1α-hydroxycholecalciferol and 25-hydroxycholecalciferol in Renal Bone Disease

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Abstract
The better control of calcium-phosphate homeostasis in uremic and chronically hemodialysed patients by the use only of phosphate binders, oral calcium supplement, high dialysate calcium, and/or more frequent dialysis, has considerably improved the course of renal osteodystrophy. Thus, progressive decrease in serum parathyroid hormone and prevention or reversal of radiographic evidence of sub-periosteal bone resorption have been reported (14). However, bone biopsies still remained quite abnormal with increased resorption and decreased calcification front (although this latter may occasionally be seen normal even in anephric patients) (14, 2, 4, 5). It may, therefore, be anticipated that the above mentioned therapeutic measures will not completely prevent fragility of the skeleton on a long-term basis, stressing the importance of additional therapeutic approaches in these patients who have now a longer life expectancy. Though it was found that large doses of vitamin D could produce marked improvement of renal osteodystrophy, the dangers of vitamin D toxicity are considerable (17). Therefore, the discovery that the kidneys were the unique site of lα-hydroxylation of 25-OH-cholecalciferol and that 1,25-(OH)2-cholecalciferol (1,25-(OH)2D3) the most rapid and the most potent vitamin D metabolite to promote calcium transport in the intestine, was undetectable in uremic patients (10) suggested that lack of 1,25-(OH)2D3 was the basic explanation for the vitamin D-resistant state and led to extensive evaluation of this compound in uremic patients. It was found that at a daily dose of 0.5 to 1.5 µg, 1,25-(OH)2 D3 was able to increase calcium absorption, decrease the high plasma levels of iPTH and even to improve the bone lesions as assessed on X-rays and on biopsies (6). However, 1,25-(OH)2 D3 is very expensive to synthetize and seems to have little effect on osteoid mineralisation. Therefore, lα-OH-D3 which is much less expensive to synthetize and which is approximately one half as active as 1,25-(OH)2 D3 in the cure of rachitic lesions in the rat, seems to be the drug of choice for extensive clinical trial. Short-term trials (6–15 days) on limited series (3 and 6 patients) have already shown that 10 µg i.v. (8) or 25 µg orally (15) can increase calcium absorption as well as plasma levels of calcium of uremic patients and decrease their elevated serum alkaline phosphatase. A long-term trial (9–10 weeks) in 3 patients at the dose of 2 µg daily has recently shown that not only calcium absorption increased but also that the calcium content of the bone as measured by a neutron activation technique, was increased (7). However, no data have yet been published on the effects of lα-OH-D3 on parathyroid secretion anthone histology of uremic patients. Therefore, we have studied the effect of lα-OH-D3 given orally in 10 uremic patients not only on calcium absorption and plasma levels of calcium, phosphate and alkaline phosphatase but also on the plasma levels of immunoreactive parathyroid hormone (iPTH) and on bone biopsy abnormalities as assessed by histomorphometry.