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ABSTRACT: BACKGROUND: Previously, we showed that black girls retained more calcium than white girls did and that salt loading negatively affected calcium retention. Racial differences likely exist in other bone minerals also, such as magnesium, in response to salt loading during growth. OBJECTIVE: We studied racial differences in magnesium metabolism in response to dietary sodium and calcium during rapid bone growth. DESIGN: Twenty-seven white and 40 black girls (11-15 y old) were studied for 3 wk while they consumed low-sodium (1.3 g/d) and high-sodium (3.8 g/d) diets by using a randomized-order, crossover metabolic study with 3 dietary calcium intakes; the magnesium dietary intake was fixed at 230 mg/d. Urine and feces were collected during each 3-wk period in 24-h pools and analyzed for magnesium. A mixed-model ANOVA was used to determine the effect of race and dietary sodium with calcium intake as a covariate. RESULTS: Salt loading or calcium intake had no significant effect on urinary magnesium excretion. Blacks excreted significantly less urinary magnesium (mean ± SD: 83.8 ± 25.6 mg/d) than did whites (94.9 ± 27.3 mg/d; P < 0.05). No effects were observed in fecal magnesium excretion. Magnesium retention was higher with the low-sodium diet (50.1 ± 44.0 mg/d) than with the high-sodium diet (39.3 ± 49.8 mg/d (P < 0.05), with no effects of race or calcium intake. Salt loading had no effect on biomarkers. Whites had higher 25-hydroxyvitamin D and insulin-like growth factor binding protein 3 but lower 1,25-dihydroxyvitamin D and parathyroid hormone concentrations. CONCLUSIONS: Blacks excreted less urinary magnesium than did whites. Magnesium retention was similar between races but higher with the low-sodium diet. Kinetic studies are needed to fully explain magnesium homeostasis. This trial was registered at clinicaltrials.gov as NCT01564238.
American Journal of Clinical Nutrition 04/2013; · 6.67 Impact Factor
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ABSTRACT: Patients with chronic kidney disease (CKD) are given calcium carbonate to bind dietary phosphorus, reduce phosphorus retention, and prevent negative calcium balance; however, data are limited on calcium and phosphorus balance during CKD to support this. Here, we studied eight patients with stage 3 or 4 CKD (mean estimated glomerular filtration rate 36 ml/min) who received a controlled diet with or without a calcium carbonate supplement (1500 mg/day calcium) during two 3-week balance periods in a randomized placebo-controlled cross-over design. All feces and urine were collected during weeks 2 and 3 of each balance period and fasting blood, and urine was collected at baseline and at the end of each week. Calcium kinetics were determined using oral and intravenous (45)calcium. Patients were found to be in neutral calcium and phosphorus balance while on the placebo. Calcium carbonate supplementation produced positive calcium balance, did not affect phosphorus balance, and produced only a modest reduction in urine phosphorus excretion compared with placebo. Calcium kinetics demonstrated positive net bone balance but less than overall calcium balance, suggesting soft-tissue deposition. Fasting blood and urine biochemistries of calcium and phosphate homeostasis were unaffected by calcium carbonate. Thus, the positive calcium balance produced by calcium carbonate treatment within 3 weeks cautions against its use as a phosphate binder in patients with stage 3 or 4 CKD, if these findings can be extrapolated to long-term therapy.Kidney Internationaladvance online publication, 19 December 2012; doi:10.1038/ki.2012.403.
Kidney International 12/2012; · 6.61 Impact Factor
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Daniel L Koller,
Hou-Feng Zheng,
David Karasik,
Laura Yerges-Armstrong,
Ching-Ti Liu,
Fiona McGuigan,
John P Kemp,
Sylvie Giroux,
Dongbing Lai,
Howard J Edenberg, [......],
Jerilynn C Prior,
Tim D Spector,
Francois Rousseau,
Jon H Tobias,
Kristina Akesson,
Michael J Econs,
Braxton D Mitchell,
J Brent Richards,
Douglas P Kiel,
Tatiana Foroud
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ABSTRACT: Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous SNPs of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n= 4,061 women, ages 20 to 45) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. Following imputation, age- and weight-adjusted BMD values were tested for association with each SNP. Association of a SNP in the WNT16 gene (rs3801387; p=1.7 x 10(-9) ) and multiple SNPs in the ESR1/C6orf97 (rs4870044; p=1.3 x 10(-8) ) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven Replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n=5,597 for femoral neck; 4,744 for lumbar spine). When the data from the Discovery and Replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p=1.3 x 10(-11) ; ESR1/C6orf97 joint p= 1.4 x 10(-10) ). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p< 1 x 10(-5) ). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period. © 2012 American Society for Bone and Mineral Research.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 10/2012; · 6.04 Impact Factor
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ABSTRACT: Low serum 25-hydroxyvitamin D [25 (OH) D] is common in healthy children particularly in blacks. However, serum 25 (OH) D concentrations for optimal bone turnover in children is unknown and few data exist that describe effects of increasing serum 25 (OH) D on bone turnover markers during puberty. The purpose of this study was to determine the relationships between serum 25 (OH) D and changes in serum 25 (OH) D and bone turnover in white and black pubertal adolescents. Bone turnover markers were measured in 318 healthy boys and girls from Georgia (34°N) and Indiana (40°N) who participated in a study of oral vitamin D(3) supplementation (0 to 4000 IU/d). Serum 25 (OH) D, osteocalcin, bone alkaline phosphatase, and urine N-telopeptide cross-links were measured at baseline and 12 weeks. Relationships among baseline 25 (OH) D and bone biomarkers, and between changes over 12 weeks were determined and tested for effects of race, sex, latitude, and baseline 25 (OH) D. Median 25 (OH) D was 27.6 ng/mL (n=318, range 10.1-46.0 ng/mL) at baseline and 34.5 ng/mL (n=302, range 9.7-95.1 ng/mL) at 12 weeks. Neither baseline nor change in 25 (OH) D over 12 weeks was associated with bone turnover. The lack of association was not affected by race, sex, latitude, or baseline serum 25 (OH) D. Serum 25 (OH) D in the range of 10-46 ng/mL appears to be sufficient for normal bone turnover in healthy black and white pubertal adolescents.
Bone 06/2012; 51(4):795-9. · 4.02 Impact Factor
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Karol Estrada,
Unnur Styrkarsdottir,
Evangelos Evangelou,
Yi-Hsiang Hsu,
Emma L Duncan,
Evangelia E Ntzani,
Ling Oei,
Omar M E Albagha,
Najaf Amin,
John P Kemp, [......],
Claes Ohlsson,
David Karasik,
J Brent Richards,
Matthew A Brown,
Kari Stefansson,
André G Uitterlinden,
Stuart H Ralston,
John P A Ioannidis,
Douglas P Kiel,
Fernando Rivadeneira
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ABSTRACT: Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
Nature Genetics 04/2012; 44(5):491-501. · 35.53 Impact Factor
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ABSTRACT: Obesity is associated with hyperparathyroidism and increased bone mass and turnover, but their pathogeneses are unclear.
Our aim was to determine in obesity interrelationships among serum levels of leptin, the mineral-regulating hormones, bone turnover markers, and sclerostin.
This case-control study was performed in 20 women having bariatric surgery and 20 control women matched for race and age. Anthropometrics and fasting serum biochemistries were measured in controls and in bariatric patients the morning of surgery.
Body mass index (48.9 vs. 25.4 kg/m(2)), weight (128.6 vs. 71.9 kg), serum leptin (74.6 vs. 25.2 ng/ml), PTH (44.5 vs. 28.8 pg/ml), fibroblast growth factor 23 (FGF23) (42.4 vs. 25.9 pg/ml), and bone alkaline phosphatase (BAP) (25.8 vs. 17.5 U/liter) were higher, but height (162.3 vs. 167.7 cm) and 1,25-dihydroxyvitamin D (1,25D) (39.2 vs. 48.7 pg/ml) were lower in bariatric surgery patients than controls. There was no difference in serum sclerostin, amino-terminal collagen cross-links, 25-hydroxyvitamin D (25D), calcium, phosphate, and creatinine between groups. In the combined sample, leptin was positively related to PTH, FGF23, and BAP but not to 1,25D or sclerostin. Multiple regression analysis demonstrated that PTH was predicted by leptin and Ca (R(2) = 0.39); 1,25D by 25D, FGF23, and phosphate (R(2) = 0.43); FGF23 by leptin and 1,25D (R(2) = 0.27); BAP by leptin, PTH, and Ca (R(2) = 0.39); and sclerostin by leptin and PTH (R(2) = 0.20).
Women having bariatric surgery had higher leptin, PTH, FGF23, and BAP and lower 1,25D than controls. Leptin predicted the serum levels of PTH, 1,25D, and FGF23, the mineral-regulating hormones, and BAP, a bone formation marker, in women with body mass index ranging from 13.9-65.8 kg/m(2). The results suggest that leptin has an endocrine or paracrine effect on PTH and FGF23 production and that PTH may be one of the signals in obesity that leads to increased bone mass.
The Journal of clinical endocrinology and metabolism 02/2012; 97(5):1655-62. · 6.50 Impact Factor
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Emily G Farrow,
Xijie Yu,
Lelia J Summers,
Siobhan I Davis,
James C Fleet,
Matthew R Allen,
Alexander G Robling,
Keith R Stayrook,
Victoria Jideonwo,
Martin J Magers,
Holly J Garringer,
Ruben Vidal,
Rebecca J Chan,
Charles B Goodwin,
Siu L Hui, Munro Peacock,
Kenneth E White
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ABSTRACT: Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in the FGF23 (176)RXXR(179)/S(180) proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This onset may occur in physiological states associated with iron deficiency, including puberty and pregnancy. To test the role of iron status in development of the ADHR phenotype, WT and R176Q-Fgf23 knock-in (ADHR) mice were placed on control or low-iron diets. Both the WT and ADHR mice receiving low-iron diet had significantly elevated bone Fgf23 mRNA. WT mice on a low-iron diet maintained normal serum intact Fgf23 and phosphate metabolism, with elevated serum C-terminal Fgf23 fragments. In contrast, the ADHR mice on the low-iron diet had elevated intact and C-terminal Fgf23 with hypophosphatemic osteomalacia. We used in vitro iron chelation to isolate the effects of iron deficiency on Fgf23 expression. We found that iron chelation in vitro resulted in a significant increase in Fgf23 mRNA that was dependent upon Mapk. Thus, unlike other syndromes of elevated FGF23, our findings support the concept that late-onset ADHR is the product of gene-environment interactions whereby the combined presence of an Fgf23-stabilizing mutation and iron deficiency can lead to ADHR.
Proceedings of the National Academy of Sciences 11/2011; 108(46):E1146-55. · 9.68 Impact Factor
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Connie M Weaver,
Wayne W Campbell,
Dorothy Teegarden,
Bruce A Craig,
Berdine R Martin,
Rajni Singh,
Michelle M Braun,
John W Apolzan,
Tamara S Hannon,
Dale A Schoeller,
Linda A DiMeglio,
Yvonne Hickey, Munro Peacock
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ABSTRACT: Dairy product and calcium consumption have been associated with modifying body fat and body weight in children and adults.
In overweight adolescent boys and girls, we aimed to determine the effect of the doubling of habitual calcium intake to the recommended intake from dairy or calcium carbonate on energy balance and purported mechanisms including fecal fat excretion, macronutrient use, and parathyroid hormone suppression.
Twenty-five girls with a mean (±SD) BMI (in kg/m(2)) of 33 ± 5 and 17 boys with a BMI of 28 ± 5, aged 12-15 y, participated in two 3-wk controlled feeding sessions that used a crossover design in random order as a summer research camp. In one session, 756 mg Ca/d was consumed; in the other session, an additional 650 mg Ca/d was provided as dairy or calcium carbonate supplements that were matched to the control in macronutrient content. Total energy and macronutrient intakes were controlled and were the same for the 2 sessions for each subject. Primary outcome measures were energy balance, fecal fat excretion, lipid oxidation, and postprandial energy expenditure.
There were no effects of quantity or source of calcium on energy or fat balance, despite calcium-induced increases (P <0.01) in postprandial serum parathyroid hormone suppression.
These data lend little evidence to support the proposed mechanisms for the relation between an increase in calcium intake from calcium carbonate or dairy and weight loss or weight maintenance in children. This trial was registered at clinicaltrials.gov as NCT00592137.
American Journal of Clinical Nutrition 09/2011; 94(5):1163-70. · 6.67 Impact Factor
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ABSTRACT: In autosomal dominant hypophosphatemic rickets (ADHR), fibroblast growth factor 23 (FGF23) resists cleavage, causing increased plasma FGF23 levels. The clinical phenotype includes variable onset during childhood or adulthood and waxing/waning of hypophosphatemia. Delayed onset after puberty in females suggests iron status may be important.
Studies were performed to test the hypothesis that plasma C-terminal and intact FGF23 concentrations are related to serum iron concentrations in ADHR.
Cross-sectional and longitudinal studies of ADHR and a cross-sectional study in healthy subjects were conducted at an academic medical center.
Participants included 37 subjects with ADHR mutations from four kindreds and 158 healthy adult controls.
The relationships of serum iron concentrations with plasma C-terminal and intact FGF23 concentrations were evaluated.
Serum phosphate and 1,25-dihydroxyvitamin D correlated negatively with C-terminal FGF23 and intact FGF23 in ADHR but not in controls. Serum iron was negatively correlated to both C-terminal FGF23 (r = -0.386; P < 0.05) and intact FGF23 (r = -0.602; P < 0.0001) in ADHR. However, control subjects also demonstrated a negative relationship of serum iron with C-terminal FGF23 (r = -0.276; P < 0.001) but no relationship with intact FGF23. Longitudinally in ADHR subjects, C-terminal FGF23 and intact FGF23 concentrations changed negatively with iron concentrations (P < 0.001 and P = 0.055, respectively), serum phosphate changed negatively with C-terminal FGF23 and intact FGF23 (P < 0.001), and there was a positive relationship between serum iron and phosphate (P < 0.001).
Low serum iron is associated with elevated FGF23 in ADHR. However, in controls, low serum iron was also associated with elevated C-terminal FGF23, but not intact FGF23, suggesting cleavage maintains homeostasis despite increased FGF23 expression.
The Journal of clinical endocrinology and metabolism 08/2011; 96(11):3541-9. · 6.50 Impact Factor
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ABSTRACT: Increasing calcium bioavailability by decreasing calcium salt particle size in the supplement may be one way to increase calcium absorption. The aim of the study was to compare (1) large versus small particle size CaCO(3) supplements and (2) small particle size CaCO(3) supplement versus placebo on calcium absorption and retention in adolescent girls.
Thirty-one adolescent girls, aged 11 to 14 years, participated in two 3-week calcium balance periods separated by a 1-week washout period. During both balance periods, the subjects consumed a controlled diet containing 804 mg/d calcium. Using a crossover design, one group (n = 19) received an additional ∼600 mg/d calcium of two ∼300-mg calcium doses as either large particle (18 μm; i.e., standard commercial form) or small particle (13.5 μm) CaCO(3). A second group (n = 12) received ∼600 mg/d calcium from small-particle CaCO(3) or placebo.
The parathyroid hormone suppression curve, following a challenge, from the first arm of the study indicated that calcium absorption from the small particle size CaCO(3) was less than that from the large particle size CaCO(3). The parathyroid hormone suppression curve from the small particle versus placebo arm indicated that calcium absorption from small particle size CaCO(3) was greater than placebo. Calcium balance (Ca intake - [urine Ca + fecal Ca]) demonstrated that the small particle size CaCO(3) supplement increased Ca retention nearly 2-fold compared with placebo (p < 0.05; 496 ± 213 and 256 ± 94 mg/d, respectively). However, there was no significant difference in Ca retention due to small versus large particle size of CaCO(3) (p > 0.05; 349.1 ± 131.6 and 322.0 ± 194.2 mg/d, respectively).
Dietary supplementation with CaCO(3) is effective in increasing calcium absorption and retention compared with placebo. But there is no advantage of small compared with large particle size CaCO(3) on calcium absorption and retention.
Journal of the American College of Nutrition 06/2011; 30(3):171-7. · 2.29 Impact Factor
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Advances in nutrition (Bethesda, Md.). 05/2011; 2(3):290-2.
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ABSTRACT: Overweight adolescents have low bone mineral content for weight and are at increased risk for fractures.
The aim was to determine whether overweight and obesity influence the positive relationship between dietary calcium intake and skeletal calcium retention in adolescents.
Analysis of pooled data from calcium balance studies in adolescents.
Participants each underwent a 3-wk calcium balance study in a controlled environment.
Participants included 280 White, Black, and Asian boys (n = 73) and girls (n = 207) ages 10-16 yr.
The relationship among body mass index (BMI), calcium intake, and calcium retention was modeled using linear regression.
Calcium intake, BMI, sex, race, and age explained 27.9% of the variation in calcium retention. At low calcium intakes, there was no effect of BMI on skeletal calcium retention, but at higher calcium intakes, BMI increased skeletal calcium retention.
Greater gains in calcium retention occur with increases in calcium intake in adolescents with higher BMI compared with those with lower BMI. Additional studies are needed to investigate whether increasing calcium intake reduces the increased risk of fracture associated with overweight and obesity in adolescents.
The Journal of clinical endocrinology and metabolism 04/2011; 96(7):2171-7. · 6.50 Impact Factor
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ABSTRACT: Low vitamin D status and hyperparathyroidism occur in obesity and may be involved in pathogenesis of obesity-associated comorbid conditions.
Our aims were to determine in obesity whether there was vitamin D insufficiency, assessed by serum 25-hydroxyvitamin D (s25D) and serum PTH (sPTH) and whether it related to comorbid conditions.
We conducted a case-control study of 48 women having bariatric surgery and 50 healthy women frequency matched for race, age, year, and season of study. Height, weight, s25D, sPTH, serum 1,25-dihydroxyvitamin D (s1,25D), serum bone alkaline phosphatase, serum cross-linked N-telopeptides of type 1 collagen, and serum calcium, phosphate, creatinine, glucose, and insulin were measured, and comorbid conditions were documented from patient files.
Weight (140 vs. 76 kg, P < 0.001), sPTH (44.4 vs. 25.6 pg/ml, P < 0.001), s1,25D (39 vs. 24 pg/ml, P < 0.001), serum bone alkaline phosphatase (19 vs. 12 ng/ml, P < 0.001), serum cross-linked N-telopeptides of type 1 collagen (9.6 vs. 7.9 nm bone collagen equivalents, P = 0.007), serum phosphate (3.45 vs. 3.24 mg/dl, P = 0.043), and serum creatinine (1.05 vs. 0.87 mg/dl, P < 0.001) were higher, and s25D (16 vs. 23 ng/ml, P <.001) was lower in bariatric-surgery women than control women. s25D was lower in bariatric-surgery women than controls in summer (17 vs. 26 ng/ml, P < 0.0001) but not winter (15 vs. 18 ng/ml, P > 0.2). Multiple regression analysis demonstrated that weight predicted s25D (P < 0.001) and sPTH (P = 0.001), but s25D did not predict sPTH or the presence of comorbid conditions except for osteoarthritis.
Women having bariatric surgery had lower s25D and higher sPTH. The major determinant of s25D and sPTH was weight. Hyperparathyroidism in obesity did not indicate vitamin D insufficiency. Low s25D was not associated with comorbid conditions, apart from osteoarthritis.
The Journal of clinical endocrinology and metabolism 02/2011; 96(5):1320-6. · 6.50 Impact Factor
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ABSTRACT: This is a study extension to evaluate the efficacy and safety of long-term treatment with denosumab in postmenopausal women with low bone mass.
Our objective was to describe changes in bone mineral density (BMD) and bone turnover markers as well as safety with 6 yr of denosumab treatment.
We conducted an ongoing 4-yr, open-label, single-arm, extension study of a dose-ranging phase 2 trial. This paper reports a 2-yr interim analysis representing up to 6 yr of continuous denosumab treatment.
This multicenter study was conducted at 23 U.S. centers.
Of the 262 subjects who completed the parent study, 200 enrolled in the study extension and 178 (89%) completed the first 2 yr.
All subjects received denosumab 60 mg sc every 6 months.
We evaluated BMD at the lumbar spine, total hip, femoral neck, and one third radius; biochemical markers of bone turnover; and safety, reported as adverse events.
Over a period of 6 yr, continuous treatment with denosumab resulted in progressive gains in BMD in postmenopausal women with low bone mass. Reduction in bone resorption was sustained over the course of continuous treatment. Independent of past treatment and discontinuation period, subjects demonstrated responsiveness to denosumab therapy as measured by BMD and bone turnover markers. The safety profile of denosumab did not change over time.
In this study, denosumab was well tolerated and effective through 6 yr of continuous treatment in postmenopausal women with low bone mass.
The Journal of clinical endocrinology and metabolism 02/2011; 96(2):394-402. · 6.50 Impact Factor
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ABSTRACT: Simultaneous and accurate measurement of vitamin D and 25-hydroxyvitamin D in biological samples is a barrier limiting our ability to define "optimal" vitamin D status. Thus, our goal was to optimize conditions and evaluate an LC-MS method for simultaneous detection and quantification of vitamin D(2) , vitamin D(3) , 25-hydroxyvitamin D(2) and 25-hydroxyvitamin D(3) in serum. Extraction and separation of vitamin D forms were achieved using acetone liquid-liquid extraction and by a reversed phase C8 column, respectively. Detection was performed on a triple quadrupole tandem mass spectrometer (QQQ-MS/MS) equipped with atmospheric pressure photo ionization source. The LOQs for all analytes tested were 1 ng/mL for hydroxylated molecules and 2 ng/mL for the parent vitamin Ds. RSD at lower LOQ (2 ng/mL) and in medium (80 ng/mL) and high (200 ng/mL) quality control samples did not exceed 20 and 15% CV, respectively. Accuracy of the method for determination of hydroxylated molecules was also validated using National Institutes of Standards and Technology standard samples and found to be in the range of 90.9-111.2%. In summary, a sensitive and reproducible method is reported for simultaneous quantification of vitamin D(2) , vitamin D(3) , 25-hydroxyvitamin D(2) and 25-hydroxyvitamin D(3) molecules in biological samples.
Journal of Separation Science 01/2011; 34(1):11-20. · 2.73 Impact Factor
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Cathy E Elks,
John R B Perry,
Patrick Sulem,
Daniel I Chasman,
Nora Franceschini,
Chunyan He,
Kathryn L Lunetta,
Jenny A Visser,
Enda M Byrne,
Diana L Cousminer, [......],
Paul M Ridker,
Tim D Spector,
Elizabeth A Streeten,
Kari Stefansson,
Unnur Thorsteinsdottir,
André G Uitterlinden,
Elisabeth Widen,
Joanne M Murabito,
Ken K Ong,
Anna Murray
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ABSTRACT: To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
Nature Genetics 12/2010; 42(12):1077-85. · 35.53 Impact Factor
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ABSTRACT: Simultaneous and accurate measurement of vitamin D and 25-hydroxyvitamin D in biological samples is a barrier limiting our ability to define "optimal" vitamin D status. Thus, our goal was to optimize conditions and evaluate an LC-MS method for simultaneous detection and quantification of vitamin D(2), vitamin D(3), 25-hydroxyvitamin D(2) and 25-hydroxyvitamin D(3) in serum. Extraction and separation of vitamin D forms were achieved using acetone liquid-liquid extraction and by a reversed phase C8 column, respectively. Detection was performed on a triple quadrupole tandem mass spectrometer (QQQ-MS/MS) equipped with atmospheric pressure photo ionization source. The LOQs for all analytes tested were 1 ng/mL for hydroxylated molecules and 2 ng/mL for the parent vitamin Ds. RSD at lower LOQ (2 ng/mL) and in medium (80 ng/mL) and high (200 ng/mL) quality control samples did not exceed 20 and 15% CV, respectively. Accuracy of the method for determination of hydroxylated molecules was also validated using National Institutes of Standards and Technology standard samples and found to be in the range of 90.9-111.2%. In summary, a sensitive and reproducible method is reported for simultaneous quantification of vitamin D(2), vitamin D(3), 25-hydroxyvitamin D(2) and 25-hydroxyvitamin D(3) molecules in biological samples.
Journal of Separation Science 11/2010; · 2.73 Impact Factor
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ABSTRACT: Primary hyperparathyroidism (PHPT) is characterized by elevated serum calcium (Ca) and increased PTH concentrations.
The objective of the investigation was to establish the efficacy of cinacalcet in reducing serum Ca in patients with PHPT across a wide spectrum of disease severity.
The study was a pooled analysis of data from three multicenter clinical trials of cinacalcet in PHPT.
Patients were grouped into three disease categories for analysis based on the following: 1) history of failed parathyroidectomy (n = 29); 2) meeting one or more criteria for parathyroidectomy but without prior surgery (n = 37); and 3) mild asymptomatic PHPT without meeting criteria for either above category (n = 15).
The intervention in this study was treatment with cinacalcet for up to 4.5 yr.
Measurements in the study included serum Ca, PTH, phosphate, and bone-specific alkaline phosphatase, and areal bone mineral density (aBMD). Vital signs, safety biochemical and hematological indices, and adverse events were monitored throughout the study period.
The extent of cinacalcet-induced serum Ca reduction, proportion of patients achieving normal serum Ca (≤10.3 mg/dl), reduction in serum PTH, and increase in serum phosphate were similar across all three categories. Except for decreased aBMD at the total femur indicated for parathyroidectomy group at 1 yr, no significant changes in aBMD occurred. The efficacy of cinacalcet was maintained for up to 4.5 yr of follow-up. AEs were mild and similar across the three categories.
Cinacalcet is equally effective in the medical management of PHPT patients across a broad spectrum of disease severity, and overall cinacalcet is well tolerated.
The Journal of clinical endocrinology and metabolism 10/2010; 96(1):E9-18. · 6.50 Impact Factor
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ABSTRACT: In healthy adolescents, cross-sectional studies show either no or negative relationships between serum 25-hydroxyvitamin D [25(OH)D] and calcium (Ca) absorption. Using a 2-period metabolic balance study, the effect of vitamin D supplementation on Ca absorption and retention in adolescent girls was investigated. Eleven girls aged 12-14 y with a mean entry serum 25(OH)D of 35.1 nmol/L consumed a controlled intake (providing 5 μg vitamin D and 1117 mg Ca/d) for two 3-wk metabolic balance periods separated by a 1-wk washout period. Sunlight exposure was minimized by sunscreen with a sun protection factor ≥ 15. After the first metabolic balance period, participants received 25 μg/d cholecalciferol supplementation for 4 wk. Fractional Ca absorption was measured in each metabolic balance period using a stable Ca isotope method. All urine and fecal samples were collected and analyzed to measure net Ca absorption and Ca retention. Paired t tests and correlations were used to analyze the data. Daily supplementation with 25 μg vitamin D resulted in a mean increase in serum 25(OH)D of 13.3 nmol/L (P < 0.01) but a decrease in fractional Ca absorption of 8.3% (P < 0.05) and no significant change in fasting serum 1,25-dihydroxyvitamin D, parathyroid hormone, net Ca absorption, or Ca skeletal retention. In pubertal girls with vitamin D status considered insufficient in adults, vitamin D supplementation of 25 μg/d for 4 wk did not improve fractional Ca absorption, net Ca absorption, or Ca retention.
Journal of Nutrition 10/2010; 140(12):2139-44. · 3.92 Impact Factor
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Elizabeth A Yetley,
Christine M Pfeiffer,
Rosemary L Schleicher,
Karen W Phinney,
David A Lacher,
Sylvia Christakos,
John H Eckfeldt,
James C Fleet,
George Howard,
Andrew N Hoofnagle, [......],
Joseph Massaro, Munro Peacock,
Bernard Rosner,
Donald Wiebe,
Regan L Bailey,
Paul M Coates,
Anne C Looker,
Christopher Sempos,
Clifford L Johnson,
Mary Frances Picciano
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ABSTRACT: A roundtable to discuss monitoring of serum 25-hydroxyvitamin D [25(OH)D] in the NHANES was held in late July 2009. Topics included the following: 1) options for dealing with assay fluctuations in serum 25(OH)D in the NHANES conducted between 1988 and 2006; 2) approaches for transitioning between the RIA used in the NHANES between 1988 and 2006 to the liquid chromatography tandem MS (LC-MS/MS) measurement procedure to be used in NHANES 2007 and later; 3) approaches for integrating the recently available standard reference material for vitamin D in human serum (SRM 972) from the National Institute of Standards and Technology (NIST) into the NHANES; 4) questions regarding whether the C-3 epimer of 25-hydroxyvitamin D3 [3-epi-25(OH)D3] should be measured in NHANES 2007 and later; and 5) identification of research and educational needs. The roundtable experts agreed that the NHANES data needed to be adjusted to control for assay fluctuations and offered several options for addressing this issue. The experts suggested that the LC-MS/MS measurement procedure developed by NIST could serve as a higher order reference measurement procedure. They noted the need for a commutability study for the recently released NIST SRM 972 across a range of measurement procedures. They suggested that federal agencies and professional organizations work with manufacturers to improve the quality and comparability of measurement procedures across all laboratories. The experts noted the preliminary nature of the evidence of the 3-epi-25(OH)D3 but felt that it should be measured in 2007 NHANES and later.
Journal of Nutrition 09/2010; 140(11):2030S-45S. · 3.92 Impact Factor
