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.     

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.     

Comparison of the effects of calcitriol and maxacalcitol on secondary hyperparathyroidism in patients on chronic haemodialysis: a randomized prospective multicentre trial.

BACKGROUND: To identify differences between the effects of calcitriol and the calcitriol analogue, maxacalcitol, on parathyroid hormone (PTH) and bone metabolisms, we conducted a randomized prospective multicentre study on patients on chronic haemodialysis. METHODS: We randomly assigned 91 patients with secondary hyperparathyroidism [intact PTH (iPTH) > or =150 pg/ml] to have either calcitriol (47 patients) or maxacalcitol (44 patients) therapy, for 12 months after a 1 month control period. Serum electrolytes, bone alkaline phosphatase (bAP), iPTH, total PTH and PTH(1-84) (whole PTH) levels were measured periodically. The first end point was a serum iPTH of <150 pg/ml, the second was the iPTH levels obtained. RESULTS: Treatment was discontinued for various reasons in nine patients in each group, but no serious side effects were observed in either group. The numbers of cases reaching the first end point were not significantly different between the two groups. Serum calcium concentration was significantly higher in the maxacalcitol than the calcitriol group during early treatment, but not at the end of treatment. Throughout the treatment period there were no significant differences between the two groups in serum iPTH, inorganic phosphate, the product of the serum calcium and inorganic phosphorus concentrations, bAP, or the ratio of whole PTH to total PTH minus whole PTH. Nor were the changes in these parameters significantly different between the two groups comparing the patients with moderate to severe hyperparathyroidism (basal iPTH > or =500 pg/ml). CONCLUSION: Calcitriol and maxacalcitol are equally effective on PTH and bone metabolism.     

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     

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.     

Growth in children with chronic renal failure on intermittent versus daily calcitriol

Calcitriol (C) treatment strategies for secondary hyperparathyroidism remain controversial regarding efficacy and safety. In children, intermittent C administration has been suspected of impairing body growth. In a prospective, randomized multicenter study, we compared the effect of daily versus twice weekly C on plasma intact parathyroid hormone (iPTH) levels and growth in 24 prepubertal children with chronic renal insufficiency (mean creatinine clearance 20+/-9 ml/min per 1.73 m(2)). After a 3-week washout period, the patients were randomly assigned to 10 ng/kg per day or 35 ng/kg twice a week oral C. The C dose was kept constant for 2 months and could then be adapted to maintain an iPTH target range of 140-280 pg/ml. Median (range) baseline iPTH levels were 567 (114-1209) pg/ml in the daily and 332 (93-614) pg/ml in the intermittent treatment group ( P=NS). After 12 months, iPTH had decreased to 255 (85-710) and 179 (51-443) pg/ml ( P<0.01). The average weekly dose of C was 76+/-34 and 62+/-34 ng/kg ( P=NS). Five episodes of calcium phosphate product>/=70 occurred in the daily group and four in the intermittent group. The change in height standard deviation score during the study period was not affected by either treatment modality (-0.18+/-0.34 vs. -0.05+/-0.52, P=NS). Daily and intermittent C do not differentially affect growth rate and are equally effective in controlling secondary hyperparathyroidism in children with chronic renal failure.     

Alterations in serum phosphate levels predict the long-term response to intravenous calcitriol therapy in dialysis patients with secondary hyperparathyroidism

Calcitriol therapy is a central strategy for the treatment of uremic secondary hyperparathyroidism. Although indiscriminate use of calcitriol may lead to worse outcomes, it is difficult to make a decision to discontinue calcitriol therapy when its parathyroid suppression effect remains unsatisfactory. In this study, intravenous calcitriol was administered to 120 chronic hemodialysis patients. Therapy continued for 48 weeks or until plasma intact parathyroid hormone (iPTH) levels decreased to below 300 pg/ml or until the development of any significant adverse effect. Of the 120 patients, the treatment goal was achieved in 47 patients during the first 4 weeks, in 10 during the next 4 weeks, and in 22 patients thereafter. Logistic regression analysis and stepwise regression analysis revealed that iPTH levels were the only significant predictor of the response to calcitriol therapy at weeks 0 and 4. Besides iPTH, the inorganic phosphate (P) levels were another significant predictor of the ultimate response to calcitriol therapy at week 8. The point of best discrimination for successful treatment was P = 6.0 mg/dl at week 8, or P level at week 8/pretreatment P level = 1.0. In conclusion, the P level at week 8 is a predictor of the response to calcitriol therapy for uremic secondary hyperparathyroidism. Changes in treatment are recommended if patients show unsatisfactory parathyroid suppression with a hyperphosphatemic tendency.     

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.     

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.     

Safety and efficacy of pulse and daily calcitriol in patients on CAPD: a randomized trial

Background: Calcitriol therapy is the mainstay of therapy for the treatment of secondary hyperparathyroidism. Oral administration of calcitriol is necessary in CAPD patients, but no studies have directly compared different routes of administration in this patient population. Methods: To determine if the peak serum calcitriol level (pulse therapy) is more important than the total delivered dose, we randomized CAPD patients with mild to moderate secondary hyperparathyroidism to receive either pulse (3.0 &mgr;g twice a week, n=10) or daily (0.75 &mgr;g a day, n=8) oral calcitriol in comparable weekly doses. The main comparison was the rate of decline of serum intact parathyroid hormone (PTH) levels to reach the desired end-point of 100 pg/ml. The patients were dialysed with low-calcium dialysate and received only calcium-containing phosphate binders. Results: Pharmacokinetic analysis after a single dose of 3.0 &mgr;g (pulse) vs 0.75 &mgr;g (daily) revealed 1,25(OH)2-vitamin D levels to be higher in the pulse group at 3 and 6 h, but equivalent by 12 h. The area under the curve for 1 week of daily and 1 week of pulse therapy was equal. The patients in the 2 arms had equivalent basal serum levels of PTH (pulse=562±291 vs daily=454±113 pg/ml), calcium (pulse=2.32±0.20 vs daily=2.32±0.12 mmol/l) and phosphorus (pulse=1.32±0.52 vs daily=1.35±0.26 mmol/l). The time required for the PTH to decrease to 100 pg/ml and rate of decline in PTH were similar (time: pulse=14.2±6.8 weeks, daily=12.2±7 weeks; rate: pulse=7.4±4.2 vs daily=8.4±4.2% PTH/week; P=NS). The serum calcium increased similarly in both groups. Hypercalcaemia (>2.9 mmol/l) was rare (pulse=3, daily=2 episodes). Conclusions: This study demonstrates that pulse and daily calcitriol are similarly effective and safe for the treatment of mild to moderate secondary hyperparathyroidism in CAPD patients despite higher peak levels of 1,25(OH)2-vitamin D with pulse therapy. Key words: calcitriol; calcium balance; CAPD; dialysis; hyperparathyroidism; renal osteodystrophy      

Parathyroid Subcutaneous Pre-sternal Transplantation after Parathyroidectomy for Renal Hyperparathyroidism. Long-term Graft Function

Background In the setting of total parathyroidectomy (TPT) and parathyroid transplantation (PTx) for renal hyperparathyroidism (RHP), we evaluated long-term parathyroid graft function after subcutaneous pre-sternal transplantation (SCPTx). Because parathyroid glands are surrounded by fatty tissue, we postulated that results of subcutaneous implantation of parathyroid tissue after total parathyroidectomy for renal hyperparathyroidism could be at least as successful as intramuscular grafting, but without its complications Patients and Methods The study, a prospective open efficacy study of postoperative (po) diagnostic monitoring of intact parathyroid hormone (iPTH) on a cohort of surgical patients, was conducted within a university hospital with a dialysis unit. Thirty five patients (19 women and 16 men) operated on for renal hyperparathyroidism underwent TPT and SCPTx for RHP at the Department of General Surgery and the Department of Nephrology. Donostia Hospital. San Sebastián. Gipuzkoa. Spain, from January 2002 to December 2005. Follow-up ranges from 6 months to 42 months (median: 15.4 months). The main outcome measure was evaluation of graft function by measurement of iPTH plasma level, based on serum levels of iPTH before operation and 24 h and 1, 3, 5, 15, 30, 60, 100, and 150 weeks after surgery Results Average preoperative iPTH values were 1,341.52 + 367.78 pg/ml (mean ± SD) (range: 493–2,180). After TPT and PSCTx, iPTH levels became undetectable in all patients at 24 h. A level of 50 pg/ml was established as the criterion of adequate parathyroid graft function. Values obtained at the various time intervals were as follows: 14.14 + 7.73 1 pg/ml (mean ± SD) (range: 6–36) after 1 week, 53 + 77.33 pg/ml (mean ± SD) (range: 35–74) after 5 weeks, 62.95 + 20.93 pg/ml (mean ± SD) (range: 11–89) after 15 weeks, 77.54 + 18.84 pg/ml (mean ± SD) (range: 24.6–104.2) after 30 weeks, 109.29 + 50.22 pg/ml (mean ± SD) (range: 54–327) after 60 weeks, 134.21 + 128.64 pg/ml (mean ± SD) (range: 43–712) after 100 weeks, and 122.84 + 117.54 pg/ml (mean ± SD) (range: 68–723) after 150 weeks. Prevalence of hypoparathyroidism (intact parathyroid hormone serum level < 20 pg/ml with a normal or low serum calcium concentration) was 2/35 (5.71%) by week 60 and recovered by week 100. Graft-related recurrence was 2.85% (1/35). Conclusions Subcutaneous pre-sternal transplantation (SCPTx) after TPT and PTx for secondary (RHP) is an adequate method to replace muscular forearm parathyroid transplantation and avoid its complications. Functioning results of total parathyroidectomy and presternal subcutaneous grafting compare favorably with the published data on other surgical techniques proposed for the treatment of renal hyperparathyroidism. Results of long-term follow-up exceed previously reported results.     

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.     

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.     

1.25 (OH)2 cholecalciferol pulse therapy and the effects of different dialysis membranes on serum PTH levels of haemodialysis patients

Either oral, intravenous or subcutaneous 1.25 (OH)₂ cholecalciferol is used in the therapy of hyperparathyroidism, which is a serious complication in patients on haemodialysis. We studied a total of 30 patients (10 women and 20 men) and divided them into two groups depending on the different types of dialysis membranes used. In the poly sulfone group, mean age was 43.7±0.97 years and the average dialysis period lasted 29.9±1.23 months. For the 15 cases in which we used cuprophane membrane the mean age was 40.2±1.31 years and the average dialysis period lasted 16.2±0.86 months. The calcium level of the dialysate in both groups was 1.5 mmol/l. According to the study protocol, the determined oral calcitriol dose was 0.07 mg/kg and it was administered intermittently. After one month on high dose calcitriol therapy, treatment was continued with a maintenance dose of 0.03 mg/kg for a further six months. As a phosphate binding agent, daily 3 g calcium carbonate was administered. Before starting this treatment protocol, patients went on a 1 mg/day calcitriol therapy, although the mean PTH level was 424.63 pg/ml and the mean serum alkaline phosphatase level was 290.2 U/l. During the pretreatment period, levels of PTH, alkaline phosphatase, ionized calcium, and total calcium remained significantly within normal limits as a result of the new therapy protocol applied. PTH and phosphorus clearance rates were compared in the patient groups in which different dialysis membranes had been used. PTH and phosphorus clearances were 15.2±3 ml/min and 239.1±19.2 ml/min, respectively, in the polysulfone membrane group, and 1.1±0.3 ml/min and 112.8±9.88 ml/min, respectively, in the cuprophane membrane group (p<0.05).     

Low-dose calcitriol prevents the rise in 1,84 iPTH without affecting serum calcium and phosphate in patients with moderate renal failure (prospective placebo-controlled multicentre trial)

BACKGROUND: Higher doses of calcitriol are effective in lowering markedlyelevated 1,84 PTH levels of patients with renal secondary hyperparathyroidism.It has not been established, however, whether prophylactic administrationof low doses of calcitriol prevents an increase of 1,84 PTHwithout causing side-effects, i.e. hypercalcaemia, hypercalciuria,or hyper-phosphataemia. STUDY DESIGN: We carried out a placebo-controlled, double-blind prospectivemulticentre trial over 12 months in 45 patients with mild tomoderate renal failure. Criteria for inclusion were S-creatinine1.4mg/dl and 1,84 PTH>6pmol/l (normal 6). Calcitriol 0.125ug/day per os was compared with placebo. The patients receivedcalcium carbonate per os if serum P exceeded 1.7 mmol/1. RESULTS: Baseline 1,84 iPTH concentrations were not significantly different,i.e. 14.0 pmol/1 (6.7–63.3) on placebo vs 16.2 (6.85–82.0)on calcitriol. Intention to treat analysis revealed a significantdifference of final 1,84 iPTH, i.e. 27.8 (4.2–68.5) onplacebo vs 18.2 (4.45–75.5) on calcitriol. On post-hocanalysis the difference was even more pronounced at S-creatinineconcentrations above 3 mg/dl. S-calcium, S-phosphate, and urinaryexcretion of calcium did not change significantly on eitherplacebo or on calcitriol. There were no episodes of hypercalcaemiaor hyperphosphataemia. There was no significant difference offinal S-creatinine or change in S-creatinine between placeboand calcitriol. One patient on calcitriol and two on placeboprogressed to terminal renal failure. Bone alkaline phosphataseas a non-invasive index of bone metabolism was not decreasedto subnormal levels. CONCLUSIONS: The results document that a therapeutic window exists in patientswith moderate renal failure and elevated of 1,84 iPTH, wherelow-dose calcitriol (0.125 ug/day) prevents the increase in1,84 iPTH without causing side-effects. This observation suggeststhat the parathyroid is more sensitive to calcitriol than intestineand bone.     

Effect of oral calcium loading on intact PTH and calcitriol in idiopathic renal calcium stone formers and healthy controls

The calciuric response after an oral calcium load (l000 mg elementalcalcium together with a standard breakfast) was studied in 13healthy male controls and 21 recurrent idiopathic renal calciumstone formers, 12 with hypercalciuria (U_CaxV>7.50 mmol/24h) and nine with normocalciuria. In controls, serum 1,25(OH)₂vitamin D3 (calcitriol) remained unchanged 6 h after oral calciumload (50.6±5.1 versus 50.9±5.0 pg/ml), whereasit tended to increase in hypercalciuric (from 53.6±3.2to 60.6±5.4 pg/ml, P=0.182) and fell in normocalciuricstone formers (from 45.9±2.6 to 38.1±3.3 pg/ml,P=0.011). The total amount of urinary calcium excreted afterOCL was 2.50±0.20 mmol in controls, 2.27±0.27mmol in normocalciuric and 3.62±0.32 mmol in hypercalciuricstone formers (P=0.005 versus controls and normocalciuric stoneformers respectively); it positively correlated with serum calcitriol6 h after calcium load (r=0.392, P=0.024). Maximum increasein urinary calcium excretion rate, Ca-E_max, was inversely relatedto intact PTH levels in the first 4 h after calcium load, i.e.more pronounced PTH suppression predicted a steeper increasein urinary calcium excretion rate. Twenty-four-hour urine calciumexcretion rate was inversely related to the ratio of calcitriol/PTH_maxafter calcium load (r=–0.653, P=0.0001), indicating thatan abnormally up-regulated synthesis of calcitriol and consecutiverelative PTH suppression induce hypercalciuria. Finally, lateabsorption of calcium as suggested by maximum urinary calciumexcretion beyond 4 h after oral calcium load was as rare inhypercalciuric stone formers (2 of 12) as in controls (1 of13) and did not occur in normocalciuric stone formers.     

Bone growth during daily or intermittent calcitriol treatment during renal failure with advanced secondary hyperparathyroidism

Calcitriol is a standard therapy for secondary hyperparathyroidism in chronic renal failure. We evaluated whether the effect of daily or intermittent calcitriol administration is more efficient in enhancing bone growth in renal failure with advanced secondary hyperparathyroidism in weanling 5/6 nephrectomized rats loaded with phosphorus to induce severe secondary hyperparathyroidism. The animals were treated daily or three times weekly with calcitriol for 4 weeks but the total weekly dose of calcitriol was the same. Although calcitriol increased the serum calcium, it did not lower parathyroid hormone (PTH) or improve tibia and body length. Animals with renal failure and advanced secondary hyperparathyroidism had decreased PTH/PTHrP, which was accompanied by an increase in the cyclin kinase inhibitor p57(Kip2). Calcitriol treatment upregulated the PTH/PTHrP receptor but also increased inhibitors of cell proliferation such as p21(Waf1/Cip1), IGFBP3, and FGFR3. Calcitriol also enhanced markers of chondrocyte differentiation, such as IGF1, Vitamin D receptor, FGF23, and bone morphogenetic protein-7. Receptor activator of nuclear factor-kappabeta ligand levels improved with calcitriol treatment but without changes in osteoprotegerin suggesting an enhancement of osteo/chondroclastogenesis and mineralization. Overall, both daily and intermittent calcitriol had similar effects on endochondral bone growth in phosphorus-loaded rats with renal failure.     

Effects of calcitriol on parathyroid function and on bone remodelling in secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (2HPT) develops in chronic renal failure due to disturbances of calcium, phosphorus and vitamin D metabolism. It is characterized by high turnover bone disease and an altered calcium-parathyroid hormone (PTH) relationship. Calcitriol has been widely used for the treatment of 2HPT. However, it remains controversial whether calcitriol is capable of inducing changes of the calcium-PTH curve. The aim of the present study was to examine this issue and to determine the effect of calcitriol on bone remodelling in patients with severe 2HPT. METHODS: We evaluated 16 chronic haemodialysis patients with severe 2HPT (PTH 899+/-342 pg/ml). Each patient underwent a dynamic parathyroid function test (by infusion of calcium gluconate and sodium citrate) and a bone biopsy before and after a 6 month period of i.v. calcitriol therapy (CTx). RESULTS: After treatment, eight patients were identified as calcitriol responders and the other eight as non-responders, based on plasma PTH level (<300 pg/ml for responders and >300 pg/ml for non-responders). The first group had higher plasma 25OHD(3) levels (39+/-8 vs 24+/-7 ng/ml, P<0.005). As to the calcium-PTH curve, we found differences in slope (-12.7+/-5.2 vs -21.7+/-11.4, P=0.05), basal/maximum PTH ratio (48.8+/-14.9 vs 71.05+/-20.1%, P=0.01) and time to achieve hypocalcaemia (79.0+/-13.5 vs 94.3+/-13.7 min, P<0.001). Initial histomorphometric parameters did not allow identification of the different groups. After the 6-month CTx, alterations in the calcium-PTH curve were clearly seen in responders [a drop in maximum PTH (from 1651+/-616 to 938+/-744 pg/ml, P<0.05) and minimum PTH (from 163+/-75.4 to 102.2+/-56.7 pg/ml, P<0.005)], associated with an increase in minimum/basal PTH ratio (from 23.3+/-11.6 to 34.5+/-20.4%, P<0.05) and maximum calcium (from 0.99+/-0.07 to 1.1+/-0.09 mmol/l, P<0.05). Set point and slope were not altered after calcitriol treatment, in responders (set point=1.17+/-0.08 vs 1.15+/-0.1 mmol/l, ns; slope=-12.7+/-5.2 vs -12.9+/-9.3, ns) or non-responders (set point=1.21+/-0.05 vs 1.21+/-0.2 mmol/l, ns; slope=-21.7+/-11.4 vs -17.3+/-8.4, ns). Bone formation parameters were reduced in all patients [osteoid surface (OS/BS)=from 57.1+/-21.6 to 41.6+/-26%, P<0.05 for responders, and from 76.7+/-12 to 47.1+/-15%, P<0.001 in non-responders], but non-responders had increased bone resorption [eroded surface (ES/BS)=7.1+/-3.4 vs 16.6+/-4.9, P<0.05]. CONCLUSION: Calcitriol had non-uniform effects on parathyroid function and bone remodelling in uraemic patients. Non-responders exhibited a decoupled remodelling process that could further influence mineral balance or possibly also bone structure. To avoid such undesirable effects, early identification of non-responder patients is crucial when using calcitriol for the treatment of 2HPT.     

No difference in intestinal strontium absorption after oral or IV calcitriol in children with secondary hyperparathyroidism. The European Study Group on Vitamin D in Children with Renal Failure

BACKGROUND: Oral and intravenous calcitriol bolus therapy are both recommended for the treatment of secondary hyperparathyroidism, but it has been claimed that the latter is less likely to induce absorptive hypercalcemia. The present study was undertaken to verify whether intravenous calcitriol actually stimulates intestinal calcium absorption less than oral calcitriol and whether it is superior in suppressing parathyroid hormone (PTH) secretion. METHODS: Twenty children (16 males, age range of 5.1 to 16.9 years, mean creatinine clearance 21.9 +/- 11.5 mL/min/1.73 m2, range of 7.4 to 52.7) with chronic renal failure (CRF) and secondary hyperparathyroidism [median intact PTH (iPTH), 327 pg/mL; range 143 to 1323] received two single calcitriol boli (1.5 mg/m2 body surface area) orally and intravenously using a randomized crossover design. iPTH and 1,25(OH)2D3 levels were measured over 72 hours, and intestinal calcium absorption was measured 24 hours after the calcitriol bolus using stable strontium (Sr) as a surrogate marker. Baseline control values for Sr absorption were obtained in a separate group of children with CRF of similar severity. RESULTS: The peak serum level of 1,25(OH)2D3 and area under the curve baseline to 72 hours (AUC0-72h) were significantly higher after intravenous (IV) calcitriol (AUC0-72h oral, 1399 +/- 979 pg/mL. hour vs. IV 2793 +/- 1102 pg/mL. hour, P < 0.01), but the mean intestinal Sr absorption was not different [SrAUC0-240min during the 4 hours after Sr administration 2867 +/- 1101 FAD% (fraction of the absorbed dose) vs. 3117 +/- 1581 FAD% with oral and IV calcitriol, respectively]. The calcitriol-stimulated Sr absorption was more then 30% higher compared with control values (2165 +/- 176 FAD%). A significant decrease in plasma iPTH was noted 12 hours after the administration of the calcitriol bolus, which was maintained for up to 72 hours without any differences regarding the two routes of administration. CONCLUSIONS: These results demonstrate that under acute conditions, intravenous and oral calcitriol boli equally stimulate calcium absorption and had a similar efficacy in suppressing PTH secretion.     

Calcitriol does not prevent bone loss in patients with asthma receiving corticosteroid therapy: a double-blind placebo-controlled trial

Introduction Oral glucocorticoid therapy reduces bone mineral density (BMD) and increases fracture risk. It is uncertain whether inhaled glucocorticoids, the most commonly used long-term therapy for asthma, have a similar effect. If bone loss does occur, it is unclear whether this is preventable by calcitriol. Patients with asthma receiving inhalational plus intermittent oral glucocorticoids lose bone, and treatment with 0.5 μg/day of calcitriol will prevent bone loss.Methods A 2-year randomized double-blind placebo-controlled trial. One hundred eight patients with asthma were stratified by gender, age, and inhaled glucocorticoid dose and treated with calcitriol (n=55) or placebo (n=53). There were 41 men (mean age 53.2±1.7 years) and 67 women (mean age 49.1±1 years) with moderate to severe asthma (requiring ≥800 μg/day of beclomethasone dipropionate or equivalent maintenance therapy). BMD values at the lumbar spine (LS) and femoral neck (FN) were measured at baseline and at 6, 12, and 24 months using dual x-ray absorptiometry.Results Changes in LS and FN BMD. Bone loss occurred in both groups at the FN (both p<0.03) and at the LS in the calcitriol (p<0.001), but not the control, group. Bone loss was not less in the calcitriol group at either site.Conclusion Patients with asthma receiving inhalational plus intermittent short courses of oral glucocorticoids lose bone. Calcitriol is unlikely to be appropriate therapy against this bone loss.