Publications

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.

How systemic hormonal signals coordinate stem cell fate decisions in adult tissues remains incompletely understood. In bone marrow, Cxcl12-abundant reticular (CAR) cells, marked by Early B-cell Factor 3 (Ebf3) expression, are multipotent mesenchymal progenitors that maintain the hematopoietic stem cell niche and serves as a major osteoblast progenitor source during adult bone remodeling. Using inducible lineage tracing coupled with single-cell transcriptomics and conditional genetics in mice, we show that intermittent parathyroid hormone (iPTH; teriparatide) drives osteogenesis from CAR cells by simultaneously engaging cell-intrinsic and cell-extrinsic mechanisms. Directly, iPTH suppresses lineage-enforcing transcription factors Ebf3, Ebf1, and Foxc1, thereby destabilizing progenitor identity and priming CAR cells for osteogenic commitment. Simultaneously, iPTH stimulates osteoclastic bone resorption, releasing TGFß which recruits these primed progenitors to bone surfaces, a process abolished by osteoclast depletion. Preventing CAR cell maturation via Sp7 deletion abrogates iPTH-induced bone gain, establishing these progenitors as essential mediators of bone anabolism. This coupled mechanism, in which intrinsic transcriptional priming converges with extrinsic niche remodeling, is conserved in human CAR cells from teriparatide-treated postmenopausal women, which show concordant suppression of EBF3 and FOXC1 and elevated TGFß-responsive gene signatures. These findings reveal a general principle by which a systemic hormone orchestrates tissue remodeling through simultaneous reprogramming of progenitor identity and remodeling of the niche microenvironment.

OBJECTIVE: To evaluate whether biomarkers of systemic inflammation and alterations in redox homeostasis, which we refer to as oxidative stress, associate with musculoskeletal injury (MSKI) during US Army Basic Combat Training (BCT) and to characterise longitudinal changes in these biomarkers throughout BCT.

METHODS: This prospective observational study included 206 Army trainees (51% female) undergoing BCT. Blood samples were collected and analysed for high-sensitivity C reactive protein (hsCRP), free oxygen radical test (FORT), free oxygen radical defence (FORD) and Oxidative Stress Index (OSI=FORT/FORD). Injuries were identified using the International Classification of Diseases, Tenth Revision (ICD-10) codes. Mixed-effects logistic regression models assessed associations between biomarker levels and injury diagnosis over three timeframes (0-7 days before draw, 1-7 days following draw and 8-14 days following draw). Models included both chronic (between-person) and acute (within-person) biomarker components.

RESULTS: Inflammation and oxidative stress biomarker associations with MSKI were strongest in the 0-7 days before and 0-7 days after injury diagnosis. Acute elevation in hsCRP (OR=1.41, 95% CI 1.03 to 1.93, p=0.034) was associated with 41% higher odds of injury diagnosis within the next 7 days. Chronically high hsCRP and OSI were also associated with increased MSKI risk (OR 2.27, 95% CI 1.22 to 4.19, p=0.01 and OR=1.72, 95% CI 1.01 to 2.92, p=0.046, respectively).

CONCLUSION: Elevated hsCRP and OSI were temporally associated with MSKI diagnoses during BCT, with the strongest associations in the week surrounding diagnosis. These associative findings may reflect heightened physiological stress and early injury-related tissue stress and repair responses.

Long-term adaptations to spaceflight outside of low earth orbit (LEO), during deep space transit, and readaptations to partial gravity environments upon reaching a destination, are unclear. The combined effect of these adaptations to the LEO environment can result in declines in mobility and balance in astronauts during and after spaceflight. This study aimed to determine if there is a gravity threshold that protects from deficits in gait and performance. To do so, we exposed mice to four gravitational loading conditions (µg; 0.33 g; 0.67 g; and 1 g), induced by centrifugation, relative to preflight measurements after a 32-day mission to the ISS. Pre-flight and post-flight gait measurements were conducted utilizing a portable gait analysis system (DigiGait, Mouse Specifics, Inc). No differences were observed in gait characteristics within the Control groups (Ground Control (GC) housed in identical conditions as FLIGHT and Vivarium (VIV) housed in standard rodent cages) from initial to final gait assessment. In contrast, significant changes in gait patterns were observed in the hind limbs and the forelimbs of the FLIGHT mice after 32 days in orbit, and between groups. Continuous exposure to 1 g via centrifugation preserved gait patterns relative to both preflight and controls. Gait patterns were preserved in a gravity-dose dependent manner; with major differences observed after 0.33 g that were then attenuated / normal at 0.67 g and normal at 1 g. Notably, mice exposed to µg could not perform (locomote linearly) at live animal return, with only 50 % able to perform in the 0.33g-exposed group. As we plan for missions to the reduced gravity environments of Moon and Mars, there is a critical need to characterize these neuromotor deficits in the microgravity and partial gravity environments, and to determine whether a g-threshold exists to better mitigate the risks associated with long-duration spaceflight both in transit and upon reaching a destination.

We have proposed 24-mo between-treatment difference (active-placebo) in mean percent change in total hip bone mineral density (%THBMD) be used to evaluate whether a drug will likely reduce fracture risk, such that a mean %THBMD change greater than the surrogate threshold effect (STE) would indicate fracture benefit. However, this approach does not consider trial size. Here, we investigate using the lower limit of the 95% confidence interval (LCL) of %THBMD as an alternative to the mean to account for the impact that trial size has on estimator uncertainty. We compared the performance of these two measures (mean and LCL of %THBMD) in indicating fracture risk reduction relative to the STE by simulating trials of various sizes (100, 250, 500, 750, and 1000) based on data re-sampling from existing large trials with THBMD at 24 mo; this included 11 studies with radiographic vertebral fracture, three studies with hip fracture, and five studies with all clinical fractures. We re-sampled the THBMD data from each study 1000 times with equal numbers in treatment groups to estimate the reliability of these measures in being consistent with the observed fracture risk reduction due to treatment. Concordance between the %THBMD-STE comparisons and observed fracture risk reduction generally converged at a sample size of 500 (250 per treatment group). For vertebral fracture using mean %THBMD, 9 of the 11 studies had ≥90% of trials consistent with the observed fracture risk reduction if the sample size exceeded 500, which decreased to 7 of the 11 studies using the LCL. For both hip and all clinical fracture, all included studies had ≥90% of trials consistent with the observed fracture risk reduction if the sample size exceeded 500, regardless of using mean or LCL. Overall, the %THBMD-STE comparisons were generally consistent with the original studies' fracture risk reduction observed.

At present, there are no FDA-approved orally-available bone anabolic agents to treat osteoporosis. PTH stimulates bone formation through an intracellular signaling cascade that involves the inhibition of salt-inducible kinase (SIK) isoforms 2 and 3. Therefore, direct small molecule SIK2/SIK3 inhibitors may represent a strategy to mimic PTH actions to treat different forms of osteoporosis. We previously described the synthesis and characterization of SK-124, a pharmacologic SIK2/SIK3 inhibitor that increases trabecular bone formation in eugonadal mice. However, the efficacy of this agent in osteoporosis mouse models remains unknown. Hypogonadism is an important cause of age-related bone loss. In this study, we investigated the therapeutic potential of SK-124 in a male hypogonadal bone loss model (orchiectomy, ORX) in BALB/c mice. Radiographic and histological analyses revealed that SK-124-treated ORX mice showed reduced bone loss compared to the vehicle-treated ORX mice. Serum bone turnover markers demonstrated that SK-124 treatment increased bone turnover, suggesting that SK-124 acts in a PTH-like manner in ORX mice. Bone RNA-sequencing analysis demonstrated novel pathways associated with increased bone formation in response to SK-124 treatment. These findings indicate that SK-124 prevents bone loss in a hypogonadal bone loss model and holds potential as an orally available therapeutic for treating osteoporosis due to testosterone deficiency.

Type 1 diabetes mellitus (T1D) is associated with a marked increase in fracture risk, a phenomenon not entirely explained by lower DXA-BMD. Emerging evidence suggests T1D may adversely affect bone microarchitecture, though findings are inconsistent. We aimed to characterize bone microarchitecture and estimated bone strength in adults with longstanding T1D. We enrolled 96 individuals with T1D (median HbA1c 7.0% [IQR 6.3,7.7], mean diabetes duration 46±10 years) and 57 individuals without diabetes, all aged >50 years. Assessments included areal BMD (aBMD) at the lumbar spine, femoral neck, and total hip via DXA, trabecular bone score (TBS), and high-resolution peripheral quantitative computed tomography (HR-pQCT) to evaluate volumetric BMD (vBMD), bone microarchitecture, and estimated failure load at the distal radius and tibia. Individuals with T1D were more likely to report prior history of fracture compared to controls (26% vs 4%, p<0.001). After adjusting for age, sex, height, and weight, aBMD and TBS did not differ between groups. HR-pQCT revealed modest cortical deficits in the T1D group, with largely preserved trabecular microarchitecture and no significant difference in estimated failure load compared to control participants. Within the T1D group, those who reported a prior fracture had lower spine aBMD and lower estimated strength at the tibia. Notably, individuals diagnosed with T1D at or before age 12 years had worse trabecular parameters at the radius than those diagnosed later, with no corresponding differences at the tibia and no differences seen on DXA. Retinopathy was associated with lower aBMD at the hip and femoral neck and with reductions in trabecular thickness, area, failure load, and stiffness at the tibia. The minor differences in bone microarchitecture observed in this study may partly contribute to the increased fracture risk among patients with T1D, though more research examining mediating factors both intrinsic and extrinsic to bone is needed.

The increased hip fracture risk in individuals with type 1 (T1D) and type 2 (T2D) diabetes is not explained by areal BMD (aBMD), indicating that diabetes increases fracture risk through mechanisms independent of aBMD. To investigate, we used QCT to compare femoral strength, volumetric BMD (vBMD), and geometry in cadaveric femora from older adults with T1D (n = 23; 13 female) and T2D (n = 21; 11 female) to controls of similar age, sex, and race (n = 19; 11 female). While aBMD and vBMD measures were similar across groups, femoral strength was lower in the diabetic groups compared to controls. Geometric strength, based on external bone shape, was lower in T1D (-15%, p = .001) and T2D (-12%, p = .014) compared to controls. When combining geometry and density, femoral strength was significantly lower in T1D (-19%, p = .044). The strength-to-density ratio was also lower in T1D and T2D (p ≤ .013), indicating greater skeletal fragility in the diabetic groups beyond what is predicted by BMD. Diabetic groups had smaller bone size, including lower femoral neck volume (-8%, p ≤ .030), neck cross-sectional area (CSA) (-8%, p ≤ .030), and trochanter CSA (-7%, p ≤ .010). These findings suggest that lower femoral strength and smaller geometry contribute to elevated fracture risk in diabetes, warranting further study in larger populations.