Secondary hyperparathyroidism (2HPT), a common disorder in patients with
chronic renal failure, develops in response to
phosphate retention and low serum
1,25-dihydroxyvitamin D(3) [
1,25 (OH) (2)D(3),
calcitriol] . Replacement
therapy with
calcitriol or its precursor 1alpha-hydroxyvitamin D(3) [1alpha (
OH) D(3),
alfacalcidol] often produces
hypercalcemia and
hyperphosphatemia in these patients. Several
vitamin D analogues have been developed that retain the direct suppressive action of
1,25 (OH) (2)D(3) on the parathyroid glands but have less calcemic activity,
therapy offering a safer and more effective means of controlling 2HPT. 1,25-D dihydroxy-19-norvitamin D(2) (19-nor D(2)) and 1alpha-hydroxyvitamin D(2) (1alphaOHD(2)) are available in the United States and 1,25-dihydrox-22-oxavitamin D(3) (22-oxacalcitriol, OCT) and 1,25-dihydroxy-26,26,26,27,27,27-hexafluorovitamin D(3) [1,25 (
OH)(2)26,27F(6)D(3),
falecalcitriol] have been approved for use in Japan. Animal studies have demonstrated that OCT and 19-nor D(2) have a wider therapeutic window for suppression of
parathyroid hormone (PTH) because of their lower calcemic activities 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 calcemic activity of 19-norD(2) diminishes with the
duration of treatment by as yet unknown mechanisms. The lower toxicity of 1alphaOHD(2), compared 1alphaOHD(3). has also been noted with chronic, but not acute administration, perhaps due to differential metabolism. The unique actions of
falecalcitriol may also result from 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.