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.

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.

Category: Ankle, Trauma Keywords: Distal Tibia, Bone Stress Injuries, Bone Mineral Density Introduction/Purpose: Repetitive loading during basic combat training (BCT) results in tibial bone adaptation. Men show increases in cortical thickness, trabecular thickness, trabecular volumetric bone density, and cortical bone density during 8-10 weeks of U.S. Army BCT, yet ~5-7% of men sustain bone stress injuries (BSIs) during training. BSIs are a leading cause of BCT attrition. Sex steroid hormones regulate bone metabolism. While testosterone supports bone formation, work in older men suggests estradiol is a stronger determinant of skeletal health.8 Whether this is true in younger men remains to be studied. We tested whether cumulative estradiol, testosterone, and free testosterone exposure during BCT is associated with favorable changes in distal tibial microarchitecture. Methods: We collected high resolution peripheral quantitative computed tomography (HR-pQCT) scans at the distal tibia (4% of tibial length) in 67 men at the beginning and end of BCT. We measured serial serum hormones by LCM/MS/MS at weeks 0, 2, 4, 6, 8 and 10. Exposures were log2-means of estradiol, total testosterone, and free testosterone across all timepoints. Outcomes included total bone mineral density (Tt.BMD), cortical BMD (Ct. BMD), Ct area (Ct.Ar), trabecular BMD (Tb.BMD), Tb Thickness (Tb.Th), and Tb spacing (Tb.Sp). We fit ANCOVA models with robust standard errors, coefficients for hormones represent change per exposure doubling. False-discovery rate control (Benjamini–Hochberg) was applied across outcomes. Results: Participants were 17-28 (mean 20.9 ± 3.7) years old with normal BMI (mean 24.9 ± 3.9 kg/m 2 ). Racial and ethnic diversity was represented: 38% identified as White, 23% as Black, and 39% as Other racial categories. Per-doubling estradiol was associated with higher distal tibial Tt.BMD (β=+2.6 mgHA/cm³, 95% CI 0.2–5.0, p=0.03), greater Ct.Ar (β=+1.13 mm2, 95% CI 0.17–2.10, p=0.02), and greater Tb.vBMD (β=+2.2 mgHA/cm³, 95% CI 0.1-4.3, p=0.04) at the end of BCT, adjusted for baseline bone parameter, age, and BMI. Other microarchitectural indices were null. Adding total or free testosterone did not attenuate estradiol effects, and testosterone measures were not independently associated with bone adaptation. Conclusion: In male trainees, greater estradiol exposure was associated with greater gains in measures of distal tibial size, density and microarchitecture independent of testosterone. These findings suggest estradiol is a key regulator of bone adaptation in young adult men. Given the modest sample and multiple outcomes, larger studies should confirm these associations and test links to tibial bone stress injury risk.

Current fracture risk assessment does not directly include fall probability, despite the fact that most hip fractures resulting from falls. Additionally, the role of trochanteric soft tissue thickness (TST) in hip fracture risk remains unclear. This study aimed to develop a subject-specific fall risk tool and test whether incorporating fall probability and TST improves hip fracture prediction beyond FRAX alone in older adults from the AGES-Reykjavik study. Baseline data from 3242 individuals (58% women) were used to predict repeated falls (≥2 in 12 mo) at follow-up (~5 yr later) via multivariate logistic regression, considering age, sex, fall history, neuromuscular function, dynamic balance, and medication use. In a case-cohort study (698 hip fractures and 1348 controls; median follow-up 10 yr), Cox proportional hazards models assessed hip fracture risk. We compared the predictive value of fall probability and TST combined with FRAX against FRAX alone using time-dependent AUC at 5-, 10-, and 16-yr follow-up. At follow-up, 295 individuals had ≥2 falls in the past year. The best model for future falls included a timed up-and-go test, fall history, and grip strength. The probability of falling predicted incident hip fracture and improved hip fracture prediction beyond FRAX, in both men and women. The improved predictive value of fall risk was greater among men than women (eg, AUC for predicting 10 yr hip fracture risk, 0.83 (95% CI: 0.79-0.87) in men vs 0.75 (95% CI: 0.72-0.78) in women). Lower TST was linked to higher hip fracture risk in women but not men. However, adding TST to a model with fall probability and FRAX among women did not enhance time-dependent AUC (p > .10). In conclusion, fall probability significantly improves hip fracture prediction beyond FRAX, particularly in men. Thus, subject-specific fall risk assessment may enhance clinical evaluation of hip fracture risk in older adults.

Both bone and muscle function decline with age and are anatomically and functionally related. However, whether and to what extent muscle function (ie, strength and power) may predict longitudinal changes in bone microarchitecture and strength is unclear. The Osteoporotic Fractures in Men (MrOS) Study included assessments of peak jump power (W) from a force plate and maximum grip strength (kg) from a dynamometer, both normalized to body weight at visit 4 (2014-2016). We investigated the associations of jump power and grip strength with annual percent change in volumetric BMD, microarchitecture, and strength at the distal tibia (DT) and radius (DR) from HR-pQCT between visit 4 and visit 5 (2020-2022; 6.2 ± 0.6 yr follow-up; N = 225; age 82.8 ± 3.0 yr; 89% White). Mean jump power was 22.9 ± 5.6 W/kg and grip strength was 0.49 ± 0.1 kg/kg. During follow-up (median [IQR]), failure load (-0.88 [-1.71, -0.31]%), total BMD (-0.57 [-1.12, -0.18]%), cortical BMD (-1.24 [-2.03, -0.67]%), trabecular BMD (-0.05 [-0.47, 0.20]%), and trabecular thickness (-0.37 [-0.64, -0.12]%) declined at the DT, while at the DR, failure load (-1.02 [-2.19, -0.04]%), total BMD (-0.64 [-1.20, -0.18]%), and cortical BMD (-1.38 [-2.15, -0.71]%) declined (all p ≤ .05). Significant increases were observed for total area at both skeletal sites (DT: 0.04 [0.01, 0.08]%; DR: 0.07[-0.06, 0.16]%; both p ≤ .05). Multivariable linear regression models were adjusted for age, White race, clinic site, respective HR-pQCT initial values, percentage weight change, alcohol consumption, medication count, chronic disease history, falls, and hip pain. Higher grip strength was significantly associated with a smaller percent/year increase in total area at the DT (p ≤ .05) but not at the DR. Neither jump power nor grip strength was associated with change in failure load, BMD, or trabecular thickness at either skeletal site. Associations between grip strength and changes in tibial bone geometry provide insight into potential mechanisms for bone loss and targets for musculoskeletal interventions to reduce fracture risk.

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.

With the goal of preventing more hip fractures, a next generation of the VirtuOst Biomechanical Computed Tomography (BCT) test was developed that integrates measurements from a clinical CT scan related to fall risk, impact force, and femoral strength, the three main determinants of hip fracture. Here, we introduce the test and validate it against BMD and FRAX. Our source population from a large healthcare system comprised of 341364 patients (≥65 yr) with an abdominal-pelvic CT during care. Using data from 3035 patients (1790 with hip fracture), we developed a "BCT Risk Score" (range: 0-100) having input risk factors of age, femoral strength, ratio of trabecular/cortical BMD, muscle area, intramuscular fat, FN volume, hip width, and posterior fat thickness. In a geographically distinct set of 2124 patients (1293 with hip fracture), we then compared the BCT Risk Score against a DXA-equivalent hip BMD T-score (lowest hip value, measured from the CT scan by VirtuOst) and FRAX hip fracture risk (with BMD but without parental fracture history) for predicting a first incident hip fracture within 5 yr. For the women, the c-statistic for predicting fracture was higher for BCT (0.89, 95% CI: 0.87-0.90) than for BMD (0.81, 0.79-0.84) or FRAX (0.85, 0.83-0.87). Using binary thresholds to identify high-risk patients, sensitivity for BCT (Risk Score ≥ 75) was higher than for BMD (T-score ≤ -2.5) and FRAX (hip risk ≥ 3.0%): 81.4% vs 47.8% vs 75.9%, respectively; positive predictive values confirmed comparable high-risk status (BCT 13.6% vs BMD 15.3% vs FRAX 12.7%). Similar trends were observed for the men, 2-yr outcomes, and identifying very-high-risk patients. We conclude that, compared to both BMD and FRAX, the integrative BCT test better predicted hip fracture and its high sensitivity should improve fracture prevention.

Fracture risk estimates can be used clinically to inform treatment decision-making in osteoporosis. Current fracture risk assessment tools have a low sensitivity in predicting fractures in males. This study aims to evaluate and validate the performance of a new fracture prediction tool-the Microarchitecture Fracture Risk Assessment Calculator ($\mu $FRAC)-in a multicentre cohort (MrOS) of older community-dwelling men. The performance of $\mu $FRAC was assessed in a population of 1586 men aged $\geq 77$ years in the United States. All participants underwent HR-pQCT scanning (61 $\mu $m) of the distal radius and distal tibia. Incident fracture information was collected every 4 months from the study visit. The $\mu $FRAC 5-year and 10-year risk of major osteoporotic fracture and any osteoporotic fracture were calculated for all participants. The model calibration was assessed by fitting fine-gray competing risk regression models. The model discrimination was assessed using receiver operator characteristic curves and area under the curve (AUCs). Over the 10-year follow-up period, 129 men experienced an incident major osteoporotic fracture. The $\mu $FRAC models showed good generalizability of the 5-year risk estimates (regression slope 0.8-1.1) to MrOS cohort. The $\mu $FRAC models displayed an improved model performance (AUC = 0.685-0.703) relative to reference models of FRAX (AUC = 0.641) and FN aBMD alone (AUC = 0.636) for the 5-year major osteoporotic fracture (MOF) risk estimates. A sub-analysis on individuals classified as moderate risk by FRAX (10%-20% MOF risk) found that $\mu $FRAC aided in stratifying risk, particularly for the 5-year risk estimates ($\mu $FRAC AUC = 0.691-0.706). The $\mu $FRAC models demonstrated strong performance and generalizability to an external cohort of older men. This validation of $\mu $FRAC suggests its potential use as an alternate assessment tool for osteoporotic fracture risk and may have value in targeting moderate-risk subgroups to aid treatment decisions.

As human space exploration advances, understanding how different gravity levels affect skeletal muscle is critical for long-term health. Among the major organ systems, skeletal muscle is particularly sensitive to gravitational unloading, yet the gravity threshold required to maintain homeostasis remains unclear. Using the Multiple Artificial-gravity Research System aboard the International Space Station, mice were exposed to graded gravity levels, microgravity, 0.33g, 0.67g, and 1g, and their muscles were analyzed postflight. In the gravity-sensitive soleus, the cross-sectional area was preserved at 0.33g, while the slow-to-fast myofiber transition was partially suppressed at 0.33g and fully prevented at 0.67g. Functional measures, including forelimb grip strength and electrical impedance myography, indicated that 0.67g was sufficient to maintain muscle performance. Plasma metabolomics identified 11 metabolites with gravity-dependent changes, suggesting potential biomarkers for monitoring physiological adaptation. Collectively, these results identify 0.67g as a critical threshold for mitigating spaceflight-induced muscle atrophy and myofiber type transitions.

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.

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; 0.33g; 0.67g; and 1g), 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 1g 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 0.33g that were then attenuated / normal at 0.67g and normal at 1g. 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.

Photon-counting computed tomography (PCCT) represents a transformative advancement in bone imaging, compared to conventional energy-integrating detector CT offering superior spatial and contrast resolution, enhanced dose efficiency, and the unique capability to perform both ultra-high-resolution and material decomposition imaging in a single acquisition. This review provides a technical overview and synthesizes evidence from preclinical studies, demonstrating that PCCT offers the possibility of accurate quantification of bone microarchitecture and mineral density with performance similar to high-resolution peripheral quantitative CT. However, translating these benefits to in vivo clinical imaging remains challenging due to the need to balance image quality with acceptable radiation dose. Further research is required to validate PCCT for cortical and trabecular bone analysis in patients. Beyond structural assessment, PCCT facilitates advanced applications such as bone marrow fat quantification and opportunistic osteoporosis screening, with early clinical studies showing strong agreement with established standards. While PCCT holds significant promise for revolutionizing bone research and clinical practice, widespread adoption will depend on optimization of image acquisition protocols, standardized image processing and analysis, and additional clinical validation.

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.

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.

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.