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)     

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.     

Effects of new vitamin D analogues on parathyroid function in chronically uraemic rats with secondary hyperparathyroidism

BACKGROUND.: Treatment with calcitriol or its analogue, alfacalcidol oftenleads to hypercalcaemia, hyperphosphataemia or both in patientswith chronic renal failure and advanced secondary hyperparathyroidism.We tested three new vitamin D analogues (CB 1093, EB 1213, GS1725) in an attempt to identify potentially non hypercalcaemiccompounds, capable of decreasing plasma parathyroid hormone(PTH) concentration. METHODS.: Male Wistar AF rats aged 12–14 weeks were fed a synthetic,phosphate-rich diet and underwent either sham surgery (control)or a standard two-step 5/6th nephrectomy. Four weeks later,renal function was mildly decreased in the latter. Chronic renalfailure rats were then divided into six groups, with 8–10rats in each group. They received daily i.p. injections, fromdays 0 to 4, of either placebo, calcitriol, or one of the followingthree active vitamin D analogues: CB1093, 0.25 µg; EB1213,0.25 or 1.25 µg; and GS1725, 0.025 µg/kg body weightper day, respectively. Sham-operated rats received no drug.On day 5, arterial blood was sampled and rats were sacrificed. RESULTS.: At predefined dosage schedules, all three compounds significantlydecreased plasma immunoreactive PTH levels (except EB1213 atlow dose). The decrement was somewhat less marked than thatobtained with calcitriol, at the dose of 0.25 µg/kg b.w.per day. However, calcitriol induced a marked increase in plasmacalcium and phosphate concentrations at that dose, whereas vitaminD analogues led to a more modest increase in plasma calciumlevel, and none to a worsening of hyperphosphataemia. CB1093treatment was even associated with a significant decrease inplasma phosphate level. CONCLUSIONS.: All three calcitriol analogues tested are promising as non-hypercalcaemicagents in the treatment of uraemic secondary hyperparathyroidism.However, more prolonged administration to uraemic rats of calcitriolanalogues with slightly modified dosage schedules and of calcitriolwith lower, non-hypercalcaemic dose is required for an optimalcomparison before considering clinical trials.     

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.     

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.     

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.     

Effects of cinacalcet on bone mineral density in patients with secondary hyperparathyroidism.

BACKGROUND: Cinacalcet, a calcimimetic agent, is effective in treating both primary and secondary hyperparathyroidism. Because hyperparathyroidism induces mineralized bone loss, we investigated the effects of cinacalcet treatment on bone mineral density (BMD) in patients with secondary hyperparathyroidism due to chronic kidney disease. METHODS: Ten patients who were receiving haemodialysis and four patients, who had stage 4 chronic kidney disease participated and completed the multicentre, randomized, double-blind, placebo-controlled trials evaluating the safety and efficacy of cinacalcet for treating secondary hyperparathyroidism. The efficacy of cinacalcet was assessed by plasma intact parathyroid hormone (iPTH) levels. A dual energy X-ray absorptiometry was performed to measure the BMD of total proximal femurs and lumbar spine (L2-L4) before and after 26 weeks of treatment. RESULTS: Cinacalcet reduced iPTH from 912+/-296 to 515+/-359 pg/ml in haemodialysis patients and from 210+/-46 to 56+/-51 pg/ml in pre-dialysis patients (means+/-SD; both P<0.05). When data from haemodialysis and pre-dialysis patients were pooled for analysis, cinacalcet treatment increased proximal femur BMD from 0.945+/-0.169 to 0.961+/-0.174 g/cm(2) (P<0.05), but did not affect lumbar spine BMD. There was a correlation between the change in femur BMD and the change in iPTH during the study period (R(2) = 0.39, P<0.05). CONCLUSIONS: Secondary hyperparathyroidism is associated with progressive bone loss. Suppression of plasma iPTH with cinacalcet appears to reverse bone loss in the proximal femur, but does not affect BMD of the lumbar spine. A larger study is warranted to confirm that cinacalcet has a beneficial effect on the skeletal system in patients with secondary hyperparathyroidism.     

Direct injections of calcitriol into enlarged parathyroid glands in chronic dialysis patients with severe parathyroid hyperfunction

Summary: Severe secondary hyperparathyroidism in chronic dialysis patients has been recently treated by supraphysiological concentration of calcitriol achieved through pulse therapy. However, there are many patients resistant to this therapy, who usually have larger parathyroid gland(s). to overcome this resistance, calcitriol was injected directly into the enlarged glands under ultrasonographic guidance. We injected 70–90% of the calculated gland volume of calcitriol solution (1 μg/mL) into the glands of 7 patients three times per week for 2 weeks. the parathyroid hormone (PTH) levels decreased significantly after 2 weeks of direct injections of calcitriol. Following a further 4 weeks of calcitriol pulse therapy, PTH levels remained suppressed and serum alkaline phosphatase activity and the volume of parathyroid glands also decreased. During the long-term follow up, five patients remained well controlled with calcitriol pulse therapy, while two patients needed ethanol injections to control hyperparathyroidism. Although we could not completely rule out a toxic effect of the vehicle, direct injection of calcitriol into parathyroid glands may be another treatment option for chronic dialysis patients. Our data further support the important role of resistance of parathyroid cells to calcitriol in the pathogenesis of parathyroid hyper function in uraemic patients.     

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.     

Long-term low-dose calcitriol treatment in predialysis chronic renal failure: can it prevent hyperparathyroid bone disease?

In an uncontrolled open study 13 patients with moderate to preterminalrenal failure were treated with low doses (average 0.36 µg/day)of calcitriol up to the time of renal transplantation, whichwas performed before dialysis had been initiated. A transiliacbone biopsy was obtained both at the start and at the end ofthe treatment period, the latter coinciding with renal transplantation.All patients who started calcitriol treatment at a creatinineclearance (C_cr) above 30 ml/min had normal bone histology atthe time of transplantation, but this was not observed whencalcitriol treatment was started at C_cr below 30 ml/min. The study suggests that full benefit of calcitriol at the bonelevel is obtained only if prophylactic administration is startedearly in the course of renal failure.     

Efficacy and safety of oral falecalcitriol in reducing parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism

Based on research conducted so far, active vitamin D₃ is known to suppress the secretion of parathyroid hormone (PTH), which is stimulated by chronic renal failure. We investigated the effect and safety of falecalcitriol, a new type of active vitamin D₃, in patients with secondary hyperparathyroidism accompanied by chronic renal failure in a multicenter study. In a double-blind study, 121 patients were randomly assigned to a falecalcitriol group (63 patients) or a placebo group (58 patients). They received daily oral falecalcitriol or placebo for 8 weeks. The change rates of intact PTH (i-PTH) , midregion PTH (m-PTH), and carboxy-terminal PTH (c-PTH) were determined as major evaluation parameters. The falecalcitriol group showed a significant suppression (P < .01) of 34.8% in i-PTH; in contrast, the placebo group recorded a significant rise (P < .01) of 12.4%, with a significant difference (P < .01) between the groups. The results for m-PTH and c-PTH were similar to those for i-PTH. Serum calcium, meanwhile, rose significantly (P < .01) in the falecalcitriol group after 2 weeks. The mean values, however, remained within the normal range, and the change rate was within 10%. Apart from the rise in serum calcium, there were no differences in adverse reactions from the placebo group. The results suggest that falecalcitriol is an effective drug against secondary hyperparathyroidism with chronic renal failure because it significantly inhibits a rise in i-PTH under conditions that cause no large changes in serum calcium. Received: June 16, 1997 / Accepted: Aug. 6, 1997     

Increased osteocyte death and mineralization inside bone after parathyroidectomy in patients with secondary hyperparathyroidism

In order to gain insight into the mechanisms underlying the dynamic changes in bone metabolism and bone quality after parathyroidectomy (PTX) in secondary hyperparathyroid patients with high levels of parathyroid hormone (PTH), we performed bone histomorphometric analysis with tetracycline labeling in iliac bone biopsy specimens taken before and after PTX, with special attention paid to osteocytes. At 2 to 4 weeks after PTX, PTH concentrations decreased markedly with evident reductions in bone turnover markers. Histomorphometry revealed that at 2 to 4 weeks following PTX, the osteoclast surface decreased to nearly 0%, with a substantial increase in osteoid volume and a reduction in fibrosis volume. Labeling with tetracycline was observed not only at the mineralization front on the bone surface but also around the osteocyte lacunar walls and canaliculi within both the basic multicellular units (BMUs) and bone structural units (BSUs), suggesting that mineralization was taking place along the lacunocanalicular system after PTX. The tetracycline‐labeled area was much greater in the BSUs than in the BMUs and at the mineralization front, and the tetracycline labeling in the BSUs was markedly increased after PTX compared with that in the low‐ and high‐PTH control groups without PTX. The osteocyte number was decreased significantly after PTX, concomitant with an increase in the number of empty lacunae and a reduction of lacunar volume. Thus the increased osteocyte death and mineralization around the lacunocanalicular system in association with a rapid decline in PTH may underlie the changes in bone metabolism and quality that occur following PTX. © 2010 American Society for Bone and Mineral Research.     

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.     

De novo expression of transforming growth factor-{alpha} in parathyroid gland tissue of patients with primary or secondary uraemic hyperparathyroidism

BACKGROUND.: The factors involved in abnormal parathyroid cell secretoryfunction and growth in patients with primary and secondary hyperparathyroidismare still incompletely understood. PATIENTS AND METHODS.: We studied the expression of transforming growth factor- (TGF-),epidermal growth factor (EGF) and EGF receptor (EGF-R) at thegene message and the protein level in parathyroid tissue obtainedfrom six patients with primary hyperparathyroidism, 15 patientswith secondary uraemic hyperparathyroidism and five subjectswith normal parathyroid tissue, using in situ hybridizationand/or immunostaining technique. RESULTS.: We found a consistent expression of TGF- mRNA and protein inparathyroid endocrine cells of all six cases of primary parathyroidadenoma and in nearly all cases of secondary hyperplasia, incontrast to the absence of expression in normal parathyroidtissue. A marked expression of EGF-R mRNA and protein was alsofound in four of five tissue samples of primary parathyroidadenoma, in 13 of 15 tissue samples of secondary parathyroidhyperplasia and in most samples of normal parathyroid glandtissue. EGF mRNA and protein expression was undetectable inthe majority of parathyroid tissue samples examined. CONCLUSION.: Since TGF- is known to bind to the EGF-R, the finding of anincreased expression of TGF- at the gene message and the proteinlevel, together with a strong expression of EGF-R, in hyperplasticand adenomatous parathyroid glands suggests that this growthfactor interacts with its receptor to promote parathyroid cellproliferation, perhaps by an autocrine mechanism.     

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     

Changes in bone turnover after parathyroidectomy in dialysis patients: role of calcitriol administration.

BACKGROUND: Available data on changes in serum levels of bone markers after parathyroidectomy (PTx) in dialysis patients are not uniform. Changes are thought to be due to either a reduction in PTH activity per se or to a direct effect of vitamin D therapy on bone cells. We aimed to verify whether treatment with vitamin D modifies serum levels of markers of bone synthesis (alkaline phosphatase (AP), osteocalcin (BGP), procollagen type I C-terminal peptide (PICP)) and resorption (collagen type I C-terminal peptide (ICTP)) within a period of 15 days in haemodialysis patients with severe secondary hyperparathyroidism following PTx. METHODS: We randomized two groups (A, treatment and B, placebo, 10 patients each) with comparable basal PTH values and measured bone markers 3, 7 and 15 days after surgery. All patients were treated with calcium supplements (i.v. and p.o.), and group A also received calcitriol (2.4+/-1.0 microg/day, p.o.). RESULTS: In both groups, PTx induced significant changes in all the markers evaluated, except for BGP in group B. Compared to basal values, ICTP decreased from 481+/-152 ng/ml in group A and 277+/-126 ng/ml in group B to 267+/-94 and 185+/-71 ng/ml (M+/-SD) respectively, and PICP increased from 307+/-139 ng/ml in group A and 309+/-200 ng/ml in group B to 1129+/-725 and 1231+/-1267 ng/ml (M+/-SD) respectively, within 3 days of surgery. AP values increased after 15 days from 1115+/-734 mU/ml in group A and 1419+/-1225 mU/ml in group B to 1917+/-1225 and 1867+/-1295 mU/ml (M+/-SD) respectively. On the contrary, mean values of BGP were never different from basal levels after PTx in either group. In the two groups, the pattern of changes of all the bone markers after PTx was almost identical. Group A patients predictably required lower doses of oral calcium supplements to correct hypocalcaemia (16. 9+/-5.7 vs 22.1+/-5.0 g/10 days; M+/-SD, P<0.04). CONCLUSIONS: The opposite behaviour of serum PICP and ICTP after PTx, in both the treated and untreated groups suggests that quantitative uncoupling between bone synthesis and resorption is responsible for hypocalcaemia. This phenomenon, as reflected by the evaluated bone markers, is unaffected by calcitriol. Based on our data we conclude that immediately after parathyroid surgery, vitamin D therapy does not influence bone cell activity, but improves hypocalcaemia mainly through its known effect on intestinal calcium absorption.     

'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.     

New insight into the pathogenesis of secondary hyperparathyroidism in chronic renal failure

Secondary hyperparathyroidism is the most frequently encountered complication of chronic renal failure. In this paper, we will summarize new insight into the pathogenesis of secondary hyperparathyroidism in chronic renal failure, with a special emphasis on the regulation of PTH synthesis and parathyroid cell proliferation.     

Abnormal calcaemic response to PTH in the uraemic rat without secondary hyperparathyroidism

BACKGROUND: Skeletal resistance to the calcaemic action of parathyroid hormone(PTH) is an important pathogenic factor in the development ofsecondary hyperparathyroidism. Since parathyroidectomy normalizesthe calcaemic response to PTH in uraemic animals, the increasein PTH levels has been advanced as a cause of skeletal resistanceto the calcaemic action of PTH. This study was designed to evaluatein uraemic rats the effect of normal PTH levels on the calcaemicresponse to PTH. METHODS: To maintain normal PTH levels, rats were parathyroidectomized(PTX) and rat 1–34 PTH was infused at a rate of 0.022µg/100 g per hour via a subcutaneously implanted miniosmoticpump; this rate of infusion was considered to be the normalPTH replacement dose since it normalized serum calcium and phosphorusin PTX rats with normal renal function. Two separate studieswere performed. In the first study, rats were maintained ona moderate-phosphorus (0.6%) diet and rats were divided intofour groups: (I) normal; (II) uraemic; (III) PTX with normalPTH replacement; and (IV) uraemic with PTX and normal PTH replacement.In a second study, the groups were the same except that a high-phosphorus(1.2%) diet was given to increase the magnitude of hyperparathyroidismin rats with intact parathyroid glands; an additional group(V) identical to group IV except that rats received daily calcitriolwas included. After 14 days, rats received a 48-h infusion ofhigh-dose rat 1–34 PTH (0.11 µg/100 g per hour)to evaluate the calcaemic response to PTH. RESULTS: The calcaemic response to PTH was similar in normal rats andPTX rats with PTH replacement on both a moderate and high-phosphorusdiet. In uraemic rats, the calcaemic response to PTH was decreasedand the maintenance of normal PTH levels by PTH replacementdid not correct the decreased calcaemic response to PTH; moreover,calcitriol supplementation did not improve the calcaemic responseto PTH. Finally, hypocalcaemia was observed in uraemic ratswith PTH replacement and was more profound than in rats on ahigh-phosphorus diet. CONCLUSIONS: This study demonstrates that the maintenance of a normal PTHlevel in uraemic rats did not correct the impaired calcaemicresponse to PTH, suggesting that factors intrinsic to uraemia,independent of phosphorus, calcitriol, and PTH participate inthe decreased calcaemic response to PTH in uraemia.