A Comparison of Oral and Intravenous Alfacalcidol in the Treatment of U Rem Ic Hyperpa Rathyroid
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A Comparison of Oral and Intravenous Alfacalcidol in the Treatment of U rem ic Hyperpa rathyroid Wan Tin Lee, Kashi Padayachi, John F. Collins and Tim Cundy2 H yperparathyroidism is a common complication W.T. Lee, J.F. Collins, Division of Renal Medicine, De- of end-stage chronic renal failure and an impor- partment of Medicine. Auckland Hospital, Auckland, tant cause of morbidity in patients on maintenance New Zealand dialysis. The main cause of hyperparathyroidism is K. Padayachi, T. Cundy, Division of Endocrinology, loss of activity ofthe renal 1 a hydroxylase enzyme and impaired production of calcitriol (1 ,25fOH12D) from its Department of Medicine. Auckland Hospital. precursor, calcidiol (25 OH D). Uremic hyperparathy- Auckland, New Zealand roidism is usually treated with derivatives ofvitamln D (J. Am. Soc. Nephrol. 1994; 5:1344-1348) which are already la hydroxylated, such as calcitriol itself or a.lfacalcidol (1 a OH D, which is rapidly con- verted in vivo to calcitriol) (1). Calcitriol can suppress ABSTRACT parathyroid hormone (Fri-I) secretion by two mecha- The i.v. bolus administration of la hydroxylated vita- nisms: indirectly through the stimulation of intestinal mm D derivatives is effective in the treatment of ure- calcium absorption and raising plasma calcium (2) mic hyperparathyroidism. However, few of the pub- and directly through actions on FF1-I gene transcrip- lished studies of this mode of treatment have been tion (3). In practice, the effectiveness of the la hy- adequately controlled, and recent reports have sug- droxylated vitamin D derivatives is limited by the gested that p.o. bolus administration may be Just as degree to which plasma concentrations ofcalcium can effective. In this study, 16 hemodialysis patients with safely be raised. There has been, therefore, consider- able interest in ways of maximizing the direct, noncal- mild to moderate hyperparathyroidism were as- cemic effect on PTH synthesis, particularly in the use signed, after a 4wk run-in period, to receive a 6-wk of intermittent injections of high doses of 1 a hydroxy- course of either thrice-weekly i.v. or p.o. alfacalcidol lated vitamin D derivatives. Although several reports (initial dose, 4 pg). Then, after a further control period, have attested to the efficacy of this approach (4-9), they received a second 6-wk course, with either p.o. others have suggested that intermittent high-dose p.o. or i.v. alfacalcidol (whichever was not given in the first therapy works just as well ( 1 0 - 1 5). However, none of treatment period). Plasma parathyroid hormone these studies have been adequately controlled. We (PTh) was measured weekly by the use of an intact report here a crossover study on maintenance hemo- hormone assay. Both routes of therapy resulted in a dialysis patients with mild to moderate hyperparathy- roidism, comparing high-dose aLfacalcidol given either significant suppression of plasma PTH (P = 0.005) and as intermittent p.o. therapy or as intermittent i.v. an elevation in plasma ionized calcium (P = 0.01). therapy. The magnitude of the responses was similar for the two treatment phases, as was the relationship be- MATERIALS AND METHODS tween the incrementin calcium and the decrement in PTH. The most complete suppression of PTH was seen Patients in those with the greatest increment in plasma cal- Sixteen adult patients (1 1 men, 5 women) with chronic cium. The incidence of hypercalcemia and the mean renal failure and mild to moderate hyperparathyroidism were dose reductions necessary were also similar in the two studied. Their ages ranged from 24 to 78 yr (median, 54), and treatment phases. Oral bolus therapy and iv. bolus they have been on maintenance hemodialysis at a hospital- based center for periods ranging from 0.3 to 14 yr (median, therapy with alfacalcidol are equally effective in sup- 3). All received thrice-weekly hemodialysis against a dialy- pressing hyperparathyroidism. The postulated advan- sate oflow calcium content (1 .2 mmol/L). Two ofthe patients tages of i.v. over p.o. therapy with la hydroxylated were being treated with la hydroxylated vitamin D deriva- vitamin D derivatives remain to be confirmed by tives before enrollment, but therapy was withdrawn 6 wk controlled studies. before beginning this study. Three patients had subtotal parathyroldectomy 3 to 5 yr earlier but had developed recur- Key Words: Hemodialysis, vitamin 0 Therapy, adults, hyper- rent hyperparathyroidism, and three patients had returned to maintenance hemodialysis after unsuccessful renal trans- calcemia. hyperphosphatemia plantation. Patients were excluded from the study if their initial total plasma calcium exceeded 2.7 mmol/L, plasma 1 ReceIved December 13. 1993. Accepted June 10, 1993. phosphate exceeded 2.0 mmol/L. plasma aluminum cx- 2 Correipondence to Dr. 1. Cundy, DIvisIon of EndOCrinOlOgy. Auckland HOspital. ceeded 3 mol/L, or plasma V1’H was less then 10 pmol/L. Private Bag 92 024, Park Rood. Grafton, Auckland, New Zealand. After a 4-wk run-in period, patients were randomized to 1O46.6673/O5O1344SO3.OO/O receive either i.v. or p.o. allacalcidol (One Alpha’: Leo Phar- Journal of the American Society of Nephrology CopyrIght C by the American Society of Nephrology maceuticals, (Ballerup, Denmark) thrice weekly for an initial 1344 Volume 5 - Number 6 ‘ 1994 Lee et al treatment period of 6 wk. This was followed by an 8-wk ples. Correlations were calculated by the Pearson method. period of observation off alfacalcidol, before a second treat- The results are expressed as the mean. with 95% confidence ment period of 6 wk. During the second period. those eight intervals, unless otherwise stated. FF1-I concentrations were patients initially randomized to thrice-weekly I.v. alfacalcidol not normally distributed: therefore, they were log10 trans- were treated with thrice-weekly p.o. alfacalcidol, and vice formed before analysis, and the results were transformed verse.. After the second treatment period, there was a final back for presentation. 4-wk observation period. The whole study thus lasted 28 wk, during which time, plasma concentrations of total and ion- RESULTS izeci calcium, phosphate, and I’TH were measured on plasma samples drawn immediately before the first dialysis treat- Both i.v. and p.o. alfacalcidol produced significant ment of each week. Intravenous alfacalcidol was adminis- increases in plasma total and ionized calcium (Table tered at the end of each hemodialysis treatment, as was p.o. 1 ; Figure 1). The mean increment in plasma calcium alfacalcidol. The initial dosages. 4 g thrice weekly. were the was greater in the p.o. alfacalcidol phase than in the same. If hypercalcemia (total calcium 3.0 mmol/L) oc- i.v. phase, but this difference was not statistically curred or if the calcium X phosphate product exceeded 6. significant. In the i.v. phase, nine patients developed then the two subsequent doses of alfacalcidol were omitted modest hypercalcemia (2.65 to 2.99 mmol/L) and, 3 and alfacalcidol was restarted at a dose of 1 g lower than previously. developed severe hypercalcemia (3.0 mmol/L). For All 16 subjects were receiving some form of phosphate the p.o. phase, the numbers were five and three, binder therapy, either with aluminum hydroxide (Alutabs’: respectively. In both phases oftreatment, plasma PTH 3M Pharmaceuticals, St. Paul, MN; 600 mg per tablet, two to concentrations decreased significantly (Fable 1 ; Fig- seven tablets per day, 14 subjects) and/or with calcium ure 1). The mean decrement in plasma PTH was carbonate (Oscal’: Marion Merrell Dow, Kansas City, MO; greater in the p.o. phase, but this difference again 1.25 g per tablet, two to nine tablets per day. 14 subjects). failed to reach statistical significance. Suppression of During the study, phosphate binder therapy was adjusted to PTH to the normal range (5 pmol/L) was achieved in try and maintain predialysis plasma phosphate concentra- 8 of 16 subjects during the i.v. phase and 6 of 16 tions at 2.0 mmol/L. The study was approved by the local Research Ethics Committee, and written informed consent during the p.o. phase. was obtained from all subjects. In each individual, the correlation between the plasma VFH and ionized calcium concentrations in Methods each run-in period and treatment period was calcu- Plasma I7TH concentrations were measured by an intact lated for both p.o. and i.v. phases. In 1 1 of the 16 hormone radioimmunometric assay (Nichols Institute. San subjects in the i.v. phase and 10 of 16 in the p.o. Juan Capistrano, CA) with a normal range of 1 to 5 pmol/L. phase, clear correlations were present (r values rang- Ionized calcium concentrations were measured by an Ion- ing from -0.63 to -0.98). The mean values for the specific electrode, with a normal range of 1. 17 to 1.29 slope and intercept of these regression lines were mmol/L. Plasma total calcium and phosphate were mea- calculated for both treatment phases and in neither sured on a Hitachi 737 autoanalyzer (Tokyo, Japan: normal case differed between groups (slope: i.v., 0.29 (0.23 to ranges: total calcium. 2.2 to 2.6 mmol/L: phosphate. 0.8 to 0.351 versus oral, 0.29 10.24 to 0.341; intercept: i.v., 1 .4 mmol/L). Plasma calcitriol concentrations (measured 44 h postdose, once per patient in each treatment period) were 4.61 (3.94 to 5.281 versus oral, 4.78 (4.25 to 5.311), measured by a competitive protein binding assay (Nichols indicating that the relationship between ionized cal- Institute) with a normal range of 18 to 62 ng/L. cium and FF1-I did not differ between the treatment phases. Ths is also ifiustrated in Figure 2, which Statistical Analysis shows the relationship between the percentage Differences between control and treatment periods and change in ionized calcium and the percentage change between treatments were assessed by t test for paired sam- in PT’!-!.