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

Kidney International, Vol. 54 (1998), pp. 907–914

CLINICAL NEPHROLOGY - EPIDEMIOLOGY - CLINICAL TRIALS

Intermittent calcitriol therapy in secondary hyperparathyroidism: A comparison between oral and intraperitoneal administration ISIDRO B. SALUSKY, BEATRIZ D. KUIZON, THOMAS R. BELIN, JORGE A. RAMIREZ, BARBARA GALES, GINO V. SEGRE, and WILLIAM G. GOODMAN Departments of Pediatrics, Biomathematics, and Medicine, UCLA School of Medicine, Los Angeles, California, and the Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA

Intermittent calcitriol therapy in secondary hyperparathyroidism: A comparison between oral and intraperitoneal administration. Background. Intermittent oral or intravenous doses of calcitriol given two or three times per week are commonly used to treat secondary hyperparathyroidism (2° HPT). This study was undertaken to compare the biochemical and skeletal responses to thrice weekly intraperitoneal (i.p.) versus oral doses of calcitriol in children with 2° HPT undergoing peritoneal dialysis (CCPD). Methods. Forty-six patients aged 12.5 6 4.8 years on CCPD for 22 6 25 months were randomly assigned to treatment with oral (p.o.) or i.p. calcitriol for 12 months; 17 subjects given p.o. calcitriol and 16 subjects given i.p. calcitriol completed the study. Bone biopsies were performed at the beginning and at the end of the study, while determinations of serum and total ionized calcium, phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and calcitriol levels were done monthly. Results. Serum total and ionized calcium levels were higher in subjects treated with i.p. calcitriol, P , 0.0001, whereas serum phosphorus levels were higher in those given p.o. calcitriol, P , 0.0001. For the i.p. group, serum PTH levels decreased from pre-treatment values of 648 6 125 pg/ml to a nadir of 169 6 57 pg/ml after nine months. In contrast, serum PTH levels did not change from baseline values of 670 6 97 pg/ml in subjects given p.o. calcitriol, P , 0.0001 by multiple regression analysis. Serum alkaline phosphatase levels were also lower in patients treated with i.p. calcitriol, P , 0.0001, but there was no difference between groups in the average dose of calcitriol given thrice weekly. The skeletal lesions of 2° HPT improved in both groups, 33% of patients developed adynamic bone lesion. Conclusion. Differences in the bioavailability of calcitriol and/or in phosphorus metabolism may account for the divergent biochemical response to p.o. and i.p. calcitriol.

Peritoneal dialysis has become the predominant mode of dialysis in children with end-stage renal disease, but persistent bone disease remains a major challenge in the clinical Key words: dialyzed children, bone histology, peritoneal dialysis, parathyroid hormone, skeletal lesion, end-stage renal disease, mineral metabolism. Received for publication November 18, 1987 and in revised form March 24, 1998 Accepted for publication March 30, 1998

© 1998 by the International Society of Nephrology

management of such patients [1]. Secondary hyperparathyroidism is the most common skeletal lesion in pediatric patients undergoing regular dialysis, and the disorder often progresses despite treatment with daily doses of oral calcitriol [2–5]. As such, alternative therapeutic approaches have been sought to improve the clinical, biochemical and histological responses to calcitriol therapy in children with secondary hyperparathyroidism due to end-stage renal disease. Large intermittent doses of calcitriol given two or three times per week have recently been used to treat secondary hyperparathyroidism both in children and in adults [6 –10]. Most studies have employed the oral or intravenous routes of administration, but there is little available information about the effect of intraperitoneal doses of calcitriol on bone and mineral metabolism in patients undergoing regular peritoneal dialysis. Increases in blood ionized calcium levels and reductions in serum PTH values have been documented in short-term studies [11], but the efficacy of intraperitoneal doses of calcitriol for the long-term management of secondary hyperparathyroidism has not been examined; indeed, the skeletal response to intermittent calcitriol therapy has yet to be fully characterized either in adults or in children. The current randomized clinical trial was undertaken to prospectively evaluate the biochemical and histological responses to intermittent calcitriol therapy using thrice weekly intraperitoneal or oral doses in pediatric patients with secondary hyperparathyroidism undergoing long-term peritoneal dialysis. Bone biopsy and quantitative histomorphometry of bone were done before and after 12 months of treatment, and biochemical indices of bone and mineral metabolism were measured at monthly intervals for the duration of study. METHODS Study design A total of 46 patients, aged 12.5 6 4.8 years, who were treated with CCPD for an average of 22 6 25 months were

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evaluated. All study candidates were medically stable patients between the ages of two and 18 years who had undergone CCPD for at least two months. For those begun on dialysis because of acute renal failure, a stabilization period of at least six months was required before subjects became eligible for study. Bone biopsy was done in all potential study candidates to document the type of renal osteodystrophy using established histologic criteria [2]. Subjects were eligible for randomization if they had bone biopsy evidence of either secondary hyperparathyroidism or normal rates of bone formation [2]. Candidates were excluded from study if they had other skeletal lesions of renal osteodystrophy such as adynamic lesions, osteomalcia or mixed skeletal lesions. Those with a documented history of poor compliance with medical treatment regimens, those who had undergone parathyroidectomy within the previous 12 months, and patients who had received either prednisone or other immunosuppressive agents while undergoing regular dialysis were also excluded. All study participants had been treated in the past with daily doses of oral calcitriol, but therapy was stopped at least four weeks before beginning intermittent calcitriol therapy. The study protocol was approved by the UCLA Human Subjects Protection Committee, and informed consent was obtained from each patient and from either parents or guardians where appropriate. Biochemical determinations were done before starting treatment and at monthly intervals over the 12 months of study. These included measurements of serum total and ionized calcium, phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and calcitriol levels. Two separate baseline PTH determinations were obtained before beginning i.p. or p.o. calcitriol therapy. Blood samples for monthly biochemical measurements were obtained 24 hours after regular thrice weekly doses of calcitriol during interval clinic visits. After 12 months of treatment, subjects underwent a second iliac crest bone biopsy to assess interim changes in bone histology. Quantitative bone histomorphometry was done as previously described [2], and terminology established by the Nomenclature Committee of the American Society for Bone and Mineral Research was used to present the results [12]. A total of thirty-three patients completed the 12-month clinical trial; 17 patients, aged 13.2 6 1.3 years, were randomly assigned to treatment with oral (p.o.) calcitriol, and 16 patients, aged 12.5 6 1.1 year, were treated with intraperitoneal (i.p.) calcitriol. The duration of CCPD was 27 6 15 months (range 3 to 100 months) and 20 6 eight months (range 3 to 120 months), respectively, in subjects given p.o. or i.p. calcitriol. Calcium carbonate was used as the primary phosphate-binding agent in all patients, and the dose was adjusted monthly, or more often when necessary, according to serum phosphorus levels. The dietary intake of calcium, phosphorus and other nutrients was determined for each month of the study using three-day

diet diaries gathered during monthly clinic visits [13]. The calcium concentration in peritoneal dialysate was 3.5 mEq/ liter for all study subjects. Patients assigned to oral therapy were given calcitriol (Rocaltrolt; Hoffman-LaRoche, Nutley, NJ, USA) thrice weekly for 12 months. Patients assigned to intraperitoneal therapy received the intravenous form of calcitriol (Calcijex®; Abbott Laboratories, Abbott Park, IL, USA) instilled thrice weekly into the peritoneal cavity with small residual volumes of peritoneal dialysate after overnight dialysis exchanges. The technique for intraperitoneal calcitriol administration has been described in detail elsewhere [14]. Doses of oral or intraperitoneal calcitriol were given Mondays, Wednesdays and Fridays in the morning at the completion of nightly dialysis treatments. Doses were adjusted based upon the results of monthly serum calcium and phosphorus determinations [7]. The average daily dose of calcitriol for each month of study and the cumulative dose of calcitriol for the full 12 months of follow-up were calculated in each patient. The initial dose of calcitriol for all subjects was 1.0 mg thrice weekly, a dosage chosen based upon data reported by Delmez et al [11] in adult CAPD patients and from our own experience in pediatric CCPD patients with severe secondary hyperparathyroidism. The dose of calcitriol was increased in increments of 0.5 mg each month if serum calcium levels remained below 10.0 mg/dl and if serum phosphorus levels were less than 6.0 mg/dl. Calcitriol therapy was discontinued temporarily if serum calcium levels exceeded 11.0 mg/dl; treatment was restarted after reducing the dose by 50% following the resolution of hypercalcemia. Patients who developed persistent hypercalcemia with serum calcium levels above 11.0 mg/dl during concurrent therapy with calcitriol and calcium carbonate were changed to dialysate containing 2.5 mEq/liter of calcium. For those remaining hypercalcemic despite the use of low-calcium dialysate and reduced doses of calcium carbonate, aluminum hydroxide was added as an alternative phosphatebinding agent [15]. Subjects were withdrawn from study if hypercalcemia persisted despite these maneuvers. Doses of calcitriol were also withheld if serum phosphorus levels exceeded 7.0 mg/dl, and treatment was resumed only after serum phosphorus values fell below 6.5 mg/dl. Subjects who developed persistent hyperphosphatemia with serum phosphorus levels above 7.5 mg/dl for more than three months were withdrawn from study. Additional withdrawal criteria included kidney transplantation, change in mode of dialysis and psychosocial factors as determined by medical staff. Biochemical determinations Serum total calcium, phosphorus and alkaline phosphatase levels and blood ionized calcium levels were measured by automated methods as previously described [2, 7, 16].

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Table 1. Characteristics of patients randomly assigned to treatment with intraperitoneal (i.p.) or oral (p.o.) doses of calcitriol thrice weekly

Number of patients (M/F) Age years Duration of dialysis months Primary renal disease Obstructive/dysplastic Glomerular Interstitial Unknown Previous kidney transplant Values are means 6

i.p. (N 5 16)

p.o. (N 5 17)

9/7 12.5 6 1.1 21 6 8

9/8 13.2 6 1.3 27 6 15

3 5 4 4 2

6 9 — 2 4

SE.

Serum PTH levels were determined using a two-site immunoradiometric assay for the intact hormone (Allegro PTH; Quest Diagnostics, San Juan Capistrano, CA, USA) [17], and serum calcitriol levels were measured by radioreceptor assay (Quest Diagnostics) [18]. Randomization technique and statistical analysis Patients were randomly assigned to treatment with either oral or intraperitoneal calcitriol by a biostatistitian using three randomization schedules, one for each skeletal lesion, that is, osteitis fibrosa, mild secondary hyperparathyroidism and normal bone formation. Randomization was done in blocks of four, six or eight with the block length determined at random. All results are expressed as mean 6 SE. Comparisons between groups for pre-treatment characteristics were done using unpaired t-tests [19]. Changes in bone histomorphometric variables in each treatment group were evaluated by paired t-tests, whereas un-paired t-tests were used to compare histologic outcomes between i.p. and p.o. therapy [19]. Paired t-tests were used to compare monthly biochemical values with pre-treatment values within each treament arm using Bonferroni adjustments for multiple comparisons. Because the dose of calcitriol varied over time, dosage values represent the amount of the sterol given during each month of study. Additional analyses considered potential differences in biochemical outcomes between treatment groups as a function of the dose of calcitriol. Thus, multiple regression analyses were done with each biochemical determination as an outcome variable using the month of study, the average calcitriol dose for the corresponding month of treatment, the average calcitriol dose during the preceding month and an indicator for treatment group as predictor variables [19]. RESULTS The age, sex distribution, primary renal disease and duration of dialysis prior to study did not differ for patients given intraperitoneal (i.p.) or oral (p.o.) calcitriol (Table 1). The number of subjects in each group that had previously

Fig. 1. Serum total (A) and blood ionized (B) calcium levels during 12 months of treatment with intermittent doses of i.p. (F) or p.o. (M) calcitriol. *P , 0.05 versus pre-treatment values in each group. For the full 12 months of treatment, levels were greater in i.p. than in p.o.; P , 0.0001 for total calcium and P , 0.001 for ionized calcium by multiple regression analysis.

received a renal transplant was also similar (Table 1). None of the patients had undergone previous parathyroidectomy, and the rates of peritonitis during study did not differ between groups (Table 1). Serum biochemical determinations Initial total serum calcium levels did not differ between groups. Values were 9.1 6 0.2 mg/dl for patients given i.p. calcitriol and 8.5 6 0.3 mg/dl for those treated with p.o. calcitriol, P 5 NS. Serum calcium levels increased during the first month of treatment in patients given i.p. calcitriol, and values remained above pre-treatment levels for most of the remaining 12 months of study (Fig. 1A). The peak serum calcium level during i.p. therapy was 10.4 6 0.5 mg/dl; this was observed after 10 months of treatment (Fig. 1A). Serum calcium concentrations also rose in patients given p.o. calcitriol but only after the fourth month of treatment; the highest average monthly serum calcium level was 9.7 6 0.4 mg/dl after ten months of study (Fig. 1A). Although serum calcium levels at each monthly interval did not differ between those given i.p. or p.o. calcitriol, values were greater overall in subjects given i.p. calcitriol when the results for the full 12 months of study were evaluated by multiple regression analysis, P , 0.001. Serum albumin

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Fig. 2. Serum phosphorus levels during 12 months of treatment with intermittent doses of i.p. or p.o. calcitriol. *P , 0.05 versus pre-treatment values in each group. For the 12 months of treatment, values were greater in p.o. (M) than in i.p. (F), P , 0.001 by multiple regression analysis.

levels did not differ between groups; initial values were 3.75 6 0.12 and 3.65 6 0.11 g/liter, respectively, in subjects given i.p. or p.o. calcitriol. Pre-treatment blood ionized calcium levels also did not differ between subjects given i.p., 1.20 6 0.02 mmol/liter, or p.o., 1.17 6 0.05 mmol/liter, calcitriol (NS), and monthly values did not change from baseline values in either group except at month seven in those given i.p. calcitriol (Fig. 1B). By multiple regression analysis, however, blood ionized calcium levels during the full 12-month study were higher in patients treated with i.p. calcitriol (P , 0.001). Dietary calcium intake did not differ between groups; values were 435 6 36 mg/day in patients receiving i.p. calcitriol and 499 6 41 mg/day in those given p.o. calcitriol (NS). Pre-treatment serum phosphorus levels averaged 6.2 6 0.3 and 6.4 6 0.3 mg/dl, respectively, in subjects treated with i.p. or p.o. calcitriol, NS. Serum phosphorus levels remained stable or decreased during i.p. calcitriol therapy, and none of the average monthly values exceeded pretreatment levels (Fig. 2). Indeed, serum phosphorus values fell below baseline values during the third, sixth and seventh month of treatment (Fig. 2). Serum phosphorus levels exceeded pre-treatment values during the second, fifth, seventh and twefth months of p.o. calcitriol therapy, although these changes were not significantly greater than baseline values (Fig. 2). Multiple regression analysis indicated that serum phosphorus levels over the 12 months of study were higher in patients given p.o. calcitriol despite similar levels of dietary phosphorus intake (P , 0.0001). Phosphorus intake throughout the study averaged 712 6 52 and 779 6 45 mg/day for patients given i.p. or p.o. calcitriol, respectively. Serum PTH levels before treatment did not differ between groups (Fig. 3A). For those treated with i.p. calcitriol, serum PTH levels decreased by 62% from pretreatment values of 648 6 125 pg/ml within the first month of study, reaching a nadir value of 169 6 57 pg/ml after nine months of therapy. In contrast, serum PTH levels did not change from pre-treatment levels of 670 6 97 pg/ml during

Fig. 3. Serum PTH (A) and alkaline phosphatase levels (B) during 12 months of treatment with intermittent doses of i.p. (F) or p.o. (M) calcitriol. *P , 0.05 versus pre-treatment values in each group. For the 12 months of treatment, values were greater in i.p. than in p.o.; P , 0.001 for PTH and P , 0.001 for alkaline phosphatase by multiple regression analysis.

p.o. calcitriol therapy (Fig. 3A). Although average monthly serum PTH values did not differ between groups, PTH levels were generally higher in those given p.o. calcitriol when multiple regression analysis was used to evaluate the results for the full 12 months of study (P , 0.0001). Serum alkaline phosphatase levels were initially similar in each treatment group (Fig. 3B). Alkaline phosphatase levels decreased, however, in subjects given i.p. calcitriol, whereas values remained unchanged in those receiving p.o. calcitriol (Fig. 3B). Overall, serum alkaline phosphatase levels were substantially greater in patients given oral calcitriol when evaluated by multiple regression analysis (P , 0.0001). Dose of calcitriol and episodes of hypercalcemia and hyperphosphatemia Serum calcitriol levels were subnormal before treatment, but baseline values did not differ between patients randomized to i.p. (12 6 6 pg/ml, or p.o., 10 6 4 pg/ml, calcitriol therapy; NS). Monthly serum calcitriol levels were within the normal range in both groups during treatment, and there were no differences between groups (Fig. 4). The dose of calcitriol for the full 12 months of study averaged 1.3 6 0.08 mg/dose for patients treated with i.p. calcitriol and 1.5 6 0.9 mg/dose for those given p.o. calcitriol; these

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triol, osteitis fibrosa resolved in seven of 12 patients, whereas the extent of marrow fibrosis diminished in five. Three subjects with osteitis fibrosa developed adynamic renal osteodystrophy during p.o. calcitriol therapy (Fig. 5). After 12 months of intermittent calcitriol therapy, bone formation was normal or reduced in 11 of 16 patients given i.p. calcitriol and in 11 of 17 subjects treated with p.o. calcitriol. The magnitude of the reduction in bone formation did not differ between groups; values decreased by an average of 67% in patients given i.p. calcitriol and by 54% in those treated with p.o. calcitriol, NS (Table 2).

Fig. 4. The serum levels of 1,25-dihydroxyvitamin D (A) and the average thrice weekly dose of calcitriol (B) during 12 months of treatment with intermittent doses of i.p. (f) or p.o. (E). *P , 0.05 versus pre-treatment value for each group.

values did not differ. During the final three months of study, patients given p.o. calcitriol received the highest average monthly dose. There were 18 episodes of hypercalcemia, defined by a serum calcium value above 11.0 mg/dl, in eight subjects given i.p. calcitriol, whereas eight episodes occurred in five patients treated with p.o. calcitriol (NS by x2 analysis). When defined as a serum phosphorus level exceeding 7.0 mg/dl, thirteen episodes of hyperphosphatemia occurred in two patients given i.p. calcitriol, whereas 18 episodes were seen in three subjects receiving p.o. calcitriol (NS). Changes in bone histology during intermittent calcitriol therapy The skeletal lesions of secondary hyperparathyroidism improved after 12 months of treatment in both groups (Fig. 5). Osteitis fibrosa persisted in two patients given i.p. calcitriol, and the extent of marrow fibrosis in both subjects was less at follow-up examination than before treatment. Three subjects with osteitis fibrosa prior to treatment with i.p. calcitriol had mild lesions of secondary hyperparathyroidism without peri-trabecular or marrow fibrosis at the end of study, whereas four had normal rates of bone formation; two subjects developed adynamic lesions of renal osteodystrophy (Fig. 5). For those given p.o. calci-

DISCUSSION The results of the current randomized, prospective clinical trial indicate that intermittent doses of calcitriol given either orally or intraperitoneally markedly improve the skeletal lesions of secondary hyperparathyroidism in a large proportion of pediatric patients undergoing regular peritoneal dialysis. As noted in earlier reports [7, 20], bone formation decreases substantially during intermittent calcitriol therapy, and adynamic lesions of renal osteodystrophy often develop [7]. Unfortunately, biochemical indices of bone and mineral metabolism are only moderately good predictors of the skeletal response to intermittent calcitriol therapy, particularly when doses are given orally. Thus, serum PTH and alkaline phosphatase levels declined substantially during treatment with i.p. calcitriol, but similar reductions were not observed in subjects given p.o. calcitriol despite equivalent decreases in bone formation and comparable improvements in bone histology. These discrepancies were apparent despite the lack of differences between groups in the pre-treatment values for serum PTH and alkaline phosphatase, in the average dose of calcitriol utilized and in the dietary intake of either calcium or phosphorus. The results suggest that the biochemical indices commonly used to monitor calcitriol therapy do not reliably reflect changes in bone formation and turnover during treatment with large intermittent oral doses of calcitriol. For subjects given i.p. calcitriol, serum calcium levels increased within the first few months of study, and this change was associated with concordant reductions in serum PTH and alkaline phosphatase levels. In contrast, serum calcium levels did not rise above baseline values until the fifth month of study in subjects treated with p.o. calcitriol, and serum PTH and alkaline phosphatase levels remained unchanged during follow-up. Although neither the monthly dose of calcitriol nor the cumulative dose over the full 12 months of study differed between groups, the adequacy of control of serum phosphorus levels during intermittent calcitriol therapy may have contributed to these divergent results. Phosphorus retention and hyperphosphatemia have long been recognized as important factors in the pathogenesis of secondary hyperparathyroidism due to chronic renal failure

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Fig. 5. The histological sub-types of renal osteodystrophy before and after 12 months of intermittent i.p. (A) or p.o. (B). Abbreviations are: OF, osteitis fibrosa; mild, mild secondary hyperparathyroidism; normal, bone formation rate within the normal range [2]. Table 2. Rate of bone formationa before and after 12 months of intermittent intraperitoneal (i.p.) or oral (p.o.) calcitriol therapy

Before After

i.p. (N 5 16)

p.o. (N 5 17)

894 6 111 297 6 118

1272 6 143b 586 6 236

Values are means 6 SE. a Range of normal, 98 to 613 mm2/mm2/day b P , 0.05 vs. i.p.

[21]. More recently, several groups of investigators have presented evidence to suggest that phosphorus can directly influence PTH gene transcription and/or message translation, leading to increases in PTH synthesis [22–24]. In the current study, serum phosphorus levels were generally higher in subjects receiving p.o. calcitriol; as such, differences in the degree of compliance with phosphate-binding medications or differences in dietary phosphorus intake could account for the persistently higher serum PTH levels in subjects treated with p.o. calcitriol. The amount of dietary phosphorus ingested did not differ, however, between subjects given i.p. or p.o. calcitriol, and both groups were repeatedly counseled during monthly clinic visits about the ongoing requirement for phosphate-binding therapy. Serum calcitriol levels increased from pre-treatment values in both groups, and serum calcitriol levels were maintained within the normal range for the full duration of study; indeed, serum calcitriol levels did not differ between groups at any monthly interval during treatment. Such

findings provide biochemical evidence that study participants received a substantial amount of prescribed doses of calcitriol. Although sub-optimal medical compliance cannot be fully excluded, the results suggest that the oral route of calcitriol administration may result in disproportionate increases in intestinal phosphorus transport and that this change accounts for greater increases in serum phosphorus levels in patients treated with large intermittent dose of oral calcitriol [25]. Previous short-term studies have also shown that serum calcitriol levels and sterol bioavailability vary with the route of calcitriol administration [26]. Serum calcitriol levels are higher during the initial three to six hours and the bioavailability of calcitriol is 50 to 60% greater within the first 24 hours following single intravenous doses when results are compared to those obtained after equivalent oral or intraperitoneal doses [26]. The bioavailability of calcitriol does not differ, however, between the oral and intraperitoneal routes of administration when injectable calcitriol is added to conventional large-volume peritoneal dialysate exchanges [26]. In the current study, a modified technique was used for intraperitoneal calcitriol administration to diminish adherence of the sterol to the plastic materials that comprise peritoneal dialysate delivery systems; thus, injectable calcitriol was instilled directly into the peritoneal cavity with only 50 to 100 ml of dialysate at the end of overnight dialysate exchanges [14]. This modified approach may have reduced the amount of each dose lost by binding to plastic

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dialysis supplies, thereby increasing the fraction of the dose available for absorption across the peritoneal membrane [26]. Although the serum levels of calcitriol at each monthly interval did not differ between groups when measured 24 hours after the previous dose, earlier work has demonstrated that the greater bioavailability of calcitriol after intravenous administration is not associated with higher serum levels compared to oral doses when calcitriol levels are determined 24 hours after single doses [26]. As such, differences in the bioavailabilty of calcitriol between treatment groups may have contributed to the disparities noted in the current study for several biochemical parameters of mineral metabolism during intermittent calcitriol therapy. The discrepancy between persistently elevated serum PTH levels and markedly reduced rates of bone formation during intermittent calcitriol therapy underscores the limitation of using single, isolated serum PTH determinations as a predictor of bone histology in patients with renal osteodystrophy, particularly during intermittent calcitriol therapy. Although the immunoradiometric assay (IRMA) for intact parathyroid hormone is a useful non-invasive tool for distinguishing among various subtypes of renal osteodystrophy both in adults and in children, these results have been obtained from cross-sectional studies of untreated patients or from assessments of those treated with small daily doses of oral calcitriol [3, 5, 27–29]. Others, however, have reported considerable discord between the serum PTH levels and bone histology in patients undergoing regular dialysis [30], and some have suggested that serum alkaline phosphatase values or serum osteocalcin levels provide better indices of bone formation activity in patients with end-stage renal disease. Considerable shortterm variations in serum PTH levels due to pulsatile PTH secretion could, in part, account for these results; moreover, Seidel et al demonstrated that serum PTH levels are reduced for up to 72 hours after large, single doses of calcitriol [31]. Such findings indicate that additional information is needed about short-term variations in serum PTH levels and about the impact of intermittent calcitriol dosage regimens on serum PTH values in patients with end-stage renal disease to more fully understand the relationship between parathyroid gland activity and bone turnover in renal osteodystrophy. These issues are particularly important for the longitudinal follow-up of patients undergoing intermittent calcitriol therapy. Despite substantial differences in the biochemical response to i.p. and p.o. calcitriol therapy, bone histology improved in most study participants regardless of the route of calcitriol administration. Twenty-seven percent of these subjects had normal rates of bone formation documented by bone biopsy after 12 months of treatment, but 33% developed adynamic lesions of renal osteodystrophy. Overall, the magnitude of the reduction in bone formation did not differ between groups. As noted previously by Andress et al [20], the percentage decrease in bone formation

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exceeded the percentage change in bone resorption as measured by the extent of eroded surface in cancellous bone. Thus, intermittent calcitriol therapy was associated with a disproportionate inhibitory effect on osteoblastic activity in both treatment groups. Such findings are consistent with earlier observations indicating that intermittent calcitriol therapy lowers osteoblastic activity and bone formation by a mechanism that is distinct from that mediated by vitamin D-induced reductions in serum PTH levels [7]. Indeed, growth velocity diminished in patients that developed the adynamic lesions of renal osteodystrophy after intermittent calcitriol therapy [32]. It may be prudent, therefore, to withhold therapy with calcitriol if serum PTH (intact molecule) levels are less than 200 pg/ml in pediatric patients undergoing maintenance dialysis to diminish the risk of developing adynamic bone. In summary, intermittent calcitriol therapy reverses many of the histological abnormalities of secondary hyperparathyroidism in pediatric patients undergoing regular peritoneal dialysis. Favorable results were obtained after 12 months of treatment with either oral or intraperitoneal doses of calcitriol using a thrice weekly dosage regimen, and there were no differences between groups in the skeletal response to intermittent calcitriol therapy. In contrast, the biochemical indices of bone and mineral metabolism, such as serum PTH and alkaline phosphatase levels, that are widely used to monitor the evolution of bone disease in patients with chronic renal failure do not accurately reflect decreases in bone formation during intermittent oral calcitriol therapy. Differences in sterol bioavailability and in phosphorus metabolism between subjects treated with oral or intraperitoneal doses of calcitriol may contribute to the divergent biochemical response to these two forms of therapy in patients with secondary hyperparathyroidism. ACKNOWLEDGMENTS This study was supported, in part, by USPHS grants DK-35423 and RR-00865 and by funds from the Casey Lee Ball Foundation. Reprint requests to Isidro B. Salusky, M.D., Division of Pediatric Nephrology, A2-383 MDCC, UCLA Medical Center, 10833 Le Conte Ave., Los Angeles, California 90095, USA. E-mail: [email protected]

REFERENCES 1. WARADY BA, HEBERT D, SULLIVAN EK, ALEXANDER SR, TEJANI A: Renal transplantation, chronic dialysis, and chronic renal insufficiency in children and adolescents. The 1995 Annual Report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 11:49 – 64, 1997 2. SALUSKY IB, COBURN JW, BRILL J, FOLEY J, SLATOPOLSKY E, FINE RN, GOODMAN WG: Bone disease in pediatric patients undergoing dialysis with CAPD or CCPD. Kidney Int 33:975–982, 1988 3. SALUSKY IB, RAMIREZ JA, OPPENHEIM WL, GALES B, SEGRE GV, GOODMAN WG: Biochemical markers of renal osteodystrophy in pediatric patients undergoing CAPD/CCPD. Kidney Int 45:253–258, 1994

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