Dynamics of skeletal resistance to parathyroid hormone in the rat: Effect of renal failure and dietary phosphorus

Secondary hyperparathyroidism develops in renal failure and is generally as cribed to factors directly affecting parathyroid hormone (PTH) production a nd/or secretion, These include hypocalcemia, phosphorus retention, and a ca lcitriol deficiency. However, not often emphasized is that skeletal resista nce to PTH is an important factor. Our study evaluated: (1) the relative ef fects of uremia and dietary phosphorus on the skeletal resistance to PTH; a nd (2) how, during a PTH infusion, the dynamics of skeletal resistance to P TH were affected by renal failure. Renal failure was surgically induced and , based on serum creatinine, rats were divided into normal, moderate renal failure, and advanced renal failure, In each group, three diets with the sa me calcium (0.6%) but different phosphorus contents were used: high (1.2%, HPD); moderate (0.6%, MPD); and low (0.2, LPD) phosphorus. The study diet w as given for 14-16 days followed by a 48 h infusion of rat PTH(1-34) (0.11 mu g/100 g per hour), a dose five times greater than the normal replacement dose. During the PTH infusion, rats received a calcium-free, low phosphoru s (0.2%) diet. In both moderate and advanced renal failure, the PTH level w as greatest in the HPD group (p < 0.05) and, despite normal serum calcium v alues, PTH was greater in the MPD than the LPD group (p < 0.05), Despite ph osphorus restriction and normal serum calcium and calcitriol levels in the azotemic LPD groups, the PTH level was greater (p < 0.05) in the LPD group with advanced rather than moderate renal failure. During PTH infusion, the increase in serum calcium was progressively less (p < 0.05) in all groups a s renal function declined, Furthermore, despite normal and similar serum ph osphorus values at the end of PTH infusion, the serum calcium concentration was less (p < 0.05) in the HPD group than the other two groups and similar in the LPD and MPD groups. In conclusion: (1) uremia and phosphorus each h ad separate and major effects on skeletal resistance to PTH; (2) skeletal r esistance to PTH was an important cause of secondary hyperparathyroidism, e ven in moderate renal failure; (3) during PTH infusion, the dynamics of ske letal resistance to PTH changed because all groups received a low phosphoru s diet, and the adaptation to a new steady state was delayed by the degree of renal failure and the previous dietary phosphorus burden; and (4) normal serum phosphorus may not be indicative of body phosphorus stores during st ates of disequilibrium. (C) 1999 by Elsevier Science Inc. All rights reserv ed.