Edgard E. Delvin

Vitamin D supplementation during pregnancy: Effect on neonatal calcium homeostasis

We assessed whether modification of vitamin D nutritional status during the last trimester of pregnancy affects maternal and neonatal calcium homeostasis. At the end of the first trimester, 40 pregnant women were randomly assigned to either of two groups, and blood taken to assess the basal values of Ca, Pi, Mg, iPTH, 25-OHD, and 1,25(OH)2D. From the sixth month on, group 1 (+D) received 1000 IU vitamin D3 daily; group 2 (-D) served as control. At the time of delivery, maternal serum 25-OHD was higher in the +D group (P less than 0.0005). Ca, Pi, iPTH, and 1,25(OH)2D were not affected. At term, venous cord 25-OHD levels were also higher in the +D group (P less than 0.0005), and 1,25(OH)2D levels slightly lower (P less than 0.05), but neither Ca, Pi, nor iPTH differed between the two groups. Serum CaT dropped significantly (P less than 0.002) at 4 days of age in the infants from both groups, although to a lesser extent in these from the +D group (P less than 0.05). Circulating iPTH increased in both groups. Serum 25-OHD remained low in the -D group, and dropped slightly in the +D group; 1,25(OH)2D remained stable during the first 4 days of life in the -D group, and increased in the +D group (P less than 0.001). Our data demonstrate the importance of providing adequate maternal vitamin D stores to ensure better perinatal handling of calcium. This is of particular importance for populations at risk for hypovitaminosis D.

Vitamin D dependency: Replacement therapy with calcitriol

Nine patients with vitamin D-dependency type I were studied. We observed that treatment with large doses of vitamin D altered the phenotypic expression of the disease, thus making a delayed diagnosis difficult. At the time of entry, eight children had hypocalcemia, and seven had hypophosphatemia. Elevated serum immunoreactive parathyroid hormone and low (less than 3 SD from control mean) 1 alpha,25-dihydroxyvitamin D values were constant findings, with no vitamin D deficiency. Despite the elevated serum iPTH, three children had normal urinary phosphate excretion and five had normal urinary cAMP excretion. In the five children tested before treatment, there was no significant change in renal phosphate excretion during an acute parathyroid hormone infusion, although in all a significant rise of urinary cAMP occured. Treatment with calcitriol (0.25 to 2 microgram/day) returned all the biochemical values to normal within four months. In two patients, both supplemented with vitamin D, histomorphometric analysis of iliac crest biopsies revealed severe osteomalacia. After nine and ten months of treatment with calcitriol, there was histologic evidence for improvement of bone mineralization. Since calcitriol requirements may vary during the course of treatment, careful monitoring of biochemical variables is essential.

Vitamin D metabolism in preterm infants: Serum calcitriol values during the first five days of life†

To ascertain the activity of the vitamin D biosynthetic pathway, the serum concentration of 1,25-dihydroxyvitamin D (calcitriol) was measured in 16 preterm infants (32 to 37 weeks of gestation) at 1 to 2 and 120 hours of age. Half of the subjects received a daily oral supplement of 2,100 IU of vitamin D3 during the five-day study period. In the first two hours of life, all subjects were hypocalcemic (8.2 +/- 0.2 mg/dl) and 14 subjects had low concentrations of 25-hydroxyvitamin D (calcidiol, 8 +/- 1 ng/ml). The latter finding probably reflects a mild degree of vitamin D deficiency in the mothers of our subjects. Calcitriol concentrations (42 +/- 3 pg/ml) were comparable to those of older children. At 120 hours of age, the control group had no significant change in calcitriol values, whereas the group supplemented with D3 had a more than threefold increase. There was a positive correlation between the circulating concentrations of calcidiol and calcitriol over the period of the study. The data show that, after 32 weeks of gestation, renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity is present, with the rate of calcitriol synthesis being apparently substrate limited. Early neonatal hypocalcemia is therefore unlikely to be caused by an impairment of vitamin D activation.

Vitamin D Metabolism in Preterm Infants

Perinatal metabolism of vitamin D was studied in premature babies with the aim of: (1) reporting the relationship between the pregnant mother and her preterm infant and the metabolism of vitamin D during the first weeks of life, and (2) assessing the effect of vitamin D metabolites on phosphorus calcium and magnesium intestinal absorption. There was only a positive correlation between plasma cord calcium and 25-hydroxyvitamin D levels and the mothers plasma levels at birth. During the hypocalcemic episode observed during the first week of life, vitamin D activation did occur, but later on rickets or osteomalacia cannot be due to the low levels of vitamin D metabolites in the preterm receiving an adequate dose of vitamin D (1,000-1,200 IU of D2). Calcitriol, the major metabolite of vitamin D, is acting on the intestine and promotes calcium absorption even in very tiny prematures. The pathogenesis of hypomineralization in the preterm infant is due to the low intake of calcium or phosphorus and/or poor absorption of calcium in the case of vitamin D deficiency.

Induction of bone resorption by parathyroid hormone in congenital malignant osteopetrosis

A male patient, afflicted with malignant congenital osteopetrosis, was studied over a 5 year period. Hypocalcemia (less than 8 mg/dl) with lack of an appropriate increase in serum immunoreactive parathyroid hormone (iPTH) prevailed at all times. Under a calcium restricted diet, a 6-hour infusion of parathyroid extract normalized serum calcium, and increased the urinary hydroxyproline excretion suggesting that bone resorption had been induced. A second attempt to induce resorption was made by infusing a synthetic amino terminal fragment of bovine PTH over a period of 3 weeks at the dose of 1.5 units/kg/hr. This infusion evoked an increase in serum calcium (8.1 to 10.5 mg/dl), urinary calcium (0.03 to 0.65 mg/g creatinine) and urinary hydroxyproline (160 to 372 mg/g creatinine); and urinary hydroxyproline (160 to 372 mg/g creatinine); increases which were reversed by calcitonin administration. Iliac crest bone biopsies were obtained before and on the last day of the 3-week infusion. Quantitative comparison of the two specimens showed that, during PTH infusion, there was a 23% decrease in bone volume due to the increase in marrow space, a 93% increase in the number of osteoclasts and 136% increment in the osteoclastic resorption surface. Electron microscopic examination of the osteoclasts in the first tissue sample showed no evidence of ruffled borders, while in the second biopsy, numerous cytoplasmic processes indicative of resorptive activity were visible at the matrix-cell interface. It is proposed that, in our patient, the osteopetrotic phenotype is the consequence of an abnormality in the interaction between PTH and osteoclasts that may be related to the synthesis of a physiologically defective PTH.

HYPOCALCEMIA IN INFANTS OF DIABETIC MOTHERS.: Studies in Circulating Calciotropic Hormone Concentrations

ABSTRACT. Twenty‐two infants of diabetic mothers (IDM) were studied and were divided into two groups: a first group of 14 IDM did not receive vitamin D3 and was studied at birth and at 2, 24, 48 and 120 hours; a second group was given daily dosage of 60 μg of vitamin D3 from 3 hours to 120 hours and was studied at 2 hours and 120 hours.

Influence of magnesium supplementation on bone turnover in the normal young mouse.

SummaryThe effect of magnesium (Mg) supplementation on bone metabolism has been studied in the normal young mouse. Weanling male mice were given Mg-supplemented drinking water (5 mM or 32 mM Mg) for 4 weeks. Mineral and skeletal changes were assessed by biochemical methods and by histomorphometric analysis of endosteal bone formation and resorption parameters evaluated on tetracycline double-labeled, undecalcified caudal vertebrae. Magnesium supplementation increased serum and urinary Mg concentrations and bone Mg content. Both the calcification rate and the extent of tetracycline double-labeled osteoid surface increased progressively in Mg-treated mice, whereas the mineralization lag time was shortened. The osteoblastic surface was reduced, leading to a fall in osteoid surface. Stimulation of bone mineralization was associated with a rise in extracellular calcium (Ca) and phosphorus (P) concentrations whereas serum 25-OHD and 1,25(OH)2D levels remained normal. The Mg supplementation increased the number of acid phosphatase stained chondroclasts and osteoclasts and the extent of resorbing surface showing histochemically stained osteoclasts. Although urinary OH-proline increased above normal, Ca, P, and cyclic adenylic acid (cAMP) excretion and phosphate concentration (TmP/GFR) remained normal, suggesting that parathyroid hormone (PTH) secretion was not altered. The trabecular bone volume remained normal, showing that the increased bone resorption was balanced by the stimulated bone mineralization. The results show that Mg supplementation influenced both bone formation and resorption in the young mouse, and that the stimulation of bone mineralization was the result of increased extracellular mineral availability. On the other hand, stimulation of osteoclastic bone resorption appeared to occur independently of PTH or of increased 1,25(OH)2D production. Therefore, this study suggests that Mg may controlin vivo bone metabolism by directly influencing bone resorbing cells activity.

Vitamin D metabolism in preterm infants. Serial serum calcitriol values during the first four days of life.

ABSTRACT. In order to evaluate after birth the changes in circulating vitamin D metabolite levels in preterm babies supplemented with vitamin D (2100 I. U./d), the serum concentration of 25‐hydroxyvitamin D [25‐OHD] and 1 α,25‐dihydroxy vitamin D [1, 25(OH)2D] were measured in 22 infants (31 to 35 weeks of gestation) from birth up to 96 hours of age. Compared to cord blood levels, serum calcium decreased significantly during the first 24 hours of life (p<0.005) and remained low until day 4. Serum immunoreactive parathyroid hormone (iPTH) levels increased from birth to 24 hours and then plateaued. The 25‐OHD levels at birth were 27.5±2.5 nmol/l and increased to 67.5±12.5 nmol/l (p<0.005) during the four days of the study. During the same period, the 1, 25(OH)2D serum levels increased steadily from 84<7 to 343<105 pmol/l (p<0.005). At all times, there was a positive correlation between 25‐OHD levels and those of 1, 25(OH)2D. Our data demonstrate that in preterm infants after 31 weeks of gestation, absorption and activation of vitamin D is present as soon as 24 hours after birth and that early neonatal hypocalcemia is unlikely to be caused by an impairment of either PTH secretion or vitamin D activation.

A simplified assay for serum 25-hydroxycalciferol

The measurement of serum 25-hydroxycalciferol (25-OH D) has proved to be a reliable index of the vitamin D nutritional status in man providing the renal 25-hydroxycalciferol-1 alpha-hydroxylase is functional. Since it is known that 25 OHD binds to alpha-globulins for its transport to the kidney, we have developed a competitive binding assay using an alpha-globulin enriched fraction (Cohns fraction IV) as the ligand protein. A detection limit of 0.1 ng 25-OHD/tube was achieved and the non specific binding amounted to less than 3% of the initial binding. The intra- and inter-assay variations were 8.9 and 8.4% respectively. The reference values (nmol/1 +/- 2 s.d.) obtained from samples of 40 children were 50.5 +/- 21.5 with extremes of 34.8 and 95.2. The method thus proved to be a reliable and sensitive tool to assess serum 25-OHD levels.

Human Neonatal Hypocalcemia

Hypocalcemia is commonly observed in the neonatal period and is usually transient from a few days to a few weeks. On only rare occasions is neonatal hypocalcemia permanent and secondary to congenital hypoparathyroidism caused by either isolated absence of parathyroid glands or in association with other malformations. Most cases of neonatal hypocalcemia fall into one of two clinical categories. Namely early neonatal hypocalcemia occurs in 24-48 h of life and it is usually observed in premature infants or infants of diabetic mothers. Late neonatal hypocalcemia is observed at the end of the first week of life. In addition of these two major categories, neonatal hypocalcemia may occur in association with hypomagnesemia.