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Drug Insight: vitamin D analogs in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease

Nature Clinical Practice Endocrinology & Metabolism volume 3, pages 134–144 (2007)Cite this article

Abstract

Secondary hyperparathyroidism commonly develops in patients with chronic kidney disease (CKD) in response to high phosphate, low calcium and low 1α,25-dihydroxyvitamin D3 (calcitriol) levels. High levels of parathyroid hormone (PTH) accelerate bone turnover, with efflux of calcium and phosphate that can lead to vascular calcification. Treatment of secondary hyperparathyroidism with calcitriol and calcium-based phosphate binders can produce hypercalcemia and oversuppression of PTH, which results in adynamic bone that cannot buffer calcium and phosphate levels, and increased risk of vascular calcification. PTH levels must, therefore, be reduced to within a range that supports normal bone turnover and minimizes ectopic calcification. Vitamin D analogs that inhibit PTH gene transcription and parathyroid hyperplasia (and have reduced calcemic activity) are a safer treatment for secondary hyperparathyroidism than calcitriol; these agents enhance the survival of patients with CKD. Several such analogs are now in use, and analogs with even greater selectivity than those currently used are in development. Parathyroid glands express both 25-hydroxylase and 1α-hydroxylase, which suggests that these enzymes might suppress parathyroid function by an autocrine mechanism. The risk of hypercalcemia with vitamin D analog therapy is reduced by the introduction of non-calcium-based phosphate binders and cinacalcet; furthermore, recent trials indicate that early intervention with vitamin D analogs in stage 3 and 4 CKD can correct PTH levels, and could prevent renal bone disease and prolong patient survival.

Key Points

  • Analogs of calcitriol (the natural, hormonally active form of vitamin D) are used to treat secondary hyperparathyroidism in patients with chronic kidney disease (CKD)

  • Early intervention with vitamin D analogs in predialysis patients with CKD can prevent or slow the progression of secondary hyperparathyroidism

  • Vitamin D analog therapy prolongs the survival of patients with CKD

  • The parathyroid glands express enzymes that can metabolize vitamin D precursors to their active forms

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Figure 1: Pathogenesis of secondary hyperparathyroidism.
Figure 2: The structures of calcitriol, its precursor alfacalcidol, and the four vitamin D analogs that are currently in clinical use as treatments for secondary hyperparathyroidism.
Figure 3: The structures of some new vitamin D analogs that are currently in development as treatments for secondary hyperparathyroidism.

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  1. in the Renal Division, AJ Brown is a Research Associate Professor of Medicine, and E Slatopolsky is the Joseph Friedman Professor of Medicine, Washington University School of Medicine, St Louis, MO, USA.,

    Alex J Brown & Eduardo Slatopolsky

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Correspondence to Alex J Brown.

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Dr Alex J Brown has received research grants and honoraria from Chugai Pharmaceuticals, Bone Care International, and Abbott Laboratories. Dr Eduardo Slatopolsky has received research grants and honoraria from Chugai Pharmaceuticals, Genzyme Corporation and Abbott Laboratories.

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Brown, A., Slatopolsky, E. Drug Insight: vitamin D analogs in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Nat Rev Endocrinol 3, 134–144 (2007). https://doi.org/10.1038/ncpendmet0394

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