Vitamin D status and its relation to age and body mass index

BACKGROUND/AIMS: While numerous studies have examined 25(OH)-vitamin D(3) (25-D) concentrations and their relation to parathyroid hormone (PTH) levels there is only limited information on the interrelation between 25-D, 1,25(OH)(2)-vitamin D(3) (1,25-D) and PTH. It was the aim of this study to assess the vitamin D endocrine system and its relation to age and body mass index (BMI). METHODS: This cross-sectional study comprised a convenience sample of 483 adults which attended the endocrinology outpatient service of a university hospital in the years 2002-2004. RESULTS: The mean concentrations of 25-D, 1,25-D, calcium and PTH were 21.0 +/- 10.6 ng/ml, 47.9 +/- 21.7 pg/ml, 9.48 +/- 0.48 mg/dl and 51.0 +/- 27.2 pg/ml, respectively. 25-D was related (p < 0.01) to BMI, age, PTH and 1,25-D. After correction for 25-D, we found no relation between BMI and 1,25-D. PTH was related (p < 0.01) to serum calcium, BMI, age and 1,25-D (p = 0015). There was a seasonal variation in both, 25-D and 1,25-D serum concentrations: 25-D levels were lowest in January and increased until July while the nadir and zenith of 1,25-D were found in April and October, respectively. CONCLUSION: Since BMI was negatively related to 25-D the prevalence of 25-D deficiency (<8.8 ng/ml) increased from 8.8% in subjects with BMI <30 kg/m(2) to 15.0% in subjects with BMI >30 kg/m(2). BMI, age and season should be taken into account when assessing a patients vitamin D status and more aggressive vitamin D supplementation should be considered for obese subjects.     

1,25-Dihydroxyvitamin D production after stimulation with synthetic human parathyroid hormone (1-34) in hypoparathyroid and renal tubular disorders

1,25-dihydroxyvitamin D production in response to two successive infusions of synthetic active 1-34 fragment of human PTH [hPTH-(1-34)] was evaluated in order to develop an understanding of the vitamin D metabolism and the rationale of vitamin D therapy in calcium disorders. Five normal controls, six hypoparathyroid patients, two patients with hypophosphatemic vitamin-D-resistant rickets, one patient with Lowe's synd. and one patient with primary Fanconi's synd. were investigated, and the following results were obtained. All normal controls showed a significant increase in serum 1,25(OH)2D[43 +/- 3.8 (m +/- SEM, n = 5, basal), 53 +/- 4.3 (three hours after the first PTH infusion), 65 +/- 7.7 (six hours) and 66 +/- 4.4 (nine hours) pg/ml]. All patients with PTH-deficient hypoparathyroidism showed a significant increase in serum 1,25(OH)2D, and serum 1,25(OH)2D values were within the normal range after hPTH-(1-34) stimulation. Serum 1,25(OH)2D remained low after hPTH-(1-34) infusions in a patient with pseudohypoparathyroidism type I who showed a significant increase in this value after infusion of dibutyryl cyclic AMP. On the other hand, a patient with normocalcemic pseudohypoparathyroidism type I had a high basal 1,25(OH)2D value, which increased further after hPTH-(1-34) infusions. An almost normal increase in serum 1,25(OH)2D was observed in two patients with hypophosphatemic vitamin-D-resistant rickets, one with Lowe's syndrome and the other with primary Franconi's syndrome. We conclude that these results ae important in obtaining an understanding of calcium and vitamin D metabolism in these disorders and that this PTH stimulation test is a useful method to use in evaluating renal responsiveness in 1,25(OH)2D production to PTH in various calcium disorders.     

Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system

The klotho gene encodes a novel type I membrane protein of beta-glycosidase family and is expressed principally in distal tubule cells of the kidney and choroid plexus in the brain. These mutants displayed abnormal calcium and phosphorus homeostasis together with increased serum 1,25-(OH)2D. In kl-/- mice at the age of 3 wk, elevated levels of serum calcium (10.9 +/- 0.31 mg/dl vs. 10.0 +/- 0.048 mg/dl in wild-type mice), phosphorus (14.7 +/- 1.1 mg/dl vs. 9.7 +/- 1.5 mg/dl in wild type) and most notably, 1,25-(OH)2D (403 +/- 99.7 mg/dl vs. 88.0 +/- 34.0 mg/dl in wild type) were observed.Reduction of serum 1,25-(OH)2D concentrations by dietary restriction resulted in alleviation of most of the phenotypes, suggesting that they are downstream events resulting from elevated 1,25-(OH)2D. We searched for the signals that lead to up-regulation of vitamin D activating enzymes. We examined the response of 1alpha-hydroxylase gene expression to calcium regulating hormones, such as PTH, calcitonin, and 1,25-(OH)2D3. These pathways were intact in klotho null mutant mice, suggesting the existence of alternate regulatory circuits. We also found that the administration of 1,25-(OH)2D3 induced the expression of klotho in the kidney. These observations suggest that klotho may participate in a negative regulatory circuit of the vitamin D endocrine system, through the regulation of 1alpha-hydroxylase gene expression.     

Serum osteocalcin levels do not change during rapidly induced hypercalcemia in healthy subjects.

Since osteocalcin has been suggested to play a role in calcium homeostasis, we investigated its serum levels in 6 healthy subjects during a rapid calcium infusion. Serum levels of intact parathyroid hormone (PTH), 25-hydroxyvitamin D [25-(OH) D3] and 1,25-dihydroxyvitamin D [1,25-(OH)2 D3] were also determined. The calcium infusion increased plasma-ionized calcium levels from 1.25 +/- 0.04 to 1.54 +/- 0.07 mmol/l at 30 min (p less than 0.05). Concomitantly, serum levels of intact PTH declined from 2.1 +/- 0.9 to 0.2 +/- 0.3 mmol/l (p less than 0.05). In contrast, serum osteocalcin levels did not change. Further, during calcium infusion, serum levels of 1,25-(OH)2 D3 decreased from 81 +/- 17 to 75 +/- 15 pmol/l (p less than 0.05) whereas serum levels of 25-(OH) D3 did not change. The results therefore suggest that calcium per se does not influence osteocalcin secretion.     

Decreased fractional urinary calcium excretion and serum 1,25-dihydroxyvitamin D and IGF-I levels in preeclampsia

During preeclampsia several alterations of calcium metabolism have been described, the most common of them is hypocalciuria, which pathophysiology is still unclear. In order to assess the contribution of calciotropic hormones to urinary calcium excretion, a cross-sectional study was done including 26 preeclamptic Mexican women (PE group) and 26 normotensive control pregnant women (NT group). Total and fractional urinary calcium excretion were significantly lower (P<0.0001) in the PE group than in the NT group (82+/-7 versus 171+/-7 mg/24h and 0.62+/-0.38 versus 1.38+/-0.71%, respectively), without significant differences in creatinine clearance, urinary sodium excretion and phosphate tubular reabsorption. In addition, serum 1,25-(OH)(2)D and IGF-I levels were significantly (P<0.05) lower in the PE than in NT group (43+/-9 versus 50+/-9 pg/mL and 195+/-67 versus 293+/-105 ng/mL, respectively), without significant differences in serum PTH levels. In the NT group, association analysis showed that total and fractional urinary calcium excretions positively correlated with serum levels of 1,25-(OH)(2)D (P<0.01) and IGF-I (P<0.001). In the PE group, total urinary calcium excretion positively correlated only with serum 1,25-(OH)(2)D (P<0.05). In conclusion, the results obtained in this study confirm that PE is associated with hypocalciuria and suggest that 1,25-(OH)(2)D and/or IGF-I may be involved in the regulation of urinary calcium excretion.     

Evidence for calcium-dependent control of 1,25-dihydroxyvitamin D3 production by rat kidney proximal tubules

The role of calcium in the parathyroid hormone-mediated increase in 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) production was evaluated using isolated proximal tubules from rats fed a low calcium diet (0.002% Ca) for 14 days. Tubules were prepared by collagenase digestion and centrifugation through Percoll. Tubules from rats fed a low calcium diet produced 1,25-(OH)2D3 at rates 10 times that of tubules from rats fed normal calcium diet (1.2% Ca). In vitro 1,25-(OH)2D3 biosynthesis was highly dependent upon extracellular calcium with inhibition in the absence of medium calcium and maximal production at 0.25 mM medium calcium (0.9 +/- 0.25 versus 15.1 +/- 2.3 nmol/mg protein/5 min, p less than 0.03). Inhibition of 1,25-(OH)2D3 production was partly due to depressed ATP content (0 versus 1.2 mM calcium, 6.8 +/- 0.6 versus 12.7 +/- 0.6 nmol/mg protein, p less than 0.006). EGTA reduced 1,25-(OH)2D3 synthesis and total cell calcium and ATP production. Ruthenium red blocked the inhibitory effects of EGTA on 1,25-(OH)2D3 production. Barium (1.0 mM) inhibited 1,25-(OH)2D3 production (7.2 +/- 0.5 versus 3.4 +/- 0.3, p less than 0.001) without altering ATP production. The calcium ionophore A23187 increased 1,25-(OH)2D3 production in a calcium-dependent manner. It is concluded that parathyroid hormone-mediated increases in 1,25-(OH)2D3 production, as during low calcium diet, require extracellular calcium. Extracellular calcium maintains mitochondrial calcium at optimal concentrations for normal ATP production, a requirement for 25-hydroxyvitamin D3-1-hydroxylase (25-OH-D3-1-hydroxylase) activity. Inhibition of 25-OH-D3-1-hydroxylase activity by barium without an alteration of ATP suggests calcium may also control 1,25-(OH)2D3 production independent of its effects on oxidative phosphorylation, perhaps through a direct interaction with one or more components of the 25-OH-D3-1-hydroxylase.     

Hypercalcemia in glucocorticoid withdrawal

We found severe hypercalcemia in the course of hydrocortisone withdrawal in a patient who had undergone unilateral adrenalectomy to resect a cortisol-hypersecreting adenoma. Serum calcium gradually but progressively increased after unilateral adrenalectomy. Severe hypercalcemia developed on the 77th postoperative day (the 15th day after discontinuing hydrocortisone replacement). The serum concentration of calcium, PTH, 25(OH)D, and 1,25(OH)2D were 8.0 mEq/l, less than 100 pg/ml, 10.1 ng/ml and 29.6 pg/ml, respectively. This hypercalcemia was accompanied by marked urinary hydroxyproline excretion and less calcium excretion in the urine than the prevailing level of serum calcium. Serum concentrations of 25(OH)D, 1,25(OH)2D and PTH were not elevated during the severe hypercalcemia. We concluded that the hypercalcemia in this patient was due in part to enhanced bone resorption and increased renal tubular reabsorption of calcium as a result of glucocorticoid withdrawal, but not to the elevation of serum PTH or serum 25(OH)D and serum 1,25(OH)2D.     

An acromegalic patient with recurrent urolithiasis

A 52-year-old man with an acromegalic appearance of prolonged duration suffered abdominal colic attacks and hematuria during the middle of the course of the disease. The patient was diagnosed as having urolithiasis caused by increased urinary calcium. The calcium metabolic disorder was not considered to be due to hyperparathyroidism because serum calcium and PTH levels were within the normal range and no abnormality was observed in a parathyroidal scintigraph. The serum 1,25-dihydroxyvitamin D (1,25-(OH)2D) levels (55.0 and 73.0 pg/ml) were higher than the normal range (27.2-53.8 pg/ml). A selective adenomectomy by the transsphenoidal route (Hardy's method) was performed, resulting in an improvement in the hypercalciuria and urolithiasis, and a decrease in the levels of serum 1,25-(OH)2D (23.0 and 23.0 pg/ml). These findings suggest that GH may promote the activation of vitamin D in the kidney in acromegaly, resulting in an acceleration of calcium absorption in the intestine through the action of activated vitamin D and the induction of increased urinary calcium excretion by the urinary excretion of excessive blood calcium.     

Calcitonin secretion during postnatal development in the rat: beta-adrenergic agents and vitamin D3 metabolites

The possible contribution of catecholamines and vitamin D3 metabolites to the high plasma calcitonin (CT) levels in suckling baby rats is unknown. So, in vivo and in vitro (using a perifusion system) effects of beta-adrenergic agents and vitamin D3 metabolites on CT release were studied in the rat during the postnatal development. In 13-day-old rats, the increase in plasma CT levels induced by isoproterenol injection (0.1 micrograms/kg b.w.) was inhibited by a previous administration of propranolol. A significant decrease in plasma CT levels was observed after propranolol injection in baby rats (0.68 +/- 0.05 ng/ml vs. 0.93 +/- 0.01 ng/ml). A daily injection of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3; 25 pmoles/rat/day during 4 days) induced a marked rise in plasma calcium (16.1 +/- 0.2 mg/dl), and a great decrease in thyroidal CT contents (approximately 70% of control values) in 13-day-old rats while no change was noted with 24,25-dihydroxycholecalciferol (24,25-(OH)2D3). A negative correlation between plasma calcium and thyroidal CT stores was found in suckling and in weaning rats treated with different doses of 1,25-(OH)2D3, suggesting an indirect effect of 1,25-(OH)2D3 on CT secretion. The mobilization of the thyroidal CT content was greater in weaning than in suckling rats in response to a given hypercalcemia. In vitro, 5 X 10(-5) M isoproterenol induced a rapid increase in CT secretion rate while 1,25-(OH)2D3 inhibited the rise in CT release induced by 3.0 mM calcium.(ABSTRACT TRUNCATED AT 250 WORDS)     

6-Fluoro-vitamin D3: a new antagonist of the biological actions of vitamin D3 and its metabolites which interacts with the intestinal receptor for 1 alpha,25(OH)2-vitamin D3

The biological activity and the binding affinity for the 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] intestinal receptor of a new fluorine-containing vitamin D compound, namely 6-fluoro-vitamin D3 (6-F-D3), is reported. A significant interaction of 6-F-D3 with the 1,25(OH)2D3 receptor was found, with a relative competitive index (RCI) of 0.26 +/- 0.04, which is intermediate between 25-hydroxyvitamin D3 (0.14 +/- 0.01) and 1 alpha-hydroxyvitamin D3 (0.46 +/- 0.08), where the RCI of 1,25(OH)2D3 is defined to be 100. In contrast, vitamin D3 was unable to interact with the 1,25(OH)2D3 receptor. Also, the biological activity of 6-F-D3 was assessed in vivo in the vitamin D-deficient chick. 6-F-D3 at doses up to 130 nmol displayed no biological action on either intestinal calcium absorption (ICA) or bone calcium mobilization (BCM) over the time interval of 14-48 h after dosing. However, when 130 nmol 6-F-D3 was given 2 h before and 6 h after vitamin D3 (1.62 nmol), a significant inhibition of vitamin D-mediated ICA was noted. Also, a dose of 130 nmol 6-F-D3 given 2 h before and 6 h after 1,25(OH)2D3 (0.26 nmol) significantly inhibited ICA, as measured at 12 h. 6-F-D3 is the first vitamin D analog found which has an ability to both bind to the 1,25(OH)2D3 receptor and to antagonize the production of biological responses by 1,25(OH)2D3.     

Which circulating level of 25-hydroxyvitamin D is appropriate?

Moderate Vitamin D deficiency causes secondary hyperparathyroidism and bone loss, leading to osteoporosis and fractures. Controversy exists which circulating level of 25-hydroxyvitamin D (25OH)D is appropriate. The high incidence of hip fractures at northern latitudes suggest a relationship with Vitamin D deficiency. However, international studies show lower serum 25(OH)D levels in southern than in northern Europe. Serum 25(OH)D was not a risk factor for hip fractures in several epidemiological studies. The required serum 25(OH)D is usually established by assessing the point where serum parathyroid hormone (PTH) starts to rise. This point varied in several studies between 30 and 78 nmol/l. However, interlaboratory variation may also influence the apparent required serum 25(OH)D level. Dietary calcium intake influences serum PTH and serum PTH may influence the turnover of Vitamin D metabolites. A low calcium intake causes an increase of serum PTH and serum 1,25(OH)2D thereby decreasing the half life of serum 25(OH)D. While a low calcium intake may aggravate Vitamin D deficiency, a high calcium intake may have a Vitamin D sparing effect. With current knowledge, a global estimate for the appropriate serum 25(OH)D is 50 nmol/l.     

Vitamin D and calcium dysregulation in the polycystic ovarian syndrome.

Over the past 30 years, numerous studies in invertebrates and vertebrates have established a role of calcium in oocyte maturation as well as in the resumption and progression of follicular development. Polycystic ovarian syndrome (PCO) is characterized by hyperandrogenic chronic anovulation, theca cell hyperplasia, and arrested follicular development. The aim of this observational study was to determine whether vitamin D and calcium dysregulation contribute to the development of follicular arrest in women with PCO, resulting in reproductive and menstrual dysfunction. Thirteen premenopausal women (mean age 31 +/- 7.9 years) with documented chronic anovulation and hyperandrogenism were evaluated. Four women were amenorrheic and nine had a history oligomenorrhea, two of whom had dysfunctional bleeding. Nine had abnormal pelvic sonograms with multiple ovarian follicular cysts. All were hirsute, two had alopecia, and five had acanthosis nigricans. The mean 25 hydrovitamin D was 11.2 +/- 6.9 ng/ml [normal (nl): 9-52], and the mean 1,25 dihydroxyvitamin D was 45.8 +/- 18 pg/ml. with one woman with a 1,25 dihydroxyvitamin D <5 pg/ml (nl: 15-60). The mean intact parathyroid hormone level was 47 +/- 19 pg/ml (nl: 10-65), with five women with abnormally elevated parathyroid hormone levels. All were normocalcemic (9.3 +/- 0.4 mg/dl). Vitamin D repletion with calcium therapy resulted in normalized menstrual cycles within 2 months for seven women, with two experiencing resolution of their dysfunctional bleeding. Two became pregnant, and the other four patients maintained normal menstrual cycles. These data suggest that abnormalities in calcium homeostasis may be responsible, in part, for the arrested follicular development in women with PCO and may contribute to the pathogenesis of PCO.     

Role of calcium and cAMP in heterologous up-regulation of the 1,25-dihydroxyvitamin D3 receptor in an osteoblast cell line.

To understand further the mechanism of action of parathyroid hormone (PTH) in the stimulation of the number of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) binding sites in UMR 106-01 cells we studied the role of cAMP and calcium. In addition to PTH other agents known to act via the cAMP signal pathway, prostaglandin E2, forskolin and dibutyryl cAMP, caused an increase in 1,25(OH)2D3 binding. Addition of the adenylate cyclase inhibitor 9-(tetrahydro-2-furyl)adenine resulted in a marked decrease of PTH-stimulated cAMP production but this was not followed by a reduction of 1,25(OH)2D3 receptor up-regulation by PTH. Increasing the intracellular calcium concentration by Bay K 8644 and A23817 independent of an activation of the cAMP signal pathway did not result in an increased 1,25(OH)2D3 binding. The calcium channel blockers nitrendipine and verapamil and chelating extracellular calcium with EGTA all reduced cAMP-mediated stimulation of 1,25(OH)2D3 binding. This reduction was not due to a reduce cAMP production as verapamil even potentiated PTH- and forskolin-stimulated cAMP production in a dose-dependent manner. The present study provides evidence for an interrelated action of calcium and cAMP in the heterologous up-regulation of the 1,25(OH)2D3 receptor. The current data show an interaction between the cAMP and calcium signal pathway at (1) the level of cAMP generation/degradation, and (2) a level located distal in the cascade leading to 1,25(OH)2D3 receptor up-regulation.     

Serum concentrations of calcitonin and parathormone in the cord blood of premature infants

Determinations of serum calcium (Ca), calcitonin (CT) and parathyroid hormone (PTH) were carried out in mixed cord blood of 23 preterm infants. Gestational age ranged between 25 and 37 weeks. 17 of theme were vaginally delivered while 6 were delivered by emergency Caesarean section. 4 neonates died because of respiratory distress syndrome. The serum was stored at -30 degrees C until the determinations. Serum Ca levels were determined by spectrophotometry while CT and PTH levels by RIA (Immuno Nuclear Co). In cord serum the mean (M +/- SE) Ca,CT and PTH concentrations of all neonates examined were respectively: 9,9 +/- 0,6 mg/dl; 176 +/- 44 pg/ml and 1100 +/- 446 pg/ml. Serum values of CT and PTH in preterm newborns delivered by emergency Caesarean section were significantly higher than in those neonates vaginally delivered (CT: 302 +/- 115 vs 94 +/- 9 pg/ml; p less than 0.005) (PTH:2655 +/- 1857 vs 466 +/- 59 pg/ml; p less than 0.05). No differences were observed between serum CT and PTH levels in preterm neonates of different gestational age. Both CT and PTH serum concentrations were higher in neonates who died. In conclusion, the preterm neonate is able to secrete both peptides and to maintain Ca homeostasis; the mode of delivery likely affects the CT and PTH secretion; unexplainable high CT and PTH serum levels were detected in poor outcome preterm infants.     

Peripheral effects of PTH are not altered after thyroid surgery in euthyroid patients

BACKGROUND: We have previously found decreased serum levels of both ionized calcium and 1,25(OH)2D and an increase in serum phosphate levels at 1 year after hemithyroidectomy. However, basal and stimulated parathyroid hormone (PTH) secretions were not altered. To investigate whether the observed biochemical changes after unilateral thyroid surgery may be due to a relative end-organ resistance to PTH, we studied the peripheral effects of infused hPTH-(1-34) in 6 patients preoperatively and 3 months after hemithyroidectomy. METHODS: Serum levels of TSH, FT4 and FT3 were measured pre- and postoperatively. hPTH-(1-34) was infused at 0.9 IU/kg/h during 6 h. Blood samples for analysis of ionized calcium, intact PTH, phosphate, 25(OH)D, 1,25(OH)2D and urinary samples for calcium, phosphate and nephrogenous(n)-cAMP analysis were taken at baseline, when the infusion was discontinued after 6 h and at 24 h. RESULTS: Three months after hemithyroidectomy, serum levels of FT3 were decreased and TSH levels increased. Pre- and postoperative hPTH-(1-34) infusions induced increased serum levels of ionized calcium, 1,25(OH)2D, increased urinary excretion of phosphate and elevated n-cAMP levels. The changes in the studied biochemical variables during the hPTH-(1-34) infusions did not differ between the two study occasions. CONCLUSION: By using a 6-hour hPTH-(1-34) infusion protocol, we have shown that the peripheral PTH effect is not altered by a slight reduction in thyroid hormone levels at 3 months after hemithyroidectomy.     

24,25(OH)2D3 attenuates the calcemic effect of 1,25(OH)2D3 in rats with reduced renal mass

The present study was undertaken to evaluate the effect of 24,25(OH)2D3 on serum calcium concentration in rats with reduced renal mass. Adult 5/6 nephrectomized male rats were divided into four groups: (i) control rats, (ii) rats treated with 1,25(OH)2D3, (iii) rats treated with 24,25(OH)2D3, and (iv) rats treated with 1,25(OH)2D3 and 24,25(OH)2D3. After 4 days, serum calcium in the 1,25(OH)2D3-treated group was 7.13 +/- 0.32 meq/liter (P less than 0.001 vs control). With the combination of 1,25(OH)2D3 and 24,25(OH)2D3 serum calcium was higher than that in control, 6.25 +/- 0.5 meq/liter (P less than 0.001 vs control), but lower than that in rats receiving 1,25(OH)2D3 alone (P less than 0.05). No change in serum calcium was seen in animals treated with 24,25(OH)2D3 alone. On the eighth day serum calcium in the 1,25(OH)2D3-treated group, 6.52 +/- 0.25, was higher than in the 1,25(OH)2D3 + 24,25(OH)2D3 group, 5.87 +/- 0.17 meq/liter, P less than 0.05, P less than 0.001 vs control. In both 1,25(OH)2D3- and 1,25(OH)2D3 + 24,25(OH)2D3-treated rats, hypercalciuria of similar magnitude occurred on the fourth and eighth day of treatment. No change in urinary calcium was seen in the control and 24,25(OH)2D3-treated rats. Thus, in 5/6 nephrectomized rats combined administration of 1,25(OH)2D3 and 24,25(OH)2D3 attenuates the calcemic response to 1,25(OH)2D3 without changes in urinary calcium excretion. These observations suggest that the effect of 24,25(OH)2D3 on serum calcium is different in 5/6 nephrectomized rats as compared to normal rats, in which an augmentation of serum calcium was observed following administration of both vitamin D metabolites. The effect of 24,25(OH)2D3 on serum calcium in rats with reduced renal mass may result from a direct effect of 24,25(OH)2D3 on the bone.     

Effect of dietary calcium, phosphate and vitamin D deprivation on the pharmacokinetics of 1,25-dihydroxyvitamin D3 in the rat

The in vivo regulation of circulating 1,25(OH)2D3 concentrations by vitamin D status and by dietary calcium and phosphate deficiency was studied. Adult rats were cannulated in the jugular vein and the clearance of physiological doses of 1,25(OH)2D3 monitored. In vitamin D-replete rats we investigated the effects of dietary calcium and phosphate deficiency on the elimination half life of 1,25(OH)2D3 The results showed no effect of dietary phosphate deficiency on the elimination half life of 1,25(OH)2D3. Dietary calcium deficiency resulted in a small increase of the 1,25(OH)2D3 elimination half life (P = 0.04) (normal diet: 16.3 +/- 1.8 hrs, n = 6; -Ca diet: 18.6 +/- 1.1 hrs, n = 5; -P diet: 16.0 +/- 1.4 hrs, n = 6; mean +/- SD). The experiments with the vitamin D deficient rats showed a marked increase in the elimination half life of 1,25(OH)2D3 (36.4 +/- 6.8 hrs, n = 7), when compared to the rats on the normal diet (P = 0.001). From the experiments in the vitamin D replete rats one can infer that regulation of circulating 1,25(OH)2D3 concentrations by dietary calcium or phosphate takes place at the production site and not by changes in elimination rate. However, vitamin D status appears to regulate circulating 1,25(OH)2D3 concentrations also through an effect on the elimination rate.     

Regulation of renal vitamin D receptor is an important determinant of 1alpha,25-dihydroxyvitamin D(3) levels in vivo

The synthesis of 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) is most strongly regulated by dietary calcium and the action of parathyroid hormone to increase 1alpha-hydroxylase (1alpha-OHase) and decrease 24-hydroxylase (24-OHase) in kidney proximal tubules. This study examines the hypothesis that 1,25-(OH)(2)D(3) synthesis, induced by dietary calcium restriction, is also the result of negative feedback regulation blockade. Rats fed a low calcium (0.02%, -Ca) diet and given daily oral doses of vitamin D (0, 0.5, 1.0, 2.0, 4.0, 8.0, and 16.0 microg) remained hypocalcemic despite increasing levels of serum calcium in relation to the vitamin D dose. Plasma levels of 1,25-(OH)(2)D(3) rose to high levels (1200 pg/ml) at the high vitamin D dose levels. As expected, thyroparathyroidectomy caused a rapid fall in serum 1,25-(OH)(2)D(3). In rats fed a 0.47% calcium diet (+Ca) supplemented with vitamin D (4 microg/day), exogenous 1,25-(OH)(2)D(3) suppressed renal 1alpha-OHase and stimulated the 24-OHase. In rats fed the -Ca diet, vitamin D was unable to suppress the renal 1alpha-OHase or stimulate the renal 24-OHase. In contrast, vitamin D was fully able to stimulate intestinal 24-OHase. Intestinal vitamin D receptor (VDR) was present under all circumstances, while kidney VDR was absent under hypocalcemic conditions and present under normocalcemic conditions. It appears that tissue-specific down-regulation of VDR by hypocalcemia blocks the 1,25-(OH)(2)D(3) suppression of the 1alpha-OHase and upregulation of the 24-OHase in the kidney, causing a marked accumulation of 1,25-(OH)(2)D(3) in the plasma.     

Reduced Parathyroid Hormone-Stimulated 1,25-Dihydroxyvitamin D Production in Vitamin D Sufficient Postmenoposual Women with Low Bone Mass and Idiopathic Secondary Hyperparathyroidism

ObjectiveDistinguishing secondary hyperparathyroidism (sHPT) from eucalcemic primary hyperparathyroidism (EC-pHPT) is important. The objective of this study was to measure parathyroid hormone (PTH)-stimulated production of 1α,25-dihydroxyvitamin D (1,25[OH]₂D) in early postmenopausal patients with idiopathic sHPT, who also fit the criteria for EC-pHPT, compared to age-matched controls.MethodsIn this pilot case-control study, postmenopausal women aged 44 to 55 years with normal serum calcium (Ca), glomerular filtration rate (GFR) ≥65 mL/min, and 25-hydroxyvitamin D (25[OH]D) ≥75 nmol/L (30 ng/mL) were given an 8 hour infusion of PTH(1-34), 12 pmol/kg/h. Patients (n = 5) had elevated PTH, normal 1,25(OH)₂D, and no hypercalciuria. Controls (n = 5) had normal PTH. At baseline, 4, and 8 hours, serum Ca, creatinine (Cr), phosphorus (P), 1,25(OH)₂D, fibroblast growth factor (FGF23), and 24,25(OH)₂D as well as urine Ca, P, Cr, and cAMP/GFR were measured. The fractional excretion of calcium (FeCa) and tubular reabsorption of phosphorus (TMP)/GFR were calculated.ResultsPatients had lower 1,25(OH)₂D levels (± SD) than controls at 4 (39.8 ± 6.9 versus 58.8 ± 6.7; P = .002) and 8 hours (56.4 ± 9.2 versus 105 ± 2.3; P = .003) of PTH infusion, attenuated after adjusting for higher body mass index (BMI) in patients (P = .05, .04), respectively. The 24,25(OH)2D levels were lower in patients than controls (1.9 ± 0.6 versus 3.4 ± 0.6, respectively; P = .007). No differences were seen in serum Ca or P, urine cAMP/GFR, TRP/GFR, FeCa, or PTH suppression at 8 hours (patients 50%, controls 64%).ConclusionVitamin D sufficient patients who fit the criteria for EC-pHPT had reduced PTH-stimulated 1,25(OH)₂D compared to controls, partially attributable to their higher BMI. Other causes of reduced 1,25(OH)₂D production ruled out were excessive catabolism of vitamin D metabolites, elevated FGF23, and CYP27B1 mutation. Elevated BMI and idiopathic reduced PTH-stimulated 1,25(OH)₂D production should be considered in the differential of sHPT. (Endocr Pract. 2013;19:91-99)