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PubMed2003

Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism.

BACKGROUND: Management of secondary hyperparathyroidism has included the use of active vitamin D or vitamin D analogs for the suppression of parathyroid hormone (PTH) secretion. Although, these agents are effective, therapy is frequently limited by hypercalcemia, hyperphosphatemia, and/or elevations in the calcium-phosphorus (Ca x P) product. In clinical studies, paricalcitol was shown to be effective at reducing PTH concentrations without causing significant hypercalcemia or hyperphosphatemia as compared to placebo. A comparative study was undertaken in order to determine whether paricalcitol provides a therapeutic advantage to calcitriol. METHODS: A double-blind, randomized, multicenter study comparing the safety and effectiveness of intravenous paricalcitol and calcitriol in suppressing PTH concentrations in hemodialysis patients was performed. A total of 263 randomized patients were enrolled at domestic and international sites. Following the baseline period, patients with serum Ca x P < 75, and a PTH level > or =300 pg/mL were randomly assigned to receive either paricalcitol or calcitriol in a dose-escalating fashion for up to 32 weeks. Dose adjustments were based on laboratory results for PTH, calcium, and Ca x P. The primary end point was the greater than 50% reduction in baseline PTH. Secondary end points were the occurrence of hypercalcemia and elevated Ca x P product. RESULTS: Paricalcitol-treated patients achieved a > or =50% reduction from baseline PTH significantly faster than did the calcitriol-treated patients (P = 0.025) and achieved a mean reduction of PTH into a desired therapeutic range (100 to 300 pg/mL) at approximately week 18, whereas the calcitriol-treated patients, as a group, were unable to achieve this range. Moreover, paricalcitol-treated patients had significantly fewer sustained episodes of hypercalcemia and/or increased Ca x P product than calcitriol patients (P = 0.008). CONCLUSION: Paricalcitol treatment reduced PTH concentrations more rapidly with fewer sustained episodes of hypercalcemia and increased Ca x P product than calcitriol therapy.

Adult↗
PubMedDate not supplied

Comparative review of the pharmacokinetics of vitamin D analogues.

This article reviews the pharmacokinetic characteristics of calcitriol, paricalcitol, and doxercalciferol, and provides an overview of the metabolism of vitamin D. Calcitriol and paricalcitol have similar pharmacokinetic profiles, with terminal half-lives ranging from 5 to 10 hours in healthy subjects to 15-30 hours in patients undergoing dialysis. Both are active on intravenous administration and little of the active agent remains in the circulation after 24 hours, although they are normally given every 48-72 hours. Doxercalciferol is a prohormone, requiring hepatic metabolism to the active metabolite 1alpha,25-(OH)2D2. The half-life of 1alpha,25-(OH)2D2 is about 34 hours in healthy subjects and about 45 hours in dialysis patients, resembling physiologic blood concentrations of endogenous vitamin D. More studies are warranted to determine the disposition of the vitamin D analogues, especially in selected populations such as pediatric and geriatric dialysis patients.

Calcitriol↗
PubMed1981

Plasma levels of vitamin D metabolites in the bovine species during the perinatal period.

Plasma vitamin D metabolites (25-OH D; 24,25-(OH)2D and 1,25-(OH)2D) were measured simultaneously in the blood plasma samples of young cows and their calves. Four of the calves were chronically catheterized in utero at least 2 weeks before the expected time of parturition. No significant hypocalcaemia occurred in the dams at calving. Plasma vitamin D metabolites showed no significant variations for 2 weeks before and 4 days after calving. But rapid changes in plasma 1,25-(OH)2D concentrations were observed in one calf during the first 48 postnatal hours. Before birth, the maternal and foetal concentrations of either 1,25-(OH)2D or 24,25-(OH)2D were positively correlated. 25-(OH) D (13 ng/ml), 24,25-(OH)2D (1 ng/ml) and 1,25-(OH)2D (76 pg/ml) were detected in one foetal plasma collected 35 days before term.

24,25-Dihydroxyvitamin D 3↗
PubMed1985

Effect of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 maternal loads on maternal and fetal vitamin D metabolite levels in the rat.

Two groups of female rats were used to investigate vitamin D metabolism in the pregnant animals and in their fetuses. In the first group, 3 micrograms of 25-hydroxyvitamin D3 (25-OH-D3) per kg of body weight were injected into intact or nephrectomized (NX) pregnant rats 3 h before sacrifice on day 21 of pregnancy; in the second group, 2 and 6 ng, respectively, of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) per day were infused continuously into pregnant rats between days 17 and 21 of pregnancy. The findings in the fetuses were obtained by quantitative analysis of extracts (Extrelut) of total fetal body lipids; the extracts were purified on Sep Pak and vitamin D sterols were further separated by high-pressure liquid chromatography. Three hours after the dams were injected with 25-OH-D3, the maternal plasma concentration (mean +/- SD) of 1,25(OH)2D3 was 221 +/- 84 pg/ml. In NX pregnant rats, the 1,25(OH)2D3 levels were still elevated: 95.6 +/- 49.0 pg/ml vs 45 +/- 22 pg/ml in control rats. In fetuses from intact or NX dams, the levels of 25-OH-D3 and 1,25(OH)2D3 were not different from the results obtained in the control fetuses but 24,25(OH)2D3 concentrations were increased (6.7 +/- 1.2 ng vs 2.2 +/- 0.7 ng/g body weight). After maternal infusion of 2 or 6 ng/day of 1,25(OH)2D3 (n = 8), plasma concentrations (mean +/- SD) of the metabolite were 64 +/- 31 and 517 +/- 356 pg/ml, respectively, the second being significantly higher than that of the control rats; 25-OH-D3 and 24,25(OH)2D3 levels did not change. 1,25(OH)2D3 contents (mean +/- SD) in fetuses from the treated dams were not different from those of control fetuses (10 +/- 2 pg/g body weight). Our results suggest that pregnant rats and their fetuses were protected against an excessive increase of 1,25(OH)2D3 concentrations in the maternal plasma; although there was some individual hypercalcemia, no significant increase in mean calcemia was detected in the dams, and 1,25(OH)2D3 either did not cross the placental barrier or was rapidly metabolized because we did not find any changes in the fetal content. As in intact or NX pregnant rats, 25-OH-D3 was metabolized into 1,25(OH)2D3, the increase of 24,25(OH)2D3 in the fetuses might be associated with a protective mechanism.

Acid Phosphatase↗
PubMed1998

Effects of 19-nor-1,25(OH)2D2, a new analogue of calcitriol, on secondary hyperparathyroidism in uremic rats.

The active metabolite of vitamin D, calcitriol [1,25(OH)2D3] suppresses parathyroid hormone (PTH) gene transcription and PTH secretion. Although 1,25(OH)2D3 is effective in suppressing secondary hyperparathyroidism in uremic patients, the mandatory use of large amounts of calcium salts to control serum phosphorus may preclude in some patients the use of ideal therapeutic doses of 1,25(OH)2D3 because of hypercalcemia. We have studied a new analogue of calcitriol,19-nor-1,25(OH)2D2 that possesses low calcemic and phosphatemic activity. We have clearly demonstrated that this analogue of calcitriol can suppress secondary hyperparathyroidism without inducing hypercalcemia or hyperphosphatemia in uremic rats. In addition, this analogue of vitamin D supresses pre-pro PTH messenger RNA in a similar fashion to that of 1,25(OH)2D3. Contrary to the effect of 1,25(OH)2D3 that increases the intestinal vitamin D receptor, this analogue of vitamin D suppresses the intestinal vitamin D receptor. This finding may be critical for the lack of calcemic activity of 19-nor-1,25(OH)2D2 seen in these studies. One of the explanations for the lack of an increasing intestinal VDR is the fact that 19-nor-1,25(OH)2D2 decreases endogenous levels of 1,25(OH)2D3. In summary, we have shown that 19-nor-1,25(OH)2D2, a new analogue of calcitriol is effective in suppressing PTH in uremic rats with secondary hyperparathyroidism. In addition, there is a significant decrease in the VDR in the intestine, which may explain in part the less calcemic and hyperphosphatemic effect of this analogue.

Animals↗
PubMed1998

Suppression of parathyroid hormone secretion in hemodialysis patients by a novel vitamin D analogue: 19-nor-1,25-dihydroxyvitamin D2.

In this double-blind, placebo-controlled, randomized, multicenter study, 35 patients with end-stage renal disease undergoing maintenance hemodialysis were treated three times weekly for 4 weeks with either 19-nor-1,25-dihydroxyvitamin D2 (paricalcitol) intravenously at doses ranging from 0.04 to 0.24 microg/kg or placebo. Eligible patients with secondary hyperparathyroidism (HPT; intact parathyroid hormone [iPTH] level > 300 pg/mL) were initially withdrawn from any existing vitamin D therapy over a 4-week washout period and then randomized to treatment for 4 weeks with either paricalcitol or placebo. Overall, there was a clinically and statistically significant reduction in iPTH level for patients receiving paricalcitol compared with placebo (P = 0.006). The study end point for efficacy was at least a 30% reduction from maximum baseline in iPTH level for 75% of the patients receiving paricalcitol per dosing group. The study end point for efficacy was at least a 30% reduction from maximum baseline in iPTH for 75% of patients receiving paricalcitol per dosing group. Sixty-eight percent (15 of 22) of patients receiving paricalcitol attained this efficacy end point regardless of dosage received (0.04, 0.08, 0.16, and 0.24 microg/kg). Eighty-three percent (5 of 6) of the patients in each of the paricalcitol groups receiving 0.16- and 0.24-microg/kg dosages attained the efficacy end point. Only two patients receiving placebo attained the iPTH end point. There were no clinically relevant differences in serum calcium (Ca) or phosphorus (P) levels between the group treated with paricalcitol and that treated with placebo. Although there was a statistically significant difference between the change from baseline to final-visit Ca levels in the paricalcitol group and the placebo group (P < 0.001), the final-visit mean Ca level in the paricalcitol group was within the normal range (9.44 mg/dL). There was no statistically significant difference between groups for the change from baseline in P level (P = 0.625). Only one patient treated with paricalcitol developed hypercalcemia before or coincident with the iPTH end point. Three other patients receiving paricalcitol experienced elevated serum Ca levels subsequent to reaching the iPTH end point, with iPTH reductions of 83% to 98%. There were no significant differences between patients treated with paricalcitol and patients treated with placebo in adverse reactions. These results show that paricalcitol safely and effectively reduces iPTH levels in hemodialysis patients with secondary HPT.

Adolescent↗
PubMed1998

Effect of hemodialysis on the pharmacokinetics of 19-nor-1alpha,25-dihydroxyvitamin D2.

The vitamin D2 analogue 19-nor-1alpha,25-dihydroxyvitamin D2 (paricalcitol) has been tested for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease. Clinical studies have shown that paricalcitol reduces serum parathyroid hormone (PTH) levels with minimal potential to cause hypercalcemia, a common side effect of vitamin D3 therapy. Paricalcitol is typically administered intravenously after hemodialysis (HD). Because the administration of paricalcitol before or during dialysis would be desirable, the effect of HD on paricalcitol pharmacokinetics was investigated. Six patients requiring HD received a single dose of paricalcitol, 0.08 microg/kg, intravenously approximately 2 hours before HD, and blood samples were collected by venipuncture immediately before and 15 minutes after HD. Also, pairs of pre- and postdialyzer blood samples were collected approximately 1 and 2 hours after the start of HD. Plasma concentrations of paricalcitol in the samples were determined by a specific high-performance liquid chromatography (HPLC)/radioreceptor assay (RRA) with a lower limit of quantification of 40 pg/mL. Compared with previous pharmacokinetic studies in HD patients, plasma concentrations (100 to 250 pg/mL) during the 4-hour period were consistent with predicted values for this dose, and there was no apparent increase in paricalcitol clearance during HD. Pre- and postdialyzer plasma concentrations of paricalcitol were compared statistically using a paired t-test. Postdialyzer concentrations tended to be slightly higher than those predialyzer, but the differences were not statistically significant (P = 0.11). Thus, HD essentially had no effect on plasma concentrations of paricalcitol, suggesting that paricalcitol can be administered at any time during dialysis.

Aged↗
PubMed1998

Therapy of secondary hyperparathyroidism with 19-nor-1alpha,25-dihydroxyvitamin D2.

Secondary hyperparathyroidism contributes to significant morbidity in patients with chronic renal failure. The treatment of this disorder with vitamin D compounds, such as calcitriol, although effective at suppressing parathyroid hormone (PTH) secretion, may promote the development of hypercalcemia and hyperphosphatemia, thus increasing the risk for metastatic calcification. A new vitamin D analogue, 19-nor-1alpha,25-(OH)2D2 (paricalcitol; Zemplar, Abbott Laboratories, Inc, Chicago, IL) has recently been developed for the treatment of secondary hyperparathyroidism, and, in experimental animals, it was found to be less calcemic and phosphatemic than calcitriol. In double-blind clinical trials, paricalcitol effectively decreased the levels of PTH by 60%, yet the mean serum calcium values remained within the normal range. The few episodes of hypercalcemia that occurred in the paricalcitol-treated patients (8 of 400 determinations > or =11.0 mg/dL in 7 patients) were associated with marked decreases in PTH levels (87% +/- 2% less than baseline) and absolute values of PTH less than 100 pg/mL in four of the seven patients. PTH values less than 100 pg/mL, however, occurred in 15 patients, but were not invariably associated with frank hypercalcemia, although serum calcium levels increased to 10.63 +/- 0.3 mg/dL, slightly greater than the upper limits of normal. Additional studies to evaluate the conversion from calcitriol to paricalcitol therapy showed that a dose ratio of 1:4 (calcitriol:paricalcitol) could maintain control of high levels of PTH without significant alterations in serum calcium and phosphorus levels. These studies indicate that effective control of hyperparathyroidism can be achieved with paricalcitol therapy with minimal perturbation of serum calcium and phosphorus levels, and may have a therapeutic advantage over current treatment strategies.

Calcium↗
PubMed2000

Intermittent doxercalciferol (1alpha-hydroxyvitamin D(2)) therapy for secondary hyperparathyroidism.

Hypercalcemia and hyperphosphatemia frequently necessitate vitamin D withdrawal in hemodialysis patients with secondary hyperparathyroidism. In short-term trials, doxercalciferol (1alpha-hydroxyvitamin D(2) [1alphaD(2)]) suppressed intact parathyroid hormone (iPTH) effectively with minimal increases in serum calcium and phosphorus (P) levels. This modified, double-blinded, controlled trial examined the efficacy and safety of 1alphaD(2) use in 138 hemodialysis patients with moderate to severe secondary hyperparathyroidism by using novel dose titration; 99 patients completed the study. Hemodialysis patients with secondary hyperparathyroidism were enrolled onto this study, consisting of washout (8 weeks), open-label 1alphaD(2) treatment (16 weeks), and randomized, double-blinded treatment with 1alphaD(2) or placebo (8 weeks). Oral 1alphaD(2) was administered at each hemodialysis session, with doses titrated to achieve target iPTH levels of 150 to 300 pg/mL. Baseline iPTH levels (897 +/- 52 [SE] pg/mL) decreased by 20% +/- 3.4% by week 1 (P: < 0.001) and by 55% +/- 2.9% at week 16; iPTH levels returned to baseline during placebo treatment but remained suppressed with 1alphaD(2) treatment. In 80% of the patients, iPTH level decreased by 70%, reaching the target level in 83% of the patients. Grouping patients by entry iPTH level (<600, 600 to 1,200, and >1,200 pg/mL) showed rapid iPTH suppression in the group with the lowest level; greater doses and longer treatment were required in the group with the highest level. During open-label treatment, serum calcium and P levels were 9.2 +/- 0.84 (SD) to 9.7 +/- 1.05 mg/dL and 5.4 +/- 1.10 to 5.9 +/- 1.55 mg/dL, respectively. During double-blinded treatment, serum calcium levels were slightly greater with 1alphaD(2) than placebo, but P levels did not differ. During double-blinded treatment, 3.26% and 0.46% of serum calcium measurements exceeded 11.2 mg/dL with 1alphaD(2) and placebo, respectively (P: < 0.01); median level was 11.6 mg/dL during hypercalcemia. Intermittent oral 1alphaD(2) therapy effectively suppresses iPTH in hemodialysis patients with secondary hyperparathyroidism, with acceptable mild hypercalcemia and hyperphosphatemia.

Adult↗
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↗
PubMed2001

A placebo-controlled trial to evaluate immunomodulatory effects of paricalcitol.

Calcitriol has shown a benefit in various small uncontrolled studies of ex vivo immune function. We hypothesized that paricalcitol, a new vitamin D derivative, will have a positive effect on the immune system with minimal adverse effects on calcium homeostasis. Thirty-one hemodialysis patients not administered vitamin D because of low intact parathyroid hormone (PTH) levels were randomized to placebo or 4 microg of paricalcitol intravenously with the hemodialysis session three times weekly for 12 weeks. Effects on in vivo and ex vivo assessments of immune function were evaluated. All patients achieved the target dose of paricalcitol. Twenty patients were anergic at the start of the study; 4 of 11 patients in the paricalcitol group and 0 of 9 patients in the placebo group converted to reactive (P = 0.09). The in vivo response to standard hepatitis B booster vaccine and in vitro proliferation and release of interleukin-2 (IL-2), IL-6, tumor necrosis factor-alpha, and interferon-gamma from stimulated lymphocytes were not different between the groups. In contrast to clinical immune effects, paricalcitol increased serum calcium levels and decreased PTH and bone alkaline phosphatase levels (all P < 0.05). However, hypercalcemia was infrequent. In vitro experiments showed that paricalcitol led to greater dose-dependent thymidine uptake than calcitriol in lymphocytes isolated from either dialysis patients or control subjects. Paricalcitol has a tendency toward improving delayed hypersensitivity reactions, but did not have other proimmune effects. However, as expected, paricalcitol had significant effects on calcium homeostasis compared with placebo. Thus, patients with low PTH levels are unlikely to experience the proimmune effects of vitamin D therapy without more profound and potentially adverse oversuppression of PTH.

Adult↗
PubMed2001

Vitamin D analogues for the management of secondary hyperparathyroidism.

Secondary hyperparathyroidism complicating chronic kidney disease requires therapy to minimize the effects of parathyroid hormone (PTH) on bone and other tissues. Low levels of calcitriol in blood play a major role in the initiation and maintenance of hyperparathyroidism. Accordingly, administration of calcitriol has been demonstrated to be an effective form of therapy. While this therapy is effective in controlling hyperparathyroidism, side effects of calcitriol, including increased intestinal absorption of calcium and phosphate, often complicate therapy by giving rise to hypercalcemia and hyperphosphatemia, which may be important risk factors for extraskeletal calcifications. Over the last several years, interest has turned toward vitamin D analogs, which may be able to affect parathyroid function with lesser effects on calcium and phosphorus in serum, and thereby, minimizing the undesirable toxicities of vitamin D therapy. Two vitamin D analogs are available in this country for the control of hyperparathyroidism in the setting of advanced kidney disease, and include 19-nor-1,25-dihydroxyvitamin D(2) (paricalcitol), and more recently, 1-alpha-hydroxyvitamin D(2) (doxercalciferol). 19-nor-1,25-dihydroxyvitamin D(2) is widely used and was evaluated extensively in animals, revealing that this vitamin D sterol had a selective effect on increasing PTH suppression, with lesser effects on calcium and phosphorus metabolism. These studies lead to clinical trials which showed the efficacy of this therapy in that PTH could be lowered satisfactorily in patients with calcium and phosphorus values within the normal range. The selectivity of 19-nor-1,25-dihydroxyvitamin D(2) seen in animals has also been found in humans, such that therapy with this sterol can achieve control of hyperparathyroidism with a wider therapeutic window than the predecessor, calcitriol. 1-alpha-hydroxyvitamin D(2) has recently been introduced, but in contrast to paracalcitol, there is little reason to believe that there is any selectivity in its actions in terms of suppressing PTH, compared with its ability to raise serum calcium or phosphorus in serum. However, this vitamin D sterol can effectively decrease PTH levels in patients with advanced renal failure. Comparative studies of paricalcitol and doxercalciferol have not been undertaken at the present time. Further studies on the mechanism of actions might explain the differences between these sterols and their effects on the intestinal absorption of calcium and phosphate. At the present, the use of vitamin D analogs can achieve control of hyperparathyroidism with a wider therapeutic window than the native sterol, calcitriol.

Animals↗
PubMed2001

Suppression of parathyroid hormone secretion in hemodialysis patients: comparison of paricalcitol with calcitriol.

Paricalcitol was introduced recently as an effective alternative to calcitriol for the suppression of parathyroid hormone (PTH) in patients with end-stage renal disease. An international, multicenter, double-blinded, randomized, comparative study of intravenous paricalcitol and calcitriol was performed. Results from 38 patients at dialysis units affiliated with the Northwestern University Medical School (Chicago and Evanston, IL) are reported here while a report of the full clinical trial is being completed. Results were evaluated in terms of obtaining the following end points: decrease of at least 50% in baseline PTH concentration and the occurrence of hypercalcemia and hyperphosphatemia. Paricalcitol therapy was started at a dose of 0.04 microgram/kg and increased by 0.04 microgram/kg increments every 4 weeks to a maximum allowable dose of 0.24 microgram/kg or until there was at least a 50% decrease in serum PTH concentration. Calcitriol therapy was started at a dose of 0.01 microgram/kg and increased by 0.01 microgram/kg increments every 4 weeks to a maximum allowable dose of 0.06 microgram/kg or until there was at least a 50% decrease in serum PTH concentration. Mean baseline serum PTH, calcium, and phosphorus concentrations were similar. Reductions in PTH occurred more rapidly in subjects administered paricalcitol compared with calcitriol, with no difference in serum calcium levels throughout the study between groups. The percentage of subjects experiencing severe hyperphosphatemia (serum phosphorus >8.0 mg/dL) was greater in those administered calcitriol compared with paricalcitol. In conclusion, our data suggest that paricalcitol reduces PTH levels more rapidly, with fewer episodes of hyperphosphatemia, than intravenous calcitriol.

Calcitriol↗
PubMed2001

Paricalcitol dosing according to body weight or severity of hyperparathyroidism: a double-blind, multicenter, randomized study.

Vitamin D therapy for patients with end-stage renal disease (ESRD) on hemodialysis therapy has relied on patient dry weight to determine the initial dose of medication. Obtaining a patient's dry weight can be difficult, and no correlation has been established between a patient's body weight and severity of secondary hyperparathyroidism. We conducted a double-blind, double-dummy, randomized, 12-week, multicenter trial to compare the incidence of hypercalcemia (single occurrence) between two dosing regimens: one regimen based on baseline intact parathyroid hormone (iPTH; PTH/80) level, and the other regimen based on patient body weight (0.04 microgram/kg). One hundred twenty-five adult patients with ESRD on maintenance hemodialysis therapy were enrolled at multiple sites. Before treatment, all patients were required to have PTH levels of 300 pg/mL or greater, calcium levels of 8.0 mg/dL or greater and 10.5 mg/dL or less, and a calcium x phosphorus (Ca x P) product of 70 or less. Patients were randomized to one of two regimens: the nonrandomized treatment was also administered as a placebo dummy. No incidence of hypercalcemia occurred in either treatment group during the study. Patients treated according to the formula iPTH/80 required fewer dose adjustments and achieved the first of four consecutive reductions from baseline PTH level of 30% or greater more rapidly than patients treated based on body weight (P = 0.0306). Incidences of elevated Ca x P product levels were similar between treatment groups. Treatment with paricalcitol injection based on degree of secondary hyperparathyroidism incurred no greater risk for hypercalcemia and achieved meaningful therapeutic results with fewer dose adjustments than dosing based on patient body weight.

Adolescent↗
PubMed2001

Paricalcitol in dialysis patients with calcitriol-resistant secondary hyperparathyroidism.

Paricalcitol was evaluated for the treatment of secondary hyperparathyroidism (SHPT) in a long-term, prospective, open-label study of 37 patients with end-stage renal failure resistant to intravenous calcitriol. All patients had an intact parathyroid hormone (iPTH) level of 600 pg/mL or greater before being converted from calcitriol to paricalcitol therapy. Paricalcitol therapy was initiated at a 1:4 calcitriol to paricalcitol dose conversion ratio for the initial 14 patients and a 1:3 dose ratio for the next 23 patients. Subsequent dosing was based on iPTH, calcium, and phosphorus determinations. All patients underwent hemodialysis three times weekly and received structured nutritional counseling. Mean iPTH level (baseline, 901 +/- 58 pg/mL) decreased rapidly during the initial 2 months and was 165 +/- 24 pg/mL at 16 months. Alkaline phosphatase levels decreased from 280 +/- 27 IU at baseline to 65 +/- 12 IU at 16 months. Mean calcium and phosphorus levels did not change significantly over the 16 months of paricalcitol therapy. The baseline mean calcium level of 9.4 +/- 0.2 mg/dL increased to 9.7 +/- 0.2 mg/dL (P = 0.86), and phosphorus level decreased from 6.1 +/- 0.2 to 5.8 +/- 0.2 mg/dL (P = 0.77). The greater paricalcitol doses afforded by the initial dose conversion ratio of 1:4 produced unacceptably rapid iPTH suppression and subsequent hypercalcemia. Mean doses of paricalcitol decreased six- to sevenfold throughout the course of therapy while maintaining acceptable iPTH suppression. Eight patients developed hypercalcemia, which successfully managed by dietary counseling, phosphate-binder adjustment, and paricalcitol dose reduction. Six patients developed hyperphosphatemia; 3 patients responded adequately to dietary manipulation and phosphate binders, but 3 patients had repeated episodes. Three patients did not respond adequately to paricalcitol therapy and required parathyroidectomy. In summary, paricalcitol was successful at controlling SHPT in patients resistant to calcitriol therapy with minimal impact on calcium and phosphorus homeostasis. The 1:3 initial dose conversion provided the smoothest iPTH control with only a single episode of hypercalcemia in patients treated with this initial dose. Doses of paricalcitol decreased over time.

Calcitriol↗
PubMed2001

Strategies to minimize bone disease in renal failure.

The skeletal disorders associated with renal insufficiency result from alterations in calcium, phosphorus, and vitamin D metabolism. Each requires intervention to prevent and control the problem. Hyperparathyroidism and its treatment can also result in extraskeletal complications. To prevent the development of parathyroid hyperplasia and the skeletal complications of chronic kidney disease, it is desirable to initiate interventions early in the course of kidney disease; however, many patients present with established hyperparathyroidism and additional strategies are necessary to suppress hyperparathyroidism. Mainstays of this approach are the control of phosphorus and the use of vitamin D analogs. Phosphorus control requires the use of phosphate binders, preferably non-calcium-containing binders, to prevent intestinal phosphorus absorption. Vitamin D analogs are used to suppress hyperparathyroidism and have the potential to have lesser toxicity than calcitriol. Paricalcitol is the most widely used vitamin D analog in this country and it effectively suppresses hyperparathyroidism with only minimal effects on calcium and phosphorus. A substantial body of data in experimental animals supports the use of paricalcitol as a preferential therapeutic agent. Recently, an additional vitamin D sterol, doxercalciferol, has been introduced, which is metabolized to 1,25-dihydroxyvitamin D(2). Although initially thought to have lesser toxicity than its vitamin D(3) counterpart, recent studies have not provided support for a major difference in this regard. Doxercalciferol is also effective in lowering parathyroid hormone (PTH), though hypercalcemia in hyperphosphatemic episodes occurred relatively frequently during the clinical studies. As these therapeutic strategies are undertaken, it is important not to oversuppress PTH and decrease bone turnover to abnormally low levels because of the risk for adynamic renal bone disease. It is possible that when bone turnover is abnormally low, the extraskeletal deposition of calcium in blood vessels and other tissues is enhanced. Accordingly, constant monitoring is required during treatment, with emphasis on minimizing the calcium load, and, if monitored correctly, a satisfactory control of hyperparathyroidism may be achieved with the agents currently available.

Animals↗
PubMed2002

Differential effects of acute administration of 19-Nor-1,25-dihydroxy-vitamin D2 and 1,25-dihydroxy-vitamin D3 on serum calcium and phosphorus in hemodialysis patients.

BACKGROUND: Treatment of hyperparathyroidism includes the use of 1,25-dihydroxy-vitamin D3 (1,25D3) to suppress parathyroid hormone (PTH), but dosing of 1,25D3 is limited by the development of hypercalcemia and a high calcium x phosphorus (Ca x P) product because of gut absorption of calcium and phosphorus and enhanced bone resorption. The vitamin D analogue 19-nor-1,25(OH)2-vitamin D2 (19-Nor) causes less hypercalcemia and elevated Ca x P, whereas it still suppresses PTH in rats. METHODS: To determine whether 19-Nor had similar effects in humans, we performed a prospective crossover study to assess bone mobilization. Ten hemodialysis patients on a low-calcium low-phosphorus diet were administered 20 microg of 1,25D3 and 120 and 160 microg of 19-Nor, and changes in calcium, phosphorus, and intact and whole PTH levels were measured over 36 hours. RESULTS: Ca x P product increased more after 1,25D3 administration than after a six- or eightfold greater dose of 19-Nor and was significantly greater at 6, 12, and 24 hours. Ca x P product at 36 hours was 60.9 +/- 3.4 (4.91 +/- 0.27 mmol2/2) after 1,25D3 administration, 53.2 +/- 2.7 (4.29 +/- 0.22 mmol2/L2) after administration of 120 microg of 19-Nor, and 54.2 +/- 2.7 (4.37 +/- 0.22 mmol2/L2) after administration of 160 microg of 19-Nor. Suppression of intact PTH at 36 hours was similar after administration of 1,25D3 (54.1% +/- 6.0%) and 120 microg of 19-Nor (54.4% +/- 3.4%) and significantly greater after administration of 160 microg of 19-Nor (63.6% +/- 2.3%). The whole PTH assay yielded values approximately 25% to 30% lower than the intact PTH assay, and the percentage of suppression was virtually identical. CONCLUSION: Consistent with animal studies, 19-Nor provides profound PTH suppression while stimulating bone resorption and/or intestinal absorption less than 1,25D3, resulting in less elevation of serum calcium and phosphorus levels.

Adult↗