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PubMed1989

Direct inhibitory effect of calcitriol on parathyroid function (sigmoidal curve) in dialysis.

The effect of intravenous calcitriol on parathyroid function was evaluated in nine chronic hemodialysis patients with secondary hyperparathyroidism. Two micrograms of calcitriol were administered intravenously after dialysis thrice weekly for ten weeks. Parathyroid function was assessed by inducing hypo- and hypercalcemia with low calcium (1.0 mEq/liter) and high calcium (4.0 mEq/liter) dialyses before and after ten weeks of intravenous calcitriol therapy. To avoid hypercalcemia during calcitriol administration, the dialysate calcium was reduced to 2.5 mEq/liter. Parathyroid hormone (PTH) values (pg/ml) from dialysis-induced hypo- and hypercalcemia were plotted against serum ionized calcium, and the sigmoidal relationship between PTH and calcium was evaluated. Basal PTH levels fell from 902 +/- 126 pg/ml to 466 +/- 152 pg/ml (P less than 0.01) after therapy without a significant change in the serum total calcium concentration. The ionized calcium-PTH sigmoidal curve shifted to the left and downward after calcitriol therapy. The maximal PTH response during hypocalcemia decreased after calcitriol from 1661 +/- 485 pg/ml before calcitriol to 1031 +/- 280 pg/ml afterward (P less than 0.05). The PTH level at maximal inhibition due to hypercalcemia decreased from 281 +/- 76 pg/ml before calcitriol to 192 +/- 48 pg/ml afterward (P less than 0.05). The slope of the sigmoidal curve changed from -2125 +/- 487 to -1563 +/- 385 (P less than 0.05). The set point of ionized calcium (4.60 +/- .11 mg/dl before vs. 4.44 +/- .07 mg/dl after) did not change significantly with calcitriol therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcitriol↗

PubMed1985

Identification of intestinal cells responsive to calcitriol (1,25-dihydroxycholecalciferol).

The location of intestinal cells taken from the base of the crypt to the tip of the villus responsive to calcitriol (1,25-dihydroxycholecalciferol) and the distribution of [3H]calcitriol within the intestinal epithelium has been determined in vitamin D-deficient rats. The calcitriol responses examined were CaBP (Ca2+-binding protein) levels as measured by immunodiffusion and alkaline phosphatase levels as determined cytochemically. Calcitriol had no effect on villus structure or on enterocyte kinetics. This made it possible to compare levels of CaBP and alkaline phosphatase activity in enterocytes at different ages in rats at known times after hormone injection. Cells from both the crypt and villus synthesized CaBP in response to calcitriol. Alkaline phosphatase activity was not detectable in crypt cells, although a pool of precursor was produced in these cells in response to calcitriol. Enzyme activity was increased in all villus cells in response to calcitriol, but the quantitative description of this effect was very different from that found for calcitriol effects on CaBP synthesis. Calcitriol injected into vitamin D-deficient rats was detected, within 2h, in all cells of the crypt and villus. Most of the binding was to sites having a high affinity for the injected hormone.

Alkaline Phosphatase↗

PubMed2003

Topical calcitriol is degraded by ultraviolet light.

Calcitriol ointment has been approved for the treatment of psoriasis in many countries around the world. It may be prescribed in conjunction with phototherapy. Our purpose was to evaluate the effect of various therapeutic ultraviolet modalities on the stability of calcitriol and, conversely, to study the effects of calcitriol ointment on transmission of different forms of ultraviolet light. Calcitriol ointment 3 microg per g was irradiated with 10 J per cm2 ultraviolet A, 100 mJ per cm2 broadband ultraviolet B, and 3.0 J per cm2 narrowband ultraviolet B, and its stability was compared with samples exposed to fluorescent light and ambient sunlight. Ultraviolet A and ultraviolet B transmission were measured through thin and thick layers of calcitriol 3 microg per g ointment and vehicle. More than 90% of calcitriol ointment is degraded upon exposure to ultraviolet A, broadband ultraviolet B, and narrowband ultraviolet B. Transmission of ultraviolet A is reduced through calcitriol ointment and its vehicle by 17%-31% and 17%-41%, respectively. Transmission of ultraviolet B is reduced by 67%-87% through vehicle and 50%-83% through calcitriol ointment. When used in conjunction with phototherapy, calcitriol ointment should be applied after ultraviolet exposure, not before. Calcipotriene, the only vitamin D analog already approved for psoriasis in the USA, has been used successfully in combination with ultraviolet B and psoralen plus ultraviolet A.

Administration, Topical↗

PubMed2003

Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy.

BACKGROUND: Elevated calcium and phosphorus levels after therapy with injectable vitamin D for secondary hyperparathyroidism may accelerate vascular disease and hasten death in patients undergoing long-term hemodialysis. Paricalcitol, a new vitamin D analogue, appears to lessen the elevations in serum calcium and phosphorus levels, as compared with calcitriol, the standard form of injectable vitamin D. METHODS: We conducted a historical cohort study to compare the 36-month survival rate among patients undergoing long-term hemodialysis who started to receive treatment with paricalcitol (29,021 patients) or calcitriol (38,378 patients) between 1999 and 2001. Crude and adjusted survival rates were calculated and stratified analyses were performed. A subgroup of 16,483 patients who switched regimens was also evaluated. RESULTS: The mortality rate among patients receiving paricalcitol was 3417 per 19,031 person-years (0.180 per person-year), as compared with 6805 per 30,471 person-years (0.223 per person-year) among those receiving calcitriol (P<0.001). The difference in survival was significant at 12 months and increased with time (P<0.001). In the adjusted analysis, the mortality rate was 16 percent lower (95 percent confidence interval, 10 to 21 percent) among paricalcitol-treated patients than among calcitriol-treated patients. A significant survival benefit was evident in 28 of 42 strata examined, and in no stratum was calcitriol favored. At 12 months, calcium and phosphorus levels had increased by 6.7 and 11.9 percent, respectively, in the paricalcitol group, as compared with 8.2 and 13.9 percent, respectively, in the calcitriol group (P<0.001). The two-year survival rate among patients who switched from calcitriol to paricalcitol was 73 percent, as compared with 64 percent among those who switched from paricalcitol to calcitriol (P=0.04). CONCLUSIONS: Patients who receive paricalcitol while undergoing long-term hemodialysis appear to have a significant survival advantage over those who receive calcitriol. A prospective, randomized study is critical to confirm these findings.

Adult↗

PubMed2004

Alendronate versus calcitriol for the prevention of bone loss after cardiac transplantation.

BACKGROUND: Osteoporosis is a well-known complication of cardiac transplantation. We conducted a randomized trial comparing alendronate with calcitriol for the prevention of bone loss during the first year after cardiac transplantation. METHODS: A total of 149 patients were randomly assigned to receive either alendronate (10 mg per day) or calcitriol (0.5 microg per day) a mean (+/-SD) of 21+/-11 days after transplantation. Estimates of bone loss and the incidence of fractures among untreated patients were obtained from a reference group of 27 prospectively recruited patients who received cardiac transplants within the same period as the intervention groups. RESULTS: At one year, the bone mineral density at the lumbar spine had decreased by a mean of 0.7 percent in the alendronate group and 1.6 percent in the calcitriol group (P=0.25 for the test of no difference). The bone mineral density at the femoral neck decreased by a mean of 1.7 percent in the alendronate group and 2.1 percent in the calcitriol group (P=0.69). In the reference group, the mean bone mineral density at the lumbar spine decreased by 3.2 percent (P=0.03 for the comparison with the alendronate group; P=0.15 for the comparison with the calcitriol group), and the mean density at the femoral neck decreased by 6.2 percent (P=0.001 for comparisons with both intervention groups). The incidence of vertebral fractures did not differ significantly among the groups (6.8 percent in the alendronate group, 3.6 percent in the calcitriol group, and 13.6 percent in the reference group). Hypercalciuria developed in 27 percent of the patients in the calcitriol group and 7 percent of those in the alendronate group (P=0.01). CONCLUSIONS: The degree of bone loss and the rates of fracture did not differ significantly between the intervention groups. Calcitriol was associated with a higher risk of hypercalciuria. Alendronate-treated patients sustained less bone loss at the spine than those in the reference group, and both intervention groups sustained less bone loss at the hip than the reference group. The requirement for monitoring the serum and urinary calcium levels in calcitriol-treated patients makes alendronate more attractive for the prevention of bone loss early after cardiac transplantation.

Alendronate↗

PubMedDate not supplied

Suppression of hyperparathyroidism by calcitriol therapy.

We reviewed the charts of 160 patients on hemodialysis and identified 33 with parathyroid hormone (PTH) > 800 pg/ml at any time during the last 3 years to confirm our impression that patients with PTH elevations for short durations of time require significantly smaller doses of calcitriol than those with prolonged PTH elevations. We divided the patients into two groups: 18 with PTH > 800 pg/ml on three or fewer occasions (Group 1, short-term hyperparathyroidism) and 15 with PTH > 800 pg/ml more than three times (Group 2, long-term hyperparathyroidism). Most patients received once weekly intravenous calcitriol, but if this failed to suppress PTH, the dose was increased gradually to three times a week, PTH was measured at mid-week, calcitriol was held if serum calcium rose to >11 mg/dl, and calcitriol was started again when calcium fell to <11 mg/dl. We found that the duration of dialysis was generally shorter in Group 1, as were maximal PTH levels. Calcitriol suppressed PTH levels to <200 pg/ml in both groups. However, the weekly dose of calcitriol needed to suppress PTH was significantly lower in Group 1 (5.4 +/- 1.2 microg in Group 1 and 11.4 +/- 1.8 microg in Group 2; p < 0.001). Further follow-up of seven patients for 1 more year showed continued suppression of PTH, and the dose of calcitriol required to maintain the suppression was lower than the initial dose. Thus patients with longer histories of dialysis and prolonged hyperparathyroidism required higher doses of calcitriol to suppress PTH to the same level as patients who were new on dialysis or with transient hyperparathyroidism. A protocol of three times weekly, high dose calcitriol with strict monitoring of serum calcium will avoid parathyroidectomy in most cases.

Calcitriol↗

PubMed1987

Production and degradation of calcitriol in renal failure rats.

We studied the metabolism of calcitriol in renal failure achieved by nephrectomy in three groups of rats. Group 1 (n = 7) had sham operation of nephrectomy. Group 2 (n = 8) had unilateral nephrectomy. Group 3 (n = 7) had 5/6 nephrectomy. Metabolic clearance rate (MCR) and production rate (PR) of calcitriol were studied 3 wk after the surgery. Serum creatinine concentrations were increased after nephrectomy for groups 2 and 3. Endogenous plasma levels of calcitriol were not different between the rats with renal failure and the controls. MCR of calcitriol were decreased in renal failure rats compared with controls (group 1, 0.24 +/- 0.01; group 2, 0.20 +/- 0.01, P less than 0.01; group 3, 0.16 +/- 0.01 ml.min-1.kg-1, P less than 0.001). The MCR of calcitriol was correlated with the endogenous creatinine clearance by linear regression analysis (r = 0.72, P less than 0.001). The PR of calcitriol were also decreased in renal failure; however, the decreases were much less than the amount of renal tissue removed. We concluded that production of calcitriol is decreased in the remnant kidney. The decreased synthesis is associated with decreased degradation of calcitriol resulting in normal concentrations of calcitriol in mild to moderately severe renal failure.

Animals↗

PubMed2002

Clinical effect of intravenous calcitriol administration on secondary hyperparathyroidism. A double-blind study among 4 doses.

BACKGROUND/AIMS: Although the PTH-suppressive effect of intravenous calcitriol has already been demonstrated by various studies, the precise dose-response to calcitriol has not been fully determined for uremic secondary hyperparathyroidism (2HPT). In order to investigate in detail the dose-response of intravenous calcitriol and the adequate initial dose against 2HPT, a randomized prospective double-blind study was conducted. METHOD: One-hundred and sixty-two patients with 2HPT undergoing hemodialysis three times per week were randomly assigned to four calcitriol (Ro21-5535) treatment groups, 0 (placebo), 1, 1.5 or 2 microg. Calcitriol or placebo was given intravenously after each dialysis for 12 weeks under double-blind conditions. RESULTS: Calcitriol dose-dependently reduced both intact-PTH and high-sensitivity assay mid-terminal (HS)-PTH levels. The rate of per-week change in intact-PTH was 0.0% in the placebo group, -7.8% in the 1-microg group, -18.9% in the 1.5-microg group and -24.1% in the 2-microg group. Calcitriol dose-dependently increased the rate of increase in serum Ca adjusted by albumin level. The per-week increases in adjusted serum Ca were -0.01, 0.08, 0.23 and 0.35 mg/dl in the placebo, 1-, 1.5- and 2-microg groups, respectively. Although the degree of PTH suppression was correlated with the adjusted serum Ca increase, by-patients investigation revealed that the number of patients with suppression of PTH despite of no or slight elevation of adjusted serum Ca level was largest in the 1-microg group among the three calcitriol groups. CONCLUSION: Intravenous calcitriol was found to have a clear dose-dependent effect on PTH reduction in patients with 2HPT, and the appropriate initial dose of this agent was determined to be 1 microg per dialysis session.

Adult↗

PubMed1990

Effect of physiological concentrations of calcitriol on lymphocyte proliferation in normal subjects and in patients with renal failure.

Specific receptors for calcitriol (1,25-dihydroxyvitamin D) have been found in immune cells, such as monocytes and activated lymphocytes, suggesting that calcitriol may play an immunoregulatory role. In fact, a marked increase in lymphocyte proliferation has been reported after treating hemodialyzed patients with 1 alpha-hydroxyvitamin D3, a precursor of calcitriol. We have studied in vitro the effect of calcitriol depletion and calcitriol addition on the phytohemagglutinin-induced mitogenesis of peripheral blood mononuclear cells from 14 healthy subjects and 8 hemodialyzed patients. The calcitriol depletion of culture medium did not modify cell proliferation. The addition of calcitriol in concentrations about the physiological range (10(-11) M) induced a small, marginally significant, 11% increase in the proliferation of lymphocytes from hemodialysis patients. Supraphysiological concentrations (10(-9)-10(-7) M) induced a marked inhibition (up to 60% of control values) of cell mitogenesis, both in patients and in healthy subjects. These results suggest that the increase in lymphocyte proliferation observed in vivo after treatment with calcitriol precursors is not mediated by a direct effect of calcitriol on circulating mononuclear cells.

Adult↗

PubMed1994

In vivo effect of calcitriol on calcium transport and calcium binding proteins in the spontaneously hypertensive rat.

The abnormal intestinal Ca2+ transport reported in spontaneously hypertensive rats (SHR) has been attributed to decreased responsiveness to calcitriol. We reexamined this hypothesis by studying the calcitriol regulation of SHR duodenal calbindin-D9K and calmodulin and the relation of calcitriol to Ca2+ uptake by isolated enterocytes. SHR and normotensive Wistar-Kyoto (WKY) rats were injected with either 50 ng/d calcitriol (vit-D) or vehicle alone (control) for 3 days. Decreased calbindin-D9K (P < .001) and cellular Ca2+ flux (P < .001) were observed in control SHR. Calcitriol increased total cell and brush border calbindin-D9K (P < .0001); this variation paralleled plasma calcitriol levels in both strains. In contrast, Ca2+ flux, which increased in vit-D animals, remained lower in SHR for plasma calcitriol levels similar to those in WKY rats. Immunoreactive calmodulin was similar in both strains whether assayed in total cell or brush border membranes. In contrast, when measured by ligand blotting (45Ca), calmodulin was lower in SHR than in WKY rats (P < .01), suggesting the existence of a calmodulin pool with reduced Ca2+ binding capacity in the hypertensive strain. Calcitriol had no effect on calmodulin in either strain. In conclusion, Ca2+ binding protein regulation by calcitriol is normal in the SHR, and decreased hormone responsiveness cannot account for the defective duodenal calcium transport of this experimental model of hypertension.

Animals↗

PubMed1985

Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol.

Although conventional therapy (pharmacologic doses of vitamin D and phosphorus supplementation) is usually successful in healing the rachitic bone lesion in patients with X-linked hypophosphatemic rickets, it does not heal the coexistent osteomalacia. Because serum 1,25-dihydroxyvitamin D levels are inappropriately low in these patients and high calcitriol concentrations may be required to heal the osteomalacia, we chose to treat five affected subjects with high doses of calcitriol (68.2 +/- 10.0 ng/kg total body weight/d) and supplemental phosphorus (1-2 g/d) performing metabolic studies and bone biopsies before and after 5-8 mo of this therapy in each individual. Of these five patients, three (aged 13, 13, and 19 yr) were receiving conventional treatment at the inception of the study and therefore showed base-line serum phosphorus concentrations within the normal range. The remaining two untreated patients (aged 2 and 37 yr) displayed characteristic hypophosphatemia before calcitriol therapy. All five patients demonstrated serum calcitriol levels in the low normal range (22.5 +/- 3.2 pg/ml), impaired renal phosphorus conservation (tubular maximum for the reabsorption of phosphate per deciliter of glomerular filtrate, 2.13 +/- 0.20 mg/dl), and osteomalacia on bone biopsy (relative osteoid volume, 14.4 +/- 1.7%; mean osteoid seam width, 27.7 +/- 3.7 micron; mineral apposition rate, 0.46 +/- 0.12 micron/d). On high doses of calcitriol, serum 1,25-dihydroxyvitamin D levels rose into the supraphysiologic range (74.1 +/- 3.8 pg/ml) with an associated increment in the serum phosphorus concentration (2.82 +/- 0.19 to 3.78 +/- 0.32 mg/dl) and improvement of the renal tubular maximum for phosphate reabsorption (3.17 +/- 0.22 mg/dl). The serum calcium rose in each patient while the immunoactive parathyroid hormone concentration measured by three different assays remained within the normal range. Most importantly, repeat bone biopsies showed that high doses of calcitriol and phosphorus supplements had reversed the mineralization defect in all patients (mineral apposition rate, 0.88 +/- 0.04 micron/d) and consequently reduced parameters of bone osteoid content to normal (relative osteoid volume, 4.1 +/- 0.7%; mean osteoid seam width, 11.0 +/- 1.0 micron). Complications (hypercalcemia and hypercalciuria) ensued in four of these five patients within 1-17 mo of documented bone healing, necessitating reduction of calcitriol doses to a mean of 1.6 +/- 0.2 micrograms/d (28 +/- 4 ng/kg ideal body weight per day). At follow-up bone biopsy, these four subjects continued to manifest normal bone mineralization dynamics (mineral apposition rate, 0.88 +/-0.10 micrometer/d) on reduced doses of 1.25-dihydroxyvitamin D with phosphorus supplements (2 g/d) for a mean of 21.3 +/- 1.3 mo after bone healing was first documented. Static histomorphometric parameters also remained normal (relative osteoid volume, 1.5 +/- 0.4%; mean osteoid seam width, 13.5 +/- 0.8 micrometer). These data indicate that administration of supraphysiologic amounts of calcitriol, in conjunction with oral phosphorus, results in complete healing of vitamin D resistant osteomalacia in patients with X-linked hypophosphatemic rickets. Although complications predictably require calcitriol dose reductions once healing is achieved, continued bone healing can be maintained for up to 1 yr with lower doses of 1,25-dihydroxyvitamin D and continued phosphorus supplementation.

Adolescent↗

PubMed1993

Effects of calcitriol, 22-oxacalcitriol, and calcipotriol on serum calcium and parathyroid hormone gene expression.

Calcitriol markedly decreases PTH gene transcription, but because of the concern about hypercalcemia, there is interest in nonhypercalcemic analogs. We have studied the effects of calcitriol, oxacalcitriol, and calcipotriol on serum calcium and PTH mRNA levels in vivo and in vitro. In vivo in rats, calcitriol was the most effective analog in decreasing PTH mRNA levels, with a maximal effect of about 70% at 25-100 pmol after 24 h. Only 100 pmol led to hypercalcemia. Oxacalcitriol led to a maximal decrease in PTH mRNA levels of 44% at 2 and 5 nmol, similar to 1 nmol calcipotriol. Oxacalcitriol at 200 and 500 pmol led to an increase in serum calcium at 3 h, but not at 6 and 24 h, unlike calcitriol (100 pmol) which caused an increase only at 24 h. In vitro, in primary cultures of bovine parathyroid cells, calcitriol and oxacalcitriol both decreased PTH mRNA levels at similar concentrations. Therefore, in vivo calcitriol is the most effective analog studied in decreasing PTH mRNA levels, including a range of doses that does not cause hypercalcemia. Oxacalcalcitriol and calcipotriol are less effective, but have a wider dose range where they do not cause hypercalcemia. The results in vitro confirm that oxacalcitriol and calcitriol both effectively decrease PTH mRNA levels at the same concentration. The marked activity of calcitriol analogs in vitro compared to in vivo probably reflects differences from calcitriol in their pharmacokinetics.

Animals↗

PubMed1998

Phosphate transport in pig proximal small intestines during postnatal development: lack of modulation by calcitriol.

The role of calcitriol in the intestinal absorption of inorganic phosphate (Pi) during postnatal development was studied in newborn [<1 week postpartum (pp)], suckling (3-4 weeks pp), and weaned (>6 weeks pp) control piglets (con) and piglets suffering from inherited calcitriol deficiency (def). In addition, a number of def piglets were treated with vitamin D3 (def-D3). Regardless of age, plasma calcitriol concentrations in def piglets were unphysiologically low (16-21 pg/ml) and differed significantly from those in respective con animals (60-69 pg/ml) and vitamin D3-treated def piglets (50-56 pg/ml). However, newborn and suckling def piglets had normal Ca (approximately 3.0 mmol/liter) and Pi (approximately 2.8 mmol/liter) plasma levels. Def piglets became hypocalcemic (1.9 mmol/liter) and hypophosphatemic (1.9 mmol/liter) between 4-6 weeks pp. Treatment with vitamin D3 significantly increased plasma Ca (3.2 mmol/liter) and Pi (2.7 mmol/liter) levels in weaned def animals. Regardless of calcitriol status, net Pi flux rates (active Pi absorption, as determined with the in vitro Ussing-chamber technique) from the upper small intestines was maximal at birth [170-224 nmol/(cm2 x h)] and decreased by approximately 80% during the first week of life before remaining constant [30-50 nmol/(cm2 x h)] during the following development. In weaned def piglets, net Pi flux rates were significantly lower by about 80% compared with those in con animals. Treatment of def piglets with vitamin D3 had no effect in newborn and suckling animals but reconstituted net Pi flux rates to normal values at weaning age. Age-dependent and calcitriol-mediated changes in net Pi flux rates were paralleled by respective maximum velocity values of Na+-dependent Pi uptake across the brush border membrane of the enterocytes (newborn piglets, 1.9-2.2 nmol/(mg protein 10 sec); suckling piglets, 0.4-0.6 nmol/(mg protein x 10 sec); weaned piglets, 0.7, 0.3, and 0.7 nmol/(mg protein x 10 sec) in con, def, and def-D3 animals, respectively). These findings suggest that the apical Pi uptake represents the major rate-limiting step of the overall transepithelial Pi transport. At weaning, Na+/Pi transport across the intestinal brush-border membrane is clearly stimulated by calcitriol, but no significant effects of age or calcitriol on the Km values (0.5-0.7 mmol/liter) were observed. In conclusion, our findings reveal calcitriol-independent mechanisms for active intestinal Pi absorption during the neonatal and suckling periods. The onset of the classical calcitriol-dependent mechanism for active intestinal Pi absorption does not occur until weaning.

Animals↗

PubMed1999

[Effects of calcitriol and alfacalcidol on an osteoporosis model in rats with hepatic failure].

To predict the potential utility of calcitriol in human osteoporosis with hepatic dysfunction, we examined the effects of calcitriol and alfacalcidol in ovariectomized (OVX) aged-rats with CCl4-induced hepatic failure. In OVX+CCl4 rats, GOT, GTP, alkaline phosphatase and total bilirubin increased and hepatic enzyme activity (cytochrome b5 and P450) decreased. Repeated oral doses of calcitriol (0.1 and 0.2 microgram/kg) for 51 days inhibited a decrease in serum calcium concentration. This effect was more potent than that of alfacalcidol at the same dose. Both drugs tended to inhibit a decrease in femoral calcium contents. Calcitriol (0.2 microgram/kg) prevented a decrease in femoral bone density (dry and ash weight per volume), unlike alfacalcidol. Soft X-ray imaging analysis revealed that both drugs tended to inhibit the decrease in femoral bone density. There were no differences in the femoral bone strength between OVX+CCl4 and sham-operated rats. The serum calcitriol concentrations increased after the last doses of calcitriol, while they did not increase after the last dose of alfacalcidol. All these effects of calcitriol were related to the serum calcitriol levels. These results suggest that calcitriol, unlike alfacalcidol, may have a clinical therapeutic effect in osteoporosis with hepatic dysfunction.

Animals↗

PubMed2025

Transcriptomic profile induced by calcitriol in CaSki human cervical cancer cell line.

The vitamin D endocrine system, primarily mediated by its main metabolite calcitriol and the vitamin D receptor (VDR), plays a critical role in numerous human physiological processes, ranging from calcium metabolism to the prevention of various tumors, including cervical cancer. In this study, we comprehensively investigated the genomic regulatory effects of calcitriol in a cervical cancer model. We examined the transcriptional changes induced by calcitriol in CaSki cells, a cervical cell line harboring multiple copies of HPV16, the primary causal agent of cervical cancer. Our microarray findings, revealed that calcitriol regulated over 1000 protein-coding genes, exhibiting a predominantly repressive effect on the CaSki cell transcriptome by suppressing twice as many genes as it induced. Calcitriol decreased EPHA2 and RARA expression while inducing KLK6 and CYP4F3 expression in CaSki cells, as validated by qPCR and Western blot. Functional analysis demonstrated that calcitriol effectively inhibited key processes involved in cancer progression, including cell proliferation and migration. This was further supported by the significant downregulation of MMP7 and MMP13 mRNA levels. Our microarray results also showed that, in addition to its effects on protein-coding genes, calcitriol significantly regulates non-coding RNAs, altering the expression of approximately 400 non-coding RNAs, including 111 microRNA precursors and 29 mature microRNAs, of which 17 were upregulated and 12 downregulated. Notably, among these calcitriol-regulated microRNAs are some involved in cervical cancer biology, such as miR-6129, miR-382, miR-655, miR-211, miR-590, miR-130a, miR-301a, and miR-1252. Collectively, these findings suggest that calcitriol exhibits a significant antitumor effect in this advanced cervical cancer model by blocking critical processes for tumor progression, underscoring the importance of maintaining adequate vitamin D nutritional status.

Humans↗

PubMed1991

The effect of long-term intravenous calcitriol administration on parathyroid function in hemodialysis patients.

Secondary hyperparathyroidism is common in dialysis patients. Intravenous calcitriol has proven to be an effective therapy for the reduction of parathyroid hormone (PTH) levels. However, the effect of i.v. calcitriol on parathyroid function, defined as the sigmoidal PTH-calcium curve developed during hypocalcemia and hypercalcemia, has not been evaluated during the prolonged administration of i.v. calcitriol. Six hemodialysis patients with marked secondary hyperparathyroidism, PTH levels greater than 500 pg/mL (normal, 10 to 65 pg/mL), were treated for 42 wk with 2 micrograms of i.v. calcitriol after each hemodialysis. Parathyroid function was evaluated before and after 10 and 42 wk of calcitriol therapy. Between baseline and 42 wk, the basal PTH level decreased from 890 +/- 107 to 346 +/- 119 pg/mL (P less than 0.02) and the maximally stimulated PTH level decreased from 1293 +/- 188 to 600 +/- 140 pg/mL (P less than 0.01). In addition, calcitriol administration significantly decreased PTH levels throughout the hypocalcemic range of the PTH-calcium curve. Although the slope of the PTH-calcium curve (with maximal PTH as 100%) decreased between baseline and 42 wk (P less than 0.05), the set point of calcium did not change. Two patients with a decrease in both basal and maximally stimulated PTH levels after 10 wk of calcitriol, developed marked hyperphosphatemia between 10 and 42 wk; this resulted in an exacerbation of hyperparathyroidism despite continued calcitriol therapy. In conclusion, prolonged i.v. calcitriol administration is an effective treatment for secondary hyperparathyroidism in hemodialysis patients provided that reasonable control of the serum phosphate is achieved. In addition, the slope of the PTH-calcium curve may be a better indicator of parathyroid cell sensitivity than the set point of calcium.

Adult↗

PubMed1991

Renal adaptation to dietary phosphate restriction in rats. Interactions with insulin and calcitriol.

Insulin may contribute to the increase in tubular reabsorption of phosphate during dietary phosphate restriction. Moreover, insulin is required for the stimulation of calcitriol under this experimental condition. To evaluate whether calcitriol plays a role in the antiphosphaturic effect of insulin during phosphate restriction, phosphate uptake was measured in brush border membrane vesicles (BBMVs) obtained from the following six experimental groups of rats: normal (0.8%)-phosphate diet for 1 wk, low (0.03%)-phosphate diet for 1 wk, normal-phosphate diet for 1 wk and streptozocin 48 h before the experiment, low-phosphate diet for 1 wk and streptozocin 48 h before the experiment, low-phosphate diet and streptozocin and exogenous insulin, and low-phosphate diet and streptozocin and exogenous calcitriol. BBMV phosphate uptake was higher in the nondiabetic rats on a low-phosphate diet than in the controls on a normal-phosphate diet. BBMV phosphate uptake was not different between diabetic rats on a normal-phosphate diet than in nondiabetic controls on the same diet. In contrast, BBMV was significantly lower in diabetic rats on a low-phosphate diet than in nondiabetic controls on the same diet. Exogenous insulin but not calcitriol restored the increase in BBMV phosphate uptake in diabetic rats on a low-phosphate diet. Plasma calcitriol levels were increased threefold in nondiabetic rats fed a low-phosphate diet. Streptozocin-induced diabetes abolished the adaptive increase in plasma calcitriol. Exogenous insulin and calcitriol administration to diabetic rats on a low-phosphate diet resulted in similar increases in plasma calcitriol levels. These results suggest that, during dietary phosphate restriction, insulin stimulates renal phosphate retention independently of its effect on calcitriol.

Acclimatization↗

PubMed1999

A Phase I trial of calcitriol (1,25-dihydroxycholecalciferol) in patients with advanced malignancy.

Vitamin D is a steroid hormone best known for its activity in regulating calcium and bone metabolism. Epidemiological evidence suggests that vitamin D may play a role in inhibiting the development of colon and prostate cancer. Vitamin D receptors are expressed in many types of malignant cells; in vitro and in vivo vitamin D and vitamin D analogues are active in suppressing the development and inhibiting the growth of numerous human and animal tumors. The major toxicity of the active form of vitamin D, 1,25-dihydroxycholecalciferol (calcitriol), is the induction of hypercalcemia. There are no data indicating the maximum tolerated dose of calcitriol administered every other day (QOD) s.c. We hypothesized that this route and schedule would permit administration of higher doses of calcitriol, which might have anticancer activity. We conducted a Phase I trial of calcitriol given s.c. QOD in patients with advanced solid tumors. Thirty-six patients were entered at doses ranging from 2 to 10 microg QOD; dose-limiting toxicity (hypercalcemia) occurred in three of three patients entered at the 10-microg QOD dose. Hypercalciuria occurred at all dose levels examined. No other toxicity was seen. Assessment of serum calcitriol concentrations by a RIA revealed a decrease in concentration-time curves on day 7 compared to day 1 of therapy. A dose-dependent increase in peak serum level and estimated area under the concentration-time curve was seen. The maximum serum levels occurred at the 10-microg QOD dose: 288 +/- 74 and 321 +/- 36 pg/ml at days 1 and 7, respectively. The normal range of calcitriol serum concentration, determined using this assay, is 16-56 pg/ml. Serum calcitriol levels were maintained at near peak concentrations for at least 8 h following s.c. injection. This study indicates that substantial doses of calcitriol can be administered via this route with tolerable toxicity. Studies to explore approaches to ameliorate the hypercalcemia induced by calcitriol and to explore alternative schedules and interactions with other agents are warranted.

Adenocarcinoma↗