Long-term control of plasma calcitriol concentration in dogs and humans. Dominant role of plasma calcium concentration in experimental hyperparathyroidism.

Abstract

Despite great interest in the elevated circulating levels of calcitriol (1,25[O-12D) associated with the clinical syndrome of human primary hyperparathyroidism, the relative potencies of known and potential stimuli/suppressors of long-term calcitriol levels have not been evaluated in either clinical or experimentally induced hyperparathyroid states. Based on reports that aparathyroid animals exhibit suppressed plasma calcitriol concentration and that acute administration of parathyroid hormone (PTH) to both humans and experimental animals or to renal slices in vitro results in increased plasma calcitriol concentration/production rate, it might be predicted that a chronic experimental model of either hypercalcemic primary hyperparathyroidism or hypocalcemic secondary hyperparathyroidism would show increased plasma calcitriol concentration. Chronic alterations in plasma calcium concentration have not been implicated as modulating calcitriol levels in any species. Accordingly, we investigated the long-term response of plasma calcitriol concentration in states of sustained experimental primary and secondary hyperparathyroidism. Intact dogs (group I) undergoing continuous intravenous PTH infusion for 12 d developed sustained hypercalcemia and hypophosphatemia, and plasma calcitriol concentration decreased from 23±3 to 14±3 pg/ml (P < 0.01). Subsequent chelator (EGTA)-induced chronic normalization of hypercalcemia during ongoing PTH infusion resulted in a large and sustained increase in plasma calcitriol concentration to supernormal levels, reversible during subsequent cessation of chelator infusion. In additional intact dogs (group II), chronic chelator-induced hypocalcemic secondary hyperparathyroidism resulted in a sustained increase in plasma calcitriol concentration despite hyperphosphatemia. In normal human subjects undergoing a 12-13-d continuous intravenous PTH infusion to result in sustained moderate hypercalcemia (12.0±0.2 mg/100 ml) and hypophosphatemia, plasma calcitriol concentration decreased significantly (P < 0.01) as in group I dogs and was followed by reversal to normal levels in a recovery period. The present results provide strong evidence in both humans and dogs that during experimentally induced chronic PTH

Chronic metabolic acidosis increases the serum concentration of 1,25-dihydroxyvitamin D in humans by stimulating its production rate. Critical role of acidosis-induced renal hypophosphatemia.

“…However, in each of the protocols in rats, chronic metabolic acidosis was associated with increased plasma ionized calcium concentration (17)(18)(19) PR and serum concentration of 1,25-(OH)2D (23,45,46). Only when hypophosphatemia/cellular phosphate depletion is severe has acidosis-induced hypercalcemia failed to suppress a hypophosphatemia-induced increase in serum 1,25-(OH)2D concentration (40).…”

“…These inconsistencies may have been due in part to the experimental difficulties in controlling acidosisinduced alterations in the plasma concentrations of known modulators of 1,25-(OH)2D production: phosphate (20)(21)(22), calcium (23), and parathyroid hormone (23,24). Moreover …”

Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

“…In some instances, factors such as TGFa, IL-1, IL-6 and TNF enhanced the hypercalcaemic effects of PTHrP. The ability of IL-6 to enhance PTHrP-mediated hypercalcaemia appeared to be due to increased production of the early osteoclast precursors by IL-6 (as measured by granulocyte macrophage colony-forming units), in combination with increased production of the more committed osteoclast precursors by PTHrP (Hulter et al 1985).…”

Increased calcium intake does not suppress circulating 1,25-dihydroxyvitamin D in normocalcemic patients with sarcoidosis.

“…1,25 (OH)2D binds to its receptors in intestinal mucosa to enhance the transport of calcium (3). Renal production of the metabolite is closely regulated by PTH (4, 5), calcium (6), and phosphate (7,8) ( 19,20) and 1,25 (OH)2D (20) and two consecutive 24-h urine samples were obtained for measurement of calcium ( 17) and inorganic phosphate ( 18). Urinary creatinine (21 ) was determined to ensure that urine collections were complete.…”