Effects of vitamin D supplementation on calcium balance and bone growth in young rats fed normal or low calcium diet

OBJECTIVE: We examined the effect of vitamin D supplementation on bone growth in young rats fed a normal or low calcium diet. METHODS: Fifty female Sprague-Dawley rats, 6 weeks of age, were randomized by stratified weight method into five groups with 10 rats in each group: baseline control, 0.5% (normal) or 0.1% (low) calcium diet, and 0.5 or 0.1% calcium diet + vitamin D (25 microg/100 g, food intake). Duration of the experiment was 10 weeks. RESULTS: Vitamin D supplementation stimulated intestinal calcium absorption and increased urinary calcium excretion in rats fed a low or normal calcium diet. Vitamin D supplementation prevented the reduction in periosteal bone gain but enhanced enlargement of the marrow cavity and reduced the maturation-related cancellous bone gain in rats fed a low calcium diet, and increased the maturation-related cancellous and cortical bone gains in rats fed a normal calcium diet. CONCLUSION: This study shows the differential effects of vitamin D supplementation on born growth in young rats fed a normal or low calcium diet.     

Effects of vitamin K2 administration on calcium balance and bone mass in young rats fed normal or low calcium diet

OBJECTIVE: The purpose of this study was to examine the effects of vitamin K2 administration on calcium balance and bone mass in young rats fed a normal or low calcium diet. METHODS: Forty female Sprague-Dawley rats, 6 weeks of age, were randomized by stratified weight method into four groups with 10 rats in each group: 0.5% (normal) calcium diet, 0.1% (low) calcium diet, 0.5% calcium diet + vitamin K2 (menatetrenone, 30 mg/100 g chow diet), and 0.1% calcium diet + vitamin K2. After 10 weeks of feeding, serum calcium and calciotropic hormone levels were measured, and intestinal calcium absorption and renal calcium reabsorption were evaluated. Bone histomorphometric analyses were performed on cortical bone of the tibial shaft and cancellous bone of the proximal tibia. RESULTS: Feeding a low calcium diet induced hypocalcemia, increased serum parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels with decreased serum 25-hydrovyvitamin D [25(OH)D] level, stimulated intestinal calcium absorption and renal calcium reabsorption, and reduced cortical bone mass as a result of decreased periosteal bone gain and enlarged marrow cavity, but did not significantly influence cancellous bone mass. Vitamin K2 administration in rats fed a low calcium diet stimulated renal calcium reabsorption, retarded the abnormal elevation of serum PTH level, increased cancellous bone mass, and retarded cortical bone loss, while vitamin K2 administration in rats fed a normal calcium diet stimulated intestinal calcium absorption by increasing serum 1,25(OH)2D level, and increased cortical bone mass. CONCLUSION: This study clearly shows the differential response of calcium balance and bone mass to vitamin K2 administration in rats fed a normal or low calcium diet.     

Effect of dietary cholecalciferol deficiency on plasma thyroid hormone concentrations in rainbow trout,Salmo gairdneri (Pisces,Salmonidae)

Synopsis Diets deficient in vitamin D effected a significant increase in plasma triiodothyronine (T3) concentration in raibow trout (Salmo gairdneri); different levels of dietary calcium exerted no effect on plasma T3 levels. These effects of vitamin D deficiency on plasma T3 levels appeared to be reversible, vitamin D supplementation after a period of vitamin D deficiency lowered T3 levels. Vitamin D3, vitamin D2 and the metabolites 25(OH)-D3 and 1, 25(OH)₂D3 were all effective in lowering plasma T3 levels; vitamin D3 appeared to be more effective than vitamin D₂. There appeared to be a correlation between weight gain and plasma T3 concentration in the groups fed different types and levels of vitamin D supplementation suggesting that the increased T3 levels may be a compensatory increase to the reduced weight gain of the vitamin D deficient fish. Plasma T4 levels were not affected by dietary vitamin D deficiency.     

维生素D与PTH相关性研究进展

维生素D是人体必需的一种脂溶性营养素,随着科学技术不断进步,维生素D对人类健康的作用逐渐被发现。已有研究表明,维生素D不仅与多种骨代谢相关疾病有关,并与心血管疾病、代谢综合征、感染、肿瘤、自身免疫疾病等关系密切。在骨代谢方面,维生素D的缺乏可能会导致软骨病、佝偻病、骨质疏松症,甚至会导致急性跌倒事件的发生和骨折的形成,而甲状旁腺激素(PTH)是骨代谢过程中的关键分子。本文综述了维生素D代谢过程及维生素D受体多样性及维生素D与甲状旁腺激素(PTH)相关性,以便有助于探究维生素D与骨代谢之间的关系。     

Vitamin D in healthy Tunisian population: Preliminary results

BackgroundVitamin D deficiency is one of the most common medical conditions worldwide. In Tunisia, several studies evaluated Vitamin D status, but this was concerning specific populations (pregnant women, obese or diabetic patients and children with asthma). The only study that evaluated Vitamin D status in a healthy Tunisian population was conducted by Meddeb and associeties in 2002. The update of data available, based on the currently recommended limits, is necessary. This study aimed to estimate the prevalence of hypovitaminosis D in a healthy Tunisian population, and correlate the values with potential risk factors.MethodsIt was conducted on 209 Tunisian healthy subjects. Data collected included clinical characteristics and dietary intakes. We measured 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), glycemia, creatinine, calcium, phosphorus, and alkaline phosphatase concentrations. Hypovitaminosis D was retained for 25(OH)D concentrations <75 nmol/L. Vitamin D deficiency was defined by 25(OH)D concentrations <25 nmol/L.ResultsThe prevalence of hypovitaminosis D and vitamin D deficiency were respectively 92.3% and 47.6%. The main factors that were significantly associated with low vitamin D levels in our multivariate analysis were veiling, living in rural areas and sunscreen use. However, sex, age, socioeconomic level, phototype, solar exposure score, smoking and bone mass index, were not statistically associated with hypovitaminosis D. The study of relationship between vitamin D status and serum PTH levels showed a significative and negative correlation (P < 0.005).ConclusionsGiven the high prevalence of vitamin D, an adapted health policy is essential. A widespread vitamin D supplementation and food fortification seems to be necessary in Tunisia.     

Role of acidosis-induced increases in calcium on PTH secretion in acute metabolic and respiratory acidosis in the dog

Recently, we showed that both acute metabolic acidosis and respiratory acidosis stimulate parathyroid hormone (PTH) secretion in the dog. To evaluate the specific effect of acidosis, ionized calcium (iCa) was clamped at a normal value. Because iCa values normally increase during acute acidosis, we now have studied the PTH response to acute metabolic and respiratory acidosis in dogs in which the iCa concentration was allowed to increase (nonclamped) compared with dogs with a normal iCa concentration (clamped). Five groups of dogs were studied: control, metabolic (clamped and nonclamped), and respiratory (clamped and nonclamped) acidosis. Metabolic (HCl infusion) and respiratory (hypoventilation) acidosis was progressively induced during 60 min. In the two clamped groups, iCa was maintained at a normal value with an EDTA infusion. Both metabolic and respiratory acidosis increased (P < 0.05) iCa values in nonclamped groups. In metabolic acidosis, the increase in iCa was progressive and greater (P < 0.05) than in respiratory acidosis, in which iCa increased by 0.04 mM and then remained constant despite further pH reductions. The increase in PTH values was greater (P < 0.05) in clamped than in nonclamped groups (metabolic and respiratory acidosis). In the nonclamped metabolic acidosis group, PTH values first increased and then decreased from peak values when iCa increased by > 0.1 mM. In the nonclamped respiratory acidosis group, PTH values exceeded (P < 0.05) baseline values only after iCa values stopped increasing at a pH of 7.30. For the same increase in iCa in the nonclamped groups, PTH values increased more in metabolic acidosis. In conclusion, 1) both metabolic acidosis and respiratory acidosis stimulate PTH secretion; 2) the physiological increase in the iCa concentration during the induction of metabolic and respiratory acidosis reduces the magnitude of the PTH increase; 3) in metabolic acidosis, the increase in the iCa concentration can be of sufficient magnitude to reverse the increase in PTH values; and 4) for the same degree of acidosis-induced hypercalcemia, the increase in PTH values is greater in metabolic than in respiratory acidosis.     

Renal clearance of phosphate and calcium in vitamin D-deficient chicks: effect of calcium loading, parathyroidectomy, and parathyroid hormone administration.

Serum and renal clearance values of phosphate and calcium were measured and compared in 4 week-old vitamin D-deficient and vitamin D-replete chickens (Gallus gallus). D-deficient chicks had significantly lower body weights and serum calcium values; however, their renal functions were not different from D-replete controls. Serum calcium values in D-deficient birds did not change in response to parathyroid hormone (PTH) administration; however, they did drop significantly in response to parathyroidectomy (PTX). Serum phosphate values of D-deficient birds, but not D-replete birds, rose significantly after PTX. Clearance of phosphate is known to increase after administration of PTH. This conspicuous effect was absent in PTH-injected vitamin D-deficient chickens. PTX caused the excretion of phosphate to drop in both D-deficient and D-replete birds to near zero. Conversely, PTX of both D-deficient and D-replete chickens stimulated the excretion of more calcium than in controls. Calcium loading elevates the fractional excretion of calcium in both D-deficient and D-replete birds. It also causes a decrease in phosphate excretion in both groups, presumably by inhibiting the secretion of PTH. PTH administration to D-replete, calcium-loaded birds caused increased phosphate excretion (as it did in normal controls), an effect that was not seen in similarly treated D-deficient birds. Therefore, most renal functions studied after calcium loading, PTH administration, or PTX are not altered by vitamin D deficiency in the chicken. The major significant finding is that vitamin D-deficient chickens do not excrete increased amounts of phosphate in response to PTH stimulus.     

Klotho lacks a vitamin D independent physiological role in glucose homeostasis, bone turnover, and steady-state PTH secretion in vivo

Apart from its function as co-receptor for fibroblast growth factor-23 (FGF23), Klotho is thought to regulate insulin signaling, intracellular oxidative stress, and parathyroid hormone (PTH) secretion in an FGF23 independent fashion. Here, we crossed Klotho deficient (Kl^−/−) mice with vitamin D receptor (VDR) mutant mice to examine further vitamin D independent functions of Klotho. All mice were fed a rescue diet enriched with calcium, phosphorus, and lactose to prevent hyperparathyroidism in VDR mutants, and were killed at 4 weeks of age after double fluorochrome labeling. Kl^−/− mice displayed hypercalcemia, hyperphosphatemia, dwarfism, organ atrophy, azotemia, pulmonary emphysema, and osteomalacia. In addition, glucose and insulin tolerance tests revealed hypoglycemia and profoundly increased peripheral insulin sensitivity in Kl^−/− mice. Compound mutants were normocalcemic and normophosphatemic, did not show premature aging or organ atrophy, and were phenocopies of VDR mutant mice in terms of body weight, bone mineral density, bone metabolism, serum calcium, serum phosphate, serum PTH, gene expression in parathyroid glands, as well as urinary calcium and phosphate excretion. Furthermore, ablation of vitamin D signaling in double mutants completely normalized glucose and insulin tolerance, indicating that Klotho has no vitamin D independent effects on insulin signaling. Histomorphometry of pancreas islets showed similar beta cell volume per body weight in all groups of animals. In conclusion, our findings cast doubt on a physiologically relevant vitamin D and Fgf23 independent function of Klotho in the regulation of glucose metabolism, bone turnover, and steady-state PTH secretion in vivo.     

Pathophysiology of primary hyperparathyroidism

Parathyroid gland is the overall regulatory organ within the systemic calcium homeostasis. Through cell surface bound calcium-sensing receptors external calcium inversely regulates release of parathyroid hormone (PTH). This mechanism, which is voltage independent and most sensitive around physiologic calcium concentrations, is regulated through a 120 kDa calcium sensing receptor, CaR. Inherited inactivation of this receptor is the cause for familial hypocalciuric hypercalcemia (FHH). Parallel research identified the 550 kDa glycoprotein megalin, which also is expressed on the parathyroid cell surface, as another potential calcium sensing protein. Although this protein expresses numerous calcium binding sites on its external domain, its main function may be calcium sensitive binding and uptake of steroid hormones, such as 25-OH-vitamin D3 (bound to vitamin D binding protein) and retinol. In hyperparathyroidism (HPT), excessive PTH is secreted and the calcium sensitivity of the cells reduced, i.e. the set-point, defined as the external calcium concentration at which half-maximal inhibition of PTH release occurs, shifted to the right. Pathological cells have reduced expression of both CaR and megalin, and reduced amount of intracellular lipids, possibly including stored steroid hormones. A number of possible genetic disturbances have been identified, indicating multifactorial reasons for the disease. In postmenopausal women, however, the individual group with highest incidence of disease, a causal relation to reduced effect of vitamin D is possible. An incipient renal insufficiency with age, lack of sunshine in the Northern Hemisphere, and an association to the baT haplotype of the vitamin D receptor supports this theory. This review summarizes data on regulation of PTH release, dysregulation in HPT, as well as proliferation of parathyroid cells.     

Vitamin D Deficiency Among Medical Residents and Its Relationship with Metabolic Indices

ObjectiveTo evaluate different elements of the cal- ciotropic system in a group of house staff physicians, comparing them with age, gender, and body mass index (BMI) matched controls.MethodsWe measured vitamin D, calcium, phosphorus, parathyroid hormone (PTH), glucose, insulin (estimating the insulin resistance index by the homeostatic model [HOMA]), and lipid levels in 20 medical residents and 20 age-, gender-, and BMI-matched controls. We looked for correlations between elements of the calciotropic system and metabolic indices.ResultsMedical residents and controls were similar in regard to gender distribution, weight, height, BMI, abdominal circumference, as well as systolic and diastolic blood pressure. No differences were found between the two groups in regard to low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, plasma insulin levels, and HOMA-IR. Vitamin D and calcium levels were significantly lower among the medical residents (P = .001 and P = .003, respectively), whereas PTH concentrations tended to be higher. We found an inverse correlation between triglyceride concentrations and vitamin D (r = −0.31, P = .04).ConclusionVitamin D deficiency among resident physicians is frequent and could have metabolic effects. Our findings highlight the consequences of the lack of sun exposure due to occupational reasons. We recommend a higher intake of vitamin D during this period. (Endocr Pract. 2013;19:59-63)     

An investigation into a possible relationship between vitamin D, parathyroid hormone, calcium and magnesium in a normally pigmented and an albino rural black population in the Northern Province of South Africa

Vitamin D levels are important in the management of patients with various disorders of calcium metabolism associated with rickets, osteomalacia, osteodystrophy osteoporosis and hypoparathyroidism. 82 albinos and 58 normally pigmented children resident at the Siloe School for the Visually Impaired were sampled. Blood samples of fasting subjects were collected over a two-day period and analyzed for vitamin D, parathyroid hormone, plasma calcium and both plasma and red blood cell magnesium measurements. The height and weight of each subject was also recorded. The results are discussed in relation to the different skin pigmented groups, for specific age groups, sex and visual status. Statistical outliers were excluded from the results. It appears that the Albino group has significantly (p = 0.06) higher vitamin D levels against the background of a similar dietary intake and similar exposure to sunlight/day length. Thus black children/subjects require a significantly higher intake of vitamin D to attain the same level as their Albino counterparts. In spite of significantly higher vit D levels, the other homeostatic control mechanisms were not altered (i.e., PTH levels are similar in both groups). This study supports the postulate that a dark complexion predisposes to sub-optimal vit D status.     

Tibial Tenderness Identifies Secondary Hyperparathyroidism Responding to High-Dose Vitamin D in Pakistani Women

ObjectiveTo assess the utility of anterior tibial tenderness (ATT) measured by visual analogue scoring (VAS) as a clinical diagnostic tool for vitamin D deficiency in a high-risk population of Pakistani women.MethodsATT was measured by VAS in 75 premenopausal women age 17 to 56 years (mean, 41.3 years) with generalized aches and pains and calcium <11 mg/dL (normal, 8 to 11 mg/dL) who were seen at a tertiary care center in Lahore, Pakistan. This was followed by administration of 1.8 million units of vitamin D3 in divided doses. ATT, vitamin D, and parathyroid hormone (PTH) levels were checked before and after the injections. Correlation between ATT, vitamin D, and PTH, as well as changes in ATT, vitamin D, and PTH following supplementation were determined.ResultsPre-intervention average calcium and vitamin D were 9.3 mg/dL (range, 8 to 10.3 mg/dL) and 12.1 ng/mL (range, 1.5 to 32.6 ng/mL), respectively. Seventy-four percent of the participants (53/75) had vitamin D deficiency and elevated PTH (>60 pg/mL). Mean PTH was 81.6 pg/mL (range, 29.1 to 370 pg/mL). Changes in ATT correlated strongly (r = 0.422; P = .013) with changes in PTH. Following supplementation, there was significant improvement in ATT (P<.01) and vitamin D level (P<.01), with a decrease in PTH level (P<.01).ConclusionATT is a valid clinical diagnostic measure of vitamin D deficiency in South Asian women. (Endocr Pract. 2013;19:596-601)     

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.     

1,25-Dihydroxyvitamin D3 has opposite effects on the expression of parathyroid secretory protein and parathyroid hormone genes

Previous studies have shown that 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] decreases levels of mRNA for prepro-PTH as well as PTH secretion after chronic exposure (24-48 h) of parathyroid cells in tissue culture. We have now extended these studies to determine the effects of the vitamin D3 metabolite on parathyroid secretory protein (PSP) gene expression. Primary cultures of bovine parathyroid cells were incubated with 10(-8) M 1,25-(OH)2D3 for periods of time ranging from 24-72 h. As observed in earlier experiments, prepro-PTH mRNA decreased to less than 50% of the control value after 72 h. In marked contrast, PSP mRNA showed a 2.5-fold increase by 24 h and greater than 7-fold stimulation by 72 h. In the same studies, PTH secretion was suppressed (to 60% of control), while PSP secretion was increased by 40% over control values. Exposure to high (2.5 mM) or low (0.5 mM) calcium had no effect on PSP mRNA, even though low calcium stimulated the secretion of PSP while high calcium suppressed secretion. These studies showed that 1,25-(OH)2D3 has opposite effects on the gene expression of PSP and PTH in bovine parathyroid cells in tissue culture.     

THE MODE OF ACTION OF VITAMIN D

1. The purpose of this review article is to re-evaluate and integrate many of the observations related to the physiological effects of vitamin D, using as a working hypothesis the concept that the vitamin may be acting analogously to a steroid hormone in terms of its ability to interact with genetic information and ultimately elicit a physiological response. Prior to this time the problem of the mechanism of action of vitamin D has primarily been approached from the point of view that the vitamin was acting as a cofactor for some specific enzymic reaction. 2. The physiological activities of vitamin D are integrated with those of parathyroid hormone to provide a homeostatic control for the regulation of primarily calcium and secondarily phosphate metabolism. It is proposed that the role of vitamin D in this homeostatic control mechanism is older and more fundamental than that of parathyroid hormone. The interaction of vitamin D on skeletal calcium metabolism may have evolved before the effects of the vitamin on intestinal calcium absorption. 3. There are several physiological defects of calcium metabolism—rickets, osteo-malacia, vitamin D-resistant rickets and idiopathic hypercalcaemia—all of which may be a consequence of an aberration in one or another of the interlocking steps of the vitamin D-dependent and calcium-dependent homeostatic control mechanism. 4. The most thoroughly established action of vitamin D in vivo is to promote or facilitate the intestinal absorption of calcium. Although the exact biochemical details of this process are not available, this may involve vitamin D-mediated synthesis of the appropriate enzyme systems or the alteration of membrane structure necessary for calcium absorption. It is not yet unequivocally established whether calcium absorption is an energy-dependent active transport process or is a passive carrier-mediated or simple diffusion process. 5. The exact action of vitamin D on bone metabolism is not as well established, but the primary effect of the vitamin is likely to mediate bone resorption. The vitamin D-dependent activities of the cell in both the intestine and bone are to absorb calcium and transfer it to the blood. 6. No direct effects of vitamin D on intestinal absorption of phosphate have been found. Furthermore the validity of a vitamin D-mediated renal reabsorption of phosphate is questioned, for the major effects of vitamin D are cation oriented. If the renal effects of vitamin D are true, it is postulated that the mechanism of action of the vitamin here on the anion, phosphate, is fundamentally different from its cation oriented mechanism. 7. There is a lag in the action of vitamin D on the vitamin mediated: (a) transport of calcium both in vivo in rats and chicks, and in vitro with everted intestinal slices; (b) the apparent increased permeability of intestinal mucosa; (c) increased levels of citric acid in serum or bone; (d) the increased incorporation of radioactive inorganic phosphorus into intestinal mucosa phospholipids. As shown by the use of radioactive vitamin D, this lag is not due to a lack of the vitamin in the target organs. 8. Whereas large, unphysiological doses of radioactive vitamin D localize in all tissues and all subcellular fractions, small physiological doses of radioactive vitamin D localize predominantly in the nucleus of the intestinal mucosa. The amount of vitamin D localized in the nucleus would appear to be too low for the vitamin to function as a cofactor, and is more indicative of an interaction on or with deoxy-ribonucleic acid. 9. Actinomycin D, an inhibitor of DNA-directed RNA synthesis, inhibits the action of vitamin D in mediating intestinal calcium absorption and bone resorption. Vitamin D also stimulates messenger-RNA synthesis in intestinal mucosa within 1/2 hr. of vitamin treatment. Vitamin D may play a crucial role, along with parathyroid hormone and calcium, in a DNA, gene-dependent, homeostatic control mechanism for cal, ium metabolism. In this system the vitamin D molecule has certain very specific structural requirements which are probably a reflection of the specificity of its receptor molecule, rather than structural requirements for a cofactor-enzyme relationship.     

Suppression of secondary hyperparathyroidism in children with chronic renal failure by high dose phosphate binders: calcium carbonate versus aluminium hydroxide.

Secondary hyperparathyroidism was suppressed over a period of one year in 12 children with chronic renal failure by using a regimen of mild dietary phosphate restriction and high dose phosphate binders. The patients were randomised to receive either aluminium hydroxide or calcium carbonate by mouth for six months and then crossed over to the other medication. Vitamin D (dihydrotachysterol) dosage was unchanged. Serum parathyroid hormone concentrations were reduced to within the normal range, urinary cyclic adenosine monophosphate values fell, plasma phosphate concentrations decreased, and the theoretical renal phosphate threshold increased significantly. Transiliac bone biopsy findings improved in four patients with adequate suppression of parathyroid hormone concentrations, deteriorated in two patients who were not compliant, and did not change in five patients in whom initial bone disease was mild. Growth velocity improved significantly. There was no difference in the clinical response, biochemical changes, or incidence of complications during treatment with the two agents. In view of the risk of aluminium toxicity the use of high dose calcium carbonate with dietary phosphate restriction and vitamin D supplementation is recommended in the control of secondary hyperparathyroidism in children with chronic renal failure.