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Fifteen acromegalic subjects were found to have elevated plasma levels of both 1,25(OH)2-vitamin D, 65 +/- 23 (SD) pg/ml [normal 33 + 15 pg/ml (SD)] and 24,25(OH)2-vitamin D, 6.8 +/- 1.6 (SD) ng/ml [normal 3.4 + 1.2 ng/ml (SD)]. Treatment with bromocriptine for 6 months reduced the plasma 1,25(OH)2-vitamin D3 level to 40 +/- 13 (SD) pg/ml, p less than 0.01 and the 24,25(OH)2-vitamin D level to 5.4 +/- 1.7 (SD) ng/ml, p less than 0.05.

We studied the effects of vitamin D metabolites in 29 patients established on chronic hemodialysis. The patients were divided into four groups; one was treated with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] 0.5 microgram/day, one with 24R,25-dihydroxyvitamin D3 [24,25-(OH)2D3] 10 micrograms/day, and one with both metabolites. The control group was not given vitamin D. Plasma levels of both metabolites were low before treatment. 1,25-(OH)2D3 levels became normal, and 24,25-(OH)2D3 increased to supranormal levels after administration of the corresponding metabolite. Combined treatment produced still higher plasma levels of 24,25-(OH)2D3, suggesting an interaction between the two metabolites. Patients receiving 1,25-(OH)2D3 alone had a greater increase in plasma calcium than those receiving both metabolites. In control patients, hyperparathyroid bone disease worsened over the 10-month observation period. 1,25-(OH)2D3 improved hyperparathyroid bone disease in most patients, as reflected by a reduction in osteoclast and osteoblast numbers, but had no demonstrable effect on mild osteomalacia. 24,25-(OH)2D3 had no significant effect on plasma biochemistry or bone histology, and the effect of combined treatment on histology was similar to that of 1,25-(OH)2D3 alone. Stainable bone aluminum increased slightly in patients given 1,25-(OH)2D3, but aluminum did not affect the response to treatment. We conclude that 1,25-(OH)2D3 is a useful agent in the treatment of renal bone disease, but no therapeutic role is apparent for 24,25-(OH)2D3.

A previous report [Science 201, 835-837 (1978)] presented evidence that the combined and simultaneous administration of the cholecalciferol (D3) metabolites 1 alpha,25-dihydroxycholecalciferol [1 alpha,25(OH)2D3] and 24R,25-dihydroxycholecalciferol [24R,25(OH)2D3] to White Leghorn hens was necessary for embryo development and normal egg hatchability; in the absence of 24R,25(OH)2D3 none of the fertile eggs hatched. The present study extends this fundamental observation to a second species, the Japanese quail, Coturnix coturnix japonica and compares the biological actions of the two stereoisomers of the 24,25(OH)2 metabolite, namely the naturally occurring 24R,25(OH)2D3 and its unnatural epimer 24S,25(OH)2D3. Groups of 12-14 vitamin D-depleted adult female Japanese quail were mated with normal male quail and eight consecutive batches of eggs (25-41 eggs from each group) were placed in an egg incubator, and egg hatchability for the fertile eggs monitored on days 21 and 22. The egg hatchability (in percent +/- SD) for each group was: D3 (56.5% +/- 12.8); 1 alpha,25(OH)2D3 (1.3% +/- 2.5); 24R,25(OH)2D3 (29.6% +/- 3.1); 24R25(OH)2D3 + 1 alpha,25-(OH)2D3 (32.8%); and 24S,25(OH)2D3 + 1 alpha,25(OH)2D3 (7.2%). Also for all treatment groups the blood level of the expected vitamin D metabolites were in the normal range, and there were no significant differences in the embryo weights and eggshell thickness (of both hatched and unhatched eggs). These results indicate that the Japanese quail have the inherent capability to discriminate between the stereoisomers of 24,25(OH)2D3 and therefore strongly support the concept that only the naturally occurring 24R,25(OH)2D3 has an identifiable, unique biological role which is different from that of 1 alpha,25(OH)2D3.

Only moderately reduced serum 1,25-dihydroxyvitamin D [1,25(OH)2D3] levels were found in 13 hypoparathyroid patients and in 1 pseudohypoparathyroid patient, indicating that factors other than parathyroid hormone are able to mediate the basal production of 1,25(OH)2D3. A significant correlation was found between the levels of circulating 25-hydroxyvitamin D (25OHD) and 1,25(OH)2D, suggesting that a high concentration of 25OHD was able to increase the renal production of 1,25(OH)2D, whereas hypocalcemia and changes in serum phosphate became less important in the present situation. The serum 25OHD and 1,25(OH)2D concentrations were followed during the change of treatment from ergocalciferol to 1 alpha-hydroxycholecalciferol (1 alpha-OHD3). A biological half-life of 3 weeks could be estimated for the plasma 25OHD. The increase in serum 1,25(OH)2D correlated with the dose of 1 alpha-OHD3 given, whereas no correlation was found between the serum calcium level and the 1,25(OH)2D concentration. Unexpected increases and decreases in serum calcium were observed at the same dose of 1 alpha-OHD3 in the same patient and at serum 1,25(OH)2D concentrations within the physiological range.

The serum levels of 1.25-dihydroxycholecalciferol [1,25(OH)2D3] were increased in five patients with primary hyperparathyroidism [60 +/- 13 (SD) pg/ml; normal value, 33 +/- 15 (SD) pg/ml] but fell rapidly after parathyroidectomy to values of 23 +/- 9 (SD) pg/ml. This was accompanied by parallel decreases in the serum concentrations of calcium and immunoreactive parathyroid hormone. Over the following 5--35 days, the serum 1,25(OH)2D3 concentrations increased markedly to levels of 59 +/- 17 (SD) pg/ml, which could most likely be explained by a stimulatory effect of the hypocalcemia per se on the renal production of 1,25(OH)2D3.

Kidney homogenates of rats produced a new metabolite of 25-hydroxyvitamin D3 which has been isolated in pure form after five column chromatographic steps. It was identified as 23,25-dihydroxy-24-oxovitamin D3 by means of ultraviolet and infrared absorption spectrophotometry, mass spectrometry, and proton nuclear magnetic resonance spectrometry. The stereochemistry at the C-23 position is as yet unknown. 25-Hydroxy-24-oxovitamin D3, which also has been isolated in pure form from this system, was found to be the precursor of the new metabolite in vitro. The production of the new metabolite was induced by two different methods: (a) perfusion of the kidneys with 1,25-dihydroxyvitamin D3 contained in the perfusate and (b) injection of 1,25-dihydroxyvitamin D3 in the intact animal. 23,25-Dihydroxy-24-oxovitamin D3 was not biologically active in an assay for intestinal calcium transport and bone calcium mobilization in the vitamin D deficient chick at a dose level of 5.3 nmol. A metabolic pathway is proposed to describe the results; it leads from 25-hydroxyvitamin D3 leads to 24(R),25-dihydroxyvitamin D3 leads to 25-hydroxy-24-oxovitamin D3 leads to 23,25-dihydroxy-24-oxovitamin D3.