperparathyroidism that persisted for 2 wk. The secondary hyperparathyroidism induced by the low protein diet was attributed to a reduction in intestinal calcium absorption (as assessed by dual stable calcium isotopes). The long-term consequences of these low protein-induced changes in calcium metabolism are not known, but they could be detrimental to skeletal health. Several recent epidemiological studies demonstrate reduced bone density and increased rates of bone loss in individuals habitually consuming low protein diets. Therefore, studies are needed to determine whether low protein intakes directly affect rates of bone resorption, bone formation or both.
Cytosolic calcium and its parathyroid hormone induced increase was evaluated in rat osteosarcoma cells by quin 2 fluorometry. Electron microscopic calcium detection in depot organelles (i.e. the recently defined calciosomes) is improved by a new precipitation method with hydroxylamine naphthoic acid and fluoride combined with X-ray microanalysis. As shown in submandibulary gland and pancreatic B cells, a new combination of GBHA staining with laser microprobe mass analysis (LAMMA) for the first time enables direct kinetical studies of calcium at the microscopical level using stable calcium isotopes (i.e. Ca44) as tracers.
Fractional absorption of calcium was determined in 9 children aged 4.9 to 16.9 yr with chronic cholestatic liver disease to determine the role of calcium malabsorption in the development of metabolic bone disease. Radiological evidence of rickets was absent in all patients, but bone density, measured by single beam photon absorptiometry of the distal radius, was reduced in eight of nine subjects. Serum calcium and phosphorus concentrations were normal in all except one subject. Serum 25-hydroxyvitamin D concentration was decreased compared with controls in only one of nine patients, but serum 1,25-dihydroxyvitamin D concentrations were diminished in seven of nine subjects. In all subjects, dietary calcium and phosphorus intakes were greater than 80% of the RDA. Fractional absorption of calcium, determined by oral and intravenous administration of stable calcium isotopes, was similar in cholestatic compared with control subjects (37.1% +/- 12.5% vs. 34.0% +/- 16.4%). In the cholestatic subjects, calcium absorption correlated with serum 1,25-dihydroxyvitamin D (r = 0.871, p less than 0.002) but not 25-hydroxyvitamin D concentrations. Calcium balance, assessed by the duplicate diet method, was positive in four of five subjects. Anthropometric measurements were performed to examine the relationship between nutritional status and bone mineral content. Heights of all subjects were less than or equal to the 10th percentile and fat stores and somatic protein stores were less than the 25th percentile in six of nine subjects. We conclude that factors other than calcium malabsorption and decreased serum 25-hydroxyvitamin D concentration contribute to diminished bone mass in children with cholestatic liver disease.
Calcium absorption tests have rarely been validated for being representative for absolute bioavailability (true absorption) or for intraindividual variation. Therefore, we investigated the reproducibility of the absolute bioavailability of strontium chloride, a marker for intestinal calcium absorption, in healthy male volunteers (n = 8) by measuring the area under the plasma strontium concentration-time curve after oral and intravenous administration of strontium. Subsequently, we selected a simple test variable as being representative of absolute bioavailability. The mean absolute bioavailability (+/- SD) was 25% +/- 7%. The best test variable appeared to be the fractional absorption at 240 min (Fc240) after oral intake, which demonstrated the highest correlation with absolute bioavailability (r = 0.66). The intraindividual variations of the data for this variable and for the absolute bioavailability are similar to those described for various absorption tests based on the use of calcium isotopes. Thus, the Fc240 of strontium offers the potential of a simple clinical test for use as a measure of intestinal calcium absorption and its modulation.
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Stable isotopic tracers of calcium have been used to characterize the absorption of dietary calcium and the subsequent distribution of this element through the body. For a group of 7 healthy children, ages 4-14, and 7 children with osteogenesis imperfecta (OI), types I, III and IV, ages 6-17, there were no detectable differences in the fractional absorption of dietary calcium, 0.29+/-0.11 and 0.28+/-0.16, respectively. The total exchangeable pool of calcium was found to be 161+/-52 mg/kg for the healthy children and 95+/-29 mg/kg for the 3 children with Type I OI, 250+/-75 mg/kg for the 3 children with Type III OI and 216 mg/kg for the child with Type IV OI.
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To identify the mechanism/s whereby calcium retention is increased by calcium intake in adolescent girls, kinetic studies were performed using stable calcium isotope tracers. Girls (n = 10; 12 +/- 1 yr old, mean +/- SD) were studied while on a controlled diet containing a low (21.2 mmol/day) and a high (47.4 mmol/day) calcium intake, in randomized order, using a cross-over design. Studies were separated by 1 month. Calcium tracers were administered after 1 week on the study diet, orally and iv; and serum, urine, and feces were collected for the following 14 days. Tracers were measured using fast atom bombardment mass spectrometry, and kinetic data were analyzed by compartmental modeling. Biochemical markers of bone turnover were measured in serum and urine samples. On high (compared with low) calcium intake, fractional absorption did not differ, absorbed calcium increased (19.6 +/- 7.5 vs. 8.0 +/- 2.5 mmol/day, mean +/- SD, P: < 0.001), calcium excreted in urine increased (2.8 +/- 1.7 vs. 2.1 +/- 1.1 mmol/day, P: < 0.01), calcium retained in bone increased (14.5 +/- 8.9 vs. 3.2 +/- 3.6 mmol/day, P: < 0.001), bone formation did not change, and bone resorption decreased by 32%. These changes, measured by kinetics, were corroborated by changes in markers of bone turnover. We conclude that increased bone retention of calcium, with high calcium intake in adolescent girls, is attributable to an increase in absorption and a decrease in bone resorption.
BACKGROUND: Physiologic adjustments in calcium homeostasis during pregnancy and lactation in women with marginal calcium intakes have not been described. OBJECTIVE: The objective was to examine longitudinal changes in various aspects of calcium homeostasis during pregnancy and lactation in 9 healthy Brazilian women who habitually consumed approximately 500 mg Ca/d. DESIGN: Calcium homeostasis was assessed at 3 time points: 10-12 (early pregnancy, EP) and 34-36 (late pregnancy, LP) wk of pregnancy and 7-8 wk postpartum (early lactation, EL). At each time point, the following variables were measured: dietary calcium intake with a 3-d weighed food record, 24-h urinary calcium excretion (UCa), intestinal calcium absorption (%CaAbs) via administration of stable calcium isotopes with a breakfast meal, serum 1,25-dihydroxyvitamin D, parathyroid hormone (PTH), insulin-like growth factor I (IGF-I), and biochemical markers of bone turnover. RESULTS: Dietary calcium did not change during the study. %CaAbs increased from 69.7 +/- 5.4% ( +/- SEM) during EP to 87.6 +/- 4.5% during LP (P < 0.05) and returned to 65.1 +/- 6.2% during EL. Compared with EP, UCa decreased 22% during LP and 68% during EL (P < 0.05). The net mean change in calcium retention was 212 mg/d during LP and 182 mg/d during EL. Several significant associations were found between the main outcome variables (%CaAbs, UCa, and markers of bone turnover) and serum hormones, especially IGF-I and PTH. CONCLUSIONS: Calcium homeostasis appears to be attained by a more efficient intestinal calcium absorption during pregnancy and by renal calcium conservation during both pregnancy and lactation. IGF-I and PTH seem to play major roles in the adjustment of calcium metabolism during pregnancy and lactation.
The 47scandium/47calcium ratio technique for studying intestinal absorption of calcium in humans offers the following advantages: neither blood sampling nor complete faecal collection are required, and there is no need for an additional marker or for knowledge of the precise dose of calcium isotope administered. In the study this technique was corrected and modified using a new equation that considerably simplifies the determination procedures. The new method was validated in rats with various intestinal calcium absorption rates. The value of scandium as an unabsorbed intestinal marker was confirmed by the use of 46scandium. A mean recovery of 96% was obtained after intragastric administration. The 47scandium/47calcium ratio technique gave results that correlated well with the faecal 47calcium recovery method over a wide range of intestinal calcium absorption rates obtained by treatment with 1,25-dihydroxycholecalciferol or 1-hydroxyethylidene-1,1-biphosphonate. Taking into account the advantages of the 47scandium/47calcium ratio technique, it appears useful not only in small animals but also in outpatients, particularly children.
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To assess the effect of different dialysis modalities on calcium turnover, we studied 57 patients on maintenance hemodialysis treatment (HD) and 38 patients on continuous ambulatory peritoneal dialysis (CAPD) with tracer kinetic studies using two calcium isotopes (45Ca by mouth and 47Ca intravenously). The two groups were comparable in age, sex and prevalence of diabetes. The groups did not differ in their serum concentrations of intact parathyroid hormone (iPTH), calcium, inorganic phosphate and 1,25-dihydroxyvitamin D. 25-hydroxy-vitamin D and alkaline phosphatase were found to be significantly higher in HD patients. Despite these similarities, CAPD patients showed a significantly lower calcium kinetic response as measured by calcium retention and plasma calcium efflux than HD patients. Mean calcium retention was 39.5% in HD patients compared to 31.2% in the CAPD group (p < 0.05). Plasma calcium efflux was significantly lower in the CAPD group (2.7 vs 3.2 respectively; p < 0.01). iPTH correlated with calcium retention and plasma calcium efflux in HD patients (r = 0.69 and r = 0.67 respectively). In CAPD patients, the correlation coefficient between iPTH and calcium retention was markedly lower (r = 0.54), whereas no correlation was found between iPTH and plasma calcium efflux (r = 0.08). In addition, the slope of the correlation curve were higher in HD patients (p < 0.01 and p < 0.001, respectively), indicating a better response of this patient group to the action of parathyroid hormone. Our data are in accordance with recently published results showing that the dialysis modality has a major impact on bone turnover and on the progression of uremic bone disease. It has been shown that CAPD is an independent risk factor for the development of the adynamic form of renal bone disease. This finding may be explained by the lower response of calcium turnover to the action of PTH as shown here with tracer kinetic studies.
OBJECTIVE: An association between the development of low turnover osteopathy and the form of dialysis treatment, that is, continuous ambulatory peritoneal dialysis (CAPD), has been described. To examine the effect of a year-long CAPD treatment on calcium (Ca) turnover, 12 patients were studied prior to and one year after initiation of CAPD treatment with a dialysate calcium of 1.75 mmol/L. DESIGN: A prospective analysis. SETTING: Academic teaching hospital dialysis unit. PATIENTS: Twelve patients with an average age of 54.8 years (range: 23-76 years) at commencement of dialysis and after 13 months of CAPD treatment. MEASUREMENTS: Calcium kinetic studies were performed using two calcium isotopes: 45Ca as an oral tracer and 47Ca as an intravenous tracer. Measurements of plasma and whole body activities were performed over a four-week period. From these measurements, kinetic parameters describing calcium turnover in different compartments were studied. These measurements were repeated after a mean time of 13.4 months. Patients were not treated with vitamin D, but received aluminum- and calcium-containing phosphate binders, in order to keep inorganic phosphate below 2.0 mmol/L and calcium within the normal range. RESULTS: After one year on CAPD, serum levels of calcium increased from 2.2 mmol/L to 2.35 mmol/L. Inorganic phosphate also increased from 1.4 mmol/L to 1.9 mmol/L, despite increased use of oral phosphate binders. Serum levels of intact parathyroid hormone (IPTH) decreased from 51.2 pmol/L to 28.3 pmol/L. Alkaline phosphatase did not change, nor did serum levels of vitamin D. Despite improvement of serum IPTH levels and better control of serum calcium, the kinetic parameters describing calcium turnover in the different calcium pools did not improve. In addition, the calcium retention of bone remained below normal range and did not rise. Perhaps more importantly, the relationship between Ca efflux and Ca retention did not change. While Ca retention remained low, plasma Ca efflux was normal. This imbalance was seen at the beginning of CAPD and did not change under CAPD. CONCLUSION: These data demonstrate that, after one year of CAPD treatment without vitamin D treatment, calcium turnover did not improve, despite a significant fall in serum IPTH levels. Studies on a larger number of patients are warranted to verify these results.