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PubMed1994

A prospective, double-blind study of growth failure in children with chronic renal insufficiency and the effectiveness of treatment with calcitriol versus dihydrotachysterol. The Growth Failure in Children with Renal Diseases Investigators.

Because controlled trials in adults have shown accelerated deterioration of renal function in a small number of patients receiving calcitriol for renal osteodystrophy, we initiated a prospective, randomized, double-blind study of the use of calcitriol versus dihydrotachysterol in children with chronic renal insufficiency. We studied children aged 1 1/2 through 10 years, with a calculated glomerular filtration rate between 20 and 75 ml/min per 1.73 m2, and with elevated serum parathyroid hormone concentrations. Ninety-four patients completed a mean of 8.0 months of control observations and were randomly assigned to a treatment period; 82 completed the treatment period of at least 6 months while receiving a calcitriol dosage (mean +/- SD) of 17.1 +/- 5.9 ng/kg per day or a dihydrotachysterol dosage of 13.8 +/- 3.3 micrograms/kg per day. With treatment the height z scores for both calcitriol- and dihydrotachysterol-treated groups showed no differences between the two groups. In relation to cumulative dose, there was a significant decrease in glomerular filtration rate for both calcitriol and dihydrotachysterol; for calcitriol the rate of decline was significantly steeper (p = 0.0026). The treatment groups did not differ significantly with respect to the incidence of hypercalcemia (serum calcium concentration > 2.7 mmol/L (> 11 mg/dl)). We conclude that careful follow-up of renal function is mandatory during the use of either calcitriol or dihydrotachysterol because both agents were associated with significant declines in renal function. There was no significant difference between calcitriol and dihydrotachysterol in promoting linear growth or causing hypercalcemia in children with chronic renal insufficiency. Dihydrotachysterol, the less costly agent, can be used with equal efficacy.

Calcitriol↗
PubMed1990

Pharmacokinetics of calcitriol in continuous ambulatory and cycling peritoneal dialysis patients.

Oral calcitriol is commonly used for the treatment of secondary hyperparathyroidism in patients undergoing long-term dialysis, but it has been suggested that intravenous (IV) or intraperitoneal (IP) administration enhances the therapeutic efficacy of the sterol. To examine potential mechanisms for this difference, the bioavailability of calcitriol was evaluated after single oral (PO), IV, and IP doses of 60 ng/kg in each of six adolescent patients with osteitis fibrosa undergoing continuous ambulatory peritoneal dialysis (CAPD) or continuous cycling peritoneal dialysis (CCPD). Serum calcitriol levels were 3.6 +/- 4.3, 8.2 +/- 7.5, and 2.5 +/- 3.0 pg/mL, respectively, before IV, PO, and IP doses of the sterol; these values increased to similar levels at 24 hours: 55.6 +/- 14.6 pg/mL after PO, 56.4 +/- 17.6 pg/mL after IV, and 53.8 +/- 20.1 pg/mL after IP. Serum calcitriol levels were higher 1, 3, and 6 hours after IV injections than after PO or IP doses; values thereafter did not differ among groups. The bioavailability of calcitriol, determined from the 24-hour area under the curve (AUC0-24) for the increase in serum calcitriol concentration above baseline values was 50% to 60% greater after IV, 2,340 +/- 523 pg.mL-1.h-1, than after PO, 1,442 +/- 467 pg.mL-1.h-1, or IP, 1,562 +/- 477 pg.mL-1.h1, dosages, P less than 0.05. These differences were due to higher values for AUC during the first 6 hours after calcitriol administration. Although IP calcitriol did not increase sterol bioavailability, radioisotope tracer studies indicated that 35% to 40% of the hormone adheres to plastic components of the peritoneal dialysate delivery system.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Pulse oral calcitriol for the treatment of hyperparathyroidism in patients on continuous ambulatory peritoneal dialysis: preliminary observations.

A direct effect of calcitriol on the regulation of the secretion of parathyroid hormone (PTH) has been shown in vitro and in vivo. In patients with renal failure on maintenance hemodialysis, it has been shown that intravenous (IV) administration of calcitriol appears to be superior to continuous oral administration. This may be due to the higher levels of calcitriol obtained in blood with consequent improved delivery of calcitriol to peripheral target tissues including the parathyroid glands. However, IV administration of calcitriol, is not practical for patients with end-stage renal disease (ESRD) who are maintained on continuous ambulatory peritoneal dialysis (CAPD). The present studies were designed to investigate whether intermittent administration of large doses of calcitriol orally ("pulse therapy") could mimic the effects of IV calcitriol in hemodialysis patients and achieve suppression of PTH secretion. Studies were performed in five patients who had been maintained on CAPD for more than 6 months. After basal determinations of calcium, phosphorus, and PTH, therapy was begun with calcitriol administered orally in a dose of 5 micrograms given twice per week. Calcium carbonate was continued as a phosphate binder. Dialysate calcium concentration was 1.75 mmol/L (3.5 mEq/L). With this therapy, PTH levels decreased rapidly, and, after 4 to 6 weeks of therapy, reached values 60% lower than pretreatment values. Mean values for serum calcium did not change significantly (2.29 +/- 0.12 mmol/L [9.6 +/- 0.5 mg/dL] before treatment compared with 2.32 +/- 0.08 mmol/L [9.7 +/- 0.25 mg/dL] after therapy). Mean serum phosphorus was also unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Relationship between urinary calcium and calcium intake during calcitriol administration.

The hypercalciuria that occurs when 1,25 (OH)2D3 (calcitriol) is given to humans with normal renal function depends on dietary Ca absorption and may also relate, in part, to enhanced bone resorption. To evaluate the relationship between urinary and dietary Ca during treatment with calcitriol, 12 metabolic balance studies were performed in normal volunteers ingesting a diet containing 350 mg/day of Ca, to which Ca gluconate was added. After 10 days on either 350 mg/day or 1550 mg/day of Ca, calcitriol, 0.5 microgram every 12 hr, was given. Then diet Ca was changed in successive 5-day treatment periods from 350 to 650, 950 and 1550 mg/day (group A) or from 1550 to 950, 650 and 350 mg/day (group B). On the lowest diet Ca, urinary Ca was less than Ca intake during calcitriol treatment (group A, 220 +/- 50 mg/day; group B, 247 +/- 40). As diet Ca was changed during calcitriol treatment, urinary Ca correlated with diet Ca (r = 0.60) until diet Ca reached 950 mg/day. With calcitriol, serum iPTH fell by 18 to 25% (P less than 0.01) and urinary hydroxyproline fell by 11 to 19% (P less than 0.05 to 0.01). Baseline serum levels of 1,25(OH)2D were 47 +/- 8 and 34 +/- 5 pg/ml in group A and B, respectively, and the values increased to 51 +/- 12 and 45 +/- 7.4 pg/ml during treatment with calcitriol. Serum Ca from fasted subjects was not affected by calcitriol, but the mean postabsorptive serum Ca (moon) was increased by 0.35 mg/dl.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Subfractions in uremic plasma ultrafiltrate inhibit calcitriol metabolism.

Previous study from our laboratory has demonstrated that uremic plasma ultrafiltrate suppresses both the production rate (PR) and metabolic clearance rate (MCR) of calcitriol in normal rats. To characterize the the substances responsible for the suppression of the synthesis and degradation of calcitriol, we fractionated 20 ml uremic plasma ultrafiltrates into 13 fractions using high-performance liquid chromatography (HPLC) and studied the effect of each fraction on calcitriol metabolism. We measured the MCR and PR of calcitriol in normal rats after they were infused for 20 hours with each fraction dissolved in 20 ml normal saline. Using a UV absorption and fluorescence emission technique, several known uremic compounds were identified as individual peaks corresponding to the fractions. We found that fractions 4, and 6 to 13 markedly reduced the MCR of calcitriol. The patterns of the MCR suppression by the HPLC fractions suggest that there were at least two groups of chemically distinguishable compounds. Infusion of a solution containing all 13 fractions of the uremic ultrafiltrate also inhibited the calcitriol synthesis. One of the 13 fractions (fraction 4, containing uric acid, xanthine, and hypoxanthine) was further fractionated into eight subfractions. Infusion of subfractions 4 to 7 markedly reduced both the PR and MCR of calcitriol. We conclude that uremic plasma ultrafiltrate contains factors that inhibit calcitriol synthesis and degradation. These substances have molecular weight less than 2,000 Daltons.

Animals↗
PubMed1996

Relative effects of PTH and dietary phosphorus on calcitriol production in normal and azotemic rats.

In moderate renal failure, the serum calcitriol level is influenced by the stimulatory effect of high PTH and the inhibitory action of phosphorus retention. Our goal was to evaluate the relative effect that high PTH levels and increased dietary phosphorus had on calcitriol production in normal rats (N) and rats with moderate renal failure (Nx). Normal and Nx (3/4 nephrectomy) rats were divided into two groups: (1) rats with intact parathyroid glands (IPTG) and (2) parathyroidectomized rats in which PTH was replaced (PTHR) by the continuous infusion of rat 1-34 PTH, 0.022 microgram/hr/100 g body wt, using a miniosmotic Alzet pump. To test the effect of dietary phosphorus, rats received either a moderate (MPD, 0.6% P) or a high phosphorus (HPD, 1.2%) diet for 14 days. The experimental design included pair-fed N and Nx rats with either IPTG or PTHR. Serum calcitriol and PTH levels in N rats fed a MPD were 69 +/- 3 and 40 +/- 5 pg/ml, respectively. In Nx rats on a MPD, serum calcitriol levels decreased only if hyperparathyroidism was not allowed to occur (76 +/- 4 vs. 62 +/- 4 pg/ml in Nx-IPTG-MPD and Nx-PTHR-MPD groups respectively, P < 0.05). Even in N rats on a HPD, high PTH levels (67 +/- 8 pg/ml in the N-IPTG-HPD group) were required to maintain normal serum calcitriol levels (69 +/- 4 vs. 56 +/- 6 pg/ml in Nx-IPTG-HPD and Nx-PTHR-HPD groups, respectively; P < 0.05). In Nx rats on a HPD, the development of secondary hyperparathyroidism (286 +/- 19 pg/ml in the Nx-IPTG-HPD group) prevented a decrease in serum calcitriol levels (68 +/- 7 pg/ml). In contrast, serum calcitriol levels were low in the Nx-PTHR-HPD group (52 +/- 4 pg/ml, P < 0.05), which were deprived of the adaptative increase in endogenous PTH production. In conclusion, our results in rats indicate that in moderate renal failure, an elevated PTH level maintains calcitriol production and overcomes the inhibitory action of phosphorus retention.

Animals↗
PubMed2003

Intra-individual comparison of the cutaneous safety and efficacy of calcitriol 3 microg g(-1) ointment and calcipotriol 50 microg g(-1) ointment on chronic plaque psoriasis localized in facial, hairline, retroauricular or flexural areas.

BACKGROUND: Psoriasis involving sensitive skin areas remains difficult to treat because of the side-effects of topical corticosteroids and the irritancy potential of vitamin D3 derivatives. Several clinical trials have demonstrated that calcitriol, the naturally occurring and hormonally active form of vitamin D3, is effective and safe at the dose of 3 microg g(-1) for the treatment of psoriasis affecting the trunk and limbs. METHODS: We compared the safety and efficacy of calcitriol 3 microg g(-1) ointment and calcipotriol 50 microg g(-1) ointment in a multicentre, randomized, investigator-blinded, left-right comparison in mild to moderate chronic plaque psoriasis affecting sensitive areas, defined as being the face, hairline, retroauricular and flexural areas. One pair of symmetrical and bilateral target lesions was selected from each area and assessed for perilesional erythema, oedema, and stinging/burning. Global assessment of local tolerability and global improvement were rated by the investigator, and the subjects were asked to evaluate the tolerability and efficacy of each product and to express their global preference. RESULTS: In the 75 subjects, calcitriol and calcipotriol both led to clearing of at least one target lesion in 21 (28%) of the subjects each. Perilesional erythema (P < 0.001), perilesional oedema (P < 0.02) and stinging/burning (P < 0.001) were all significantly less severe with calcitriol than with calcipotriol. The subjects' evaluation of local tolerability was significantly (P < 0.0001) in favour of calcitriol. Ten treatment-related dermatological events occurred in eight subjects, including one subject who experienced skin discomfort on both sides. All other events occurred only on the calcipotriol-treated side (irritant dermatitis, six subjects; contact dermatitis, one subject). Global assessment of improvement from baseline by the investigators was significantly greater for the calcitriol-treated lesions (P < 0.02). The subjects' global preference was significantly in favour of calcitriol (P < 0.02). CONCLUSIONS: In the present study, calcitriol ointment was found to be better tolerated and would appear to be more effective than calcipotriol ointment in the treatment of psoriasis in sensitive areas.

Adolescent↗
PubMed2000

Production and action of transforming growth factor-beta in human osteoblast cultures: dependence on cell differentiation and modulation by calcitriol.

BACKGROUND: Transforming growth factor beta (TGF-beta) plays an important role in skeletal remodelling. However, few studies have examined its effects on cultured human osteoblasts. Our aim is to characterise the biological effects of TGF-beta1 on human osteoblasts and to examine the interaction between TGF-beta1 and calcitriol. DESIGN: In vitro study employing two models of normal human osteoblasts: human bone marrow stromal cells [hMS/(OB)] containing osteoprogenitor cells and trabecular bone osteoblasts (hOB), which are mature osteoblasts. A reverse-transcriptase-polymerase-chain-reaction assay was employed to measure steady state mRNA levels of TGF-beta(s) isoforms and receptors. Effects of short-term treatment of TGF-beta1 on osteoblast proliferation and differentiation markers were assessed. The effect of cotreatment of calcitriol (10-8 M) and TGF-beta1 on osteoblast differentiation was also determined. RESULTS: Both hMS(OB) and hOB cells expressed mRNA transcripts of TGF-beta1, TGF-beta2, TGF-beta 3, TGF-beta type I and type II receptors. TGF-beta 1 stimulated osteoblast proliferation in hMS(OB) and in hOB cultures. In hOB cultures, TGF-beta1 stimulated AP production and cotreatment with calcitriol induced a synergistic increase in AP levels to 250 +/- 61% of calcitriol-treated controls. Effects of TGF-beta1 and calcitriol were less pronounced in hMS(OB) cultures. TGF-beta1 inhibited collagen type I production in hMS(OB) cells and these effects were abolished in presence of calcitriol. In presence of calcitriol, TGF-beta1 increased collagen type I production in hOB cells. In both hOB and hMS(OB) cultures, TGF-beta1 inhibited osteocalcin production. CONCLUSIONS: TGF-beta increases osteoblastic cell proliferation irrespective of the differentiation state. In presence of calcitriol, it initiates osteoblast cell differentiation and matrix formation. As TGF-beta inhibits osteocalcin production, other factors are necessary for inducing terminal differentiation of osteoblasts. The observed effects of TGF-beta on human osteoblasts in vitro may represent important regulatory steps in controlling osteoblast cell proliferation and differentiation in vivo.

Activin Receptors, Type I↗
PubMed1998

Calcitriol and transforming growth factor-beta upregulate 5-lipoxygenase mRNA expression by increasing gene transcription and mRNA maturation.

Differentiation of the human monocytic cell line Mono Mac 6 with calcitriol plus transforming growth factor-beta (TGFbeta) strongly induces 5-lipoxygenase (5-LO) mRNA and protein expression. The mechanism of 5-LO mRNA induction by these agents was investigated. Analysis of mature 5-LO mRNA by reverse-transcriptase-PCR gave a 42-fold induction which was not due to alterations in 5-LO half life and which was only in part due to an induction of gene transcription. There was an up to fivefold increase in 5-LO primary transcripts by TGFbeta and calcitriol, which could be inhibited by cycloheximide. No significant effects on 5-LO transcription were observed with TGFbeta or calcitriol alone. However, treatment of the cells with either calcitriol or TGFbeta and addition of the corresponding second inducer lead to an about fourfold induction of primary transcript levels. Addition of cycloheximide together with the second inducer inhibited only the TGFbeta but not the calcitriol effects, which indicated that there is a direct stimulation of 5-LO transcription by calcitriol in the presence of TGFbeta-induced proteins. In order to investigate the effects of TGFbeta/calcitriol on 5-LO transcript, elongation and maturation, the relative changes in immature and mature 5-LO RNA species were analyzed by reverse-transcription-PCR. Analysis of exons 1-5 indicated an about threefold induction of 5-LO transcripts by calcitriol/TGFbeta, respectively. However, when exons 6-14 were determined, more pronounced increments were found (3.6-12-fold). Selective analysis of polyadenylated and spliced 5-LO mRNA species gave a 42-fold induction. The effects of both TGFbeta and calcitriol on transcript elongation and maturation were inhibited by cycloheximide. Our results show that induction of 5-LO mRNA by calcitriol and TGFbeta is due to a modest increase in 5-LO gene transcription and to the stimulation of transcript elongation and maturation.

Arachidonate 5-Lipoxygenase↗
PubMed2000

Effect of the vitamin D analogues paricalcitol and calcitriol on bone mineral in vitro.

Paricalcitol (19-nor-1,25-dihydroxyvitamin D(2)), a new vitamin D analogue, recently became available for the treatment of hyperparathyroidism in patients with end-stage renal disease. It is safe and effective in suppressing parathyroid hormone, with apparently less propensity for hypercalcemia than calcitriol (1, 25-dihydroxyvitamin D(3)). However, the mechanism of action on bone has not been fully elucidated. This study compares the effects of paricalcitol and calcitriol on the bone mineral. Neonatal (5- to 7-day-old) mouse calvariae were incubated in the absence or presence of either paricalcitol or calcitriol for 48 hours, and calcium flux, osteocalcin and acid and alkaline phosphatase activity, and interleukin-6 (IL-6) release were determined. Increasing concentrations of both calcitriol and paricalcitol increased calcium efflux. At lower concentrations, paricalcitol had no effect on acid phosphatase activity; however, at 10(-8) mol/L, paricalcitol caused a significant increase similar to that of calcitriol at 10(-9) mol/L. Increasing concentrations of paricalcitol had no effect on alkaline phosphatase activity, whereas calcitriol (10(-8) mol/L) caused significant inhibition. At low concentrations, paricalcitol had no effect on osteocalcin release; however, at 10(-8) mol/L, both compounds significantly increased osteocalcin production. Neither compound had an effect on IL-6 release. These data show that: (1) at low concentrations, both compounds induce a similar calcium efflux from cultured bone; (2) at low concentrations, paricalcitol has no effect on osteocalcin or acid and alkaline phosphatase activity; (3) at greater concentrations, paricalcitol and calcitriol have similar effects on acid phosphatase and osteocalcin activity; (4) calcitriol, but not paricalcitol, inhibits alkaline phosphatase release; and (5) the bone-resorbing effect of both compounds is independent of IL-6 release. Thus, although both compounds have similar effects on calcium efflux from bone, at therapeutic concentrations, paricalcitol does not seem to inhibit osteoblast activity. This may explain, in part, the lower calcemic effect of paricalcitol.

Acid Phosphatase↗
PubMed2003

Effect of oral calcitriol pulse therapy on the lipid, calcium, and glucose homeostasis of hemodialysis-patients: its safety in a combination with oral calcium carbonate.

OBJECTIVE: To more clearly elucidate the conflicting results that have been obtained after oral calcitriol pulse therapy on lipid, glucose, and calcium levels in hemodialysis (HD) patients, and to determine safety of oral calcitriol pulse therapy in a combination with calcium carbonate. DESIGN: A randomized, crossover, placebo-controlled study. SETTING: HD centers in 3 teaching university hospitals. PATIENTS: Forty-eight chronic HD patients. METHODS: HD patients were randomized into 2 groups. Each group (n = 24), in addition to 4.5 g calcium carbonate daily, received either oral calcitriol pulse therapy or placebo twice weekly at the end of HD, sessions for 3 months, after which the 2 therapeutic groups were crossed-over, and for an additional 3 months, the calcitriol group received placebo, and the placebo group was put on calcitriol. Serum triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), total calcium, alkaline phosphatase, proteins, phosphorus, parathyroid hormone (PTH), blood pH, and glucose were measured at random and at the end of 3 and 6 months of the trial. RESULTS: After calcitriol therapy, triglyceride, serum PTH, total alkaline phosphatase, and fasting blood sugar significantly decreased, but total serum calcium significantly increased, whereas other examined parameters remained unchanged compared with the other groups. Calcium, phosphorus, calcium x phosphorus product, PTH levels, and all of these parameters were optimized in 18 (37.5%), 22 (45.8%), 34 (70.8%), 30 (62.5%), and 12 (%25) cases, respectively, in the calcitriol groups. No significant side effect was seen during the trial. CONCLUSION: Our findings indicate that short-term oral calcitriol pulse therapy in combination with calcium carbonate is safe and beneficial for metabolic abnormalities of HD patients; however, its safety for prolonged therapy is yet to be proved.

Adult↗
PubMed2003

Effects of calcitriol on parathyroid function and on bone remodelling in secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (2HPT) develops in chronic renal failure due to disturbances of calcium, phosphorus and vitamin D metabolism. It is characterized by high turnover bone disease and an altered calcium-parathyroid hormone (PTH) relationship. Calcitriol has been widely used for the treatment of 2HPT. However, it remains controversial whether calcitriol is capable of inducing changes of the calcium-PTH curve. The aim of the present study was to examine this issue and to determine the effect of calcitriol on bone remodelling in patients with severe 2HPT. METHODS: We evaluated 16 chronic haemodialysis patients with severe 2HPT (PTH 899+/-342 pg/ml). Each patient underwent a dynamic parathyroid function test (by infusion of calcium gluconate and sodium citrate) and a bone biopsy before and after a 6 month period of i.v. calcitriol therapy (CTx). RESULTS: After treatment, eight patients were identified as calcitriol responders and the other eight as non-responders, based on plasma PTH level (<300 pg/ml for responders and >300 pg/ml for non-responders). The first group had higher plasma 25OHD(3) levels (39+/-8 vs 24+/-7 ng/ml, P<0.005). As to the calcium-PTH curve, we found differences in slope (-12.7+/-5.2 vs -21.7+/-11.4, P=0.05), basal/maximum PTH ratio (48.8+/-14.9 vs 71.05+/-20.1%, P=0.01) and time to achieve hypocalcaemia (79.0+/-13.5 vs 94.3+/-13.7 min, P<0.001). Initial histomorphometric parameters did not allow identification of the different groups. After the 6-month CTx, alterations in the calcium-PTH curve were clearly seen in responders [a drop in maximum PTH (from 1651+/-616 to 938+/-744 pg/ml, P<0.05) and minimum PTH (from 163+/-75.4 to 102.2+/-56.7 pg/ml, P<0.005)], associated with an increase in minimum/basal PTH ratio (from 23.3+/-11.6 to 34.5+/-20.4%, P<0.05) and maximum calcium (from 0.99+/-0.07 to 1.1+/-0.09 mmol/l, P<0.05). Set point and slope were not altered after calcitriol treatment, in responders (set point=1.17+/-0.08 vs 1.15+/-0.1 mmol/l, ns; slope=-12.7+/-5.2 vs -12.9+/-9.3, ns) or non-responders (set point=1.21+/-0.05 vs 1.21+/-0.2 mmol/l, ns; slope=-21.7+/-11.4 vs -17.3+/-8.4, ns). Bone formation parameters were reduced in all patients [osteoid surface (OS/BS)=from 57.1+/-21.6 to 41.6+/-26%, P<0.05 for responders, and from 76.7+/-12 to 47.1+/-15%, P<0.001 in non-responders], but non-responders had increased bone resorption [eroded surface (ES/BS)=7.1+/-3.4 vs 16.6+/-4.9, P<0.05]. CONCLUSION: Calcitriol had non-uniform effects on parathyroid function and bone remodelling in uraemic patients. Non-responders exhibited a decoupled remodelling process that could further influence mineral balance or possibly also bone structure. To avoid such undesirable effects, early identification of non-responder patients is crucial when using calcitriol for the treatment of 2HPT.

Adult↗
PubMed1995

Suppression of circulating calcitriol and duodenal active Ca transport by ketoconazole in pregnant rats.

Active Ca transport in the duodenum and the circulating level of calcitriol are elevated during pregnancy and lactation in the rat. Because calcitriol stimulates Ca transport in nonmated rats, we investigated its contribution to the increased transport during pregnancy and lactation. Rapid suppression of calcitriol from 28 +/- 3 to 8 +/- 0.4 pg/ml with the steroid hydroxylase inhibitor ketoconazole resulted in a 34% suppression of Ca transport in nonmated rats. At the end of pregnancy, when calcitriol concentration was suppressed from 64 +/- 7 to 12 +/- 2 pg/ml, the transport ratio decreased by 44%. Ca transport did not correlate with calcitriol levels between 40 and 80 pg/ml, suggesting a threshold level for maximal Ca transport stimulation. During lactation at even higher calcitriol levels, ketoconazole treatment again resulted in marked reduction in calcitriol from 124 +/- 1 to 71 +/- 12 pg/ml, but without any concurrent reduction in Ca transport in the duodenum. We conclude that in the vitamin D-replete rat the pregnancy-mediated, and probably also the lactation-mediated, increase in active Ca transport capacity is dependent on an increase in circulating calcitriol up to a certain threshold level.

Animals↗
PubMed1998

Intravenous calcitriol improves anaemia and reduces the need for erythropoietin in haemodialysis patients.

In cases with severe hyperparathyroidism, anaemia improves after parathyroidectomy. The objective of this study was to investigate the influence of treatment with intravenous calcitriol on anaemia in 28 haemodialysis patients. The patients showed moderate to severe hyperparathyroidism (mean parathyroid hormone level 811.6 +/- 327 pg/ml) and were treated with calcitriol (2 microg i.v.) after haemodialysis. The follow-up period was 12 months. 21 out of the 28 patients had been receiving erythropoietin (EPO) prior to calcitriol administration; the remaining 7 did not receive EPO. 24 patients received oral or intravenous iron. The doses of EPO and iron were modified throughout the study period to maintain a haematocrit equal to or higher than 30% and ferritin levels above 150 ng/ml, respectively. EPO needs were evaluated according to the relation EPO dose/haematocrit. We found a significant rise in haematocrit and haemoglobin at 3 and 12 months on calcitriol therapy, with no modification of the EPO dose nor ferritin levels. This improvement in anaemia was observed both in those patients who received EPO initially (p < 0.01) and in those who did not (p < 0.05). Upon dividing the patients according to the response of hyperparathyroidism to the intravenous calcitriol treatment, we observed in the responding patients (n = 19) significant increases in haematocrit (from 31.7 +/- 4.2 to 36.3 +/- 4.9%) and haemoglobin(from 10.6 +/- 1.5 to 12.2 +/- 1.5 g/dl; p < 0.001) at 12 months on intravenous calcitriol therapy, while this was not true of the non-responding patients. The EPO needs diminished in the group of responding patients and increased in the non-responders, although these changes were not statistically significant. We found no direct correlation between the decrease of parathyroid hormone and EPO needs in the group of responding patients. However, an inverse correlation between parathyroid hormone levels and EPO needs (r = -0.799, p < 0.05) was seen in the group of non-responding patients. Treatment with intravenous calcitriol in patients on haemodialysis controls secondary hyperparathyroidism, improves anaemia, and decreases the need for EPO. Studies including a larger number of patients are necessary to clarify the mechanisms underlying the improvement of anaemia upon control of secondary hyperparathyroidism with intravenous calcitriol treatment and to confirm our findings.

Alkaline Phosphatase↗
PubMed1991

Hypercalciuria due to combined growth hormone and calcitriol therapy in uremia: effects of growth hormone on mineral homeostasis in 75% nephrectomized weanling rats.

The administration of growth hormone (GH) in conjunction with calcitriol in uremia may increase urinary calcium and decrease renal phosphate excretion, which could have an adverse effect on the kidney in chronic renal insufficiency. The effect of 40 d of ovine GH, calcitriol, and the combination of GH and calcitriol on mineral excretion was studied in rapidly growing uremic rats. Uremia was produced by 75% nephrectomy, and the animals were fed a diet containing 8% protein with equal quantities of calcium (0.6%) and phosphate (0.6%). The uremic rats treated with ovine GH were significantly longer and heavier than the uremic control rats and the uremic rats treated with calcitriol alone. However, the combination of calcitriol and GH abolished the beneficial effect of GH on growth and increased urinary calcium excretion 4-fold over uremic controls whether expressed as calcium excretion per 100 g body weight, urine calcium to creatinine ratio, or as fractional calcium excretion. Calcitriol therapy alone also significantly increased calcium excretion, but not to the extent that the combination therapy did. This increased urinary calcium excretion in the GH plus calcitriol group was not associated with an increase in calcium and sodium intake, plasma ionized calcium, or urinary sodium excretion. The calcium content of the femurs from all uremic rat groups was significantly lower than that of the sham control rats; however, there was also no further decrease in bone calcium content in the GH plus calcitriol group compared with uremic controls. This indicated that bone was not the source of this excess urinary calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Antitumorigenic and antiinsulinogenic effects of calcitriol on insulinoma cells and solid beta-cell tumors.

Malignant insulinoma is a rare form of cancer with a poor prognosis because of metastatic dissemination and untreatable hypoglycemia. Effective chemotherapy of patients who are not cured by surgery is needed. Calcitriol has known anticancer properties on different neoplastic cell lines, but no data are available regarding its activity on tumorigenic pancreatic beta-cells. We analyzed the in vitro effects of calcitriol on the murine insulinoma cell line betaTC(3) and primary cultures of human isolated islets and benign insulinoma. The effect of in vivo calcitriol administration on insulinoma of recombinant insulin/Simian virus 40 oncogene-expressing transgenic mice was also investigated. In betaTC(3), calcitriol induced growth inhibition; apoptosis; down-regulation of insulin gene expression; and nongenomic activation of the MAPK pathway. MAPK kinase inhibitor (UO126) and staurosporine reduced calcitriol-mediated betaTC(3) death, and down-regulation of insulin gene transcription was prevented by staurosporine but not UO126. Calcitriol significantly decreased insulin release and mRNA levels of human islets and insulinoma cells. Finally, recombinant insulin/Simian virus 40 oncogene-expressing transgenic mice treated with calcitriol showed reduced insulinoma volumes because of increased apoptosis of adenomatous cells. Together, these findings provide the rationale for testing the efficacy of calcitriol in the treatment of patients with solid beta-cell tumors.

Animals↗
PubMed2000

Calcitriol-induced apoptosis in LNCaP cells is blocked by overexpression of Bcl-2.

While the role of vitamin D in bone and mineral metabolism has been investigated extensively, the role of the vitamin D receptor in other tissues is less well understood. 1,25-Dihydroxyvitamin D3 (calcitriol) can act as a differentiating agent in normal tissues and can inhibit the growth of many cancer cell lines including LNCaP prostate cancer cells. We have shown previously that calcitriol causes LNCaP cell accumulation in the G0/G1 phase of the cell cycle. In this study, we demonstrate that calcitriol also induces apoptosis of LNCaP cells. The calcitriol-induced apoptosis is accompanied by a down-regulation of Bcl-2 and Bcl-X(L) proteins, both of which protect cells from undergoing apoptosis. Other proteins important in apoptotic control, Bax, Mcl-1, and Bcl-X(S), are unaffected by calcitriol treatment. We find that overexpression of Bcl-2 blocks calcitriol-induced apoptosis and reduces, but does not eliminate, calcitriol-induced growth inhibition. We conclude that both regulation of cell cycle and the apoptotic pathway are involved in calcitriol action in prostate cancer cells.

Apoptosis↗
PubMed1991

Differential stimulation of fos and jun family members by calcitriol in osteoblastic cells.

We have looked at the effects of calcitriol (1 alpha,25-dihydroxyvitamin D3) on the expression of the members of the fos and jun families of protooncogenes in an osteoblastic cell line and in primary cultures of osteoblasts. Calcitriol treatment of starved, confluent cultures of MC3T3-E1 cells induced a rapid and transient stimulation of the expression of c-fos, fos-B, c-jun, and jun-B with varying kinetics. The expression of fra-1 and jun-D was not affected by calcitriol in those cells. The selective stimulation of fos and jun family members by calcitriol was also observed in primary cultures of osteoblasts isolated from newborn mouse calvaria, suggesting that this modulation is a physiological response of the bone cells and not an artefact of the established cell line. The calcitriol effect was specific and dose-dependent. The expression of the c-Fos protein correlated with the expression of the mRNA in calcitriol-treated cells. The calcitriol-induced stimulation of c-fos expression was modulated, at least in part, at the level of the initiation and elongation of transcription, whereas its effects on c-jun and jun-B expression was controlled at the posttranscriptional level by a mechanism that does not implicate stabilization of their respective mRNAs. The differential stimulation of the expression of certain members of the fos and jun families by calcitriol support a role for these oncoproteins in bone cell physiology.

Animals↗