Biologic effect of 1,24(R)(OH)2D3 versus 1,25(OH)2D3 administration in chronic renal failure.

1,24(R)(OH)2D3 is a synthetic analogue of 1,25(OH)2D3 which binds to the same receptors as the physiologic metabolite with a lower affinity. The aim of the present study was to compare the activity of 1,24(R)(OH)2D3 and 1,25(OH)2D3 on several target organs in patients with chronic renal failure. Treatment with 1,24(R)(OH)2D3 at doses of either 1 or 2 micrograms daily was carried out in two groups of 9 patients, with serum creatinine of 4.61 +/- 1.59 and 4.66 +/- 1.46 mg/dl, respectively. Doses of 1,25(OH)2D3 were 0.5 and 1 microgram daily and were administered to 9 and 13 patients, serum creatinine of 4.52 +/- 1.67 and 4.3 +/- 1.16 mg/dl, respectively. Treatment periods were of 2 weeks. Administration of 1,25(OH)2D3, 1 microgram, induced significant increments of intestinal calcium absorption (ICA), ionized calcium, osteocalcin, serum creatinine, urine Ca/GFR, and a decrease in iPTH. 1,25(OH)2D3, 0.5 microgram, induced a significant increase in ICA and osteocalcin and a decrease in iPTH. Similarly 1,24(OH)2D3, 2 micrograms daily, significantly stimulated ICA and raised serum levels of osteocalcin and creatinine while lowering serum iPTH. In addition, 1,24(R)(OH)2D3 administration induced a significant fall of serum 1,25(OH)2D3. Following 1 microgram, only osteocalcin increased. Therefore, the dose of 2 micrograms of 1,24(R)(OH)2D3 has biologic activity similar to 0.5 microgram 1,25(OH)2D3 (4:1). However the activity ratio on osteocalcin production appears to be 2:1. In addition, 1,24(R)(OH)2D3 is able to inhibit renal tubular 1 alpha-hydroxylase. In conclusion 1,24(R)(OH)2D3 may prove to be useful in the treatment of metabolic bone disease.

Plasma insulin-like growth factor-1 and bone formation parameters in predialysis chronic renal failure.

Insulin-like growth factor-1 (IGF-1), produced by osteoblasts following parathormone (PTH) stimulation, is a local hormone with autocrine and paracrine functions on bone formation. To evaluate whether circulating IGF-1 is also important in stimulating bone formation, a study was carried out on 28 patients with slowly progressing nondialytic chronic renal failure. 9 patients were treated with 1,25(OH)2D3, while 19 did not receive vitamin D metabolites. In all patients a transiliac bone biopsy for histomorphometric studies was obtained, and the following determinations were made: immunoreactive PTH (iPTH), osteocalcin, alkaline phosphatase, IGF-1, serum calcium, phosphate and creatinine. Serum IGF-1 levels were similar in the two groups of patients, and higher than normal. iPTH and osteocalcin were positively correlated with serum creatinine, osteoblast surface and the eroded surface, but did not correlate with IGF-1. A negative (n.s.) relationship was found between dynamic bone parameters and circulating IGF-1, with the mineral apposition rate reaching a significant level (p less than 0.05). In conclusion, the circulating levels of IGF-1 are not correlated with bone formation parameters, thus apparently showing no role in bone turnover or dependency on bone production of the growth factor. The results may favor the hypothesis of a negative feedback control of circulating IGF-1 by suppressive signals originating from active bone metabolic units.

Severe vitamin D deficiency in a case of primary hyperparathyroidism caused by parathyroid lipoadenoma, effect of 25OHD3 treatment.

This report describes the case of a 60-year-old woman with severe metabolic bone disease and fractures due to vitamin D deficiency and hyperparathyroidism. 25OHDH3 and 1,25(OH)2D3 serum levels were undetectable and increased immediately following 25OHD3 oral administration. Serum 1,25(OH)2D3 following vitamin D repletion reached values above the normal range, and remained elevated with strict dependence on the serum 25OHD3 levels. Parathyroid hormone and alkaline phosphatase decreased during treatment, without reaching normality during 1 year of observation. Bone biopsies before and after 8-month 25OHD3 treatment showed disappearance of the osteomalacic and hyperparathyroid lesions. During treatment an increase in serum and urine calcium and formation of renal stones were observed. The patient underwent neck exploration with the finding and removal of a lipoadenoma, a rare parathyroid tumor, followed by complete and permanent remission of the disease. In conclusion, this case is suggestive of the key role played by the long-term vitamin D status in the clinical expression of primary hyperparathyroidism.

Osteocalcin, iPTH, alkaline phosphatase and hand X-ray scores as predictive indices of histomorphometric parameters in renal osteodystrophy.

To evaluate the relationship between hyperparathyroid bone X-ray lesion, biochemical parameters and bone histology in chronic renal failure, 59 patients (52 +/- 14.9 years; Crs 4.7 +/- 2.2 mg/dl, mean +/- SD) on conservative treatment and 103 (48 +/- 14 years) on hemodialysis (from 48.4 +/- 36.7 months) were studied. Right-hand X-ray was carried out for evaluation of the scores (0-3) of acroosteolysis (score A) and subperiosteal resorption (score B). Serum iPTH, osteocalcin and alkaline phosphatase (AP) were measured. In addition in a subset of 53 patients, 30 in predialysis and 23 in dialysis, a bone biopsy was performed for histomorphometry. In predialysis the scores A and B correlated with bone GLA protein (BGP) (p less than 0.01), AP (p less than 0.05) and osteoid surface (p less than 0.05) and 0.01 respectively). In hemodialysis the same level of significant correlation (p less than 0.001) was found between the scores and the three humoral parameters. Score A correlated with active osteoblastic surface and active resorption surface while score B correlated with active osteoblastic surface (p less than 0.01), osteoid surface and active resorption surface (p less than 0.05). Multiple regression analysis carried out to establish the predictive variables of bone histologic lesions (active resorption surface and active osteoblastic surface) singled out BGP in predialysis and AP and the two scores in dialysis. We conclude that serum BGP, as compared to PTH and AP, prevails as a valid marker of hyperparathyroid bone lesion in predialysis, while in dialysis it does not seem to add further information to that carried by other variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Procollagen type I C-terminal extension peptide in predialysis chronic renal failure.

Collagen type 1 is the most abundant protein of bone. Serum levels of type 1 procollagen carboxy-terminal extension peptide (Procoll-1-C) may give a measure of the rate of synthesis of the collagen of bone and be therefore a marker of bone turnover. We have studied 38 patients with predialysis chronic renal failure; 14 of them were under long-term treatment with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] for prevention of secondary hyperparathyroidism. In all patients a transiliac bone biopsy for histomorphometry and determination of dynamic parameters was performed following double tetracycline labeling. In addition serum Procoll-1-C, intact and C-terminal parathyroid hormone (PTH), osteocalcin and alkaline phosphatase were determined. In the patients not receiving 1,25(OH)2D3, serum levels of Procoll-1-C were higher than normal. Procoll-1-C did not correlate with any of the humoral parameters, including serum creatinine, nor with static histomorphometric parameters. Contrarily to osteocalcin, the collagen type 1 marker correlated significantly with all dynamic parameters. Treatment with 1,25(OH)2D3 was accompanied by lower levels of osteocalcin, iPTH (n.s.), osteoblastic surface and by normal levels of Procoll-1-C (p < 0.001, compared to untreated patients), without substantial change in bone formation parameters (bone formation rate). In conclusion Procoll-1-C in predialysis chronic renal failure is a marker of bone turnover unparalleled by other markers. 1,25(OH)2D3 administration is associated with lower serum levels of the peptide unaccompanied by a decrement of bone formation parameters, therefore with an apparently better utilization of collagen type 1 in the mineralization process.(ABSTRACT TRUNCATED AT 250 WORDS)

Deferoxamine test and PTH serum levels are useful not to recognize but to exclude aluminum-related bone disease.

The use of noninvasive diagnostic tools, like the deferoxamine (DFO) test and serum iPTH, to identify aluminum-related bone disease has proved to be inadequate due to false-negative cases; therefore, bone biopsy becomes a necessary diagnostic procedure. Our purpose was to verify whether these non-invasive parameters, appropriately used, may result valid in the identification of patients not at risk of Al toxicity, therefore restricting the need for histologic evaluation. We studied 68 hemodialyzed patients, aged 49.0 +/- 11.6 years, with a M/F ratio of 37/31 and a dialytic age of 85.0 +/- 47.0 months, by means of bone biopsy, DFO test and serum C-PTH. 19.1% of the cases had positive stainable Al and/or high bone Al content (greater than 60 mg/kg/dw) and could be intoxicated. To obtain the highest sensitivity, we selected the following limit values: the lower limit of increment so far proposed for DFO test positivity (greater than 150 micrograms/l) and a value capable of selecting patients with pathologic osteoclasia for C-PTH (greater than 15 ng/ml). With these limits, four different groups of patients were recognized: group A, DFO test positive and PTH high, n = 12; group B, DFO test positive and PTH low, n = 6; group C, DFO test negative and PTH high, n = 30; group D, DFO test negative and PTH low, n = 20. In group B, which could be anticipated as being at higher risk, we actually found the highest (p less than 0.05) bone Al content as compared to other groups, associated with a reduced bone formation rate.(ABSTRACT TRUNCATED AT 250 WORDS)