Vitamin D analogs: Actions and role in the treatment of secondary hyperparathyroidism

Martin, Kévin; González, Esther A.

doi:10.1016/j.semnephrol.2004.06.013

Cited by 44 publications

(27 citation statements)

References 40 publications

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“…[1][2][3][4] The efficacy of 1,25-dihydroxyvitamin D (calcitriol, 1,25D), the hormonal form of vitamin D, to suppress PTH gene expression and parathyroid cell growth has rendered calcitriol or its less calcemic analogs the treatment of choice for secondary hyperparathyroidism (SH) 5 ; however, as kidney disease progresses, parathyroid vitamin D receptor (VDR) levels decrease in parallel with the severity of parathyroid hyperplasia, 6,7 rendering nodular hyperplasia, the most aggressive form of SH, 6 unresponsive to calcitriol (analog) therapy. 7 The lack of appropriate experimental models has impeded earlier characterization of the pathogenesis of the association between the severity of parathyroid hyperplasia and the re-duction of VDR.…”

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confidence: 99%

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Arcidiacono

Sato²,

Alvarez-Hernandez³

et al. 2008

Journal of the American Society of Nephrology

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Calcitriol, acting through vitamin D receptors (VDR) in the parathyroid, suppresses parathyroid hormone synthesis and cell proliferation. In secondary hyperparathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF-␣ is required for the development of parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown. With the use of the same rat model, it was found that pharmacologic inhibition of EGFR activation with erlotinib prevented the upregulation of parathyroid TGF-␣, the progression of growth, and the reduction of VDR. Increased TGF-␣/EGFR activation induced the synthesis of liver-enriched inhibitory protein, a potent mitogen and the dominant negative isoform of the transcription factor CCAAT enhancer binding protein-␤, in human hyperplastic parathyroid glands and in the human epidermoid carcinoma cell line A431, which mimics hyperplastic parathyroid cells. Increases in liver-enriched inhibitory protein directly correlated with proliferating activity and, in A431 cells, reduced VDR expression by antagonizing CCAAT enhancer binding protein-␤ transactivation of the VDR gene. Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF-␣ activation of the EGFR was associated with an 80% reduction in VDR mRNA levels. Thus, in SH, EGFR activation is the cause of both hyperplastic growth and VDR reduction and therefore influences the efficacy of therapy with calcitriol.

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mentioning

confidence: 99%

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Arcidiacono

Sato²,

Alvarez-Hernandez³

et al. 2008

Journal of the American Society of Nephrology

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“…1,25-Dihydroxyvitamin D 3 and its analogs, such as 19-nor-1␣,25(OH) 2 D 2 (paricalcitol) or 1␣-hydroxyvitamin-D 2 , that activate vitamin D receptor (VDR) in vivo are commonly used to manage secondary hyperparathyroidism associated with CKD (Martin and Gonzalez, 2004). Recent retrospective clinical observations show that vitamin D analogs provide a survival benefit for stage 5 CKD patients with an effectiveness order of paricalcitol Ͼ calcitriol Ͼ no vitamin D analog therapy, independent of the PTH and calcium levels (Teng et al, 2003(Teng et al, , 2005Nakai et al, 2004); the survival benefit of vitamin D analogs is associated with a decrease in cardiovascular-related mortality (Shoji et al, 2004).…”

mentioning

confidence: 99%

Role of Phosphorus and Vitamin D Analogs in the Pathogenesis of Vascular Calcification

Wu-Wong¹,

Noonan²,

Ma³

et al. 2006

J Pharmacol Exp Ther

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Vascular calcification is a mortality risk factor for stage 5 chronic kidney disease patients. We investigated the role of phosphorus and vitamin D analogs in the pathogenesis of vascular calcification using in vivo, ex vivo, and in vitro models. Our results demonstrate that uremic rats receiving a hyperphosphatemia-inducing diet did not exhibit aortic calcification despite elevated levels of serum phosphorus and calciumphosphorus (CaxP) product. The vitamin D analog 1␣-hydroxyvitamin-D 2 [1␣(OH)D 2 ] at 0.17 g/kg raised serum calcium, phosphorus, CaxP product, and aortic calcification in the uremic rats, but 19-nor-1␣,25(OH) 2 D 2 (19-nor) at the same dose had no significant effect. At 0.67 g/kg, both 1␣(OH)D 2 and 19-nor had similar effects on serum calcium, phosphorus, and CaxP product, but only 1␣(OH)D 2 induced significant aortic calcification. Only aortic rings from 1␣(OH)D 2 -treated uremic rats exhibited a significant increase in 45 Ca uptake ex vivo. When aortic rings from normal rats or a primary culture of human coronary artery smooth muscle cells were treated with phosphorus or vitamin D analogs in vitro, high phosphorus induced calcium accumulation and/or 45 Ca uptake in a dose-or time-dependent manner, whereas vitamin D analogs including 1␣(OH)D 2 up to 100 nM had no significant effect despite the presence of a functional vitamin D receptor. However, serum from 1␣(OH)D 2 -treated uremic rats induced 45 Ca uptake into smooth muscle cells cultured in high phosphorus. These results suggest that the regulation of vascular calcification in vivo cannot be easily replicated in the ex vivo or in vitro models, and high phosphorus and some vitamin D analogs such as 1␣(OH)D 2 exert interactive effects on modulating vascular calcification.

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“…25 Furthermore, observational studies support that the newer VDRAs (paricalcitol and doxercalciferol) have better outcomes than traditional therapy with calcitriol. 29 This may be due to the tendency of calcitriol to cause hypercalcemia and hyperphosphatemia. Alternatively, VDRAs may act on different biologic targets.…”

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confidence: 99%

Intravenous Alfacalcidol Once Weekly Pulse Therapy for Secondary Hyperparathyroidism in Hemodialysis Patients

et al. 2011

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Background: This study was carried out to assess the efficacy of intravenous administration of alfacalcidol once weekly versus thrice weekly in patients with poorly controlled secondary hyperparathyroidism. Methods: Thirty-six hemodialysis patients with intact parathyroid hormone (i-PTH) > 31.8 pmol/L were divided into two groups. Eighteen patients (Group 1) were given once weekly alfacalcidol for 6 months. The starting dose was 3 μg, which was increased or decreased by 1 μg per week. Eighteen patients (Group 2) were given thrice weekly alfacalcidol for 6 months. The starting dose was 1 μg, which was increased or decreased by 0.5 μg per dose. The dose was increased or decreased according to serum-corrected calcium (CCa), phosphorus (P), and i-PTH. Serum-CCa and P were measured weekly, whereas serum i-PTH and alkaline phosphatase were determined every month. Results: Intact-PTH reduced significantly (p < 0.001) from 86 ± 33.20 pmol/L to 31.04 ± 7.77 pmol/L and from 83.64 ± 32.12 pmol/L to 33.09 ± 11.37 pmol/L post-treatment in Groups 1 and 2, respectively. Fifty-six percent of the patients had i-PTH ≤ 31.8 pmol/L at the last observation. Serum alkaline phosphatase reduced significantly (p < 0.001) from 227.94 ± 129.86 IU/L to 163.17 ± 95.29 IU/L and from 285.39 ± 232.36 IU/L to 202.56 ± 165.84 IU/L post-treatment in Groups 1 and 2, respectively. There were no significant differences in serum levels of CCa, P, or their product. Conclusion: Intravenous alfacalcidol thrice or once weekly is safe and effectively reduced the levels of i-PTH in hemodialysis patients.

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Vitamin D analogs: Actions and role in the treatment of secondary hyperparathyroidism

Cited by 44 publications

References 40 publications

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Role of Phosphorus and Vitamin D Analogs in the Pathogenesis of Vascular Calcification

Intravenous Alfacalcidol Once Weekly Pulse Therapy for Secondary Hyperparathyroidism in Hemodialysis Patients

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