Identification of non-Hodgkin lymphoma patients at risk for treatment-related vertebral density loss and fractures.

Information on bone loss in treated non-Hodgkin's lymphoma patients is limited. In this study, we used CT to analyze bone loss as well as prevalent and incident fractures. We found severe bone loss, a high rate of fractures, and a novel association between bone loss and the international prognostic index. INTRODUCTION: To investigate bone loss and fracture risk in non-Hodgkin-lymphoma (NHL) patients by (i) comparing treatment-related vertebral density (VD) loss in NHL patients with control subjects and (ii) investigating associations of VD loss versus fracture risk. Further, associations of VD loss and clinical parameters were investigated. METHODS: VD of 123 NHL patients was measured pre- and post-treatment in the L1, L2, and L3 vertebrae in routine computed tomography (CT) scans, performed between Jan 2016 and Mar 2017. Control measurements (n = 52) were obtained from CT colonographies between Sept 2003 and Sept 2017 and their subsequent follow-up-exams (10-137 months). Prevalent and incident (between baseline and follow-up) fractures were assessed in all subjects, and VD loss per year was calculated. Linear regression models were used to (i) compare VD loss between patients and controls and (ii) identify associations between VD loss and clinical parameters. Using logistic regression models, ORs for fractures per SD change in VD were assessed in patients. Analyses were adjusted for age, sex, and contrast application. RESULTS: NHL patients experienced significantly greater VDL1-3 loss than controls (P = 0.003), and greater VDL1-3 loss was associated with a greater likelihood of incident fractures (OR, [95%-CI], P 1.90, [1.03, 3.51], 0.04). Patients with an initial international prognostic index (IPI) of 5 suffered significantly greater VD loss compared with an IPI of 0 (P = 0.01). CONCLUSION: Using VD measurements in routine CT scans, substantial vertebral bone loss in NHL patients could be documented with a high incidence of fractures.

Hip load capacity and yield load in men and women of all ages.

Quantitative computed tomography (QCT) based finite element (FE) models can compute subject-specific proximal femoral strengths, or fracture loads, that are associated with hip fracture risk. These fracture loads are more strongly associated with measured fracture loads than are DXA and QCT measures and are predictive of hip fracture independently of DXA bone mineral density (BMD). However, interpreting FE-computed fracture loads of younger subjects for the purpose of evaluating hip fracture risk in old age is challenging due to limited reference data. The goal of this study was to address this issue by providing reference data for male and female adult subjects of all ages. QCT-based FE models of the left proximal femur of 216 women and 181 men, age 27 to 90 years, from a cohort of Rochester, MN residents were used to compute proximal femoral load capacities, i.e. the maximum loads that can be supported, in single-limb stance and posterolateral fall loading (Stance_LC and Fall_LC, respectively) [US Patent No. 9,245,069] and yield load under fall loading (Fall_yield). To relate these measures to information about hip fracture, the CT scanner and calibration phantom were cross-calibrated with those from our previous prospective study of hip fracture in older fracture and control subjects, the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. We then plotted Stance_LC, Fall_LC and Fall_yield versus age for the two cohorts on the same graphs. Thus, proximal femoral strengths in individuals above 70 years of age can be assessed through direct comparison with the FE data from the AGES cohort which were analyzed using identical methods. To evaluate younger individuals, reductions in Stance_LC, Fall_LC and Fall_yield from the time of evaluation to age 70 years can be cautiously estimated from the average yearly cross-sectional decreases found in this study (108 N, 19.4 N and 14.4 N, respectively, in men and 120 N, 19.4 N and 21.6 N, respectively, in women), and the projected fracture loads can be compared with data from the AGES cohort. Although we did not set specific thresholds for identifying individuals at risk of hip fracture, these data provide some guidance and may be used to help establish diagnostic criteria in future. Additionally, given that these data were nearly entirely from Caucasian subjects, future research involving subjects of other races/ethnicities is necessary.

The comparability of HR-pQCT bone measurements is improved by scanning anatomically standardized regions.

We investigated the sensitivity of distal bone density, structure, and strength measurements by high-resolution peripheral quantitative computed tomography (HR-pQCT) to variability in limb length. Our results demonstrate that HR-pQCT should be performed at a standard %-of-total-limb-length to avoid substantial measurement bias in population study comparisons and the evaluation of individual skeletal status in a clinical context. INTRODUCTION: High-resolution peripheral quantitative computed tomography (HR-pQCT) measures of bone do not account for anatomic variability in bone length: a 1-cm volume is acquired at a fixed offset from an anatomic landmark. Our goal was to evaluate HR-pQCT measurement variability introduced by imaging fixed vs. proportional volumes and to propose a standard protocol for relative anatomic positioning. METHODS: Double-length (2-cm) scans were acquired in 30 adults. We compared measurements from 1-cm sub-volumes located at the default fixed offset, and the average %-of-length offset. The average position corresponded to 4.0% ± 1.1 mm for radius, and 7.2% ± 2.2 mm for tibia. We calculated the RMS difference in bone parameters and T-scores to determine the measurement variability related to differences in limb length. We used anthropometric ratios to estimate the mean limb length for published HR-pQCT reference data, and then calculated mean %-of-length offsets. RESULTS: Variability between fixed vs. relative scan positions was highest in the radius, and for cortical bone in general (RMS difference Ct.Th = 19.5%), while individuals had T-score differentials as high as +3.0 SD (radius Ct.BMD). We estimated that average scan position for published HR-pQCT reference data corresponded to 4.0% at the radius, and 7.3% at tibia. CONCLUSION: Variability in limb length introduces significant bias to HR-pQCT measures, confounding cross-sectional analyses and limiting the clinical application for individual assessment of skeletal status. We propose to standardize scan positioning using 4.0 and 7.3% of total bone length for the distal radius and tibia, respectively.

Operator variability in scan positioning is a major component of HR-pQCT precision error and is reduced by standardized training.

In this study, we determined that operator positioning precision contributes significant measurement error in high-resolution peripheral quantitative computed tomography (HR-pQCT). Moreover, we developed software to quantify intra- and inter-operator variability and demonstrated that standard positioning training (now available as a web-based application) can significantly reduce inter-operator variability. INTRODUCTION: HR-pQCT is increasingly used to assess bone quality, fracture risk, and anti-fracture interventions. The contribution of the operator has not been adequately accounted in measurement precision. Operators acquire a 2D projection ("scout view image") and define the region to be scanned by positioning a "reference line" on a standard anatomical landmark. In this study, we (i) evaluated the contribution of positioning variability to in vivo measurement precision, (ii) measured intra- and inter-operator positioning variability, and (iii) tested if custom training software led to superior reproducibility in new operators compared to experienced operators. METHODS: To evaluate the operator in vivo measurement precision, we compared precision errors calculated in 64 co-registered and non-co-registered scan-rescan images. To quantify operator variability, we developed software that simulates the positioning process of the scanner's software. Eight experienced operators positioned reference lines on scout view images designed to test intra- and inter-operator reproducibility. Finally, we developed modules for training and evaluation of reference line positioning. We enrolled six new operators to participate in a common training, followed by the same reproducibility experiments performed by the experienced group. RESULTS: In vivo precision errors were up to threefold greater (Tt.BMD and Ct.Th) when variability in scan positioning was included. The inter-operator precision errors were significantly greater than the short-term intra-operator precision (p < 0.001). New trained operators achieved comparable intra-operator reproducibility to experienced operators and lower inter-operator reproducibility (p < 0.001). Precision errors were significantly greater for the radius than for the tibia. CONCLUSION: Operator reference line positioning contributes significantly to in vivo measurement precision and is significantly greater for multi-operator datasets. Inter-operator variability can be significantly reduced using a systematic training platform, now available online ( http://webapps.radiology.ucsf.edu/refline/ ).

Polyunsaturated fatty acids in relation to incident mobility disability and decline in gait speed; the Age, Gene/Environment Susceptibility-Reykjavik Study.

BACKGROUND/OBJECTIVES: Low intake of long chain polyunsaturated fatty acids (PUFAs) are associated with physical disability; however, prospective studies of circulating PUFAs are scarce. We examined associations between plasma phospholipid n-3 and n-6 PUFAs with risk of incident mobility disability and gait speed decline. SUBJECTS/METHODS: Data are from a subgroup of the Age, Gene/Environment Susceptibility-Reykjavik Study, a population-based study of risk factors for disease and disability in old age. In this subgroup (n = 556, mean age 75.1 ± 5.0 years, 47.5% men), plasma phospholipid PUFAs were assessed at baseline using gas chromatography. Mobility disability and usual gait speed were assessed at baseline and after 5.2 ± 0.2 years. Mobility disability was defined as the following: having much difficulty, or being unable to walk 500 m or climb up 10 steps; decline in gait speed was defined as change ⩾ 0.10 m/s. Logistic regression analyses were performed to determine associations between sex-specific s.d. increments in PUFAs with risk of incident mobility disability and gait speed decline. Odds ratios (95% confidence intervals) adjusted for demographics, follow-up time, risk factors and serum vitamin D were reported. RESULTS: In women, but not men, every s.d. increment increase of total n-3 PUFAs and docosahexaenoic acid (DHA) was associated with lower mobility disability risk, odds ratio 0.48 (0.25; 0.93) and odds ratio 0.45 (0.24; 0.83), respectively. There was no association between n-6 PUFAs and the risk of incident mobility disability or gait speed decline. CONCLUSIONS: Higher concentrations of n-3 PUFAs and, particularly, DHA may protect women from impaired mobility but does not appear to have such an effect in men.

Volumetric femoral BMD, bone geometry, and serum sclerostin levels differ between type 2 diabetic postmenopausal women with and without fragility fractures.

UNLABELLED: While type 2 diabetes (T2D) is associated with higher skeletal fragility, specific risk stratification remains incompletely understood. We found volumetric bone mineral density, geometry, and serum sclerostin differences between low-fracture risk and high-fracture risk T2D women. These features might help identify T2D individuals at high fracture risk in the future. INTRODUCTION: Diabetic bone disease, an increasingly recognized complication of type 2 diabetes mellitus (T2D), is associated with high skeletal fragility. Exactly which T2D individuals are at higher risk for fracture, however, remains incompletely understood. Here, we analyzed volumetric bone mineral density (vBMD), geometry, and serum sclerostin levels in two specific T2D subsets with different fracture risk profiles. We examined a T2D group with prior history of fragility fractures (DMFx, assigned high-risk group) and a fracture-free T2D group (DM, assigned low-risk group) and compared their results to nondiabetic controls with (Fx) and without fragility fractures (Co). METHODS: Eighty postmenopausal women (n = 20 per group) underwent quantitative computed tomography (QCT) to compute vBMD and bone geometry of the proximal femur. Additionally, serum sclerostin, vitamin D, parathyroid hormone (PTH), HbA1c, and glomerular filtration rate (GFR) levels were measured. Statistical analyses employed linear regression models. RESULTS: DMFx subjects exhibited up to 33 % lower femoral neck vBMD than DM subjects across all femoral sites (-19 % ≤ ΔvBMD ≤ -33 %, 0.008 ≤ p ≤0.021). Additionally, DMFx subjects showed significantly thinner cortices (-6 %, p = 0.046) and a trend toward larger bone volume (+10 %, p = 0.055) relative to DM women and higher serum sclerostin levels when compared to DM (+31.4 %, p = 0.013), Fx (+25.2 %, p = 0.033), and control (+22.4 %, p = 0.028) subjects. CONCLUSION: Our data suggest that volumetric bone parameters by QCT and serum sclerostin levels can identify T2D individuals at high risk of fracture and might therefore show promise as clinical tools for fracture risk assessment in T2D. However, future research is needed to establish diabetes-specific QCT- and sclerostin-reference databases.

Effect of finite element model loading condition on fracture risk assessment in men and women: the AGES-Reykjavik study.

Proximal femoral (hip) strength computed by subject-specific CT scan-based finite element (FE) models has been explored as an improved measure for identifying subjects at risk of hip fracture. However, to our knowledge, no published study has reported the effect of loading condition on the association between incident hip fracture and hip strength. In the present study, we performed a nested age- and sex-matched case-control study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. Baseline (pre-fracture) quantitative CT (QCT) scans of 5500 older male and female subjects were obtained. During 4-7years follow-up, 51 men and 77 women sustained hip fractures. Ninety-seven men and 152 women were randomly selected as controls from a pool of age- and sex-matched subjects. From the QCT data, FE models employing nonlinear material properties computed FE-strength of the left hip of each subject in loading from a fall onto the posterolateral (FPL), posterior (FP) and lateral (FL) aspects of the greater trochanter (patent pending). For comparison, FE strength in stance loading (FStance) and total femur areal bone mineral density (aBMD) were also computed. For all loading conditions, the reductions in strength associated with fracture in men were more than twice those in women (p≤0.01). For fall loading specifically, posterolateral loading in men and posterior loading in women were most strongly associated with incident hip fracture. After adjusting for aBMD, the association between FP and fracture in women fell short of statistical significance (p=0.08), indicating that FE strength provides little advantage over aBMD for identifying female hip fracture subjects. However, in men, after controlling for aBMD, FPL was 424N (11%) less in subjects with fractures than in controls (p=0.003). Thus, in men, FE models of posterolateral loading include information about incident hip fracture beyond that in aBMD.

Lifelong physical activity in maintaining bone strength in older men and women of the Age, Gene/Environment Susceptibility-Reykjavik Study.

UNLABELLED: We examined if lifelong physical activity is important for maintaining bone strength in the elderly. Associations of quantitative computerized tomography-acquired bone measures (vertebral and femoral) and self-reported physical activity in mid-life (mean age, 50 years), in old age (≥65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. Results conclude lifelong physical activity with continuation into old age (≥65 years) best maintains better bone health later in life. INTRODUCTION: Skeletal loading is thought to modulate the loss of bone in later life, and physical activity is a chief means of affecting bone strength by skeletal loading. Despite much discussion regarding lifelong versus early adulthood physical activity for preventing bone loss later in life, inconsistency still exists regarding how to maintain bone mass later in life (≥65 years). METHODS: We examined if lifelong physical activity is important for maintaining bone strength in the elderly. RESULTS: The associations of quantitative computerized tomography-acquired vertebral and femoral bone measures and self-reported physical activity in mid-life (mean age, 50 years), in old age (≥65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. CONCLUSION: Our findings conclude that lifelong physical activity with continuation into old age (≥65 years) best maintains better bone health in the elderly.

Age-related loss of proximal femoral strength in elderly men and women: the Age Gene/Environment Susceptibility Study--Reykjavik.

The risk of hip fracture rises rapidly with age, and is particularly high in women. This increase in fracture risk reflects both the age-related change in the risk of falling and decrements in the strength of the proximal femur. To better understand the extent to which proximal femoral density, structure and strength change with age as a function of gender, we have carried out a longitudinal analysis of proximal femoral volumetric quantitative computed tomographic (vQCT) images in men and women, analyzing changes in trabecular and cortical bone properties, and using subject-specific finite element modeling (FEM) to estimate changes in bone strength. In the AGES-Reykjavik Study vQCT scans of the hip were performed at a baseline visit in 2002-2006 and at a second visit 5.05±0.25 years later. From these, 223 subjects (111 men, 112 women, aged 68-87 years) were randomly selected. The subjects were evaluated for longitudinal changes in three bone variables assessed in a region similar to the total femur region quantified by DXA: areal bone mineral density (aBMD), trabecular volumetric bone mineral density (tBMD) and the ratio of cortical to total tissue volume (cvol/ivol). They were also evaluated for changes in bone strength using FEM models of the left proximal femur. Models were analyzed under single-limb stance loading (F(Stance)), which approximates normal physiologic loading of the hip, as well as a load approximating a fall onto the posterolateral aspect of the greater trochanter (F(Fall)). We computed five-year absolute and percentage changes in aBMD, tBMD, cvol/ivol, F(Fall) and F(Stance). The Mann-Whitney Test was employed to compare changes in bone variables between genders and the Wilcoxon Signed Rank Test was used to compare changes in bone strength between loading conditions. Multiple (linear) regression was employed to determine the association of changes in F(Fall) and F(Stance) with baseline age and five-year weight loss. Both men and women showed declines in indices of proximal femoral density and structure (aBMD: men -3.9±6.0%, women -6.1±6.2%; tBMD: men -14.8±20.3%, women -23.9±26.8%; cvol/ivol: men -2.6±4.6%, women -4.7±4.8%, gender difference: p<0.001). Both men and women lost bone strength in each loading condition (F(Stance): men -4.2±9.9%, women -8.3±8.5%; F(Fall): men -7.0±15.7%, women -12.8±13.2%; all changes from baseline p<0.0001). The gender difference in bone strength loss was statistically significant in both loading conditions (p<0.001 for F(Stance) and P<0.01 for F(Fall)) and F(Fall) was lost at a higher rate than F(Stance) in men (p<0.01) and women (p<0.0001). The gender difference in strength loss was statistically significant after adjustment for baseline age and weight loss in both loading conditions (p<0.01). In these multi-linear models, men showed increasing rates of bone loss with increasing age (F(Fall): p=0.002; F(Stance): p=0.03), and women showed increasing bone strength loss with higher degrees of weight loss (F(Stance): p=0.003). The higher loss of F(Fall) compared to F(Stance) supports previous findings in animal and human studies that the sub-volumes of bone stressed under normal physiologic loading are relatively better protected in aging. The gender difference in hip bone strength loss is consistent with the higher incidence of hip fracture among elderly women.

Male-female differences in the association between incident hip fracture and proximal femoral strength: a finite element analysis study.

Hip fracture risk is usually evaluated using dual energy X-ray absorptiometry (DXA) or quantitative computed tomography (QCT) which provide surrogate measures for proximal femoral strength. However, proximal femoral strength can best be estimated explicitly by combining QCT with finite element (FE) analysis. To evaluate this technique for predicting hip fracture in older men and women, we performed a nested age- and sex-matched case-control study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. Baseline (pre-fracture) QCT scans of 5500 subjects were obtained. During 4-7 years follow-up, 51 men and 77 women sustained hip fractures. Ninety-seven men and 152 women were randomly selected as age- and sex-matched controls. FE-strength of the left hip of each subject for stance (F(Stance)) and posterolateral fall (F(Fall)) loading, and total femur areal bone mineral density (aBMD) were computed from the QCT data. F(Stance) and F(Fall) in incident hip fracture subjects were 13%-25% less than in control subjects (p ≤ 0.006) after controlling for demographic parameters. The difference between FE strengths of fracture and control subjects was disproportionately greater in men (stance, 22%; fall, 25%) than in women (stance, 13%; fall, 18%) (p ≤ 0.033), considering that F(Stance) and F(Fall) in fracture subjects were greater in men than in women (p < 0.001). For men, F(Stance) was associated with hip fracture after accounting for aBMD (p = 0.013). These data indicate that F(Stance) provides information about fracture risk that is beyond that provided by aBMD (p = 0.013). These findings support further exploration of possible sex differences in the predictors of hip fracture and of sex-specific strategies for using FE analysis to manage osteoporosis.

Effects of age and sex on the strength and cortical thickness of the femoral neck.

A group of 48 men (22 aged 65-75 years, 26 aged 80-90 years) and 59 women (32 aged 65-75 years, 27 aged 80-90 years) were enrolled in the Age, Gene/Environment Susceptibility-Reykjavik study and imaged with in vivo volumetric Quantitative Computed Tomography (QCT) to investigate the effects of age and sex on femoral neck structure and strength. Femoral neck cross-sectional moment of inertia for bending directions near those of standing and walking (I(AP)), bending strength (M(y)), and axial compressive strength (F(y)) were computed at the location of minimum cross-sectional area (minCSA). Local cortical thickness was computed in the inferior femoral neck based on density profiles extending through the cortex of the minCSA femoral neck section. Multivariate models accounting for height, weight, and age group (younger or older) showed that men had a 46% higher M(y) and a 23% higher F(y) than women, while women had a 13% thicker inferior cortex than men. Cortical thickness in the inferoposterior region of the femoral neck was significantly related to bending and axial strength after adjusting for overall volumetric bone mineral density. Both minCSA and I(AP) were higher in the older, gender-pooled age group, but F(y) and M(y) did not differ between the two age groups. The results suggest that age-related expansion of the femoral neck primarily occurs in the superior and inferior directions and helps maintain homeostasis of femoral neck stiffness and strength. The higher bending strength of the male femoral neck may partly explain why elderly men have a lower risk of hip fracture than elderly women.

Genetic analysis of vertebral trabecular bone density and cross-sectional area in older men.

We investigated 383 bone candidate genes for associations between single nucleotide polymorphisms and vertebral trabecular volumetric bone mineral density (vBMD) and cross-sectional area (CSA) in 2,018 Caucasian men aged ≥ 65 years. SNPs in TGFBR3, SOST, KL, CALCR, LEP, CSF1R, PTN, GNRH2, FGFR2, and MEPE were associated with vBMD and SNPs in CYP11B1, DVL2, DLX5, WNT4, and PAX7 were associated with CSA in independent study samples (p < 0.005). INRODUCTION: Vertebral bone mineral density and cross-sectional area are important determinants of vertebral bone strength. Little is known about the specific genetic variants that influence these phenotypes in humans. METHODS: We investigated the potential genetic variants associated with vertebral trabecular volumetric BMD and CSA measured by quantitative computed tomography. We initially tested for association between these phenotypes and 4608 tagging and potentially functional single nucleotide polymorphisms (SNPs) in 383 candidate genes in 862 community-dwelling Caucasian men aged ≥ 65 years in the Osteoporotic Fractures in Men Study. RESULTS: SNP associations were then validated by genotyping an additional 1,156 randomly sampled men from the same cohort. We identified 11 SNPs in 10 genes (TGFBR3, SOST, KL, CALCR, LEP, CSF1R, PTN, GNRH2, FGFR2, and MEPE) that were consistently associated with trabecular vBMD and five SNPs in five genes (CYP11B1, DVL2, DLX5, WNT4, and PAX7) that were consistently associated with CSA in both samples (p < 0.005). CONCLUSION: None of the SNPs associated with trabecular vBMD were associated with CSA. Our findings raise the possibility that at least some of the loci for vertebral trabecular BMD and bone size may be distinct.

Adult presentations of medium-chain acyl-CoA dehydrogenase deficiency (MCADD).

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of mitochondrial fatty acid oxidation which is usually diagnosed in infancy or through neonatal screening. In the absence of population screening, adults with undiagnosed MCADD can be expected. This review discusses 14 cases that were identified during adulthood. The mortality of infantile patients is approximately 25% whereas in this adult case series it was shown it to be 50% in acutely presenting patients and 29% in total. Therefore, undiagnosed individuals are at risk of sudden fatal metabolic decompensation with high mortality. This review illustrates the need to consider the possibility of a fatty acid oxidation defect in an adult who presents with unexplained sudden clinical deterioration, particularly if precipitated by fasting or alcohol consumption. A history of unexplained sibling death may also raise the index of suspicion. There also needs to be appropriate clinical support for those patients identified clinically or as a result of family studies (sibling or parent).

Reduction in proximal femoral strength due to long-duration spaceflight.

Loss of bone mass is a well-known medical complication of long-duration spaceflight. However, we do not know how changes in bone density and geometry ultimately combine to affect the strength of the proximal femur as a whole. The goal of this study was to quantify the changes in proximal femoral strength that result from long-duration spaceflight. Pre-and post-flight CT scan-based patient-specific finite element models of the left proximal femur of 13 astronauts who spent 4.3 to 6.5 months on the International Space Station were generated. Loading conditions representing single-limb stance and a fall onto the posterolateral aspect of the greater trochanter were modeled, and proximal femoral strength (F(FE)) was computed. Mean F(FE) decreased from 18.2 times body weight (BW) pre-flight to 15.6 BW post-flight for stance loading and from 3.5 BW pre-flight to 3.1 BW post-flight for fall loading. When normalized for flight duration, F(FE) under stance and fall loading decreased at mean rates of 2.6% (0.6% to 5.0%) per month and 2.0% (0.6% to 3.9%) per month, respectively. These values are notably greater than previously reported reductions in DXA total femoral bone mineral density (0.4 to 1.8% per month). In some subjects, the magnitudes of the reductions in proximal femoral strength were comparable to estimated lifetime losses associated with aging. Although average post-flight proximal femoral strength is greater than forces expected to occur due to falls or normal activities, some subjects have small margins of safety. If proximal femoral strength is not recovered, some crew members may be at increased risk for age-related hip fractures decades after their missions.

Practical difficulties in the diagnosis of transient non-ketotic hyperglycinaemia.

Making a diagnosis of transient non-ketotic hyperglycinaemia (tNKH) can be difficult. We report an infant who presented in the neonatal period with symptoms of NKH. Metabolic studies performed on day 2 of life showed raised cerebrospinal fluid (CSF) and plasma glycine, and a CSF:plasma glycine ratio consistent with NKH; however, a liver biopsy performed on day 5 revealed normal liver glycine cleavage system activity. Subsequently, the child's clinical condition improved in the absence of any therapeutic medication. Clinical assessment and developmental follow-up at 5 months, 1 year, and 2 years were age-appropriate. Guidance for the investigation and management of future suspected cases of tNKH is discussed.

Recovery of spaceflight-induced bone loss: bone mineral density after long-duration missions as fitted with an exponential function.

The loss of bone mineral in NASA astronauts during spaceflight has been investigated throughout the more than 40 years of space travel. Consequently, it is a medical requirement at NASA Johnson Space Center (JSC) that changes in bone mass be monitored in crew members by measuring bone mineral density (BMD), with dual-energy X-ray absorptiometry (DXA) before and after flight, of astronauts who serve on long-duration missions (4-6 months). We evaluated this repository of medical data to track whether there is recovery of bone mineral that was lost during spaceflight. Our analysis was supplemented by BMD data from cosmonauts (by convention, a space traveler formally employed by the Russia Aviation and Space Agency or by the previous Soviet Union) who had also flown on long-duration missions. Data from a total of 45 individual crew members - a small number of whom flew on more than one mission - were used in this analysis. Changes in BMD (between 56 different sets of pre- and postflight measurements) were plotted as a function of time (days after landing). Plotted BMD changes were fitted to an exponential mathematical function that estimated: (i) BMD change on landing day (day 0) and (ii) the number of days after landing when 50% of the lost bone would be recovered ("50% recovery time") in the lumbar spine, trochanter, pelvis, femoral neck and calcaneus. In sum, averaged losses of bone mineral after long-duration spaceflight ranged between 2% and 9% across all sites with our recovery model predicting a 50% restoration of bone loss for all sites to be within 9 months.

Influence of anthropometric parameters and bone size on bone mineral density using volumetric quantitative computed tomography and dual X-ray absorptiometry at the hip.

PURPOSE: To evaluate the influence of anthropometric parameters (age, height, and weight) and bone size on bone mineral density (BMD) using volumetric quantitative computed tomography (QCT) and dual X-ray absorptiometry (DXA) in a group of elderly women. MATERIAL AND METHODS: BMD values were obtained with DXA and QCT at the spine and hip in a cohort of 84 elderly women (mean age 73 +/- 6 years). QCT measures included trabecular, integral, and cortical BMD assessed at the hip and spine as well as cross-sectional areas of the mid-vertebrae and proximal femora. Spinal integral and femoral neck BMD measures were well matched to the regions of bone quantified on anteroposterior (AP) spine DXA and the femoral neck region of hip DXA. RESULTS: When QCT parameters were linearly regressed against body height and weight, only the relationships with weight were found to be statistically significant. Except for cortical BMD at the femoral neck, all BMD and geometric parameters measured from both DXA and QCT showed statistically significant associations with body weight (r2 = 0.4, 0.0001 < P < 0.02). The strongest associations with weight were found for DXA Neck (DXA_NECK) and DXA lumbar spine (DXA_LSP) (r2 = 0.4, P < 0.0001). CONCLUSION: The relationship of DXA BMD is stronger than QCT BMD with body weight and it encompasses the response of both bone size and density to increasing body mass.

Effect of spinal degenerative changes on volumetric bone mineral density of the central skeleton as measured by quantitative computed tomography.

PURPOSE: To evaluate the impact of degenerative changes due to osteoarthritis (OA) at the spine on volumetric bone mineral density (BMD) as measured by volumetric quantitative computed tomography (vQCT). MATERIAL AND METHODS: Eighty-four elderly women (mean age 73 +/- 6 years), comprising 33 with vertebral fractures assessed by radiographs and 51 without vertebral fractures, were studied. Trabecular, cortical, and integral BMD were examined at the spine and hip using a helical CT scanner and were compared to dual X-ray absorptiometry (DXA) measurements at the same sites. OA changes visible on the radiographs were categorized into two grades according to severity. Differences in BMD measures obtained in the two groups of patients defined by OA grade using the described radiologic methods were compared using analysis of variance. Standardized difference (effect sizes) was also compared between radiologic methods. RESULTS: Spinal trabecular BMD did not differ significantly between OA grade 0 and OA grade 1. Spinal cortical and integral BMD measures showed statistically significant differences, as did the lumbar spine DXA BMD measurement (13%, P = 0.02). The QCT measurements at the hip were also higher in OA 1 subjects. Femoral trabecular BMD was 13-15% higher in OA grade 1 subjects than in OA grade 0 subjects. The cortical BMD measures in the CT_TOT_FEM and CT_TROCH ROI's were also higher in the OA 1 subjects. The integral QCT BMD measures in the hip showed difference between grades OA 1 and 0. The DXA measurements in the neck and trochanter ROI's showed smaller differences (9 and 11%, respectively). There were no statistically significant differences in bone size. CONCLUSION: There is no evidence supporting that trabecular BMD measurements by QCT are influenced by OA. Instead, degenerative changes have an effect on both cortical and integral QCT, and on DXA at the lumbar spine and the hip. For subjects with established OA, assessment of BMD by volumetric QCT may be suggested.

Iatrogenic copper deficiency following information and drugs obtained over the Internet.

We report the case of a 56-year-old woman with a 7-year history of metastatic cancer who presented with severe copper deficiency following self-treatment with the copper-chelating agent tetrathiomolybdate. This compound was used with the aim of inhibiting tumour angiogenesis and was obtained from the USA by placing an order on the internet. The patient exhibited severe neutropenia as her serum copper concentration fell from 19.8 micromol/L to 3.3 micromol/L and her caeruloplasmin concentration from 35 mg/dL to 4 mg/dL.