Alpha D3 Research Articles

Effects of 1?-hydroxyvitamin D3 on lumbar bone mineral density and vertebral fractures in patients with postmenopausal osteoporosis

The effects of 1 alpha-hydroxyvitamin D3 [1 alpha(OH)D3] on bone mineral density, fracture incidence, and bone metabolism were evaluated by a double-blind, placebo-controlled study. Eighty postmenopausal osteoporotic Japanese women (71.9 +/- 7.3 years, mean +/- SD) were randomly assigned to 1 microgram of 1 alpha(OH)D3 daily or inactive placebo for 1 year. All patients were given supplemental calcium (300 mg of elemental calcium daily). Lumbar (L2-L4) bone mineral density (BMD) determined by dual energy X-ray absorptiometry increased 0.65% with 1 alpha(OH)D3 treatment and decreased 1.14% with placebo (P = 0.037). BMD in both the femoral neck and Ward's triangle did not yield any significant differences between the two groups, whereas trochanter BMD in the 1 alpha(OH)D3-treated group increased 4.20% and decreased 2.37% with placebo (P = 0.055). X-ray analysis demonstrated that new vertebral fractures occurred in two patients with 1 alpha(OH)D3 and in seven patients with placebo. The vertebral fracture rate in the treated group was significantly less (75/1000 patient years) than in the control group (277/1000 patient years; P = 0.029). Hypercalcemia (12.1 mg/100 ml) occurred in one patient receiving 1 alpha(OH)D3; however, the serum calcium level in this patient promptly decreased to the reference range after cessation of the treatment. There were no significant changes in serum creatinine level in either group. A significant increase in urinary excretion of calcium was found but there was no significant change in urinary excretion of hydroxyproline in the treated group. The serum level of bone-derived alkaline phosphatase activity significantly decreased by -26 +/- 26 (mU/ml) after the treatment (P = 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of risk factors on secondary hyperparathyroidism undergoing long-term haemodialysis with vitamin D3

In order to evaluate the clinical outcome as well as the effect of vitamin D3 treatment on secondary hyperparathyroidism (SHPT) in the patients undergoing long-term dialysis therapy, we conducted a long-term follow-up survey on the demographic characteristics of 425 patients who were observed for more than 3 years. All patients were treated with daily 1 alpha (OH)D3 treatment after the initiation of dialysis. Among them the percentage of patients needing parathyroidectomy was 4.9%; aggravation of SHPT, 11.8%; an increase of the parathyroid hormone (PTH) level without radiographical abnormalities, 17.4%; stable, 56.2%; and a decrease of the PTH level, 9.7% at the final observation. The average PTH levels increased year by year irrespective of the difference of original renal disease. Gender, age at the start of dialysis, original renal disease, duration of dialysis treatment, the decade of starting dialysis, the degree of phosphate control, and the PTH level at starting dialysis were analysed as potential risk factors for SHPT, and assessed by multivariate analysis. Multivariate analysis revealed that only the terms of duration of dialysis and the PTH level at starting dialysis were the significant risks for developing overt SHPT. Logistic regression analysis revealed that the relative risk was significantly higher in the patients with more than 10 years history of dialysis and in those with the carboxyterminal PTH levels at the start of dialysis being more than 5 ng/ml. These results suggest that the treatment with daily low-dose vitamin D3 administration after dialysis initiation is imperfect; therefore some prophylactic therapy from the predialysis stage is necessary to prevent overt SHPT, which will occur after long-term haemodialysis.

Effect of Desmodium styracifolium-triterpenoid on calcium oxalate renal stones.

We have studied the inhibitory effects of Desmodium styracifolium-triterpenoid (Ds-t) (extracted from Desmodium styracifolium (Osbeck) Merr, a herbal medicine) on the formation of calcium oxalate renal stones induced experimentally by ethylene glycol (EG) and 1 alpha(OH)D3 (1 alpha D3) in rats. The incidence of urinary stone formation was 81% in the control group, which received EG and 1 alpha D3, and 29% in the Ds-t group, which received EG and 1 alpha D3 supplemented by Ds-t. The serum calcium (Ca) concentration in the Ds-t group was significantly elevated and urinary Ca excretion was markedly reduced. Urinary excretion of citrate (Cit), a factor that prevents stone formation, was significantly increased in the Ds-t group. Excretion of urinary phosphorus (P), which was elevated to a significantly greater extent in the controls than in the Ds-t group, was increased in both groups. The increase in urine volume in the Ds-t group was significantly greater than in the control group. The 24-h creatinine clearance rate (Ccr) was significantly lower in the controls. These findings suggest that Ds-t inhibits the formation of Ca oxalate stones in rat kidneys by increasing the output of urine, decreasing the excretion of calcium and increasing the urinary excretion of citrate. Ds-t may be useful in preventing the recurrence of urinary Ca oxalate stones in the clinical setting.

Toxicity of vitamin D analogues in rats fed diets with standard or low calcium contents.

Sprague-Dawley rats were fed either a standard diet with 0.9/0.7% Ca/P or a semisynthetic low-calcium diet with 0.5/0.4% Ca/P and treated orally for 28 days with 1 alpha-hydroxycholecalciferol [1 alpha (OH)D3], a synthetic analogue of the physiologically active form of vitamin D3, 1 alpha,25-dihydroxycholecalciferol [1 alpha,25(OH)2D3], at dose levels of 0.2 and 2.0 micrograms kg/day. The high dose caused severe hypercalcaemia with retarded growth, nephrosis, and structural bone changes in rats fed the standard diet. The same dose caused only slight hypercalcaemia without growth retardation or bone changes, and only minimally affected the kidneys in rats fed the low-calcium diet. Hypercalcaemia with less pronounced pathological changes was found in the standard diet low-dose rats, whereas no hypercalcemia or pathological changes were found in the low-calcium diet low-dose group. The rats fed the low-calcium diet tolerated 1 alpha(OH)D3 at dose levels up to 10 times higher than rats on the standard diet. The use of diets low in calcium and low in phosphorus will thus allow the administration of higher dosages of vitamin D compounds without causing hypercalcaemia. This may permit a better evaluation of the pharmacologic and toxic effects not directly associated with the calcium-regulating properties of vitamin D metabolites and analogues.

Differentiating and antitumor activities of 1 alpha,25-dihydroxyvitamin D3 in vitro and 1 alpha-hydroxyvitamin D3 in vivo on human osteosarcoma.

The differentiating and antitumor activities of 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3) in vitro and 1 alpha-hydroxyvitamin D3 (1 alpha(OH)D3) in vivo were studied with a human osteosarcoma cell line (OST strain). Anti-tumor activity was estimated with the use of 3-(4,5-dimethylthiazol)-2, 5-diphenyltetrazolium bromide (MTT) assay, colony-forming assay, and athymic mouse assay. The intracellular alkaline phosphatase (ALP) activity of tumor cells and production of bone Gla protein (BGP) in culture media were measured to mark osteoblastic differentiation. In addition, the combination of 1 alpha,25(OH)2D3 and cis-dichlorodiammineplatinum(II) (CDDP) was tested by the colony-forming assay and the measurement of ALP activity and BGP production for differentiating and antitumor effects. The assays revealed that 1 alpha,25(OH)2D3 exerted a dose-related, growth-inhibitory influence. In the colony-forming assay, the 1 alpha,25(OH)2D3-treated colonies were smaller than the untreated colonies. The ALP activity and the BGP production also increased in relation to dose. In the assay in athymic mice, the relative weight of tumors treated with 1 alpha(OH)D3 at 2.5 nmol/kg was significantly smaller than that of the controls, and no side effects were observed in the 1 alpha(OH)D3-treated mice. Marked tumor chondrogenesis was observed in human osteosarcoma treated with 1 alpha(OH)D3 in athymic mice. The combination of 1 alpha,25(OH)2D3 at 10(-8) M and CDDP at 2 micrograms/ml significantly enhanced both the differentiation and the growth inhibition in vitro. Our study apparently is the first demonstration that vitamin D3 metabolites have an antitumor and differentiating effect on human osteosarcoma cells in vitro and in athymic mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of psoriasis with calcipotriol and other vitamin D analogues

The discovery of a high-affinity receptor for the bioactive form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25[OH]D3), in most skin cells has led to the finding of previously unknown effects of vitamin D on epidermal growth and on the skin immune system. 1,25(OH)2D3 inhibits epidermal proliferation and promotes epidermal differentiation. These properties provided the rationale for introducing 1,25(OH)2D3 in the treatment of psoriasis vulgaris. In addition to 1,25(OH)2D3, the synthetic vitamin D3 analogues 1 alpha(OH)D3, 1,24(OH)2D3, and calcipotriol have undergone clinical evaluation. Calcipotriol has been studied most extensively. Compared with 1,25(OH)2D3, calcipotriol is about 200 times less potent in its effects on calcium metabolism, although similar in receptor affinity. In double-blind, placebo-controlled, randomized studies, topical calcipotriol (50 micrograms/gm, up to 100 gm weekly) has been shown to be efficacious and safe for the treatment of psoriasis. A similar therapeutic profile has been seen in long-term studies. In comparative studies topical calcipotriol is slightly more efficacious than betamethasone 17-valerate and dithranol. The mode of action of calcipotriol and other vitamin D3 analogues in psoriasis is not known. Although vitamin D3 analogues affect epidermal growth, their immunosuppressive properties may be equally important for their antipsoriatic effect.

1 alpha-hydroxyvitamin D3, hypercalcemia, and growth suppression of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors.

1 alpha-hydroxyvitamin D3 [1 alpha(OH)D3] was administered to female Sprague-Dawley rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. 1 alpha(OH)D3 suppressed the growth of the rat mammary tumors dose-dependently, and in the high dose groups treated with 0.5-1.0 micrograms/kg of 1 alpha(OH)D3, significant inhibition of tumor growth was observed. But daily oral administration of 1 alpha(OH)D3 for four consecutive weeks caused side effects such as hypercalcemia and weight loss. We compared 0.5 microgram/kg of 1 alpha(OH)D3 three times weekly with the same dose six times weekly to discover whether or not the side effects can be reduced by treatment schedule. Both groups showed a significant oncostatic effect, compared with the control group, while the side effects were relieved in the three times weekly group. Regarding estrogen receptors (ER) in the tumors, there was no significant difference among the groups. These results suggested that the antitumor effect of 1 alpha(OH)D3 on DMBA-induced mammary tumors was not related to ER status. Combined use of 1 alpha(OH)D3 with 5-fluorouracil (5-FU) or medroxyprogesterone acetate (MPA) was also examined. No significant augmentation of the antitumor effect was seen in the two combinations, although the combined therapy with MPA showed a significant inhibition of weight loss in the rats.

Effects of 1α(OH)-Vitamin D<sub>3 </sub>and 24,25(OH)<sub>2</sub>-Vitamin D<sub>3 </sub>on Long Bones of Glucocorticoid-Treated Rats

Glucocorticoids may induce osteopenia in experimental animals and in man. In order to study the possible effects of vitamin D metabolites in the prevention of glucocorticoid-induced osteopenia in rats, we administered 1 alpha(OH)-vitamin D3, 24,25(OH)2-vitamin D3 or a combination of both metabolites, by intragastric intubation, to rats treated daily by intramuscular injections of 10 mg/kg cortisone acetate. Treatment with the vitamin D metabolites started after 1 month of glucocorticoid therapy, at the time osteopenia was already present. Cortisone acetate decreased the gain weight, increased alkaline phosphatase (AP) and decreased Ca serum levels. It also decreased tibial wet and ash weight and tibial Ca content. Computerized histomorphometry of sections from the upper tibia showed decreased epiphyseal bone volume and increased bone marrow volume; decreased height of hypertrophic cartilage in the growth plate and decreased amount of persisting cartilage in the metaphyseal bone trabeculae were also observed. Administration of 24,25(OH)2D3 alone did not reduce these glucocorticoid-induced bone changes and sometimes even worsened them. 1 alpha(OH)D3 reversed many of the deleterious effects of cortisone acetate. It reduced serum AP levels, increased serum Ca levels, increased bone ash weight, epiphyseal and metaphyseal bone volume, with a concomitant reduction in epiphyseal and metaphyseal bone marrow volume. The best results were obtained by a combination of 1 alpha(OH)D3 and 24,25(OH)2D3. It is presumed that both metabolites are needed to reduce the impact of glucocorticoids on bone. 1 alpha(OH)2D3 acts on the gut, increasing Ca absorption (which was decreased by glucocorticoids), and 24,25(OH)2D3 directly acts on bone to enhance bone formation and mineralization.

Atrophie villositaire associée à une hypoparathyroïdie idiopathique corrigée par la 1 alpha-hydroxyvitamine D 3 et le calcium

We record the case of a 82 years old woman with an idiopathic hypoparathyroïdism (calcemia: 1,28 mmol/l; PTHi: 5,7 pg/ml) associated to a complete villous atrophy. Restitutio ad integrum of the intestinal mucosa was obtained by the sole treatment of hypoparathyroïdism with calcium and 1 alpha (OH) D3.

Pachydermoperiostosis with myelofibrosis and anemia: Report of a case of anemia of multifactorial causes and its improvement with steroid pulse and iron therapy.

A 26-year-old male patient with pachydermoperiostosis is reported. He had severe anemia with myelofibrosis. Treatment with iron, prednisolone, oxymethorone and 1 alpha (OH)D3 were not satisfactory. But steroid pulse therapy with parenteral iron improved his anemia and pancytopenia, but was not sufficient to relieve the bone marrow fibrosis or splenomegaly. The mechanism of anemia which was considered to be multifactorial including gastro-intestinal bleeding associated with peptic ulcer or erosion and bone marrow failure due to myelofibrosis, is discussed.

Osteodystrophy in liver cirrhosis: Detection and treatment evaluation using 99Tc m methylene diphosphonate bone scintigraphy

To investigate osteodystrophy in liver cirrhosis, 99Tcm MDP (methylene diphosphonate) bone scintigraphy was performed on 36 patients with liver cirrhosis. Abnormal lesions were detected in 17 out of 36 scans (47.2%). On the other hand, areas of increased uptake were uncommon in patients with chronic active hepatitis (1/11 cases). Plasma vitamin D3 fractions [25(OH)D3, 24.25(OH)2D3 and 1.25(OH)2D3] were decreased. Statistically significant depletion of 1.25(OH)2D3 was observed in cases with positive bone scintigraphy. 1 alpha(OH)D3 (1-2 micrograms/day) was administered for 6 months to nine patients having abnormal bone scans. Six of them showed improvement without any apparent side-effects. We conclude that hepatic cirrhotic osteodystrophy can be diagnosed positively by 99Tcm MDP bone scintigraphy and can be treated accordingly.

Treatment of myelodysplastic syndromes with retinoic acid and 1α‐hydroxy‐vitamin D3 in combination with low‐dose ara‐C is not superior to ara‐C alone. Results from a randomized study

63 evaluable patients with myelodysplastic syndromes (MDS) and 15 with acute myelogenous leukemia (AML) were randomized between low-dose ara-C (arm A) and low dose ara-C in combination with 13-cis-retinoic acid (13-CRA) and 1 alpha-hydroxy-vitamin D3 (1 alpha D3) (arm B). 69 patients were evaluable and 18 (26.1%) responded to therapy. The addition of 13-CRA and 1 alpha D3 had no positive influence on survival of the patients, remission rates or duration of remissions. 12/27 patients in arm A and 6/29 patients in arm B progressed from MDS to AML during the course of the study (p = 0.0527). Arm B gave significantly more side-effects than arm A (p = 0.005). Therapeutic effects of 13-CRA and 1 alpha D3 on MDS is not supported by this study. However, an inhibiting effect on AML development in some MDS subgroups cannot be excluded.

Nongenomic Activation of the Calcium Message System by Vitamin D Metabolites in Osteoblast-like Cells

1,25-dihydroxycholecalciferol (1,25(OH)2D3) rapidly affects calcium (Ca2+) transport in several cell systems, suggesting physiological actions independent of genomic activation. To test this hypothesis, we studied immediate to early effects (0.5-300 sec) of 1,25(OH)2D3 on cytosolic Ca2+ [Ca2+]i in single osteogenic sarcoma ROS 17/2.8 cells loaded with fura-2. An acute rise in [Ca2+]i was observed in 40% of the cells following addition of 1,25(OH)2D3, with a threshold concentration of 10(-11) M. In most cases, the [Ca2+]i rise was transient, with return to baseline within 1 min; less frequently a more prolonged effect was observed, with variable recovery times. 25-hydroxycholecalciferol (25(OH)D3) reproduced the effect of 1,25(OH)2D3 on [Ca2+]i, with equal potency and similar responses, whereas 24,25-dihydroxycholecalciferol, 1 alpha-hydroxycholecalciferol, and 22 oxa-1,25(OH)2D3 were not effective. 1,25(OH)2D3 also increased [Ca2+]i in ROS 24/1 cells, which are defective of receptors for the vitamin D metabolites. At high doses (10(-8)-10(-7) M) of 1,25(OH)2D3 the [Ca2+]i rise in ROS 17/2.8 cells was due to both influx of extracellular Ca2+ and release of Ca2+ from intracellular stores, as the effect was only partially inhibited by Ca2(+)-channel blockade by nifedipine. At low doses (10(-9)-10(-10) M), the effect was entirely dependent on extracellular Ca2+. 1,25(OH)2D3 also increased the production of inositol 1,4,5 trisphosphate (Ins(1, 4, 5)P3) and diacylglycerol, at a threshold dose of 10(-9) M, indicating activation of phospholipase C (PLC). In two thirds of the cells studied, a second addition of 1,25(OH)2D3 within 5 min to cells prestimulated with equimolar doses of the vitamin D metabolite resulted in a [Ca2+]i transient of higher amplitude than the first, a phenomenon occurring at all doses of the hormone, and associated with production of Ins(1, 4, 5)P3. This response amplification was not produced by 25(OH)D3, and pretreatment with 1 alpha(OH)D3 did not significantly enhance 1,25(OH)2D3-induced production of Ins(1, 4, 5)P3. In conclusion, activation of the Ca2+ message system by vitamin D metabolites is a rapid, nongenomic effect; 1,25(OH)2D3 specifically activates both PLC and dihydropyridine-sensitive Ca2+ channels, and "primes" the cells to respond with an enhanced [Ca2+]i rise to a subsequent homologous stimulation; the presence of both the 1 alpha and 25 hydroxyl groups is necessary to express the full hormonal action of vitamin D on [Ca2+]i.

Cytokines and Osteoporosis

Bone remodeling is controlled by systemic factors such as parathyroid hormone (PTH), calcitonin (CT), and 1,25(OH)2 vitamin D and by local factors including cytokines and growth factors such as IL-1, IL-2, TNF alpha, TGF beta, IFN alpha, and IFN gamma. Derangement of such control mechanisms leading to an imbalance between osteoclastic bone resorption and osteoblastic bone formation could cause osteoporosis. Conditions associated with immune dysfunction such as aging, corticosteroid therapy, and rheumatoid arthritis are associated with osteoporosis, which is also more common in females than in males, like most of the autoimmune-collagen diseases. Peripheral lymphocyte subsets CD4/CD8 were higher in patients with senile osteoporosis than in the age-matched controls, and returned to normal after 1 month of 1 alpha(OH)vitamin D3 treatment. On multiple regression analysis of histomorphometric data and lymphocyte subsets, a negative correlation was found between CD4 lymphocytes and bone resorption. High CD4 is thus associated with a low level of osteoclastic bone resorption or low turnover osteoporosis. Plasma interferon reflecting macrophage function decreased with advance in age and increased in response to 1 alpha(OH)D3 treatment. As one of the immunoregulators, vitamin D tends to stimulate the macrophage-natural killer system and suppress the lymphocyte system, stimulating TGF beta and TNF alpha activity. Senile osteoporosis of low turnover thus appears to be associated with vitamin D deficiency, low macrophage function, high CD4 lymphocyte proportion, low IL-1 and high IL-2 activity, low IFN alpha and high IFN gamma activity, and low TGF beta and TNF alpha activity. Treatment with vitamin D derivatives tends to reverse these changes.

Administration of calcium carbonate with adequate doses of vitamin D metabolite to patients on hemodialysis improves mild secondary hyperparathyroidism.

The effects of CaCO3 with vitamin D metabolite and without vitamin D metabolite on secondary hyperparathyroidism were investigated in 18 patients undergoing maintenance hemodialysis. 9 patients (Group 1) were treated with 1 microgram/day 1 alpha (OH)D3 and 2 g/day Al(OH)3, and the other 9 patients (Group 2) received 2 g/day Al(OH)3 without vitamin D metabolite. CaCO3 at amounts of 3 g/day was subsequently administered to all patients instead of Al(OH)3. The levels of mid portion-parathyroid hormone (M-PTH) in Group 2 and of 1,25-dihydroxyvitamin D3 in Group 1 during the baseline period were significantly increased as compared to those in the other group, respectively. In Group 1 only, the level of serum ionized calcium was appreciably elevated at the 4th and 12th weeks as compared to the baseline value, and the level of M-PTH was significantly decreased at the 4th and 12th weeks as compared to the baseline value. The levels of serum phosphate, calcitonin, magnesium and bicarbonate in both groups at the 4th and 12th weeks were not appreciably different from the baseline values. The level of serum aluminum in all patients of both groups were reduced at the 12th week as compared to the baseline values. A close correlation was recognized between M-PTH and the level of intact parathyroid hormone. It is concluded that prescription of 3g/day CaCO3, together with adequate doses of vitamin D metabolite, can ameliorate mild secondary hyperparathyroidism.

1??,25(OH)2D3 Exerts Cytostatic Effects on Murine Osteosarcoma Cells and Enhances the Cytocidal Effects of Anticancer Drugs

The effects of 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25-(OH)2D3), 1 alpha-hydroxyvitamin D3 (1 alpha(OH)D3), and dexamethasone on colony formation of Dunn osteosarcoma cells (TA 102 cells) were investigated. Concentrations of 1 alpha,25(OH)2D3, 1 alpha(OH)D3, and dexamethasone at which they exerted 50% reduction of the total area of TA 102 colony formation were 9 X 10(-9) M, 9 X 10(-8) M, and 5 X 10(-6) M, respectively. Effects of anticancer drugs on TA 102 cells were also investigated and concentrations needed for 50% growth inhibition (50% inhibitory concentration values) of cis-platinum, mitomycin C (MMC), methotrexate (MTX), and Adriamycin (ADR) against TA 102 cells were calculated to be 0.07 microgram/ml, 0.0008 microgram/ml, 0.0008 microgram/ml, and 0.0005 microgram/ml, respectively. The simultaneous treatment of TA 102 cells with 10(-8) M of 1 alpha,25(OH)2D3 and anticancer drugs significantly enhanced the respective inhibitory effects on colony formation. In this treatment, the IC50 value of MMC was calculated to be 6.4 X 10(-6) micrograms/ml, which was 1/160 of the expected IC50 value of MMC (8 X 10(-4) micrograms/ml). Similar synergistic effects were observed when the cells were treated with 1 alpha,25(OH)2D3 and low concentrations of cis-platinum, MTX, or ADR.

A SYNTHETIC ANALOGUE OF VITAMIN D3, 22-OXA-lα,25-DIHYDROXYVITAMIN D3IS A POTENT MODULATOR OF IN VIVO IMMUNOREGULATING ACTIVITY WITHOUT INDUCING HYPERCALCEMIA IN MICE

The in vivo immunoregulating activity and the hypercalcemic action of 4 synthetic analogues of vitamin D3 with an oxygen atom in the side chain were compared with those of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] in mice. Oral administration of these vitamin D3 compounds augmented the primary immune response, induced by immunization with a suboptimal number of sheep erythrocytes, without inducing hypercalcemia. The order of the in vivo potency to induce the immune response was 22-oxa-1 alpha,25(OH)2D3 greater than 1 alpha,25(OH)2D3 not equal to 20-oxa-1 alpha,25(OH)2D3 not equal to 22-oxa-1 alpha(OH)D3 greater than 1 alpha(OH)D3 not equal to 20-oxa-1 alpha(OH)D3. 22-Oxa-1 alpha,25(OH)2D3 was about 50 times more potent than 1 alpha,25(OH)2D3 in inducing the in vivo primary immune response, but the former was only 1/100 as active as the latter in inducing hypercalcemia. These results suggest that the immunoregulating activity of vitamin D compounds can be separated structurally from their hypercalcemic action in vivo.

Effect of Intravenous 1-Alpha-Hydroxyvitamin D<sub>3</sub> on Secondary Hyperparathyroidism in Chronic Uremic Patients on Maintenance Hemodialysis

The effect of intravenous 1 alpha(OH)D3 on circulating intact parathyroid hormone (PTH) and COOH-terminal immunoreactive PTH was examined in 21 patients on chronic hemodialysis. The patients were treated for 3 months with increasing doses of 1 alpha(OH)D3 under careful control of serum Ca2+. 1 alpha(OH)D3 was given intravenously at doses of up to 4 micrograms three times a week, and blood samples were obtained every week, including 1 week before treatment (basal control). No patients were treated with oral vitamin D metabolites. At the end of the study intact PTH levels were reduced by an average of 67 +/- 6%, and COOH-terminal immunoreactive PTH levels were reduced by 35 +/- 6%. Serum Ca2+ was kept within normal levels, but showed a slight increase from 1.17 to 1.30 mmol/l. An effect of calcium on PTH secretion could not be excluded, but an effect of 1 alpha(OH)D3, independent of serum Ca2+ was also found. This effect may be mediated by 1,25(OH)2D3, assuming a large capacity of the 25-hydroxylase in the liver to convert 1 alpha(OH)D3 to 1,25(OH)2D3. Also, the parathyroid glands may possess receptors for 1 alpha(OH)D3 with an effect similar to that established for the 1,25(OH)2D3 receptors. Thus, although the exact mechanisms of the action of 1 alpha(OH)D3 have not yet been completely clarified, it is concluded that intravenous administration of 1 alpha(OH)D3 may be of benefit in the treatment of secondary hyperparathyroidism of uremia.

Supplemental administration of 1 alpha-hydroxyvitamin D3 inhibits promotion by intrarectal instillation of lithocholic acid in N-methyl-N-nitrosourea-induced colonic tumorigenesis in rats.

The effect of 1 alpha-hydroxyvitamin D3 [1 alpha(OH)D3] on promotion by intrarectal instillation of lithocholic acid (LC) in N-methyl-N-nitrosourea (MNU)-induced colonic tumorigenesis was studied in a rodent model. Ninety-two female F344 rats received intrarectal injection of 2.5 mg of MNU twice in one week followed by 1 mg of LC or its vehicle alone three times weekly for 48 weeks. Those which received LC were given a concomitant intragastric administration of 0.04 micrograms of 1 alpha(OH)D3 or its vehicle alone three times weekly. In the group receiving MNU alone (n = 30) five rats bore colonic tumors; in the MNU + LC group (n = 32) 15 and in the MNU + LC + 1 alpha(OH)D3 group (n = 30) six rats bore colonic tumors (MNU + LC versus MNU + LC + 1 alpha(OH)D3 group, P less than 0.05). These results indicated that promotion of MNU-induced colonic tumorigenesis by LC was suppressed by supplemental administration of 1 alpha(OH)D3.

Influence of 1 alpha-hydroxy vitamin D3 (0.25 micrograms/day) and calcium carbonate on patients with chronic renal failure at the predialytic stage.

The influence of a small amount of 1 alpha (OH)D3 on patients with chronic renal failure at the predialytic stage (CRFPS patients) receiving CaCO3 was investigated. 7 patients given CaCO3 (3 g/day) were administered 1 alpha (OH)D3 (0.25 micrograms/day) over a period of 12 weeks. 2 patients were eliminated from the study because of obvious deterioration of renal function. The others revealed no significant changes in levels of serum creatinine, adjusted calcium, phosphate, calcium x phosphate product, alkaline phosphatase, C-terminal parathyroid hormone, pH and bicarbonate. Our results indicated that even 0.25 micrograms/day 1 alpha (OH)D3 should not be prescribed to CRFPS patients given 3 g/day CaCO3. We recommend a little sole use of CaCO3 in CRFPS patients, paying attention to any exacerbation of renal function due to a rise in serum calcium concentration, when therapy for secondary hyperparathyroidism is required.