Prevalence of osteoporosis in older male veterans receiving hip-containing computed tomography scans: opportunistic use of biomechanical computed tomography analysis (BCT).

Osteoporosis care in men is suboptimal due to low rates of testing and treatment. Applying biomechanical computed tomography (BCT) analysis to existing CT scans, we found a high proportion of men with osteoporosis have never been diagnosed or treated. BCT may improve identification of patients at high risk of fracture. PURPOSE: Osteoporosis care in men is suboptimal due to low rates of DXA testing and treatment. Biomechanical computed tomography analysis (BCT) can be applied "opportunistically" to prior hip-containing CT scans to measure femoral bone strength and hip BMD. METHODS: In this retrospective, cross-sectional study, we used BCT in male veterans with existing CT scans to investigate the prevalence of osteoporosis, defined by hip BMD (T-score ≤ - 2.5) or fragile bone strength (≤ 3500 N). 577 men, age ≥ 65 with abdominal/pelvic CTs performed in 2017-2019, were randomly selected for BCT analysis. Clinical data were collected via electronic health records and used with the femoral neck BMD T-score from BCT to estimate 10-year hip fracture risks by FRAX. RESULTS: Prevalence of osteoporosis by BCT increased with age (13.5% age 65-74; 18.2% age 75-84; 34.3% age ≥ 85), with an estimated overall prevalence of 18.3% for men age ≥ 65. In those with osteoporosis (n = 108/577), only 38.0% (41/108) had a prior DXA and 18.6% (7/108) had received osteoporosis pharmacotherapy. Elevated hip fracture risk by FRAX (≥ 3%) did not fully capture those with fragile bone strength. In a multivariate logistic regression model adjusted for age, BMI, race, and CT location, end stage renal disease (odds ratio 7.4; 95% confidence interval 2.3-23.9), COPD (2.2; 1.2-4.0), and high-dose inhaled corticosteroid use (3.7; 1.2-11.8) were associated with increased odds of having osteoporosis by BCT. CONCLUSION: Opportunistic BCT in male veterans provides an additional avenue to identify patients who are at high risk of fractures.

Longitudinal Assessment of Body Composition and Its Association With Survival Among Participants of the ACTIVE/ADIPOSE Study.

OBJECTIVES: The importance of muscle wasting as a predictor of mortality in the hemodialysis population is not clear. Lack of association of muscle mass with survival in some studies could be related to reliance on single measures or to incorporation of excess extracellular water (ECW) into estimates of muscle mass. We examined changes in body composition over a 2-year period and the association of body composition with survival. DESIGN AND METHODS: We analyzed data from 325 adults receiving hemodialysis in the Bay Area. We estimated ECW, intracellular water (ICW), and fat mass by whole-body bioimpedance spectroscopy (BIS) at 0, 12, and 24 months from enrollment. We used linear mixed modeling to examine changes in body mass index and BIS-derived estimates of body composition and Cox modeling with BIS-derived estimates as time-varying independent variables to examine associations between body composition and survival in multivariable analyses. RESULTS: Body mass index declined over time. Considering individual components of body composition, ICW declined (-0.09 kg/m2 per year, 95% confidence interval -0.14 to -0.04), but fat mass and ECW did not change significantly. There were 120 deaths over a median of 5.2 years. The relationship between ICW and mortality was not linear such that the association was steeper at low values of ICW, whereas higher ICW was associated with better survival that was relatively stable above 9 kg/m2. Higher ECW was associated with higher mortality, and fat mass was not associated with survival. These associations were independent of markers of inflammation and nutritional status. CONCLUSIONS: ICW declined over 2 years in this cohort, whereas fat mass and ECW remained relatively stable. Higher ICW was associated with better survival, but higher fat mass was not. Higher ECW was associated with worse survival. These results suggest that muscle mass may predict survival among patients on hemodialysis.

Correlates and Consequences of High Serum Irisin Concentration in Patients on Hemodialysis: A Longitudinal Analysis.

OBJECTIVE: Irisin is a hormone released by muscle in response to exercise that acts on white adipose cells to stimulate browning of adipose tissue. We aimed to examine irisin correlates and consequences of irisin in patients receiving hemodialysis. DESIGN AND METHODS: A prospective cohort study was conducted using data from 749 prevalent patients receiving hemodialysis. Multivariable linear regression and multivariable generalized estimating equations were used to determine correlates of baseline and change in serum irisin concentration. Proportional hazards (Cox) regression was used to assess the association between serum irisin concentration and time to death. RESULTS: Age and body mass index were inversely associated with baseline and change in serum irisin concentration. Lower muscle mass as estimated by serum creatinine concentration was associated with lower irisin concentration (-1.38% per mg/dL (95% confidence interval [CI]: -2.45, -0.21) and with a 0.72% decrease in irisin concentration (95% CI: -1.48, -0.04) from baseline to 12 months. Each 50% higher serum interleukin-6 (IL-6) concentration was associated with 1.52% higher serum irisin concentration (95% CI: 0.38, 2.66) at baseline and an increase of 1.04% in irisin concentration over 1 year (95% CI: 0.47, 1.61). Irisin concentration at baseline was associated with higher hazard of death (hazards ratio: 1.45, 95% CI: 1.05 2.00); an increase in irisin concentration over 1 year was associated with a higher hazard of death (hazards ratio: 1.34, 95% CI: 1.01, 1.79). In formal mediation analysis, serum IL-6 was a mediator in the association between serum irisin and mortality. CONCLUSIONS: Lower serum creatinine (reflecting lower muscle mass) and higher serum IL-6 were associated with higher serum irisin concentrations. Higher serum irisin concentrations were associated with higher mortality, which may be mediated by inflammation.

Low testosterone is associated with frailty, muscle wasting and physical dysfunction among men receiving hemodialysis: a longitudinal analysis.

BACKGROUND: Despite the high prevalence of frailty among patients receiving hemodialysis, few preventable or treatable contributing causes have been identified. Hypogonadism is also common in this population and low serum testosterone concentrations share several clinical phenotypes with frailty. We hypothesized that low serum testosterone concentrations would be associated with frailty and several of its individual components. METHODS: We used data from 440 men from A Cohort Study To Investigate the Value of Exercise in ESRD/Analysis Designed to Investigate the Paradox of Obesity and Survival in ESRD, a longitudinal study that recruited participants from 14 dialysis centers in Atlanta, GA and the San Francisco, CA Bay Area from 2009 to 2011. We assessed frailty using the Fried Frailty Phenotype. We examined the association between free testosterone (as a continuous and dichotomous variable) and frailty, individual frailty components, sarcopenia, lower extremity function and muscle mass estimation by creatinine and body impedance spectroscopy over 12 months using generalized estimating equations. RESULTS: The mean age was 56.1 ± 14.2 years and 27% were white. A 50% lower concentration of free testosterone was associated with 1.40-fold higher odds of being frail [95% confidence interval (CI) 1.05-1.53] and 1.40-fold higher odds of becoming frail over 12 months (95% CI 1.07-1.73). This association was mainly due to an association with two components of frailty: grip strength and gait speed. In addition, 50% lower free testosterone concentration was associated with a 1.55-fold higher odds of having sarcopenia (95% CI 1.09-2.02) and 1.72-fold higher odds for developing sarcopenia (95% CI 1.13-2.33) as well as with lower muscle mass and a decrease in muscle mass over 12 months as estimated by serum creatinine and by bioelectrical impedance spectroscopy. CONCLUSION: Serum free testosterone concentration was associated with frailty, physical function, sarcopenia and muscle mass as well as with changes in these outcomes over 12 months. Testosterone replacement may be a feasible therapeutic target toward prevention of frailty, although clinical trials are needed to test this possibility.

Vitamin D Levels, Body Composition, and Metabolic Factors in Asian Indians: Results from the Metabolic Syndrome and Atherosclerosis in South Asians Living in America Pilot Study.

BACKGROUND/AIMS: Asian Indians have a high prevalence of vitamin D deficiency and metabolic syndrome. Vitamin D deficiency is associated with an increased risk of cardiovascular disease and diabetes. METHODS: We performed a cross-sectional study of 150 Asian Indians (50% male) from the San Francisco Bay Area. We assessed the association between 25-OH vitamin D (25-OHD) levels and vitamin D deficiency with body composition (anthropometric and radiographic measures) and metabolic outcomes. RESULTS: In both men and women, the presence of vitamin D deficiency was associated with higher systolic (p = 0.004) and diastolic (p = 0.01) blood pressure, and fasting glucose (p = 0.01). Only in women, vitamin D deficiency status was associated with higher body mass index (BMI), waist-to-hip ratio, visceral fat area, and hepatic fat content after adjusting for age, income, and physical activity level. In women, 25-OHD was also associated with fasting glucose after adjusting for age, income, and physical activity and further adjusting for BMI and waist circumference (ß -2.1, 95% CI -0.86 to -0.01, p = 0.04). This association between vitamin D deficiency and metabolic parameters was not significant in men. CONCLUSIONS: A lower level of 25-OHD and vitamin D deficiency were associated with higher levels of metabolic factors among Asian Indians. Our findings suggest that 25-OHD metabolism may differ by the distribution of adipose tissue and involve previously unexplored pathways accounting for the variability in the role of vitamin D in cardiovascular disease.

Fibroblast Growth Factor 23 is Associated With Adiposity in Patients Receiving Hemodialysis: Possible Cross Talk Between Bone and Adipose Tissue.

OBJECTIVE: Fibroblast growth factor 23 (FGF-23) may be involved in signaling between bone and adipose tissue in dialysis patients, but its role is uncertain. We sought to examine the association between FGF-23 and adiposity and whether this association is mediated in part by leptin. DESIGN/SETTING: We performed univariate and multivariate linear regression analyses using data from 611 participants in a cohort of prevalent hemodialysis patients recruited from dialysis centers in Atlanta, GA and San Francisco, CA from 2009 to 2011. We also investigated the role of leptin in these relationships. SUBJECTS: Participants were aged ≥18 years, English or Spanish speaking, and receiving hemodialysis for at least 3 months. MAIN OUTCOME MEASURES: Outcome measures of adiposity included body mass index, waist circumference, and body fat measured by bioelectrical impedance spectroscopy. RESULTS: Mean age was 56 ± 14 years, 39.8% were female, and median serum FGF-23 was 807 pg/mL. In fully adjusted models, FGF-23 was inversely associated with body mass index (-0.24 kg/m2 per 50% higher FGF-23, 95% confidence interval [CI]: -0.38 to -0.10), waist circumference (-0.44 cm per 50% higher FGF-23, 95% CI: -0.79 to -0.08), and percent body fat (-0.58% per 50% higher FGF-23, 95% CI: -0.79 to -0.37). Leptin was inversely associated with FGF-23. Addition of leptin to body composition models attenuated the associations between FGF-23 and measures of adiposity, but FGF-23 remained significantly associated with percent body fat (-0.17% per 50% higher FGF-23, 95% CI: -0.32 to -0.02). CONCLUSION: We found a negative association between FGF-23 and adiposity that appears to be mediated in part by leptin. As adipose tissue provides a "protective energy depot" for patients with chronic illness, a decrease in adipose tissue may be one mechanism in which higher FGF-23 levels may contribute to increased mortality in dialysis patients.

Comparative Uptake Patterns of Radioactive Iodine and [18F]-Fluorodeoxyglucose (FDG) in Metastatic Differentiated Thyroid Cancers.

Background: Metastatic differentiated thyroid cancer (DTC) represents a molecularly heterogeneous group of cancers with varying radioactive iodine (RAI) and [18F]-fluorodeoxyglucose (FDG) uptake patterns potentially correlated with the degree of de-differentiation through the so-called "flip-flop" phenomenon. However, it is unknown if RAI and FDG uptake patterns correlate with molecular status or metastatic site. Materials and Methods: A retrospective analysis of metastatic DTC patients (n = 46) with radioactive 131-iodine whole body scan (WBS) and FDG-PET imaging between 2008 and 2022 was performed. The inclusion criteria included accessible FDG-PET and WBS studies within 1 year of each other. Studies were interpreted by two blinded radiologists for iodine or FDG uptake in extrathyroidal sites including lungs, lymph nodes, and bone. Cases were stratified by BRAF V600E mutation status, histology, and a combination of tumor genotype and histology. The data were analyzed by McNemar's Chi-square test. Results: Lung metastasis FDG uptake was significantly more common than iodine uptake (WBS: 52%, FDG: 84%, p = 0.04), but no significant differences were found for lymph or bone metastases. Lung metastasis FDG uptake was significantly more prevalent in the papillary pattern sub-cohort (WBS: 37%, FDG: 89%, p = 0.02) than the follicular pattern sub-cohort (WBS: 75%, FDG: 75%, p = 1.00). Similarly, BRAF V600E+ tumors with lung metastases also demonstrated a preponderance of FDG uptake (WBS: 29%, FDG: 93%, p = 0.02) than BRAF V600E- tumors (WBS: 83%, FDG: 83%, p = 1.00) with lung metastases. Papillary histology featured higher FDG uptake in lung metastasis (WBS: 39%, FDG: 89%, p = 0.03) compared with follicular histology (WBS: 69%, FDG: 77%, p = 1.00). Patients with papillary pattern disease, BRAF V600E+ mutation, or papillary histology had reduced agreement between both modalities in uptake at all metastatic sites compared with those with follicular pattern disease, BRAF V600E- mutation, or follicular histology. Low agreement in lymph node uptake was observed in all patients irrespective of molecular status or histology. Conclusions: The pattern of FDG-PET and radioiodine uptake is dependent on molecular status and metastatic site, with those with papillary histology or BRAF V600E+ mutation featuring increased FDG uptake in distant metastasis. Further study with an expanded cohort may identify which patients may benefit from specific imaging modalities to recognize and surveil metastases.

Validation of Biomechanical Computed Tomography for Fracture Risk Classification in Metastatic Hormone-sensitive Prostate Cancer.

BACKGROUND: Guidelines recommend dual-energy x-ray absorptiometry (DXA) screening to assess fracture risk and benefit from antiresorptive therapy in men with metastatic hormone-sensitive prostate cancer (mHSPC) on androgen deprivation therapy (ADT). However, <30% of eligible patients undergo DXA screening. Biomechanical computed tomography (BCT) is a radiomic technique that measures bone mineral density (BMD) and bone strength from computed tomography (CT) scans. OBJECTIVE: To evaluate the (1) correlations between BCT- and DXA-assessed BMD, and (2) associations between BCT-assessed metrics and subsequent fracture. DESIGN, SETTING, AND PARTICIPANTS: A multicenter retrospective cohort study was conducted among patients with mHSPC between 2013 and 2020 who received CT abdomen/pelvis or positron emission tomography/CT within 48 wk before ADT initiation and during follow-up (48-96 wk after ADT initiation). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used univariate logistic regression to assess the associations between BCT measurements and the primary outcomes of subsequent pathologic and nonpathologic fractures. RESULTS AND LIMITATIONS: Among 91 eligible patients, the median ([interquartile range) age was 67 yr (62-75), 44 (48.4%) were White, and 41 (45.1%) were Black. During the median follow-up of 82 wk, 17 men (18.6%) developed a pathologic and 15 (16.5%) a nonpathologic fracture. BCT- and DXA-assessed femoral-neck BMD T scores were strongly correlated (R2 = 0.93). On baseline CT, lower BCT-assessed BMD (odds ratio [OR] 1.80, 95% confidence interval or CI [1.10, 3.25], p = 0.03) was associated with an increased risk of a pathologic fracture. Lower femoral strength (OR 1.63, 95% CI [0.99, 2.71], p = 0.06) was marginally associated with an increased risk of a pathologic fracture. Neither BMD (OR 1.52, 95% CI [0.95, 2.63], p = 0.11) nor strength (OR 1.14, 95% CI [0.75, 1.80], p = 0.57) was associated with a nonpathologic fracture. BCT identified nine (9.9%) men eligible for antiresorptive therapy, of whom four (44%) were not treated. Limitations include low fracture numbers resulting in lower power to detect fracture associations. CONCLUSIONS: Among men diagnosed with mHSPC, BCT assessments were strongly correlated with DXA, predicted subsequent pathologic fracture, and identified additional men indicated for antiresorptive therapy. PATIENT SUMMARY: We assess whether biomechanical computer tomography (BCT) from routine computer tomography (CT) scans can identify fracture risk among patients recently diagnosed with metastatic prostate cancer. We find that BCT and dual-energy x-ray absorptiometry-derived bone mineral density are strongly correlated and that BCT accurately identifies the risk for future fracture. BCT may enable broader fracture risk assessment and facilitate timely interventions to reduce fracture risk in metastatic prostate cancer patients.

Non-Iodine-Avid Disease Is Highly Prevalent in Distant Metastatic Differentiated Thyroid Cancer With Papillary Histology.

CONTEXT: Patients with radioactive iodine (RAI) refractory metastatic differentiated thyroid cancer (DTC) have poor prognosis. Early identification of RAI refractoriness may improve care. OBJECTIVE: This work aimed to characterize DTC patients with distant metastases (DM) at diagnosis who presented with non-iodine-avid disease. METHODS: Retrospective analyses of DTC patients with DM at diagnosis who presented between 2012 and 2020 were performed. Iodine uptake in DM was correlated with tumor histology and mutational profile. The difference in uptake between BRAFV600E-like (BVL) and RAS-like (RL) cancers based on insights from The Cancer Genome Atlas was evaluated. RESULTS: Among 78 patients, 48.7% had negative uptake in DM on the first posttherapy scan. Negative scans were highly prevalent in papillary thyroid carcinoma (PTC) with papillary architecture, PTC with BRAFV600E mutation, and PTC with both BRAFV600E and TERT promoter mutations (71.1%, 80.9%, and 100%, respectively). BVL and RL tumors exhibited distinct uptake patterns with negative scan prevalence of 76.9% and 14.3% (P = .005). Multivariate logistical regression confirmed high odds of negative uptake in BVL tumors with either BVL mutations or papillary architecture, 19.8 (95% CI, 2.72-144), and low odds of negative uptake in RL tumors with either RL mutations or follicular architecture, 0.048 (95% CI, 0.006-0.344), after adjusting for age, sex, race, RAI preparation method, bone metastases, and RAI dose. Patients with negative scans were significantly older (62.4 vs 47.0 years, P = .03). CONCLUSION: Among DTC patients with DM at diagnosis, non-iodine-avid disease is highly prevalent in patients with BVL cancers, particularly with BRAFV600E and TERT promoter mutations, and is associated with an older age. Better strategies are needed to improve RAI treatment response for these patients.

SEVERE INSULIN RESISTANCE WITH DIABETIC KETOACIDOSIS AFTER BRENTUXIMAB TREATMENT.

OBJECTIVE: To increase awareness of unusual inflammatory and other responses including severe insulin resistance (IR) associated with the use of targeted immunotherapies such as brentuximab. METHODS: We report the case of a man without any previous diagnosis of diabetes who developed diabetic ketoacidosis complicated by severe IR (unresponsive to >600 units of intravenous insulin per hour) after receiving brentuximab for Hodgkin lymphoma. RESULTS: Autoantibodies to the insulin receptor were not detected in the patient's serum, thus excluding a diagnosis of type B IR. CONCLUSION: We hypothesize that brentuximab administration led to a rare reaction leading to systemic cytokine release with extreme IR in our patient.