Diane Krueger

A Prospective Randomized Controlled Trial of the Effects of Vitamin D Supplementation on Cardiovascular Disease Risk

Vitamin D (VitD) supplementation has been advocated for cardiovascular risk reduction; however, supporting data are sparse. The objective of this study was to determine whether VitD supplementation reduces cardiovascular risk. Subjects in this prospective, randomized, double-blind, placebo-controlled trial of post-menopausal women with serum 25-hydroxyvitamin D concentrations >10 and <60 ng/mL were randomized to Vitamin D3 2500 IU or placebo, daily for 4 months. Primary endpoints were changes in brachial artery flow-mediated vasodilation (FMD), carotid-femoral pulse wave velocity (PWV), and aortic augmentation index (AIx). The 114 subjects were mean (standard deviation) 63.9 (3.0) years old with a 25-hydroxyvitamin D level of 31.3 (10.6) ng/mL. Low VitD (<30 ng/mL) was present in 47% and was associated with higher body-mass index, systolic blood pressure, glucose, CRP, and lower FMD (all p<0.05). After 4 months, 25-hydroxyvitamin D levels increased by 15.7 (9.3) ng/mL on vitamin D3 vs. −0.2 (6.1) ng/mL on placebo (p<0.001). There were no significant differences between groups in changes in FMD (0.3 [3.4] vs. 0.3 [2.6] %, p = 0.77), PWV (0.00 [1.06] vs. 0.05 [0.92] m/s, p = 0.65), AIx (2.7 [6.3] vs. 0.9 [5.6] %, p = 0.10), or CRP (0.3 [1.9] vs. 0.3 [4.2] mg/L, p = 0.97). Multivariable models showed no significant interactions between treatment group and low VitD status (<30 ng/mL) for changes in FMD (p = 0.65), PWV (p = 0.93), AIx (p = 0.97), or CRP (p = 0.26).In conclusion, VitD supplementation did not improve endothelial function, arterial stiffness, or inflammation. These observations do not support use of VitD supplementation to reduce cardiovascular disease risk. Trial Registration ClinicalTrials.gov NCT00690417 Trial Registration ClinicalTrials.gov NCT01049048

Evaluation of Ergocalciferol or Cholecalciferol Dosing, 1,600 IU Daily or 50,000 IU Monthly in Older Adults

CONTEXT Whether ergocalciferol (D(2)) and cholecalciferol (D(3)) are equally effective to increase and maintain serum 25-hydroxyvitamin D [25(OH)D] concentration is controversial. OBJECTIVE The aim of the study was to evaluate the effect of daily and once monthly dosing of D(2) or D(3) on circulating 25(OH)D and serum and urinary calcium. DESIGN, SETTING AND PARTICIPANTS In a university clinical research setting, 64 community dwelling adults age 65+ were randomly assigned to receive daily (1,600 IU) or once-monthly (50,000 IU) D(2) or D(3) for 1 yr. MAIN OUTCOME MEASURES Serum 25(OH)D, serum calcium, and 24-h urinary calcium were measured at months 0, 1, 2, 3, 6, 9, and 12. Serum PTH, bone-specific alkaline phosphatase, and N-telopeptide were measured at months 0, 3, 6, and 12. RESULTS Serum 25(OH)D was less than 30 ng/ml in 40% of subjects at baseline; after 12 months of vitamin D dosing, levels in 19% of subjects (n = 12, seven receiving daily doses and five monthly doses) remained low, despite compliance of more than 91%. D(2) dosing increased 25(OH)D(2) but produced a decline (P < 0.0001) in 25(OH)D(3). Substantial between-individual variation in 25(OH)D response was observed for both D(2) and D(3). The highest 25(OH)D observed was 72.5 ng/ml. Vitamin D administration did not alter serum calcium, PTH, bone-specific alkaline phosphatase, N-telopeptide, or 24-h urine calcium. CONCLUSIONS Overall, D(3) is slightly, but significantly, more effective than D(2) to increase serum 25(OH)D. One year of D(2) or D(3) dosing (1,600 IU daily or 50,000 IU monthly) does not produce toxicity, and 25(OH)D levels of less than 30 ng/ml persist in approximately 20% of individuals. Substantial between-individual response to administered vitamin D(2) or D(3) is observed.

Recalculation of the NHANES Database SD Improves T‐Score Agreement and Reduces Osteoporosis Prevalence

In attempt to improve diagnostic agreement between manufacturers, a recent software update incorporated NHANES III data in GE Lunar densitometers. As a result, the femur neck and trochanter T‐scores were lowered, and osteoporosis prevalence was increased. Use of a recalculated young‐normal SD for the GE Lunar‐adjusted NHANES III database improved diagnostic agreement and is recommended.

Lateral vertebral assessment : a valuable technique to detect clinically significant vertebral fractures

Although many vertebral fractures are clinically silent, they are associated with increased risk for subsequent osteoporotic fractures. A substantial number of these fractures are demonstrable using instant vertebral assessment with Hologic densitometers. Whether similar recognition is possible using dual-energy lateral vertebral assessment (LVA) with GE Lunar densitometers remains uncertain. Thus, we evaluated the ability of clinicians using LVA to detect prevalent vertebral fractures. Dual-energy LVA and conventional thoracic and lumbar spine radiographs were concurrently obtained in 80 postmenopausal women. Using an established visual semiquantitative system, vertebral fractures were identified individually by two non-radiologist clinicians on LVA images, and the results were compared with spinal radiograph evaluation by an expert radiologist. Using LVA, 95% of vertebral bodies from T7 through L4 were evaluable, but a majority (66%) of vertebrae from T4 to T6 were not adequately visualized. In the LVA-evaluable vertebrae, prevalent fractures were identified in 40 vertebral bodies by radiography. In this regard, the clinicians using LVA detected 17 of 18 radiographically evident vertebral fractures of grade 2 or 3, a false negative rate of 6%. They identified 50% (11/22) of grade 1 fractures. Additionally, the vast majority of evaluable non-fractured vertebrae, (764/794, 96.2%) were correctly classified as normal by LVA. Thus, clinicians utilizing LVA correctly identified the vast majority of grade 2 or 3 vertebral compression fractures and normal vertebral bodies, although detection of grade 1 fractures was less effective. In conclusion, the low-radiation, dual-energy LVA technique provides a rapid and convenient way for clinicians to identify patients with, and without, grade 2 or 3 vertebral fractures, thereby enhancing care of osteoporotic patients.

Current Status of Clinical 25-hydroxyvitamin D Measurement: An Assessment of Between-Laboratory Agreement

BACKGROUND Historically, methodological differences and lack of standardization led to between-laboratory variability in 25(OH)D results. Recent observations raised concern about persisting variability. This quality assurance exercise investigated 25(OH)D result comparability between laboratories. METHODS Serum pools (n=25) were prepared to contain endogenous 25(OH)D(2) and 25(OH)D(3) at 25(OH)D concentrations from ~12 to 150 nmol/l (5-60 ng/ml). Aliquots were sent to 8 laboratories utilizing various 25(OH)D assay methods including high performance liquid chromatography with ultraviolet detection (LC-UV), LC with tandem mass spectroscopy detection (LC-MS/MS) or an automated immunoassay (Diasorin Liaison). The LC-UV results were selected as a referent to which all others were compared using linear regression and Bland-Altman analysis. RESULTS Good correlation (R(2)=0.87 to 0.97) was observed for all laboratories. Modest systematic bias was observed for some laboratories ranging from a positive mean bias of 10.5 nmol/l (4.2 ng/ml) to a negative mean bias of 3.5 nmol/l (1.4 ng/ml). For the laboratory with the greatest bias, 22/25 results were numerically higher (mean +15.7%) than LC-UV results. For Liaison, the primary error was likely random, whereas the major LC-MS/MS assay error source was biases likely due to calibration issues. CONCLUSIONS Modest inter-laboratory variability persists in serum 25(OH)D measurement. The National Institute of Standards and Technology 25(OH)D Standard Reference and calibration materials will further improve between-laboratory agreement for chromatography-based assays.

Spine Trabecular Bone Score Subsequent to Bone Mineral Density Improves Fracture Discrimination in Women

Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is used to diagnose osteoporosis and assess fracture risk. However, DXA cannot evaluate trabecular microarchitecture. This study used a novel software program (TBS iNsight; Med-Imaps, Geneva, Switzerland) to estimate bone texture (trabecular bone score [TBS]) from standard spine DXA images. We hypothesized that TBS assessment would differentiate women with low trauma fracture from those without. In this study, TBS was performed blinded to fracture status on existing research DXA lumbar spine (LS) images from 429 women. Mean participant age was 71.3 yr, and 158 had prior fractures. The correlation between LS BMD and TBS was low (r = 0.28), suggesting these parameters reflect different bone properties. Age- and body mass index-adjusted odds ratios (ORs) ranged from 1.36 to 1.63 for LS or hip BMD in discriminating women with low trauma nonvertebral and vertebral fractures. TBS demonstrated ORs from 2.46 to 2.49 for these respective fractures; these remained significant after lowest BMD T-score adjustment (OR = 2.38 and 2.44). Seventy-three percent of all fractures occurred in women without osteoporosis (BMD T-score > -2.5); 72% of these women had a TBS score below the median, thereby appropriately classified them as being at increased risk. In conclusion, TBS assessment enhances DXA by evaluating trabecular pattern and identifying individuals with vertebral or low trauma fracture. TBS identifies 66-70% of women with fracture who were not classified with osteoporosis by BMD alone.

An Overlying Fat Panniculus Affects Femur Bone Mass Measurement

Dual-energy X-ray absorptiometry (DXA) is currently the gold standard technique for osteoporosis diagnosis. However, DXA has limitations, including artifacts, such as degenerative disease or metallic foreign bodies, that may confound bone mineral density (BMD) results. Because fat folds overlying the proximal femur may alter soft-tissue density in a nonuniform manner, this may be a currently unappreciated confounder of proximal femur BMD measurement. This possibility was evaluated in 127 patients (52 women/75 men) referred for routine BMD measurement who were identified as having a fat panniculus overlying their proximal femur scan area. Presence of a fat panniculus within the scan field was confirmed by visual assessment of images obtained utilizing a GE Lunar Expert-XL. Subsequently, these individuals were rescanned while retracting their fat panniculus away from the femur scan area without other repositioning between scans. In 49% of the men, and 56% of the women, either the femoral neck, trochanter, or total femur BMD differed by more than the least significant change at our facility. No pattern was observed to predict whether BMD would increase or decrease upon fat retraction. Subsequently, 30 patients were scanned using the standard and retracted technique twice, with repositioning between scans to establish precision. Retracted and standard precision was similar. In conclusion, an overlying fat panniculus may alter proximal femur BMD measurement, which would be expected to impair the ability to accurately diagnose low bone mass and monitor osteoporosis therapy. When a fat panniculus overlays the proximal femur scan area, its retraction should be part of routine densitometric practice.

What's in a name revisited: should osteoporosis and sarcopenia be considered components of "dysmobility syndrome?"

Sarcopenia and osteoporosis are age-related declines in the quantity and quality of muscle and bone respectively, with shared pathogeneses and adverse health consequences. Both absolute and relative fat excess, i.e., obesity and sarcopenic obesity, contribute to disability, falls, and fractures. Rather than focusing on a single component, i.e., osteoporosis, sarcopenia, or obesity, we realized that an opportunity exists to combine clinical factors, thereby potentially allowing improved identification of older adults at risk for disability, falls, and fractures. Such a combination could be termed dysmobility syndrome, analogous to the approach taken with metabolic syndrome. An arbitrary score-based approach to dysmobility syndrome diagnosis is proposed and explored in a small cohort of older adults. Further evaluation of such an approach in large population-based and prospective studies seems warranted.

25-Hydroxyvitamin D Measurement, 2009: A Review for Clinicians

As clinicians are more widely appreciating the endemic nature of low vitamin D status, measurement of serum 25-hydroxyvitamin D (25(OH)D), the accepted measure of vitamin D status, has increased. Challenges to 25(OH)D measurement include the presence of 2 forms of vitamin D-ergocalciferol and cholecalciferol (vitamin D(2) and vitamin D(3), respectively)- and the hydrophobic nature of vitamin D. The current state of 25(OH)D measurement is reviewed; modest differences between methodologies persist and confound the application of a single cut point (e.g., 30 ng/mL/75 nmol/L) for the diagnosis of low vitamin D status. The absence of standard calibrators contributes to between-laboratory differences in 25(OH)D measurement. Until there is improved assay standardization and subsequent evidence-based consensus, it seems premature to recommend widespread screening 25(OH)D measurement. Selectively obtaining 25(OH)D measurement in individuals at clinical risk for vitamin D deficiency and/or those most likely to promptly experience benefits from supplementation seems appropriate.

Interobserver Reproducibility of Criteria for Vertebral Body Exclusion

We studied reproducibility of the ISCD vertebral exclusion criteria among four interpreters. Surprisingly, agreement among interpreters was only moderate, because of differences in threshold for diagnosing focal structural defects and choice of which vertebra among a pair discordant for T‐score, area, or BMC to exclude. Our results suggest that reproducibility may be improved by specifically addressing the sources of interobserver disagreement.