Synthesis of 2?-heteroarylalkyl active vitamin d3 with therapeutic effect on enhancing bone mineral density in vivo.
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ABSTRACT:
SUBMITTER: Matsuo M
PROVIDER: S-EPMC4027143 | biostudies-literature | 2013 Jul
REPOSITORIES: biostudies-literature
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Synthesis of 2α-heteroarylalkyl active vitamin d3 with therapeutic effect on enhancing bone mineral density in vivo.
Matsuo Miki M Hasegawa Asami A Takano Masashi M Saito Hiroshi H Kakuda Shinji S Chida Takayuki T Takagi Ken-Ichiro K Ochiai Eiji E Horie Kyohei K Harada Yoshifumi Y Takimoto-Kamimura Midori M Takenouchi Kazuya K Sawada Daisuke D Kittaka Atsushi A
ACS medicinal chemistry letters 20130528 7
2α-Heteroarylethyl-1α,25-dihydroxyvitamin D3 analogues, which were designed to form a hydrogen bond between Arg274 of human vitamin D receptor (hVDR) and a nitrogen atom of the heteroaromatic ring at the 2α-position, were synthesized. Among them, 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D3 showed higher osteocalcin promoter transactivation activity in human osteosarcoma (HOS) cells and a greater therapeutic effect in ovariectomized (OVX) rats, osteoporosis model animals, on enhancing b ...[more]
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Project description:BackgroundIn meta-analyses supplementation with vitamin D appears to reduce incidence of fractures, and in cross-sectional studies there is a positive association between serum 25-hydroxyvitamin D (25(OH)D) levels and bone mineral density (BMD). However, the effect of supplementation with high doses of vitamin D on BMD is more uncertain and could in theory have both positive and negative effects.MethodsThe study was a one year, double blind placebo-controlled intervention trial performed at the University Hospital of North Norway. 421 subjects, 21 - 70 years old, were included and 312 completed the study. The subjects were randomized to vitamin D3 40.000 IU per week (DD group), vitamin D3 20.000 IU per week (DP group), or placebo (PP group). All subjects were given 500 mg calcium daily. Serum 25(OH)D, osteoprotegrin (OPG), receptoractivator of nuclear factor-kappaB ligand (RANKL), and BMD at the lumbar spine and the hip were measured before and at the end of the study.ResultsAt baseline the mean serum 25(OH)D levels were 58 nmol/L (all subjects) and increased to 141 and 100 nmol/L in the DD and DP groups, respectively. After one year, no significant differences were found between the three groups regarding change in BMD, serum OPG or RANKL.ConclusionsSupplementation with high doses of vitamin D for one year does not appear to have a negative effect on BMD in healthy subjects. In order to disclose a positive effect, subjects with low BMD and/or low serum 25(OH)D levels need to be studied.Trial registrationThe trial was registered at ClinicalTrials.gov (NCT00243256).
| S-EPMC2818614 | biostudies-literature
Project description:Studies examining the relationship between total circulating 25-hydroxyvitamin D [25(OH)D] levels and bone mineral density (BMD) have yielded mixed results. Vitamin D-binding protein (DBP), the major carrier protein for 25(OH)D, may alter the biologic activity of circulating vitamin D. We hypothesized that free and bioavailable 25(OH)D, calculated from total 25(OH)D, DBP, and serum albumin levels, would be more strongly associated with BMD than levels of total 25(OH)D. We measured total 25(OH)D, DBP, and serum albumin levels in 49 healthy young adults enrolled in the Metabolic Abnormalities in College-Aged Students (MACS) study. Lumbar spine BMD was measured in all subjects using dual-energy X-ray absorptiometry. Clinical, diet, and laboratory information also was gathered at this time. We determined free and bioavailable (free + albumin-bound) 25(OH)D using previously validated formulas and examined their associations with BMD. BMD was not associated with total 25(OH)D levels (r = 0.172, p = .236). In contrast, free and bioavailable 25(OH)D levels were positively correlated with BMD (r = 0.413, p = .003 for free, r = 0.441, p = .002 for bioavailable). Bioavailable 25(OH)D levels remained independently associated with BMD in multivariate regression models adjusting for age, sex, body mass index, and race (p = .03). It is concluded that free and bioavailable 25(OH)D are more strongly correlated with BMD than total 25(OH)D. These findings have important implications for vitamin D supplementation in vitamin D-deficient states. Future studies should continue to explore the relationship between free and bioavailable 25(OH)D and health outcomes.
| S-EPMC3351032 | biostudies-literature
Project description:ObjectivesTo compare the effects of 12 months of vitamin D3 supplementation with that placebo on lean mass, bone mineral density (BMD), and muscle strength in overweight or obese postmenopausal women completing a structured weight-loss program.DesignDouble-blind, placebo-controlled randomized clinical trial.SettingFred Hutchinson Cancer Research Center, Seattle, Washington.ParticipantsPostmenopausal women aged 50 to 75 with a body mass index (BMI) of 25 kg/m(2) or greater and a serum 25-hydroxyvitamin D (25(OH)D) concentration between 10.0 and 32.0 ng/mL (insufficient) (N = 218).InterventionOral vitamin D3 2,000 IU/d or placebo in combination with a lifestyle-based weight loss intervention consisting of a reduction of 500 kcal to 1,000 kcal per day and 225 min/wk of moderate- to vigorous-intensity aerobic exercise.MeasurementsSerum 25(OH)D, body composition, and muscle strength were measured before randomization (baseline) and at 12 months. Mean changes of the groups were compared (intention to treat) using generalized estimating equations.ResultsChange in 25(OH)D was significantly different between the vitamin D and placebo groups at 12 months (13.6 ng/mL vs -1.3 ng/mL, P < .001), but no differences in change in lean mass (-0.8 kg vs -1.1 kg, P = .53) or BMD of the spine (-0.01 g/cm(2) vs 0.0 g/cm(2) , P = .82) or right femoral neck (both -0.01 g/cm(2) , P = .49) were detected between the groups. Leg strength decreased in the vitamin D group but not in the placebo group (-2.6 pounds vs 1.8 pounds, P = .03). In women randomized to vitamin D, achieving repletion (25(OH)D ≥ 32 ng/mL) did not alter results.ConclusionVitamin D3 supplementation during weight-loss decreased leg strength but did not alter changes in lean mass or BMD in postmenopausal women with vitamin D insufficiency.
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Project description: Not available
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Project description:BackgroundVitamin K modulates cytokines involved in bone turnover, including interleukin-6 (IL-6) and osteoprotegerin in vitro.ObjectiveThe objective of this study was to assess 1) associations between measures of vitamin K status [plasma phylloquinone and serum percentage of undercarboxylated osteocalcin (%ucOC)] and IL-6, osteoprotegerin, and C-reactive protein (CRP) concentrations and 2) the effect of daily 500 mug phylloquinone supplementation for 3 y on cytokine concentrations.DesignConcentrations of IL-6, osteoprotegerin, and CRP and bone mineral density (BMD) were measured at baseline and after 3 y of follow-up in 379 healthy men and women (60-81 y; 58.5% women) participating in a randomized trial that studied the effect of vitamin K supplementation on bone loss.ResultsCross-sectionally, plasma phylloquinone was inversely associated with IL-6 and CRP, whereas serum %ucOC was inversely associated with IL-6. Osteoprotegerin was associated positively with plasma phylloquinone and inversely with %ucOC. No differences were observed in the 3-y change in IL-6, osteoprotegerin, and CRP concentrations between participants who received phylloquinone supplementation and those who did not. Overall, no association was observed between the 3-y changes in circulating cytokines and BMD.ConclusionsPoor vitamin K status was associated with high concentrations of cytokines involved in bone turnover, but vitamin K supplementation did not confer a decrease in cytokine concentrations. The healthy status of this cohort may explain a lack of effect of vitamin K supplementation on cytokine concentrations. This trial was registered with www.clinicaltrials.gov as NCT00183001.
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Project description:Previous studies demonstrate associations of low 25-hydroxyvitamin D (25(OH)D) concentrations with low bone mineral density (BMD) and fractures, motivating widespread use of vitamin D supplements for bone health. However, previous studies have been limited to predominantly White populations despite differences in the distribution and metabolism of 25(OH)D by race/ethnicity. We determined associations of serum 25(OH)D, 24,25-dihydroxyvitamin D (24,25(OH2)D3), and parathyroid hormone (PTH) with BMD among 1773 adult participants in the Multi-Ethnic Study of Atherosclerosis (MESA) in a staggered cross-sectional study design. Vitamin D metabolites were measured using liquid chromatography-mass spectroscopy and PTH using a 2-site immunoassay from serum collected in 2000-2002. Volumetric trabecular lumbar BMD was measured from computed tomography scans performed in 2002-2005 expressed as g/cm(3). We used linear regression and graphical methods to compare associations of vitamin D metabolite and PTH concentrations with BMD as the outcomes measure among White (n=714), Black (n=353), Chinese (n=249), and Hispanic (n=457) participants. Serum 25(OH)D and 24,25(OH2)D3 concentrations were highest among Whites and lowest among Blacks. BMD was greatest among Black participants. Higher serum 25(OH)D was only associated with higher BMD among Whites and Chinese participants (P-for-interaction=0.054). Comparing the lowest category of 25(OH)D (<20 ng/ml) to the highest (≥30 ng/ml), the adjusted mean difference in BMD was -8.1g/cm3 (95% CI -14.8, -1.4) for Whites; -10.2g/cm3 (-20.4, 0.0) for Chinese vs. 8.8 g/cm3 (-2.8, 20.5) for Black and -1.1g/cm3 (-8.3, 6.2) for Hispanic. Similar results were observed for serum 24,25(OH2)D3. Serum PTH was not associated with BMD. In a multi-ethnic population, associations of 25(OH)D with BMD were strongest among White and Chinese participants and null among Black and Hispanic participants. Further studies are needed to determine optimal biomarkers for bone health for multiple ethnic groups.
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Project description:BACKGROUND:Low bone mineral density (BMD) is a significant comorbidity in HIV. However, studies evaluating vitamin D supplementation on bone health in this population are limited. This study investigates changes in bone health parameters after 12 months of supplementation in HIV-infected youth with vitamin D insufficiency. METHODS:This is a randomized, active-control, double-blind trial investigating changes in bone parameters with 3 different vitamin D3 doses [18,000 (standard/control dose), 60,000 (moderate dose), and 120,000 IU/monthly (high dose)] in HIV-infected youth 8-25 years old with baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations <30 ng/mL. BMD and bone turnover markers were measured at baseline and 12 months. RESULTS:One hundred two subjects enrolled. Over 12 months, serum 25(OH)D concentrations increased with all doses, but the high dose (ie, 120,000 IU/monthly) maintained serum 25(OH)D concentrations in an optimal range (?30 or ?20 ng/mL) throughout the study period for more subjects (85% and 93%, respectively) compared with either the moderate (54% and 88%, respectively) or standard dose (63% and 80%, respectively). All dosing groups showed some improvement in BMD; however, only the high-dose arm showed significant decreases in bone turnover markers for both procollagen type 1 aminoterminal propeptide (-3.7 ng/mL; P = 0.001) and ?-CrossLaps (-0.13 ng/mL; P = 0.0005). CONCLUSIONS:High-dose vitamin D supplementation (120,000 IU/mo) given over 12 months decreases bone turnover markers in HIV-infected youth with vitamin D insufficiency, which may represent an early, beneficial effect on bone health. High vitamin D doses are needed to maintain optimal serum 25(OH)D concentrations.
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Project description:Low serum 25-hydroxyvitamin D (25OHD) is associated with osteoporosis and osteoporotic fracture, but it remains uncertain whether these associations are causal. We conducted a Mendelian randomization (MR) study of 1,824 postmenopausal Chinese women to examine whether the detected associations between serum 25OHD and bone mineral density (BMD) and bone metabolism markers were causal. In observational analyses, total serum 25OHD was positively associated with BMD at lumbar spine (P = 0.003), femoral neck (P = 0.006) and total hip (P = 0.005), and was inversely associated with intact parathyroid hormone (PTH) (P = 8.18E-09) and procollagen type 1 N-terminal propeptide (P1NP) (P = 0.020). By contract, the associations of bioavailable and free 25OHD with all tested outcomes were negligible (all P > 0.05). The use of four single nucleotide polymorphisms, GC-rs2282679, NADSYN1-rs12785878, CYP2R1-rs10741657 and CYP24A1-rs6013897, as candidate instrumental variables in MR analyses showed that none of the two stage least squares models provided evidence for associations between serum 25OHD and either BMD or bone metabolism markers (all P > 0.05). We suggest that after controlling for unidentified confounding factors in MR analyses, the associations between genetically low serum 25OHD and BMD and bone metabolism markers are unlikely to be causal.
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Project description:UNLABELLED:New models describing anthropometrically adjusted normal values of bone mineral density and content in children have been created for the various measurement sites. The inclusion of multiple explanatory variables in the models provides the opportunity to calculate Z-scores that are adjusted with respect to the relevant anthropometric parameters. INTRODUCTION:Previous descriptions of children's bone mineral measurements by age have focused on segmenting diverse populations by race and sex without adjusting for anthropometric variables or have included the effects of a single anthropometric variable. METHODS:We applied multivariate semi-metric smoothing to the various pediatric bone-measurement sites using data from the Bone Mineral Density in Childhood Study to evaluate which of sex, race, age, height, weight, percent body fat, and sexual maturity explain variations in the population's bone mineral values. By balancing high adjusted R(2) values with clinical needs, two models are examined. RESULTS:At the spine, whole body, whole body sub head, total hip, hip neck, and forearm sites, models were created using sex, race, age, height, and weight as well as an additional set of models containing these anthropometric variables and percent body fat. For bone mineral density, weight is more important than percent body fat, which is more important than height. For bone mineral content, the order varied by site with body fat being the weakest component. Including more anthropometrics in the model reduces the overlap of the critical groups, identified as those individuals with a Z-score below -2, from the standard sex, race, and age model. CONCLUSIONS:If body fat is not available, the simpler model including height and weight should be used. The inclusion of multiple explanatory variables in the models provides the opportunity to calculate Z-scores that are adjusted with respect to the relevant anthropometric parameters.
| S-EPMC4768717 | biostudies-literature
Project description:Objectives: To assess the effect of vitamin D supplementation on bone mineral density (BMD) in rheumatoid arthritis (RA) patients with osteoporosis and determine whether supplementation of more than 800 IU/day, which is the currently recommended dose, is beneficial. Methods: RA patients with osteoporosis who received bisphosphonate were included. Patients were classified into four groups according to the dose of vitamin D supplementation (0, 400, 800, and ≥1,000 IU/day). Multivariable linear regression models were performed to evaluate the effect of each dose of vitamin D supplementation on 1-year% change of BMD. Results: In total, 187 RA patients with osteoporosis were included. In the multivariate model adjusted for potential confounders, patients receiving vitamin D supplementation had a significantly higher increase in 1-year % change in lumbar spine BMD (400 IU/day: β = 2.51 [95% CI: 0.04-4.99], 800 IU/day: β = 2.90 [95% CI: 0.47-5.33], and ≥1,000 IU/day: β = 6.01 [95% CI: 3.71-8.32]) and femoral neck BMD (400 IU/day: β = 3.88 [95% CI: 1.83-5.94], 800 IU/day: β =4.30 [95% CI: 2.25-6.35], and ≥1,000 IU/day: β = 6.79 [95% CI: 4.87-8.71]) than those not receiving the supplementation. Notably, the ≥1,000-IU/day group had a significantly higher increase in 1-year % change in lumbar spine BMD (β = 3.11 [95% CI: 0.86-5.37]) and femoral neck BMD (β = 2.50 [95% CI: 0.63-4.36]) than the 800-IU/day group. Conclusion: In RA patients with osteoporosis receiving bisphosphonates, vitamin D supplementation was associated with a higher increase in BMD. This effect was higher in the vitamin D supplementation dose of ≥1,000 IU/day than in 800 IU/day.
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