Publications

Purpose: Anorexia nervosa (AN) is associated with significant changes in bone density and microstructure. However, the extent and nature of skeletal recovery following weight restoration is unclear. The aim of this study was to investigate these changes in bone during simulated AN in rats across short- and long-term recovery. Methods: Female Sprague Dawley rats were exposed to 50-60% food restriction for 30 days to simulate AN, followed by recovery periods of 5, 15, and 30 days. Bone parameters were assessed longitudinally using peripheral quantitative computed tomography (pQCT) and micro-computed tomography (µCT). Bodyweight and muscle strength were correlated with bone parameters. Results: AN resulted in significant reductions in total and trabecular bone density, as well as impairments in cortical and trabecular microarchitecture. Even with weight restoration, these deficits persisted and the compensatory responses were not sufficient for bone recovery. Bodyweight showed an association with total and trabecular bone density. Measures of muscle strength also correlated with total and trabecular density and were additive in multiple regression analysis prediction of total and trabecular bone density when combined with bodyweight. Conclusion: Recovery from AN-induced bone disorders is incomplete even after weight restoration and likely requires targeted interventions beyond nutritional rehabilitation. Furthermore, muscle function is an important predictor of bone health when combined with bodyweight.

This study examined whether hormonal and body composition responses to 10-weeks of U.S. Army Basic Combat Training (BCT) differ by baseline testosterone and sex. Methods: Male (n=97) and female (n=105) trainees were stratified at baseline as having LOW (men <10.4 nmol/L; women <0.82 nmol/L) or NORMAL baseline testosterone. We measured serum total and free testosterone, sex hormone binding globulin (SHBG), luteinizing hormone (LH) and estradiol (E2) at weeks 0, 2, 4, 6, 8, and 9 and cortisol weekly; dual-energy X-ray absorptiometry (DXA) assessed body composition at week 0 and 9. Linear mixed models tested time and group effects; generalized linear models related baseline testosterone status and testosterone area under the curve with changes in body composition. Results: In LOW women, testosterone increased at each timepoint (all p<0.01), reaching concentrations 53% higher at week 9 compared to week 0 (30.2± 7.8 vs 19.7± 3.2 ng/dl). In men, testosterone increased (LOW: +76%; NORMAL: +23%) across BCT (all p<0.05), except at week 2. Among LOW men, concentrations stabilized by week 4 (344.8± 81.4 ng/dl) and remained normal. Cortisol was highest at baseline and declined in all men and in NORMAL women. LH and E2 remained stable in both sexes, while SHBG declined only in women, independent of baseline testosterone. Neither baseline testosterone nor cumulative exposure were associated with changes in lean or fat mass. Conclusions: SHBG and cortisol trajectories differed by sex and baseline testosterone status. Testosterone changes were sex specific, reflecting an anabolic training environment in men and modest increased androgen availability in LOW women.

CONTEXT: Cardiometabolic disease (CMD) may increase vertebral fracture risk through deterioration in bone structure and/or tissue properties, compromising bone strength.

OBJECTIVE: Evaluate the relationship between CMD and vertebral bone measures.

DESIGN: Cross-sectional.

PARTICIPANTS: Coronary Artery Risk Development in Young Adults (CARDIA) study participants with year 25 (2010-2011) abdominal computed tomography (CT) scans (n = 2728).

EXPOSURE: CMD (abdominal obesity, diabetes mellitus, dyslipidemia, or hypertension) status (≥1 vs 0) and burden (0, 1, 2, ≥3).

OUTCOME MEASURES: Vertebral strength, volumetric bone mineral density (vBMD), and bone mass, obtained via biomechanical CT analysis.

METHODS: Multivariable linear regression evaluated the association between CMD and vertebral bone measures. Sex-specific models were adjusted for age, race, height, weight, and additional social determinants of health, lifestyle factors, and comorbidities. Effect modification by race, age, and menopausal status was evaluated.

RESULTS: Overall, at least 1 CMD was identified in 72.3% of men and 70.5% of women. In the fully adjusted model, CMD status was significantly associated with lower total (β = -6.32 mg/cm3; P = .018), trabecular (β = -4.53 mg/cm3; P = .048), and cortical (β = -6.63 mg/cm3; P = .034) vBMD in men. Greater CMD burden was associated with lower total and trabecular vBMD. The negative association between CMD and vBMD was stronger in men ≤50 years. There was no association in women.

CONCLUSION: In this biracial cohort of Black and White adults from the United States, CMD was associated with significantly lower total and subcompartment vertebral vBMD in men.

INTRODUCTION: Bone stress injuries (BSIs) are common overuse injuries in athletes and are associated with prolonged recovery and high rates of reinjury. Despite their clinical importance, there is no consensus on how to define or assess BSI healing. Clinical, functional and imaging outcomes for BSI healing are used inconsistently across studies, limiting comparability and the development of evidence-based return-to-sport guidelines. This study aims to identify and characterise candidate outcomes for assessing BSI healing in runners, including their time course and variability across function, imaging and clinical domains.

METHODS AND ANALYSIS: This is a 1 year, multi-site prospective cohort study of male and female runners with a recent MRI-confirmed BSI of the tibia, metatarsals, femoral neck or sacrum. We will enrol participants across four clinical and academic research sites in the USA and Canada, within 3 weeks of diagnostic MRI and follow them longitudinally for 1 year through recovery, return to sport and full sport participation. Candidate outcomes for BSI healing include time to pain-free functional milestones (eg, hopping, jogging), completion of a return-to-run protocol, medical clearance for unrestricted activity, and changes in MRI grade and clinical severity scores. Secondary and exploratory measures include training patterns, wearable-derived activity and sleep metrics, biomechanical assessments, and serum proteomic profiles. We will use descriptive statistics to characterise the time course and variability of candidate outcomes. We will explore associations between outcomes and subsequent BSIs within 1 year using regression models.

ETHICS AND DISSEMINATION: This study has received institutional review board approval at all participating institutions. We will obtain written informed consent from all participants prior to any study procedures (and assent with parental consent for minors). We will disseminate results through peer-reviewed publications and scientific conferences.

BACKGROUND: While ultra-high-resolution (UHR) photon-counting detector CT (PCD-CT) shows promising agreement with high resolution peripheral quantitative CT for bone microarchitecture evaluation, clinical translation requires balancing noise, resolution, and dose. Conventional optimization relies on objective metrics and may not reflect task-based perception. A hybrid approach integrating objective and subjective assessment may better guide the development of clinically robust PCD-CT UHR bone imaging protocols.

PURPOSE: To apply a hybrid objective-subjective approach to optimize PCD-CT UHR bone imaging protocol at clinically acceptable dose levels.

METHODS: Four cadaveric specimens (one lumbar vertebra and three proximal femora) along with the Mindways phantom (Model 3), were imaged with PCD-CT (NAEOTOM Alpha.Peak VB20, Siemens Healthineers) at 120kVp. Six total acquisitions were performed at three dose levels, IQ-75 (3.0-4.3mGy), IQ-150 (6.0-8.6mGy), and IQ-450 (17.9-25.7mGy) across two pitch settings (0.35 and 0.85). For each acquisition, images were reconstructed using three kernels (Br76, Br89, Br98) and two levels of Quantum Iterative Reconstruction (QIR2 and QIR4), yielding 35 unique protocols. Protocol performance was evaluated using both objective and subjective assessment. Objective metrics included SNR, CNR, and task-based transfer function (TTF) f50 for spatial resolution. Task-based protocol performance was independently assessed by four radiologists using a 5-point Likert scale for cortical sharpness, trabecular visibility, and noise. Statistical analysis for SNR, CNR, TTF-f50 and Likert ratings were performed, and heatmaps were generated to evaluate protocol performance. Interrater reliability was assessed using a two-way random-effects, absolute-agreement intraclass correlation coefficient (ICC).

RESULTS: SNR and CNR were highest with Br76 kernel, QIR4, and highest exposure (IQ-450), while noise was lowest for Br76, increased with sharper kernels (Br89, Br98) and lower IQ, and was markedly reduced with QIR4; pitch had minimal impact (figures 1, 2). Variance analysis showed that QIR had the greatest impact (η² = 0.54, 0.52), followed by kernel (η² = 0.29, 0.32) and IQ (η² = 0.09, 0.08), while pitch had no significant effect. For Br76, TTF-f50 was consistently higher with QIR2 than QIR4 (1.62 vs 1.36 at IQ-75, pitch 0.85), with minimal dependence on IQ and pitch. Consistently, Br76 achieved the highest scores (mean Likert 4.2), outperforming Br89 (3.88) and Br98 (3.02), with scores improving with increasing IQ and at QIR2, and minimal impact from pitch. Interrater reliability was excellent (ICC = 0.92).

CONCLUSION: Br76 provided the best objective-subjective performance for trabecular bone assessment, with QIR4 minimizing noise and maximizing SNR/CNR, while QIR2 better preserved spatial resolution; pitch had no significant effect. Protocol optimization of PCD-CT for UHR imaging of trabecular bone at a clinically acceptable radiation dose is essential to unlock its full potential in clinical research.

OBJECTIVE: To gain insight into higher fracture risk in individuals with type 2 diabetes, we determined the association of type 2 diabetes glycemic status and severity with longitudinal changes in peripheral bone density and microarchitecture.

RESEARCH DESIGN AND METHODS: We conducted a longitudinal study of 769 participants from the Framingham Study who underwent high-resolution, peripheral, quantitative computed tomography (HR-pQCT) at the tibia and radius, in 2012-2016 and 2021-2023 (mean 8-year follow-up). Linear regression models estimated mean 8-year percent changes in bone measures, across indicators of diabetes severity, adjusting for age, sex, weight, and height.

RESULTS: The mean age was 67 ± 7 years, and 59% of participants were women. More than half (57%) were normoglycemic (fasting plasma glucose [FPG] <100 mg/dL, not on any treatment), 31% had prediabetes (100 ≤ FPG ≤125 mg/dL), and 12% had type 2 diabetes (FPG >125 mg/dL or on treatment). Adjusted mean percent changes in HR-pQCT bone measures were similar across diabetes severity, including glycemic status, use of diabetes medications, duration of diabetes, and HbA1c. For example, cortical volumetric bone mineral density at the radius changed by -1.50% (95% CI -2.43, -0.56) in type 2 diabetes and -1.96% (-2.53, -1.39), in prediabetes, compared with -2.42% (-2.86, -1.97) in normoglycemia (reference group; all P > 0.05).

CONCLUSIONS: The magnitude of peripheral bone loss over 8 years did not differ between individuals with type 2 diabetes and those with normoglycemia, suggesting that bone deterioration alone does not explain the higher fracture risk in older adults with type 2 diabetes. Future studies should address other contributors to skeletal fragility.