Vitamin D analogues for secondary hyperparathyroidism

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Abstract
Secondary hyperparathyroidism (2HPT), a common disorder in patients with chronic renal failure, develops in response to phosphate retention and low serum 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol). Replacement therapy with calcitriol or its precursor 1α-hydroxyvitamin D3 (1αOHD3, alfacalcidol) often produces hypercalcaemia, especially when combined with calcium-based phosphate binders. In addition, these vitamin D compounds can aggravate the hyperphosphataemia in these patients. Several vitamin D analogues have been developed that retain the direct suppressive action of 1,25(OH)2D3 on the parathyroid glands but have less calcaemic activity, thereby offering a safer and more effective means of controlling 2HPT. 1,25-Dihydroxy-19-norvitamin D2 (19-norD2) and 1α-hydroxyvitamin D2 (1αOHD2) are available in the US and 1,25-dihydroxy-22-oxavitamin D3 (22-oxacalcitriol, OCT) and 1,25-dihydroxy-26,26,26,27,27,27-hexafluorovitamin D3 (1,25(OH)226,27F6 D3, falecalcitriol) have been approved for use in Japan. Animal studies have demonstrated that OCT and 19-norD2 have a wider therapeutic window for suppression of parathyroid hormone (PTH) because of their lower calcaemic and phosphataemic activities. The low calcaemic activity of OCT has been attributed to its rapid clearance, which prevents sustained effects on intestinal calcium absorption and bone resorption, but still allows a prolonged suppression of PTH gene expression and parathyroid cell growth. The calcaemic activity of 19-norD2 diminishes with the duration of treatment by as yet unknown mechanisms. The lower toxicity of 1αOHD2, compared with 1αOHD3, has also been noted with chronic, but not acute administration, perhaps due to differential metabolism. The unique actions of falecalcitriol may also result from an altered metabolism. A clear understanding of the molecular basis for the selectivity of vitamin D analogues on parathyroid function may allow the design of even more effective analogues.

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