Daily intermittent decreases in serum levels of parathyroid hormone have an anabolic-like action on the bones of uremic rats with low-turnover bone and osteomalacia

The calcium receptor agonist (calcimimetic) compound NPS R-568 causes rapid decreases in circulating levels of parathyroid hormone (PTH) in rats and h umans. We hypothesized that daily intermittent decreases in serum PTH level s may have different effects on bone than do chronically sustained decrease s. To test this hypothesis, we compared two NPS R-568 dosing regimens in ra ts with chronic renal insufficiency induced by two intravenous injections o f adriamycin. Fourteen weeks after the second adriamycin injection, creatin ine clearance was reduced by 52%, PTH levels were elevated similar to 2.5-f old, and serum 25(OH)D-3 and 1,25(OH)(2)D-3 levels were reduced substantial ly. Treatment by daily per os gavage, which decreased PTH levels intermitte ntly, or continuous subcutaneous infusion, which resulted in a sustained su ppression of serum PTH levels, then began for 8 weeks. Despite the hyperpar athyroidism, the adriamycin-injected rats developed a low-turnover bone les ion with osteomalacia (fourfold increase in osteoid volume in the proximal tibial metaphysis) and osteopenia (67% decrease in cancellous bone volume a nd an 18% reduction in bone mineral density at the distal femur). Daily adm inistered (but not infused) NPS R-568 significantly increased cancellous bo ne volume solely by normalizing trabecular thickness, and increased femoral bone mineral density by 14%. These results indicate that daily intermitten t, but not sustained, decreases in PTH levels have an "anabolic-like" effec t on bones with a low-turnover lesion in this animal model of chronic renal insufficiency. (C) 2000 by Elsevier Science Inc. All rights reserved.