24,25-Dihydroxy Vitamin D 3 treatment inhibits parathyroid-stimulated adenylate cyclase in iliac crest biopsies from uremic patients

Abstract

Renal osteodystrophy with increased bone resorption is a major clinical problem in patients with chronic renal failure. Previous reports have shown that treatment with 24,25-dihydroxy vitamin D 3 (24,25(OH) 2D 3) may result in decreased bone resorption. The present study addresses basic mechanisms for the action of 24,25(OH) 2D 3 in bone of patients with elevated serum parathyroid hormone (PTH) levels due to chronic renal disease. Twenty-four patients 56 ± 17 years old (mean ± SE) with chronic kidney disease in the predialytic state ( serum creatinine > 150 μmol l ) and elevated serum midregion PTH > 1.2 μg l were randomly assigned to oral treatment with either 1,25-dihydroxy vitamin D 3 (1,25(OH) 2D 3) (0.25–0.50 μg/day), 24,25(OH) 2D 3 (daily dose of 15 μg), or a combination of the two vitamin D 3 analogs. The control group received calcium carbonate (maximal dosage of 1 g × 3). Selected variables in serum and urine as well as hormone sensitive adenylate cyclase (AC) in iliac crest biopsies were assessed before treatment and during follow-up after two and six months. Serum levels of 1,25(OH) 2D 3 and 24,25(OH) 2D 3, were significantly ( P < 0.05) increased after two and six months in the respective treatment groups. Net bone PTH-enhanced AC (PTH-AC) fell abruptly ( P < 0.01) after two months of treatment and was nearly abolished ( P < 0.01) after six months with 24,25(OH) 2D 3 given alone or in combination with 1,25(OH) 2D 3. An inverse relationship ( r = −0.57, P < 0.05, n = 48) between net PTH-AC in bone and serum levels of 24,25(OH) 2D 3 was demonstrated. In all groups, serum total calcium (s-Ca) was maintained within normal range. Immunoreactive PTH was insignificantly altered by either of the vitamin D 3 analogs or by the combination regimen. These studies indicate that 24,25(OH) 2D 3 administered orally in pharmacological doses may represent an effective way to inhibit PTH-induced osseous cAMP production in uremic patients without causing significant side effects.