To clarify the role of the intestine, kidney, and bone in maintaining calcium homeostasis during pregnancy and lactation and after the resumption of menses, a longitudinal comparison was undertaken of 14 well-nourished women consuming approximately 1200 mg Ca/d. Measurements were made before conception (prepregnancy), once during each trimester of pregnancy (T1, T2, and T3), early in lactation at 2 mo postpartum (EL), and 5 mo after resumption of menses. Intestinal calcium absorption was determined from the enrichment of the first 24-h urine sample collected after administration of stable calcium isotopes. Bone mineral of the total body and lumbar spine was measured by dual-energy X-ray absorptiometry and quantitative computerized tomography, respectively. Twenty-four-hour urine and fasting serum samples were analyzed for calcium, calcitropic hormones, and biochemical markers of bone turnover. Despite an increase in calcium intake during pregnancy, true percentage absorption of calcium increased from 32.9+/-9.1% at prepregnancy to 49.9+/-10.2% at T2 and 53.8+/-11.3% at T3 (P < 0.001). Urinary calcium increased from 4.32+/-2.20 mmol/d at prepregnancy to 6.21+/-3.72 mmol/d at T3 (P < 0.001), but only minor changes in maternal bone mineral were detected. At EL, dietary calcium and calcium absorption were not significantly different from that at prepregnancy, but urinary calcium decreased to 1.87+/-1.22 mmol/d (P < 0.001) and trabecular bone mineral density of the spine decreased to 147.7+/-21.2 mg/cm3 from 162.9+/-25.0 mg/cm3 at prepregnancy (P < 0.001). Calcium absorption postmenses increased nonsignificantly to 36.0+/-8.1% whereas urinary calcium decreased to 2.72+/-1.52 mmol/d (P < 0.001). We concluded that fetal calcium demand was met by increased maternal intestinal absorption; early breast-milk calcium was provided by maternal renal calcium conservation and loss of spinal trabecular bone, a loss that was recovered postmenses.

Female weanling rats from a colony maintained on a diet low in vitamin D were raised on a diet that was deficient in vitamin D but was otherwise adequate. Vitamin D deficiency was confirmed in the rats by hypocalcemia and the absence of vitamin D metabolites in blood. These females gave birth to litters that were slightly smaller than control litters from females maintained on a vitamin D-containing diet. The pups from the vitamin D-deficient mothers appeared normal throughout lactation, and at weaning had normal concentrations of calcium and phosphate in the plasma. These results indicate that vitamin D and its metabolites are not necessary for reproduction and fetal development in the rat.

To define the role of vitamin D in calcium transport in the intestine during early development, female weanling rats were placed on vitamin D-replete or vitamin D-deficient diets, grown to maturity, and mated with normal males. Pups born to vitamin D-replete and vitamin D-deficient mothers were killed at various times after parturition, and calcium transport in the small intestine as well as the concentrations of calcium and phosphate in the plasma were measured. Transport of calcium in pups from vitamin D-replete and vitamin D-deficient litters was identical at 3 and 14 days postpartum but was threefold greater in pups from vitamin D-replete litters at weaning and 3 wk postweaning. 1,25-dihydroxyvitamin D3 had no effect on calcium transport at 14 days postpartum but did induce transport at weaning. Plasma concentrations of calcium at 3 days postpartum were nearly normal but decreased during the suckling period from 10.3 mg/100ml to 7.2 mg/100 ml in vitamin D-deficient rats. These results suggest that calcium transport in the intestine during early development is not mediated by vitamin D but that a vitamin D-sensitive transport system develops late in the suckling period.

We have previously observed elevated serum 1,25-dihydroxyvitamin D3 [1,25-(OH)2D] levels in male rats treated with oral cyclosporin-A (CsA). This elevation was independent of changes in PTH, ionized calcium, or phosphate. This paper investigates the potential sources and mechanisms for this increase in both rats and mice. Kidney homogenates from rats treated for 14 days with (15 mg/kg) had a significant increase in 25-hydroxyvitamin D (25OHD)-24-hydroxylase (24-hydroxylase) activity (149 +/- 20 vs. 89 +/- 16 fmol/mg.min; P less than 0.05), but nonsignificant increases in 25OHD-1 alpha-hydroxylase (1 alpha-hydroxylase) activity compared to controls. Kidney homogenates from C57b16J mice after the administration of 30-50 mg/kg CsA for 3 days revealed a linear dose-related increase in renal 1 alpha-hydroxylase (r = 0.96; P less than 0.05), which became significant with doses of 30 mg/kg CsA or more (P less than 0.05). To investigate the source of this 1,25-(OH)2D production, serum 1,25-(OH)2D was measured before and 48 h after bilateral nephrectomy in rats receiving CsA for 16 days. The percent decrease in serum 1,25-(OH)2D values was not significantly different in CsA-treated and untreated rats (33.9 +/- 4.9% vs. 47.5 +/- 4.9%), indicating little or no contribution from nonrenal sources. Studies of MCRs and production rates (PRs) revealed that the elevated 1,25-(OH)2D values were due to enhanced production and not altered clearance (PR, 12.4 +/- 1.2 vs. 19.1 +/- 1.9 fmol/mg.min; P less than 0.01). CsA increases 1 alpha-hydroxylase activity and produces significant elevations in serum 1,25-(OH)2D levels in both rats and mice. This increase may have an impact on bone mineral metabolism and immune modulation in postorgan transplantation patients.

Administration of 1,25-dihydroxyvitamin D [1,25(OH)2D] can increase the metabolic clearance rate (MCR) of 25-hydroxyvitamin D [25(OH)D]. To determine whether administration of 1,25(OH)2D can also influence the metabolic clearance rates (MCR) of 1,25(OH)2D and 24,25-dihydroxyvitamin D 24,25(OH)2D, we measured metabolic clearance of 1,25(OH)2D, 24,25(OH)2D, and 25(OH)D in rats in which the serum concentration of 1,25(OH)2D was increased by continuous infusion. Infusion of 1,25(OH)2D (12 days at 75 pmol/day) increased serum 1,25(OH)2D from 128 +/- 11 to 244 +/- 14 pg/ml (P less than 0.005) and increased MCR from 169 +/- 13 to 210 +/- 9 microliters.min-1.kg-1 or 24% (P less than 0.025). Increasing serum 1,25(OH)2D to 330-360 pg/ml increased MCR 72%. Infusion of 1,25(OH)2D decreased serum 24,25(OH)2D from 3.5 +/- 0.5 to 2.4 +/- 0.3 ng/ml (P less than 0.05), increased MCR from 25 +/- 2 to 48 +/- 6 microliters.min-1.kg-1 (P less than 0.0025), and increased the production rate (PR) from 70 +/- 11 to 124 +/- 26 pg.min-1.kg-1 (P less than 0.05). Infusion of 1,25(OH)2D decreased serum 25(OH)D from 13.0 +/- 0.5 to 8.0 +/- 0.5 ng/ml (P less than 0.005) and increased MCR from 45 +/- 1 to 75 +/- 7 microliters.min-1.kg-1 (P less than 0.001) but had no effect on PR. The data indicate that increasing serum 1,25(OH)2D by chronic administration can increase the MCR of 1,25(OH)2D and suggest that 1,25(OH)2D can feedback regulate its serum concentration by regulating its MCR. The data also suggest that 1,25(OH)2D administration can increase the MCRs of 24,25(OH)2D and 25(OH)D.

To investigate the biological importance of 24R-hydroxylation of 25-hydroxyvitamin D to the early development of rats, the potency of 24,24-difluoro-25-hydroxyvitamin D3 had been compared to that of 25-hydroxyvitamin D3 in young rat pups born to vitamin D-deficient mothers. 24,24-Difluoro-25-hydroxyvitamin D3 and 25-hydroxyvitamin D3 were equally active in stimulating active calcium transport in the intestine, maintaining normal concentrations of calcium and phosphorus in the plasma and promoting bone growth and mineralization. These results provide strong evidence that the presence of a hydroxyl group at the 24 position of vitamin D3 is not required for the maintenance of calcium-phosphate homeostasis during growth and in the development and mineralization of bone.

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Radii and ulnae from 19-day fetal rats from normal or vitamin D-deficient mothers were treated with 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, or parathyroid hormone in vitro. Both sets of bones resorbed in response to all three agents. Statistical analysis indicated a purely additive model for the effects of vitamin D status and the bone-resorbing agents, with no evidence for interaction. The results suggest that the impaired calcemic response to parathyroid hormone seen in vitamin D-deficient animals in vivo is not the result of a specific unresponsiveness of vitamin D-deficient bone to parathyroid hormone.