Vitamin D and the syndromes of azotaemic osteodystrophy.

Intestinal malabsorption of calcium and the development of osteomalacia in conservatively treated renal failure is explained by a quantitative deficiency of 1,25-dihydroxycholecalciferol, which also contributes to the development of hypocalcaemia. Excess of 25-hydroxycholecalciferol can substitute for this deficiency. The presence and healing of azotaemic osteomalacia is unrelated to the prevailing plasma [Ca] x [P] product. The data suggest that "vitamin D" acts directly on bone mineralisation, but the claim that this apparent effect is normally due to 25-hydroxycholecalciferol is considered unproven. Most of the phenomena of azotaemic osteodystrophy are encountered in simple vitamin D deficiency; as in that condition, deficiency of 1,25-dihydroxycholecalciferol may be of primary significance in causing secondary hyperparathyroidism in renal failure.

Vitamin D and hyperparathyroidism: the Lumleian Lecture 1981.

Vitamin D appears to influence parathyroid function indirectly through its effects on calcium metabolism rather than by a direct action of its metabolites on the parathyroid glands. In states of both secondary and primary hyperparathyroidism, the quantitative production of 1,25-(OH)2D may be determined by the prevailing concentration of serum 25-(OH)D but there appears to be some constraint that limits the formation of 1,25-0(OH)2D when the provision of its precursor exceeds the physiological. From the absence of this constraint in 'type 2 vitamin D dependency' it is inferred that it may operate through 'self-inhibition' of the renal production of 1,25-(OH)2D. It is shown that the level of serum 25-(OH)D may always exert some influence on the production of 1,25-(OH)2D and that this effect is facilitated by hyperparathyroidism. In developing vitamin D deficiency the reactive secondary hyperparathyroidism may thus function as an adaptive mechanism that sustains the level of serum 1,25-(OH)2D in the face of a diminishing serum 25-(OH)D. Failure of this adaptation and the development of a critical deficiency of 1,25-(OH)2D is regarded as the direct cause of defective mineralisation of bone. This concept would explain the absence of osteomalacia in some patients with very low levels of serum 25-(OH)D and the occurrence of defective osseous mineralisation in hypoparathyroidism.

Vitamin d and the kidney.

The biologically active form of vitamin D3, 1,25-dihydroxycholecalciferol is produced by the kidney. The biosynthesis of 1,25-dihydroxycholecalciferol from 25-hydroxycholecalciferol is apparently controlled and important factors in this control are dietary calcium and phosphorus, and parathyroid hormone secretion. The direct effects of vitamin D and its metabolites on renal function are uncertain. Patients with chronic renal failure have defective synthesis of 1,25-dihydroxycholecalciferol. Uremic patients treated with small doses of 1,25-dihydroxycholecalciferol or 1 alpha-hydroxycholecalciferol show increased intestinal calcium absorption and bone healing.

The metabolism of a physiological dose of radioactive cholecalciferol (vitamin D3) to its hydroxylated metabolites in man.

1. The metabolism of an intravenous pulse-dose of 65 nmol (25 microgram) of double-isotope-labelled cholecalciferol has been studied in 28 individuals. The subjects comprised 19 with serum concentrations of 25-hydroxycalciferol (25-(OH)D) less than or equal to 25 nmol/l, of whom 12 had clinical osteomalacia, and nine with serum 25-(OH)D > 25 nmol/l (30-125 nmol/l). 2. The concentrations in serum of radioactive cholecalciferol, 25-hydroxycholecalciferol (25-(OH)D3) and the three dihydroxylated metabolites: 1,25-, 24,25- and 25,26-dihydroxycholecalciferol (1,25-(OH)2D3, 24,25-(OH)2D3 and 25,26-(OH)2D3) were measured for up to 10 days after the injection. 3. The temporal relationships between the formation of individual radioactive metabolites and factors apparently influencing their production are described and their molar concentrations in serum calculated. 4. Formation of radioactive 1,25-(OH)2D3 was detectable only in vitamin D-deficient subjects. Between individuals, its maximum serum concentration was correlated significantly and inversely with serum calcium but with not other measured variable. In the individual, concentrations of radioactive serum 1,25-(OH)2D3 varied directly with radioactive serum 25-(OH)D3. 5. The failure to detect formation of radioactive 1,25-(OH)2D3 in vitamin D-replete subjects suggests that current estimates of the daily turnover of the hormone in the normal individual may be severalfold too high. 6. Radioactive 25,26-(OH)2D3 was produced rapidly by all subjects and in greater amounts by vitamin D-deficient individuals. Between subjects and in the individual its concentration in serum correlated only with the radioactive serum 25-(OH)D3. Production of this metabolite appeared to be unregulated and dependent solely on the concentration of its precursor. 7. In vitamin D-replete subjects, production of 24,25-(OH)2D3 was also apparently determined by precursor concentration. In vitamin D-depleted subjects, production of radioactive 24,25-(OH)2D3 was variably delayed for up to or more than 10 days. 8. There appeared to be a constraint on the quantitative hepatic production of 25-(OH)D which is not explained by simple feed-back inhibition. 9. If sterols other than 1,25-(OH)2D3 are required to initiate the mineralization of osteomalacic bone, after correction of vitamin D deficiency in man, 25-(OH)D3 and 25,26-(OH)2D3 are produced sufficiently rapidly to meet this hypothetical requirement, but not 24,25-(OH)2D3.

1,25-dihydroxycholecalciferol in hypoparathyroidism.

8 patients with hypoparathyroidism have been treated successfully with 1,25-dihydroxycholecalciferol (0-25-1-0 mug/day) for 4-24 mo. Normal serum-calcium levels were restored in all patients, but half the patients required supplementary oral calcium. Treatment reduced serum-phosphorus in all patients, but values remained high in 3, and the renal-tubular reabsorption of phosphate returned to normal in only 2 of the 8 patients. A comparison is made with the effects of oral therapy with massive amounts of calcium salts. The data obtained are discussed in relation to the probable mode of therapeutic action of 1,25-dihydroxycholecalciferol.

Vitamin D metabolism and parathyroid function in man.

1. The metabolism of an intravenous pulse dose of double-isotope-labelled cholecalciferol has been studied in control subjects with widely differing states of vitamin D nutrition and in patients with primary disorders of parathyroid function. 2. The formation of labelled 1,25-dihydroxy-cholecalciferol [1,25-(OH)2D3] and labelled 24,25-dihydroxycholecalciferol [24,25-(OH)2D3] has been related to the prevailing concentrations in serum of 25-hydroxycholecalciferol [25-(OH)D3], immunoreactive parathyroid hormonel, calcium and orthophosphate (Pi). 3. In control subjects with relative vitamin D deficiency [serum 25-(OH)2D3 was related inversely to the serum 25-(OH)D3 and serum calcium, and directly to serum immunoreactive parathyroid hormone. No formation of 1,25-(OH)2D3 was detectable to form labelled 24,25(OH)2D3 preferentially. 4. No control subject produced significant amounts of both labelled 1,25-(OH)2D3 and labelled 24,25-(OH)2D3 simultaneously. 5. All subjects with primary hyperparathyroidism produced significant amounts of labelled 1,25-(OH)2D3 and labelled 24,25-(OH)2D3 simultaneously; the renal turnover of 25-(OH)D3 was apparently greater than in nutritionally matched controls. Serum labelled 1,25-(OH)2D3 in this disease was not correlated with serum 25-(OH)D3, immunoreactive parathyroid hormone, calcium or Pi. Production of labelled 24,25-(OH)2D3 was inappropriately high for the prevailing nutritional state. 6. The indirectly estimated their concentration of 1,25-(OH)2D3 showed only a fourfold variation in control subjects (45-180 pmol/l), compatible with its having a regulated hormonal function. 7. The data suggest that the production of 1,25-(OH)2D3 from a pulse dose of cholecalciferol is normally regulated, directly or indirectly, by the parathyroid hormone.