Effect of 22-oxa-calcitriol on calcium metabolism in rats with severe secondary hyperparathyroidism

Kubrusly, Marcos; Gagné, Eve-Reine; Ureña, Pablo; Hanrotel, Catherine; Chabanis, Sophie; Lacour, Bernard; Drüeke, Tilman B.; Jehenne, Guillaume; Duchambon, Patricia; Banide, Hélène; Pacher, Nathalie

doi:10.1038/ki.1993.280

Cited by 44 publications

(29 citation statements)

References 27 publications

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“…The concept of vitamin D resistance in uremia has been put forward by several authors [4,32] and has been linked to decreased vitamin D receptor density and to impaired binding of 1.25(OH)2D3 to DNA in uremia [9]. In our studies, no direct evidence for a vitamin D resis tance was found.…”

Section: Discussioncontrasting

confidence: 54%

“…(l,25(OH)2D3) is an important factor for control of parathyroid hormone (PTH) synthesis and secretion [1][2][3][4][5]. Disturbances of the l,25(OH)2D3-PTH axis in uremia resulting in relative or absolute 1.25(OH)2D3 deficiency are involved in initiation and maintenance of secondary hyperparathyroidism in renal failure [6], The actions of l,25(OH)2D3 arc mediated through binding to the cellular vitamin D receptor (VDR) [7].…”

Section: Introductionmentioning

confidence: 99%

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Abnormal Expression and Regulation of Vitamin D Receptor in Experimental Uremia

Szabó

Ritz²,

Schmidt-Gayk³

et al. 1996

Nephron

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The low concentration of the biologically active metabolite of vitamin D, namely lα,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), is critical to the pathogenesis of secondary hyperparathyroidism in chronic renal failure. The actions of 1,25(OH)₂D₃ are mediated through binding to a cellular receptor protein, the vitamin D receptor (VDR). In order to further investigate expression and regulation of VDR in uremia, we measured specific [³H]-1,25(OH)₂D₃ binding capacity and VDR mRNA concentration in intestinal mucosa and in parathyroid glands of subtotally nephrectomized rats (Nx) and compared Nx to sham-operated rats with normal kidney function (Intact). Intestinal [³H]-1,25(OH)₂D₃ binding capacity in short-term Nx (6-10 days after nephrectomy) was 663 ± 114 fmol/mg protein; it was 517 ± 34 in Intact (p = 0.06, n = 6 experiments). Intestinal VDR mRNA concentration was comparable between Nx and Intact. Specific 1,25(OH)₂D₃ binding capacity in parathyroid glands was higher in Nx (195 ± 9 fmol/mg protein) than in Intact (116 ± 14 fmol/mg protein, n = 5, p < 0.05). The affinity of the VDR for l,25(OH)₂D₃ (KD) did not change in Nx. The 1,25(OH)₂D₃ binding capacity in intestinal mucosa of more long-term uremic animals (14-16 weeks after subtotal Nx) was 519 ± 32 fmol/mg protein versus 349 ± 31 in Intact (n = 3, p < 0.01). Parathyroid VDR was 171 ± 9 fmol/mg protein in long-term Nx and 125 ± 3 in Intact (p < 0.01). These results were confirmed when 1,25(OH)₂D₃ binding capacity in uremic rats with hereditary polycystic kidney disease was compared to control rats with normal kidney function (757 ± 54 fmol/mg protein versus 495 ± 59 in intestinal mucosa, p < 0.05; 273 ± 48 versus 104 ± 27 in parathyroid glands, p < 0.05). In parallel to changes in intestinal 1,25(OH)₂D₃ binding capacity, 1,25(OH)₂D₃-mediated stimulation of intestinal 25(OH)D₃-24-hydroxylase activity was significantly higher in long-term subtotally Nx (1.43 ± 0.06 pmol 24,25-dihydroxyvitamin D₃/mg protein) than in sham-operated normal rats (1.04 ± 0.10, p < 0.05). Administration of 1,25(OH)₂D₃ to sham-operated normal rats resulted in an increase of 1,25(OH)₂D₃ binding capacity by 20-40% in intestinal mucosa and by 40-50% in parathyroid glands. In contrast, 1,25(OH)₂D₃ caused down-regulation of mean 1,25(OH)₂D₃ binding capacity in short-term Nx by 38% in intestinal mucosa (p < 0.01) and by 43% in parathyroid glands (p < 0.01). In long-term Nx, mean 1,25(OH)₂D₃ binding capacity was reduced by 20% in intestinal mucosa (p < 0.05) and by 22% in parathyroid glands (p < 0.01). After prolonged exposure to 1,25(OH)₂D₃ for 6 weeks, intestinal 1,25(OH)₂D₃ bin...

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Section: Discussioncontrasting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Abnormal Expression and Regulation of Vitamin D Receptor in Experimental Uremia

Szabó

Ritz²,

Schmidt-Gayk³

et al. 1996

Nephron

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“…In uremic dogs, OCT at an intravenous dose of 5 pg is able to decrease the PTH levels during 69 h by 80%, without inducing hyper calcemia [184]. The administration during 14 days of increasing doses of OCT (up to 0.125 pg/kg) inhibits the PTH secretion in uremic rats by 40% without a frank hypercalcemic effect (calcemia increased from 9.9 to 10.7 mg/dl) [185], These data have recently been con firmed by a study using a dose of 0.625 pg/kg for 3 months [186], However, the work ofKubrusly et al [187] does not confirm the absolute superiority of OCT relative to calci triol, as far as its possibility to suppress PTH secretion without inducing hypercalcemia is regarded; in fact, with the same dose of 0.3 pg given during 2 days, OCT has been demonstrated to be hypercalcemic, although at a milder degree as compared with calcitriol. but also to be less effective in reducing PTH secretion.…”

Section: Advantages O F 2425(oh) 2d3?mentioning

confidence: 78%

1-Alpha-Hydroxyvitamin D3 Derivatives in the Treatment of Renal Bone Diseases: Justification and Optimal Modalities of Administration

Fournier

Morinière

Oprisiu

et al. 1995

Nephron

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The use of 1 α-hydroxyvitamin D3 [ 1 α(OH)D3] derivatives in a uremic patient is justified only in the treatment of hyperparathyroidism (i.e. when plasma intact parathyroid hormone -PTH – levels are above five or three times the upper limit of normal according to whether the patient is on continuous ambulatory peritoneal dialysis or on hemodialysis and between 0.5-1.5, 1-2 and 2-3 times the upper limit of normal for a creatinine clearance of, respectively, 30, between 30 and 10, or below 10 ml/min/1.73m²). The following prerequisites have however to be satisfied: (1) a good vitamin D3 repletion should be secured by plasma 25(OH)D levels of 20-30 ng/ml (if necessary by administration of native vitamin D or 25(OH)D3), and (2) phosphate retention (which is aggravated by the increased phosphate intestinal absorption induced by the 1α(OH)D derivatives) and the consequent possible hyperphosphatemia should be prevented or corrected by the oral administration of alkaline salts of calcium given before the meals as phosphate binders without inducing hypercalcemia. These prerequisites explain the narrow therapeutical margin of lα(OH)D₃ derivatives in uremic patients before dialysis (more so in the adult than in the child) and the possible broadening of this margin in the patients on dialysis by the use of low dialysate calcium concentrations (1.25-1.00 mmol/l) in order to prevent hypercalcemia by inducing a negative perdialytic calcium balance. Once hyperphosphatemia is prevented by oral calcium, 1α(OH)D₃ derivatives have the advantage to suppress the transcription of the prepro PTH gene by a mechanism independent of an increase in plasma calcium. Controlled randomized trials have not confirmed the claimed advantage in efficacy and safety of the parenteral versus the oral route nor of the intermittent versus the daily mode of their administration. The advantages of using the so called ‘nonhy-percalcemic hyperphosphatemic’ vitamin D3 derivatives in combination with oral calcium over 1α(OH)D3 derivatives in the treatment of uremic hyperparathyroidism are still waiting for clinical demonstration. Vitamin D derivatives have no place in the treatment of aluminic bone diseases which necessitate long term deferoxamine treatment and prevention of aluminum exposure by the dialysate and the phosphate binders. They are not indicated in the treatment of’idiopathic’ adynamic bone disease which is due to uremia per se combined with an excessive PTH suppression for the degree of renal failure. This low bone turnover pattern is associated with an increased risk of hypercalcemia and hyperphosphatemia and necessitates only a stimulation of PTH secretion by inducing a negative calcium balance with a lower dialysate calcium concentration or simply by discontinuing the oral calcium supplement in the uremic patient not yet dialyzed. In rare cases this pattern is due to a granulomatosis and is corrected by prednisone.

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“…In the past, another vitamin D analog, 22-oxacalcitriol, has been shown to suppress plasma PTH levels in rats in the early phase of chronic renal failure [16]as well as in uremic dogs [17]. Later on, however, other authors found that the effect of oxacalcitriol on plasma PTH levels in uremic rats might even be smaller than that of the native substance [18]. Other analogs with low calcemic activity have been studied as to PTH suppressing potential: the compound 1α(OH)D 2 has been shown to suppress PTH secretion with hypercalcemia of a relatively low degree in hemodialysis patients with moderate to severe secondary hyperparathyroidism [22].…”

Section: Discussionmentioning

confidence: 99%

1,25-(OH)2-16ene-23yne-D3 Reduces Secondary Hyperparathyroidism in Uremic Rats with Little Calcemic Effect

Lippuner

Perrelet²,

Casez³

et al. 2004

Horm Res Paediatr

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Objectives: To compare the effects of vitamin D analogs versus calcitriol on serum levels of Ca, P and parathyroid hormone (PTH). A compound better than calcitriol should increase the Ca x P product less than calcitriol for an equivalent decrease in PTH levels. Methods: Biological activity of 4 vitamin D analogs, 1,25-(OH)₂-16ene- D₃ (RO₁), 1,25-(OH)₂-16ene-23yne-D₃ (RO₂), 1,25-(OH)₂-26,27-hexafluoro-16ene-23yne-D₃ (RO₃) and 1,25-(OH)₂-16ene-23yne-26,27-hexafluoro-19nor-D₃ (RO₄) was tested vs. calcitriol in parathyroidectomized rats. In a second set of experiments, the effects of RO₂, RO₄ and calcitriol were studied in 5/6 nephrectomized rats with secondary hyperparathyroidism. Results: In parathyroidectomized rats, all analogs (250 pmol/day) led calcemia to rise after 7 days. In uremic rats, all treatments reduced PTH levels. RO₄ revealed toxicity. RO₂ was as effective as calcitriol in suppressing PTH in a dose dependent manner. Mean plasma ionized calcium did not change from baseline to day 14 and day 28 on RO₂ (250 or 500 pmol/day) whereas it increased significantly on RO₂ (1,000 pmol/day) and calcitriol (125 or 250 pmol/day). Increasing the dose of calcitriol led Ca × P to rise more dramatically than increasing the dose of RO₂, which appears to have a wider therapeutic window than calcitriol. Conclusion: 1,25-(OH)₂-16ene-23yne-D₃ (RO₂) may represent a novel candidate for the treatment of renal osteodystrophy in humans.

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Effect of 22-oxa-calcitriol on calcium metabolism in rats with severe secondary hyperparathyroidism

Cited by 44 publications

References 27 publications

Abnormal Expression and Regulation of Vitamin D Receptor in Experimental Uremia

Abnormal Expression and Regulation of Vitamin D Receptor in Experimental Uremia

1-Alpha-Hydroxyvitamin D<sub>3 </sub>Derivatives in the Treatment of Renal Bone Diseases: Justification and Optimal Modalities of Administration

1,25-(OH)<sub>2</sub>-16ene-23yne-D<sub>3</sub> Reduces Secondary Hyperparathyroidism in Uremic Rats with Little Calcemic Effect

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