Calcitriol pulse therapy is not more effective than daily calcitriol therapy in controlling secondary hyperparathyroidism in children with chronic renal failure

Calcitriol oral pulse therapy has been suggested as the treatment of choice for secondary hyperparathyroidism, but its efficacy and safety are still under discussion. The present randomized multicenter study compares the effect of an 8-week course of daily versus intermittent (twice weekly) calcitriol therapy on parathyroid hormone (PTH) suppression in 59 children (mean age 8.4±4.7 years) with chronic renal insufficiency (mean C_cr 22.4±11.6 ml/min per 1.73 m²) and secondary hyperparathyroidism. After a 3-week washout period, the patients were randomly assigned to treatment with daily oral calcitriol (10 ng/kg per day) or intermittent oral calcitriol (35 ng/kg given twice a week). The calcitriol dose was not changed throughout the study period of 8 weeks. At start of the study, the median intact PTH (iPTH) level was 485 pg/ml (range 83–2032) in the daily group (n=29) and 315 pg/ml (range 93–1638) in the intermittent group (n=30). After 8 weeks, the respective median iPTH concentrations were 232 pg/ml (range 63–1614) and 218 pg/ml (range 2–1785) (ns). The mean iPTH decrease from baseline was 19.2±57.8% and 13.7±46.7% respectively (not significant). Calcitriol reduced the iPTH concentration in 23/29 patients in the daily group and in 21/30 in the intermittent group. One episode of hypercalcemia (>11.5 mg/dl) was observed in both groups and a single episode of hyperphosphatemia (>7.5 mg/dl) was observed in the daily group. It is concluded that oral calcitriol pulse therapy does not control secondary hyperparathyroidism more effectively than the daily administration of calcitriol in children with chronic renal failure prior to dialysis. Received: 29 September 1999 / Revised: 2 February 2000 / Accepted: 9 February 2000     

Different effects of calcitriol and parathyroidectomy on the PTH--calcium curve in dialysis patients with severe hyperparathyroidism

BACKGROUND: The PTH–calcium sigmoidal curve is shifted to the right,the slope of the curve is steeper, and the set point of calciumis increased in dialysis patients with secondary hyperparathyroidism,compared to patients with low-turnover bone disease. These findingscould be related to increased parathyroid cell mass and increasedsensitivity of parathyroid cells to serum calcium variationsin these patients. Calcitriol therapy has been documented toreduce PTH levels by shifting the curve to the left and downward.The effect of a surgical reduction of parathyroid gland masson the PTH-calcium curve has not yet been investigated. In thisstudy we compared the effects of calcitriol and subtotal parathyroidectomy(PTH) on the dynamics of PTH secretion in response to acutechanges of serum calcium in two groups of dialysis patientswith severe hyperparathyroidism. METHODS: Fourteen dialysis patients treated for 6 months with high-dosei.v. calcitriol (1–2 µg thrice weekly), and 10 dialysispatients who underwent subtotal PTx were studied. The PTH–calciumrelationship obtained by inducing hypo- and hypercalcaemia bymeans of low and high calcium dialysis was evaluated beforeand 2–6 months after treatment. RESULTS: Both calcitriol and subtotal PTx significantly decreased PTH(respectively from 797±595 to 380±244 and from1036±250 to 70±34 pg/ml), as well as maximal PTHresponse to hypocalcaemia (PTHmax), and maximal PTH suppressionduring hypercalcaemia (PTHmin). When the PTH–calcium curveswere constructed using PTHmax as 100% to factor for differencesin absolute PTH levels and to provide an assessment of individualparathyroid cell function, a shift of the sigmoidal curve tothe left and downward, and a significant decrease in the setpoint of ionized calcium (from 1.31±0.05 to 1.26±0.05and from 1.36±0.09 to 1.22±0.07 mmol/1) was documentedwith both treatments. However, the slope of the PTH–calciumcurve increased after subtotal PTx indicating that the sensitivityof the parathyroid cell to serum calcium changes increased withPTx, while on the contrary it decreased with calcitriol. CONCLUSIONS: PTH secretion decreases proportionally more with calcitriolthan with surgery for a given decrease in the functional massof parathyroid cells. The change in the PTH–ICa sigmoidalcurve induced by subtotal PTx is due to the removal of a largemass of parathyroid tissue with advanced hyperplasia.     

High-dose oral calcitriol and zero calcium peritoneal solutions in CAPD patients with refractory secondary hyperparathyroidism

Abstract. We evaluated the effect of pulse oral calcitriol (4µg three times weekly for 6 months) on parathyroid functionin nine CAPD patients with hyperparathyroidism refractory toconventional lowdose oral calcitriol. Zero calcium peritonealsolutions were used to prevent the development of hypercalcaemia.The peritoneal loss of calcium increased from 168á40to 417á48 mg/day using zero calcium solutions. Pulseoral calcitriol resulted in a significant decrease in PTH (from617á272 to 382á299 pg/ml) by the 15th day of therapy,while serum iCa did not change from baseline. During the firstmonth of therapy the mean PTH levels remained significantlyreduced compared to baseline, thereafter PTH increased in fourof nine patients. Hyperphosphataemia was not satisfactorilycontrolled in four patients, despite large amounts of bindersused; seven of nine patients developed hypercalcaemia and requiredeither the substitution of calcium acetate for calcium carbonateor reduction of calcitriol dose. Three patients showed a progressiveincrease in PTH. In conclusion our data suggest that in mostCAPD patients with severe hyperparathyroidism oral calcitriolpulse therapy is not effective in maintaining a permanent suppressionin PTH levels.     

Implications of intermittent calcitriol therapy on growth and secondary hyperparathyroidism

Secondary hyperparathyroidism is the most common skeletal lesion in pediatric patients undergoing maintenance dialysis. The present review summarizes a prospective randomized study that evaluated the biochemical and skeletal responses to intermittent calcitriol therapy in 33 pediatric patients on peritoneal dialysis with secondary hyperparathyroidism. Also, the effect of intermittent calcitriol therapy on linear growth was evaluated in 16 of 33 patients who had completed the clinical trial. Serum parathyroid hormone levels decreased by 62% from 648±125 pg/ml in patients treated with intermittent intraperitoneal (IP) calcitriol, and values remained unchanged from pre-treatment levels of 670±97 pg/ml with oral calcitriol therapy. Overall serum total and ionized calcium levels were higher in patients treated with IP calcitriol during the study. In contrast to these biochemical findings, the skeletal lesions of secondary hyperparathyroidism improved after 12 months of treatment in both groups and adynamic bone occurred in 33% of the patients. Z-scores for height decreased from –1.80±0.3 to –2.00±0.3, P<0.01, after 12 months of intermittent calcitriol therapy. Such findings suggest that an intermittent schedule of calcitriol administration adversely affects chondrocyte activity within epiphyseal cartilage in pre-pubertal children with end-stage renal disease. Received: 20 August 1999 / Revised: 2 February 2000 / Accepted: 9 February 2000     

Effect of chronic intravenous calcitriol on parathyroid function and set point of calcium in dialysis patients with refractory secondary hyperparathyroidism.

This study evaluates the effect of intravenous calcitriol on parathyroid function and ionized calcium-PTH sigmoidal curve obtained during low- and high-calcium haemodialysis in 10 patients with osteitis fibrosa whose secondary hyperparathyroidism was refractory to conventional therapy. After 4 months of intravenous calcitriol, serum ionized calcium increased from 1.28 +/- 0.08 to 1.37 +/- 0.11 mmol/l (P less than 0.001), serum phosphate from 1.54 +/- 0.18 to 1.79 +/- 0.4 mmol/l (P NS), serum calcitriol from 16.7 +/- 9.9 to 34.3 +/- 6.4 pg/ml (P less than 0.001), while alkaline phosphatase decreased from 366 +/- 340 to 226 +/- 180 IU/l (P less than 0.05), osteocalcin from 46.4 +/- 20 to 34.5 +/- 15.3 ng/ml (P less than 0.05), and basal intact PTH from 1069 +/- 700 to 305 +/- 270 (P less than 0.01). Basal PTH started to decrease after 1 month of treatment prior to the increase in the ionized calcium. Because of hypercalcaemia the dialysate calcium was decreased from 1.75 to 1.5 mmol/l in three of five patients on haemodialysis, and calcium-containing solutions were replaced by calcium-free fluids in four of five patients on haemodiafiltration. Calcitriol dose, at the first month of therapy was 5.6 +/- 0.8 micrograms/week, but it was successively decreased because of hypercalcaemia to a final dose of 3.6 +/- 1.3 micrograms/week. After intravenous calcitriol the ionized calcium-PTH sigmoidal curve shifted to the left and downward. Maximally stimulated PTH and maximally inhibited PTH obtained during low- and high-calcium dialysis significantly decreased, as well as the ratio of basal PTH/PTHmax and the set point of calcium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Direct inhibitory effect of calcitriol on parathyroid function (sigmoidal curve) in dialysis

The effect of intravenous calcitriol on parathyroid function was evaluated in nine chronic hemodialysis patients with secondary hyperparathyroidism. Two micrograms of calcitriol were administered intravenously after dialysis thrice weekly for ten weeks. Parathyroid function was assessed by inducing hypo- and hypercalcemia with low calcium (1.0 mEq/liter) and high calcium (4.0 mEq/liter) dialyses before and after ten weeks of intravenous calcitriol therapy. To avoid hypercalcemia during calcitriol administration, the dialysate calcium was reduced to 2.5 mEq/liter. Parathyroid hormone (PTH) values (pg/ml) from dialysis-induced hypo- and hypercalcemia were plotted against serum ionized calcium, and the sigmoidal relationship between PTH and calcium was evaluated. Basal PTH levels fell from 902 +/- 126 pg/ml to 466 +/- 152 pg/ml (P less than 0.01) after therapy without a significant change in the serum total calcium concentration. The ionized calcium-PTH sigmoidal curve shifted to the left and downward after calcitriol therapy. The maximal PTH response during hypocalcemia decreased after calcitriol from 1661 +/- 485 pg/ml before calcitriol to 1031 +/- 280 pg/ml afterward (P less than 0.05). The PTH level at maximal inhibition due to hypercalcemia decreased from 281 +/- 76 pg/ml before calcitriol to 192 +/- 48 pg/ml afterward (P less than 0.05). The slope of the sigmoidal curve changed from -2125 +/- 487 to -1563 +/- 385 (P less than 0.05). The set point of ionized calcium (4.60 +/- .11 mg/dl before vs. 4.44 +/- .07 mg/dl after) did not change significantly with calcitriol therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of the mode of calcitriol administration on PTH-ionized calcium relationship in uraemic patients with secondary hyperparathyroidism

To assess the effect of the different modes of calcitriol administrationon PTH-ionized calcium relationship we conducted a prospectiveclinical trial in 33 patients on chronic haemodialysis withsecondary hyperparathyroidism (four times upper normal limitintact PTH) who were randomly assigned, with stratificationto PTH levels, to receive daily oral, intermittent oral, orintermittent intravenous calcitriol at the same dose of 0.045µg/kg/weekly. PTH-iCa curves were generated by inducinghypo- or hypercalcaemia in sequential haemodialysis 1 week apart,before and after 10 weeks on treatment. All patients were dialysedagainst a dialysate calcium concentration of 2.5 mEq/l throughoutthe study period. After drop-outs, 26 patients completed the study: 11 on intravenouscalcitriol (mean basal PTH±SD: 666±280 pg/ml),eight on intermittent oral calcitriol (mean basal PTH: 831±361),and seven on daily oral calcitriol (mean basal PTH: 719±280).Serum ionized calcium and phosphorus significantly increasedin intravenous and daily oral groups after calcitriol treatment,but not in the intermittent oral group. Basal PTH did not significantlychange in the three groups after 10 weeks on treatment. MaximalPTH significantly decreased in intravenous group (1449±660versus 1122±691 pg/ml, P=0.0085) and at the limit ofstatistical significance in the intermittent oral group (1701±774versus 1445±634, P=0.12), but it did not change in thedaily oral group. Minimal PTH did not modify in the three groups.In all three groups, a shift to the right in the PTH-iCa relationshipswere observed, with significant changes in the set point ofcalcium. The slope of the post-treatment curves only becameless steep in the intermittent oral and intravenous groups. In conclusion, intermittent administration of calcitriol seemsto be more effective in reducing maximal PTH than daily oraladministration, but at the conditions under which this studywas carried out all the modes of calcitriol administration shiftedPTH-iCa relationships to the right.     

Randomized trial comparing pulse calcitriol and alfacalcidol for the treatment of secondary hyperparathyroidism in haemodialysis patients

Aim: Calcitriol and alfacalcidol are used extensively for the treatment of secondary hyperparathyroidism. Unfortunately, there is limited published data comparing the efficacy and tolerability of both active vitamin D sterols. This study was undertaken to determine whether calcitriol provides a therapeutic advantage to alfacalcidol. Methods: This was a randomized, active controlled study. Patients with intact parathyroid hormone (iPTH) >32 pmol/L were randomized to receive orally calcitriol or alfacalcidol after each haemodialysis for up to 24 weeks. Reduction of PTH, changes of plasma albumin‐corrected calcium and phosphorus were analysed. The initial dose of alfacalcidol was twice that of calcitriol. Results: Sixteen patients were randomized into each group. At baseline, plasma albumin‐corrected calcium, phosphorus and PTH were no different between groups. At 24 weeks, PTH changes were ?50.8 ± 31.8% and ?49.4 ± 32.5% from the baseline in the calcitriol and alfacalcidol groups, respectively (P = 0.91). The patients who achieved target PTH of 16–32 pmol/L were 82% in the calcitriol and 67% in the alfacalcidol group (P = 0.44). Plasma albumin‐corrected calcium and phosphorus were not significantly different but showed trends toward gradually increasing from baseline in both groups (calcium, 6.0 ± 7.2% vs 10.9 ± 6.5% (P = 0.10); phosphorus, 13.0 ± 29.4% vs 16.7 ± 57.2% (P = 0.83) in calcitriol and alfacalcidol, respectively). The mean dose of calcitriol and alfacalcidol were 4.1 and 6.9 µg/week, respectively (P < 0.0001). Conclusion: Alfacalcidol can be used to control secondary hyperparathyroidism at doses of 1.5–2.0 times that of calcitriol. The two drugs are equally efficacious and lead to similar changes in calcium and phosphorus.     

Local Calcitriol Injections as a Suppressive Treatment of Secondary Hyperparathyroidism in Chronic Dialysis Patients

Aim. A prospective study was made of the effectiveness of repeatable local calcitriol injections therapy to suppress secondary hyperparathyroidism resistant to conventional therapy in chronic dialysis patients. Methods. Under ultrasonographic guidance, six injections at an interval of two days were performed in 14 chronic dialysis patients. The total amount of calcitriol to be injected each time was estimated as 100% of the calculated gland volume. Calcitriol was given in doses 1 μg of medicine per 1 cubic cm (as measured by USG) of parathyroid tissue. Parathormone concentration, total calcium, ionized calcium, phosphate, and alkaline phosphatase levels were assessed on the first and last day of the treatment period. Results. Prior to therapy, the mean gland volumes were 0.62 (0.15–3.0) ml, and they increased to 0.85 (0.2–3.9) after 14 days (NS). Seven patients were found to have decreased their PTH levels to 909 ± 387 pg/mL after 14 days of treatment when compared with the first day mean values of 1588 ± 440 pg/mL (p < 0.05). After completion of the therapy, four patients were reported to be free from any clinical symptoms of ostalgia or arthralgia. Others reported an alleviation of pain. Conclusions. Parathyroid adenoma injection is an alternative method of treatment for some patients resistant to treatment by means of vitamin D3 pulses or intravenous administration of calcitriol. The success of treatment is to a great extent determined by proper selection of patients and the taking of decisions when the period of secondary hyperparathyroidism is not very advanced.     

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

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

Effect of calcitriol on insulin secretion in uraemia

To evaluate the role of calcitriol on insulin secretion in uraemia, nine patients on maintenance haemodialysis, never treated with vitamin D nor with calcium-channel blockers, were studied. Baseline glucose, insulin, C peptide, calcium, intact PTH, and calcitriol serum values were measured, and after an oral load of 75 g glucose, insulin and C peptide were also determined at 15, 30, 45, 60, and 120 min. Following 14 days of treatment with oral calcitriol (0.5 microgram/day), the same study protocol was applied. Serum calcitriol values, which were low as expected, increased after therapy, but did not reach the values observed in healthy controls. Despite no change in total serum calcium, intact PTH values decreased significantly (182 vs 88.3 ng/ml, P less than 0.003). Baseline serum insulin was significantly increased after calcitriol (7.5 vs 35 microU/ml, P less than 0.001). Similarly, an enhancement in insulin secretion following calcitriol was observed at 15 min (34 vs 70, P less than 0.01) and 30 min (57 vs 96 microU/ml, P less than 0.01). Computation of the total area under the curve confirmed these results. Changes in C peptide profile paralleled those described for insulin. These data confirm that vitamin D modulates pancreatic beta-cell secretion and suggest that calcitriol may regulate insulin release in uraemic patients.     

Pulse oral calcitriol for the treatment of hyperparathyroidism in patients on continuous ambulatory peritoneal dialysis: preliminary observations.

A direct effect of calcitriol on the regulation of the secretion of parathyroid hormone (PTH) has been shown in vitro and in vivo. In patients with renal failure on maintenance hemodialysis, it has been shown that intravenous (IV) administration of calcitriol appears to be superior to continuous oral administration. This may be due to the higher levels of calcitriol obtained in blood with consequent improved delivery of calcitriol to peripheral target tissues including the parathyroid glands. However, IV administration of calcitriol, is not practical for patients with end-stage renal disease (ESRD) who are maintained on continuous ambulatory peritoneal dialysis (CAPD). The present studies were designed to investigate whether intermittent administration of large doses of calcitriol orally ("pulse therapy") could mimic the effects of IV calcitriol in hemodialysis patients and achieve suppression of PTH secretion. Studies were performed in five patients who had been maintained on CAPD for more than 6 months. After basal determinations of calcium, phosphorus, and PTH, therapy was begun with calcitriol administered orally in a dose of 5 micrograms given twice per week. Calcium carbonate was continued as a phosphate binder. Dialysate calcium concentration was 1.75 mmol/L (3.5 mEq/L). With this therapy, PTH levels decreased rapidly, and, after 4 to 6 weeks of therapy, reached values 60% lower than pretreatment values. Mean values for serum calcium did not change significantly (2.29 +/- 0.12 mmol/L [9.6 +/- 0.5 mg/dL] before treatment compared with 2.32 +/- 0.08 mmol/L [9.7 +/- 0.25 mg/dL] after therapy). Mean serum phosphorus was also unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peritonfal Dialysis in the Treatment of Severe Hypercalcemia

A 56-year-old man with multiple myeloma and compromised renal function underwent peritoneal dialysis for the treatment of severe hypercalcemia. During dialysis, peritoneal clearances, of total calcium, unbound calcium, urea, and creatinine were assessed. Clearances of total calcium (4.8 ± 0.4 ml/min) and unbound calcium (7.8 ± 0.5 ml/min) were shown to vary directly with the clearances of urea (15.5 ± 1.3 ml/min) and creatinine (8.5 ± 0.8 ml/min). Despite relatively low clearances of all these solutes, during the period of 42 hours, 1,638 mg of calcium was removed in the dialy-sate and total serum calcium decreased from 17.6 mg/dl to 10.2 mg/dl. Our data indicates that peritoneal dialysis is an effective adjunct in controlling severe hypercalcemia and should be considered when other forms of therapy are inadequate.     

Effect of Calcitonin on Hemodialysis Patients with Hypercalcemia and Renal Osteodystrophy

Because calcitonin administration has been shown to decrease the serum calcium level in certain hypercalcemic conditions, 10 patients on maintenance dialysis with renal osteodystrophy and persistent hypercalcemia were treated with salmon calcitonin for 3 months. While plasma calcium concentrations were reduced by calcitonin therapy in four patients, therapy was ceased in two patients due to a worsening of their hypercalcemia, although in another two patients the initial worsening of the hypercalcemia settled with continued therapy. No significant changes in calcium levels occurred in the remaining two patients. Analysis of the data suggests that a hypocalcemic effect of calcitonin was most likely in the presence of osteomalacia, while predominant osteitis fibrosa favored a hypercalcemic response. Calcitonin administration caused a mean increase in parathyroid hormone (PTH) secretion 3.6 ± 1.5 to 6.5 ± 1.7 ng/ml; p < 0.05) after 6 weeks of therapy. Three patients reported improvement in their bone pain. These studies show that despite possible symptomatic and morphological effects of calcitonin, its hypocalcemic effect in patients with renal osteodystrophy and hypercalcemia is inconsistent.     

A controlled trial of the early treatment of secondary hyperparathyroidism with calcitriol in hemodialysis patients

BACKGROUND: Calcitriol is widely used in conjunction with phosphorus-binders containing calcium to treat secondary hyperparathyroidism in dialysis patients. Its efficacy in patients with severe hyperparathyroidism is diminished, in part, due to glandular hyperplasia associated with decreased calcitriol and calcium receptors. SUBJECTS AND METHODS: We, therefore, developed a prospective, randomized trial comparing i.v. calcitriol plus calcium carbonate (CaCO3) compared to CaCO3 alone (control) in patients with mild to moderate hyperparathyroidism who were within the first year of initiating hemodialysis. Patients underwent calcium (Ca) suppression/stimulation testing at baseline and after six and twelve months of treatment to indirectly assess parathyroid gland hyperplasia. RESULTS: In the calcitriol group, the amino-terminal parathyroid hormone (N-PTH) decreased significantly from a baseline value of 70 +/- 12 pg/ml at month zero to 22 +/- 7 and 19 +/- 6 pg/ml at months 6 and 12, respectively (the conversion factor of amino-terminal PTH to intact PTH is 6, i.e., 10 pg/ml N-PTH equals 60 pg/ml intact PTH). In contrast, the N-PTH levels in the CaCO3 alone group did not change. The change in nadir N-PTH levels at month 12 compared to month zero decreased by 14 +/- 7% in the calcitriol group but increased by 96 +/- 59% in the control group (p < 0.05). In addition, the increment in N-PTH levels during hypocalcemic stimulation decreased by 68 +/- 6% at month 12 compared to month zero but increased by 61 +/- 42% in the control group. Although total calcium and phosphorus levels were not different between the two groups, ionized calcium values were higher in the calcitriol group. The incidence of hypercalcemia was the same in both groups and the episodes were asymptomatic. CONCLUSION: Pulse calcitriol therapy is effective in preventing progression of secondary hyperparathyroidism in hemodialysis patients with mild to moderate disease. Based on Ca suppression/stimulation tests, calcitriol was more successful in preventing gland growth than CaCO3 alone. Further studies are needed to determine if the strategy of early treatment of mild to moderate hyperparathyroidism by pulse calcitriol is safe and effective in hemodialysis in patients.     

Response of different PTH assays to therapy with sevelamer or CaCO<Subscript>3</Subscript> and active vitamin D sterols

Amino-terminally truncated parathyroid hormone (PTH) fragments are detected to differing degrees by first- and second-generation immunometric PTH assays (PTH-IMAs), and acute changes in serum calcium affect the proportion of these fragments in circulation. However, the effect of chronic calcium changes and different vitamin D doses on these PTH measurements remains to be defined. In this study, 60 pediatric dialysis patients, aged 13.9 ± 0.7 years, with secondary hyperparathyroidism were randomized to 8 months of therapy with oral vitamin D combined with either calcium carbonate (CaCO₃) or sevelamer. Serum phosphorus levels did not differ between groups. Serum calcium levels rose from 9.3 ± 0.1 to 9.7 ± 0.1 mg/dl during CaCO₃ therapy (p < 0.01 from baseline) but remained unchanged during sevelamer therapy. In the CaCO₃ and sevelamer groups, baseline serum PTH levels (1st PTH-IMA; Nichols Institute Diagnostics, San Clemente, CA) were 964 ± 75 and 932 ± 89 pg/ml, and levels declined to 491 ± 55 and 543 ± 59 pg/ml, respectively (nonsignificant between groups). Patients treated with sevelamer received higher doses of vitamin D than those treated with CaCO₃. The PTH values obtained by first- and second-generation PTH-IMAs correlated closely throughout therapy and the response of PTH was similar to both PTH-IMAs, despite differences in serum calcium levels.     

Effect of calcitriol replacement on serum calcitonin and parathyroid hormone levels in CAPD patients

Calcitonin-secreting cells, ‘C cells’, have specificreceptors for calcitriol, thus the calcitriol deficiency inuraemia may affect calcitonin secretion and/or production. Theaim of the present study was to evaluate in CAPD patients theeffect of calcitriol replacement (4 weeks of oral calcitriol,0.5 ng/day) on both, basal calcitonin concentration and calcitoninresponse to calcium infusion (calcium gluconate, 3 mg/kg/h). Calcitriol replacement produced a normalization of serum calcitriollevel without a significant change in serum calcium concentration.After calcitriol replacement, basal calcitonin increased from78 ± 15 to 101 ± 13pg/ml, P<0.05. The incrementin calcitonin induced by a calcium infusion was lower after(15±4pg/ml) than before (29±4pg/ml) calcitriolreplacement. In addition, calcitriol administration induceda decrease in serum PTH level. Replacement of calcitriol in CAPD patients produced an increasein serum calcitonin concentration and a decrease in the calcitoninresponse to hypercalcaemia.     

'Pulse' oral calcitriol in uraemic patients: rapid modification of parathyroid response to calcium.

We performed dynamic parathyroid function tests, with generation of parathyroid hormone/ionized calcium (PTH/iCa) response curves, obtained during sequential hypercalcaemic and hypocalcaemic dialysis, on six haemodialysis patients before and after 4-weekly 'pulse' doses of oral calcitriol. There were no significant changes in the pretreatment, 2-week and 4-week values of blood ionized calcium, serum total calcium, phosphate, and alkaline phosphatase. PTH decreased significantly after 4 weeks of treatment with calcitriol (P less than 0.03), and the post-treatment PTH/iCa curves were all displaced leftwards and downwards, indicating a marked inhibitory effect of calcitriol on parathyroid responsiveness across and beyond the physiological range of calcaemia. The mean shift of the PTH/iCa relationship was equivalent to a reduction of iCa of 0.2 mM for any given concentration of PTH, and conversely to a 70% reduction of PTH for any given blood iCa. The results suggest that wide spacing of oral 'pulse' doses of calcitriol can achieve favourable modification of the PTH/iCa relationship, and that dosing interval and dose size, rather than route of administration, may be the major determinants of the previously reported superiority of intravenous over daily oral calcitriol regimens.     

Advantages of adjusting the initial dose of intravenous calcitriol according to PTH levels

BACKGROUND: To assess the usefulness of starting calcitriol therapy with a dose proportional to the degree of hyperparathyroidism, 141 patients from 28 centers were treated with intravenous calcitriol for 6 months. The aim was to achieve a final PTH between 125 and 250 pg/mL. Patients with serum PTH>250 pg/mL were included in the study and divided into 4 groups according to baseline PTH levels. METHODS: The study was completed by 100 patients, a third of which were treated strictly according to the protocol, labeled "compliants"; thus, calcitriol was started according to baseline PTH levels. Two thirds of patients, labeled "noncompliants," showed one or more violation in the dosage regimen. RESULTS: After 2 months of treatment with calcitriol, 59% of the "compliants" and 35% of the "noncompliants" decreased their PTH levels>40% (P = 0.022), 70%, and 49%, respectively after 3 months of treatment. After 3 months of treatment, 67% of the "compliants" reached the target (PTH 125 to 250 pg/mL) in contrast with 23% of the "noncompliants" (P < 0.001). The number of hypercalcemic and hyperphosphatemic episodes was significantly lower in the "compliants" group (P < 0.006). CONCLUSION: These results demonstrate several advantages when calcitriol therapy is started with a dose proportional to the severity of hyperparathyroidism.     

Calcitriol per os once, twice or three times a week: effect of different schedules of administration in hemodialysis patients

Administration of a single dose of 1,25-OH(2)D(3) can lower PTH levels for up to 4 days in chronic hemodialysis patients. Our purpose was to verify the effects of the same weekly dose of calcitriol per os given in one, two or three administrations, to patients on dialysis with secondary hyperparathyroidism. Thirty patients were studied, divided in to three groups each of 10 patients. Calcitriol therapy in group A was given as a single weekly dose of 0.08 microg/kg b.w. In group B the same total weekly dose was divided in two equal doses. In group C the same total weekly dose was divided in three times. Treatment lasted 2 months. After 8 weeks of therapy the fall in intact PTH was statistically significant in each group, respectively with one-way ANOVA: p<0.02 (A); p<0.002 (B); p<0.001 (c). Two-way ANOVA for comparison of PTH % variation among the three groups was statistically significant p<0.003. Significance was due to difference between group A and groups B and C. The present study confirms the efficacy of single dose in suppressing significantly intact PTH. However, when the same weekly dose is divided into two or in three time-spaced administrations, the suppressive effects are definitely increased.