Effect of cardiometabolic risk factors on the relationship between adiposity and bone mass in girls.

BACKGROUND/OBJECTIVE: Childhood obesity has been separately associated with cardiometabolic risk factors (CMRs) and increased risk of fracture. However, both augmented and compromised bone mass have been reported among overweight/obese children. Metabolic dysfunction, often co-existing with obesity, may explain the discrepancy in previous studies. The aim of this study was to examine whether the relationship between adiposity and dual-energy X-ray absorptiometry (DXA) derived bone mass differed in young girls with and without CMR(s). SUBJECTS/METHODS: Whole-body bone and body composition measures by DXA and measures of CMR (fasting glucose, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), systolic and diastolic blood pressure, waist circumference (WC)) were obtained from 307, 9- to 12-year-old girls. Girls with 1 or ≥ 2 CMR(s) were considered to be at risk (vs. no CMR). Multiple linear regression was used to test the relationship of total fat mass with total body bone mineral content (BMC) after controlling for height, lean mass, CMR risk, and other potential confounders. RESULTS: There was a significant interaction between CMR risk and total body fat mass. When girls were stratified by CMR group, all groups had a significant positive relationship between fat mass and BMC (p < 0.05), however, girls with ≥ 2 CMRs had a lower BMC for a given level of body fat. Total body fat was not significantly related to bone mineral density (p > 0.05). CONCLUSION: Fat mass has a positive relationship with BMC even after controlling for lean mass. However, the positive relationship of fat mass with BMC may be attenuated if multiple CMRs are present.

Validation of Peripheral Quantitative Computed Tomography-Derived Thigh Adipose Tissue Subcompartments in Young Girls Using a 3 T MRI Scanner.

The ability to assess skeletal muscle adipose tissue is important given the negative clinical implications associated with greater fat infiltration of the muscle. Computed tomography and magnetic resonance imaging (MRI) are highly accurate for measuring appendicular soft tissue and muscle composition, but have limitations. Peripheral quantitative computed tomography (pQCT) is an alternative that investigators find valuable because of its low radiation, fast scan time, and comparatively lower costs. The present investigation sought to assess the accuracy of pQCT-derived estimates of total, subcutaneous, skeletal muscle, intermuscular, and calculated intramuscular adipose tissue areas, and muscle density in the midthigh of young girls using the gold standard, 3 T MRI, as the criterion. Cross-sectional data were analyzed for 26 healthy girls aged 9-12 years. Midthigh soft tissue composition was assessed by both pQCT and 3 T MRI. Mean tissue area for corresponding adipose compartments by pQCT and MRI was compared using t tests, regression analysis, and Bland-Altman plots. Muscle density was regressed on MRI skeletal muscle adipose tissue, intermuscular adipose tissue, and intramuscular adipose tissue, each expressed as a percentage of total muscle area. Correlations were high between MRI and pQCT for total adipose tissue (r2 = 0.98), subcutaneous adipose tissue (r2 = 0.95), skeletal muscle adipose tissue (r2 = 0.83), and intermuscular adipose tissue (r2 = 0.82), and pQCT muscle density correlated well with both MRI skeletal muscle adipose tissue (r2 = 0.70) and MRI intermuscular adipose tissue (r2 = 0.70). There was a slight, but statistically significant underestimation by pQCT for total and subcutaneous adipose tissue, whereas no significant difference was observed for skeletal muscle adipose tissue. Both pQCT-estimated intramuscular adipose tissue and muscle density were weakly correlated with MRI-intramuscular adipose tissue. We conclude that pQCT is a valid measurement technique for estimating all adipose subcompartments, except for intramuscular adipose tissue, for the midthigh region in young/adolescent girls.

Relationship between fat distribution and cardiometabolic risk in Hispanic girls.

OBJECTIVE: In adults, certain body fat depots have greater impact on cardiometabolic risk than total adiposity. Whether similar relationships exist in children is uncertain. The aim of this study was to examine the relationships among dual x-ray absorptiometry (DXA) measures of body fat distribution and total body adiposity with cardiometabolic risk factors in Hispanic girls. METHODS: Measures of total percent body fat, percent of total fat within the android, gynoid, leg, and trunk regions, and cardiometabolic biomarkers (insulin, glucose, homeostatic model assessment of insulin resistance (HOMA-IR), triglycerides (TG), low and high lipoprotein cholesterol (LDL-C, HDL-C)) were obtained from 232 Hispanic girls (age 10.7 ±1.1 years). Regression models for each metabolic parameter were run against adiposity measures. Partial correlations of the adiposity measures were used to compare associations between adiposity measures and the cardiometabolic risk factors, controlling for somatic maturation. RESULTS: Total and regional adiposity were significantly related with cardiometabolic risk factors (P < 0.05) except fasting glucose. The partial correlations of total and regional adiposity measures with each cardiometabolic biomarker were similar. More variance was explained for insulin and the HOMA-IR (33%-43%) than other risk factors. Partial correlations for the percentage of total fat in the gynoid and leg regions with insulin, HOMA-IR, TG, and LDL-C were negative, and positive with HDL-C. CONCLUSION: Measures of total and regional fat perform similarly in predicting cardiometabolic risk in Hispanic girls. A higher proportion of fat distributed in the gynoid or leg region is associated with lower cardiometabolic risk.

Comparison of direct measures of adiposity with indirect measures for assessing cardiometabolic risk factors in preadolescent girls.

BACKGROUND: Childhood overweight and obesity remains high, contributing to cardiometabolic risk factors at younger ages. It is unclear which measures of adiposity serve as the best proxies for identifying children at metabolic risk. This study assessed whether DXA-derived direct measures of adiposity are more strongly related to cardiometabolic risk factors in children than indirect measures. METHODS: Anthropometric and DXA measures of adiposity and a comprehensive assessment of cardiometabolic risk factors were obtained in 288, 9-12 year old girls, most being of Hispanic ethnicity. Multiple regression models for each metabolic parameter were run against each adiposity measure while controlling for maturation and ethnicity. In addition, regression models including both indirect and direct measures were developed to assess whether using direct measures of adiposity could provide a better prediction of the cardiometabolic risk factors beyond that of using indirect measures alone. RESULTS: Measures of adiposity were significantly correlated with cardiometabolic risk factors (p < 0.05) except fasting glucose. After adjusting for maturation and ethnicity, indirect measures of adiposity accounted for 29-34% in HOMA-IR, 10-13% in TG, 14-17% in HDL-C, and 5-8% in LDL-C while direct measures accounted for 29-34% in HOMA-IR, 10-12% in TG, 13-16% in HDL-C, and 5-6% in LDL-C. The addition of direct measures of adiposity to indirect measures added significantly to the variance explained for HOMA-IR (p = 0.04). CONCLUSION: Anthropometric measures may perform as well as the more precise direct DXA-derived measures of adiposity for assessing most CVD risk factors in preadolescent girls. The use of DXA-derived adiposity measures together with indirect measures may be advantageous for predicting insulin resistance risk. TRIAL REGISTRATION: NCT02654262 . Retrospectively registered 11 January 2016.

Standardizing evaluation of pQCT image quality in the presence of subject movement: qualitative versus quantitative assessment.

Peripheral quantitative computed tomography (pQCT) is an essential tool for assessing bone parameters of the limbs, but subject movement and its impact on image quality remains a challenge to manage. The current approach to determine image viability is by visual inspection, but pQCT lacks a quantitative evaluation. Therefore, the aims of this study were to (1) examine the reliability of a qualitative visual inspection scale and (2) establish a quantitative motion assessment methodology. Scans were performed on 506 healthy girls (9-13 years) at diaphyseal regions of the femur and tibia. Scans were rated for movement independently by three technicians using a linear, nominal scale. Quantitatively, a ratio of movement to limb size (%Move) provided a measure of movement artifact. A repeat-scan subsample (n = 46) was examined to determine %Move's impact on bone parameters. Agreement between measurers was strong (intraclass correlation coefficient = 0.732 for tibia, 0.812 for femur), but greater variability was observed in scans rated 3 or 4, the delineation between repeat and no repeat. The quantitative approach found ≥95% of subjects had %Move <25 %. Comparison of initial and repeat scans by groups above and below 25% initial movement showed significant differences in the >25 % grouping. A pQCT visual inspection scale can be a reliable metric of image quality, but technicians may periodically mischaracterize subject motion. The presented quantitative methodology yields more consistent movement assessment and could unify procedure across laboratories. Data suggest a delineation of 25% movement for determining whether a diaphyseal scan is viable or requires repeat.

Real-World Health Care Resource Utilization and Costs Among US Patients with Knee Osteoarthritis Compared with Controls.

PURPOSE: To determine the prevalence, healthcare resource utilization and costs (HCRU&C) of knee osteoarthritis (OA) patients versus controls. PATIENTS AND METHODS: Retrospective, matched-cohort administrative claims analysis using IBM MarketScan databases (2011-2017). Newly diagnosed, adult (18+ yrs) knee OA patients identified by ICD9/10 code were matched 1:1 to controls by age, sex, payer, and geography; alpha level set to 0.05. Prevalence was estimated for 2017. All-cause and knee OA-related HCRU&C reported per-patient-per-year (PPPY) over follow-up period up to 4 years. RESULTS: Overall 2017 knee OA prevalence was 4% (615,514 knee OA/15.4M adults). A total of 510,605 patients meeting inclusion criteria were matched 1:1 with controls. The knee OA cohort had mean age 60 years and was 58% female. Versus controls, knee OA patients had significantly more PPPY outpatient (84.5 versus 45.0) and pharmacy (29.8 versus 19.8) claims, and significantly higher PPPY outpatient costs ($12,571 versus $6,465), and pharmacy costs ($3,655 versus $2,038). Knee OA patients incurred $7,707 more PPPY total healthcare costs than controls, of which $4,674 (60.6%) were knee OA-related medical claims and $1,926 (25%) were knee OA-related medications of interest. PPPY costs for nonselective NSAIDs, cyclooxygenase-2 (COX-2) inhibitors, intraarticular hyaluronic acid, non-acute opioids, and knee replacement were higher for knee OA patients than controls. Using median and mean all-cause total cost ($9,330 and $24,550, respectively), the estimated sum cost of knee OA patients in MarketScan ranged from $5.7B to $15B annually. CONCLUSION: This retrospective analysis demonstrated an annual 2017 prevalence of 4.0% (≥18 years) and 13.2% (≥65 years) for newly diagnosed knee OA patients. Compared with controls, all-cause costs were significantly higher for knee OA patients, nearly double that of matched controls, attributable to increased medical and treatment costs and comorbidity treatment burden. Additionally, the estimated annual cost of knee OA treatment was substantial, ranging between $5.7 billion and $15 billion.

Influence of Changes in Soft Tissue Composition on Changes in Bone Strength in Peripubertal Girls: The STAR Longitudinal Study.

Obesity and osteoporosis remain two major public health concerns. Soft tissue composition and bone are interrelated; however, it is still not well understood how changes in adiposity during adolescence affect bone development. The aim of this study was to assess how changes in DXA-derived total body lean mass (TBLM) and total body fat mass (TBFM) associate with 2-year changes in bone outcomes at the 20% femur, 66% tibia, 66% radius, and 4% tibia, as measured by pQCT, during the years surrounding the onset of menarche in a cohort of 9- to 12-year-old (baseline) adolescent girls (70% Hispanic). From baseline to 2-year follow-up, girls showed statistically significant increases in all bone outcomes, except radial endosteal circumference. In separate linear regression models, change in TBLM and change in TBFM were both positively associated with 2-year changes in bone outcomes at all measured bone sites, after controlling for relevant covariates. However, when change in TBLM and change in TBFM were included in the same model, change in TBLM was the predominant predictor of bone outcomes, explaining 4% to 14% of the variance in bone strength outcomes. Change in TBFM remained a positive predictor of tibia polar strength strain index (SSIp) (2% variance explained). A significant interaction between change in TBFM and menarcheal status was identified at the radius for SSIp and indicated that greater gains in TBFM were beneficial for SSIp in girls that were premenarcheal at baseline but detrimental for girls who were postmenarcheal at baseline. The overall findings suggest that changes in TBLM during the peripubertal years have a greater influence on bone outcomes than changes in TBFM. While gains in TBFM might benefit the weight bearing 66% tibia, greater gains in TBFM may be detrimental to bone development at the non-weight bearing 66% radius after the onset of menarche. © 2020 American Society for Bone and Mineral Research (ASBMR).

Relationship of cardiometabolic risk biomarkers with DXA and pQCT bone health outcomes in young girls.

BACKGROUND: Excess weight exerts the positive effect of mechanical loading on bone during development whereas obesity-related metabolic dysfunction may have a detrimental impact. In adults, the presence of metabolic syndrome and type 2 diabetes has been associated with compromised bone density, quality, and strength, and an increased incidence of fractures. The few studies that have investigated the role of cardio-metabolic disease risk biomarkers (CMR) on bone strength in children have given conflicting results. The aim of this study was to assess the combined and independent relationships of cardio-metabolic biomarkers with total body and regional bone parameters in young girls. METHODS: In 306, 9-12 year old girls, measures of whole body fat and lean mass, areal bone mineral density (aBMD), bone mineral content (BMC), and bone area (BA) were obtained by dual-energy x-ray absorptiometry (DXA). Bone mineral density (vBMD), geometry, and strength of metaphyseal and diaphyseal regions of the femur and tibia and a diaphyseal region of the radius were measured using peripheral quantitative computed tomography (pQCT). Fasting serum measures of CMRs included, fasting glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), high-density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride (TG), systolic and diastolic blood pressure (SBP and DBP), and C-reactive protein (CRP). Multiple linear regression was used to assess the independent associations of a single CMR with total body and peripheral measures of bone strength after controlling for the other CMRs, plus total body soft tissue, and other relevant covariates. Also, a standardized total CMR composite score, calculated by standardizing to z-scores and then summing z-scores of each CMR biomarker, was regressed with total body and regional bone measures to assess the relationship of a cluster of risk factors with bone health. RESULTS: Total CMR composite score had inverse associations (p < 0.001) with DXA total BMC and BA. Inverse associations (p < 0.05) of CMR risk score with pQCT regional bone measures occurred with total and trabecular BA at the 4% tibia. Of the individual CMRs, HOMA-IR and CRP were significant predictors of total body bone measures by DXA accounting for ~1-5% of the variance in BMC, BA, and/or aBMD. HOMA-IR was the main predictor of regional pQCT bone outcomes, accounting for the most variance in trabecular vBMD (2.6%) and BSI (3.8%) at the 4% tibia. Most markers of dyslipidemia (TG, HDL-C, LDL-C) and hypertension (SBP, DBP) were not associated (p > 0.05) with any total body or regional bone outcomes with the exception of the inverse relationship of LDL-C with total and trabecular BA and the positive relationship of DBP with cortical vBMD at the radius. CONCLUSION: Of the obesity-related metabolic impairments, insulin resistance and chronic inflammation may compromise whole body bone development in young girls. In particular, trabecular bone, such as that found at the metaphysis of long bones, may be more susceptible to the detrimental effects associated with obesity-related metabolic dysfunction.

Anthropometry Versus Imaging for Prediction of Inflammation Among Hispanic Girls.

OBJECTIVE: This study aimed to compare total and regional estimates of body composition, by direct and indirect techniques, for the optimal prediction of C-reactive protein (CRP) among young (aged 9-12 years) Hispanic girls (N = 232). METHODS: Standard anthropometric techniques were used to measure height, weight, and waist circumference. Dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) assessed body composition. Fasting serum CRP was measured by the AU5812 Clinical Chemistry Analyzer (Beckman Coulter, Brea, California). Associations between each total and regional body composition parameter and CRP were tested using linear regression (log-transformed, continuous CRP) and ordinal logistic regression (CRP < 1.0, ≥ 1.0-2.9, and ≥ 3.0 mg/L), controlling for maturation, dietary energy, physical activity, and medications. RESULTS: All measures of total and regional body fat were positively associated with CRP (P < 0.0001) except for intermuscular fat by pQCT. There were no clinically relevant differences in their association with CRP between anthropometric (BMI; waist circumference) and DXA-derived (total fat and regional fat: trunk, gynoid, android fat, leg) measures of fat. CONCLUSIONS: Measurement of body habitus in Hispanic girls, by multiple commonly available means, predicts CRP equally well.

Relative contributions of lean and fat mass to bone strength in young Hispanic and non-Hispanic girls.

BACKGROUND: With the high prevalence of childhood obesity, especially among Hispanic children, understanding how body weight and its components of lean and fat mass affect bone development is important, given that the amount of bone mineral accrued during childhood can determine osteoporosis risk later in life. The aim of this study was to assess the independent contributions of lean and fat mass on volumetric bone mineral density (vBMD), geometry, and strength in both weight-bearing and non-weight-bearing bones of Hispanic and non-Hispanic girls. METHODS: Bone vBMD, geometry, and strength were assessed at the 20% distal femur, the 4% and 66% distal tibia, and the 66% distal radius of the non-dominant limb of 326, 9- to 12-year-old girls using peripheral quantitative computed tomography (pQCT). Total body lean and fat mass were measured by dual-energy x-ray absorptiometry (DXA). Multiple linear regression was used to assess the independent relationships of fat and lean mass with pQCT bone measures while adjusting for relevant confounders. Potential interactions between ethnicity and both fat and lean mass were also tested. RESULTS: Lean mass was a significant positive contributor to all bone outcomes (p < 0.05) with the exception of vBMD at diaphyseal sites. Fat mass was a significant contributor to bone strength at weight bearing sites, but did not significantly contribute to bone strength at the non-weight bearing radius and was negatively associated with radius cortical content and thickness. Bone measures did not significantly differ between Hispanic and non-Hispanic girls, although there was a significant interaction between ethnicity and fat mass with total bone area at the femur (p = 0.02) and 66% tibia (p = 0.005) as well as bone strength at the femur (p = 0.03). CONCLUSION: Lean mass is the main determinant of bone strength for appendicular skeletal sites. Fat mass contributes to bone strength in the weight-bearing skeleton but does not add to bone strength in non-weight-bearing locations and may potentially be detrimental. Bone vBMD, geometry, and strength did not differ between Hispanic and non-Hispanic girls; fat mass may be a stronger contributor to bone strength in weight-bearing bones of Hispanic girls compared to non-Hispanic.

Assessment of statin therapy, LDL-C levels, and cardiovascular events among high-risk patients in the United States.

BACKGROUND: Statins have demonstrated significant benefit in reducing cardiovascular disease (CVD) risk. OBJECTIVE: To evaluate statin treatment patterns by intensity, elevated low-density lipoprotein cholesterol (LDL-C) levels, and cardiovascular (CV) events in high-risk CVD patients. METHODS: Patients included were aged ≥ 18 years, with a coronary heart disease (CHD; Jan 1, 2007-Dec 31, 2011, index date) or CHD risk equivalent (CHD RE) diagnosis (Jan 1, 2007-Dec 31, 2010, index date), in the Truven MarketScan claims database, continuously enrolled for 2 years pre- and up to 1 (CHD) or 2 (CHD RE) years post-index. Patients with CHD, CHD RE, rhabdomyolysis, or chronic kidney disease any time pre-index were excluded. Statin therapy was assessed at baseline, 30, 90, and 365 days post-index. LDL-C values were captured in patients with available data at 30-day intervals up to 1 year. CV events were evaluated up to 1 year post-index. Descriptive statistics were used to report results. RESULTS: There were 175,103 CHD and 68,290 CHD RE patients; 3333 CHD RE patients had post-index CV events. At 1 year, 38.7% of CHD patients and 44.3% of CHD RE patients with post-index CV events were not prescribed statins. Most patients who were prescribed statins, received a moderate-intensity statin. The percentage of patients with LDL-C ≥ 100 mg/dL reduced over time, but at 1 year, 29.3% of CHD and 30.0% of CHD RE patients with post-index CV events had LDL-C ≥ 100 mg/dL. At 1 year post-index, 9.9% CHD and 7.3% CHD RE patients had at least 1 CV event. CONCLUSION: There is room for better LDL-C management among high-risk CVD patients to reduce their overall CV risk.

Pharmacotherapy Treatment Patterns, Outcomes, and Health Resource Utilization Among Patients with Heart Failure with Reduced Ejection Fraction at a U.S. Academic Medical Center.

STUDY OBJECTIVE: To assess clinical characteristics, pharmacotherapy treatment patterns, resource utilization and associated charges, and morbidity and mortality outcomes among a real-world cohort of patients with heart failure with reduced ejection fraction (HFrEF) in an academic medical center setting. DESIGN: Retrospective analysis. DATA SOURCE: Electronic health record database that includes clinical, laboratory, and administrative data for all facilities of the University of Utah Health Care System. PATIENTS: A total of 989 adults with prevalent (preexisting) HFrEF, identified by using the International Classification of Diseases, Ninth Revision, Clinical Modification code 428.x (heart failure) between January 1, 2007, and June 30, 2013, and who had a left ventricular ejection fraction of 40% or lower. MEASUREMENTS AND MAIN RESULTS: The cohort had a mean age of 64 ± 15 years and was predominantly white (71%) and male (74%). Patients received ß-blockers, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), and aldosterone receptor antagonists (ARAs) at rates of 79%, 69%, and 29%, respectively. Patients achieved target doses of ß-blockers, ACEIs, and ARBs at rates of only 24%, 31%, and 13%, respectively. Overall, 58% of patients were prescribed dual therapy with a ß-blocker and an ACEI or ARB, and 19% were prescribed triple therapy (ß-blocker, an ACEI or ARB, and an ARA). Univariate and multivariate logistic regression models were used to assess the association between baseline characteristics with the presence of triple therapy. Two variables were statistically significant in both models: increasing age was associated with a lower odds of triple therapy (univariate: odds ratio [OR] 0.760, 95% confidence interval [CI] 0.673-0.857; multivariate: OR 0.768, 95% CI 0.625-0.942), whereas receipt of an implantable cardiac device was associated with a 2-fold increase in the odds of triple therapy (univariate: OR 2.1, 95% CI 1.4-3.1; multivariate: OR 2.1, 95% CI 1.3-3.5). During a mean ± SD follow-up of 36 ± 27 months, all-cause mortality was 0.12 per person-year. There were 1311 all-cause hospitalizations of which 611 (47%) were for worsening heart failure. The rate of all-cause and heart failure-specific hospitalizations was 0.44 and 0.21 per person-year of follow-up, respectively. The median length of stay was 6.4 ± 8.8 days, and the median charge was $22,310. The 30-day all-cause readmission rate was 20%, and the primary reason for readmission was heart failure in 65% of cases. CONCLUSION: This study demonstrates the continuing significant disease and economic burden for patients with HFrEF. Challenges remain in utilization of established disease-modifying therapy and in the treatment of patients with HFrEF and multiple comorbidities.

Cost of palliative external beam radiotherapy (EBRT) use for bone metastases secondary to prostate cancer.

BACKGROUND: Evaluations of the costs of palliative external beam radiation therapy (EBRT) for treatment of bone metastases are limited. OBJECTIVE: To summarize EBRT lifetime care patterns in deceased men with metastatic prostate cancer treated in a cancer hospital in the United States. METHODS: A retrospective review of electronic health records identified deceased adult prostate cancer (ICD-9 185.xx) patients with bone metastases (ICD-9 198.5) and who were treated for bone pain and metastasis management with EBRT between January 1, 1995 and December 17, 2012. Common Procedural Terminology codes were used to identify all EBRT episodes (total billed EBRT services; initial and final evaluation) to calculate length of EBRT treatments and per episode costs (2011 US$). Bootstrapping approximated the 95% confidence interval for final cost estimates. RESULTS: 176 men were identified; 19 (10.8%) had bone metastases in >1 site. Eighty-nine men (50.6%) received >1 EBRT episode (range, 1-6; median, 2), with first episode length ranging from 1-44 calendar days (mean, 13.4; SD, 8.4) at a mean cost of $7,084 (SD, $4,028). About 70% of costs were attributable to hospital charges and 30% to physician charges. LIMITATIONS: Small sample size limits broad applicability to large populations of men with prostate cancer. CONCLUSION: Care costs for EBRT constitute one of many costs that should be taken into account when planning for palliative care of prostate cancer and bone metastasis.

Top 10 research questions related to body composition.

An understanding of body composition is crucial to understanding human health, disease, and function. Research in body composition has focused on the development of assessment methods, description of normal changes in body composition with growth and development and aging, and the changes that occur in body composition in response to challenges ranging from illness to planned interventions. Each focus is significant, and in a sense, they are interdependent, because technological advances allow more sophisticated questions to be addressed, which in turn drives the development of better methods. Significant advances have been made in each area, although perhaps surprisingly basic questions remain. For example, growth trajectories are often estimated from cross-sectional data, given the resources needed for long-term observational studies, and thus, longitudinal descriptive data are still needed. Along with advances in laboratory methods, development of field methods remains relevant for screening and clinical practice. Despite recognition of wide interindividual differences in intervention response, average outcomes continue to be emphasized. With technological advances, it is now possible to examine genetic along with nongenetic factors that underlie changes in body composition, and these techniques need to be applied in long-term, well-controlled trials. In this article, we review 10 key questions in related areas in which research is needed to continue to advance the field.

Effects of physical activity and muscle quality on bone development in girls.

INTRODUCTION: Poor muscle quality and sedentary behavior are risk factors for metabolic dysfunction in children and adolescents. However, because longitudinal data are scarce, relatively little is known about how changes in muscle quality and physical activity influence bone development. PURPOSE: In a 2-yr longitudinal study, we examined the effects of physical activity and changes in muscle quality on bone parameters in young girls. METHODS: The sample included 248 healthy girls age 9-12 yr at baseline. Peripheral quantitative computed tomography was used to measure calf and thigh muscle density, an indicator of skeletal muscle fat content or muscle quality, as well as bone parameters at diaphyseal and metaphyseal sites of the femur and tibia. Physical activity was assessed using a validated questionnaire specific for youth. RESULTS: After controlling for covariates in multiple regression models, increased calf muscle density was independently associated with greater gains in cortical (ß = 0.13, P < 0.01) and trabecular (ß = 0.25, P < 0.001) volumetric bone mineral density and the bone strength index (ß = 0.25, P < 0.001) of the tibia. Importantly, these relationships were generalized, as similar changes were present at the femur. Associations between physical activity and changes in bone parameters were weaker than those observed for muscle density. Nevertheless, physical activity was significantly (all P < 0.05) associated with greater gains in trabecular volumetric bone mineral density and the bone strength index of the distal femur. CONCLUSIONS: These findings suggest that poor muscle quality may put girls at risk for suboptimal bone development. Physical activity is associated with more optimal gains in weight-bearing bone density and strength in girls, but to a lesser extent than changes in muscle quality.

Estimation of whole body fat from appendicular soft tissue from peripheral quantitative computed tomography in adolescent girls.

OBJECTIVE: Assess the utility of peripheral quantitative computed tomography (pQCT) for estimating whole body fat in adolescent girls. RESEARCH METHODS AND PROCEDURES: Our sample included 458 girls (aged 10.7 ± 1.1y, mean BMI = 18.5 ± 3.3 kg/m2) who had DXA scans for whole body percent fat (DXA %Fat). Soft tissue analysis of pQCT scans provided thigh and calf subcutaneous percent fat and thigh and calf muscle density (muscle fat content surrogates). Anthropometric variables included weight, height and BMI. Indices of maturity included age and maturity offset. The total sample was split into validation (VS; n = 304) and cross-validation (CS; n = 154) samples. Linear regression was used to develop prediction equations for estimating DXA %Fat from anthropometric variables and pQCT-derived soft tissue components in VS and the best prediction equation was applied to CS. RESULTS: Thigh and calf SFA %Fat were positively correlated with DXA %Fat (r = 0.84 to 0.85; p <0.001) and thigh and calf muscle densities were inversely related to DXA %Fat (r = -0.30 to -0.44; p < 0.001). The best equation for estimating %Fat included thigh and calf SFA %Fat and thigh and calf muscle density (adj. R2 = 0.90; SEE = 2.7%). Bland-Altman analysis in CS showed accurate estimates of percent fat (adj. R2 = 0.89; SEE = 2.7%) with no bias. DISCUSSION: Peripheral QCT derived indices of adiposity can be used to accurately estimate whole body percent fat in adolescent girls.

Longitudinal relationships between whole body and central adiposity on weight-bearing bone geometry, density, and bone strength: a pQCT study in young girls.

UNLABELLED: Longitudinal relationships between adiposity (total body and central) and bone development were assessed in young girls. Total body and android fat masses were positively associated with bone strength and density parameters of the femur and tibia. These results suggest adiposity may have site-specific stimulating effects on the developing bone. INTRODUCTION: Childhood obesity may impair bone development, but the relationships between adiposity and bone remain unclear. Failure to account for fat pattern may explain the conflicting results. PURPOSE: Longitudinal associations of total body fat mass (TBFM) and android fat mass (AFM) with 2-year changes in weight-bearing bone parameters were examined in 260 girls aged 8-13 years at baseline. Peripheral quantitative computed tomography was used to measure bone strength index (BSI, square milligrams per quartic millimeter), strength-strain index (SSI, cubic millimeters), and volumetric bone mineral density (vBMD, milligrams per cubic centimeter) at distal metaphyseal and diaphyseal regions of the femur and tibia. TBFM and AFM were assessed by dual-energy x-ray absorptiometry. RESULTS: Baseline TBFM and AFM were positively associated with the change in femur BSI (r = 0.20, r = 0.17, respectively) and femur trabecular vBMD (r = 0.19, r = 0.19, respectively). Similarly, positive associations were found between TBFM and change in tibia BSI and SSI (r = 0.16, r = 0.15, respectively), and femur total and trabecular vBMD (r = 0.12, r = 0.14, respectively). Analysis of covariance showed that girls in the middle thirds of AFM had significantly lower femur trabecular vBMD and significantly higher tibia cortical vBMD than girls in the highest thirds of AFM. All results were significant at p < 0.05. CONCLUSIONS: Whereas baseline levels of TBFM and AFM are positive predictors of bone strength and density at the femur and tibia, higher levels of AFM above a certain level may impair cortical vBMD growth at weight-bearing sites. Future studies in obese children will be needed to test this possibility.

Predicting visceral adipose tissue by MRI using DXA and anthropometry in adolescents and young adults.

OBJECTIVE: Accumulation of intra-abdominal (visceral) adipose tissue, independent of total adiposity, is associated with development of metabolic abnormalities such as insulin resistance and type-2 diabetes in children and adults. The objective of this study was to develop prediction equations for estimating visceral adiposity (VAT) measured by magnetic resonance imaging (MRI) using anthropometric variables and measures of abdominal fat mass from DXA in adolescents and young adults. METHODS: Cross-sectional data was collected from a multiethnic population of seventy males and females, aged 12-25 years, with BMI ranging from 14.5-38.1 kg/m2. Android (AFM; android region as defined by manufacturers instruction) and lumbar L1-L4 regional fat masses were assessed using DXA (GE Lunar Prodigy; GE Lunar Corp, Madison, WI, USA). Criterion measures of intra-abdominal visceral fat were obtained using single-slice MRI (General Electric Signa Model 5x 1.5T) and VAT area was analyzed at the level OF L4-L5. Image analysis was carried out using ZedView 3.1. RESULTS: DXA measures of AFM (r=0.76) and L1-L4 (r=0.71) were significantly (P<0.0001) correlated with MRI-measured VAT. DXA AFM, together with gender and weight, explained 62% of the variance in VAT (SEE=10.06 cm2). DXA L1-L4 fat mass with gender explained 54% of the variance in VAT (SEE=11.08 cm2). Addition of the significant interaction, gender × DXA fat mass, improved prediction of VAT from AFM (Radj2=0.61, SEE=10.10cm2) and L1-L4 (Radj2=0.59, SEE=10.39cm2). CONCLUSION: These results demonstrate that VAT is accurately estimated from regional fat masses measured by DXA in adolescents and young adults.

Quantifying bone-relevant activity and its relation to bone strength in girls.

UNLABELLED: Physical activity (PA) is critical for maximizing bone development during growth. However, there is no consensus on how well existing PA measurement tools predict bone strength. PURPOSE: The purposes of this study were to compare four methods of quantifying PA (pedometer, 3-d PA recall (3DPAR), bone-specific PA questionnaire (BPAQ), and past year PA questionnaire (PYPAQ)), in young girls and to evaluate their ability to predict indices of bone strength. METHODS: A total of 329 girls aged 8-13 yr completed a pedometer assessment, the 3DPAR, the BPAQ, and a modified PYPAQ. Peripheral quantitative computed tomography was used to assess bone strength index (BSI) at metaphyseal (4% distal femur and tibia) sites and strength-strain index (SSI) at diaphyseal (femur = 20%, tibia = 66%) sites of the nondominant leg. Correlations and hierarchical multiple regression were used to assess relationships among PA measures and indices of bone strength. RESULTS: After adjusting for maturity, correlations between PA measures and indices of bone strength were positive, although low (r = 0.01-0.20). Regression models that included covariates (maturity, body mass, leg length, and ethnicity) and PA variables showed that PYPAQ score was significantly (P < 0.05) associated with BSI and SSI at all sites and explained more variance in BSI and SSI than any other PA measure. Pedometer steps were significantly (P < 0.05) associated with metaphyseal femur and tibia BSI, and 3DPAR score was significantly (P < 0.05) associated with metaphyseal femur BSI. BPAQ score was not significantly (P > 0.05) associated with BSI or SSI at any sites. CONCLUSIONS: A modified PYPAQ that accounts for the duration, frequency, and load of PA predicted indices of bone strength better than other PA measures.

Skeletal muscle fat content is inversely associated with bone strength in young girls.

Childhood obesity is an established risk factor for metabolic disease. The influence of obesity on bone development, however, remains controversial and may depend on the pattern of regional fat deposition. Therefore, we examined the associations of regional fat compartments of the calf and thigh with weight-bearing bone parameters in girls. Data from 444 girls aged 9 to 12 years from the Jump-In: Building Better Bones study were analyzed. Peripheral quantitative computed tomography (pQCT) was used to assess bone parameters at metaphyseal and diaphyseal sites of the femur and tibia along with subcutaneous adipose tissue (SAT, mm(2) ) and muscle density (mg/cm(3) ), an index of skeletal muscle fat content. As expected, SAT was positively correlated with total-body fat mass (r = 0.87-0.89, p < .001), and muscle density was inversely correlated with total-body fat mass (r = -0.24 to -0.28, p < .001). Multiple linear regression analyses with SAT, muscle density, muscle cross-sectional area, bone length, maturity, and ethnicity as independent variables showed significant associations between muscle density and indices of bone strength at metaphyseal (ß = 0.13-0.19, p < .001) and diaphyseal (ß = 0.06-0.09, p < .01) regions of the femur and tibia. Associations between SAT and indices of bone strength were nonsignificant at all skeletal sites (ß = 0.03-0.05, p > .05), except the distal tibia (ß = 0.09, p = .03). In conclusion, skeletal muscle fat content of the calf and thigh is inversely associated with weight-bearing bone strength in young girls.