24-25-dihydroxyvitamin-d-3 and Bone-Diseases--Metabolic

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.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Bone Density Conservation Agents; Bone Diseases, Metabolic; Bone Remodeling; Calcifediol; Calcitriol; Humans; Receptors, Calcitriol; Signal Transduction; Treatment Outcome; Vitamins

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.. 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.. 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).. 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.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Bone Diseases, Metabolic; Bone Resorption; Female; Hydroxycholecalciferols; Muridae; Osteogenesis; Ovariectomy; Rats; Rats, Inbred Strains

Glucocorticoids may induce osteopenia in experimental animals and in man. In order to study the possible effects of vitamin D metabolites in the prevention of glucocorticoid-induced osteopenia in rats, we administered 1 alpha(OH)-vitamin D3, 24,25(OH)2-vitamin D3 or a combination of both metabolites, by intragastric intubation, to rats treated daily by intramuscular injections of 10 mg/kg cortisone acetate. Treatment with the vitamin D metabolites started after 1 month of glucocorticoid therapy, at the time osteopenia was already present. Cortisone acetate decreased the gain weight, increased alkaline phosphatase (AP) and decreased Ca serum levels. It also decreased tibial wet and ash weight and tibial Ca content. Computerized histomorphometry of sections from the upper tibia showed decreased epiphyseal bone volume and increased bone marrow volume; decreased height of hypertrophic cartilage in the growth plate and decreased amount of persisting cartilage in the metaphyseal bone trabeculae were also observed. Administration of 24,25(OH)2D3 alone did not reduce these glucocorticoid-induced bone changes and sometimes even worsened them. 1 alpha(OH)D3 reversed many of the deleterious effects of cortisone acetate. It reduced serum AP levels, increased serum Ca levels, increased bone ash weight, epiphyseal and metaphyseal bone volume, with a concomitant reduction in epiphyseal and metaphyseal bone marrow volume. The best results were obtained by a combination of 1 alpha(OH)D3 and 24,25(OH)2D3. It is presumed that both metabolites are needed to reduce the impact of glucocorticoids on bone. 1 alpha(OH)2D3 acts on the gut, increasing Ca absorption (which was decreased by glucocorticoids), and 24,25(OH)2D3 directly acts on bone to enhance bone formation and mineralization.

Topics: 24,25-Dihydroxyvitamin D 3; Alkaline Phosphatase; Animals; Bone Density; Bone Diseases, Metabolic; Calcium; Female; Glucocorticoids; Hydroxycholecalciferols; Magnesium; Phosphorus; Radiography; Rats; Weight Gain

Twenty-four female Sprague-Dawley rats (10 weeks old, 200g BW) were either sham-operated (n = 6) or ovariectomized (ovx). Ovx rats were divided into 3 groups (n = 6 each): ovx; ovx + 1,25-(OH)2D3; ovx + 1,25(OH)2D3 + 1,24,25-(OH)3D3. The vitamin D metabolites were fed orally starting the day after surgery. After 7 weeks all rats were sacrificed and the proximal tibiae were processed undecalcified for quantitative histomorphometry. Conventional histomorphometric analysis of the distal zone (greater than 1 mm from the growth cartilage) of the tibial metaphysis revealed a dramatic loss of cancellous bone mass in ovx rats. Both 1,25(OH)2D3 and the combination of 1,25(OH)2D3 with 1,24,25(OH)3D3 prevented the bone loss in the distal zone in ovx animals. Measurements in the proximal zone (less than 1 mm from the growth cartilage) of the tibial metaphysis were performed with a newly developed technique that utilizes the advantages of automatic image analysis, and that we propose to name "linear scanning". This method revealed a significantly decreased hard tissue mass at about 100 microns and within 800 to 950 microns distance from the growth plate in ovx rats. However, ovx rats reached normal amounts of hard tissue within 250 to 450 microns from the growth plate. The results obtained by linear scanning suggest that the obvious loss of cancellous bone mass in the distal zone of the tibial metaphysis in growing ovx rats is not a consequence of structural changes in the proximal zone.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Bone Density; Bone Diseases, Metabolic; Calcitriol; Female; Growth Plate; Image Processing, Computer-Assisted; Ovariectomy; Rats; Rats, Inbred Strains; Tibia

Forty Fischer-344 rats (10 weeks old, 130 g BW) were either bilaterally ovariectomized (OVX) or sham-operated (SHAM). The rats were allocated to the following groups: SHAM; OVX; OVX + 15 ng 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]/rat/d; OVX + 30 ng 1 alpha,24R,25-trihydroxyvitamin D3 [1,24,25(OH)3D3]/rat/d; OVX + 15 ng 1,25(OH)2D3/rat/d + 30 ng 1,24,25(OH)3D3/rat/d. The vitamin D metabolites were fed orally starting 4 weeks after surgery. Urine and blood samples were taken at several time points during the experiment. Twenty-one weeks after surgery all rats were sacrificed, and the proximal tibiae and the first lumbar vertebrae were processed undecalcified for static bone histomorphometry. Ovariectomy induced a 40% reduction in vertebral cancellous bone area, and a 69% reduction in tibial cancellous bone area. This bone loss in OVX rats was associated with moderately increased biochemical and histomorphometric indices of bone formation and resorption as compared to values in sham-operated animals. Through inhibition of bone resorption, treatment of OVX rats with 1,25(OH)2D3, 1,24,25(OH)3D3, and the metabolite combination prevented the ovariectomy-induced osteopenia in the lumbar vertebra, and partially prevented cancellous bone osteopenia in the tibial metaphysis. However, OVX rats receiving 1,25(OH)2D3 alone or in combination with 1,24,25(OH)3D3 exhibited hypercalcemia, hyperphosphatemia, hypercalciuria, and impaired bone mineralization. Treatment of OVX rats with 1,24,25(OH)3D3 alone, on the other hand, only slightly increased serum calcium levels and did not impair bone mineralization. Furthermore, the inclusion of 1,24,25(OH)3D3 with 1,25(OH)2D3 partially antagonized the untoward effects of 1,25(OH)2D3 on bone mineralization. These data suggest that the actions of 1,24,25(OH)3D3 on bone metabolism might differ from that of 1,25(OH)2D3, and that 1,25(OH)2D3 and, particularly, 1,24,25(OH)3D3 may be potentially effective agents for the prophylaxis of postmenopausal osteoporosis.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Body Weight; Bone Diseases, Metabolic; Bone Resorption; Calcitriol; Female; Hydroxycholecalciferols; Lumbar Vertebrae; Ovariectomy; Rats; Rats, Inbred F344; Tibia

From the demonstration of etiopathogenetic mechanisms of osteopenia 7 different histologically and histomorphometrically defined pictures of the state (diseases) of the skeleton are derived. From this 4 different possibilities of the influence on the permanent transformation of the skeleton--the remodeling are the result. The medicamentous support of the blockade or stimulation of osteoclasts and the optimization of the mineralization are the basis of therapeutic considerations. In the light of these pathogenetically orientated treatment strategies the real and at present practicable therapy regimes of the various clinical manifestations of the osteopenia and new beginnings especially also of the therapy of osteoporosis are discussed.

Topics: 24,25-Dihydroxyvitamin D 3; Anabolic Agents; Bone and Bones; Bone Diseases, Metabolic; Calcitonin; Calcium; Dihydroxycholecalciferols; Diphosphonates; Drug Therapy, Combination; Estradiol Congeners; Fluorides; Humans; Minerals; Parathyroid Hormone

Uraemic rats maintained on either a high or a low phosphate diet for 12 weeks were allocated to one of the following oral vitamin D treatment groups and received: 1,25-dihydroxycholecalciferol [1, 25-(OH)2D3], 24,25-dihydroxycholecalciferol [24,25-(OH)2D3], both 1,25-(OH)2D3 and 24,25-(OH)2D3, or no vitamin D supplements. Mean serum creatinine concentrations were elevated to a similar extent in all groups. Mean serum concentrations of calcium, phosphate and alkaline phosphatase were not significantly different from normal in any of the groups. In the group receiving the high phosphate diet and no vitamin D supplements, calcified bone area measured by quantitative computerized histomorphometry was significantly lower than in the group receiving the low phosphate diet and no vitamin D supplements (0.01 greater than P greater than 0.001), and in the groups receiving high phosphate diet and either 1,25-(OH)2D3 (0.01 greater than P greater than 0.001) or 24,25-(OH)2D3 (0.01 greater than P greater than 0.001). We conclude that uraemic rats maintained on a high phosphate diet for 12 weeks develop skeletal demineralization, this process does not occur in rats on a low phosphate diet, and a decrease in calcified bone area may be prevented by treatment with either 1,25-(OH)2D3 or 24,25-(OH)2D3.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Bone Diseases, Metabolic; Calcinosis; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Creatinine; Dihydroxycholecalciferols; Male; Nephrectomy; Phosphates; Rats; Rats, Inbred Strains; Uremia