24-25-dihydroxyvitamin-d-3 and Osteoporosis

Topics: 24,25-Dihydroxyvitamin D 3; Amino Acid Sequence; Animals; Base Sequence; Brain Diseases; Cholestanetriol 26-Monooxygenase; Cholestanols; Cytochrome P-450 Enzyme System; Gene Deletion; Humans; Mitochondria, Liver; Molecular Sequence Data; Osteoporosis; Point Mutation; Steroid Hydroxylases; Xanthomatosis

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

A rat model of postmenopausal osteoporosis was introduced, using ovariectomized rats on a low Ca diet. CT treatment of these animals for one month prevented the decrease in both mineral contents and physical properties of the femoral bone. Treatment of the animals with 1,25(OH)2D3 was effective in increasing bone mineral contents and maintaining positive mineral balance, but did not increase the physical tolerance of bones. In contrast, 24,25(OH)2D3 increased the breaking force of the femoral bone, with minimal effect on bone mineral contents and mineral balance. These results suggest that 1,25(OH)2D3 and 24,25(OH)2D3 act differently on the matrix phase and mineral phase of bones, but that they act together to maintain mineral balance and structural integrity of bones. The mechanism of how these vitamin D metabolites affect bone metabolism remain to be clarified.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Bone and Bones; Bone Development; Calcitonin; Calcitriol; Calcium; Dihydroxycholecalciferols; Disease Models, Animal; Female; Intestinal Absorption; Menopause; Minerals; Osteoporosis; Ovariectomy; Rats; Rats, Inbred Strains; Vitamin D

The effect of oral 24R,25(OH)2-vitamin D3 as a prophylactic for postmenopausal bone loss was examined. Fifty-eight healthy, early postmenopausal women entered a double blind therapeutic trial for 2 years. After an initial examination the women were randomized to treatment with 10 micrograms 24R,25(OH)2D3 daily or placebo. Participants were thereafter examined every 3 months (nine examinations in all). In both groups the forearm bone mineral (measured by single photon absorptiometry), the lumbar spine mineral, and the total body mineral (measured by dual photon absorptiometry) fell significantly and at the same magnitude. Furthermore, serum calcium, serum alkaline phosphatase concentration, and fasting urinary hydroxyproline were unchanged, as were the 24-hour urinary calcium excretion and the intestinal radiocalcium absorption. Our findings demonstrate that 24R,25(OH)2D3 treatment has no prophylactic effect on postmenopausal bone loss and does not alter calcium metabolic variables.

Topics: 24,25-Dihydroxyvitamin D 3; Bone and Bones; Calcifediol; Calcitriol; Dihydroxycholecalciferols; Female; Humans; Menopause; Middle Aged; Minerals; Osteoporosis; Spectrophotometry, Atomic

The effect of two different estrogen/gestagen regimens and 24R,25-(OH)2-cholecalciferol on bone formation was studied in a randomized trial with 144 healthy postmenopausal women. Urinary excretion (UE) of 99m-technetium-diphosphonate and serum alkaline phosphatase (AP) was determined before and then once a year for 2 years of treatment. Both estimates of bone formation showed highly significant decreases (p less than .001) to normal premenopausal levels in women receiving unopposed 17 beta-estradiol or in a sequential combination with progestagen, whereas unchanged high values were found in the groups receiving 24R,25-(OH)2D3 and placebo. The data show that bone turnover increases in early postmenopausal women concomitantly with the loss of bone mass, and that hormonal substitutional therapy normalizes the total skeletal turnover as well as preventing bone loss.

Topics: 24,25-Dihydroxyvitamin D 3; Alkaline Phosphatase; Bone Regeneration; Clinical Trials as Topic; Dihydroxycholecalciferols; Diphosphonates; Double-Blind Method; Drug Therapy, Combination; Estrogens; Female; Humans; Menopause; Middle Aged; Osteoporosis; Progestins; Radionuclide Imaging; Random Allocation; Technetium; Technetium Compounds

In male hypogonadism associated with bone loss, it is important to determine whether bone loss continues with ageing and an increased risk of fracture. We studied bone metabolism in 86 male leprosy patients, who were classified according to the presence or absence of osteoporosis. Osteoporosis was present when men had lumbar compression fractures or a mean BMD-2SD that of normal Japanese men in each age decade. Four men had fractures. Serum concentrations of 1,25-dihydroxyvitamin D and high-sensitivity parathyroid hormone were almost normal in both groups, whereas free testosterone and oestradiol were significantly lower in the osteoporosis group than in the non-osteoporosis group (free testosterone: P < 0.01, oestradiol: P < 0.05). The urinary concentrations of pyridinoline and deoxypyridinoline, as a marker of bone absorption, were significantly higher in the osteoporosis group than in the non-osteoporosis group (pyridinoline: P < 0.01, deoxypyridinoline: P < 0.01). The serum concentration of osteocalcin, a marker of bone formation, was significantly higher in the osteoporosis group than in the non-osteoporosis group (P < 0.01). Elevated concentration means that bone repair is increased possibly because of compensation mechanisms for increased bone loss. In the osteoporosis group, hypogonadism occurred, and high bone turnover continued even in older men. We recommend clinical studies of treatment such as replacement therapy to prevent bone loss and increasing risk of fractures in older men with leprosy.

Topics: 24,25-Dihydroxyvitamin D 3; Aged; Aged, 80 and over; Amino Acids; Bone Density; Bone Remodeling; Estradiol; Humans; Hypogonadism; Leprosy; Male; Middle Aged; Osteocalcin; Osteoporosis; Parathyroid Hormone; Testosterone

A new, highly sensitive HPLC assay method using an electrochemical detector (ECD) for multiple assay of vitamin D metabolites is reported. The assay involves extracting lipids from plasma with methylene chloride and methanol, purification on Zorbax SIL column with 5.5% (v/v) iso-propanol in hexane and quantification by HPLC-ECD. A coulometric system, composed of the dual electrode analytical cell and a guard cell, was used for ECD of the eluting compounds. The potentials applied to detectors 1 and 2 in a dual electrode analytical cell were adjusted to +0.20 V and +0.60 V, respectively. This method is sensitive to 20 pg of 25-hydroxyvitamin D3 [25(OH)D3] and of 24R,25-dihydroxyvitamin D3 [24,25(OH)2D3]. Calibration curves gave linearity from 20-1000 pg for 25(OH)D3 and 24,25(OH)2D3. The detection limit was approximately 50 pg ml-1 for 25(OH)D3 and 24,25(OH)2D3 in plasma. This sensitivity combined with an overall recovery of 25(OH)D3 (81.5 +/- 2.6%, mean +/- S.E.) allows the measurement of trace amount of 25(OH)D3 with only 20 microliters of plasma. Intra- and interassay RSD values were 5.3 and 9.7% for 25(OH)D3 and 6.3 and 9.7% for 24,25(OH)2D3, respectively. Plasma levels of 25(OH)D3 and 24,25(OH)2D3 in normal adults were 15.9 +/- 2.8 ng ml-1 (n = 10) and 1.4 +/- 0.5 ng ml-1 (n = 10), respectively. This method allows the determination of 25(OH)D2 and 25(OH)D3 for evaluating their nutritional and clinical status. From these results, it is concluded that the proposed HPLC-ECD assay system is useful for the determination of vitamin D metabolites in biological fluids as a highly sensitive physicochemical method.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Case-Control Studies; Chromatography, High Pressure Liquid; Electrochemistry; Humans; Leukemia; Liver Cirrhosis; Osteoporosis; Reference Values; Reproducibility of Results; Sensitivity and Specificity; Vitamin D

We previously found that 3,9-bis(N,N-dimethylcarbamoyloxy)-5H- benzofuro[3,2-c]quinoline-6-one (KCA-098) inhibited bone resorption in organ culture. In this study, to determine if KCA-098 is therapeutically applicable for the treatment of osteoporosis, we compared the effect of KCA-098 on bone tissues with that of ipriflavone, a drug that is clinically used for the treatment of osteoporosis. Both KCA-098 and ipriflavone inhibited parathyroid hormone-, prostaglandin E2-, 1 alpha,25-dihydroxyvitamin D3- and interleukin 1 beta-induced bone resorption of fetal rat bones, but the inhibitory activity of KCA-098 was more potent than that of ipriflavone. In fact, the effective concentrations of KCA-098 were 10 to 100 times lower than those of ipriflavone. Oral administration of KCA-098 (1 and 3 mg/kg) or ipriflavone (100 mg/kg) to ovariectomized rats on a low-calcium diet increased the breaking force and bone density of the femora, indicating that KCA-098 is an effective on the whole animal as ipriflavone. Furthermore, KCA-098 increased the length and calcium content of 9-day chick embryonic femora cultured in vitro, whereas ipriflavone did not, suggesting that KCA-098 had a direct stimulatory effect on bone mineralization. Therefore, KCA-098 seems to be more potent than ipriflavone in stimulating bone tissue formation and may thus be expected to become a useful agent for the treatment of osteoporosis.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Bone and Bones; Bone Density; Bone Resorption; Calcification, Physiologic; Calcium; Calcium, Dietary; Chick Embryo; Coumestrol; Dinoprostone; Female; Femur; Interleukin-1; Isoflavones; Osteoporosis; Ovariectomy; Parathyroid Hormone; Rats; Rats, Wistar

Previous investigations have suggested that a lower-than-normal serum 1,25(OH)2D is found in elderly women with postmenopausal osteoporosis. We examined the fundamental aspects of this theory by investigating serum vitamin D metabolites in four representative samples of Caucasian women. These included 44 early postmenopausal women divided into two subgroups: fast bone losers, that is, bone loss greater than 3%/year (n = 20), and "physiological" bone loss (n = 24); and 28 70-year-old women divided into two subgroups: with and without osteoporotic fractures. Serum 1,25(OH)2D concentrations were virtually the same in all groups thus contradicting the previous reports of low 1,25(OH)2D in elderly women. Furthermore, mean 25OHD and 24,25(OH)2D did not differ between the groups. We conclude that 1,25(OH)2D is unlikely to be significant in the development or treatment of a majority of women with postmenopausal osteoporosis.

Topics: 24,25-Dihydroxyvitamin D 3; Aged; Aging; Dihydroxycholecalciferols; Female; Fractures, Bone; Humans; Hydroxycholecalciferols; Menopause; Middle Aged; Osteolysis, Essential; Osteoporosis

Twelve of fourteen female patients with primary biliary cirrhosis, receiving vitamin D supplementation, exhibited unequivocal signs of osteoporosis but not of osteomalacia. Vitamin D treatment reproduced normal 25-hydroxyvitamin D levels in all but two patients and the 1,25 and 24,25-dihydroxyvitamin D metabolic pathways appeared to be unimpaired. A possible mechanism for the vitamin D resistant osteoporosis has been identified following the observation that, in those patients with severe cirrhosis, the circulating concentration of intact PTH was elevated. The increase in intact hormone appears to be at the expense of the carboxyl-regional PTH produced by hepatic Kupffer cell mediated cleavage of intact PTH. As a defect in Kupffer cell function is documented in primary biliary cirrhosis we postulate that the increased intact PTH/decreased carboxyl-regional PTH concentrations arise as a result of diminished Kupffer cell mediated cleavage. The reduced generation of cleaved PTH, due to this loss of Kupffer cell activity, would thus contribute to the development of osteoporosis in primary biliary cirrhosis.

Topics: 24,25-Dihydroxyvitamin D 3; 25-Hydroxyvitamin D 2; Adult; Aged; Calcitriol; Calcium; Cholecalciferol; Dihydroxycholecalciferols; Ergocalciferols; Female; Humans; Kupffer Cells; Liver; Liver Cirrhosis, Biliary; Middle Aged; Osteoporosis; Parathyroid Hormone

Previous studies from our laboratory have demonstrated that 25-hydroxyvitamin D3 (25OHD3) therapy is effective in raising the impaired intestinal calcium absorption (alpha) associated with postmenopausal osteoporosis. In the present study we have assessed the effects of long term 25-OHD3 therapy (50 micrograms/day; mean treatment period, 1.3 yr) in 12 women with postmenopausal osteoporosis (mean age, 62.5 yr). Our results indicate that there was a significant increase in alpha for the group during therapy. However, we found that the patients could be divided into 2 groups based upon their ability to raise alpha in response to 25OHD3 therapy. In those who responded (n = 7), alpha increased from 0.36 +/- 0.05 to 0.49 +/- 0.08 (+/- SD; P less than 0.005) while no significant change was observed for the nonresponders (0.44 +/- 0.03 to 0.48 +/- 0.07). During therapy, there were significant increases in serum 25OHD and 24,25-dihydroxyvitamin D [25,25-(OH)2D] for both groups. Serum 1,25-(OH)2D significantly increased in the responders (21 +/- 8 to 39 +/- 13 pg/ml; P less than 0.01), but not in nonresponders (25 +/- 11 to 28 +/- 8 pg/ml). Between-group comparisons for responders vs. nonresponders before therapy disclosed significant reductions in 24,25-(OH)2D (0.4 +/- 0.3 vs. 2.2 +/- 0.8 ng/ml; P less than 0.005) and alpha (0.36 +/- 0.05 vs. 0.44 +/- 0.03; P less than 0.01). During therapy, there were no significant differences in any parameter between the two groups, except for serum I,25-(OH)2D which was significantly higher in the responders (39 +/- 13 vs. 28 +/- 8 pg/ml; P less than 0.05). These data would suggest that in postmenopausal osteoporosis, the ability to raise alpha in response to 25OHD3 therapy is due in part to increases in serum 1,25-(OH)2D during therapy. This suggests that in some patients with menopausal osteoporosis, renal 25OHD3-1 alpha-hydroxylase may be impaired.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Aged; Calcifediol; Calcitriol; Calcium; Dihydroxycholecalciferols; Female; Humans; Intestinal Absorption; Menopause; Middle Aged; Osteoporosis

Severe hypokinesia of rats given the diet with a ratio of Ca:P = 1:0.5-1:3 was accompanied by hypocalcemia, development of osteoporosis, and some intensification of renal calcinosis. The decrease of phosphorus consumption (Ca:P = 1:0.5-1:1) prevented a development of these changes in intact animals and increased bone mineralization in hypokinetic ones. Excessive phosphorus consumption (Ca:P = 1:3) produced hypocalcemia, hyperphosphatemia, and some osteoporotic changes in the bones of intact animals and intensified these changes with hypokinesia. Administration of 24,25-dihydroxycholecalciferol, an active metabolite of vitamin D3, at a dose of 1.25 micrograms/d prevented a development of bone disorders, thus effectively stimulating diaphyses and epiphyses mineralization and correcting hypocalcemia in hypokinetic rats. 24,25(OH)2D3 at the same dose did not intensify nephocalcinosis and produced no toxic symptoms with hypokinetic animals.

Topics: 24,25-Dihydroxyvitamin D 3; Alkaline Phosphatase; Animals; Bone and Bones; Bone Diseases; Calcinosis; Calcium; Diet; Dihydroxycholecalciferols; Hypocalcemia; Kidney; Male; Osteoporosis; Phosphorus; Rats; Rats, Inbred Strains; Restraint, Physical

This study was carried out to evaluate the effects of an iv injection of parathyroid extract on serum levels of 1,25-dihydroxyvitamin D [1,25-(OH)2D3] in elderly osteopenic patients and age-matched nonosteopenic controls. Serum concentrations of 1,25-(OH)2D were reduced in elderly osteopenic subjects (mean +/- SEM, 20 +/- 3 pg/ml) compared with values in age-matched nonosteopenic controls (35 +/- 3 pg/ml), whereas no differences were found in serum 24,25-dihydroxyvitamin D levels (1.5 +/- 0.3 and 2.2 +/- 0.5 ng/ml, respectively). An iv injection of parathyroid extract was followed by a significant increase in serum 1,25-(OH)2D levels in both osteopenic patients (16 +/- 6 pg/ml) and controls (15 +/- 5 pg/ml). The mean 4-h increases in serum 1,25-(OH)2D of 11-18 pg/ml were not significantly different in the two groups. The results indicate that the reduced 1,25-(OH)2D concentrations in the osteopenic patients are secondary to changes in factors that normally stimulate this enzyme system.

Topics: 24,25-Dihydroxyvitamin D 3; 25-Hydroxyvitamin D 2; Aged; Aging; Calcitriol; Calcium; Dihydroxycholecalciferols; Ergocalciferols; Female; Humans; Male; Middle Aged; Osteoporosis; Parathyroid Hormone; Phosphates; Time Factors; 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

Five patients with involutional osteoporosis were treated with 24,25 dihydroxycholecalciferol (24,25-(OH)2D3) for 6 months, in doses sufficient to double plasma levels at that time. Dietary calcium absorption transiently improved by nearly 2 mmol Ca per day at 2 weeks, but this effect was lost by 6 months. The calcium and phosphate balances followed the trends in calcium absorption. Only twenty-five dihydroxyvitamin D levels changed little. Histomorphometric and kinetic indices of new bone formation and bone blood flow remained stable but there was an increase in urine hydroxyproline at 6 months, which was of borderline statistical significance. Treatment at this dosage of 24,25(OH)2D3, which increased plasma levels within the physiological range, conferred no measurable long-term benefit on our patients. Larger doses, or combination therapy, may warrant further clinical evaluation in osteoporosis.

Topics: 24,25-Dihydroxyvitamin D 3; Calcium; Dihydroxycholecalciferols; Dose-Response Relationship, Drug; Humans; Osteoporosis; Time Factors

Six women (mean age, 62 yr; range, 48--77 yr) who were considered to have postmenopausal osteoporosis, as demonstrated by radiological evidence of vertebral crush fractures, low intestinal calcium (Ca) absorption, and bone biopsies consistent with this diagnosis, received a pharmacological dose of 25-hydroxyvitamin D3 (25OHD3; 20 microgram/day) for 3 months. This treatment increased the serum concentration of 25OHD from 8.7 +/- 4.6 to 30.2 +/- 9.5 (SD) ng/ml (P less than 0.0025), increased the serum concentration of 24,25-dihydroxyvitamin D from 1.2 +/- 1.2 to 7.7 +/- 2.7 ng/ml (P less than 0.025) in three patients, and increased the serum concentration of 1,25-dihydroxyvitamin D from 2.1 +/- 1.7 to 4.3 +/- 1.5 ng/dl (P less than 0.025). Moreover, there were commensurate increases in fractional intestinal Ca absorption from 0.38 +/- 0.03 to 0.49 +/- 0.06 (P less than 0.025) and in urinary Ca from 69 +/- 31 to 127 +/- 67 mg/day (P less than 0.025). There were no significant changes in serum Ca (9.6 +/- 0.5 vs. 9.5 +/- 0.4 mg/dl), serum phosphorus (3.4 +/- 0.2 vs. 3.6 +/- 0.4 mg/dl) or alkaline phosphatase (87 +/- 27 vs. 91 +/- 30 IU/liter) before or after therapy. It is concluded that orally administered 25OHD3 is not only effective in raising the low intestinal Ca absorption observed in postmenopausal osteoporosis but also in increasing the serum concentrations of 24,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D.

Topics: 24,25-Dihydroxyvitamin D 3; Aged; Calcifediol; Calcitriol; Calcium; Dihydroxycholecalciferols; Female; Humans; Hydroxycholecalciferols; Intestinal Absorption; Male; Menopause; Middle Aged; Osteoporosis