24,25-Dihydroxy Vitamin D3 treatment inhibits parathyroid-stimulated adenylate cyclase in iliac crest biopsies from uremic patients

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 D3 (24,25(OH)2D3) may result in decreased bone resorption. The present study addresses basic mechanisms for the action of 24,25(OH)2D3 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 μmoll) and elevated serum midregion PTH > 1.2 μgl were randomly assigned to oral treatment with either 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) (0.25–0.50 μg/day), 24,25(OH)2D3 (daily dose of 15 μg), or a combination of the two vitamin D3 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)2D3 and 24,25(OH)2D3, 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)2D3 given alone or in combination with 1,25(OH)2D3. An inverse relationship (r = −0.57, P < 0.05, n = 48) between net PTH-AC in bone and serum levels of 24,25(OH)2D3 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 D3 analogs or by the combination regimen. These studies indicate that 24,25(OH)2D3 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.