Update on pharmacologically-relevant vitamin D analogues.

Pharmacologists have been interested in vitamin D since its metabolism was elucidated in the early 1970s. Despite the synthesis of thousands of vitamin D analogues in the hope of separating its calcemic and anti-proliferative properties, few molecules have reached the market for use in the treatment of clinical conditions from psoriasis to chronic kidney disease. This review discusses vitamin D drugs, recently developed or still under development, for use in various diseases, but in particular bone disease. In the process we explore the mechanisms postulated to explain the action of these vitamin D analogues including action through the vitamin D receptor, action through other receptors e.g. FAM57B2 and dual action on transcriptional processes.

Enhanced Response of Acute Monocytic Leukemia Cells to Low-dose Cytarabine by 1,25-dihydroxyvitamin D3.

Low-dose cytarabine combined with differentiating or DNA hypomethylating agents, such as vitamin D compounds, is a potential regimen to treat acute myeloid leukemia (AML) patients who are unfit for high-intensity chemotherapy. The present study aimed to determine which subset of AML would be most responsive to low-dose cytarabine with the differentiating agent 1,25-dihydroxyvitamin D3 (1,25-D3). Here, firstly, cBioPortal database was used and we found out that vitamin D receptor (VDR) was highly expressed in acute monocytic leukemia (M5) and high VDR expression was associated with a poor survival of AML patients. Then, we confirmed that 1,25-D3 at clinical available concentration could induce more significant differentiation in acute monocytic leukemia cell lines (U937, MOLM-13, THP-1) and blasts from M5 patients than in non-monocytic cell lines (KGla and K562) and blasts from M2 patient. Finally, it was shown that the combination of 1,25-D3 and low-dose cytarabine further increased the differentiating rate, growth inhibition and G0/G1 arrest, while mild changes were found in the apoptosis in acute monocytic leukemia cell lines. Our study demonstrates that the enhanced response of acute monocytic leukemia cells to low-dose cytarabine by 1,25-D3 might indicate a novel therapeutic direction for patients with acute monocytic leukemia, especially for elderly and frail ones.

Anti-inflammatory effect of vitamin D on gingivitis: a dose-response randomised control trial.

PURPOSE: To assess the anti-inflammatory effect of vitamin D on gingivitis at various doses. MATERIALS AND METHODS: In this randomized controlled trial, daily oral vitamin D supplementation was given in doses of 2000 IU for group A, 1000 IU for group B, 500 IU for group C and a placebo for group D over a 3-month period. The changes in gingival scores were measured after the 1st, 2nd and 3rd months. RESULTS: The gingivitis score changed in direct proportion to the dose of vitamin D supplementation. In group A, the mean gingival scores were 2.4 (baseline), 1.7 after the first month, 0.8 after the second month and 0.3 after the third month. The group B mean baseline gingival score of 2.3 decreased to 2.0 in the first month, 1.1 after the second month and 0.5 after the third month. In group C, the baseline gingival scores were 2.2 and 1.9 after one month, 1.4 after two months and 0.8 by the last visit. Comparing baseline gingivitis scores with the later-visit score using the Wilcoxon paired test, the significant anti-inflammatory effect was seen in group A after one month, in group B at two months and in group C at three months after oral vitamin D supplementation (P < 0.0001). However, group D did not show a significant antiinflammatory effect. CONCLUSION: There is a dose-dependent anti-inflammatory effect of vitamin D on gingivitis. Vitamin D is a safe and effective anti-inflammatory agent in doses ranging from 500 IU to 2000 IU. Results are apparent earlier with the higher dose of 2000 IU.

Is 24,25(OH)D level really high in dialysis patients with high FGF23 levels?

Deficiency of 1,25-dihydroxyvitamin D [1,25(OH)(2)D] and excessive fibroblast growth factor (FGF23) are suggested to be associated with increased mortality in patients with chronic kidney disease (CKD). Generally, 24-hydroxylation has been considered the first step in the degradation pathway of 1,25(OH)(2)D and 25(OH)D. 24,25-dihydroxyvitamin D [24,25(OH)(2)D] was believed to be a degradation product, with no important biological effects. However, some data have accumulated showing that 24,25(OH)(2)D has biological effects on its own. Under conditions of eucalcemia, the synthesis of 24,25(OH)(2)D is increased, and the synthesis of 1,25(OH)(2)D is decreased. In patients with CKD, both high parathyroid hormone levels, which decrease the activity of enzyme CYP24A1 (24-hydroxylase), and high FGF23 levels, which increase the activity of enzyme CYP24A1, were often detected. However, information about 24,25(OH)(2)D levels in these patients is very limited. Whether compensatory changes in levels of FGF23 and 24,25(OH)(2)D in CKD patients are protective or harmful remain unknown issues. Therefore, more studies are needed to identify the nature of the interactions between these molecules and to fully elucidate their clinical significance.

Treatment of osteoporotic ovariectomized rats with 24,25(OH)2D3.

BACKGROUND: Antiresorptive therapeutic regimens are the mainstay of current management of osteoporosis. Treatments that are promoting new bone formation are less available and less affordable. Previous studies have suggested that 24,25(OH)(2)D(3) could enhance bone formation. The effect of 24,25(OH)(2)D(3) on bone formation in ovariectomized osteopenic rats (OVX) was evaluated in this study. MATERIALS AND METHODS: Mature Sabra rats were divided into two groups: sham-operated and OVX. Three months after surgery the OVX and sham-operated rats were divided into the following subgroups: (1) sham rats injected with vehicle, (2) sham rats injected with 24,25(OH)(2)D(3), (3) OVX rats injected with vehicle, and (4) OVX rats injected with 24,25(OH)(2)D(3). After 2 weeks' treatment, histomorphometry of the right tibiae was performed. RESULTS: Ovariectomy resulted in a decrease in total bone volume (TBV/TV) and in bone formation (BFR/BS), P < 0.005 and P < 0.05 respectively, when compared with the sham-operated rats. Beside the decrease in TBV and BFR, the OVX rats showed an increase in osteoclastic bone resorption (P < 0.001 vs. sham). Administration of 24,25(OH)(2)D(3) was followed by an increase in all static and dynamic bone-forming parameters. The TBV/BV (P < 0.025), osteoblast surface (Ob.S/BS) (P < 0.001), as well as the BFR/BS (P < 0.005), increased in the OVX-treated group when compared with the OVX-untreated and sham-operated rats. This increment in bone formation was associated with a decrease in bone resorption (P < 0.001 in OVX-treated vs. OVX-untreated rats). CONCLUSIONS: This study shows that 24,25(OH)(2)D(3) may be of benefit in experimental osteopenia following ovariectomy, both by suppressing osteoclastic hyperactivity and by stimulating bone formation.

Chemopreventive effect of 24R,25-dihydroxyvitamin D(3) in N, N'-dimethylhydrazine-induced rat colon carcinogenesis.

In this study we investigated the effects of 24R,25-dihydroxyvitamin D(3) [24R,25(OH)(2)D(3)] on N,N'-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. For experiments 1 and 2, 50 F344 male, 6-week-old rats were divided into five groups in each experiment. Animals were given s.c. injections of DMH once a week for 4 weeks. Those in groups 1-5 were given 24R,25(OH)(2)D(3) in the diet (10, 5, 2.5, 1.25 or 0 p.p.m., respectively) during the post-initiation stage in experiment 1 and during the initiation stage in experiment 2. At termination, the numbers of aberrant crypt foci (ACF) in the rat colonic mucosa were decreased dose-dependently in rats treated with 24R,25(OH)(2)D(3) during the post-initiation stage, but not in the initiation stage. For experiment 3, 15 male, 9-week-old rats were divided into three groups and given 24R,25(OH)(2)D(3) in the diet (10, 5 or 0 p.p.m.). Animals were injected with 5-bromo-2'-deoxyuridine (BrdU) i.p. 1 h before death to examine DNA synthesis in the colon mucosa. BrdU labeling indices were decreased dose-dependently in colonic crypts of rats treated with 24R, 25(OH)(2)D(3). In experiment 4, using the multicarcinogenic protocol we could analyze our data with respect to not only one separate organ, but at the organism level. Sixty-eight male, 6-week-old rats were treated with DMH, N-methylnitrosourea, 2, 2'-dihydroxy-di-n-propylnitrosamine, diethylnitrosamine and N-butyl-N-(4-hydroxybutyl)nitrosamine in weeks 1-4 and were then given 24R,25(OH)(2)D(3) in the diet (5, 1 or 0 p.p.m.) throughout weeks 5-30. Examination of the development of tumors and preneoplastic lesions in various organs revealed that 24R, 25(OH)(2)D(3) inhibited colonic tumor development significantly but exerted no effects on tumor induction in other organs. In conclusion, these results strongly indicate that 24R,25(OH)(2)D(3) inhibits colon carcinogenesis specifically, without any enhancement of carcinogenesis in other organs, when administered in the post-initiation phase.

24,25-dihydroxyvitamin D3 in combination with 1,25-dihydroxyvitamin D3 ameliorates renal osteodystrophy in rats with chronic renal failure.

AIMS: This study compares the effects of 1,25(OH)2D3 and 24,25(OH)2D3 alone or in combination on renal osteodystrophy in rats with chronic renal failure (CRF). MATERIAL AND METHOD: One month subsequent to 5/6 nephrectomy animals were divided into four groups and treated for one or four weeks with either vehicle, 1,25(OH)2D3, 24,25(OH)2D3 or 1,25(OH)2D3 + 24,25(OH)2D3. A sham-operated group with normal renal function matched for age and weight was used as control. At the termination of the study blood chemistry, parathyroid hormone (PTH) level and bone histomorphometry were analyzed. RESULTS: The main findings were: amelioration of 1,25(OH)2D3-induced hypercalcemia by 24,25(OH)2D3, and similar suppression of PTH by the two metabolites of vitamin D when administered alone or in combination. Bone histomorphometry showed that 1,25(OH)2D3 alone exerts a potent proliferative effect on the osteoblasts but severely depresses their mineralizing capacity in a dose- and time-dependent manner. By contrast, 24,25(OH)2D3 improved the mineralizing activity with only a limited effect on osteoblast proliferation. Addition of 24,25(OH)2D3 potentiated the beneficial effect of 1,25(OH)2D3 on bone-resorbing parameters and corrected the mineralization failure. CONCLUSIONS: Based on the above observations we suggest that the combined treatment with 1,25(OH)2D3 and 24,25(OH)2D3 markedly improves the morphologic and metabolic abnormalities of renal osteodystrophy.

Medical management and complications of X-linked hypophosphatemic vitamin D resistant rickets.

To improve the growth failure, bowed legs, and biochemical and radiological abnormalities in patients with X-linked hypophosphatemic vitamin D resistant rickets (XLH), combined therapy of phosphate and calcitriol is the best therapeutic approach at present. However, the complications involving combined therapy, such as hypercalcemia, nephrocalcinosis and hyperparathyroidism, are not fully solved. To achieve better control, new therapeutic approaches have been reported recently, for example, growth hormone (GH) or new vitamin D analogs. GH improved linear growth, decreased phosphate reabsorption and increased 1-alpha-hydroxylase activity. Furthermore, 24R,25-dihydroxyvitamin D3 (24,25) improved the bone lesions in hypophosphatemic (Hyp) mice, and also in XLH, without the adverse effects such as hypercalcemia or hypercalciuria compared with 1,25-dihydroxyvitamin D3. These new approaches should be considered for the treatment of patients with XLH.

Inhibition of development of N,N'-dimethylhydrazine-induced rat colonic aberrant crypt foci by pre, post and simultaneous treatments with 24R,25-dihydroxyvitamin D3.

It has recently been reported that new vitamin D3 derivatives can exert inhibitory effects on colon carcinogenesis in rats. In the present study the chemopreventive potential of 24R,25-dihydroxyvitamin D3 (24R,25(OH)2vitamin D3) was assessed in a murine model of colon carcinogenesis. In experiment 1, male 6-week-old F344 rats were administered N,N'-dimethylhydrazine (DMH) 20 mg/kg s.c. once a week 4 times. The rats were fed 24R,25(OH)2vitamin D3 at 10 ppm in the diet prior to (pre), together with (simultaneous) or after (post) DMH treatment. Modifying effects were assessed using aberrant crypt foci (ACF), putative preneoplastic lesions, as the end point markers in this model of colon carcinogenesis. After 8 weeks, pre and more markedly simultaneous administration of 24R,25(OH)2vitamin D3 was found to have reduced the total numbers of ACF and significantly inhibited the development of foci. After 16 weeks, numbers of foci with > or = 4 crypts, which are more likely to progress to tumors, were significantly reduced. The most pronounced inhibition of ACF development was noted in rats fed the 24R,25(OH)2vitamin D3 after DMH administration. The reduction was particularly marked in the proximal colon. Blood levels of calcium were not significantly increased over the control levels in groups administered DMH and the vitamin. Immunohistochemical staining showed numbers of proliferating cell nuclear antigen-positive cells to be lower in the colonic epithelia of rats fed the vitamin D3 metabolite than in the controls. In experiment 2, the effect of 24R,25(OH)2vitamin D3 on the alterations in c-fos, c-myc and c-jun oncogene expression in response to DMH administration was examined by northern blot analysis. The early increase in expression of ornithine decarboxylase (ODC) activity was not altered by 24R,25(OH)2vitamin D3. The results suggest that 24R,25(OH)2vitamin D3 is a cancer chemopreventive agent which may suppresses DMH induction of lesions and their subsequent development via an antiproliferative action.

24R,25-dihydroxyvitamin D3 promotes bone formation without causing excessive resorption in hypophosphatemic mice.

To clarify the differences in the action of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and 24,25-(OH)2D3 in hypophosphatemic (Hyp) mice, a model for familial X-linked hypophosphatemic rickets in humans, we carried out histomorphometric examinations of the effects of these agents in the lumbar vertebra of these mice. The Hyp mice received 1-1000 micrograms/kg.day 24,25-(OH)2D3, 0.01-0.1 micrograms/kg.day 1,25.(OH)2D3, or vehicle alone given daily for 28 days by ip injection. Histomorphometrically, 1,25-(OH)2D3 and 24,25-(OH)2D3 showed similar effects on bone formation. The parameters of bone formation, mineralized bone volume/bone volume, mineral apposition rate, and bone formation rate/bone surface, were improved to a similar extent in a dose-dependent manner by 1,25-(OH)2D3 and 24,25-(OH)2D3, but there were remarkable differences in the indexes of the bone resorption between these two metabolites. In 24,25-(OH)2D3-treated Hyp mice, osteoclast number/bone perimeter and osteoclast surface/bone surface, the parameters of bone resorption, increased to control levels and did not change according to the dose of 24,25-(OH)2D3. However, in 1,25-(OH)2D3-treated Hyp mice, these values increased remarkably, exceeding the control level. That is, 24,25-(OH)2D3 normalized bone resorption in the rachitic mice, whereas 1,25-(OH)2D3 caused excessive stimulation of bone resorption. This qualitative difference between the two compounds contributes to the superior effects exerted by 24,25-(OH)2D3 in improving the bone lesion in Hyp mice. At doses from 1-1000 micrograms/kg.day, 24,25-(OH)2D3 had dose-dependent effects in increasing bone formation without promoting excessive bone resorption, as shown by histomorphometric analysis.

24,25 Dihydroxyvitamin D supplementation corrects hyperparathyroidism and improves skeletal abnormalities in X-linked hypophosphatemic rickets--a clinical research center study.

Therapy for X-linked hypophosphatemia (XLH) only partially corrects skeletal lesions and is often complicated by hyperparathyroidism. 24,25(OH)2 D3 improves skeletal lesions in a murine model of XLH and suppresses PTH secretion in animals. Therefore, we undertook a placebo-controlled trial of 24,25(OH)2 D3 supplementation to standard treatment in patients with XLH to improve bone disease and reduce hyperparathyroid complications. Fifteen subjects with XLH receiving standard treatment [1,25(OH)2 D3 or dihydrotachysterol plus phosphate] were evaluated, supplemented with placebo, and reevaluated one yr later. 24,25(OH)2 D3 supplementation was then begun and studies repeated after another year. Each patient underwent a detailed evaluation of calcium homeostasis over a 24-h period. Rachitic abnormalities were assessed radiographically in children. Adults underwent bone biopsies. 24,25(OH)2 D3 normalized PTH values in nine subjects (peak PTH was 46.5 +/- 6.6 pmol/L at entry, 42.3 +/- 5.9 pmol/L after placebo, and 23.3 +/- 5.4 pmol/L after 24,25(OH)2 D3). Nephrogenous cAMP decreased at night, coincident with the decrease in PTH, and serum phosphorus was slightly greater with 24,25(OH)2 D3. Radiographic features of rickets improved during 24,25(OH)2 D3 supplementation in children, and osteoid surface decreased in adults. 24,25(OH)2 D3 is a useful adjunct to standard therapy in XLH by effecting correction of hyperparathyroidism and improvement of rickets and osteomalacia.

Vitamin D3 analogs and salmon calcitonin partially reverse the development of renal osteodystrophy in rats.

We have previously established an uremic rat model which is suitable for investigating the effect of various treatment modalities on the progression of renal osteodystrophy [1]. Four months subsequent to 5/6 nephrectomy, animals were treated three times a week for 3 months with either vehicle, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], 1,25(OH)2D3 + 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25(OH)2D3 + calcitonin (CT), or 1,25(OH)2D3 + 24,25(OH)2D3 + CT. At termination of the study, clinical chemistry, chemical composition, and mechanical properties of femurs, calvarial parathyroid hormone (PTH)-elicited adenylate cyclase (AC), and phospholipase C (PL-C) activities, femoral cross-sectional area, and bone histomorphometry were analyzed. The main findings were that 1,25(OH)2D3 +/- 24,25(OH)2D3 treatment enhanced elasticity as well as time to fracture at the femoral metaphysis. CT potentiated the increase in elasticity obtained by 1,25(OH)2D3 +/- 24,25(OH)2D3 treatment. Only 24,25(OH)2D3 administration rectified the supernormal PTH-stimulated uremic bone AC, and only 1,25(OH)2D3 medication normalized the diminished CT-elicited AC. The obliterated uremic bone PTH-sensitive PL-C was fully normalized by all drug regimens. Femoral shaft inner zone diameter was enhanced by uremia, however, all drug treatments normalized it. Ditto effect was registered with either drug treatment on the subnormal outer and inner zone widths. Histomorphometrical analyses showed that 1,25(OH)2D3 administration reduced both eroded and osteoid surfaces. Most prominently, adjuvant 24,25(OH)2D3 or CT administration potentiated the beneficial effect of 1,25(OH)2D3 on fibrosis and osteomalacia. We assert that vitamin D3 treatment markedly reverses the development of renal osteodystrophy, and CT potentiates the effect of vitamin D3.

Measurement of bone resorption by strontium excretion in prelabelled rats.

The body handles strontium (Sr) in a similar way to calcium (Ca) in that Sr is absorbed by the gut, concentrated in bone and excreted in urine and feces. In this study, rats were labelled with Sr during growth and later subjected to various treatments affecting bone resorption and Sr excretion was measured during and after treatment. Six weeks old Wistar rats were repeatedly s.c. injected with SrCl2. After a period of 2 weeks after the last Sr injection the rats were subjected to various treatments. Sr clearance was then measured weekly for 2 weeks. In the first experiment, the Sr labelled rats were sham-operated (sham) or ovariectomized (ovx) and urine collected afterwards. Sham rats were either treated with 4 daily s.c. clodronat injections at the beginning of the urine sampling, fed a low Ca diet (0.08% Ca) during the second sampling week or injected with saline. Urinary Sr excretion was decreased in the clodronate group during the first sampling week and increased in the Ca depleted group during feeding the low Ca diet. Sr excretion by ovx rats was similar to the sham control. In the second experiment, the effect of high-dose treatment with 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) or clodronate on bone resorption induced by Ca depletion was assessed by Sr output in urine and feces. Sr labelled rats were fed a low Ca diet and daily injected with 24,25(OH)2D3 or clodronate for 14 consecutive days. Clodronate significantly decreased Sr output during both sampling weeks. Treatment with 24,25(OH)2D3 resulted in an increased Sr output indicating an increase in bone resorption.

Effect of 1,25-dihydroxyvitamin D3 treatment on bone formation by transplanted cells from normal and X-linked hypophosphatemic mice.

Bone cells isolated from the Hyp mouse, the murine homologue for hypophosphatemic vitamin D-resistant rickets, produce abnormal bone when transplanted to either normal or phosphate-supplemented Hyp mice. To assess whether correction of the bone formation by mutant cells transplanted into either normal or Hyp mice could be achieved in the presence of supraphysiologic serum concentrations of 1.25-dihydroxyvitamin D3 (1.25-(OH)2D3), recipient mice of both genotypes were infused continuously with 1.25-(OH)2D3 (0.2 micrograms/kg/day). Bone nodules present in transplants recovered after 14 days were characterized by measuring the osteoid thickness and volume. Administration of 1.25-(OH)2D3 to Hyp mice corrected the defective bone formation by normal cells but not by pair-transplanted Hyp cells, despite normalization of serum phosphate levels and 3-fold increases in serum 1.25-(OH)2D3. The osteoid thickness and volume in Hyp transplants into 1.25-(OH)2D3-treated Hyp mice were, however, markedly reduced down to values observed for Hyp transplants into recipient normal mice. Administration of 1.25-(OH)2D3 to normal mice improved further bone formation by mutant cells without affecting that by pair-transplanted normal cells. Administration of 24.25-(OH)2D3 (1 microgram/kg/day) combined with 1.25-(OH)2D3 to recipient mice of both genotypes prevented the sharp fall in serum 24.25-(OH)2D3 but was not more beneficial than 1.25-(OH)2D3 alone for improving bone formation by transplanted Hyp cells. These observations demonstrate an abnormal response of the mutant cells to the extracellular environment and support the concept of an intrinsic osteoblast defect in the Hyp mouse.

Effects of 24R,25-dihydroxyvitamin D3 in combination with 1 alpha-hydroxyvitamin D3 in predialysis renal insufficiency: biochemistry and histomorphometry of cancellous bone.

The effect of combined administration of 24R,25-dihydroxyvitamin D3 (24,25-(OH)2D3) and 1 alpha-hydroxyvitamin D3 (1 alpha-(OH)D3) was studied in 24 non-dialyzed patients with chronic renal insufficiency (CRI), matched pairwise as to age, sex, and creatinine clearance (Cr.cl). Low Ca intake had been supplemented beforehand. Then, 1 alpha-(OH)D3 (mean dose 0.55 micrograms daily) was given orally to all patients for 3 months (T0 to T3). Subsequently, patients were assigned randomly to 6 months further treatment either with 1 alpha-(OH)D3 alone (Group A) or with 1 alpha-(OH)D3 plus a high dosage of 24,25-(OH)2D3 (50 micrograms orally, twice weekly) (Group B). Histomorphometry was performed at T0, T3, and T9. In both groups iPTH was equally suppressed, into the lower normal range. Whereas in Group A, serum Ca rose steadily and Cr.cl declined, in Group B both parameters levelled off between T6 and T9. At T9, in Group A the elevated resorption and osteoid indices had normalized markedly, but osteoblasts (Ob.Pm) and mineralizing boundaries (M.Bd) were depressed considerably between T3 and T9. In contrast, in Group B, preservation of Ob.Pm and improved mineralizing activity were observed (M.Bd at T9 > T3 > T0). Resorption indices hardly changed. In the patients with high Ob.Pm at T0, cancellous bone area increased significantly. This was not observed in Group A. Thus, in Group B, osteoblast recruitment appeared maintained and M.Bd appeared normalized. Decline of remodeling toward an adynamic state with an increased risk of hypercalcemia appeared prevented.

Treatment of secondary hyperparathyroidism with intermittent oral high doses of 1-alpha-OHD3 plus pharmacological dose of 24,25(OH)2D3.

The present study examined the effect of intermittent oral high doses of 1-alpha-OHD3 in combination with a pharmacological dose of 24,25(OH)2D3 on parathyroid hormone (PTH) secretion. Twenty hemodialysis (HD) patients (10 males, aged 26-72 years, on regular hemodialysis for 7-128 months) with secondary hyperparathyroidism resistant to long-term low-dose 1-alpha-OHD3 therapy were studied for 24 weeks. At the outset of the study they were randomly divided into two groups: group 1 received high-dose 1-alpha-OHD3 plus 24,25(OH)2D3 (2 x 5 micrograms/day) and group 2 was on monotherapy with 1-alpha-OHD3. 1-alpha-OHD3 was given three times a week in the evening before each HD in gradually increased doses from 1 to 4 micrograms adjusted to keep serum calcium levels below 2.6 mmol/L. During the therapy mean serum calcium and ionized calcium levels increased but remained in the normal ranges without differences between the two groups. However, the frequency of hypercalcemia episodes was different in the two groups. In the first 12 weeks the number of hypercalcemia episodes was significantly lower in group 1 than in group 2 (6 vs. 12; p < .05), allowing the use of significantly higher 1-alpha-OHD3 doses in group 1. In the second 12 weeks of the study the 1-alpha-OHD3 dose in group 1 had to be reduced due to more frequent appearance of hypercalcemia. So, the 1-alpha-OHD3 doses became similar in the two groups during the second 12 weeks of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in serum and urine parameters reflecting bone turnover in uremic patients during treatment with 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3.

Previously we demonstrated that bone resorption in uremic patients appears to be related to increased serum parathyroid hormone (PTH) and to osseous PTH-stimulated adenylate cyclase (AC), the latter being inversely correlated to serum 24,25-dihydroxyvitamin D3 [24,25(OH)2D3]. In this study, we continue to examine the possible modulatory role of vitamin D3 analogs on the progression of the uremic condition. Four groups of predialytic uremic patients received oral administrations of CaCO3 (control), 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3] (0.25-0.50 microgram/day), 24,25(OH)2D3 (15 micrograms/day) or a combination of the two vitamin D3 analogs for 6 months. In the treatment groups receiving single or combined therapy, respectively, the low pretrial serum levels of 1,25(OH)2D3 were raised (p < 0.05) within upper normal range, while the serum levels of 24,25(OH)2D3 were increased (p < 0.05) to twice the average physiological level. Neither regimens alone resulted in significant changes in serum levels of calcium of PTH. 1,25(OH)2D3 moderately hampered bone formation by reducing serum alkaline phosphatase (ALP) by some 15%. 24,25(OH)2D3 significantly decreased (p < 0.01) bone PTH-AC up to 98% after 2 and 6 months. However, no correlation was found between serum 24,25(OH)2D3 and the bone turnover parameters serum ALP, serum osteocalcin and urine hydroxyproline/creatinine ratio. These parameters were all positively correlated (p < 0.05) to serum PTH, indicating an on-going bone turnover. These biochemical events strongly indicate that 24,25(OH)2D3 may retard the PTH-dependent progression in bone demineralization occurring in uremic patients. This effect is apparently not reduced by concomitant 1,25(OH)2D3 administration.

Assessment of combined 24,25(OH)2D3 and 1 alpha (OH)D3 therapy for bone disease in dialysis patients.

An increasing body of experimental data suggests a role for 24,25(OH)2D3 in bone metabolism. The present study was carried out to assess a possible therapeutic role of this vitamin D metabolite in renal osteodystrophy. Twenty-two chronic dialysis patients, most of whom were previously maintained on 1 alpha (OH)D3 therapy, received additional treatment with 10 micrograms/day 24,25(OH)2D3 and were compared to 19 patients receiving 1 alpha (OH)D3 alone. Analysis of transiliac bone biopsies obtained at study entry and following 10-16 months of treatment revealed that the combined therapy produced a decrease in bone turnover. Specifically, the addition of 24,25(OH)2D3 inhibited an increase in trabecular bone volume (BV/TV) and suppressed osteoclastic parameters. Thus BV/TV increased from 26.2 +/- 8.6 to 32.1 +/- 7.5% (p < 0.01) in the 1 alpha (OH)D3 group, but it remained unchanged in the combined therapy group. In contrast, the eroded surface (ES/BS), the osteoclast surface (Oc.S/BS), and the osteoclast numbers were significantly suppressed in patients receiving both 24,25(OH)2D3 and 1 alpha (OH)D3, as compared with those receiving 1 alpha (OH)D3 alone (p < 0.01, p < 0.01, and p < 0.001, respectively). These improvements were independent of changes in 1 alpha (OH)D3 dosage. The extent of bone aluminium deposits was unrelated to the administration of 24,25(OH)2D3 or to its effect. 24,25(OH)2D3 therapy was not associated with any adverse effects.

[The effect of conservative and surgical management for secondary hyperparathyroidism and their problems].

We compared the effect of conservative treatment with that of surgical treatment after applying them on secondary hyperparathyroidism patients (2nd HPT) in order to study the application of surgery on 2nd HPT patients. We selected the test subject of 39 maintenance dialysis patients with complications of 2nd HPT. The conservative treatments were; elcitonine administration (40 u x 3/W) (group 1), ipriflavon administration (200 mg x 3/day) (group 2), and pulse treatment (1.25 (OH)2D3 6 micrograms/W) (group 3). For surgical treatment, we adopted total parathyroidectomy with auto-transplantation into the arm (PTX). The transition of serum parathyroid hormone (PTH-C), alkali-phosphatase (ALP), bone scintigraphy of every 6 months, and change of bone mineral content (BMC) were compared to judge the effects of treatments. We measured 1/3, 1/6 radial region with single photon absorptiometry (SPA) and L3 region with dual photon absorptiometry (DPA) to obtain BMC. We were forced to transfer the patients in groups 1 and 2 (conservative treatment) to pulse treatment or PTX as 12 months later they showed increase in serum PTH-C, ALP and significant drop (P less than 0.05) in BMC average change rate (1/3). In group 3 of pulse treatment, though significant decrease in serum ALP (P less than 0.01) was detected for 10 cases out of 12, serum PTH-C was either unchanged or increased for 4 cases with the value of more than 30 ng/ml. Furthermore the average change rate of BMC stayed at the same level.(ABSTRACT TRUNCATED AT 250 WORDS)