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Importance: U.S. Army Basic Combat Training (BCT) improves tibial volumetric bone mineral density (BMD) and structure in most, but not all soldiers. Few studies have investigated whether changes in serum bone biomarkers during BCT are associated with changes in tibial BMD and bone structure following BCT., Objective: To characterize bone biomarker changes during BCT and to investigate the relationship between changes in bone biomarkers and changes in tibial BMD and bone structure., Methods: We enrolled 235 trainees entering BCT in this ten-week prospective observational study. Trainees provided fasted blood samples and questionnaires weekly throughout BCT. Procollagen type 1 N-terminal propeptide (PINP) and C-terminal telopeptide of type 1 collagen (CTX) were measured by enzyme-linked immunoabsorbent assays every two weeks during BCT. We evaluated body composition and mass via dual-energy X-ray absorptiometry and bone structure, microarchitecture, and mineral density at the distal tibia via high-resolution peripheral quantitative computed tomography at baseline and post-BCT., Results: Both male (n = 110) and female trainees (n = 125) were young (20.9 ± 3.7 and 20.7 ± 4.3 years, respectively), with normal to overweight BMIs (25.2 ± 4.1 and 24.2 ± 3.6 kg/m 2 , respectively). In female trainees, PINP increased during and post-BCT compared to baseline, with the greatest increase in PINP at week four (45.4 % ± 49.6, p < 0.0001), whereas there were no changes in CTX. PINP also increased in male trainees, but only at weeks two and four (21.9 % ± 24.5, p = 0.0027 and 35.9 % ± 35.8, p < 0.0001, respectively). Unlike female trainees, in males, CTX was lower than baseline at weeks four, eight, and post-BCT. The change in PINP from baseline to week four of BCT was positively associated with changes in tibial BMD, Tb.BMD, Tb.Th, Tb.BV/TV, Ct.Th, Ct.Ar, and Ct.Po from the baseline to post-BCT., Conclusion: The bone formation marker PINP increases during U.S. Army BCT, especially during the first four weeks. Increases in PINP, but not CTX, were correlated with improved BMD and bone structure in the distal tibia., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose. Furthermore, the opinions and assertions presented in the study are the private views of the authors and should not be considered official or reflective of the views of the U.S. Army or the U.S. Department of Defense., (Copyright © 2024. Published by Elsevier Inc.)

Understanding the genetic basis of cortical bone traits can allow for the discovery of novel genes or biological pathways regulating bone health. Mice are the most widely used mammalian model for skeletal biology and allow for the quantification of traits that cannot easily be evaluated in humans, such as osteocyte lacunar morphology. The goal of our study was to investigate the effect of genetic diversity on multi-scale cortical bone traits of 3 long bones in skeletally-mature mice. We measured bone morphology, mechanical properties, material properties, lacunar morphology, and mineral composition of mouse bones from 2 populations of genetic diversity. Additionally, we compared how intrabone relationships varied in the 2 populations. Our first population of genetic diversity included 72 females and 72 males from the 8 inbred founder strains used to create the Diversity Outbred (DO) population. These 8 strains together span almost 90% of the genetic diversity found in mice ( Mus musculus ). Our second population of genetic diversity included 25 genetically unique, outbred females and 25 males from the DO population. We show that multi-scale cortical bone traits vary significantly with genetic background; heritability values range from 21% to 99% indicating genetic control of bone traits across length scales. We show for the first time that lacunar shape and number are highly heritable. Comparing the 2 populations of genetic diversity, we show that each DO mouse does not resemble a single inbred founder, but instead the outbred mice display hybrid phenotypes with the elimination of extreme values. Additionally, intrabone relationships (eg, ultimate force vs. cortical area) were mainly conserved in our 2 populations. Overall, this work supports future use of these genetically diverse populations to discover novel genes contributing to cortical bone traits, especially at the lacunar length scale., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Several new peripheral dual-energy X-ray absorptiometry (DXA) devices designed for assessment of bone and body composition in rodents have been developed. We compared the performance (accuracy and precision) of two of these devices, the InAlyzer and the iNSiGHT, to those of an established device, the PIXImus. We measured total body bone mineral content (BMC), bone mineral density (BMD), and body composition (lean and fat mass) on the three DXA devices in 18 male C57Bl/6 J mice (6 each of ages 8, 14, and 24 weeks, weighing 22 to 33 g). DXA body composition measures were compared to whole-body nuclear magnetic resonance (NMR) outcomes. BMC of the femur was also compared to ex vivo micro-computed tomography (microCT). Total body BMD from the InAlyzer and iNSiGHT devices was strongly correlated to that from PIXImus (R 2  = 0.83 and 0.82, respectively), but was ~25 % higher than PIXImus. Total body BMC measures by InAlyzer were strongly associated with those from PIXImus (R 2  = 0.86), whereas those from iNSiGHT were only weakly correlated (R 2  = 0.29). Femur BMC from InAlyzer was strongly correlated with microCT outcomes, whereas iNSiGHT was only weakly correlated. InAlyzer and iNSiGHT fat mass measures were very strongly correlated with PIXImus and NMR outcomes (R 2  = 0.91 to 0.97), with slightly weaker associations for lean mass (R 2  = 0.81 to 0.76). Short-term precision of InAlyzer and iNSiGHT measurements were excellent, and akin to those from the PIXImus for both body composition and bone measures, ranging between 0.39 and 3.2 %. With faster scan times, closed X-ray source and excellent precision, the new devices are both satisfactory replacements for the now discontinued PIXImus system. However, given the accuracy of the bone and body composition measures, the InAlyzer may be preferable for studies where musculoskeletal changes are the main interest., Competing Interests: Declaration of competing interest The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2023. Published by Elsevier Inc.)

Astronauts have an increased risk of back pain and disc herniation upon returning to Earth. Thus, it is imperative to understand the effects of spaceflight and readaptation to gravity on the musculoskeletal tissues of the spine. Here we investigated whether ~6 months of spaceflight led to regional differences in bone loss within the vertebral body. Additionally, we evaluated the relationships between vertebral bone density and paraspinal muscle morphology before flight, after flight, and after readaptation on Earth. We measured vertebral trabecular bone mineral density (Tb.BMD), paraspinal muscle cross-sectional area (CSA), and muscle density in 17 astronauts using computed tomography (CT) images of the lumbar spine obtained before flight (before flight, n  = 17), after flight (spaceflight, n  = 17), and ~12 months of readaptation to gravitational loading on Earth (follow-up, n  = 15). Spaceflight-induced declines in Tb.BMD were greater in the superior region of the vertebral body (-6.7%) than the inferior (-3.1%, p  = 0.052 versus superior region) and transverse regions (-4.3%, p  = 0.057 versus superior region). After a year of readaptation to Earth's gravity, Tb.BMD in the transverse region remained significantly below preflight levels (-4.66%, p  = 0.0094). Paraspinal muscle CSA and muscle density declined -1.0% ( p  = 0.005) and -0.83% ( p  = 0.001) per month of spaceflight, respectively. Ultimately, bone loss in the superior vertebral body, along with fatty infiltration of paraspinal muscles and incomplete recovery even after a year of readaptation on Earth, may contribute to spinal pathology in long-duration astronauts. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

The age at which astronauts experience microgravity is a critical consideration for skeletal health and similarly has clinical relevance for musculoskeletal disuse on Earth. While astronauts are extensively studied for bone and other physiological changes, rodent studies enable direct evaluation of skeletal changes with microgravity. Yet, mouse spaceflight studies have predominately evaluated tissues from young, growing mice. We evaluated bone microarchitecture in tibiae and femurs from Young (9-week-old) and Mature (32-weeks-old) female, C57BL/6N mice flown in microgravity for ~2 and ~3 weeks, respectively. Microgravity-induced changes were both compartment- and site-specific. Changes were greater in trabecular versus cortical bone in Mature mice exposed to microgravity (-40.0% Tb. BV/TV vs -4.4% Ct. BV/TV), and bone loss was greater in the proximal tibia as compared to the distal femur. Trabecular thickness in Young mice increased by +25.0% on Earth and no significant difference following microgravity. In Mature mice exposed to microgravity, trabecular thickness rapidly decreased (-24.5%) while no change was detected in age-matched mice that were maintained on Earth. Mature mice exposed to microgravity experienced greater bone loss than Young mice with net skeletal growth. Moreover, machine learning classification models confirmed that microgravity exposure-driven decrements in trabecular microarchitecture and cortical structure occurred disproportionately in Mature than in Young mice. Our results suggest that age of disuse onset may have clinical implications in osteoporotic or other at-risk populations on Earth and may contribute to understanding bone loss patterns in astronauts., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The current standard approach for analyzing cortical bone structure and trabecular bone microarchitecture from micro-computed tomography (microCT) is through classic parametric (e.g., ANOVA, Student's T-test) and nonparametric (e.g., Mann-Whitney U test) statistical tests and the reporting of p -values to indicate significance. However, on their own, these univariate assessments of significance fall prey to a number of weaknesses, including an increased chance of Type 1 error from multiple comparisons. Machine learning classification methods (e.g., unsupervised, k-means cluster analysis and supervised Support Vector Machine classification, SVM) simultaneously utilize an entire dataset comprised of many cortical structure or trabecular microarchitecture measures, thus minimizing bias and Type 1 error that are generated through multiple testing. Through simultaneous evaluation of an entire dataset, k-means and SVM thus provide a complementary approach to classic statistical analysis and enable a more robust assessment of microCT measures., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors. Published by Elsevier B.V.)

Purpose of Review: Bone mineral density and systemic factors are used to assess skeletal health in astronauts. Yet, even in a general population, these measures fail to accurately predict when any individual will fracture. This review considers how long-duration human spaceflight requires evaluation of additional bone structural and material quality measures that contribute to microgravity-induced skeletal fragility., Recent Findings: In both humans and small animal models following spaceflight, bone mass is compromised via reduced bone formation and elevated resorption levels. Concurrently, bone structural quality (e.g., trabecular microarchitecture) is diminished and the quality of bone material is reduced via impaired tissue mineralization, maturation, and maintenance (e.g., mediated by osteocytes). Bone structural and material quality are both affected by microgravity and may, together, jeopardize astronaut operational readiness and lead to increased fracture risk upon return to gravitational loading. Future studies need to directly evaluate how bone quality combines with diminished bone mass to influence bone strength and toughness (e.g., resistance to fracture). Bone quality assessment promises to identify novel biomarkers and therapeutic targets.

Bone fragility fractures are caused by low bone mass or impaired bone quality. Osteoblast/osteoclast coordination determines bone mass, but the factors that control bone quality are poorly understood. Osteocytes regulate osteoblast and osteoclast activity on bone surfaces but can also directly reorganize the bone matrix to improve bone quality through perilacunar/canalicular remodeling; however, the molecular mechanisms remain unclear. We previously found that deleting the transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-motif (TAZ) from osteoblast-lineage cells caused lethality in mice due to skeletal fragility. Here, we tested the hypothesis that YAP and TAZ regulate osteocyte-mediated bone remodeling by conditional ablation of both YAP and TAZ from mouse osteocytes using 8 kb-DMP1-Cre. Osteocyte-conditional YAP/TAZ deletion reduced bone mass and dysregulated matrix collagen content and organization, which together decreased bone mechanical properties. Further, YAP/TAZ deletion impaired osteocyte perilacunar/canalicular remodeling by reducing canalicular network density, length, and branching, as well as perilacunar flourochrome-labeled mineral deposition. Consistent with recent studies identifying TGF-β as a key inducer of osteocyte expression of matrix-remodeling enzymes, YAP/TAZ deletion in vivo decreased osteocyte expression of matrix proteases MMP13, MMP14, and CTSK. In vitro, pharmacologic inhibition of YAP/TAZ transcriptional activity in osteocyte-like cells abrogated TGF-β-induced matrix protease gene expression. Together, these data show that YAP and TAZ control bone matrix accrual, organization, and mechanical properties by regulating osteocyte-mediated bone remodeling. Elucidating the signaling pathways that control perilacunar/canalicular remodeling may enable future therapeutic targeting of bone quality to reverse skeletal fragility. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

As it is getting increasingly difficult to achieve gains in the density and power efficiency of microelectronic computing devices because of lithographic techniques reaching fundamental physical limits, new approaches are required to maximize the benefits of distributed sensors, micro-robots or smart materials. Biologically-inspired devices, such as artificial neural networks, can process information with a high level of parallelism to efficiently solve difficult problems, even when implemented using conventional microelectronic technologies. We describe a mechanical device, which operates in a manner similar to artificial neural networks, to solve efficiently two difficult benchmark problems (computing the parity of a bit stream, and classifying spoken words). The device consists in a network of masses coupled by linear springs and attached to a substrate by non-linear springs, thus forming a network of anharmonic oscillators. As the masses can directly couple to forces applied on the device, this approach combines sensing and computing functions in a single power-efficient device with compact dimensions.