Intermittent doxercalciferol (1α-Hydroxyvitamin D2) therapy for secondary hyperparathyroidism

Intermittent Doxercalciferol (1␣-Hydroxyvitamin D2) Therapy for Secondary Hyperparathyroidism Joa˜o M. Fraza˜o, MD, PhD, Loganathan Elangovan, MD, Hla M. Maung, MD, Russell W. Chesney, MD, Sergio R. Acchiardo, MD, John D. Bower, MD, Bobby J. Kelley, MD, Hector J. Rodriguez, MD, PhD, Keith C. Norris, MD, John A. Robertson, MD, Barton S. Levine, MD, William G. Goodman, MD, Dominick Gentile, MD,† Richard B. Mazess, PhD, Darlene M. Kyllo, RAC, Laura L. Douglass, RN, Charles W. Bishop, PhD, and Jack W. Coburn, MD ● Hypercalcemia and hyperphosphatemia frequently necessitate vitamin D withdrawal in hemodialysis patients with secondary hyperparathyroidism. In short-term trials, doxercalciferol (1␣-hydroxyvitamin D2 [1␣D2]) 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 1␣D2 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 1␣D2 treatment (16 weeks), and randomized, double-blinded treatment with 1␣D2 or placebo (8 weeks). Oral 1␣D2 was administered at each hemodialysis session, with doses titrated to achieve target iPTH levels of 150 to 300 pg/mL. Baseline iPTH levels (897 ⴞ 52 [SE] pg/mL) decreased by 20% ⴞ 3.4% by week 1 (P < 0.001) and by 55% ⴞ 2.9% at week 16; iPTH levels returned to baseline during placebo treatment but remained suppressed with 1␣D2 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 ⴞ 0.84 (SD) to 9.7 ⴞ 1.05 mg/dL and 5.4 ⴞ 1.10 to 5.9 ⴞ 1.55 mg/dL, respectively. During double-blinded treatment, serum calcium levels were slightly greater with 1␣D2 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 1␣D2 and placebo, respectively (P < 0.01); median level was 11.6 mg/dL during hypercalcemia. Intermittent oral 1␣D2 therapy effectively suppresses iPTH in hemodialysis patients with secondary hyperparathyroidism, with acceptable mild hypercalcemia and hyperphosphatemia. © 2000 by the National Kidney Foundation, Inc. INDEX WORDS: Intact parathyroid hormone (iPTH); renal osteodystrophy; 1␣-hydroxyvitamin D2 (1␣D2); doxercalciferol (1␣D2); vitamin D; renal failure; hemodialysis (HD); therapeutic trial; placebo-controlled.

From the Medical and Research Services, Veterans Affairs West Los Angeles Healthcare Center; Department of Medicine, University of California–Los Angeles School of Medicine; Charles R. Drew University, Los Angeles, CA; Departments of Pediatrics and Medicine, University of Tennessee at Memphis, TN; Nephrology Division, University of Mississippi, Jackson, MS; and Bone Care International, Inc, Madison, WI. †Deceased. Received January 19, 2000; accepted in revised form April 14, 2000. Supported in part by a grant from Bone Care International, Inc; and grant no. 1 P20 RR11145-01 from the National Institutes of Health, National Center for Research Resources (K.C.N.). Address reprint requests to Jack W. Coburn, MD, Nephrology Section (111L), VA West Los Angeles Healthcare Center, 11301 Wilshire Blvd, Los Angeles, CA 90073. E-mail: [email protected] © 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3603-0012$3.00/0 doi:10.1053/ajkd.2000.16193 550

T

HE SEARCH FOR vitamin D sterols that can suppress the secretion of parathyroid hormone (PTH) with minimal calcemic and phosphatemic actions has led to the study of several vitamin D analogues, including maxicalcitol (22-oxacalcitriol),1,2 falecalcitriol (26,27-hexafluorocalcitriol),3,4 paricalcitol (19-nor-1,25dihydroxyvitamin D2),5,6 and doxercalciferol (1␣-hydroxyvitamin D2 [1␣D2]).7,8 The last sterol, 1␣D2, is converted primarily to 1,25-dihydroxyvitamin D2 in the liver; hence, the need for renal 1-hydroxylation is bypassed. When administered in oral doses of 10 ␮g with each hemodialysis session, 1␣D2 was shown to suppress intact PTH (iPTH) levels effectively in preliminary trials of hemodialysis patients without causing significant hypercalcemia and hyperphosphatemia.8,9 This experience8,9 provided the basis for the present controlled study of

American Journal of Kidney Diseases, Vol 36, No 3 (September), 2000: pp 550-561

1␣D2 IN SECONDARY HYPERPARATHYROIDISM

a large population of hemodialysis patients with moderate to severe secondary hyperparathyroidism (pretreatment plasma iPTH, 442 to 4,706 pg/mL). The present study consisted of 8 weeks of washout with no calcitriol, 16 weeks of openlabel 1␣D2 treatment, and 8 weeks of doubleblinded crossover to either placebo or continued 1␣D2 treatment. Open-label treatment was performed first because it was considered unethical to withhold vitamin D therapy for up to 32 weeks in patients with severe secondary hyperparathyroidism. Dosing with 1␣D2 was initiated at a high level, 10 ␮g with each dialysis session, and then adjusted to maintain plasma iPTH levels within a preselected range. This approach contrasts with the usual method for treating secondary hyperparathyroidism with calcitriol and alfacalcidol (1␣D3), in which the initial doses are cautiously low and adjustments are guided by changes in serum calcium levels. The primary goals of the present study are to evaluate the efficacy and safety of intermittent high oral doses of 1␣D2 for treating moderate to severe secondary hyperparathyroidism. A secondary goal is to evaluate the effect of severity of hyperparathyroidism on the doses required and the therapeutic response. PATIENTS AND METHODS

Patients This randomized, double-blinded, placebo-controlled trial with 1␣D2 enrolled 211 hemodialysis patients with moderate to severe secondary hyperparathyroidism selected from 18 hemodialysis units in two disparate geographic areas; southern California and western Tennessee, eastern Arkansas, and Mississippi. The protocol was approved by the institutional review board at each center, and informed consent was obtained from each patient. The protocol was designed to enroll patients with secondary hyperparathyroidism with no limit on severity, determined by the entry plasma iPTH level. For safety reasons, the only limitations were degree of hypercalcemia or hyperphosphatemia on entry. Inclusion criteria for entering washout included: (1) age 20 to 75 years; (2) hemodialysis therapy duration greater than 4 months; (3) iPTH value greater than 400 pg/mL when off calcitriol therapy; (4) serum albumin level greater than 3.5 g/dL; (5) average serum phosphorus (P) level between 2.5 and 6.9 mg/dL during 2 recent months; and (6) no intake of aluminum-containing phosphate binders for 12 months, combined with a serum aluminum level less than 40 ␮g/L. Exclusion criteria were: (1) a medical condition, such as malabsorption syndrome or liver disease, that might alter the absorption or metabolism of 1␣D2; (2) a condition, such as alcoholism, drug abuse, malignancy, or psychiatric disorder,

551

that would preclude participation in the study; and (3) parathyroid surgery within 12 months.

Study Design The study lasted 32 weeks and consisted of washout (8 weeks), open-label treatment (16 weeks), and doubleblinded, placebo-controlled treatment (8 weeks). During washout, calcitriol was withdrawn from the 115 patients to whom it had been administered. Patients were excluded from entering open-label treatment if during the first 7 weeks of washout, they failed to show: (1) an average predialysis serum P level of 2.5 to 6.9 mg/dL; (2) an average predialysis serum calcium level less than 10.6 mg/dL; (3) an average calcium X P product of 70 or less; and (4) at least one plasma iPTH value greater than 400 pg/mL at enrollment or a mean iPTH level during washout greater than 350 pg/mL. During open-label treatment, 1␣D2 was administered at a dose of 10 ␮g orally with each hemodialysis session. Week 1 was defined as the first week of treatment. The dosage was adjusted, as described next, to maintain plasma iPTH levels within a target range of 150 to 300 pg/mL, values associated with normal or near-normal bone formation and minimal features of secondary hyperparathyroidism among hemodialysis patients.10,11 Dosing continued uninterrupted as the patients passed from open-label into double-blinded treatment, during which approximately 50% of the patients were switched to placebo, according to previous blinded assignments made in each patient on their entry into washout by a centrally located, unaffiliated statistician who used a randomization code. Throughout the study, only calcium carbonate and/or calcium acetate were used as phosphate binders, with the doses adjusted to maintain serum P levels less than 6.9 mg/dL. All patients underwent thrice-weekly hemodialysis sessions for 3 to 4 hours, using a dialysate calcium concentration of 2.5 mEq/L (n ⫽ 93); 2.0 mEq/L (n ⫽ 19); 3.0 mEq/L (n ⫽ 21), or 3.5 mEq/L (n ⫽ 5), at the discretion of the local nephrologist. In 93.5% of the patients, the dialysate calcium concentration remained constant throughout the study.

Dose Adjustments Blood samples for determination of serum calcium and P and plasma iPTH levels were drawn before each midweek dialysis session. Treatment was suspended if the plasma iPTH level decreased to less than the target range (150 to 300 pg/mL) and was resumed 1 week later at a dose that was 2.5 ␮g less than the previous dose. For safety reasons, treatment was also suspended for moderate hypercalcemia (serum calcium ⬎ 11.2 mg/dL), confirmed significant hyperphosphatemia (serum P ⬎ 8.0 mg/dL), or persistently elevated serum calcium X P product (⬎75.0). When treatment was interrupted for safety reasons, serum calcium and P levels were monitored before each hemodialysis session until the serum calcium level decreased to less than 10.6 mg/dL, serum P level decreased to less than 7.0 mg/dL, and calcium X P product decreased to less than 70. Treatment was resumed at a dose reduced by 2.5 ␮g, and such a

FRAZA˜O ET AL

552

reduction was repeated, as needed, to a lowest dose of 2.5 ␮g with each dialysis treatment. The protocol was designed so the dose could also be increased if plasma iPTH level had not decreased to within the target range and was not suppressed by 50% from the baseline value (defined next). At week 8 and at subsequent 8-week intervals, the dose of 1␣D2 could be increased by 2.5 or 5 ug per hemodialysis session in patients meeting these criteria; the maximum dose was 20 ␮g thrice weekly.

Data are expressed as mean ⫾ SE, unless stated otherwise. Treatment groups were compared with respect to each baseline parameter using t-test or Wilcoxon two-sample test, as appropriate. Fisher’s exact test was used for evaluation of probability for variables with binomial distribution. For comparison of multiple independent subsets of data, analysis of variance was applied using the Bonferroni correction. All computations were performed using the Statistical Analysis System (SAS Institute, Cary, NC). Two-tailed P less than 0.05 is considered significant.

Biochemical Measurements Serum calcium and P and plasma iPTH levels were measured weekly throughout the 24 weeks of the study. Baseline values for calcium, P, and iPTH represent the mean of the values during the last 3 weeks of washout. Additional blood samples were drawn at the start of open-label treatment (time 0) and at weeks 4, 8, 12, 16, 20, and 24 for a chemistry profile and plasma levels of 1␣,25-(OH)2D2 and 1␣,25-(OH)2D3. Serum calcium and P levels, chemistry profile, and plasma iPTH levels were measured at the same central laboratory (Lifechem Laboratories, Woodland Hills, CA). iPTH was measured by an immunoradiometric method using the Nichols Institute Allegro Kit (San Juan Capistrano, CA). After the present study was designed and completed, it was recognized that the so-called iPTH assay used in the present study does not measure true 1-84 PTH levels and overestimates the true PTH level by 30% to 35%.12,13 Nonetheless, we believe the data using this iPTH assay are valid in that there are good correlations between the present iPTH assay and the new true PTH level; also, the major studies with bone biopsy data used this same immunoassay method. Serum calcium, P, albumin, and total alkaline phosphatase were measured using an Hitachi 736 analyzer (Hitachi, Indianapolis, IN). Plasma 1␣,25-(OH)2D2 and 1␣,25-(OH)2D3 levels were determined at Bone Care Int (Madison, WI) by means of a radioreceptor assay after high-performance liquid chromatography.14,15 The detection limits were 5.0 pg/mL for 1,25-(OH)2D2 and 10.0 pg/mL for 1␣,25-(OH)2D3. For the calculation of mean concentrations, undetectable levels were assigned values of 5.0 pg/mL for 1,25-(OH)2D2 and 10.0 pg/mL for 1␣,25-(OH)2D3. The normal reference ranges are as follows: iPTH, 12.1 to 60.6 pg/mL; calcium, 8.4 to 10.2 mg/dL; P, 2.6 to 4.5 mg/dL; total alkaline phosphatase, 39 to 117 U/L; bone-specific alkaline phosphatase, 15.0 to 41.3 U/L for men, 11.6 to 30.6 U/L for women aged 25 to 55 years, and 14.8 to 30.6 U/L for women aged older than 55 years; osteocalcin levels, 3.4 to 11.7 ng/mL; 1,25(OH)2D3, 20 to 50 pg/mL; and 1,25(OH)2D2, less than 10 pg/mL. Serum levels of 25(OH)-vitamin D were not determined.

Statistical Analysis Data from 99 patients who followed the study per protocol for 32 weeks are included in the efficacy analysis of the suppression of iPTH levels. The analysis of side effects included data from all 138 patients who entered into openlabel treatment (intent to treat). The efficacy results were also evaluated for the 138 intent-to-treat patients. There were no significant differences between results from the per-protocol and intent-to-treat analyses.

RESULTS

Of the 211 patients meeting the eligibility criteria for entry into washout, 73 patients failed to qualify for open-label treatment. The major reason for disqualification of these patients was an inadequate elevation of plasma iPTH level (53.4% of the 73 patients). Other reasons included hyperphosphatemia, with mean serum P levels greater than 6.9 mg/dL (13.6%); intake of a disallowed drug (aluminum gel or calcitriol; 9.6%); death during washout (8.3%); altered dialysis modality (eg, to continuous ambulatory peritoneal dialysis, 6.8%; and all others, 8.3%). The latter included two patients with hypercalcemia and one patient with an elevated calcium X P product value. Ninety-nine of the 138 patients who entered open-label treatment completed 24 weeks per protocol. The reasons for exclusion of 39 patients are listed in Table 1. During doubleblinded treatment, there were 11 protocol violations among 71 patients treated with 1␣D2 and 4 violations among 67 placebo-treated patients. Eight of the patients treated with 1␣D2 and 1 placebo patient were disqualified because the protocol excluded from analysis those patients with mean serum P levels outside the range of 2.5 to 6.9 mg/dL throughout the 24 treatment weeks (ratio of 1␣D2 patients versus placebo, P ⫽ 0.045). Two protocol violations occurred during open-label treatment. Table 2 compares the demographics and baseline biochemical observations of patients assigned to placebo compared with those assigned to 1␣D2. There were no differences with regard to baseline biochemical data or sex and race distribution. The patients assigned to placebo during double-blinded treatment were slightly younger, had smaller body weights, and had undergone hemodialysis for a longer time compared with those assigned to 1␣D2 treatment. Serial changes of plasma iPTH levels and

1␣D2 IN SECONDARY HYPERPARATHYROIDISM Table 1.

553

Reasons for Withdrawal or Exclusion of Intent-to-Treat Patients

Open Label Reason

Protocol violations IV calcitriol treatment Al-hydroxide use Mean serum P ⬎ allowable limit† Noncompliance Excess dietary P intake Prolonged hospitalization Miscellaneous Cardiac death Change in dialysis site or mode Parathyroidectomy Renal transplantation Voluntary withdrawal Nausea, vomiting Leg pain Serum P “too high” “Feared” possible placebo treatment Total

Table 2. Demographics and Baseline Biochemical Data of Patients Assigned to 1␣D2 or Placebo During Blinded Treatment

Double Blinded

(1␣D2/Placebo)* 1␣D2 Placebo

1/0 0/1

3 0

3 0

0/0

8

1‡

1/0 1/0

0 0

0 0

0/0

1

2

4/1 1/1 0/1

1 0 0

0 1 0

1/2 1/0 0/2

0 0 0

0 0 0

0/1 10/9

0 13

0 7

NOTE. Intent-to-treat patients numbered 39 of 138 patients. Abbreviations: IV, intravenous; Al-hydroxide, aluminum hydroxide. * Preassigned treatment group for subsequent doubleblinded treatment. † Mean serum P level of 6.9 mg/dL or greater over 24 treatment weeks excluded patient from analysis. ‡ Ratio of active versus placebo, P ⫽ 0.045.

serum levels of calcium and P are shown in Figs 1 and 2. Measured serum calcium levels are reported because correction for serum albumin level less than 4.0 g/dL did not change the results. The baseline plasma iPTH level of 897 ⫾ 52 pg/mL decreased after 1 week of 1␣D2 treatment to 80.2% ⫾ 3.43% of baseline (P ⬍ 0.001) and continued to decrease thereafter, reaching 44.7% ⫾ 2.87% of baseline at week 16 (P ⬍ 0.001). When patients were switched to placebo during double-blinded treatment, the median plasma iPTH level increased 28.7% (25:75 percentiles, ⫹1.3%:⫹100.5%) between weeks 16 and 17 (P ⬍ 0.001). Thereafter, iPTH levels increased further and did not differ from baseline by week 20, only 4 weeks after the withdrawal of 1␣D2. In contrast, plasma iPTH levels remained suppressed in patients who continued to receive

1␣D2 (n ⫽ 71) Age (y) Dialysis duration (mon) Weight (kg) Sex (F/M) Race (W/B/H) iPTH (pg/mL) S-Ca (mg/dL) S-P (mg/dL)

55 ⫾ 12.4 (30-75)

Placebo (n ⫽ 67) 49 ⫾ 14.9 (22-75)*

45 ⫾ 44.8 (4-231) 64 ⫾ 57.0 (7-251)* 80 ⫾ 20.6 (43.7-153) 74 ⫾ 20.2 (31.5-132.5)* 36/35 34/33 11/57/3 9/54/4 899 ⫾ 522 928 ⫾ 636 8.9 ⫾ 0.72 9.1 ⫾ 0.84 5.05 ⫾ 1.05 4.90 ⫾ 1.17

NOTE. Data expressed as mean ⫾ SD (range). Abbreviations: W, white; B, black; H, Hispanic; S-Ca, serum calcium; S-P, serum phosphorus. * P ⬍ 0.05.

1␣D2. From weeks 17 through 24, the magnitude of PTH suppression differed significantly between the placebo and 1␣D2 groups. For the 138 intent-to-treat patients, baseline iPTH levels averaged 914.0 ⫾ 49.6 pg/mL (P ⫽ not significant compared with the 99 per protocol patients). After 1 week of treatment, iPTH levels decreased to 80.3% ⫾ 2.81% of baseline (P ⬍ 0.001) and decreased thereafter to reach 50.2% ⫾ 3.44% of

Fig 1. Changes in plasma iPTH values shown as percentage of baseline value (see text). All patients were administered 1␣D2 during open-label treatment; after week 16, they were randomized to either continued 1␣D2 treatment (dark line) or placebo (shaded line). Includes 99 patients completing 24 weeks per protocol. Data expressed as mean ⴞ SE. Significantly different from baseline, *P < 0.001. Significant difference between placebo and 1␣D2 treatment, #P < 0.01, ##P < 0.001.

FRAZA˜O ET AL

554

Fig 2. Values of serum calcium (S-Ca) and phosphorus (S-P) during open-label treatment with 1␣D2 and after patients were randomized to continued 1␣D2 treatment (dark line) or placebo (lighter shaded line). Includes all 138 patients (intent to treat) who entered open-label treatment; numbers indicate the number of patients at the various times of observation. Data expressed as mean ⴞ SE. Significantly different from baseline (week 0), *P < 0.01, **P < 0.001. Significant difference between placebo and 1␣D2 treatment, #P < 0.05; ##P <0.01.

baseline at week 16 (data not shown). At no time did the degree of suppression differ between the intent-to-treat and per-protocol groups. Table 3 lists the effect of 1␣D2 treatment on the numbers and percentages for the 99 perprotocol patients and the 138 intent-to-treat patients who achieved varying degrees of PTH suppression. Nearly 92% of the 99 patients completing the study per protocol had iPTH suppressed by more than 50%; approximately 83% reached the target range. The fractions of the 138 intent-to-treat patients were only slightly less despite the withdrawal of 11 patients by week 8 or earlier. The plasma iPTH response of patients with varying severity of secondary hyperparathyroidism was examined by dividing the 99 patients into three groups depending on the baseline iPTH level: group I, iPTH level less than 600 pg/mL (n ⫽ 33); group II, 600 to 1,200 pg/mL (n ⫽ 48); and group III, greater than 1,200 pg/mL (n ⫽ 18). For weeks 16 through 24, only the patients randomized to 1␣D2 therapy are included, with 16, 22, and 10 patients in groups I, II, and III, respectively. Baseline levels of iPTH, total alkaline phosphatase, bone-specific alkaline

phosphatase, and osteocalcin are listed in Table 4, and the changes in iPTH suppression, given as the percentage of baseline values, are shown in Fig 3. The differences among the groups for total and bone-specific alkaline phosphatase and osteocalcin provide further evidence that there were differences in skeletal manifestations for the three groups. The mean serum iPTH level for group I decreased rapidly, reaching the target after 2 weeks. The level for group II decreased for 10 to 11 weeks before it reached a plateau in the target range, and the iPTH levels of group III decreased even more slowly over the 24 weeks. Because the groups were divided according to baseline iPTH level, it is not surprising that the mean iPTH levels of each group differed from the other two groups at weeks 1 through 4. Thereafter, iPTH levels did not differ between groups I and II. iPTH values of group III remained significantly greater than those for groups I and II from weeks 2 through 24, except for week 17. In the patients administered placebo from each group, iPTH levels returned to values that were not different from baseline by 4 to 5 weeks after changing from 1␣D2 to placebo (data not shown). As noted, changes in serum calcium and P levels are considered side effects, and data are shown for the 138 intent-to-treat patients. Serum calcium levels (Fig 2) increased slightly during the first weeks of open-label treatment, reaching significance by week 2. Thereafter, serum calcium levels remained greater than baseline values. During open-label treatment, mean serum Table 3. Number of Patients Who Showed Various Degrees of iPTH Suppression During Treatment With 1␣D2

PTH decreased ⬎50%† PTH decreased ⬎70%† PTH reached target†

Per Protocol (n ⫽ 99)

Intent to Treat (n ⫽ 138)*

No.

%

No.

%

91/99

91.9

114/138

82.6

79/99

79.8

92/138

66.7

82/99

82.8

100/138

72.5

NOTE. Target iPTH level is 150 to 300 pg/mL. * Includes 11 patients treated less than 8 weeks. † Two or more iPTH measurements required to qualify the changes.

1␣D2 IN SECONDARY HYPERPARATHYROIDISM Table 4.

555

Baseline Values for iPTH, Total and Bone Alkaline Phosphatase, and Osteocalcin of 99 Patients With Subgroups Based on Entry iPTH Levels Severity of Secondary Hyperparathyroidism by Plasma iPTH (pg/mL)

iPTH (pg/mL) Total AP (U/L) Bone AP (U/L) Osteocalcin (ng/mL)

Total Group

I: ⬍600 (n ⫽ 33)

II: 600-1,200 (n ⫽ 48)

897 ⫾ 517 198 ⫾ 195 68.4 ⫾ 89.5 74.4 ⫾ 35.8

440 ⫾ 78.8 127 ⫾ 58.3* 32.8 ⫾ 19.2* 52.3 ⫾ 16.9*

903 ⫾ 183 165 ⫾ 73.2 51.1 ⫾ 26.2 79.9 ⫾ 35.9‡

III: ⬎1,200 (n ⫽ 18)

1,714 ⫾ 599 417 ⫾ 367† 165 ⫾ 160† 106 ⫾ 26.5†

NOTE. Data expressed as mean ⫾ SD. See text for details. Abbreviation: AP, alkaline phosphatase. * Group I versus group III, P ⬍ 0.05. † Group II versus group III, P ⬍ 0.05. ‡ Group I versus group II, P ⬍ 0.05.

calcium levels ranged from 9.23 ⫾ 0.84 (SD) to 9.74 ⫾ 1.05 mg/dL. During double-blinded treatment, serum calcium levels decreased slightly in the placebo group (Fig 2) and differed significantly from those of the 1␣D2 group at all times except week 19. Serum P levels increased slightly from baseline during open-label treatment in the 138 intentto-treat patients (Fig 2) and were greater than baseline at weeks 1 through 16. During open-

Fig 3. Plasma iPTH levels (mean ⴞ SE) of 99 perprotocol patients divided into three groups according to baseline iPTH levels: group I, iPTH less than 600 pg/mL; group II, 600 to 1,200 pg/mL; and group III, greater than 1,200 pg/mL. Dotted lines encompass the target iPTH range (150 to 300 pg/mL). The numbers of patients before and after randomization are 33 and 16 in group I, 48 and 22 in group II, and 18 and 10 in group III, respectively. aGroup I differs from group II; bgroup I differs from group III; cgroup II differs from group III, each P < 0.05.

label treatment, mean serum P levels ranged from 5.42 ⫾ 1.10 (SD) to 5.86 ⫾ 1.55 mg/dL. With double-blinded treatment, serum P levels decreased slightly in the placebo group; the mean values differed significantly between the placebo and 1␣D2 groups only at weeks 18 and 19. For the three iPTH groups shown in Fig 3, mean serum calcium and P levels (not shown) did not differ among the three groups at any time during the 24 weeks of study. This occurred despite the substantial differences in dosage of 1␣D2 administered to the three groups (Fig 4). The prevalence of hypercalcemia and hyperphosphatemia, defined as both serum calcium level greater than 11.2 mg/dL and greater than 10.5 mg/dL and serum P level as both greater than 8.0 mg/dL and greater than 6.9 mg/dL for the 138 intent-to-treat patients, respectively, are shown in Fig 5. An elevation of serum calcium level greater than 11.2 mg/dL occurred in 0.19% of the measurements during washout and 3.84% during open-label treatment (P ⬍ 0.001). During double-blinded treatment, the incidence of such hypercalcemia was 0.46% and 3.26% in the placebo and 1␣D2-treated patients, respectively (P ⬍ 0.01). The median serum calcium level was 11.6 mg/dL during the episodes with serum calcium levels greater than 11.2 mg/dL. Serum calcium levels exceeded 13.0 mg/dL in only two patients, representing 0.08% of the 2,398 calcium determinations during therapy; the greatest value was 14.7 mg/dL. No patient had symptoms attributable to hypercalcemia. After 1␣D2 treatment was interrupted because of hypercalcemia,

556

Fig 4. Weekly doses (mean ⴞ SE) of 1␣D2 among the three groups (I, II, and III) stratified according to baseline iPTH levels shown in Fig 3. aGroup I differs from group II; bgroup I differs from group III; cgroup II differs from group III, each P < 0.05.

serum calcium levels decreased to less than 11.2 mg/dL within 7 days in all but one instance. Throughout the 32 weeks of observation, 46 patients among the 138 intent-to-treat patients accounted for all the episodes with serum calcium levels greater than 11.2 mg/dL. The prevalence of serum calcium levels greater than 10.5 mg/dL was 3.62% during washout, 15.3% during

FRAZA˜O ET AL

open-label treatment, 5.50% during placebo, and 15.0% during blinded 1␣D2 treatment. Significant increases in serum P levels to greater than 8.0 mg/dL occurred in 1.14% of measurements during washout and 6.37% during open-label treatment (P ⬍ 0.001). During doubleblinded treatment, hyperphosphatemia was observed in 2.32% and 7.14% of the measurements in placebo and 1␣D2 groups, respectively (P ⬍ 0.01). With less marked hyperphosphatemia, with serum P levels greater than 6.9 mg/dL, the prevalence was 6.64% during washout, 18.9% during open-label treatment, 9.74% during placebo, and 16.9% during blinded 1␣D2 treatment. The average doses of calcium-based phosphate binder, expressed as the quantity of calcium ingested, were 2,153 ⫾ 1,224 (SD) mg/d at week 16 and 2,207 ⫾ 1,700 and 1,984 ⫾ 1,296 mg/d at week 24 in the placebo and 1␣D2-treated groups, respectively. The amount of phosphate binders administered to the patients did not differ between the treatment periods. The mean weekly dose of 1␣D2 administered during 16 weeks of open-label treatment decreased from 28.7 ⫾ 0.34 ␮g/wk during week 1 to 17.5 ⫾ 1.51 ␮g/wk during week 16. During double-blinded treatment, the number of placebo

Fig 5. Prevalence of two levels of hypercalcemia and hyperphosphatemia during washout, open-label treatment with 1␣-hydroxyvitamin D2 (Open Rx), and double-blinded placebo-controlled treatment (Blinded Rx, [D2 versus Placebo, PBO]) in the 138 patients entering open-label treatment (intent to treat). Prevalence is given as the percentage of measurements. P compare the ratios during washout and open-label treatment and between 1␣D2 and placebo during double-blinded treatment.

1␣D2 IN SECONDARY HYPERPARATHYROIDISM

557

DISCUSSION

Fig 6. Plasma levels of 1,25-dihydroxyvitamin D2 according to the dosage of 1␣D2 administered during the week before the measurement. Data shown as mean ⴞ SE. The numbers of measurements are shown in brackets.

capsules increased in placebo patients, and the doses of 1␣D2 remained low in the 1␣D2 group (data not shown). The mean plasma levels of 1␣,25-(OH)2D2 correlated with the average 1␣D2 dose administered over the preceding week (Fig 6). To exclude the possibility of an accumulation of serum levels of 1,25(OH)2D2, we compared 65 paired results of serum 1,25(OH)2D2 levels in 45 patients administered the same weekly doses of 1␣D2. From the mean serum 1,25(OH)2D2 level of 39 ⫾ 3.7 pg/mL at week 4, the change in serum 1,25(OH)2D2 level from week 4 was –2.1 ⫾ 2.5 pg/mL at weeks 8, 12, and 16 (P ⫽ not significant). The average weekly doses of 1␣D2 for the groups separated according to baseline iPTH levels are shown in Fig 4. The doses for group I were less than those for group III during weeks 3 through 8; after week 8, when the protocol permitted upward dose adjustment, the doses for group III increased and exceeded the doses for groups I or II throughout, except for week 17. The average doses differed significantly between groups I and II despite the lack of difference between iPTH values during weeks 9 through 16. Plasma levels of 1␣,25-(OH)2D3 (not shown) were essentially undetectable and did not change during the study; mean values were 10.8 ⫾ 0.22 pg/mL at baseline and 10.3 ⫾ 0.13 pg/mL at week 16.

This multicenter study shows that intermittent treatment with oral 1␣D2 effectively suppresses plasma iPTH levels in hemodialysis patients with moderate to severe secondary hyperparathyroidism, observations that confirm the earlier and smaller pilot studies.8,9 This occurred as serum calcium levels increased slightly but generally remained within the normal range. During the double-blinded phase of the present study, there were marked differences in PTH suppression with 1␣D2 treatment compared with placebo. Vitamin D2 (ergocalciferol), which differs from vitamin D3 (cholecalciferol) only in its sidechain structure, was used more widely in the past than vitamin D3 because of the lower cost of the former; also, vitamin D2 and D3 were believed to be equally potent in humans and many other mammals.16 However, considerable data reviewed elsewhere8,17 indicate that vitamin D2 is less toxic than vitamin D3 in various animal models. The activities of 1␣D2 and alfacalcidol (1␣-hydroxyvitamin D3 [1␣D3]) differ: small doses of 1␣D2 and 1␣D3 are equipotent in vitamin D-deficient rats to stimulate calcium absorption, mobilize bone calcium, and heal rickets.18 However, pharmacological doses of 1␣D2 are far less toxic than 1␣D3 in both rats19 and mice.20 These data in animals indicate that moderate to large doses of 1␣D2 produce less hypercalcemia than 1␣D3 or its active form, calcitriol. The reasons for different potencies of sterols with the vitamin D2 side chain compared with those with a vitamin D3 side chain are uncertain. In vitamin D–deficient humans, the administration of vitamin D2 leads to unique and significant hepatic hydroxylation at the 24-carbon position of the side chain21; this metabolic conversion does not occur with vitamin D3. The 24-hydroxylation of 1␣D2 has also been observed in human hepatoma cells in vitro.22 Such bioconversion occurring in vivo could account for the reduced toxicity of pharmacological doses of 1␣D2. Whether 1␣D2 will be less calcemic than 1␣D3 or calcitriol in clinical trials in patients must await studies with direct comparisons of these sterols. The present results show that the time required for suppression of plasma iPTH levels increases with the severity of secondary hyperparathyroidism. They also show that greater doses of 1␣D2

558

are needed to suppress iPTH in patients with very severe secondary hyperparathyroidism compared with patients with mild to moderate hyperparathyroidism. Among patients with iPTH levels less than 1,200 pg/mL, the suppression of iPTH into the target range was generally achieved within 12 weeks or less. Conversely, patients with iPTH levels greater than 1,200 pg/mL had a slower but progressive decrease throughout the entire 24-week duration of treatment with 1␣D2. The observations that substantial time elapses before plasma iPTH levels decreased toward the desired levels in patients with severe hyperparathyroidism are consistent with prior reports on the use of intravenous calcitriol.23-25 Llach et al25 reported successful treatment of 10 selected hemodialysis patients with iPTH levels greater than 1,200 pg/mL by using large doses of intravenous calcitriol for 40 to 72 weeks. The mechanism for a delayed response is unclear, but it may be caused by the slow upregulation of vitamin D receptors, which are known to be reduced in the very large nodular parathyroid glands associated with severe secondary hyperparathyroidism.26 In the present study, the sustained administration of large doses of 1␣D2 effectively and safely suppressed plasma iPTH levels, even in patients with very severe secondary hyperparathyroidism. The current study documents that plasma iPTH levels increased promptly when 1␣D2 was replaced with placebo during double-blinded treatment; mean plasma iPTH levels reached values no different from pretreatment levels within 4 weeks after the withdrawal of 1␣D2. This finding is consistent with earlier observations that serum iPTH level increased in pediatric dialysis patients soon after stopping oral calcitriol treatment27 and in adults with mild secondary hyperparathyroidism after intravenous calcitriol treatment was stopped.28 The rapid increase in iPTH levels after the withdrawal of 1␣D2 suggests that 4 months of therapy caused little reduction of the size of the parathyroid glands. Earlier reports suggesting that intermittent doses of calcitriol produced significant regression in parathyroid gland size29,30 were not confirmed by subsequent observations31 or by studies of experimental animals with uremia and secondary hyperparathyroidism.32,33 Whether more prolonged treatment

FRAZA˜O ET AL

with 1␣D2 could produce involution of parathyroid gland hyperplasia must await further study. The effect of 1␣D2 treatment on serum calcium levels was small, although there was a statistically significant increase to a slightly greater steady-state value. There was an increased frequency of mild hypercalcemic episodes that were readily managed by reducing 1␣D2 dose or the intake of calcium-containing, phosphate-binding agents. There was no increase in the number of hypercalcemic episodes when the dosage of 1␣D2 was increased to 60 ␮g/wk, in comparison to our previous trials that used a maximal dose of 30 ␮g/wk8,9; such observations provide evidence of a favorable safety profile for 1␣D2. The measurements of serum levels of 1,25(OH)2D2 showed no tendency for an accumulation of this active sterol that is generated during treatment with 1␣D2. The recognition that hyperphosphatemia can impact on the mortality of dialysis patients34 and that hyperphosphatemia correlates with certain cardiovascular abnormalities in such patients35 may have far-reaching implications on the ideal approach to the management of mineral metabolism in patients with end-stage renal disease. The present study permitted the entry of patients with serum P levels of 6.5 to 6.9 mg/dL; moreover, serum P levels increased slightly with 1␣D2 treatment. Concern about this previously unrecognized risk for hyperphosphatemia suggests there should be greater attention to the control of serum P with phosphate-binding agents when vitamin D sterols are administered to dialysis patients with secondary hyperparathyroidism. One may question whether our protocol design may have made the results more favorable by the exclusion of patients with hypercalcemia or severe hyperphosphatemia. The safety issue would seem to preclude long-term vitamin D treatment in such patients. It should be noted that the prevalence of serum P level elevation to levels greater than 6.9 mg/dL observed during both open-label and blinded therapy with 1␣D2 is considerably less than the prevalence of 31% to 32% reported by Block et al34 among 6,400 hemodialysis patients. The design of the present study and our earlier trials with 1␣D28,9 differ from clinical trials using vitamin D sterols to manage secondary hyper-

1␣D2 IN SECONDARY HYPERPARATHYROIDISM

parathyroidism in that dose adjustments were targeted to reduce iPTH levels to a specific range of 150 to 300 pg/mL; these values are associated with bone turnover that is close to normal and histological features of secondary hyperparathyroidism that are either absent or mild in hemodialysis patients.10,11 This target level was somewhat greater than that recommended by Solal-Cohen et al,36 who studied iPTH levels and bone biopsies in only 24 patients; this was done to minimize the risk for inducing a state of low bone turnover, which may develop in the face of greater levels of iPTH after therapy with vitamin D.37-39 It remains to be determined whether the greater cost of measuring iPTH levels compared with serum calcium levels will be cost-effective to reduce the incidence of states with low bone turnover. In the present study, plasma levels of 25hydroxy-vitamin D were not determined. There is growing evidence that nutritional vitamin D deficiency, identified by low serum 25(OH)vitamin D levels, is not uncommon in the United States.40 Moreover, such hypovitaminosis D can contribute to the severity of secondary hyperparathyroidism.41 Such observations would have no impact on the present successful results of therapy with 1␣D2, but the measurement of 25(OH)vitamin D levels is important to identify a pathogenic factor that can contribute to the development of secondary hyperparathyroidism. How 1␣D2 compares with calcitriol, alfacalcidol (1␣D3), or paricalcitol in terms of efficacy and safety cannot be answered without direct comparisons with these sterols. The present study compares favorably with our earlier pilot study8; those results with 1␣D2 were compared with prospective studies using calcitriol or 1␣D3 in patients with moderate to severe hyperparathyroidism.8 Both the present multicenter study and our earlier studies8,9 achieved suppression of iPTH similar to the best results of trials performed in single centers using pulse intravenous calcitriol or 1␣D3 and administering only calcium-based phosphate-binders.25,42,43 Moreover, the incidence of hyperphosphatemia and hypercalcemia were acceptable despite the high doses of 1␣D2 used and the exclusive use of large doses of calcium-containing phosphate-binding agents.

559

The mechanism by which 1␣D2 suppresses iPTH is unknown. 1␣D2, an inactive prodrug, is hydroxylated in the liver primarily to 1␣,25(OH)2D2 and secondarily to 1␣,24(S)-(OH)2D2. One or both of these may act in a manner similar to calcitriol, although with greater safety. Both could act directly on the parathyroid gland to suppress the secretion of PTH. The small increase in serum calcium level, which likely arises from enhanced intestinal calcium absorption, undoubtedly contributes to PTH suppression. However, there was a poor correlation between the changes in the levels of serum calcium and those of iPTH. Further studies are needed to determine the precise mechanism of action of this vitamin D analogue. The present large trial shows unequivocally that 1␣D2 administered at the dosage regimens studied is efficacious for the treatment of hemodialysis patients with moderate to severe secondary hyperparathyroidism and is safe in uremic patients with secondary hyperparathyroidism. In the future, studies that directly compare 1␣D2 with other vitamin D sterols will be needed to provide proof of its relative safety. ACKNOWLEDGMENT The following persons and institutions participated in this multicenter study: Principal Investigators: Jack W. Coburn, MD, University of California at Los Angeles School of Medicine and Veterans Affairs West Los Angeles Healthcare Center, Los Angeles, CA; Russell W. Chesney, MD, College of Medicine, University of Tennessee, Memphis, TN. Coinvestigators: Dominick Gentile, MD (deceased), St Joseph Hospital, Orange; William G. Goodman, MD, University of California at Los Angeles Medical Center, Los Angeles; Alex U. Tan, MD, Joao Frazao, MD, Barton S. Levine, MD, Veterans Affairs West Los Angeles Healthcare Center, Los Angeles; Keith C. Norris, MD, Charles R. Drew University, Los Angeles; Hector Rodriguez, MD, Cedars Sinai Medical Center, Los Angeles; John A. Robertson, MD, California Kidney Centers, Riverside and San Bernardino, CA; Sergio R. Acchiardo, College of Medicine, University of Tennessee, Memphis, TN; B.J. Kelley, MD, Gambro Healthcare, Memphis, TN; John D. Bower, MD, University of Mississippi Medical Center, Jackson, MS. Study Coordinators and Assisting Personnel: Sally Shupien, CCRC, Gail Uyehara, RN, Venice Avila, RN, David Akin, RN, Veterans Affairs West Los Angeles Healthcare Center, Los Angeles; May Marooney, RN, St Joseph Hospital, Orange, CA; Jane Bandini, RN, Lisa Burk, RN, Susan J. Smith, RN, Susan O. Smith, RD, University of Tennessee, Memphis, TN; Bernadine Trenier, RN, USHAWLDoctors and US Health and Welfare Laboratories (USHAWL)-Cedars Sinai Towers, Los Angeles, CA; Robin

FRAZA˜O ET AL

560

Maxwell, RN, Gambro Healthcare, East Memphis, TN; Edna Curry, RN, Kidney Care Hemodialysis Centers–North and –South, Jackson, MS; Shirley Capsavage, RN, Sue Estrada, RN, Linda Mullen, RN, California Kidney Center, San Bernardino, CA; Patrice Anderson, BS, Suzanne Schweitzer, MPH, Cindy Chou, BS, Judah White, JD, Lucy Nguyen, BS, University of California at Los Angeles Medical Center, Los Angeles, CA; Anita Karst, RN, BMA-North Parkway Dialysis, Memphis, TN; Gwendolyn Sampson, RN, Hank Williams, Pacific Coast Dialysis Center, Inglewood, CA; Jan Crawford, MN, Sue Baughman, RN, BMAEast Arkansas, West Memphis, TN, and BMA-St Francis County Dialysis Center, Forest City, AR; Mary Reed, RN, Joan Butler, RN, BMA-Graceland, Memphis, TN; James Zarara, PhD, Curtis Johnson, Raquel Rosales, Sharon Campbell, LifeChem Laboratories, Woodland Hills, CA. Bone Care International Staff: Laura L. Douglass, RN, Thomas. L. Manley, BSN, Kathy Keehn, BA, Lisa M. DeLacy, Diane M. Pauk, GBS, Beth Griffin, BA, Naomi Fields, BA, Kathy Olson, Sheri B. Bernard, MS, Kari Brausen, Leon W. LeVan, PhD, Charles R. Valliere, BS, John T. Banach, BS, Gina M. Accola, BS, Matthew A. Carmean, BS, Anne M. Lumby, BS, Darlene M. Kyllo, RAC, Charles W. Bishop, PhD.

REFERENCES 1. Brown AJ, Ritter CS, Finch JL, Morrissey J, Martin KJ, Murayama E, Nishii Y, Slatopolsky E: The noncalcemic analogue of vitamin D, 22-oxacalcitriol, suppresses parathyroid hormone synthesis and secretion. J Clin Invest 84:728732, 1989 2. Kurokawa K, Akizawa T, Suzuki M, Akiba T, Ogata E, Slatopolsky E: Effect of 22-oxacalcitriol on hyperparathyroidism of dialysis patients: Results of a preliminary study. Nephrol Dial Transplant 11:S121-S124, 1996 (suppl 3) 3. Morii H, Ogura Y, Koshikawa S, Mimura N, Suzuki M, Kurokawa K, Marumo F, Kawaguchi Y, Maeda K, Nishizawa Y, Inoue S, Fujimi S: Efficacy and safety of oral falecalcitriol in reducing parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism. J Bone Miner Metab 16:34-43, 1998 4. Akiba T, Marumo F, Owada A, Kurihara S, Inoue A, Chida Y, Ando R, Shinoda T, Ishida Y, Ohashi Y: Controlled trial of falecalcitriol versus alfacalcidol in suppression of parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism. Am J Kidney Dis 32:238-246, 1998 5. Slatopolsky E, Finch J, Ritter C, Denda M, Morrissey J, Brown A, DeLuca H: A new analog of calcitriol, 19-nor1,25(OH)2D2, suppresses parathyroid hormone secretion in uremic rats in the absence of hypercalcemia. Am J Kidney Dis 25:852-860, 1995 6. Martin KJ, Gonza´lez EA, Gellens M, Hamm LL, Abboud H, Lindberg J: 19-Nor-1-␣-25-dihydroxyvitamin D2 (paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol 9:1427-1432, 1998 7. Coburn JW, Tan AU Jr, Levine BS, Mazess RB, Kyllo DM, Knutson JC, Bishop CW: 1␣-Hydroxy-vitamin D2: A new look at an ‘old’ compound. Nephrol Dial Transplant 11:S153-S157, 1996 (suppl 3)

8. Tan AU Jr, Levine BS, Mazess RB, Kyllo DM, Bishop CW, Knutson JC, Kleinman KS, Coburn JW: Effective suppression of parathyroid hormone by 1␣-hydroxyvitaminD2 in hemodialysis patients with moderates to severe secondary hyperparathyroidism. Kidney Int 51:317-323, 1997 9. Frazao JM, Levine BS, Tan AU Jr, Mazess RB, Kyllo DM, Knutson JC, Bishop CW, Coburn JW: Efficacy and safety of intermittent oral 1␣ (OH)-vitamin D2 in suppressing 2o hyperparathyroidism in hemodialysis patients. Dial Transplant 26:583-595, 1997 10. Quarles LD, Lobaugh B, Murphy G: Intact parathyroid hormone overestimates the presence and severity of parathyroid-mediated osseous abnormalities in uremia. J Clin Endocrinol Metab 75:145-150, 1992 11. Sherrard DJ, Hercz G, Pei Y, Maloney NA, Greenwood C, Manuel A, Saiphoo C, Fenton SS, Segre GV: The spectrum of bone disease in end-stage renal failure—An evolving disorder. Kidney Int 43:436-435, 1993 12. Brossard JH, Chautier M, Roy L, Lepage R, GasconBarre M, D’Amour P: Accumulation of a non (1-84) molecular form of parathyroid hormone (PTH) detected by intact PTH assay in renal failure: Importance of the interpretation of PTH values. J Clin Endocrinol Metab 81:2923-2929, 1996 13. Lepage R, Roy L, Brossard JH, Rousseau L, Dorais C, D’Amour P: A non-(1-84) circulating parathyroid hormone (PTH) fragment interferes significantly with intact PTH commercial assay measurement in uremic samples. Clin Chem 44:805-809, 1998 14. Hollis BW: Assay of circulating 1,25-dihydroxyvitamin D involving a novel single-cartridge extraction and purification procedure. Clin Chem 32:2060-2063, 1986 15. Horst RL, Koszewski NJ, Reinhardt TA: 1-Alphahydroxylation of 24-hydroxyvitamin D2 represents a minor physiological pathway for the activation of vitamin D2 in mammals. Biochemistry 29:578-582, 1990 16. Hunt RD, Garcia FG, Hegsted DM, Kaplinsky N: Vitamin D2 and vitamin D3 in New World primates: Influence on calcium absorptions. Science 158:943-947, 1967 17. Hunt RD, Garcia FG, Hegsted DM: Hypervitaminosis D in the New World monkeys. Am J Clin Nutr 22:358366, 1969 18. Sjo¨den G, Lindgren JU, DeLuca HF: Antirachitic activity of 1␣-hydroxyergocalciferol and 1␣-hydroxycholecalciferol in rats. J Nutr 114:2043-2046, 1984 19. Sjo¨den G, Smith C, Lindgren U, DeLuca HF: 1␣Hydroxyvitamin D2 is less toxic than 1␣-hydroxyvitamin D3 in the rat. Proc Soc Exp Biol Med 178:432-436, 1985 20. Sato F, Ouchi Y, Okamoto Y, Kaneki M, Nakamura T, Ikekawa N, Orimo H: Effects of vitamin D2 analogs on calcium metabolism in vitamin D-deficient rats and in MC3T3 osteoblastic cells. Res Exp Med 191:235-242, 1991 21. Mawer EB, Jones G, Davies M, Still PE, Byford V, Schroeder NJ, Makin HLJ, Bishop CW, Knutson JC: Unique 24-hydroxylated metabolites represent a significant pathway of metabolism of vitamin D2 in humans: 24-Hydroxyvitamin D2 and 1,24-dihydroxyvitamin D2 detectable in human serum. J Clin Endocrinol Metab 83:2156-2166, 1998 22. Strugnell S, Byford V, Makin HLJ, Moriarty RM, Gilardi R, Levan LW, Knutson JC, Bishop CW, Jones G: The 1␣,24(S)-dihydroxy vitamin D2: A biologically active prod-

1␣D2 IN SECONDARY HYPERPARATHYROIDISM

uct of 1␣-OH-D2 made in the human hepatoma, Hep 3B. Biochem J 310:233-241, 1995 23. Coburn JW: Use of oral and parenteral calcitriol in the treatment of renal osteodystrophy. Kidney Int 38:S54S61, 1990 (suppl 29) 24. Sprague SM, Moe SM: Safety and efficacy of longterm treatment of secondary hyperparathyroidism by lowdose intravenous calcitriol. Am J Kidney Dis 19:532-539, 1992 25. Llach F, Hervas J, Cerezo S: The importance of dosing intravenous calcitriol in dialysis patients with severe hyperparathyroidism. Am J Kidney Dis 26:845-851, 1995 26. Fukuda N, Tanaka H, Tominaga Y, Fukagawa M, Kurokawa K, Seino Y: Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 92:1436-1443, 1993 27. Klaus G, Mehls O, Hinderer J, Ritz E: Is intermittent oral calcitriol safe and effective in renal secondary hyperparathyroidism? Lancet 337:800-801, 1991 28. Slatopolsky E, Weerts C, Thielan J, Horst RL, Harter H, Martin KJ: Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxycholecalciferol in uremic patients. J Clin Invest 74:21362143, 1984 29. Fukagawa M, Orazaki R, Takano K, Kaname S-Y, Ogata E, Kitoaka M, Karada S-I, Sekine N, Matsumoto T, Kurokawa K: Regression of parathyroid hyperplasia by calcitriol-pulse therapy in patients on long-term dialysis. N Engl J Med 323:421-422, 1990 30. Cannella G, Bonucci E, Rolla D, Ballanti P, Moriero E, De Grandi R, Augeri C, Claudiani F, Di Maio G: Evidence of healing of secondary hyperparathyroidism in chronically hemodialyzed uremic patients treated with long-term intravenous calcitriol. Kidney Int 46:1124-1132, 1994 31. Quarles LD, Yohay DA, Carroll BA, Spritzer CE, Minda SA, Bartholomay D, Lobaugh BA: Prospective trial of pulse oral versus intravenous calcitriol treatment of hyperparathyroidism in ESRD. Kidney Int 45:1710-1721, 1994 32. Szabo A, Merke J, Beier E, Mall G, Ritz E: 1,25(OH)2 Vitamin D3 inhibits parathyroid cell proliferation in experimental uremia. Kidney Int 35:1049-1056, 1989 33. Takahashi F, Finch JL, Denda M, Dusso AS, Brown AJ, Slatopolsky E: A new analog of 1,25(OH)2D3, 19-nor1,25(OH)2D2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content. Am J Kidney Dis 30:105-112, 1997

561

34. Block GA, Hulbert-Shearon TE, Levin NW, Port FK: Association of serum phosphorus and calcium X phosphate product with mortality risk in chronic hemodialysis patients: A national study. Am J Kidney Dis 31:607-617, 1998 35. Marchais SJ, Metivier F, Guerin AP, London GM: Association of hyperphosphatemia with haemodynamic disturbances in end-stage renal disease. Nephrol Dial Transplant 14:2178-2183, 1999 36. Solal-Cohen M, Sebert JL, Boudailliez B, Annick M, Moriniere P, Gueris J, Bouillon R, Fournier A: Comparison of intact, midregion, and carboxy terminal assays of parathyroid hormone for the diagnosis of bone disease in hemodialyzed patients. J Clin Endocrinol Metab 73:516-524, 1991 37. Andress DL, Norris KC, Coburn JW, Slatopolsky EA, Sherrard DJ: Intravenous calcitriol in the treatment of refractory osteitis fibrosa of chronic renal failure. N Engl J Med 321:274-279, 1989 38. Goodman WG, Ramirez JA, Belin TR, Chon Y, Gales B, Segre GV, Salusky IB: Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy. Kidney Int 46:1160-1166, 1994 39. Kuizon BD, Goodman WG, Ju¨ppner H, Boechat I, Nelson P, Gales B, Salusky IB: Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD. Kidney Int 53:205-211, 1998 40. Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Dick IM, Prince RL, Finkelstein JS: Hypovitaminosis D in medical inpatients. N Engl J Med 338:777-783, 1998 41. Ghazali A, Fardellone P, Pruna A, Atik A, Achard J-M, Oprisiu R, Brazier M, Remond A, Moriniere P, Garabedian M, Eastwood J, Fournier A: Is low plasma 25(OH) vitamin D a major risk factor for hyperparathyroidism and Looser’s zones independent of calcitriol. Kidney Int 55:21692177, 1999 42. Malberti F, Surian M, Cosci P: Effect of chronic intravenous calcitriol on parathyroid function and set point of calcium in dialysis patients with refractory secondary hyperparathyroidism. Nephrol Dial Transplant 7:822-828, 1992 43. Moriniere P, Esper NE, Viron B, Judith D, Bourgeon B, Farquet C, Gheerbrandt JD, Chapuy MC, Orshoven AV, Pamphile R, Fournier A: Improvement of severe secondary hyperparathyroidism in dialysis patients by intravenous 1␣(OH) vitamin D3, oral CaCO3 and low dialysate calcium. Kidney Int 43:S121-S124, 1993 (suppl 41)