Bone age assessment using the Greulich and Pyle atlas is widely used in pediatrics but is subject to substantial reader variability. As artificial intelligence (AI) systems increasingly support clinical workflows, understanding the magnitude and structure of human variability is essential for contextualizing AI performance. To quantify human variability in pediatric bone age assessment across multiple institutions and to compare human variability with two automated bone age estimation methods. In this multi-reader, multi-case study, 1,285 left-hand and wrist radiographs from five US academic centers were independently interpreted by four radiologists per case from a centrally administered pool of 22 radiologists recruited across nine institutions. Bone age estimates were obtained using the Greulich and Pyle atlas. Variability was assessed at the image, rater, and institution levels using mixed-effects modeling. Inter-reader variability was estimated while accounting for patient age and sex. Performance of two automated methods (BoneXpert and a deep-learning algorithm) was evaluated in an interchangeability analysis using a three-rater consensus reference. Accuracy metrics included mean absolute error (MAE), root mean square error (RMSE), and rates of substantial deviation (>1.8 years). Within-image variability among radiologists was higher in younger patients (<12 years) than in older patients (standard deviation (SD) 8.7 months vs. 4.2 months, P<0.001). Between-institution variability decreased substantially after adjustment for patient age (8.9 months to 0.3 months). Inter-rater variability remained stable after adjustment (1.2 months). Variability was greater in male patients and younger age groups. Several radiologists demonstrated systematic biases related to age or sex. In comparison with individual human readers, BoneXpert showed lower error (MAE 4.8 months vs. 6.5 months) and variability, while the deep-learning algorithm performed similarly to human readers (MAE 6.3 months). Substantial deviations occurred in 0.7

Objectives:Obesity and sarcopenia commonly coexist in RA, compounding metabolic risk and disability. Intentional weight loss may improve outcomes but raises concern for accelerated muscle loss. We conducted a post-hoc analysis of a randomized controlled trial (RCT) of a hypocaloric, high-protein diet in adults with RA and obesity to determine whether diet-induced weight loss was associated with disproportionate reductions in muscle mass. Methods:Adults with RA and obesity were randomized to a 12-week hypocaloric, high-protein diet or to control dietary advice (NCT02881307). DXA was performed at baseline and 12 weeks. Fat mass index (FMI), appendicular lean mass index (ALMI) and adiposity-adjusted ALMI (ALMIFMI) were derived and standardized to Z-scores using national reference data. Between-group differences in change were compared using t-tests, with FDR-adjusted P values reported for all analyses. Results:Participants in the dietary intervention achieved significant reductions in total fat mass (mean change in FMI Z-score -0.35 vs 0.04; P = 0.003). Changes in ALMI Z-score (-0.37 vs -0.43; P = 0.92) and ALMIFMI Z-score (-0.15 vs -0.55; P = 0.92) did not differ significantly between groups. In the intervention group there was minimal decline in ALMFMI, suggesting parallel reductions in lean and fat tissue. Conclusion:In adults with RA and obesity, diet-induced weight loss reduced adiposity without evidence of disproportionate muscle loss. These findings support the safety of structured, protein-adequate weight-loss interventions in this population.

PURPOSE:Rheumatoid cachexia has been described as a process of concurrent muscle loss and gain of adipose tissue. We evaluated longitudinal changes in body composition in patients with rheumatoid arthritis (RA) to evaluate the changes in adiposity that accompany loss of lean mass. METHODS:We combined and assessed three independent longitudinal RA cohorts that included assessments of body composition. Whole body DXA was performed in all participants to quantify appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2). Independent associations between loss of ALMI during follow-up and FMI over the same time-period were assessed adjusting for age, sex, race, baseline body composition and study using mixed-effects regression to account for clustering by study. Changes in adipokines (adiponectin and leptin) were also assessed over time in similar models. Visceral fat area was determined from DXA (cm2) in one of the cohorts and was also assessed. RESULTS:Among 451 patients with a mean (SD) age of 58.3 (10.5), the mean (SD) ALMI was 6.97 (1.41) kg/m2. Longitudinal analyses were conducted in 361 participants with follow-up data [average follow-up 2.65 (0.71) years]. Of these, 195 lost lean mass (experienced a negative change in ALMI during follow-up), while 166 gained lean mass. Participants that lost lean mass had greater reductions in BMI [-0.77 (95% CI: -1.21, -0.33) v. +1.07 (95% CI: 0.56, 1.59)], greater reductions in FMI [-0.17 (95% CI: -0.48, 0.14) v. +0.46 (95% CI: 0.08, 0.83) p = 0.07] and a greater odds of having a reduction in FMI [OR: 2.30 (1.31, 4.05) p = 0.004], and had declining leptin levels and visceral fat area. Associations were strongest among those with high FMI at baseline. CONCLUSIONS:In RA, loss of lean mass tends to occur in the context of a loss of weight and a loss of both total and visceral adiposity. These observations help to inform our understanding of the mechanisms leading to loss of muscle and rheumatoid cachexia in RA as well as to inform potential screening practices.

PURPOSE:To assess longitudinal changes in the microarchitecture and mechanical competence of trabecular and cortical bone over a two-year period following kidney transplantation using high-resolution MRI. METHODS:MR images at 1.5 T were acquired at the distal tibia and thoracolumbar spine (n = 60, 31 males, ages 20-60 years) at the time of transplantation and six, 12, and 24 months post kidney transplantation. Patients were matched with healthy participants (n = 59) based on age, sex, and body-mass index at baseline. Whole-bone tibia stiffness was estimated using a finite-element model of uniaxial compression tests. Microarchitectural measures of the distal tibia, as well as spine deformity indices of thoracic and lumbar vertebrae, were computed. DXA-derived BMD of the total hip, femoral neck, spine and radius was measured at all time points in kidney transplant recipients. RESULTS:MRI-derived parameters indicate decreased bone quality in kidney transplant recipients compared to healthy participants at baseline. At six months, recipients had a significant deterioration in trabecular thickness (p < 0.001), cortical porosity (p = 0.006), bone volume fraction (BVF, p = 0.005), and tibia stiffness (p < 0.001). However, there were no differences between baseline and 24 months for trabecular thickness (p = 1), BVF (p = 0.19), and cortical porosity (p = 1). Interval glucocorticoid exposure was negatively associated with changes in tibia stiffness (p < 0.0001), BVF (p = 0.049), and trabecular thickness (p = 0.02). By 24 months, total hip BMD increased (p = 0.04), while lumbar spine BMD decreased (p = 0.009). CONCLUSIONS:Two years after kidney transplantation and despite sustained low-dose glucocorticoid therapy, MRI noninvasively detected selective and incomplete recovery in some bone microstructural indices while bone stiffness remained persistently reduced.

RATIONALE & OBJECTIVE:Kidney transplant (KT) ameliorates the underlying abnormalities contributing to skeletal fragility in chronic kidney disease, but fracture rates increase after transplant. This study sought to assess the impact of changes in body composition and mineral metabolism on bone mineral density (BMD) and structure following kidney KT. STUDY DESIGN:24-month prospective cohort study. SETTING & PARTICIPANTS:60 incident KT recipients and 361 healthy controls aged 20-60 years. OUTCOMES:Tibia volumetric BMD (vBMD) and cortical dimensions measured using peripheral quantitative computed tomography and areal BMD (aBMD), appendicular lean mass index (ALMI), and fat mass index measured using dual-energy X-ray absorptiometry. ANALYTICAL APPROACH:Analytical Approach: Outcomes were converted to sex-specific z scores for age and compared with those in 361 controls. Quasi-least-squares regression models identified correlates of change. RESULTS:At baseline, ALMI, trabecular and cortical vBMD, cortical thickness, and total hip, femoral neck, and ultradistal radius aBMD were lower in KT recipients versus controls (P ≤ 0.003). During the first 6 months after KT, ALMI, fat mass index, and body mass index (BMI) increased (P < 0.001), whereas tibia trabecular vBMD and lumbar spine aBMD decreased (P ≤ 0.005). Cortical vBMD increased from 6 months onward (P < 0.001) in association with decreasing parathyroid hormone levels (P = 0.004). Cortical thickness decreased between 6 and 24 months (P = 0.002) because of a loss of endocortical bone. Total hip and femoral neck aBMD remained stable for 6 months, then improved through 24 months (P ≤ 0.02). Ultradistal radius aBMD decreased throughout the study (P ≤ 0.003). Higher BMI and ALMI were associated with gains in hip and spine aBMD and trabecular vBMD (all P ≤ 0.02). Corticosteroid dose was negatively associated with changes in spine and hip aBMD and cortical and trabecular vBMD (all P ≤ 0.02). Higher bone turnover marker levels and loss of cortical vBMD and thickness were associated with increases in serum calcium concentrations (P ≤ 0.03). LIMITATIONS:Not generalizable to older KT recipients. CONCLUSIONS:Skeletal deficits in KT recipients largely stabilize or improve beyond 6 months, with the exception of progressive cortical thinning. Strategies are needed to preserve cortical bone before and after KT. Gains in BMI and ALMI may improve bone health in the weight-bearing skeleton following KT. PLAIN-LANGUAGE SUMMARY:We enrolled 60 adults at the time of kidney transplant (KT) and compared measures of bone and muscle mass versus those in 361 healthy individuals. At the time of transplant, KT recipients had low muscle mass, low bone density, and thin bones compared with healthy individuals. After transplant, KT recipients rapidly gained muscle and fat. Despite the adverse effect of corticosteroid medications on bone, hip bone density improved significantly between 6 and 24 months. More muscle was associated with greater gains in hip and spine bone density over 2 years. In contrast, long bones got progressively thinner in association with biomarkers of bone breakdown. This study improves our understanding of the contributions of corticosteroids, muscle, and mineral metabolism on changes in bone density and thickness after KT, as well as the potential for recovery of bone density at selected skeletal sites.

KEY POINTS:Cystinosis is associated with deficits in muscle mass and strength beyond what is noted in CKD. Cystinosis is associated with low proximal femur bone mineral density. BACKGROUND:Cystinosis is associated with growth failure, myopathy, and multiple risk factors for impaired bone development. The objectives of this study were to quantify muscle mass, muscle strength, and bone mineral density (BMD) in children and adults with cystinosis. METHODS:This cross-sectional study assessed dual-energy X-ray absorptiometry regional lean mass, spine and hip BMD, handgrip, and leg strength in 38 participants with cystinosis (ages 5-37 years) and 289 healthy controls. All BMD, muscle mass, and muscle strength measures were expressed as sex-specific Z -scores relative to age and adjusted for height Z -score or limb length. Linear regression models were used to assess muscle strength relative to muscle mass (muscle specific force) and determine the effect of adjusting BMD results for muscle status. RESULTS:Among adults, arm and leg lean mass ( P < 0.001), handgrip strength ( P <0.001), proximal and distal leg strength ( P < 0.001), muscle specific force ( P < 0.01), and femoral neck and total hip BMD ( P < 0.001) were markedly low, compared with controls. On average, muscle strength was more than two SD below normal due to both low muscle mass and poor muscle quality. Among the children and adolescents, upper extremity lean mass and grip strength were preserved. However, leg lean mass ( P < 0.01), strength ( P < 0.001), muscle specific force ( P < 0.001), and femoral neck and total hip BMD ( P < 0.01) were reduced, compared with controls, approaching deficits seen in adults. Adjustment for lean mass and muscle strength markedly attenuated the BMD deficits. CONCLUSIONS:Cystinosis is associated with deficits in muscle mass and strength that far exceed those observed in CKD alone and is associated with low proximal femur BMD. Future studies are needed to determine if physical activity or other interventions to address sarcopenia in cystinosis will improve physical function and bone strength.

INTRODUCTION:Bone health screening is established in cystic fibrosis (CF). Given the unknown status of bone quality in primary ciliary dyskinesia (PCD), these recommendations have not been adopted. We aimed to evaluate the bone phenotype in PCD compared to healthy controls and CF. METHODS:In this exploratory cross-sectional study, we assessed bone mineral density (BMD) at the whole body and lumbar spine using dual-energy X-ray absorptiometry (DXA), and tibial bone microarchitecture using high-resolution peripheral quantitative computed tomography (HR-pQCT) in 15 individuals with PCD and 45 with CF, aged 12-20 years. Measures were compared to healthy controls matched one-to-one by pubertal stage and sex. Disease-to-healthy differences were compared between PCD and CF, and associations with body mass index (BMI), lean mass, and lung function were analysed. RESULTS:DXA-measured areal BMD and HR-pQCT-derived total volumetric BMD showed no differences between PCD and controls. HR-pQCT revealed reduced cortical thickness, area, and BMD at the ultra-distal tibia in PCD compared to controls. While PCD and CF did not differ, the PCD bone phenotype more closely resembled pancreatic-insufficient than pancreatic-sufficient CF. Dimensional cortical deficits were largely explained by BMI or lean mass, especially in CF, but remained reduced in PCD after adjustment, indicating potentially intrinsic disease-related alterations. Lung function did not clearly correlate with bone outcomes in PCD. CONCLUSION:Skeletal health appears compromised in young people with PCD. Despite mostly normal densitometry, tibial bone microarchitecture was altered. This study positions bone health as a research priority in PCD and supports the need for larger confirmatory studies.

Objectives: Relative Energy Deficiency in Sport (REDs) is a syndrome driven by problematic low energy availability, impairing physiological and/or psychological function. While REDs assessment typically utilizes dual energy X-ray absorptiometry (DXA) of areal bone mineral density (BMD), high-resolution peripheral quantitative computed tomography (HR-pQCT) offers additional insight into bone microarchitecture, geometry, and volumetric BMD. This study aimed to evaluate bone health among female runners at risk for REDs using DXA and HR-pQCT measures. Methods: Female runners aged 18-30 years, training at least 5 hours/week, were recruited and underwent anthropometric measurements, VO2 max testing, clinical laboratories, DXA scans, and HR-pQCT imaging of the tibia. REDs risk was assessed using validated questionnaires, clinical laboratories, and physician interviews. Participants were categorized as no-risk (green) or at-risk (yellow/orange/red) for REDs. Results: Twenty-one participants (age 26 ± 3 years) completed the study. Six were classified as no-risk and fifteen as at-risk for REDs. Sub-clinically low BMD (z-score ≤-1) was the most prevalent indicator in at-risk participants. The at-risk group reported significantly higher weekly mileage (>40 miles/week: 66.7% vs 33.3%, p=0.043) and lower maximum extensor strength on muscular endurance testing (p=0.015). While no other between-group differences reached statistical significance, 12 of 14 HR-pQCT values showed poorer outcomes in the at-risk group. Conclusions: Despite the small sample size, this pilot revealed consistent HR-pQCT trends suggesting potential links between REDs risk and compromised bone geometry, microarchitecture, and volumetric BMD. Integration of HR-pQCT with REDs screening may provide a more comprehensive characterization of bone health compared to DXA alone. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by Stanford Women′s Health and Sex Differences in Medicine Center. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board of Stanford University (IRB 69308) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data relevant to the study are included in the article or uploaded as online supplemental material. Additional data are available upon reasonable request.

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 (DTrabBMDz) was an independent predictor of cIMTz increase (R2 = 0.48, b = 0.40, P = 0.03). Young people who demonstrated statural growth (n = 33) had lower DTrabBMDz 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.

OBJECTIVE:We determined the prevalence of sarcopenic obesity in patients with RA using multiple methods and assessed associations with physical functioning.METHODS:This study evaluated data from three RA cohorts. Whole-body dual-energy absorptiometry (DXA) measures of appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI) were converted to age, sex and race-specific Z-Scores and categorized using a recently validated method and compared it to a widely-used existing method. The prevalence of body composition abnormalities in RA was compared with two reference populations. In the RA cohorts, associations between body composition and change in the HAQ and the Short Physical Performance Battery (SPPB) in follow-up were assessed using linear and logistic regression, adjusting for age, sex, race and study.RESULTS:The prevalence of low lean mass and sarcopenic obesity was higher in patients with RA (14.2; 12.6%, respectively) compared with the reference population cohorts (7-10%; 4-4.5%, respectively, all P <0.05). There was only moderate agreement among methods of sarcopenic obesity categorization (Kappa 0.45). The recently validated method categorized fewer subjects as obese, and many of these were categorized as low lean mass only. Low lean mass, obesity and sarcopenic obesity were each associated with higher HAQ and lower SPPB at baseline and numerically greater worsening.CONCLUSION:RA patients had higher rates of low lean mass and sarcopenic obesity than the general population. The recently validated methods characterized body composition changes differently from traditional methods and were more strongly associated with physical function.

OBJECTIVE:We determined associations between adipokines and abnormal body composition in patients with rheumatoid arthritis (RA). METHODS:Combining data from three RA cohorts, whole-body dual-energy absorptiometry measures of appendicular lean mass and fat mass indices were converted to age-, sex-, and race- and ethnicity-specific Z scores. Lean mass relative to fat mass was determined based on prior methods. Independent associations between body composition profiles and circulating levels of adiponectin, leptin, and fibroblast growth factor (FGF)-21 were assessed using linear and logistic regression models adjusting for demographic characteristics and study cohort. We also determined the improvement in the area under the curve (AUC) for prediction of low lean mass when adipokines were added to predictive models that included clinical factors such as demographic characteristics, study, and body mass index (BMI). RESULTS:Among 419 participants, older age was associated with higher levels of all adipokines, whereas higher C-reactive protein level was associated with lower adiponectin levels and higher FGF-21 levels. Greater fat mass was strongly associated with lower adiponectin levels and higher leptin and FGF-21 levels. Higher levels of adiponectin, leptin, and FGF-21 were independently associated with low lean mass. The addition of adiponectin and leptin levels to regression models improved prediction of low lean mass when combined with demographic characteristics, study, and BMI (AUC 0.75 vs. 0.66). CONCLUSION:Adipokines are associated with both excess adiposity and low lean mass in patients with RA. Improvements in the prediction of body composition abnormalities suggest that laboratory screening could help identify patients with altered body composition who may be at greater risk of adverse outcomes.

ObjectiveControversy remains as to whether low serum urate or uric acid (UA) levels contribute to adverse outcomes. We evaluated the relation between low serum UA levels and sarcopenia and assessed whether sarcopenia confounds associations between these low levels and mortality.MethodsWe utilized data from the National Health and Nutrition Examination Survey (1999–2006). Participants with available whole‐body dual x‐ray absorptiometry body composition measurements and serum UA concentrations were included. Body composition assessments included body mass index (BMI), waist circumference, maximum lifetime BMI, and age‐, sex‐, and race‐specific appendicular lean mass index (ALMI) and fat mass index (FMI) Z scores. We also calculated Z scores for ALMI relative to FMI (ALMIFMI). We evaluated associations between serum UA levels and body composition using logistic regression and assessed associations between serum UA levels and mortality before and after adjusting for differences in body composition using Cox proportional hazards regression.ResultsAmong the 13,979 participants, low serum UA concentrations (<2.5 mg/dl in women, <3.5 mg/dl in men) were associated with low lean mass (ALMI and ALMIFMI Z scores), underweight BMI (<18.5 kg/m2), and higher rates of weight loss. The proportion of patients with low ALMI Z scores was 29% in the low serum UA group and 16% in the normal serum UA group (P = 0.001). Low serum UA levels were associated with increased mortality before we adjusted for body composition (hazard ratio 1.61 [95% confidence interval 1.14–2.28]; P = 0.008) but was attenuated and not significant after adjustment for body composition and weight loss (hazard ratio 1.30 [95% confidence interval 0.92–1.85], P = 0.13).ConclusionSarcopenia and weight loss are more common among patients with low serum UA concentrations. Differences in body composition may help to explain associations between low levels of serum UA and higher mortality.

AbstractBackgroundSurvival from paediatric high‐risk neuroblastoma (HR‐NBL) has increased, but cis‐retinoic acid (cis‐RA), the cornerstone of HR‐NBL therapy, can cause osteoporosis and premature physeal closure and is a potential threat to skeletal structure in HR‐NBL survivors. Sarcopenia is associated with increased morbidity in survivors of paediatric malignancies. Low muscle mass may be associated with poor prognosis in HR‐NBL patients but has not been studied in these survivors. The study objective was to assess bone density, body composition and muscle strength in HR‐NBL survivors compared with controls.MethodsThis prospective cross‐sectional study assessed areal bone mineral density (aBMD) of the whole body, lumbar spine, total hip, femoral neck, distal 1/3 and ultradistal radius and body composition (muscle and fat mass) using dual‐energy X‐ray absorptiometry (DXA) and lower leg muscle strength using a dynamometer. Measures expressed as sex‐specific standard deviation scores (Z‐scores) included aBMD (adjusted for height Z‐score), bone mineral apparent density (BMAD), leg lean mass (adjusted for leg length), whole‐body fat mass index (FMI) and ankle dorsiflexion peak torque adjusted for leg length (strength‐Z). Muscle‐specific force was assessed as strength relative to leg lean mass. Outcomes were compared between HR‐NBL survivors and controls using Student's t‐test or Mann–Whitney U test. Linear regression models examined correlations between DXA and dynamometer outcomes.ResultsWe enrolled 20 survivors of HR‐NBL treated with cis‐RA [13 male; mean age: 12.4 ± 1.6 years; median (range) age at therapy initiation: 2.6 (0.3–9.1) years] and 20 age‐, sex‐ and race‐matched controls. Height‐Z was significantly lower in HR‐NBL survivors compared with controls (−1.73 ± 1.38 vs. 0.34 ± 1.12, P < 0.001). Areal BMD‐Z, BMAD‐Z, FMI‐Z, visceral adipose tissue and subcutaneous adipose tissue were not significantly different in HR‐NBL survivors compared with controls. Compared with controls, HR‐NBL survivors had lower leg lean mass‐Z (−1.46 ± 1.35 vs. − 0.17 ± 0.84, P < 0.001) and strength‐Z (−1.13 ± 0.86 vs. − 0.15 ± 0.71, P < 0.001). Muscle‐specific force was lower in HR‐NBL survivors compared with controls (P < 0.05).ConclusionsBone mineral density and adiposity are not severely impacted in HR‐NBL survivors with growth failure, but significant sarcopenia persists years after treatment. Future studies are needed to determine if sarcopenia improves with muscle‐specific interventions in this population of cancer survivors.

Rationale & Objective: Low muscle mass relative to fat mass (relative sarcopenia) has been associated with mortality and disability but has not been examined after kidney transplantation. We studied how measures of body composition change after receipt of a kidney allograft. Study Design: Prospective longitudinal cohort study. Setting & Participants: 60 kidney transplant recipients, aged 20-60 years, at the University of Pennsylvania. Exposure: Kidney transplantation. Outcome: Dual-energy x-ray absorptiometry measures of fat mass index (FMI) and appendicular lean mass index (ALMI, representing muscle mass), computed tomography measures of muscle density (low density represents increased intramuscular adipose tissue), dynamometer measures of leg muscle strength, and physical activity. ALMI relative to FMI (ALMFMI) is an established index of relative sarcopenia. Analytical Approach: Measures expressed as age, sex, and race-specific z scores for transplant recipients were compared with 327 healthy controls. Regression models were used to identify correlates of change in outcome z scores and compare transplant recipients with controls. Results: At transplantation, ALMI, ALMI(FMI), muscle strength, and muscle density z scores were lower versus controls (all P <= 0.001). Transplant recipients received glucocorticoids throughout. The prevalence of obesity increased from 18% to 45%. Although ALMI increased after transplantation (P < 0.001) and was comparable with the controls from 6 months onward, gains were outpaced by increases in FMI, resulting in persistent ALMIFMI deficits (mean z score of -0.31 at 24 months; P = 0.02 vs controls). Muscle density improved after transplantation despite gains in FMI (P = 0.02). Muscle strength relative to ALMI also improved (P = 0.04) but remained low compared with controls (P = 0.01). Exercise increased in the early months after transplantation (P < 0.05) but remained lower than controls (P = 0.02). Limitations: Lack of muscle biopsies precluded assessment of muscle histology and metabolism. Conclusions: The 2-year interval after kidney transplantation was characterized by gains in muscle mass and strength that were outpaced by gains in fat mass, resulting in persistent relative sarcopenia.

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 (β = -0.43 , P < 0.0001), ALP (β = -0.36, P < 0.0001) and Ca (β = 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.

Objective Rheumatoid arthritis (RA) is associated with low muscle density due to the accumulation of intramuscular fat. The present study was undertaken to identify predictors of changes in muscle density and to determine whether low muscle density predicted changes in strength and physical function. Methods Patients with RA, ages 18-70 years, completed whole-body dual-energy x-ray absorptiometry and peripheral quantitative computed tomography to quantify lean and fat mass indices and muscle density. Dynamometry was used to measure strength at the hand, knee, and lower leg. Disability and physical function were measured with the Health Assessment Questionnaire (HAQ) and the Short Physical Performance Battery (SPPB). Assessments were performed at baseline and at follow-up. Regression analyses assessed associations between patient characteristics, muscle density, and deteriorations in strength and function. Results Muscle density was assessed at baseline in 107 patients with RA. Seventy-nine of these patients (74%) returned for a follow-up assessment at a median follow-up time of 2.71 years (interquartile range 2.35-3.57). Factors associated with declines in muscle density included female sex, higher disease activity, smoking, and lower insulin-like growth factor 1 (IGF-1) levels. Greater muscle density Z score at baseline (per 1 SD) was associated with less worsening per year according to HAQ, SPPB, and 4-meter walk time scores and a lower risk of a clinically important worsening in HAQ score (odds ratio [OR] 1.90 [95% confidence interval (95% CI) 1.06, 3.42]; P = 0.03) and walking speed (OR 2.87 [95% CI 1.05, 7.89]; P = 0.04). Conclusion Worsening of skeletal muscle density occurred in patients with higher disease activity, in smokers, and in those with lower IGF-1. Low muscle density was associated with worsening of physical function. Interventions addressing reductions in muscle quality might prevent functional decline.