Effects of Thyroparathyroidectomy, Exogenous Calcium, and Short-Term Calcitriol Therapy on the Growth Plate in Renal Failure

Abstract

Abstract. Several factors have been implicated in the development of adynamic bone, including the use of calcium-containing phosphate binding agents, aggressive calcitriol therapy, and parathyroidectomy. To evaluate the effects of these interventions on the growth plate, weanling rats underwent sham nephrectomy (Control, n ϭ 10) and 5/6 nephrectomy (Nx). In the nephrectomized group, animals underwent (a) thyroparathyroidectomy (Nx-TPTX, n ϭ 7), (b) received exogenous calcium (Nx-Calcium, n ϭ 10), (c) received short-term calcitriol therapy (Nx-D, n ϭ 10), or (d) nephrectomized control (NxControl, n ϭ 10). Higher serum calcium and lower PTH levels were demonstrated in Nx-Calcium and Nx-D animals. A decline in growth was demonstrated in Nx-Calcium and Nx-TPTX accompanied by shorter tibial lengths. The width of the growth plate was wider in Nx-Calcium animals due to an increase in the width of the hypertrophic zone and a decrease in the proliferative zone; these changes were accompanied by an impairment of chondroclastic resorption, lower gelatinase B/MMP-9 activity, decline in insulin-like growth factor-I (IGF-I) receptor, and lower histone-4 mRNA expression. Such findings in the growth plate, may partially contribute to the diminution of growth in these animals. Although growth was impaired in the Nx-TPTX animals, there were no significant changes demonstrated in the growth plate cartilage. Histone-4 transcripts, IGF-I receptor expression, and histochemical staining for chondroclasts were decreased in Nx-D animals. Thus, treatments used in the management of secondary hyperparathyroidism in renal failure have diverse effects on the growth plate of the young skeleton, and concurrent use of these interventions needs further evaluation. cpsanchez@facstaff.wisc.eduThe prevalence of adynamic bone disease has increased in both adult and pediatric patients with chronic renal failure. The use of large doses of exogenous calcium as phosphate binding agents, aggressive calcitriol therapy, presence of diabetes, and parathyroidectomy may contribute to the development of adynamic bone in these patients (1,2).Adynamic bone is characterized by low to normal serum intact parathyroid hormone levels (PTH), low alkaline phosphatase, and episodes of hypercalcemia (3,4). In the skeleton, there is diminished bone formation rate, a decrease in osteoblast and osteoclast number, and a decline in osteoid formation (4 -6). Linear growth has been reported to decline in prepubertal children who developed adynamic bone during treatment of secondary hyperparathyroidism with high intermittent doses of calcitriol (7). Reductions in tibial length have been demonstrated in nephrectomized rats given exogenous calcium accompanied by reductions in growth (8). Iwasaki et al. (9) have reported that parameters of bone formation were decreased in nephrectomized rats that underwent thyroparathyroidectomy and were given high-calcium diet. In addition, diminution of body weight and inhibition of skeletal growth were reported in young rats with normal renal ...

Bone elongation in rats with renal failure and mild or advanced secondary hyperparathyroidism

“…Compared to our previous experiments, there was a significant increase in mortality rate from 5% to 10% in our earlier studies [2,12] to approximately 25% in the current set of experiments. The rats used in this study were much younger with body weights between 50 to 60 g compared to 60 to 80 g in our previous studies.…”

Growth plate height of uremic rats is influenced by severity and duration of renal failure

“…However, an increased growth plate cartilage height has not been consistently found in uremic rats. Uremic growth plate size greater than [1,6,9,11,12,14], similar to [2,4,5,8,10,11,13,14] or even smaller than [7,8] that of control animals has been reported. The reasons for this disparity are unknown.…”

“…Several studies have analyzed the tibial growth plate of young uremic rats in an attempt to clarify the mechanisms underlying growth impairment in chronic renal failure [1,2,3,4,5,6,7,8,9,10,11,12,13,14]. There is interest in studying the growth plate in this animal model because this is where longitudinal growth takes place and it cannot be studied in children.…”

Alterations of the growth plate in chronic renal failure

“…The height of growth cartilage has been found to be greater [1,6,9,11,12,14,15], equal [2,4,5,8,10,11,13,14,16], or smaller [7,8] than that of the control animals. The reasons for this discrepancy are not apparent, although the different animal protocols followed in these studies might, to a certain extent, explain the differences observed in the growth cartilage height.…”

“…The uremic rat model has been used extensively to investigate growth impairment in chronic renal failure. However, a relatively small number of reports have focused on analysis of the modifications induced by uremia in the rat GP [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]. The growing importance of autocrine and paracrine mechanisms in the hormonal control of growth adds further interest to the study of the GP in situations of growth impairment.…”