24-25-dihydroxyvitamin-d-3 and Osteomalacia

Evidence has emerged over the last several years indicating that aluminum accumulation in patients with chronic renal failure can cause certain forms of renal osteodystrophy, in particular osteomalacia and an aplastic lesion. The lines of evidence include epidemiological associations, chemical measurement and histological staining of bone aluminum, animal models of aluminum loading, and a favorable response to the removal of aluminum by chelation therapy. The primary sources of aluminum are dialysate solutions prepared from water with a high aluminum content and the oral ingestion of aluminum-containing phosphate binders. Desferrioxamine, a chelating agent with a high affinity for aluminum, can be used to remove aluminum during dialysis by increasing ultrafilterable plasma aluminum; preliminary results show that symptomatic patients markedly improve, both clinically and in their bone histology, after long-term chelation therapy with desferrioxamine. Treating water to ensure that aluminum levels are appropriately reduced in dialysate and the development of non-aluminum-containing phosphate binders are necessary to prevent aluminum-related osteodystrophy.

Topics: 24,25-Dihydroxyvitamin D 3; Aluminum; Animals; Bone and Bones; Calcitriol; Caseins; Chronic Kidney Disease-Mineral and Bone Disorder; Deferoxamine; Diet; Dihydroxycholecalciferols; Dogs; Drug Therapy, Combination; Humans; Osteomalacia; Parathyroid Hormone; Parenteral Nutrition, Total; Protein Hydrolysates; Rats; Renal Dialysis; Syndrome; Water Supply

Topics: 24,25-Dihydroxyvitamin D 3; Absorption; Adrenal Cortex Hormones; Anticonvulsants; Calcifediol; Calcitriol; Calcium; Chemical Phenomena; Chemistry; Chronic Kidney Disease-Mineral and Bone Disorder; Digestive System Diseases; Dihydroxycholecalciferols; Fanconi Syndrome; Female; Humans; Hydroxycholecalciferols; Hypocalcemia; Hypoparathyroidism; Hypophosphatemia, Familial; Infant, Newborn; Kidney Diseases; Kinetics; Liver Diseases; Menopause; Neoplasms; Osteomalacia; Osteoporosis; Rickets; Vitamin D

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Birds; Bone and Bones; Calcitriol; Calcium; Chemical Phenomena; Chemistry; Cholecalciferol; Cytochrome P-450 Enzyme System; Dihydroxycholecalciferols; Fluorine; Intestinal Absorption; Kinetics; Minerals; Mixed Function Oxygenases; Osteoclasts; Osteomalacia; Parathyroid Hormone; Receptors, Calcitriol; Receptors, Steroid; Rickets; Stereoisomerism; Steroid Hydroxylases; Vitamin D3 24-Hydroxylase

The available data with regard to the use of calcitriol, 1 alpha-hydroxyvitamin D3 (1 alpha-OH D3), and 24,25-dihydroxyvitamin D3 (24,25-[OH]2D3) in the management of chronic renal insufficiency are reviewed. Patients with mild to moderate osteitis fibrosa experience substantial improvement with either calcitriol or 1 alpha-OH D3 therapy. However, few patients experience a reversal to normal in histologic characteristics of bone. The conditions of patients with osteomalacia do not respond to either calcitriol or 1 alpha-OH D3 therapy. The bone lesion appearing in these patients is most likely a toxic effect of aluminum. The prognosis is usually poor, but the conditions of some patients may respond to administration of 24,25-(OH)2D3 together with calcitriol. Preliminary data suggest that use of chelating agents may be beneficial. In this group of patients, 24,25-(OH)2D3 administration together with calcitriol may be beneficial.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Alkaline Phosphatase; Animals; Bone and Bones; Calcitriol; Chelating Agents; Child; Densitometry; Dihydroxycholecalciferols; Drug Therapy, Combination; Humans; Hydroxycholecalciferols; Hypercalcemia; Kidney Failure, Chronic; Magnesium; Osteitis Fibrosa Cystica; Osteomalacia; Parathyroid Hormone; Phosphates; Prognosis; Radiography; Rats; Renal Dialysis

Topics: 24,25-Dihydroxyvitamin D 3; Adolescent; Adult; Aged; Animals; Bone and Bones; Calcifediol; Calcium; Child; Chronic Kidney Disease-Mineral and Bone Disorder; Dihydroxycholecalciferols; Female; Humans; Hydroxycholecalciferols; Kidney Diseases; Middle Aged; Osteomalacia; Phosphates; Pregnancy; Rickets; Vitamin D

Fifteen patients with dialysis osteomalacia were treated with 24,25-dihydroxyvitamin D3 in dosages up to 10 micrograms per day for two to 24 months. All had previously had no improvement during treatment with calcitriol but had been remarkably susceptible to hypercalcemia. When 24,25-dihydroxyvitamin D3 was given with either calcitriol or dihydrotachysterol, serum calcium levels were significantly lower than during treatment with calcitriol or dihydrotachysterol alone. Eight of nine patients who received combined therapy with 24,25-dihydroxyvitamin D3 and calcitriol for longer than two months had clinical improvement; six patients underwent repeated bone biopsy and showed evidence of improved bone mineralization. Patients who received 24,25-dihydroxyvitamin D3 alone did not improve clinically. Since 24,25-dihydroxyvitamin D3 appears to improve calcium homeostasis and bone mineralization in some patients with severe dialysis osteomalacia when administered with 1-hydroxylated vitamin D metabolites, further controlled studies are warranted.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Alkaline Phosphatase; Biopsy; Bone Resorption; Calcitriol; Calcium; Child, Preschool; Clinical Trials as Topic; Dihydrotachysterol; Dihydroxycholecalciferols; Drug Therapy, Combination; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteomalacia; Renal Dialysis; Time Factors

Five patients with symptomatic osteomalacia undergoing chronic hemodialysis took 24R,25-dihydroxycholecalciferol, 10 micrograms/day, for periods of 6-20 months. Four patients took calcitriol simultaneously in doses consistent with normocalcemia, but the 5th was unable to do so because of recurrent hypercalcemia. In the group as a whole, despite achievement of physiologic plasma concentrations of 24,25-dihydroxyvitamin D, we could demonstrate no metabolic or histologic benefit of therapy. Substantial osteomalacia persisted in all posttreatment biopsy specimens, appearing more severe in some cases and less severe in others. At the doses prescribed, the results of treatment of dialysis osteomalacia with 24R,25-dihydroxycholecalciferol were clinically unsatisfactory.

Topics: 24,25-Dihydroxyvitamin D 3; Biopsy; Bone and Bones; Dihydroxycholecalciferols; Female; Humans; Male; Osteomalacia; Renal Dialysis; Time Factors

To assess the correlation between osteoid and vitamin D in patients with a proximal femoral fracture, bone biopsies of the fracture site and the iliac crest were studied; and vitamin-D levels were measured in fasting blood taken on the day of admission. No osteomalacia was found at either site in any of the 95 patients investigated. In 65/95 patients, levels of 25-hydroxy-vitamin D (25-OHD) and 24,25-dihydroxy-vitamin D (24, 25-OH2D) were within the normal range, whereas 30/95 patients were deficient. Because there was no correlation between the amount of osteoid and vitamin-D metabolites in our patients, we concluded that osteomalacia was not a contributory factor in the pathogenesis of the hip fracture.

Topics: 24,25-Dihydroxyvitamin D 3; Aged; Aged, 80 and over; Biopsy; Evaluation Studies as Topic; Female; Femur Neck; Hip Fractures; Humans; Ilium; Male; Middle Aged; Osteomalacia; Vitamin D; Vitamin D Deficiency

Abnormalities in plasma vitamin D metabolites and an increased prevalence of osteomalacia have been described in elderly patients sustaining a fracture of the femoral neck. In order to investigate whether the plasma concentrations of the vitamin D metabolites are normal, and whether vitamin D deficient osteomalacia in patients with femoral fracture can be diagnosed using biochemical criteria alone, we have studied before and after 7 days of 40 micrograms oral 25-hydroxyvitamin D3 elderly patients admitted to hospital with a femoral fracture, elderly patients undergoing elective replacement of the femoral head and elderly control patients in hospital with no clinical evidence of bone disease. Plasma 25-hydroxyvitamin D (25(OH)D) and 24,25-dihydroxyvitamin D increased after 7 days of oral 25-hydroxyvitamin D3 to the same levels in the three groups, but in contrast to the controls there was no significant increase in plasma 1,25-dihydroxyvitamin D or radiocalcium absorption in femoral fracture and hip replacement patients. However, when femoral fracture patients were restudied 6-12 months after fracture, plasma 1,25-dihydroxyvitamin D increased after oral 25-hydroxyvitamin D3 to the same extent as it had in the control patients. We conclude that reduced calcium absorption due to low plasma 25(OH)D levels, i.e., vitamin D insufficiency is common in all elderly patients. Furthermore biochemical criteria for diagnosis of vitamin D-deficient osteomalacia are of very limited use at the time of fracture in elderly patients since there is a failure of production of 1,25 dihydroxyvitamin D which resolves within 6-12 months of the fracture. This failure makes the 1,25-dihydroxyvitamin D response to oral 25(OH)D an unreliable guide to the presence of vitamin D-deficient osteomalacia at the time of fracture. The abnormality in 1,25-dihydroxyvitamin D is also present in patients undergoing hip replacement surgery, and is therefore unlikely to be involved in the aetiology of femoral neck fracture. It may, however, contribute to the morbidity after fracture.

Topics: 24,25-Dihydroxyvitamin D 3; Absorption; Aged; Calcifediol; Calcitriol; Calcium; Creatinine; Cyclic AMP; Dihydroxycholecalciferols; Female; Femoral Neck Fractures; Hip Prosthesis; Humans; Osteomalacia; Parathyroid Hormone; Vitamin D; Vitamin D Deficiency

The common marmoset, a New World monkey, requires a large amount of vitamin D3 to maintain its normal growth. This monkey is reported to have an end-organ resistance to 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3). In this study, the bone morphology of marmosets fed a high vitamin D3 diet (intake of vitamin D3, 110 IU/day/100 g of body weight) was compared by X-ray and histological examinations with that of rhesus monkeys (Old World monkey) fed a normal diet (intake of vitamin D3, 5 IU/day/100 g of body weight). Three of 20 marmosets were found by X-ray examination to have osteomalacic changes in their bones despite the high daily intake of vitamin D3, whereas none of the 5 rhesus monkeys showed any signs of osteomalacia. Osteomalacic marmosets had distinct increases in osteoid surface, relative osteoid volume, and active osteoclastic bone resorption, whereas non-osteomalacic marmosets had no increase in osteoid tissues in their bones. None of the marmosets, either osteomalacic or non-osteomalacic, was hypercalcemic despite the extremely high circulating levels of 1 alpha,25(OH)2D3. However, the serum 25-hydroxyvitamin D3 (25OHD3) and 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) levels were significantly lower in the osteomalacic than in the non-osteomalacic marmosets. These results suggest that the marmoset is likely to exhibit osteomalacic bone changes despite the high daily intake of vitamin D3. These changes resemble those in vitamin D-dependent rickets, type II.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Bone and Bones; Calcifediol; Calcitriol; Callitrichinae; Diet; Dihydroxycholecalciferols; Disease Models, Animal; Female; Macaca mulatta; Male; Osteomalacia; Rickets; Species Specificity

We studied the effects of vitamin D metabolites in 29 patients established on chronic hemodialysis. The patients were divided into four groups; one was treated with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] 0.5 microgram/day, one with 24R,25-dihydroxyvitamin D3 [24,25-(OH)2D3] 10 micrograms/day, and one with both metabolites. The control group was not given vitamin D. Plasma levels of both metabolites were low before treatment. 1,25-(OH)2D3 levels became normal, and 24,25-(OH)2D3 increased to supranormal levels after administration of the corresponding metabolite. Combined treatment produced still higher plasma levels of 24,25-(OH)2D3, suggesting an interaction between the two metabolites. Patients receiving 1,25-(OH)2D3 alone had a greater increase in plasma calcium than those receiving both metabolites. In control patients, hyperparathyroid bone disease worsened over the 10-month observation period. 1,25-(OH)2D3 improved hyperparathyroid bone disease in most patients, as reflected by a reduction in osteoclast and osteoblast numbers, but had no demonstrable effect on mild osteomalacia. 24,25-(OH)2D3 had no significant effect on plasma biochemistry or bone histology, and the effect of combined treatment on histology was similar to that of 1,25-(OH)2D3 alone. Stainable bone aluminum increased slightly in patients given 1,25-(OH)2D3, but aluminum did not affect the response to treatment. We conclude that 1,25-(OH)2D3 is a useful agent in the treatment of renal bone disease, but no therapeutic role is apparent for 24,25-(OH)2D3.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Aged; Alkaline Phosphatase; Aluminum; Bone Diseases; Calcitriol; Calcium; Dihydroxycholecalciferols; Drug Therapy, Combination; Female; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Male; Middle Aged; Osteomalacia; Parathyroid Hormone; Phosphorus; Renal Dialysis

Topics: 24,25-Dihydroxyvitamin D 3; Aged; Calcium; Dihydroxycholecalciferols; Female; Humans; Hyperparathyroidism; Osteomalacia; Phosphorus; Vitamin D Deficiency

The hypophosphatemic male mouse (Hyp/y), the proposed model for human vitamin D-resistant rickets (VDRR), is characterized by chronic hypophosphatemia, dwarfism, and rachitic and osteomalacic bone lesions. We have reported that treatment of Hyp/y mice with phosphate salts (Pi) heals rickets but does not correct the defective endosteal bone mineralization. In an attempt to cure osteomalacia, mutant male animals were treated with Pi combined with 25-hydroxyvitamin D3 (25OHD3, 1 microgram/kg/day), 24,25-dihydroxyvitamin D3 [24,25(OH)2D3, 0.5 microgram/kg/day], or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3, 0.05--0.25 microgram/kg/day] infused constantly for 3 weeks. The biochemical and skeletal effects of treatment were assessed by analytical methods and bone histomorphometry. The results show that only 1,25(OH)2D3 produced a dose-dependent elevation of serum calcium and phosphorus, and greatly improved bone mineralization at doses high enough to increase serum calcium and phosphorus concentrations within or above the normal range. Better improvement of bone mineralization was obtained when Pi was combined to 1,25(OH)2D3. In conjunction with the correction of hypocalcemia, Pi + 1,25(OH)2D3 suppressed the stimulation of bone turnover induced by Pi supplementation. The results show that, as in VDRR children, 1,25(OH)2D3 produces beneficial effects on bone lesions in Hyp/y mice, mainly through enhancement of mineral availability. However, the persistence of osteomalacia despite correction of serum mineral concentrations suggests that there is a specific bone cell resistance to mineral and/or hormonal influences in Hyp/y mice.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Bone and Bones; Calcitriol; Calcium; Dihydroxycholecalciferols; Disease Models, Animal; Dose-Response Relationship, Drug; Hydroxycholecalciferols; Hypophosphatemia, Familial; Male; Mice; Mice, Inbred C57BL; Osteomalacia; Phosphates; Phosphorus; Rats; Vitamin D

Topics: 24,25-Dihydroxyvitamin D 3; Calcifediol; Calcitriol; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Dihydroxycholecalciferols; Ergocalciferols; Humans; Hydroxycholecalciferols; Hypoparathyroidism; Intestinal Absorption; Osteomalacia; Osteoporosis; Rickets; Tetany; Vitamin D

Vitamin D metabolites were measured in 21 patients with hypophosphatemic osteomalacia of juvenile onset. In eight patients who had not received any antirachitic treatment, serum 25-hydroxyvitamin D(25-OH-D) and 1,25-dihydroxyvitamin D (1,25-[OH]2D) values were normal, whereas serum 24,25-dihydroxyvitamin D (24,25-[OH]2D) values were lower than in normal subjects. In 13 patients who were receiving ergocalciferol and oral elemental phosphorus, serum 25-OH-D and 24,25-(OH)2D concentrations were elevated and serum 1,25-(OH)2D values were low. The findings in untreated patients supported the hypothesis that vitamin D metabolism is abnormal in hypophosphatemic rickets/osteomalacia. The reduction of serum 1,25-(OH)2D levels with ergocalciferol and phosphate therapy gives further support to a therapeutic role for 1,25-(OH)2D in this disorder.

Topics: 24,25-Dihydroxyvitamin D 3; Adolescent; Adult; Aged; Alkaline Phosphatase; Calcifediol; Calcitriol; Child; Child, Preschool; Dihydroxycholecalciferols; Ergocalciferols; Female; Humans; Male; Middle Aged; Osteomalacia; Parathyroid Hormone; Phosphates; Phosphorus; Rickets; Vitamin D

The serum concentrations of the vitamin D metabolites 25-hydroxyvitamin D (25OHD), 24,25-dihydroxyvitamin D (24,25(OH)2D), and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured in 18 epileptic patients and 10 controls. The patients were divided according to the anti-convulsant treatment they had been receiving for at least 1 year: 9 patients had received phenytoin and 9 patients carbamazepine, as the sole anti-convulsant therapy. The serum 25OHD was decreased in the patients on phenytoin (P less than 0.01), whereas the other serum vitamin D metabolites were normal. Moreover, serum alkaline phosphatase was increased (P less than 0.001) and serum calcium was decreased (P less than 0.001) in this patient group. In the patient group treated with carbamazepine (a negligible, liver inductor), changes in serum 25OHD and serum alkaline phosphatase were less pronounced (P less than 0.05), but the same degree of hypocalcaemia (P less than 0.001) was present. Our data suggest that liver induction in epileptic patients on anti-convulsant drugs cannot explain the pathophysiology behind anti-convulsant osteomalacia.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Aged; Alkaline Phosphatase; Calcifediol; Calcitriol; Calcium; Carbamazepine; Dihydroxycholecalciferols; Epilepsy; Female; Humans; Male; Middle Aged; Osteomalacia; Phenytoin

The efficacy of vitamin D2 in the dose of 2000 IU daily in reversing anticonvulsant osteomalacia was studied in nine epileptic inpatients. The treatment with vitamin D2 was associated with increased serum 25-hydroxycalciferol and 24,25-dihydroxyvitamin D concentrations and partial healing of osteomalacic changes in the cancellous bone of the iliac crest. But it was concluded that the dose of vitamin D2, 2000 IU daily, was too small and that calcium supplementation may be needed in addition to vitamin D therapy.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Alkaline Phosphatase; Anticonvulsants; Bone and Bones; Calcifediol; Calcium; Dihydroxycholecalciferols; Epilepsy; Ergocalciferols; Female; Humans; Male; Middle Aged; Osteomalacia; Phosphates

We have examined the effects of metabolites of vitamin D [25OHD3, 1,25(OH)2D3, 24,25(OH)2D3, and 25,26(OH)2D3] on serum calcium and iPTH in human deficient-D osteomalacia. The four metabolites decreased iPTH, but only for 1,25(OH)2D3 was a significant correlation between increase of serum calcium and decrease of iPTH observed. The 24,25(OH)2D3 and 25,26(OH)2D3 decreased iPTH despite a decrease of serum calcium at the beginning of treatment. The 25OHD decreased iPTH before increased serum calcium. These results could be interpreted as a direct effect of metabolites of vitamin D on PTH secretion. However, the conversion of other metabolites and the calcium concentration in parathyroid cells must be determined before this hypothesis can be accepted.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Calcifediol; Calcium; Dihydroxycholecalciferols; Humans; Hydroxycholecalciferols; Middle Aged; Osteomalacia; Parathyroid Hormone