Publications

The increase in chest CT volumes affords radiologists the opportunity to systematically assess imaging biomarkers including coronary and thoracic arterial calcification, emphysema, airway dysanapsis, adipose tissue in various compartments, skeletal muscle (in terms of both quantity and quality), and vertebral body bone attenuation (as a measure of bone mineral density), extending from the T1 through T12 vertebral body levels (1). These biomarkers represent a spectrum of disease-induced changes or increases in risk for developing disease. This Special Series review provides an overview of these established and emerging imaging biomarkers on chest CT scans, aiming to serve as a reference for practicing radiologists. We discuss the imaging biomarkers' importance for patient care, highlight recent developments, present approaches for interpretation and integration into clinical workflows with attention to the role of reference values, consider challenges in serial assessment resulting from variations in technical parameters, describe the biomarkers' incorporation into societal guidelines, and summarize FDA-approved AI tools to aid evaluation.

BACKGROUND: Bone stress injury (BSI) is a common overuse injury in female athletes that can occur in a variety of bones, including both proximal (pelvis, sacrum, femoral neck) or distal (tibia, fibula, metatarsals) locations. Prior work has demonstrated differences in running biomechanics in those with BSI; however, this was not separated by anatomy. We hypothesised that both female athletes with distal BSI and female athletes with proximal BSI would have lower cadence, higher centre of mass (COM) and lower duty factor than those without prior BSI.

METHODS: Cross-sectional study of 45 female athletes (15 with prior distal BSI, 15 with prior proximal BSI and 15 with no BSI history). Each ran on an instrumented treadmill at self-selected and 5-kilometre race speeds, with data collected in a fresh and exerted state. A series of analysis of variance tests (ANOVAs, group by condition) were used to analyse the results.

RESULTS: Participants with previous proximal BSI ran with greater vertical COM excursion compared with those with no previous BSI at race speed (10.2±1.7 cm vs 8.5±0.8 cm (p<0.001)). The proximal BSI population had a lower cadence than the no prior BSI population at race speed (170±13 steps per minute vs 180±10 steps per minute (p=0.012)). Duty factor was lower in the proximal BSI group compared with the distal BSI group at the race speed (32±3% vs 34±3% (p=0.013)).

CONCLUSION: COM and cadence should be further investigated for association with proximal BSI.

IMPORTANCE: Musculoskeletal injuries (MSKIs) are pervasive problems in novice training environments. Evaluation of modifiable and nonmodifiable risk factors of MSKI risk prior to entry into these environments is largely understudied.

OBJECTIVE: To provide military leaders, civilian and military clinicians, and physical training instructors with an MSKI risk model for identifying low-, moderate-, and high-risk profiles among individuals starting US Army Basic Combat Training (BCT) or a physical training program.

DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study, data collection was conducted between August 5, 2017, and April 15, 2023, at 2 US Army BCT sites. The sample consisted of volunteer trainees between the ages of 17 and 41 years. They were followed up from the start of BCT. Data analyses were conducted from April to September 2024.

EXPOSURES: Data for the factors potentially associated with MSKI were collected during the first week of BCT and included blood draws, total body dual-energy x-ray absorptiometry, and muscle power test results; surveys of demographics, medical history, physical activity, psychological characteristics, and sleep patterns; and physical fitness results.

MAIN OUTCOMES AND MEASURES: MSKIs identified using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes. Logistic regression-based models estimating the risk of MSKI were generated using 5-fold internal cross-validation for the total cohort, males, and females. Traffic light model examples of low (green), moderate (amber), and high (red) MSKI risk tiers were produced.

RESULTS: In this cohort study of 2988 Army trainees (median [IQR] age, 19.0 [19.0-22.0] years; 1880 males [62.9%]), 729 females (49.0%) and 758 males (51.0%) had an ICD-10 code-identified MSKI, and 1067 (35.7%) had more than 1 ICD-10 code-identified MSKI. Factors associated with increased MSKI risk in the total cohort and female- and male-specific MSKI risk models (with areas under the receiver operator characteristic curve of 0.701, 0.678, and 0.661, respectively) encompassed 7 variable categories: demographics; anthropometrics and body composition; nutritional status; medical and health history; history of sports and past or current physical activity or fitness; psychological factors (ie, pain, grit, and hardiness); and sleep parameters.

CONCLUSIONS AND RELEVANCE: This cohort study presents a tiered approach to identifying persons at increased MSKI risk before the start of a physical training program. Applying a tiered quantification risk metric and incorporating multifactorial interventions from these findings may play a role in reduced MSKI risk.

Parathyroid hormone (PTH) analogs with improved actions in vivo could lead to optimized treatments for bone and mineral ion diseases. Rapid clearance from the circulation and short dwell times on the PTH receptor limit the efficacies of conventional PTH peptides currently in medical use. Here, we seek to enhance PTH peptide efficacy using two distinct peptide lipidation strategies. First, we append a lipid chain to the peptide's C-terminus in a fashion to promote binding to serum albumin and hence prolong the peptide's circulation half-life in vivo. Second, we append a lipid chain to a lysine side chain in a fashion designed to anchor the peptide to the cell membrane as the ligand is bound to the receptor and hence increase its dwell time on the receptor. We find that both strategies of lipidation can profoundly enhance the efficacy of PTH peptides in vitro and in mice. Our results could lead to the development of modified PTH analogs with optimized therapeutic utility.

Bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) and adjustable gastric banding (AGB) lead to long-term deficits in bone density but are also accompanied by decreased weight, which may lower the impact force with falls. The aim of this study was to compare the long-term skeletal impact of RYGB and AGB using a biomechanical evaluation of load-to-strength ratio at the distal radius as a surrogate for wrist fracture risk. We conducted a cross-sectional study evaluating bone microarchitectural parameters and bone turnover in adults who received either RYGB or AGB surgery ≥10 yr ago (RYGB: n = 22; AGB: n = 23). Bone strength at the distal radius was estimated by microfinite element analysis from HR-pQCT. We used a single-spring biomechanical model to estimate impact force and then calculated load-to-strength ratio as a ratio of impact force to bone strength, with higher load-to-strength ratios representing a higher susceptibility to fracture. In multivariable analyses, the RYGB group had higher bone resorption marker C-telopeptide (CTX) levels, lower volumetric bone density, and worse cortical and trabecular microarchitectural parameters than the AGB group. Furthermore, estimated bone strength at the radius was lower in the RYGB group (3725 ± 139 N vs 4141 ± 157 N, p = .030), and the load-to-strength ratio was higher in RYGB group as compared with AGB (0.84 ± 0.04 vs 0.72 ± 0.05, p = .035), suggestive of higher propensity for wrist fracture. Taken together, these results indicate the long-term deleterious skeletal effects are more concerning with RYGB than AGB.

We have proposed to the Food and Drug Administration (FDA) that treatment-related increases in total hip BMD (TH BMD) at 2 yr could be a surrogate endpoint for fracture risk reduction in clinical trials. The qualification of a surrogate includes a strong association of the surrogate with the clinical outcome. We compiled a large database of individual patient data (IPD) through the Foundation for the National Institutes of Health-American Society for Bone and Mineral Research- A Study to Advance BMD as a Regulatory Endpoint (FNIH-ASBMR-SABRE) project, and this analysis aimed to assess the relationship between baseline BMD and fracture risk in the placebo groups. We estimated the association of baseline TH, femoral neck (FN), and lumbar spine (LS) BMD with fracture risk using IPD from the combined placebo groups, which included data from 46 666 placebo participants in 25 RCTs. We estimated the relative risk (RR) of fracture per SD decrease in baseline BMD using logistic regression models for radiographic vertebral fractures and proportional hazards models for hip, non-vertebral, "all," and "all clinical" fractures. Total person-years in the combined placebo groups was 250 662 (mean baseline age 70.2 ± 7.2 yr, mean TH BMD T-score -1.97 ± 0.90). We observed significant relationships between baseline TH BMD and vertebral (RR = 1.55/SD), hip (RR = 2.27), non-vertebral (RR = 1.31), all (RR = 1.43), and all clinical (RR = 1.35) fracture risk. Fracture risk estimates were similar for FN BMD and after adjustment for age, race, and study. Fracture incidence increased with decreasing TH BMD quintile, confirming the strong graded association between TH BMD and fracture risk. There was a strong relationship between LS BMD and vertebral fracture risk (RR = 1.56/SD), but only a weak association with non-vertebral (RR = 1.07) and no association with hip (RR = 1.01) fracture risk. These data support the very strong relationship between hip BMD and fracture risk and provide supporting rationale for change in TH BMD as a surrogate for fracture risk reduction in future RCTs.

UNLABELLED: Up to 40% of elite athletes experience bone stress injuries (BSIs), with 20-30% facing reinjury. Early identification of runners at high risk of subsequent BSI could improve prevention strategies. However, the complex etiology and multifactorial risk factors of BSIs makes identifying predictive risk factors challenging. In a study of 30 female recreational athletes with tibial BSIs, 10 experienced additional BSIs over a 1-year period, prompting investigation of systemic biomarkers of subsequent BSIs using aptamer-based proteomic technology. We hypothesized that early proteomic signatures could discriminate runners who experienced subsequent BSIs. 1,500 proteins related to metabolic, immune, and bone healing pathways were examined. Using supervised machine learning and genetic programming methods, we analyzed serum protein signatures over the 1-year monitoring period. Models were also created with clinical metrics, including standard-of-care blood analysis, bone density measures, and health histories. Protein signatures collected within three weeks of BSI diagnosis achieved the greatest separation by sparse partial least squares discriminant analysis (sPLS-DA), clustering single and recurrent BSI individuals with a mean accuracy of 96 ± 0.02%. Genetic programming models independently verified the presence of candidate biomarkers, including fumarylacetoacetase, osteopontin, and trypsin-2, which significantly outperformed clinical metrics. Time-course differential expression analysis highlighted 112 differentially expressed proteins in individuals with additional BSIs. Gene set enrichment analysis mapped these proteins to pathways indicating increased fibrin clot formation and decreased immune signaling in recurrent BSI individuals. These findings provide new insights into biomarkers and dysregulated protein pathways associated with recurrent BSI and may lead to new preventative or therapeutic intervention strategies.

ONE SENTENCE SUMMARY: Our study identified candidate serum biomarkers to predict subsequent bone stress injuries in female runners, offering new insights for clinical monitoring and interventions.

Type 1 diabetes (T1D) is associated with an increased risk of hip fracture beyond what can be explained by reduced bone mineral density, possibly due to changes in bone material from accumulation of advanced glycation end-products (AGEs) and altered matrix composition, though data from human cortical bone in T1D are limited. The objective of this study was to evaluate cortical bone material behavior in T1D by examining specimens from cadaveric femora from older adults with long-duration T1D (≥50 yr; n = 20) and age- and sex-matched nondiabetic controls (n = 14). Cortical bone was assessed by mechanical testing (4-point bending, cyclic reference point indentation, impact microindentation), AGE quantification [total fluorescent AGEs, pentosidine, carboxymethyl lysine (CML)], and matrix composition via Raman spectroscopy. Cortical bone from older adults with T1D had diminished postyield toughness to fracture (-30%, p = .036), elevated levels of AGEs (pentosidine, +17%, p = .039), lower mineral crystallinity (-1.4%, p = .010), greater proline hydroxylation (+1.9%, p = .009), and reduced glycosaminoglycan (GAG) content (-1.3%, p < .03) compared to nondiabetics. In multiple regression models to predict cortical bone toughness, cortical tissue mineral density, CML, and Raman spectroscopic measures of enzymatic collagen crosslinks and GAG content remained highly significant predictors of toughness, while diabetic status was no longer significant (adjusted R2 > 0.60, p < .001). Thus, the impairment of cortical bone to absorb energy following long-duration T1D is well explained by AGE accumulation and modifications to the bone matrix. These results provide novel insight into the pathogenesis of skeletal fragility in individuals with T1D.

Vertebral compression fractures (VFs) and spinal degeneration are both common causes of back pain, particularly in older adults. Previous cross-sectional studies have shown a potential association between these entities, but there is limited evidence on the role of VFs in spinal degeneration. In this longitudinal study, we evaluated the association between prevalent VFs and the subsequent progression of facet joint osteoarthritis (FJOA) and intervertebral disc height narrowing (DHN), using data from the Framingham Heart Study Offspring and Third Generation Multi-Detector Computed Tomography study. Summary indices representing the total burden of each spinal parameter (VFs, DHN and FJOA) were calculated for each individual. We hypothesized that prevalent VFs are associated with worsening spinal degeneration. 370 (31%) of 1197 participants, had a baseline (prevalent) VF. The change in summary index of DHN over the follow-up period was significantly higher in those with versus without prevalent VF (difference in change in DHN 0.38, 95% CI 0.18 to 0.59, P<.001), but the change in summary index of FJOA was similar between those with and without prevalent VF. However, once adjusted for age, sex, cohort, smoking status, body mass index, and baseline DHN, the change in summary index of DHN did not differ by prevalent VF status. There was a modestly higher change in the FJOA summary index in those with prevalent VFs compared to those without in the fully adjusted model (difference in change in FJOA 0.62, 95% CI -0.01 to 1.24, P=.054), driven primarily by those with severe (grade 3) VF (difference in change in FJOA 4.48, 95% CI 1.99 to 6.97). Moreover, there was greater change in the summary index of FJOA with increasing severity of prevalent VF (linear trend P=.005). Beyond the established morbidity and mortality associated with VFs, our study suggests that VFs may also lead to worsening spine osteoarthritis.