[Show abstract][Hide abstract] ABSTRACT: Ferritin, a 24-mer heteropolymer of heavy (H) and light (L) subunits, is the main cellular iron storage protein and plays a pivotal role in iron homeostasis by modulating free iron levels thus reducing radical-mediated damage. The H subunit has ferroxidase activity (converting Fe(II) to Fe(III)), while the L subunit promotes iron nucleation and increases ferritin stability. Previous studies on the H gene (Fth) in mice have shown that complete inactivation of Fth is lethal during embryonic development, without ability to compensate by the L subunit. In humans, homozygous loss of the L gene (FTL) is associated with generalized seizure and atypical restless leg syndrome, while mutations in FTL cause a form of neurodegeneration with brain iron accumulation. Here we generated mice with genetic ablation of the Fth and Ftl genes. As previously reported, homozygous loss of the Fth allele on a wild-type Ftl background was embryonic lethal, whereas knock-out of the Ftl allele (Ftl-/-) led to a significant decrease in the percentage of Ftl-/- newborn mice. Analysis of Ftl-/- mice revealed systemic and brain iron dyshomeostasis, without any noticeable signs of neurodegeneration. Our findings indicate that expression of the H subunit can rescue the loss of the L subunit and that H ferritin homopolymers have the capacity to sequester iron in vivo. We also observed that a single allele expressing the H subunit is not sufficient for survival when both alleles encoding the L subunit are absent, suggesting the need of some degree of complementation between the subunits as well as a dosage effect.
[Show abstract][Hide abstract] ABSTRACT: Objective: This report summarizes data on traditional and nontraditional manifestations of primary hyperparathyroidism (PHPT) that have been published since the last International Workshop on PHPT. Participants: This subgroup was constituted by the Steering Committee to address key questions related to the presentation of PHPT. Consensus was established at a closed meeting of the Expert Panel that followed. Evidence: Data from the 5-year period between 2008 and 2013 were presented and discussed to determine whether they support changes in recommendations for surgery or nonsurgical follow-up. Consensus Process: Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was undertaken. After extensive review and discussion, the subgroup came to agreement on what changes in the recommendations for surgery or nonsurgical follow-up of asymptomatic PHPT should be made to the Expert Panel. Conclusions: 1) There are limited new data available on the natural history of asymptomatic PHPT. Although recognition of normocalcemic PHPT (normal serum calcium with elevated PTH concentrations; no secondary cause for hyperparathyroidism)is increasing,data on the clinical presentation and natural history of this phenotypeare limited. 2) Although there are geographic differences in the predominant phenotypes of PHPT (symptomatic, asymptomatic, normocalcemic), they do not justify geography-specific management guidelines. 3) Recent data using newer, higher resolution imaging and analytic methods have revealed that in asymptomatic PHPT, both trabecular bone and cortical bone are affected. 4) Clinically silent nephrolithiasis and nephrocalcinosis can be detected by renal imaging and should be listed as a new criterion for surgery. 5) Current datadonot support a cardiovascular evaluation or surgery for the purpose of improving cardiovascular markers, anatomicalor functional abnormalities. 6) Some patients with mildPHPT have neuropsychological complaints and cognitive abnormalities, and some of these patients may benefit from surgical intervention. However, it is not possible at this time to predict which patients with neuropsychological complaints or cognitive issues will improve after successful parathyroid surgery.
[Show abstract][Hide abstract] ABSTRACT: Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
[Show abstract][Hide abstract] ABSTRACT: Urinary excretion of calcium tracers in labeled individuals decreases in response to antiresorptive therapy, providing a tool to rapidly screen potential therapies. Using teriparatide, we demonstrate in this study that anabolic therapy also decreases tracer excretion, confirming that this method can also be used to screen potential anabolic therapies.
Osteoporosis International 06/2014; 25(10). · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context: Though animal studies suggest that adenovirus 36 (Ad36) infection is linked to obesity and systemic inflammation, human data are scant and equivocal. Objective: Associations of Ad36 infection with total body adiposity and inflammatory-related markers were determined in 291 children ages 9-13 years (50% female, 49% black). Design: Fasting blood samples were measured for presence of Ad36-specific antibodies and tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein-1 (MCP-1). Fat mass and fat-free soft tissue (FFST) mass were measured by dual-energy X-ray absorptiometry. Results: The overall prevalence of Ad36 seropositivity [Ad36(+)] was 42%. There were a higher percentage of Ad36(+) children in the highest tertiles of TNF-α and IL-6 compared to their respective middle and lowest tertiles (both P<0.03). There was also a trend toward a higher prevalence of Ad36(+) children in the highest tertile of VEGF compared to Tertiles 1 and 2 (P=0.05). Multinomial logistic regression, adjusting for age, race, sex, and FFST mass, revealed that compared to children with the lowest TNF-α, IL-6 and VEGF levels (Tertile 1), the adjusted odds ratios for Ad36(+) were 2.2 (95% CI: 1.2-4.0), 2.4 (95% CI: 1.4-4.0) and 1.8 (95% CI: 1.0-3.3), respectively, for those in the highest TNF-α, IL-6 and VEGF levels (Tertile 3). No association was observed between Ad36(+) and greater levels of fat mass or MCP-1 (all P>0.05). Conclusions: In children, our data suggest that Ad36(+) may be associated with biomarkers implicated in inflammation, but not with greater levels of fat mass.
[Show abstract][Hide abstract] ABSTRACT: Mexican Americans are an understudied ethnic group for determinants of bone health, although the risk of age-related osteoporosis is high in this rapidly growing sector of the U.S. population. Thus, the objective of the present study was to establish the dietary calcium requirements for bone health in Mexican-American adolescents by measuring calcium retention calculated from balance in response to a range of dietary calcium intakes and to determine predictors of skeletal calcium retention. Adolescents aged 12-15 y were studied twice on paired calcium intakes ranging from 600 to 2300 mg/d using randomized-order, crossover 3-wk balance studies. Skeletal calcium retention was calculated as dietary calcium intake minus calcium excreted in feces and urine over the last 2 wk of balance. A linear model was developed to explain the variation on calcium retention. Boys (n = 20) were taller and had higher lean mass, usual dietary calcium intake, bone mineral content, and serum alkaline phosphatase compared with girls, whereas girls (n = 20) had higher Tanner scores and greater fat mass. Calcium retention increased with calcium intake (P < 0.0001) and did not differ by sex (P = 0.66). In boys and girls considered together, calcium intake explained 33% of the variation in calcium retention. Serum alkaline phosphatase explained an additional 11% of the variation in calcium retention. Other variables measured, including urine N-telopeptide of type I collagen/creatinine ratio, Tanner score, serum parathyroid hormone and 25-hydroxyvitamin D, weight, height, and body mass index, did not contribute to the variance in calcium retention. In adolescence, calcium retention in both Mexican-American boys and girls was higher than studied previously in adolescent nonHispanic white girls. This trial was registered at clinicaltrials.gov as NCT01277185.
Journal of Nutrition 05/2014; 144(8). · 4.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Soluble maize fibre (SCF) has been found to significantly improve bone mineral density and strength in growing rats compared with several other novel prebiotic fibres. The objective of the present study was to investigate the effect of SCF on Ca absorption and retention in pubertal children by studying the potential absorption mechanisms of the intestinal microbiota. A total of twenty-four adolescent boys and girls (12-15 years) participated in two 3-week metabolic balance studies testing 0 g/d SCF (control (CON) treatment) and 12 g/d SCF (SCF treatment) in a random order by inclusion in a low-Ca diet (600 mg/d). Fractional Ca absorption was measured at the end of the two intervention periods using a dual-stable isotope method. Diet composites and faecal and urine samples were collected daily and analysed for Ca content. Ca retention was calculated as dietary Ca intake minus Ca excretion in faeces and urine over the last 2 weeks. Microbial community composition in the faecal samples collected at the beginning and end of each session was determined by 454 pyrosequencing of the PCR-amplified 16S ribosomal RNA gene. Fractional Ca absorption was 12 % higher (41 mg/d) after the SCF treatment compared with that after the CON treatment (0·664 (sd 0·129) and 0·595 (sd 0·142), respectively; P= 0·02), but Ca retention was unaffected. The average proportion of bacteria of the phylum Bacteroidetes was significantly greater in the participants after the SCF treatment than after the CON treatment. These results suggest that moderate daily intake of SCF, a well-tolerated prebiotic fibre, increases short-term Ca absorption in adolescents consuming less than the recommended amounts of Ca.
British Journal Of Nutrition 05/2014; · 3.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis is a common complex disorder with reduced bone mineral density (BMD) and increased susceptibility to fracture. Peak BMD is one of the primary determinants of osteoporotic fracture risk, and is under substantial genetic control. Extracellular matrix, a major component of bone, influences BMD by regulating mineral deposition and maintaining cellular activity. It contains several SIBLING family proteins, null mutations of which cause mineralization defects in humans. In this study, we tested 59 single-nucleotide polymorphisms (SNPs) located in the 5 SIBLING family genes (DSPP, DMP1, IBSP, MEPE and SPP1) for association with normal variation in peak BMD in healthy men and women. We measured femoral neck (FN) and lumbar spine (LS) areal BMD by dual energy x-ray absorptiometry (DXA) in 1,692 premenopausal European-American women, 512 premenopausal African-American women and 715 European-American men. SNPs were tested for association with FN and LS BMD in the 3 subsamples. In the European-American women, we observed association (p≤0.005) with LS-BMD for SNPs in DSPP, IBSP and MEPE, and for FN-BMD with SNPs in DMP1 and IBSP. Allele specific regulation of gene expression (ASE) is an important mechanism in which an allele giving rise to modest influence in transcript abundance might result in a predisposition to disease. To identify whether there was ASE of SIBLING family genes at these SNPs, we examined 52 human bone samples obtained from the femoral neck during surgical hip replacement (27 female, 25 male; 44 European-American and 8 African-American). We observed unidirectional ASE for the IBSP gene, with lower expression of the G allele compared to the A allele for SNP rs17013181. Our data suggest that SNPs within the SIBLING genes may contribute to normal variation of peak BMD. Further studies are necessary to identify the functional variants and to determine the mechanisms underlying the differences in ASE and how these differences relate to the pathophysiology of osteoporosis.
[Show abstract][Hide abstract] ABSTRACT: Background. X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH. Methods. Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003-0.3 mg/kg i.v. or 0.1-1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days. Results. KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)2D compared with that of placebo (P < 0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8-15 days) compared with that seen with i.v. dosing (0.5-4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)2D correlated with serum KRN23 concentrations. The mean t1/2 of KRN23 was 8-12 days after i.v. administration and 13-19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine. Conclusion. KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)2D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients. Trial registration. Clinicaltrials.gov NCT00830674. Funding. Kyowa Hakko Kirin Pharma, Inc.
The Journal of clinical investigation 02/2014; · 15.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis is a common complex disorder with reduced bone mineral density (BMD) and increased susceptibility to fracture. Peak BMD is one of the primary determinants of osteoporotic fracture risk, and is under substantial genetic control. Extracellular matrix, a major component of bone, influences BMD by regulating mineral deposition and maintaining cellular activity. It contains several SIBLING family proteins, null mutations of which cause mineralization defects in humans. In this study, we tested 59 single-nucleotide polymorphisms (SNPs) located in the 5 SIBLING family genes (DSPP, DMP1, IBSP, MEPE and SPP1) for association with normal variation in peak BMD in healthy men and women. We measured femoral neck (FN) and lumbar spine (LS) areal BMD by dual energy x-ray absorptiometry (DXA) in 1,692 premenopausal European-American women, 512 premenopausal African-American women and 715 European-American men. SNPs were tested for association with FN and LS BMD in the 3 subsamples. In the European-American women, we observed association (p ≤ 0.005) with LS-BMD for SNPs in DSPP, IBSP and MEPE, and for FN-BMD with SNPs in DMP1 and IBSP. Allele specific regulation of gene expression (ASE) is an important mechanism in which an allele giving rise to modest influence in transcript abundance might result in a predisposition to disease. To identify whether there was ASE of SIBLING family genes at these SNPs, we examined 52 human bone samples obtained from the femoral neck during surgical hip replacement (27 female, 25 male; 44 European-American and 8 African-American). We observed unidirectional ASE for the IBSP gene, with lower expression of the G allele compared to the A allele for SNP rs17013181. Our data suggest that SNPs within the SIBLING genes may contribute to normal variation of peak BMD. Further studies are necessary to identify the functional variants and to determine the mechanisms underlying the differences in ASE and how these differences relate to the pathophysiology of osteoporosis.
[Show abstract][Hide abstract] ABSTRACT: Context:Changes in serum vitamin D metabolites and calcium absorption with varying doses of oral vitamin D3 in healthy children are unknown.Objective:Our objective was to examine the dose-response effects of supplemental vitamin D3 on serum vitamin D metabolites and calcium absorption in children living at two U.S. latitudes.Design:Black and white children (n = 323) participated in a multisite (U.S. latitudes 34° N and 40° N), triple-masked trial. Children were randomized to receive oral vitamin D3 (0, 400, 1000, 2000, and 4000 IU/d) and were sampled over 12 weeks in winter. Serum 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured using RIA and intact PTH (iPTH) by immunoradiometric assay. Fractional calcium absorption was determined from an oral stable isotope (44)Ca (5 mg) in a 150-mg calcium meal. Nonlinear and linear regression models were fit for vitamin D metabolites, iPTH, and calcium absorption.Results:The mean baseline 25(OH)D value for the entire sample was 70.0 nmol/L. Increases in 25(OH)D depended on dose with 12-week changes ranging from -10 nmol/L for placebo to 76 nmol/L for 4000 IU. Larger 25(OH)D gains were observed for whites vs blacks at the highest dose (P < .01). Gains for 1,25(OH)2D were not significant (P = .07), and decreases in iPTH were not dose-dependent. There was no dose effect of vitamin D on fractional calcium absorption when adjusted for pill compliance, race, sex, or baseline 25(OH)D.Conclusion:Large increases in serum 25(OH)D with vitamin D3 supplementation did not increase calcium absorption in healthy children living at 2 different latitudes. Supplementation with 400 IU/d was sufficient to maintain wintertime 25(OH)D concentrations in healthy black, but not white, children.
The Journal of Clinical Endocrinology and Metabolism 10/2013; · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: FGF23 gain of function mutations can lead to autosomal dominant hypophosphatemic rickets (ADHR) disease onset at birth, or delayed onset following puberty or pregnancy. We previously demonstrated that the combination of iron deficiency and a knock-in R176Q FGF23 mutation in mature mice induced FGF23 expression and hypophosphatemia that paralleled the late onset ADHR phenotype. As anemia in pregnancy and in premature infants is common, the goal of this study was to test whether iron deficiency alters phosphate handling in neonatal life. Wild type (WT) and ADHR female breeder mice were provided control or iron-deficient diets during pregnancy and nursing. Iron-deficient breeders were also made iron replete. Iron deficient WT and ADHR pups were hypophosphatemic, with ADHR pups having significantly lower serum phosphate (P < 0.01) and widened growth plates. Both genotypes increased bone FGF23 mRNA (>50 fold; P < 0.01). WT and ADHR pups receiving low iron had elevated intact serum FGF23 with ADHR mice affected to a greater degree (P < 0.01). Iron deficient mice also showed increased Cyp24a1 and reduced Cyp27b1, and low serum 1,25(OH)2 vitamin D. Iron repletion normalized most abnormalities. Because iron deficiency can induce tissue hypoxia, oxygen deprivation was tested as a regulator of FGF23, and was shown to stimulate FGF23 mRNA in vitro and serum C-terminal FGF23 in normal rats in vivo. These studies demonstrate that FGF23 is modulated by iron status in young WT and ADHR mice and that hypoxia independently controls FGF23 expression in situations of normal iron. Therefore, disturbed iron and oxygen metabolism in neonatal life may have important effects on skeletal function and structure through FGF23 activity on phosphate regulation.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 07/2013; · 6.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We assessed the influence of serum 25-hydroxyvitamin D (25[OH]D) and parathyroid hormone (PTH) concentrations on oral glucose tolerance, body composition, and muscle strength in older, nondiabetic adults who performed resistance exercise training (RT) while consuming diets with either 0.9 or 1.2 g protein kg(-1) d(-1). We hypothesized that individuals with insufficient 25(OH)D and/or high PTH would have less improvement in glucose tolerance after 12 weeks of RT compared with individuals with sufficient 25(OH)D and lower PTH. Sixteen men and 19 women (aged 61 ± 8 years; range, 50-80 years; body mass index, 26.3 ± 3.6 kg/m(2)) performed RT 3 times/wk for 12 weeks, with oral glucose tolerance tests done at baseline and postintervention. Protein intake did not influence the responses described below. Plasma glucose area under the curve (P = .02) and 2-hour plasma glucose concentration (P = .03) were higher for vitamin D-insufficient subjects (25[OH]D <50 nmol/L, n = 7) vs vitamin D-sufficient subjects (25[OH]D ≥50 nmol/L, n = 28). These differences remained significant after adjustment for age and body mass index. Resistance exercise training reduced fat mass (mean ± SD, -6% ± 7%; P < .001) and increased lean body mass (2% ± 3%, P < .001) and whole-body muscle strength (32% ± 17%, P < .001) in these weight-stable subjects but did not affect 25(OH)D or PTH concentrations. Oral glucose tolerance improved after RT (-10% ± 16% in glucose area under the curve and -21% ± 40% in 2-hour glucose, P = .001), but baseline 25(OH)D and PTH did not influence these RT-induced changes. These findings indicate that vitamin D status and RT independently affect glucose tolerance, and a training-induced improvement in glucose tolerance does not offset the negative effect of insufficient vitamin D status in older, nondiabetic adults.
Nutrition research 05/2013; 33(5):349-357. · 2.59 Impact Factor
[Show abstract][Hide abstract] 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; 97(5). · 6.50 Impact Factor
[Show abstract][Hide abstract] 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; · 8.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Calcium (Ca) deposition into vascular tissue was measured in Ossabaw miniature pigs with and without metabolic syndrome (MetS) using Ca tracer kinetics and coronary atherosclerosis measured with intravascular ultrasound. Pigs with MetS had higher Ca uptake into coronary arteries than lean pigs. INTRODUCTION: Ca deposition into arteries is a common disease in humans. The Ossabaw pig develops MetS when fed an atherogenic diet. The aim of this study was to measure Ca deposition into arteries of lean vs. MetS pigs. METHODS: Male pigs were fed for 5 months with chow diet (healthy, lean; n = 7) or atherogenic diet (n = 8) consisting of chow supplemented with 2 % cholesterol, 43 % kcal from fat, and 20 % kcal from fructose. Pigs were verified to have MetS by obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, and hypertension. Two pigs received 50 nCi of (41)Ca i.v. and blood was drawn frequently for 24 h, and 2, 3, 6, 8, 10, 15, 20, and at sacrifice at 28 days after injection. Peripheral arteries were biopsied four times per pig over the 28th day and coronary artery sampled at sacrifice. Tissues were analyzed for (41)Ca:Ca. A compartmental model was used to estimate rates of Ca deposition into the arteries. RESULTS: The MetS swine had higher (41)Ca and atherosclerosis in coronary arteries than lean pigs. CONCLUSIONS: This pig model is a suitable model for studying vascular calcification in humans.
Osteoporosis International 12/2012; · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteoporotic fracture rates differ according to race with Blacks having up to half the rate of Whites. The current study demonstrates that racial divergence in cortical bone properties develops in early childhood despite lower serum 25-hydroxyvitamin D in Blacks. INTRODUCTION: Racial differences in bone structure likely have roots in childhood as bone size develops predominantly during growth. This study aimed to compare cortical bone health within the tibial diaphysis of Black and White children in the early stages of puberty and explore the contributions of biochemical variables in explaining racial variation in cortical bone properties. METHODS: A cross-sectional study was performed comparing peripheral quantitative computed tomography-derived cortical bone measures of the tibial diaphysis and biochemical variables in 314 participants (n = 155 males; n = 164 Blacks) in the early stages of puberty. RESULTS: Blacks had greater cortical volumetric bone mineral density, mass, and size compared to Whites (all p < 0.01), contributing to Blacks having 17.0 % greater tibial strength (polar strength-strain index (SSI(P))) (p < 0.001). Turnover markers indicated that Blacks had higher bone formation (osteocalcin (OC) and bone-specific alkaline phosphatase) and lower bone resorption (N-terminal telopeptide) than Whites (all p < 0.01). Blacks also had lower 25-hydroxyvitamin D (25(OH)D) and higher 1,25-dihydroxyvitamin D (1,25(OH)(2)D) and parathyroid hormone (PTH) (all p < 0.05). There were no correlations between tibial bone properties and 25(OH)D and PTH in Whites (all p ≥ 0.10); however, SSI(P) was negatively and positively correlated with 25(OH)D and PTH in Blacks, respectively (all p ≤ 0.02). Variation in bone cross-sectional area and SSI(P) attributable to race was partially explained by tibial length, 25(OH)D/PTH, and OC. CONCLUSIONS: Divergence in tibial cortical bone properties between Blacks and Whites is established by the early stages of puberty with the enhanced cortical bone properties in Black children possibly being explained by higher PTH and OC.
Osteoporosis International 10/2012; · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In a phase 2 study, continued denosumab treatment for up to 8 years was associated with continued gains in bone mineral density and persistent reductions in bone turnover markers. Denosumab treatment was well tolerated throughout the 8-year study. INTRODUCTION: The purpose of this study is to present the effects of 8 years of continued denosumab treatment on bone mineral density (BMD) and bone turnover markers (BTM) from a phase 2 study. METHODS: In the 4-year parent study, postmenopausal women with low BMD were randomized to receive placebo, alendronate, or denosumab. After 2 years, subjects were reallocated to continue, discontinue, or discontinue and reinitiate denosumab; discontinue alendronate; or maintain placebo for two more years. The parent study was then extended for 4 years where all subjects received denosumab. RESULTS: Of the 262 subjects who completed the parent study, 200 enrolled in the extension, and of these, 138 completed the extension. For the subjects who received 8 years of continued denosumab treatment, BMD at the lumbar spine (N = 88) and total hip (N = 87) increased by 16.5 and 6.8 %, respectively, compared with their parent study baseline, and by 5.7 and 1.8 %, respectively, compared with their extension study baseline. For the 12 subjects in the original placebo group, 4 years of denosumab resulted in BMD gains comparable with those observed during the 4 years of denosumab in the parent study. Reductions in BTM were sustained over the course of continued denosumab treatment. Reductions also were observed when the placebo group transitioned to denosumab. Adverse event profile was consistent with previous reports and an aging cohort. CONCLUSION: Continued denosumab treatment for 8 years was associated with progressive gains in BMD, persistent reductions in BTM, and was well tolerated.
Osteoporosis International 07/2012; 24(1). · 4.04 Impact Factor