Naturally occurring stable calcium isotope ratios are a novel biomarker of bone calcium balance in chronic kidney disease.

Dysregulated calcium homeostasis is common in chronic kidney disease and causally associated with disorders of bone mineralization. However, radiological measures and biomarkers do not allow accurate evaluation of bone calcium balance. Non-radioactive calcium isotopes, 42Ca and 44Ca, are present in our diet and sequestered into body compartments following principles of kinetic isotope fractionation. Isotopically light 42Ca is preferentially incorporated into bone, while heavier 44Ca is excreted. The ratio (44/42Caserum) increases when bone formation exceeds resorption and vice versa, reflecting bone calcium balance. We measured these calcium isotopes by inductively coupled plasma mass-spectrometry in blood, urine and feces of 42 children with chronic kidney disease and 92 receiving dialysis therapy. We compared the isotope ratios with bone biomarkers and determined total bone mineral content by dual-energy x-ray absorptiometry and peripheral quantitative CT expressed as age-adjusted z-scores. The 44/42Caserum ratio positively correlated with serum calcium, 25-hydroxyvitamin D and alkaline phosphatases and inversely with serum parathyroid hormone and other bone resorption markers. The 44/42Caserum ratio positively correlated with age-adjusted z-scores of tibial trabecular bone mineral density and total bone mineral content measured by peripheral quantitative CT, and hip bone mineral density measured by dual-energy X-ray absorptiometry. Significant and independent predictors of total bone mineral content, measured by, were the 44/42Caserum ratio and parathyroid hormone. The 44/42Caserum ratio, repeated after four weeks, highly correlated with baseline values. When adjusted for calcium-containing medications and kidney impairment, the 44/42Caserum ratio in patients receiving dialysis was 157% lower than that of age-matched children and 29% lower than levels in elderly women with osteoporosis, implying significantly lower bone mineral content. Thus, calcium isotope ratios may provide a novel, sensitive and non-invasive method of assessing bone calcium balance in chronic kidney disease.

Routine serum biomarkers, but not dual-energy X-ray absorptiometry, correlate with cortical bone mineral density in children and young adults with chronic kidney disease.

BACKGROUND: Biomarkers and dual-energy X-ray absorptiometry (DXA) are thought to be poor predictors of bone mineral density (BMD). The Kidney Disease: Improving Global Outcomes guidelines suggest using DXA if the results will affect patient management, but this has not been studied in children or young adults in whom bone mineral accretion continues to 30 years of age. We studied the clinical utility of DXA and serum biomarkers against tibial cortical BMD (CortBMD) measured by peripheral quantitative computed tomography, expressed as Z-score CortBMD, which predicts fracture risk. METHODS: This was a cross-sectional multicentre study in 26 patients with CKD4 and 5 and 77 on dialysis. RESULTS: Significant bone pain that hindered activities of daily living was present in 58%, and 10% had at least one low-trauma fracture. CortBMD and cortical mineral content Z-scores were lower in dialysis compared with CKD patients (P = 0.004 and P = 0.02). DXA BMD hip and lumbar spine Z-scores did not correlate with CortBMD or biomarkers. CortBMD was negatively associated with parathyroid hormone (PTH; r = -0.44, P < 0.0001) and alkaline phosphatase (ALP; r = -0.22, P = 0.03) and positively with calcium (Ca; r = 0.33, P = 0.001). At PTH <3 times upper limit of normal, none of the patients had a CortBMD below -2 SD (odds ratio 95% confidence interval 7.331 to infinity). On multivariable linear regression PTH (ß = -0.43 , P < 0.0001), ALP (ß = -0.36, P < 0.0001) and Ca (ß = 0.21, P = 0.005) together predicted 57% of variability in CortBMD. DXA measures did not improve this model. CONCLUSIONS: Taken together, routinely used biomarkers, PTH, ALP and Ca, but not DXA, are moderate predictors of cortical BMD. DXA is not clinically useful and should not be routinely performed in children and young adults with CKD 4-5D.

Assessment of Bone Density by DXA in Poorly Controlled Children With ß-Thalassemia: Correction for Hepatic Iron Overload by Manual Analysis.

INTRODUCTION: Beta thalassemia major (BTM) is characterized by anemia and iron overload, especially with inadequate chelation therapy. Dual energy x-ray absorptiometry software (DXA) may misanalyse bone measurements due to iron deposition in organs such as the liver. Our objective was to study difference between the posterior-anterior spine measurements of bone mineral content (BMC), area (BA) and density (BMD) in poorly chelated beta thalassemia patients with and without inclusion of the liver in the DXA analysis. METHODS: We studied hemoglobin and serum ferritin concentrations in 208 patients with BTM (children n = 177, young adults n = 31). Posteroanterior spine measurements BMC, BA and areal BMD were performed using a GE iDXA. Using the tissue point typing feature (EnCore software, version 16), analysis was carried out including and excluding (manually) the iron overloaded liver. Machine generated Z-scores of L1-L4 BMD were used for analysis. RESULTS: The mean age of the study group was 12.9 ± 5.4 yr. Mean hemoglobin and serum ferritin concentrations were 8.0 ± 1.7 g/dl and 2256.9 ± 1978.0 ng/ml, respectively. The mean BMC, BA, and aBMD at the lumbar spine were 23.2 ± 11.4 g, 29.9 ± 8.5 cm2 and 0.736 ± 0.173 g/cm2 respectively with inclusion of liver that is standard machine analysis. After the liver was excluded from the analysis, the mean BMC, BA, and aBMD were 23.9 ± 11.6 g, 30.0 ± 8.6 cm2 and 0.757 ±0.173 g/cm2, respectively and the BMC and aBMD were significantly greater (p < 0.05). Mean BMD Z-score was -1.5 ± 1.2, which significantly (p < 0.05) improved to -1.3 ± 1.2 after exclusion of the liver from the analysis. CONCLUSION: In poorly chelated patients with thalassemia, inclusion of the iron-overloaded liver in the tissue analysis may exaggerate the deficit in bone parameters. Iron overloaded tissues need to be manually excluded during analysis of the PA spine.

Increased central adiposity and decreased subcutaneous adipose tissue 11ß-hydroxysteroid dehydrogenase type 1 are associated with deterioration in glucose tolerance-A longitudinal cohort study.

OBJECTIVE AND CONTEXT: Increasing adiposity, ageing and tissue-specific regeneration of cortisol through the activity of 11ß-hydroxysteroid dehydrogenase type 1 have been associated with deterioration in glucose tolerance. We undertook a longitudinal, prospective clinical study to determine if alterations in local glucocorticoid metabolism track with changes in glucose tolerance. DESIGN, PATIENTS, AND MEASUREMENTS: Sixty-five overweight/obese individuals (mean age 50.3 ± 7.3 years) underwent oral glucose tolerance testing, body composition assessment, subcutaneous adipose tissue biopsy and urinary steroid metabolite analysis annually for up to 5 years. Participants were categorized into those in whom glucose tolerance deteriorated ("deteriorators") or improved ("improvers"). RESULTS: Deteriorating glucose tolerance was associated with increasing total and trunk fat mass and increased subcutaneous adipose tissue expression of lipogenic genes. Subcutaneous adipose tissue 11ß-HSD1 gene expression decreased in deteriorators, and at study completion, it was highest in the improvers. There was a significant negative correlation between change in area under the curve glucose and 11ß-HSD1 expression. Global 11ß-HSD1 activity did not change and was not different between deteriorators and improvers at baseline or follow-up. CONCLUSION: Longitudinal deterioration in metabolic phenotype is not associated with increased 11ß-HSD1 activity, but decreased subcutaneous adipose tissue gene expression. These changes may represent a compensatory mechanism to decrease local glucocorticoid exposure in the face of an adverse metabolic phenotype.

Bone Density in the Obese Child: Clinical Considerations and Diagnostic Challenges.

The prevalence of obesity in children has reached epidemic proportions. Concern about bone health in obese children, in part, derives from the potentially increased fracture risk associated with obesity. Additional risk factors that affect bone mineral accretion, may also contribute to obesity, such as low physical activity and nutritional factors. Consequences of obesity, such as inflammation, insulin resistance, and non-alcoholic fatty liver disease, may also affect bone mineral acquisition, especially during the adolescent years when rapid increases in bone contribute to attaining peak bone mass. Further, numerous pediatric health conditions are associated with excess adiposity, altered body composition, or endocrine disturbances that can affect bone accretion. Thus, there is a multitude of reasons for considering clinical assessment of bone health in an obese child. Multiple diagnostic challenges affect the measurement of bone density and its interpretation. These include greater precision error, difficulty in positioning, and the effects of increased lean and fat tissue on bone health outcomes. Future research is required to address these issues to improve bone health assessment in obese children.

Habitual physical activity is associated with the maintenance of neutrophil migratory dynamics in healthy older adults.

BACKGROUND: Dysfunctional neutrophils with advanced age are a hallmark of immunosenescence. Reduced migration and bactericidal activity increase the risk of infection. It remains unclear why neutrophil dysfunction occurs with age. Physical activity and structured exercise have been suggested to improve immune function in the elderly. The aim of this study was to assess a comprehensive range of neutrophil functions and determine their association with habitual physical activity. METHOD: Physical activity levels were determined in 211 elderly (67±5years) individuals by 7-days of accelerometry wear. Twenty of the most physically active men and women were matched for age and gender to twenty of the least physically active individuals. Groups were compared for neutrophil migration, phagocytosis, oxidative burst, cell surface receptor expression, metabolic health parameters and systemic inflammation. Groups were also compared against ten young participants (23±4years). RESULTS: The most active group completed over twice as many steps/day as the least active group (p<0.001), had lower BMI's (p=0.007) and body fat percentages (p=0.029). Neutrophils migrated towards IL-8 better in the most active group compared to the least active (p<0.05) and was comparable to that of the young (p>0.05). These differences remained after adjusting for BMI, body fat and plasma metabolic markers which were different between groups. Correlations revealed that steps/day, higher adiponectin and lower insulin were positively associated with migratory ability (p<0.05). There was no difference in expression of the chemokine receptors CXCR1 or CXCR2 (p>0.05 for both). CD11b was higher in the most active group compared to the least active (p=0.048). No differences between activity groups or young controls were observed for neutrophil phagocytosis or oxidative burst in response to Escherichia coli (p>0.05). The young group had lower concentrations of IL-6, IL-8, MCP-1, CRP, IL-10 and IL-13 (p<0.05 for all) with no differences between the two older groups. CONCLUSION: These data suggest that impaired neutrophil migration, but not bactericidal function, in older adults may be, in part, the result of reduced physical activity. A 2-fold difference in physical activity is associated with better preserved neutrophil migratory dynamics in healthy older people. As a consequence increasing habitual physical activity may be beneficial for neutrophil mediated immunity.

Cardiovascular, muscular and perceptual contributions to physical fatigue in prevalent kidney transplant recipients.

Physical fatigue is debilitating and common among kidney transplant recipients (KTRs). This study investigated the mechanistic aetiology of physical fatigue in this setting through examinations of muscle mass, muscular and cardiovascular function, and perceived exertion. The incidence of physical fatigue, its association with quality of life (QoL), and the predictors of perceived exertion, were evaluated. This single-centre observational cross-sectional study enrolled 55 KTRs. Muscle mass was quantified using dual-energy x-ray absorptiometry. Muscular function was assessed by jumping mechanography. Cardiovascular function (maximal oxygen consumption and oxygen pulse) was estimated during submaximal exercise testing, with perceived exertion determined using age-adjusted Borg scale-ratings. Physical fatigue was measured using Multi-Dimensional Fatigue Inventory-20. QoL was assessed using Medical Outcomes Study Short Form-36. Demographic, clinical, nutritional, psychosocial and behavioural predictors of perceived exertion were assessed. Of clinical importance, increased perceived exertion was the only independent predictor of physical fatigue (P = 0.001), with no association found between physical fatigue and muscular or cardiovascular parameters. Physical fatigue occurred in 22% of KTRs, and negatively impacted on QoL (P < 0.001). Predictors of heightened perception included anxiety (P < 0.05) and mental fatigue (P < 0.05). Perception is a key determinant of physical fatigue in KTRs, paving the way for future interventions.

The relationship between bone mass and body composition in children with hypothalamic and simple obesity.

INTRODUCTION: Obesity has been associated with a positive influence on bone mass. This is thought to be due to a mechanical load exerted on the skeleton, together with various hormones and adipocytokines that control appetite and weight, such as leptin, some of which directly affect bone mass. However, there are conflicting reports of the association between fat mass and bone mass in children. Animal studies demonstrate increased bone mass where there is impaired central leptin signalling. Hypothalamic damage can cause abnormal central leptin action, which contributes to the development of obesity. OBJECTIVE: The objective of this study was to investigate the relationship between body composition and bone mass in hypothalamic and simple childhood obesity, in conjunction with the effect of the adipocytokines, leptin and adiponectin. DESIGN: This was a cross-sectional study of three groups of children, those with hypothalamic obesity (HO), those with congenital hypopituitarism (CH) and those with simple obesity (SO). RESULTS: A total of 65 children (HO = 26 [11 males], CH = 17 [eight males] and SO = 22 [15 males]) had body composition assessed using dual-energy X-ray absorptiometry together with measurement of serum leptin and adiponectin. No significant differences were seen in bone mass once bone density (BMD) was adjusted for differences in body size between groups. Significantly elevated levels of leptin and adiponectin were seen in the HO group compared with the SO group (P < 0·01, P < 0·05, respectively). CONCLUSION: Adiposity is associated with increased bone mass; however, this relationship is complex. Despite the presence of hyperleptinaemia, increased bone mass in the HO group was not seen. This may be due to the effects of other factors such as adiponectin, abnormal hypothalamic signalling, pituitary hormone deficiencies and disruption of normal homoeostatic mechanisms within the hypothalamus.

Dual-energy X-ray absorptiometry interpretation and reporting in children and adolescents: the revised 2013 ISCD Pediatric Official Positions.

The International Society for Clinical Densitometry Official Revised Positions on reporting of densitometry results in children represent current expert recommendations to assist health care providers determine which skeletal sites should be measured, which, if any, adjustments should be made, reference databases to be used, and the elements to include in a dual-energy X-ray absorptiometry report. The recommended scanning sites remain the total body less head and the posterior-anterior spine. Other sites such as the proximal femur, lateral distal femur, lateral vertebral assessment, and forearm are discussed but are only recommended for specific pediatric populations. Different methods of interpreting bone density scans in children with short stature or growth delay are presented. The use of bone mineral apparent density and height-adjusted Z-scores are recommended as suitable size adjustment techniques. The validity of appropriate reference databases and technical considerations to consider when upgrading software and hardware remain unchanged. Updated reference data sets for all contemporary bone densitometers are listed. The inclusion of relevant demographic and health information, technical details of the scan, Z-scores, and the wording "low bone mass or bone density" for Z-scores less than or equal to -2.0 standard deviation are still recommended for clinical practice. The rationale and evidence for the development of the Official Positions are provided. Changes in the grading of quality of evidence, strength of recommendation, and worldwide applicability represent a change in current evidence and/or differences in opinion of the expert panelists used to validate the position statements for the 2013 Position Development Conference.

Lumbar spine bone mineral adaptation: cricket fast bowlers versus controls.

Elite adult male fast bowlers have high lumbar spine bone mineral, particularly on the contralateral side to their bowling arm. It is thought that bone possesses its greatest ability to adapt to loading during adolescence, but it is unknown at what age the greatest changes in lumbar bone mineral and asymmetry develops in fast bowlers. Objectives: This study aims to evaluate the adaptation of the lumbar vertebrae in fast bowlers compared to controls and how this is associated with age. Methods: 91 male fast bowlers and 84 male controls aged 14-24 years had between one and three annual anterior-posterior lumbar spine dual-energy-X-ray absorptiometry scans. Total (L1-L4) and regional ipsilateral and contralateral L3 and L4 (respective to bowling arm) bone mineral density and content (BMD/C) were derived. Multilevel models examined the differences in lumbar bone mineral trajectories between fast bowlers and controls. Results: At L1-L4 BMC and BMD, and contralateral BMD sites, fast bowlers demonstrated a greater negative quadratic pattern to their accrual trajectories than controls. Fast bowlers had greater increases in BMC in L1-L4 between 14 and 24 years of 55% compared with controls (41%). Within vertebra, asymmetry was evident in all fast bowlers and increased by up to 13% in favour of the contralateral side. Conclusions: Lumbar vertebral adaptation to fast bowling substantially increased with age, particularly on the contralateral side. The greatest accrual was during late adolescence and early adulthood, which may correspond with the increasing physiological demands of adult professional sport.

Bone Mineral Density and Vascular Calcification in Children and Young Adults With CKD 4 to 5 or on Dialysis.

Introduction: Older adults with chronic kidney disease (CKD) can have low bone mineral density (BMD) with concurrent vascular calcification. Mineral accrual by the growing skeleton may protect young people with CKD from extraosseous calcification. Our hypothesis was that children and young adults with increasing BMD do not develop vascular calcification. Methods: This was a multicenter longitudinal study in children and young people (5-30 years) with CKD stages 4 to 5 or on dialysis. BMD was assessed by tibial peripheral quantitative computed tomography (pQCT) and lumbar spine dual-energy X-ray absorptiometry (DXA). The following cardiovascular imaging tests were undertaken: cardiac computed tomography for coronary artery calcification (CAC), ultrasound for carotid intima media thickness z-score (cIMTz), pulse wave velocity z-score (PWVz), and carotid distensibility for arterial stiffness. All measures are presented as age-adjusted and sex-adjusted z-scores. Results: One hundred participants (median age 13.82 years) were assessed at baseline and 57 followed up after a median of 1.45 years. Trabecular BMD z-score (TrabBMDz) decreased (P = 0.01), and there was a nonsignificant decrease in cortical BMD z-score (CortBMDz) (P = 0.09). Median cIMTz and PWVz showed nonsignificant increase (P = 0.23 and P = 0.19, respectively). The annualized increase in TrabBMDz (ΔTrabBMDz) was an independent predictor of cIMTz increase (R 2 = 0.48, ß = 0.40, P = 0.03). Young people who demonstrated statural growth (n = 33) had lower ΔTrabBMDz and also attenuated vascular changes compared with those with static growth (n = 24). Conclusion: This hypothesis-generating study suggests that children and young adults with CKD or on dialysis may develop vascular calcification even as their BMD increases. A presumed buffering capacity of the growing skeleton may offer some protection against extraosseous calcification.

Weight regulation and bone mass: a comparison between professional jockeys, elite amateur boxers, and age, gender and BMI matched controls.

The aim of this study was to compare bone mass between two groups of jockeys (flat: n = 14; national hunt: n = 16); boxers (n = 14) and age, gender and BMI matched controls (n = 14). All subjects underwent dual energy X-ray absorptiometry (DXA) scanning for assessment of bone mass, with measurements made of the total body, vertebra L2-4 and femoral neck. Body composition and the relative contribution of fat and lean mass were extrapolated from the results. Data were analysed in accordance with differences in body composition, in particular, height, lean mass, fat mass and age. Both jockey groups were shown to display lower bone mass than either the boxers or control group at a number of sites including total body bone mineral density (BMD) (1.019 ± 0.06 and 1.17 ± 1.05 vs. 1.26 ± 0.01 and 1.26 ± 0.06 g cm(-2) for flat, national hunt, boxer and control, respectively), total body bone mineral content (BMC) less head, L2-4 BMD and femoral neck BMD and BMC (p < 0.05). Regression analysis revealed that lean mass and height were the primary predictors of total body BMC, although additional group-specific influences were present which reduced bone mass in the flat jockey group and enhanced it in the boxers (R (2) = 0.814). Reduced bone mass in jockeys may be a consequence of reduced energy availability in response to chronic weight restriction and could have particular implications for these athletes in light of the high risk nature of the sport. In contrast, the high intensity, high impact training associated with boxing may have conveyed an osteogenic stimulus on these athletes.

Digital health interventions for osteoporosis and post-fragility fracture care.

The growing burden from osteoporosis and fragility fractures highlights a need to improve osteoporosis management across healthcare systems. Sub-optimal management of osteoporosis is an area suitable for digital health interventions. While fracture liaison services (FLSs) are proven to greatly improve care for people with osteoporosis, such services might benefit from technologies that enhance automation. The term 'Digital Health' covers a variety of different tools including clinical decision support systems, electronic medical record tools, patient decision aids, patient apps, education tools, and novel artificial intelligence (AI) algorithms. Within the scope of this review are AI solutions that use algorithms within health system registries to target interventions. Clinician-targeted, patient-targeted, or system-targeted digital health interventions could be used to improve management and prevent fragility fractures. This review was commissioned by The Royal Osteoporosis Society and Bone Research Academy during the production of the 2020 Research Roadmap (https://theros.org.uk), with the intention of identifying gaps where targeted research funding could lead to improved patient health. We explore potential uses of digital technology in the general management of osteoporosis. Evidence suggests that digital technologies can support multidisciplinary teams to provide the best possible patient care based on current evidence and to support patients in self-management. However, robust randomised controlled studies are still needed to assess the effectiveness and cost-effectiveness of these technologies.

Increased prevalence of fractures in inadequately transfused and chelated Indian children and young adults with beta thalassemia major.

INTRODUCTION: In patients with beta thalassemia major, inadequate transfusion and chelation may compromise bone health and increase risk of fractures. The objective of this study was to describe the prevalence of fractures in Indian inadequately transfused and chelated children, adolescents and young adults with beta thalassemia major. METHODS: We studied 179 patients with beta thalassemia (3.6-28.3 years; 105 boys). Medical, transfusion, chelation and fracture history were recorded. Vertebral fracture assessment (VFA) was performed using lateral spine images acquired using the GE Lunar iDXA (Wisconsin, MD). Fractures were classified according to an adapted semi-quantitative method. RESULTS: History of non-traumatic long bone fractures was observed in 21% patients (n = 37); there were significantly greater (p < 0.05) number of males (n = 30) than females (n = 15). The 21% fracture prevalence in the present study is higher than the reported fractures of 9% in healthy Indian children and adolescents. The prevalence of vertebral fractures was 4.5% (n = 8) in the study group. Of those with fractures, four patients had both long bone and vertebral fractures, and (any, long bone or vertebral fractures) sixteen patients had more than 1 fracture; eleven patients had 2 fractures, four patients had 3 fractures and one patient had 5 fractures. Thus, in 179 patients, there were a total of 68 single fractures which translates to 307 fractures per 10,000 patient years. CONCLUSION: This study found increased prevalence of non-traumatic long bone and vertebral fractures in children and adolescents with thalassemia major.

A Three-Year Longitudinal Study Comparing Bone Mass, Density, and Geometry Measured by DXA, pQCT, and Bone Turnover Markers in Children with PKU Taking L-Amino Acid or Glycomacropeptide Protein Substitutes.

In patients with phenylketonuria (PKU), treated by diet therapy only, evidence suggests that areal bone mineral density (BMDa) is within the normal clinical reference range but is below the population norm. AIMS: To study longitudinal bone density, mass, and geometry over 36 months in children with PKU taking either amino acid (L-AA) or casein glycomacropeptide substitutes (CGMP-AA) as their main protein source. METHODOLOGY: A total of 48 subjects completed the study, 19 subjects in the L-AA group (median age 11.1, range 5-16 years) and 29 subjects in the CGMP-AA group (median age 8.3, range 5-16 years). The CGMP-AA was further divided into two groups, CGMP100 (median age 9.2, range 5-16 years) (n = 13), children taking CGMP-AA only and CGMP50 (median age 7.3, range 5-15 years) (n = 16), children taking a combination of CGMP-AA and L-AA. Dual X-ray absorptiometry (DXA) was measured at enrolment and 36 months, peripheral quantitative computer tomography (pQCT) at 36 months only, and serum blood and urine bone turnover markers (BTM) and blood bone biochemistry at enrolment, 6, 12, and 36 months. RESULTS: No statistically significant differences were found between the three groups for DXA outcome parameters, i.e., BMDa (L2-L4 BMDa g/cm2), bone mineral apparent density (L2-L4 BMAD g/cm3) and total body less head BMDa (TBLH g/cm2). All blood biochemistry markers were within the reference ranges, and BTM showed active bone turnover with a trend for BTM to decrease with increasing age. CONCLUSIONS: Bone density was clinically normal, although the median z scores were below the population mean. BTM showed active bone turnover and blood biochemistry was within the reference ranges. There appeared to be no advantage to bone density, mass, or geometry from taking a macropeptide-based protein substitute as compared with L-AAs.

Growth and Body Composition in PKU Children-A Three-Year Prospective Study Comparing the Effects of L-Amino Acid to Glycomacropeptide Protein Substitutes.

Protein quality and quantity are important factors in determining lean body (muscle) mass (LBM). In phenylketonuria (PKU), protein substitutes provide most of the nitrogen, either as amino acids (AA) or glycomacropeptide with supplementary amino acids (CGMP-AA). Body composition and growth are important indicators of long-term health. In a 3-year prospective study comparing the impact of AA and CGMP-AA on body composition and growth in PKU, 48 children were recruited. N = 19 (median age 11.1 years, range 5-15 years) took AA only, n = 16 (median age 7.3 years, range 5-15 years) took a combination of CGMP-AA and AA, (CGMP50) and 13 children (median age 9.2 years, range 5-16 years) took CGMP-AA only (CGMP100). A dual energy X-ray absorptiometry (DXA) scan at enrolment and 36 months measured LBM, % body fat (%BF) and fat mass (FM). Height was measured at enrolment, 12, 24 and 36 months. No correlation or statistically significant differences (after adjusting for age, gender, puberty and phenylalanine blood concentrations) were found between the three groups for LBM, %BF, FM and height. The change in height z scores, (AA 0, CGMP50 +0.4 and CGMP100 +0.7) showed a trend that children in the CGMP100 group were taller, had improved LBM with decreased FM and % BF but this was not statistically significant. There appeared to be no advantage of CGMP-AA compared to AA on body composition after 3-years of follow-up. Although statistically significant differences were not reached, a trend towards improved body composition was observed with CGMP-AA when it provided the entire protein substitute requirement.

Opportunistic diagnosis of osteoporosis, fragile bone strength and vertebral fractures from routine CT scans; a review of approved technology systems and pathways to implementation.

Osteoporosis causes bones to become weak, porous and fracture more easily. While a vertebral fracture is the archetypal fracture of osteoporosis, it is also the most difficult to diagnose clinically. Patients often suffer further spine or other fractures, deformity, height loss and pain before diagnosis. There were an estimated 520,000 fragility fractures in the United Kingdom (UK) in 2017 (costing £4.5 billion), a figure set to increase 30% by 2030. One way to improve both vertebral fracture identification and the diagnosis of osteoporosis is to assess a patient's spine or hips during routine computed tomography (CT) scans. Patients attend routine CT for diagnosis and monitoring of various medical conditions, but the skeleton can be overlooked as radiologists concentrate on the primary reason for scanning. More than half a million CT scans done each year in the National Health Service (NHS) could potentially be screened for osteoporosis (increasing 5% annually). If CT-based screening became embedded in practice, then the technique could have a positive clinical impact in the identification of fragility fracture and/or low bone density. Several companies have developed software methods to diagnose osteoporosis/fragile bone strength and/or identify vertebral fractures in CT datasets, using various methods that include image processing, computational modelling, artificial intelligence and biomechanical engineering concepts. Technology to evaluate Hounsfield units is used to calculate bone density, but not necessarily bone strength. In this rapid evidence review, we summarise the current literature underpinning approved technologies for opportunistic screening of routine CT images to identify fractures, bone density or strength information. We highlight how other new software technologies have become embedded in NHS clinical practice (having overcome barriers to implementation) and highlight how the novel osteoporosis technologies could follow suit. We define the key unanswered questions where further research is needed to enable the adoption of these technologies for maximal patient benefit.

Regional changes in bone area and bone mineral content in boys with duchenne muscular dystrophy receiving corticosteroid therapy.

OBJECTIVE: To examine the functional and skeletal effects of 30 months of steroid treatment in boys with Duchenne muscular dystrophy. STUDY DESIGN: Lumbar spine (L(2)L(4)) and subcranial dual energy X-ray absorptiometry scanning was performed on 25 boys (mean age 7.4 years) at baseline and after 30 months of steroid treatment. RESULTS: At baseline, L(2)L(4) bone mineral content (BMC) was significantly low for projected bone area although appropriate for reduced lean body mass (LBM). Subcranial bone area for height and subcranial BMC for area and LBM were all significantly reduced. After 30 months of steroid therapy there was a significant increase in subcranial bone area for height but a significant reduction of subcranial BMC for area. At the lumbar spine there were no significant changes in bone area but small increases in L(2)L(4) BMC both for bone area and LBM. CONCLUSION: At baseline reduced mechanical load from diminished muscle function results in narrow light bones more noticeable in the subcranial region than the lumbar spine. Increases observed in subcranial bone area at 30 months suggest a gradual adaptation to increased gravitational load whereas at the spine there were no apparent detrimental effects on bone after 30 months of steroid therapy.

Diagnostic performance of morphometric vertebral fracture analysis (MXA) in children using a 33-point software program.

BACKGROUND: There is significant inter and intraobserver variability in diagnosing vertebral fractures in children. PURPOSE: We aimed to evaluate the diagnostic accuracy of morphometric vertebral fracture analysis (MXA) using a 33-point software program designed for adults, on dual-energy x-ray absorptiometry (DXA) images of children. MATERIALS AND METHODS: Lateral spine DXA images of 420 children aged between 5 and 18 years were retrospectively reviewed. Vertebral fracture assessment (VFA) by an expert pediatric radiologist using Genant's semiquantitative scoring system served as the gold standard. All 420 DXA scans were analyzed by a trained radiographer, using semi-automated software (33-point morphometry). VFA of a random sample of 100 DXA was performed by an experienced pediatric clinical scientist. MXA of a random sample of 30 DXA images were analyzed by three pediatric radiologists and the pediatric clinical scientist. Diagnostic accuracy and inter and intraobserver agreement (kappa statistics) were calculated. RESULTS: Overall sensitivity, specificity, false positive (FP) and false negative (FN) rates for the radiographer using the MXA software were 80%, 90%, 10%, and 20% respectively and for mild fractures alone were 46%, 92%, 8%, and 54% respectively. Overall sensitivity, specificity, FP, and FN rates for the four additional observers using MXA were 89%, 79%, 21%, and 11% respectively and for mild fractures alone were 36%, 86%, 14%, and 64% respectively. Agreement between two expert observers was fair to good for VFA and MXA [kappa = 0·29 to 0·76 (95% CI: 0·17-0·88) and 0·29 to 0·69 (95% CI: 0·17-0·83)] respectively. CONCLUSION: MXA using a 33-point technique developed for adults is not a reliable method for the identification of mild vertebral fractures in children. A pediatric standard is required which not only incorporates specific vertebral body height ratios but also the age-related physiological changes in vertebral shape that occur throughout childhood.

The UK Biobank imaging enhancement of 100,000 participants: rationale, data collection, management and future directions.

UK Biobank is a population-based cohort of half a million participants aged 40-69 years recruited between 2006 and 2010. In 2014, UK Biobank started the world's largest multi-modal imaging study, with the aim of re-inviting 100,000 participants to undergo brain, cardiac and abdominal magnetic resonance imaging, dual-energy X-ray absorptiometry and carotid ultrasound. The combination of large-scale multi-modal imaging with extensive phenotypic and genetic data offers an unprecedented resource for scientists to conduct health-related research. This article provides an in-depth overview of the imaging enhancement, including the data collected, how it is managed and processed, and future directions.