Intermittent Calcitriol Therapy Research Articles

Diagnosis, assessment, and treatment of bone turnover abnormalities in renal osteodystrophy

HE ABNORMALITIES of the skeleton in chronic kidney disease (CKD), collectively known as renal osteodystrophy, are an important cause of morbidity and decreased quality of life. In the management of patients with kidney disease, it is necessary to have a rational approach to the diagnosis and assessment of renal osteodystrophy in order to devise a treatment plan that hopefully will lead to an improved outcome. In the past, the term renal osteodystrophy was mainly equated only with abnormalities of bone turnover, but as described in the article by Cunningham and Sprague 1 in this same issue, renal osteodystrophy is a complex disorder of compromised bone strength in CKD patients. While osteoporosis is a term used to describe fragile bones prone to fracture in the general population and is most often assessed by dual x-ray absorptiometry (DEXA), renal osteodystrophy should be the principal term to describe fragile bones prone to fracture and other morbidities in CKD. Renal osteodystrophy is a function of bone turnover (assessed by bone biopsy), bone density (assessed by DEXA or quantitative CT [qCT]), and bone architecture, but the principal determinant of bone fragility in CKD is abnormal bone turnover. However, diagnosing and treating bone turnover abnormalities remains challenging. Our discussion group met to assess the current state of knowledge, understand the basis of our current therapy, and identify the information that needs to be gathered to improve the therapy of bone turnover and thereby improve the disorder of renal osteodystrophy. A number of important questions, listed in Table 1, were considered.

Implications of intermittent calcitriol therapy on growth and secondary hyperparathyroidism.

Secondary hyperparathyroidism is the most common skeletal lesion in pediatric patients undergoing maintenance dialysis. The present review summarizes a prospective randomized study that evaluated the biochemical and skeletal responses to intermittent calcitriol therapy in 33 pediatric patients on peritoneal dialysis with secondary hyperparathyroidism. Also, the effect of intermittent calcitriol therapy on linear growth was evaluated in 16 of 33 patients who had completed the clinical trial. Serum parathyroid hormone levels decreased by 62% from 648+/-125 pg/ml in patients treated with intermittent intraperitoneal (IP) calcitriol, and values remained unchanged from pre-treatment levels of 670+/-97 pg/ml with oral calcitriol therapy. Overall serum total and ionized calcium levels were higher in patients treated with IP calcitriol during the study. In contrast to these biochemical findings, the skeletal lesions of secondary hyperparathyroidism improved after 12 months of treatment in both groups and adynamic bone occurred in 33% of the patients. Z-scores for height decreased from -1.80 /-0.3 to -2.00+/-0.3, P<0.01, after 12 months of intermittent calcitriol therapy. Such findings suggest that an intermittent schedule of calcitriol administration adversely affects chondrocyte activity within epiphyseal cartilage in pre-pubertal children with end-stage renal disease.

Modulation of endochondral bone formation: roles of growth hormone, 1,25-dihydroxyvitamin D and hyperparathyroidism

Impairment of linear growth occurs invariably in children with chronic renal failure. Recombinant human growth hormone and 1,25-dihydroxyvitamin D (calcitriol) are widely utilized to improve linear growth in children. Large doses of calcitriol, however, have been shown to suppress chondrocyte proliferation and may lead to the development of adynamic bone. Substantial reductions of growth have been shown in children with chronic renal failure treated with intermittent calcitriol therapy. These findings suggest that calcitriol can modify chondrocyte proliferation and/or differentiation in epiphyseal growth plate cartilage and may counteract the effects of growth hormone therapy in increasing linear growth in children with chronic renal failure. Parathyroid hormone related peptide (PTHrP) and its receptor (PTH/PTHrP receptor) play critical roles in regulating chondrocyte differentiation in the growth plate. The expression of PTH/PTHrP receptor mRNA is downregulated in animals with chronic renal failure and advanced secondary hyperparathyroidism; calcitriol and growth hormone therapy may modify the expression of PTH/PTHrP receptor. This article summarizes the separate and combined effects of growth hormone and calcitriol on endochondral bone formation in chronic renal failure and secondary hyperparathyroidism.

Consequences of Intermittent Calcitriol Therapy in Pediatric Patients with Secondary Hyperparathyroidism

T he renal bone diseases represent a spectrum of skeletal disorders ranging from the high-turnover lesions of secondary hyperparathyroidism to the lowturnover lesions of osteomalacia and adynamic bone. Secondary hyperparathyroidism is the most common skeletal lesion in pediatric patients undergoing regular dialysis; in contrast, the adynamic lesion of renal osteodystrophy without aluminum has become pre dominant in adult patients treated with continuous ambulatory peritoneal dialysis (CAPD) (1-3). Peritoneal dialysis, on the other hand, is the most common dialytic modality for children with end-stage renal disease, and persistent bone disease remains a major challenge in the clinical management of these patients. Treatment with daily doses of calcitriol or with 1,25dihydroxyvitamin D has been recommended for pediatric patients with chronic renal failure to improve linear growth and to prevent bone deformities. However, secondary hyperparathyroidism persists in a substantial proportion of patients treated with daily calcitriol therapy and receiving peritoneal dialysis (1,4). More recently, large intermittent doses of calcitriol given two or three times per week have been used to treat secondary hyperparathyroidism in both children and adults (5-7). Most studies have employed the oral or intravenous routes of calcitriol adminis tration, but there is little available information about the effect of intraperitoneal (IP) doses of calcitriol on bone and mineral metabolism in patients undergoing regular peritoneal dialysis. We have recently completed a prospective randomized clinical trial to evaluate the biochemical and his tological responses to intermittent calcitriol therapy using thrice weekly IP or oral (PO) doses in pediat

Intermittent calcitriol therapy in secondary hyperparathyroidism: A comparison between oral and intraperitoneal administration

Intermittent oral or intravenous doses of calcitriol given two or three times per week are commonly used to treat secondary hyperparathyroidism (secondary HPT). This study was undertaken to compare the biochemical and skeletal responses to thrice weekly intraperitoneal (i.p.) versus oral doses of calcitriol in children with secondary HPT undergoing peritoneal dialysis (CCPD). Forty-six patients aged 12.5+/-4.8 years on CCPD for 22+/-25 months were randomly assigned to treatment with oral (p.o.) or i.p. calcitriol for 12 months; 17 subjects given p.o. calcitriol and 16 subjects given i.p. calcitriol completed the study. Bone biopsies were performed at the beginning and at the end of the study, while determinations of serum and total ionized calcium, phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and calcitriol levels were done monthly. Serum total and ionized calcium levels were higher in subjects treated with i.p. calcitriol, P < 0.0001, whereas serum phosphorus levels were higher in those given p.o. calcitriol, P < 0.0001. For the i.p. group, serum PTH levels decreased from pre-treatment values of 648+/-125 pg/ml to a nadir of 169+/-57 pg/ml after nine months. In contrast, serum PTH levels did not change from baseline values of 670+/-97 pg/ml in subjects given p.o. calcitriol, P < 0.0001 by multiple regression analysis. Serum alkaline phosphatase levels were also lower in patients treated with i.p. calcitriol, P < 0.0001, but there was no difference between groups in the average dose of calcitriol given thrice weekly. The skeletal lesions of secondary HPT improved in both groups, 33% of patients developed adynamic bone lesion. Differences in the bioavailability of calcitriol and/or in phosphorus metabolism may account for the divergent biochemical response to p.o. and i.p. calcitriol.

Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD

Daily calcitriol therapy has been reported to improve linear growth in children with renal bone disease, and 1,25-dihydroxyvitamin D is a key regultor of chondrocyte proliferation and differentiation. Whereas large intermittent doses of calcitriol can lower serum parathyroid hormone (PTH) levels and reverse the skeletal changes of secondary hyperparathyroidism, the impact of intermittent calcitriol therapy on linear growth in children is not known. Thus, we studied 16 pre-pubertal patients with bone biopsy-proven secondary hyperparathyroidism who completed a 12-month prospective clinical trial of intermittent calcitriol therapy. Biochemical results and growth data obtained during intermittent calcitriol therapy were compared to values determined during the preceding 12 months of daily calcitriol therapy in each study subject; changes in bone histology were assessed after one year of intermittent calcitriol therapy. Z-scores for height did not change during 12 months of daily calcitriol therapy. Although the skeletal lesions of secondary hyperparathyroidism improved in most patients, Z-scores for height decreased from -1.8 +/- 0.32 to -2.0 +/- 0.33, P < 0.01, during intermittent calcitriol therapy. The largest reductions were seen in patients who developed adynamic bone lesions after 12 months of treatment. Delta Z-scores for height correlated with serum PTH, r = 0.71, P < 0.01, and alkaline phosphatase levels, r = 0.67, P < 0.01, during intermittent calcitriol therapy but not during daily calcitriol therapy. The data suggest that high dose intermittent calcitriol therapy adversely affects linear growth, particularly in patients with the adynamic lesion. The higher doses of calcitriol or the intermittent schedule of calcitriol administration may directly inhibit chondrocyte activity within growth plate cartilage of children with end-stage renal disease.

Parathyroid gland function in secondary hyperparathyroidism.

The parathyroid glands play a critical role in the maintenance of calcium homeostasis. It has been suggested that the set-point for calcium-regulated parathyroid hormone (PTH) release is higher in uremic patients than normal subjects. However, these assessments of parathyroid gland function have been performed using methods that differed from the original four-parameter model. Dynamic testing of the parathyroid glands has been performed with standardized infusions of calcium gluconate and sodium citrate in dialysis patients with secondary hyperparathyroidism and in normal volunteers. In addition, similar studies have been carried out before and after 4 months of intermittent calcitriol therapy. The derived values for the set-point were 1.21 + 0.04 mmol/l and 1.24 + 0.06 mmol/l, respectively in control and dialyzed patients (NS). Furthermore, the values for set-point were 1.21 + 0.01 and 1.22 + 0.01 mmol/l (NS), before and after calcitriol therapy. In addition, when subjects were grouped according to the severity of secondary hyperparathyroidism, the set-point calcium-regulated PTH release did not differ between the groups. Calcitriol therapy alters the secretory capacity of the parathyroid glands during hypocalcemia. The degree of parathyroid enlargement and the type of cell proliferation may be more important determinants of the severity of secondary hyperparathyroidism.

Calcitriol therapy and calcium-regulated PTH secretion in patients with secondary hyperparathyroidism

Calcitriol lowers serum parathyroid hormone (PTH) levels in patients with secondary hyperparathyroidism, but its effect on calcium-regulated PTH release remains controversial. Thus 11 patients with secondary hyperparathyroidism underwent dynamic tests of parathyroid function before and after 4 mo of intermittent calcitriol therapy. Serum calcitriol levels rose from 8 +/- 1 to 55 +/- 9 (SE) pg/ml, P < 0.01, serum total and ionized calcium levels increased, and serum PTH levels decreased from 584 +/- 154 to 154 +/- 31 pg/ml, P < 0.05. The maximum increase in serum PTH during hypocalcemia did not differ before (248 +/- 78 pg/ml) or after (280 +/- 100 pg/ml) treatment, but the increase in PTH, expressed as a percentage of preinfusion values, was greater after treatment (329 +/- 73 vs. 132 +/- 10%, P < 0.05). The decreases in serum PTH during calcium infusions did not differ before (70 +/- 5%) or after (73 +/- 5%) therapy, and the set point for PTH release did not change (1.20 +/- 0.03 vs. 1.23 +/- 0.01 mmol/l, not significant). Calcitriol modifies PTH secretion during hypocalcemia in secondary hyperparathyroidism without affecting the set point for PTH release; although calcitriol lowers serum PTH levels, it may also restore the secretory reserve of hyperplastic parathyroid tissues during hypocalcemia.

Development of adynamic bone in patients with secondary hyperparathyroidism after intermittent calcitriol therapy

Intermittent calcitriol therapy is commonly used to treat secondary hyperparathyroidism in patients undergoing regular dialysis, but there is little available information about the histologic response of bone to this form of therapy. Accordingly, 14 children and adolescents with biopsy-proven secondary hyperparathyroidism were treated with intermittent oral or intraperitoneal doses of calcitriol for 12 months. Biochemical indices of mineral metabolism including serum intact PTH levels were measured monthly throughout the study, and bone biopsies were repeated at the end of treatment. Before treatment, 11 patients had osteitis fibrosa and three had mild lesions of secondary hyperparathyroidism. Histologic improvement was seen in 12 of 14 patients, and osteitis fibrosa resolved in 10 of 11 cases. Bone formation decreased in all patients during intermittent calcitriol therapy, falling from 861 +/- 380 to 150 +/- 170 microns2/mm2/day, P < 0.001. Bone formation decreased to normal in six patients, but six patients developed adynamic lesions of bone with subnormal bone formation rates. Serum PTH and alkaline phosphatase levels declined in those who developed adynamic bone, but values remained elevated in patients with normal rates of bone formation at follow-up evaluation. Neither the mean dose of calcitriol nor the average dose per kilogram body weight differed in patients with adynamic lesions. Thus, adynamic renal osteodystrophy develops in a substantial number of patients during intermittent calcitriol therapy. Although declining serum PTH and alkaline phosphatase levels suggest the development of the adynamic lesion, bone formation decreases in some patients despite persistently high serum PTH levels. Calcitriol may directly suppress osteoblastic activity in patients with secondary hyperparathyroidism when given in large doses to patients undergoing peritoneal dialysis.

Recent advances in the management of renal osteodystrophy in children.

Secondary hyperparathyroidism remains the predominant histologic lesion in pediatric patients undergoing regular dialysis, but recent evidence indicates that the regulation of parathyroid hormone secretion by calcium does not differ substantially between patients with osteitis fibrosa and subjects with normal renal function. Growth retardation and skeletal deformities are major findings in pediatric patients with renal osteodystrophy, and alterations in vitamin D metabolism and insulin-like growth factor almost certainly contribute to these findings. Avoidance of aluminum-containing medications and the introduction of intermittent calcitriol therapy provide newer approaches to the effective management of secondary hyperparathyroidism in pediatric patients with end-stage renal disease.