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PubMed2000

In vitro and in vivo effects of vitamin D (calcitriol) administration on the normal neonatal and prepubertal prostate.

PURPOSE: Although many studies have investigated the role of calcitriol in the growth regulation of normal and cancerous prostates, little is known about its role in early prostatic development. The interactions between calcitriol and androgens, and their actions on the normal prostate have similarly been proposed but not evaluated. Previous studies in our laboratory have revealed that in utero administration of 1,25-dihydroxycholecalciferol or calcitriol can influence prostate growth and differentiation throughout the life of the animal. We further examined the influence of calcitriol on the normal prostate in vitro and in vivo by focusing on early stages of prostatic development. MATERIALS AND METHODS: The effects of calcitriol on the growth of the normal human neonatal prostatic epithelial cell line 267B-1 was determined in the presence and absence of dihydrotestosterone (DHT). We also examined the effect of calcitriol on the growth of maturing rat prostates in vivo. Before puberty 4 groups of rats 27 to 38 days old were treated with vehicle (controls) or calcitriol. When the rats reached adulthood at age 100 to 110 days a control group and a calcitriol group were sacrificed. The other 2 groups were given exogenous DHT for 5 days. For the animals to become adapted to DHT they were kept alive for 1 additional week and sacrificed at about age 120 days. RESULTS: In vitro studies demonstrated that 267B-1 cells possess vitamin D receptors and their growth was inhibited by calcitriol with an IC50 (concentration resulting in 50% cytotoxicity) of 30 microM. Proliferation of these neonatal prostate cells was also inhibited by calcitriol in the presence of DHT in vitro. Our studies indicate that, although calcitriol was administered at the apparently important prepubertal period, there was no difference in prostatic weights between the control and calcitriol treated rats. Exogenous administration of DHT decreased prostatic weight of control rats but in rats treated with 1,25-dihydroxycholecalciferol DHT did not have any significant effect on prostatic weight. No statistically significant differences were observed in seminal vesicle weights among the different groups of animals. Analysis of the nuclear matrix protein composition of the prostatic tissue showed differences in composition between the DHT, and calcitriol and DHT treated rat prostates. CONCLUSIONS: These studies indicate that calcitriol administered just before puberty does not significantly influence prostatic growth in the presence of endogenous or exogenous administered DHT, and has an inhibitory effect on neonatal prostate epithelial cell growth in vitro in the presence and absence of DHT. Treatment with calcitriol and DHT also results in differences in nuclear matrix protein composition. Prepubertal administration of calcitriol may inhibit the exogenous DHT action in decreasing epithelial growth and stimulating stromal proliferation in the rat prostate.

Animals↗
PubMed1997

No effect of calcitriol on insulin-mediated glucose uptake in healthy subjects.

Administration of active vitamin D (calcitriol) improves insulin sensitivity in uraemic patients. These patients have subnormal plasma calcitriol concentrations in parallel with increased intact parathyroid hormone (PTH) concentrations. It is therefore unclear whether the improvement in insulin sensitivity results from a direct effect of calcitriol or from amelioration of secondary hyperparathyroidism. So far, no evidence has been presented that insulin sensitivity is specifically affected by calcitriol in healthy subjects. We investigated the effect of (supra)therapeutic doses of calcitriol on insulin sensitivity in healthy volunteers. In a double-blind parallel group design, 18 healthy male subjects received in random order either placebo or 1.5 micrograms of calcitriol per day by mouth for 7 days. Insulin-mediated glucose uptake, i.e. insulin sensitivity, was assessed using the euglycaemic clamp technique. Mean glucose disposal rate, i.e. M-value, was not significantly affected by placebo or calcitriol treatment (placebo: 7.1 +/- 1.3 mg kg-1 min-1 before and 7.2 +/- 1.5 mg kg-1 min-1 after treatment; calcitriol 7.0 +/- 1.4 mg kg-1 min-1 and 7.2 +/- 1.4 mg kg-1 min-1). There were no significant changes in mean plasma glucose, insulin, phosphate, bicarbonate and ionized calcium concentrations after administration of placebo or calcitriol. Furthermore, platelet intracellular calcium concentration (assessed by fluorescence spectroscopy) and mean arterial blood pressure (24 h ambulatory measurement) did not change with placebo and calcitriol treatment. On the other hand, mean intact PTH concentration decreased significantly (P < 0.01) with calcitriol treatment, but not with placebo. In addition, mean 24 h urinary calcium excretion increased significantly (P < 0.05) with calcitriol administration but was unchanged with placebo. Administration of (supra)physiological doses of calcitriol has no effect on insulin sensitivity in healthy subjects, despite a significant decrease in PTH concentrations. These observations are compatible with the notion that the effect of calcitriol on insulin sensitivity is present only in uraemic calcitriol-depleted patients.

Administration, Oral↗
PubMed2001

Effect of calcitriol treatment and withdrawal on hyperparathyroidism in haemodialysis patients with hypocalcaemia.

BACKGROUND: Calcitriol is used to treat secondary hyperparathyroidism in dialysis patients. For similarly elevated parathyroid hormone (PTH) levels, the PTH response to calcitriol treatment is believed to be better in hypocalcaemic dialysis patients than in dialysis patients with higher serum calcium values. Furthermore, few studies have evaluated the rapidity of the rebound in serum PTH values after prolonged treatment with calcitriol. Our goal was to evaluate (i) the PTH response to calcitriol treatment in hypocalcaemic haemodialysis patients, (ii) the rapidity of rebound in PTH after calcitriol treatment was stopped, and (iii) whether the effect of calcitriol treatment on PTH levels could be separated from those produced by changes in serum calcium and phosphate values. METHODS: Eight haemodialysis patients (29+/-3 years) with hypocalcaemia and hyperparathyroidism were treated thrice weekly with 2 microg of intravenous calcitriol and were dialysed with a 3.5 mEq/l calcium dialysate. Parathyroid function (PTH-calcium curve) was determined before and after 30 weeks of calcitriol treatment and 15 weeks after calcitriol treatment was stopped. RESULTS: Pretreatment PTH and ionized calcium values were 907+/-127 pg/ml and 3.89+/-0.12 mg/dl (normal, 4.52+/-0.07 mg/dl). During calcitriol treatment, one patient did not respond, but basal (predialysis) PTH values in the other seven patients decreased from 846+/-129 to 72+/-12 pg/ml, P<0.001 and in all seven patients, the decrease exceeded 85%. During the 15 weeks after calcitriol treatment was stopped, a slow rebound in basal PTH values in the seven patients was observed, 72+/-12 to 375+/-44 pg/ml. Covariance analysis was used to evaluate the three tests of parathyroid function (0, 30, and 45 weeks), and showed that calcitriol treatment was associated with reductions in maximal PTH values while reductions in basal PTH were affected by ionized calcium and serum phosphate. The basal/maximal PTH ratio and the set point of calcium were associated with changes in ionized calcium. CONCLUSIONS: In haemodialysis patients with hypocalcaemia, (i) moderate to severe hyperparathyroidism responded well to treatment with calcitriol, (ii) reductions in maximal PTH were calcitriol dependent while reductions in basal PTH were affected by the ionized calcium and serum phosphate concentrations, (iii) changes in the basal/maximal PTH ratio and the set point of calcium were calcium dependent, and (iv) the delayed rebound in basal PTH levels after withdrawal of calcitriol treatment may have been due to the long duration of treatment and the marked PTH suppression during treatment.

Adult↗
PubMed1998

Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD.

Daily calcitriol therapy has been reported to improve linear growth in children with renal bone disease, and 1,25-dihydroxyvitamin D is a key regultor of chondrocyte proliferation and differentiation. Whereas large intermittent doses of calcitriol can lower serum parathyroid hormone (PTH) levels and reverse the skeletal changes of secondary hyperparathyroidism, the impact of intermittent calcitriol therapy on linear growth in children is not known. Thus, we studied 16 pre-pubertal patients with bone biopsy-proven secondary hyperparathyroidism who completed a 12-month prospective clinical trial of intermittent calcitriol therapy. Biochemical results and growth data obtained during intermittent calcitriol therapy were compared to values determined during the preceding 12 months of daily calcitriol therapy in each study subject; changes in bone histology were assessed after one year of intermittent calcitriol therapy. Z-scores for height did not change during 12 months of daily calcitriol therapy. Although the skeletal lesions of secondary hyperparathyroidism improved in most patients, Z-scores for height decreased from -1.8 +/- 0.32 to -2.0 +/- 0.33, P < 0.01, during intermittent calcitriol therapy. The largest reductions were seen in patients who developed adynamic bone lesions after 12 months of treatment. Delta Z-scores for height correlated with serum PTH, r = 0.71, P < 0.01, and alkaline phosphatase levels, r = 0.67, P < 0.01, during intermittent calcitriol therapy but not during daily calcitriol therapy. The data suggest that high dose intermittent calcitriol therapy adversely affects linear growth, particularly in patients with the adynamic lesion. The higher doses of calcitriol or the intermittent schedule of calcitriol administration may directly inhibit chondrocyte activity within growth plate cartilage of children with end-stage renal disease.

Adolescent↗
PubMed2001

The anti-proliferative effect of calcitriol on HL-60 cells is neutralized by uraemic biological fluids.

BACKGROUND: It has been demonstrated that uraemic serum/ultrafiltrate inhibits cell-mediated immune response in vitro, and that it suppresses calcitriol synthesis and its biological actions. METHODS: In the present in vitro study, the effect of calcitriol, uraemic ultrafiltrate (UUF) and a combination of both on the human promyelocytic leukaemia cell line, HL-60, was studied by evaluating bromodeoxyuridine (BrdU) incorporation into the DNA, luminol-amplified chemiluminescence (CL) production, expression of CD14, and levels of vitamin D receptor mRNA (VDR mRNA) and CD14 mRNA. RESULTS: The ability of calcitriol to block cell proliferation (37.4+/-5.4 to 30.5+/-5.6% cells incorporating BrdU, P:<0.01) was neutralized when UUF was applied together with calcitriol (53.4+/-21.3% cells incorporating BrdU, P:<0.01 vs calcitriol alone). Similarly to what was observed for BrdU incorporation, the CL production of HL-60 cells was enhanced in the presence of calcitriol (20126+/-10154 to 61528+/-24021 cpm, P:<0.01), and was suppressed again in the presence of calcitriol and UUF (20916+/-12075 cpm, P:<0.01 vs calcitriol alone); finally UUF also inhibited the calcitriol-induced CD14 expression (71.1+/-11.2 to 54.9+/-17.7% CD14 positive cells, P:<0.05). On the other hand, the calcitriol-induced CD14 mRNA levels were not significantly different in the presence of calcitriol and UUF compared to calcitriol alone. This points to an inhibition by UUF at a post-transcriptional level. Similar data were found for VDR mRNA levels. UUF was fractionated by HPLC in four fractions, hydrophilic uraemic solutes being eluted first (F1) and hydrophobic solutes being eluted last (F4); fractions 1, 2 and 3 simultaneously affected both BrdU incorporation and CL production in a significant way. CONCLUSIONS: It is concluded that UUF contains factors that impair calcitriol-activated function of HL-60 cells. Hence, the differentiation and immune response of these promyelocytic leukaemia cells, as induced by the supplementation of calcitriol, is neutralized in the presence of uraemic biological fluids. This may be of relevance for the propensity to infection and malignancy of the uraemic patient.

Biological Factors↗
PubMed2003

A limited sampling method for the estimation of serum calcitriol area under the curve in cancer patients.

Pharmacokinetic (PK) data from 34 cancer patients receiving 2 to 10 micrograms of calcitriol subcutaneously (s.c.) were used to develop a limited sampling method for predicting serum calcitriol area under curve (AUC) based on three samples instead of the full complement of 12 to 16 samples. Serum calcitriol levels were measured by 1, 25-dihydroxyvitamin D3-[I125] radioimmunoassay. Individual patient-corrected serum calcitriol AUC0-12 h was calculated by the trapezoidal rule after subtracting the pretreatment serum calcitriol level. PK data were split into "training" and "evaluation" sets based on calcitriol dose and chronological order of enrollment. Linear regression models of log-corrected AUC0-12 h versus individual log calcitriol serum levels in the hour 1, 2, 3, 4, 6, and 8 samples were established using the training data set of 17 patients. The fit was tested on the evaluation data set of 17 patients using mean squared error (MSE) as the fit criterion. The best single time point predictor of log AUC0-12 h was the log serum (calcitriol) at hour 6 (MSE = 0.0061). The best prediction of log AUC0-12 h using two time points was found to involve hour 6 and hour 2 (MSE = 0.0018). The prediction equation for the latter model was as follows: Log AUC = 1.125 + 0.3756.log (calcitriol) at hour 2 + 0.5859.log (calcitriol) at hour 6. This limited sampling method was further evaluated in 83 cancer patients treated with 4 to 38 micrograms of oral (p.o.) calcitriol; observed and predicted calcitriol AUC0-12 h were highly correlated (r > or = 0.90, p = 0.0001). These results show that serum calcitriol AUC0-12 h after s.c. and p.o. calcitriol administration is accurately estimated using pretreatment and 2- and 6-hour blood samples.

Area Under Curve↗
PubMed2005

Reversibility of calcitriol-induced medial artery calcification in rats with intact renal function.

UNLABELLED: VC is an important clinical entity; however, very little information is available on its resolution. Induction and regression of calcitriol-induced VC was studied in 47 rats. After calcitriol withdrawal, there was a relatively rapid regression of VC mediated by an active cellular process. INTRODUCTION: Vascular calcifications (VCs) represent an important risk factor for cardiovascular death. Although VCs are prevalent in relevant diseases (e.g., chronic kidney disease, osteoporosis, diabetes), the reversibility of extraskeletal calcifications is an unresolved issue. This study was conducted to investigate (1) the in vivo effect of calcitriol on VC and (2) whether calcitriol-induced VC would regress after suppression of calcitriol treatment. MATERIALS AND METHODS: The calcifying effect of calcitriol was studied in four groups of rats (n = 8) that received calcitriol (1 mug/kg, IP) for 2, 4, 6, and 8 days. The reversibility of VC was studied in three additional groups (n = 5) treated with 1 mug/kg of calcitriol for 8 days that were subsequently killed 1, 2, and 9 weeks after the last calcitriol dose. Aortic VC was assessed by histology and by quantification of aortic calcium and phosphorus content. The aortic wall was studied by histology and immunohistochemistry. Statistical analysis was performed by ANOVA and t-tests. RESULTS: Calcitriol administration resulted in a time-dependent induction of VC, with aortic calcium and phosphorus being significantly increased at 6 and 8 days. Treatment with calcitriol for 8 days resulted in massive medial calcification of the aorta with a 10- to 30-fold increase in the aortic Ca and P content. After suppressing calcitriol administration, a progressive decrease in von Kossa staining and aortic Ca (from 32.8 +/- 2.5 to 9.3 +/- 1.8 mg/g of tissue, p < 0.001) and P (from 11.9 +/- 1.2 to 2.7 +/- 1.8 mg/g of tissue, p = 0.001) content was evidenced. Histology of the aortic wall showed monocytes adhered to the aortic endothelium and macrophages involved in the reabsorption of calcium deposits. CONCLUSIONS: Our results show that calcitriol treatment induces time-dependent VC. After calcitriol withdrawal, VC regress rapidly with aortic calcium and phosphorus decreasing by 75% in the course of 9 weeks. An active cellular process seems to be involved in regression of VC.

Animals↗
PubMed1997

Regulation of serum calcitriol by serum ionized calcium in rats during pregnancy and lactation.

Serum calcitriol concentrations in rats follow a biphasic pattern during reproduction, with elevated levels during late pregnancy, a decline after parturition, and a rise to even higher levels during peak lactation. We have previously shown that serum calcitriol in rats at peak lactation correlates significantly with, and appears to be regulated by, serum ionized Ca (Ca2+), with parathyroid hormone (PTH) serving a permissive role. We have extended this study by determining if serum calcitriol also correlates with serum Ca2+ during late pregnancy, when calcitriol levels are clearly elevated, and during early lactation, when only modest increases in serum calcitriol are observed. Analyses of data combined from nonmated, 21-day pregnant (P), and 1-day lactating rats (L) revealed a significant regression (p < 0.001) of calcitriol on Ca2+, but a nonsignificant regression (p = 0.34) of calcitriol on serum PTH. An even stronger correlation (p < 0.001) between calcitriol and Ca2+ was found for the combined data for 5-, 8-, and 14-day L rats. The partial correlation coefficient for calcitriol versus Ca2+, with PTH as the independent variable, was highly significant (p < 0.01) for the data from both combined groups. However, the coefficient for calcitriol versus PTH, with Ca2+ as the independent variable, was not significant (p > 0.05). Fetal weights (uterus and contents) correlated significantly with both maternal calcitriol and Ca2+ concentrations (p < 0.01), but not with maternal PTH levels. Litter weights for 14-day-old pups likewise correlated significantly with maternal calcitriol and Ca2+ (p < 0.001). We conclude that hypocalcemia, induced by the demands for Ca for fetal calcification and milk production, appears to be a controlling factor in serum calcitriol elevation in late pregnancy and throughout lactation, whereas PTH may be important for calcitriol synthesis without playing a direct regulatory role.

Animals↗
PubMed1993

Effects of ascorbic acid, calcitriol, and retinoic acid on the differentiation of preosteoblasts.

The responses of the immortalized rat preosteoblast UMR-201-10B to ascorbic acid (AA), 1,25(OH)2D3 (calcitriol), and retinoic acid (RA) were examined. UMR-201-10B cells have an undetectable basal alkaline phosphatase (ALP) activity that is induced after 24 h of treatment with 10(-6) M RA (4.64 +/- 0.06 mumol/h/mg of protein). The addition of 10(-8) M calcitriol resulted in a slight induction of ALP activity after 72 h (0.43 +/- 0.07 mumol/h/mg of protein). When calcitriol was added to RA, however, over the same period ALP activity was enhanced significantly compared with treatment with RA alone (RA and calcitriol, 12.29 +/- 0.86 mumol/h/mg of protein). Treatment with AA (50 micrograms/ml) alone had no effect on ALP activity but increased RA-induced ALP activity to 6.78 +/- 0.28 mumol/h/mg of protein at 24 h. In contrast, AA inhibited calcitriol-induced ALP activity after 7 days of combined treatment with calcitriol (calcitriol, 7.73 +/- 0.16 mumol/h/mg of protein; AA and calcitriol, 1.44 +/- 0.06 mumol/h/mg of protein). Individually, RA and calcitriol induced mRNA expression for ALP, matrix-gla protein (MGP), and osteopontin (OP). The steady state level of pro-alpha 1(I) collagen mRNA also was increased significantly by treatment with RA and AA individually. The combination of RA and calcitriol had a synergistic effect on ALP, OP, and especially MGP mRNA expression but significantly reduced the expression of pro-alpha 1(I) collagen mRNA. AA enhanced the effect of RA on the expression of pro-alpha 1(I) collagen, MGP, and ALP mRNAs as well as the effect of calcitriol on OP and MGP. The addition of AA to RA resulted in a decrease in the steady state level of OP, whereas its cotreatment with calcitriol caused a decrease in pro-alpha 1(I) collagen and ALP mRNA. In conclusion, these studies identify RA, calcitriol, and AA as regulators of differentiated osteoblast function.

Alkaline Phosphatase↗
PubMed2007

Novel pathways that contribute to the anti-proliferative and chemopreventive activities of calcitriol in prostate cancer.

Calcitriol, the hormonally active form of Vitamin D, inhibits the growth and development of many cancers through multiple mechanisms. Our recent research supports the contributory role of several new and diverse pathways that add to the mechanisms already established as playing a role in the actions of calcitriol to inhibit the development and progression of prostate cancer (PCa). Calcitriol increases the expression of insulin-like growth factor binding protein-3 (IGFBP-3), which plays a critical role in the inhibition of PCa cell growth by increasing the expression of the cell cycle inhibitor p21. Calcitriol inhibits the prostaglandin (PG) pathway by three actions: (i) the inhibition of the expression of cyclooxygenase-2 (COX-2), the enzyme that synthesizes PGs, (ii) the induction of the expression of 15-prostaglandin dehydrogenase (15-PGDH), the enzyme that inactivates PGs and (iii) decreasing the expression of EP and FP PG receptors that are essential for PG signaling. Since PGs have been shown to promote carcinogenesis and progression of multiple cancers, the inhibition of the PG pathway may add to the ability of calcitriol to prevent and inhibit PCa development and growth. The combination of calcitriol and non-steroidal anti-inflammatory drugs (NSAIDs) result in a synergistic inhibition of PCa cell growth and offers a potential therapeutic strategy. Mitogen activated protein kinase phosphatase 5 (MKP5) is a member of a family of phosphatases that are negative regulators of MAP kinases. Calcitriol induces MKP5 expression in prostate cells leading to the selective dephosphorylation and inactivation of the stress-activated kinase p38. Since p38 activation is pro-carcinogenic and is a mediator of inflammation, this calcitriol action, especially coupled with the inhibition of the PG pathway, contributes to the chemopreventive activity of calcitriol in PCa. Mullerian Inhibiting Substance (MIS) has been evaluated for its inhibitory effects in cancers of the reproductive tissues and is in development as an anti-cancer drug. Calcitriol induces MIS expression in prostate cells revealing yet another mechanism contributing to the anti-cancer activity of calcitriol in PCa. Thus, we conclude that calcitriol regulates myriad pathways that contribute to the potential chemopreventive and therapeutic utility of calcitriol in PCa.

Animals↗
PubMed1998

Effects of short-term treatment with prednisolone and calcitriol on bone and mineral metabolism in normal men.

To study the effects of treatment with glucocorticoid and calcitriol on biochemical markers of calcium and bone metabolism, 48 normal male volunteers (aged 21-54 years) were randomized to treatment for 7 days with either (A) prednisolone, 10 mg twice daily, (B) prednisolone, 10 mg twice daily, and calcitriol, 1 microg twice daily, (C) calcitriol 1 mg twice daily, or (D) placebo. The study period was 28 days. Renal calcium excretion increased (mean maximal increase +44.7%, p < 0.01) as well as serum parathyroid hormone (PTH) (max. +18.5%, p < 0.01) during prednisolone treatment. Concomitant treatment with calcitriol or calcitriol alone equally enhanced renal calcium excretion (max. +185.2%, p < 0.001) and decreased serum PTH (max. -43.1%, p < 0.001). Prednisolone administration was followed by prompt declines in markers of bone formation [serum osteocalcin (max. -34.7%, p < 0.001) and serum procollagen type I C-terminal propeptide (PICP) (max. -25.9%, p < 0.05)], whereas serum bone alkaline phosphatase (bone AP) remained unchanged. Calcitriol in combination with prednisolone attenuated the decrease in PICP (max. -8.9%, not significant), but it had no effect on osteocalcin (max. -40.1%, p < 0.001), and decreased bone AP (max. -22.2%, p < 0.05). Calcitriol alone increased osteocalcin (max. +37.8%, p < 0.03) and PICP (max. +26.0%, p < 0.05). Among markers of bone degradation, prednisolone suppressed serum C-terminal telopeptide of type I collagen (ICTP) (max. -28.4%, p < 0.001), but not the fasting renal excretion of hydroxyproline (OHP) and collagen type I N-terminal telopeptide (NTx). Calcitriol partially antagonized the decrease in ICTP (max. -17.2%, p < 0.001). Calcitriol alone had no effect on resorptive markers. Extraosseous matrix synthesis was suppressed by prednisolone evaluated by serum procollagen type III N-terminal propeptide (max. -30.8%, p < 0.001) and was not affected by concomitant treatment with calcitriol or calcitriol alone. In conclusion, short-term administration of prednisolone to healthy men leads to fast and protracted suppression of biochemical markers of bone formation and extraosseous connective tissue metabolism. The effect on bone was partially antagonized by simultaneous calcitriol treatment, and points toward a potential role of calcitriol in the prevention of steroid induced osteoporosis.

Adult↗
PubMed1988

Calcitriol deficiency with retained synthetic reserve in chronic renal failure.

Serum calcitriol and the free calcitriol index together with factors considered to regulate calcitriol production were measured in eleven patients with moderate chronic renal failure (MCRF) and eleven age- and sex-matched normal subjects. Although the serum dialysable calcium levels were similar in the two groups, there was depression of calcitriol levels and an elevation of PTH and nephrogenous cyclic AMP (NcAMP) levels in the MCRF patients. Furthermore, plasma phosphate levels were higher and the renal phosphate threshold was depressed in this patient group. When all subjects were grouped together calcitriol was positively correlated with GFR. When calcitriol levels were factored for GFR, to permit an assessment of calcitriol production per unit functioning renal mass, there was no significant difference between normal and MCRF subjects. To determine whether reserve for calcitriol production existed, six of the MCRF patients and six of the age- and sex-matched normal subjects received a low calcium diet for one week supplemented by cellulose phosphate to bind calcium within the gut. In both groups there was a significant rise in calcitriol, although the absolute levels were much lower in the MCRF patients than the normal subjects. These results suggest that calcitriol deficiency is a major feature of MCRF despite marked hyperparathyroidism. The rise in calcitriol levels in MCRF suggests persistent reserve secretory capacity in this condition. Therefore, the low serum calcitriol concentration may be due not only to structural renal damage, but also to suppression of calcitriol formation perhaps due to altered renal phosphate handling.

Adult↗
PubMed1998

Intermittent calcitriol therapy in secondary hyperparathyroidism: a comparison between oral and intraperitoneal administration.

BACKGROUND: Intermittent oral or intravenous doses of calcitriol given two or three times per week are commonly used to treat secondary hyperparathyroidism (secondary HPT). This study was undertaken to compare the biochemical and skeletal responses to thrice weekly intraperitoneal (i.p.) versus oral doses of calcitriol in children with secondary HPT undergoing peritoneal dialysis (CCPD). METHODS: Forty-six patients aged 12.5+/-4.8 years on CCPD for 22+/-25 months were randomly assigned to treatment with oral (p.o.) or i.p. calcitriol for 12 months; 17 subjects given p.o. calcitriol and 16 subjects given i.p. calcitriol completed the study. Bone biopsies were performed at the beginning and at the end of the study, while determinations of serum and total ionized calcium, phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and calcitriol levels were done monthly. RESULTS: Serum total and ionized calcium levels were higher in subjects treated with i.p. calcitriol, P < 0.0001, whereas serum phosphorus levels were higher in those given p.o. calcitriol, P < 0.0001. For the i.p. group, serum PTH levels decreased from pre-treatment values of 648+/-125 pg/ml to a nadir of 169+/-57 pg/ml after nine months. In contrast, serum PTH levels did not change from baseline values of 670+/-97 pg/ml in subjects given p.o. calcitriol, P < 0.0001 by multiple regression analysis. Serum alkaline phosphatase levels were also lower in patients treated with i.p. calcitriol, P < 0.0001, but there was no difference between groups in the average dose of calcitriol given thrice weekly. The skeletal lesions of secondary HPT improved in both groups, 33% of patients developed adynamic bone lesion. CONCLUSION: Differences in the bioavailability of calcitriol and/or in phosphorus metabolism may account for the divergent biochemical response to p.o. and i.p. calcitriol.

Administration, Oral↗
PubMed1997

'Pulse oral' versus intravenous calcitriol therapy in chronic hemodialysis patients. A prospective and randomized study.

The aim of this prospective and randomized study was to compare the efficacy, side effects, and costs of 'pulse oral' versus intravenous calcitriol in the treatment of secondary hyperparathyroidism in hemodialysis (HD) patients. A total of 20 patients were randomized to receive over a 4-month period pulse orally administered calcitriol (pulse oral group; n = 10) or intravenous calcitriol (intravenous group; n = 10). All patients used standard dialysate calcium (1.75 mmol/l) throughout the study period. In accordance with the study design calcium dialysate concentrations were reduced when this was necessary to avoid hypercalcemic crises. The patients were stratified into two subgroups according to their initial serum PTH levels: patients with mild or moderate degree of hyperparathyroidism (17 patients) and patients with severe hyperparathyroidism (3 patients). Intravenous and pulse oral cacitriol did not significantly reduce serum PTH concentrations in patients with severe hyperparathyroidism (1,157 +/- 156 vs. 807 +/- 228 pg/ml [corrected], p = 0.09). Intermittent calcitriol, administered by intravenous or oral route, significantly reduced serum PTH levels (326 +/- 119 vs. 109 +/- 79 pg/ml [corrected], p = 0.0001) in patients with mild or moderate hyperparathyroidism. In patients with mild or moderate hyperparathyroidism, intravenous calcitriol significantly reduced PTH concentrations at the end of the 1st month, before the increase of serum ionized calcium levels, whereas 'pulse oral' calcitriol significantly suppressed parathyroid activity at the end of the 2nd month. Calcium dialysate concentration was reduced in 9 out of 10 (90%) patients of the pulse oral group and in all patients (10/10) of intravenous group. The incidence of hypercalcemic crises was 24% (39/160) in the pulse oral group and 14% (27/160) in the intravenous group. Analysis of costs showed that intravenous calcitriol was more expensive compared to pulse oral calcitriol. These data indicate that intermittent intensive calcitriol therapy, regardless of the route of administration, is effective in suppressing parathyroid activity in HD patients with mild or moderate hyperparathyroidism. In contrast, intermittent calcitriol therapy has a limited ability to achieve sustained serum PTH reductions in HD patients with severe hyperparathyroidism. Intravenous calcitriol was more expensive than pulse oral calcitriol, and we recommend the use of pulse oral calcitriol in HD patients with mild or moderate secondary hyperparathyroidism.

Administration, Oral↗
PubMed1985

Long-term control of plasma calcitriol concentration in dogs and humans. Dominant role of plasma calcium concentration in experimental hyperparathyroidism.

Despite great interest in the elevated circulating levels of calcitriol (1,25-[OH]2D) associated with the clinical syndrome of human primary hyperparathyroidism, the relative potencies of known and potential stimuli/suppressors of long-term calcitriol levels have not been evaluated in either clinical or experimentally induced hyperparathyroid states. Based on reports that aparathyroid animals exhibit suppressed plasma calcitriol concentration and that acute administration of parathyroid hormone (PTH) to both humans and experimental animals or to renal slices in vitro results in increased plasma calcitriol concentration/production rate, it might be predicted that a chronic experimental model of either hypercalcemic primary hyperparathyroidism or hypocalcemic secondary hyperparathyroidism would show increased plasma calcitriol concentration. Chronic alterations in plasma calcium concentration have not been implicated as modulating calcitriol levels in any species. Accordingly, we investigated the long-term response of plasma calcitriol concentration in states of sustained experimental primary and secondary hyperparathyroidism. Intact dogs (group I) undergoing continuous intravenous PTH infusion for 12 d developed sustained hypercalcemia and hypophosphatemia, and plasma calcitriol concentration decreased from 23 +/- 3 to 14 +/- 3 pg/ml (P less than 0.01). Subsequent chelator (EGTA)-induced chronic normalization of hypercalcemia during ongoing PTH infusion resulted in a large and sustained increase in plasma calcitriol concentration to supernormal levels, reversible during subsequent cessation of chelator infusion. In additional intact dogs (group II), chronic chelator-induced hypocalcemic secondary hyperparathyroidism resulted in a sustained increase in plasma calcitriol concentration despite hyperphosphatemia. In normal human subjects undergoing a 12-13-d continuous intravenous PTH infusion to result in sustained moderate hypercalcemia (12.0 +/- 0.2 mg/100 ml) and hypophosphatemia, plasma calcitriol concentration decreased significantly (P less than 0.01) as in group I dogs and was followed by reversal to normal levels in a recovery period. The present results provide strong evidence in both humans and dogs that during experimentally induced chronic PTH excess, alterations in plasma calcium concentration dictate the directional response of circulating calcitriol concentrations. The long-term potency of plasma calcium concentration as a modulator of calcitriol metabolism is sufficient to override opposing modulation by plasma phosphorus concentration and PTH.

25-Hydroxyvitamin D 2↗
PubMed1994

Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin lymphoma.

OBJECTIVE: To determine the following: a reference range for serum calcitriol during hypercalcemia in a control group of patients with myeloma in whom calcitriol production is known to be appropriately suppressed; the incidence of elevated serum calcitriol levels in hypercalcemic patients with non-Hodgkin lymphoma according to this derived reference range; and the incidence of abnormal calcium metabolism in normocalcemic patients with non-Hodgkin lymphoma. DESIGN: Prospective clinical study. SETTING: Referral cancer center. PATIENTS: 2 groups of hypercalcemic patients: 16 control patients with myeloma and 22 patients with non-Hodgkin lymphoma divided into those with elevated or normal serum calcitriol levels; 1 group of 22 normocalcemic patients with non-Hodgkin lymphoma. MEASUREMENTS: Serum chemistries and intact parathyroid hormone, calcitriol, parathyroid hormone-related protein, and urinary electrolyte levels. RESULTS: On the basis of the mean serum calcitriol level of the control group plus 3 standard deviations, the reference range for serum calcitriol during hypercalcemia was defined as less than 42 pg/mL. Although serum calcium and parathyroid hormone levels in the study patients were similar to those in controls, 12 of the 22 hypercalcemic patients with non-Hodgkin lymphoma (55%) had serum calcitriol levels greater than 42 pg/mL (range, 51 to 170 pg/mL). No features distinguished the patients with elevated serum calcitriol levels from those with normal levels. Seventy-one percent of normocalcemic patients with non-Hodgkin lymphoma were hypercalciuric, and 18% had serum calcitriol levels greater than the normocalcemic reference range (20 to 76 pg/mL). CONCLUSIONS: Serum calcitriol levels are elevated in most hypercalcemic patients with non-Hodgkin lymphoma in the absence of elevated serum levels of parathyroid hormone, which implicates extrarenal calcitriol production in the pathogenesis of this syndrome. Abnormal calcium metabolism, hypercalciuria, and dysregulated calcitriol production are also common in normocalcemic patients with non-Hodgkin lymphoma.

Adult↗
PubMed1987

Induction of monocytic differentiation by calcitriol (1,25-dihydroxyvitamin D3) in the human promyelocytic leukemic cell line (HL-60) in serum-free medium.

The effect of calcitriol on the induction of differentiation in human promyelocytic leukemic cell line (HL-60) cultured in serum-free chemically defined medium (SFM) was investigated. The utilization of SFM containing RPMI-1640 basal medium supplemented with insulin (5 micrograms/ml), transferrin (5 micrograms/ml), sodium selenite (5 ng/ml), and bovine serum albumin (0.5 micrograms/ml), transferrin examination of the cellular/molecular mechanism of calcitriol's action in HL-60 cell differentiation without interference of components present in serum. HL-60 cells grown in SFM were induced to differentiate into monocytes/macrophages by calcitriol as indicated by induction of differentiation-associated biological and biochemical parameters: chemiluminescent (CL) responsiveness, lysozyme activity, nonspecific esterase, expression of cell surface antigens, and reduced proliferation. The exposure of HL-60 cells in SFM to calcitriol (from 10(-10) to 10(-8)M) resulted in dose-dependent induction of these parameters, which was similar to those obtained with cells grown in 10% fetal calf serum containing medium (10% SCM). However, calcitriol was 5-fold more potent for HL-60 cells cultured in SFM than those cultured in 10% SCM as indicated by shifts in dose-response curves for induction of CL responsiveness and lysozyme activity. The effect of calcitriol on the proliferation and acquisition of several monocyte-associated cell surface antigens was also more sensitive for HL-60 cells cultured in SFM than for cells grown in 10% SCM. We characterized and quantitated calcitriol receptors in HL-60 cells cultured in SFM in comparison to those in 10% SCM after exposing intact cells to radiolabeled calcitriol. Cells cultured in either SFM or 10% SCM exhibited calcitriol receptors that migrated at 3.4S as a single peak on sucrose gradients and elicited inherent DNA binding ability. There was essentially no difference in the apparent dissociation constants (Kd) nor in the number of calcitriol binding sites per HL-60 cell, that is approximately 6.0 X 10(-11) M and approximately 3000 binding sites/cell respectively. It is concluded that culturing HL-60 cells in SFM results in full expression of calcitriol-induced phenotypic changes excluding the possibility that such changes result from the indirect effect of calcitriol mediated by identified and/or unidentified components present in serum.

Calcitriol↗
PubMed2004

Anti-tumor activity of calcitriol: pre-clinical and clinical studies.

1,25-Dihydroxycholecalciferol (calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G0/G1 arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose calcitriol+dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that calcitriol has potential as an anti-cancer agent.

Antineoplastic Agents↗