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For prostate cancer patients who experience biochemical progression during androgen deprivation therapy (ADT), prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) has not been prospectively compared to planar bone scan plus CT. This was a single-arm, head-to-head, prospective phase II trial (NCT04928820) designed to enroll 102 men with prostate cancer who experienced biochemical progression (rising prostate-specific antigen [PSA] ≥ 1 ng/mL) during ADT. All patients received 68Ga-PSMA-11 PET/CT and 99mTc-MDP planar bone scans. Each scan was interpreted by three central independent readers. The primary endpoint was the per-patient bone metastasis detection rate of PSMA PET/CT versus planar bone scan and CT. Secondary endpoints compared the number of bone metastases detected per patient and the inter-reader agreement of each imaging modality. Twenty-two men were enrolled between July 2021 and June 2022. Due to slow accrual following approval of PSMA PET radiotracers in the U.S. and a lack of a statistical signal between the two imaging modalities on interim analysis, this trial was closed early on October 2022. Median PSA was 8.5 ng/mL (interquartile range: 1.6-77.6). There was 100% agreement between the two scans. Six patients (27%) had negative findings and 16 patients (73%) had positive findings on both scans. PSMA PET/CT and bone scan plus CT detected an equal number of bone lesions for 14 patients (64%), PSMA PET/CT detected more bone lesions for six patients (27%), and bone scan plus CT detected more bone lesions for two patients (9.1%) (p = 0.092). The inter-reader agreement rates of PSMA PET/CT and bone scan plus CT were 96% and 82%, respectively (p = 0.25). In men with biochemical progression during ADT, 68Ga-PSMA-11 PET/CT and 99mTc-MDP planar bone scan plus CT had identical bone metastasis detection rates. Bone scan plus CT can continue to serve as a cost-effective and readily accessible restaging modality in patients with biochemical progression. ClinicalTrials.gov NCT04928820. Registered 16/06/2021.

Stable isotope analysis of bone provides insight into animal foraging and allows for ecological reconstructions over time, however pre-treatment is required to isolate collagen. Pre-treatments typically consist of demineralization to remove inorganic components and/or lipid extraction to remove fats, but these protocols can differentially affect stable carbon (δ13C) and nitrogen (δ15N) isotope values depending on the chemicals, tissues, and/or species involved. Species-specific methodologies create a standard for comparability across studies and enhance understanding of collagen isolation from modern cetacean bone. Elemental analyzers coupled to isotope ratio mass spectrometers were used to measure the δ13C and δ15N values of powdered killer whale (Orcinus orca) bone that was intact (control) or subjected to one of three experimental conditions: demineralized, lipid-extracted, and both demineralized and lipid-extracted. Additionally, C:N ratios were evaluated as a proxy for collagen purity. Lastly, correlations were examined between control C:N ratios vs. historical age and control C:N ratios vs. sample characteristics. No significant differences in the δ15N values were observed for any of the experimental protocols. However, the δ13C values were significantly increased by all three experimental protocols: demineralization, lipid extraction, and both treatments combined. The most influential protocol was both demineralization and lipid extraction. Measures of the C:N ratios were also significantly lowered by demineralization and both treatments combined, indicating the material was closer to pure collagen after the treatments. Collagen purity as indicated via C:N ratio was not correlated with historical age nor sample characteristics. If only the δ15N values from killer whale bone are of interest for analysis, no pre-treatment seems necessary. If the δ13C values are of interest, samples should be both demineralized and lipid-extracted. As historical age and specimen characteristics are not correlated with sample contamination, all samples can be treated equally.

In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.

PURPOSE: To investigate the feasibility and application of a novel imaging technique, a three-dimensional dual adiabatic inversion recovery prepared ultrashort echo time (3D DIR-UTE) sequence, for high contrast assessment of cartilaginous endplate (CEP) imaging with head-to-head comparisons between other UTE imaging techniques. METHOD: The DIR-UTE sequence employs two narrow-band adiabatic full passage (AFP) pulses to suppress signals from long T2 water (e.g., nucleus pulposus (NP)) and bone marrow fat (BMF) independently, followed by multispoke UTE acquisition to detect signals from the CEP with short T2 relaxation times. The DIR-UTE sequence, in addition to three other UTE sequences namely, an IR-prepared and fat-saturated UTE (IR-FS-UTE), a T1-weighted and fat-saturated UTE sequence (T1w-FS-UTE), and a fat-saturated UTE (FS-UTE) was used for MR imaging on a 3 T scanner to image six asymptomatic volunteers, six patients with low back pain, as well as a human cadaveric specimen. The contrast-to-noise ratio of the CEP relative to the adjacent structures-specifically the NP and BMF-was then compared from the acquired images across the different UTE sequences. RESULTS: For asymptomatic volunteers, the DIR-UTE sequence showed significantly higher contrast-to-noise ratio values between the CEP and BMF (CNRCEP-BMF) (19.9 ± 3.0) and between the CEP and NP (CNRCEP-NP) (23.1 ± 1.7) compared to IR-FS-UTE (CNRCEP-BMF: 17.3 ± 1.2 and CNRCEP-NP: 19.1 ± 1.8), T1w-FS-UTE (CNRCEP-BMF: 9.0 ± 2.7 and CNRCEP-NP: 10.4 ± 3.5), and FS-UTE (CNRCEP-BMF: 7.7 ± 2.2 and CNRCEP-NP: 5.8 ± 2.4) for asymptomatic volunteers (all P-values

This paper reports a high-resolution isotopic study of medieval horse mobility, revealing their origins and in-life mobility both regionally and internationally. The animals were found in an unusual horse cemetery site found within the City of Westminster, London, England. Enamel strontium, oxygen, and carbon isotope analysis of 15 individuals provides information about likely place of birth, diet, and mobility during the first approximately 5 years of life. Results show that at least seven horses originated outside of Britain in relatively cold climates, potentially in Scandinavia or the Western Alps. Ancient DNA sexing data indicate no consistent sex-specific mobility patterning, although three of the five females came from exceptionally highly radiogenic regions. Another female with low mobility is suggested to be a sedentary broodmare. Our results provide direct and unprecedented evidence for a variety of horse movement and trading practices in the Middle Ages and highlight the importance of international trade in securing high-quality horses for medieval London elites.

Magnetic resonance imaging (MRI) is increasingly used to evaluate the microstructural and compositional properties of bone. MRI-based biomarkers can characterize all major compartments of bone: organic, water, fat, and mineral components. However, with a short apparent spin-spin relaxation time (T2*), bone is invisible to conventional MRI sequences that use long echo times. To address this shortcoming, ultrashort echo time MRI sequences have been developed to provide direct imaging of bone and establish a set of MRI-based biomarkers sensitive to the structural and compositional changes of bone. This review article describes the MRI-based bone biomarkers representing total water, pore water, bound water, fat fraction, macromolecular fraction in the organic matrix, and surrogates for mineral density. MRI-based morphological bone imaging techniques are also briefly described.

BackgroundWe investigated the relationship of two commonly used quantitative ultrasound (QUS) parameters, speed of sound (SoS) and attenuation coefficient (α), with water and macromolecular contents of bovine cortical bone strips as measured with ultrashort echo time (UTE) magnetic resonance imaging (MRI).MethodsSoS and α were measured in 36 bovine cortical bone strips utilizing a single-element transducer with nominal 5 MHz center frequency based on the time of flight principles after accommodating for reflection losses. Specimens were then scanned using UTE MRI to measure total, bound, and pore water proton density (TWPD, BWPD, and PWPD) as well as macromolecular proton fraction and macromolecular transverse relaxation time (T2-MM). Specimens were also scanned using microcomputed tomography (μCT) at 9-μm isometric voxel size to measure bone mineral density (BMD), porosity, and pore size. The elastic modulus (E) of each specimen was measured using a 4-point bending test.Resultsα demonstrated significant positive Spearman correlations with E (R = 0.69) and BMD (R = 0.44) while showing significant negative correlations with porosity (R = -0.41), T2-MM (R = -0.47), TWPD (R = -0.68), BWPD (R = -0.67), and PWPD (R = -0.45).ConclusionsThe negative correlation between α and T2-MM is likely indicating the relationship between QUS and collagen matrix organization. The higher correlations of α with BWPD than with PWPD may indicate that water organized in finer structure (bound to matrix) provides lower acoustic impedance than water in larger pores, which is yet to be investigated thoroughly.Relevance statementThis study highlights the importance of future investigations exploring the relationship between QUS measures and all major components of the bone, including the collagenous matrix and water. Investigating the full potential of QUS and its validation facilitates a more affordable and accessible tool for bone health monitoring in clinics.Key points• Ultrasound attenuation demonstrated significant positive correlations with bone mechanics and mineral density. • Ultrasound attenuation demonstrated significant negative correlations with porosity and bone water contents. • This study highlights the importance of future investigations exploring the relationship between QUS measures and all major components of the bone.

How will the scientific community and authoritative bodies define future nutritional requirements for vitamin D? At the International Symposium on Nutritional Aspects of Musculoskeletal Health, the authors debated the strength of current evidence for setting vitamin D intake recommendations from diet: the positive side of the strength of the evidence (PRO) suggests there is a physiological requirement for vitamin D and the opposing view (CON) that in light of negative results from large, recent trials, particularly those with fractures and bone health outcomes, we are left rudderless. Should we provide recommendations based on empiric treatment of vitamin D for most groups and conditions? It is becoming increasingly evident that vitamin D plays a role in many physiological functions and processes associated with long-term human health; however, to what extent are these benefits apparent beyond what is needed for adequate nutritional status, measured as serum 25-hydroxyvitamin D levels, for active calcium absorption? The meeting attendees voted for the PRO vs. CON position at the end of the session. [ABSTRACT FROM AUTHOR]

Exercise has numerous health benefits in patients with autoimmune inflammatory rheumatic diseases (AIRDs). Regular physical activity can help maintain/improve bone health. The aim of the present article was to review current knowledge on the effects of exercise on bone health in patients with AIRDs, particularly in those experiencing a high corticosteroid burden. The article also aimed to discuss potential mechanisms underlying the benefits of physical activity/exercise on bone tissue. Potential explanations regarding the role of exercise on bone health in AIRDs include anti‐inflammatory effects, mechanical loading, improvement in muscle strength, hormonal changes, improvement in balance, and effects on telomere erosion, deoxyribonucleic acid methylation, and gene expression. Current evidence regarding the outcomes of exercise on bone health in patients with AIRDs is predominantly derived from studies focused on rheumatoid arthritis. Expanding research to include other rheumatic conditions would enhance the overall understanding of this topic. [ABSTRACT FROM AUTHOR]

PURPOSE OF REVIEW: The purpose of this review is to summarize current approaches and provide recommendations for imaging bone in pediatric populations using high-resolution peripheral quantitative computed tomography (HR-pQCT). RECENT FINDINGS: Imaging the growing skeleton is challenging and HR-pQCT protocols are not standardized across centers. Adopting a single-imaging protocol for all studies is unrealistic; thus, we present three established protocols for HR-pQCT imaging in children and adolescents and share advantages and disadvantages of each. Limiting protocol variation will enhance the uniformity of results and increase our ability to compare study results between different research groups. We outline special cases along with tips and tricks for acquiring and processing scans to minimize motion artifacts and account for growing bone. The recommendations in this review are intended to help researchers perform HR-pQCT imaging in pediatric populations and extend our collective knowledge of bone structure, architecture, and strength during the growing years.

Aneurysmal bone cyst (ABC) is a rare and usually painful condition, representing about 1% of all bone tumors. A geographical lytic, expansile, and septated radiological pattern, with fluid–fluid levels on MRI, is classically displayed. ABC can be a primary bone lesion (70% of patients) or can arise in an underlying condition and is subsequently named "ABC-like changes" (30%). ABC-like changes are more frequently encountered in skeletal segments affected by chondroblastoma, fibrous dysplasia, giant cell tumor, osteoblastoma, non-ossifying fibroma, and osteosarcoma. In this article, we describe the first case of ABC-like changes developed in association with an ultra-rare sclerosing bone disease: melorheostosis. Melorheostosis is characterized by recognizable patterns on radiological studies with a pathological increased bone density and a cortical thickening within the periosteal or endosteal space, usually with a "dripping candle wax" appearance. More rarely, other different radiological patterns can be observed, such as "osteopatia striata-like," "osteoma-like," "myositis ossificans-like," and mixed patterns. Pain and limb hypotrophy are the most common clinical manifestations. We report the case of a Caucasian male with a clinic-radiological diagnosis of melorheostosis (with epiphyseal osteopoikilosis) since the age of twelve. At the age of nineteen, he suffered from increased pain in the proximal right thigh, and the radiological control revealed an expansive septated lesion at the right proximal femoral bone. The diagnosis of ABC-like changes developed in melorheostosis was obtained after CT-guided bone biopsy and confirmed by open-incisional biopsy. [ABSTRACT FROM AUTHOR]

Many hand surgeons treat benign bone tumors without referral to orthopedic oncologists. However, there have been considerable advances in medical therapy for some of these tumors, with which hand surgeons may not be as familiar. This review focuses on the mechanism and uses of denosumab in the treatment of benign tumors of bone. Although the hand surgeon may not be directly prescribing this therapy, they are often the only physician treating the patient for these conditions. As such, awareness regarding the use of this therapy in reducing pain, decreasing tumor volume, and treatment of potential lung metastases is critical to those taking on these cases without the support of an orthopedic oncologist. This article aims to familiarize hand surgeons with denosumab to help promote knowledge of this therapeutic option and the potential role of this medication in the treatment of primary bone tumors in the hand.

Prostate cancer (PCa) is an increasingly prevalent health problem in the developed world. Effective treatment options exist for localized PCa, but metastatic PCa has fewer treatment options and shorter patient survival. PCa and bone health are strongly entwined, as PCa commonly metastasizes to the skeleton. Since androgen receptor signaling drives PCa growth, androgen-deprivation therapy whose sequelae reduce bone strength constitutes the foundation of advanced PCa treatment. The homeostatic process of bone remodeling - produced by concerted actions of bone-building osteoblasts, bone-resorbing osteoclasts, and regulatory osteocytes - may also be subverted by PCa to promote metastatic growth. Mechanisms driving skeletal development and homeostasis, such as regional hypoxia or matrix-embedded growth factors, may be subjugated by bone metastatic PCa. In this way, the biology that sustains bone is integrated into adaptive mechanisms for the growth and survival of PCa in bone. Skeletally metastatic PCa is difficult to investigate due to the entwined nature of bone biology and cancer biology. Herein, we survey PCa from origin, presentation, and clinical treatment to bone composition and structure and molecular mediators of PCa metastasis to bone. Our intent is to quickly yet effectively reduce barriers to team science across multiple disciplines that focuses on PCa and metastatic bone disease. We also introduce concepts of tissue engineering as a novel perspective to model, capture, and study complex cancer-microenvironment interactions.

Purpose of reviewThe relationships between bone vasculature and bone microstructure and strength remain incompletely understood. Addressing this gap will require in vivo imaging capabilities. We describe the relevant vascular anatomy of compact bone, review current magnetic resonance imaging (MRI)-based techniques that allow in vivo assessment of intracortical vasculature, and finally present preliminary studies that apply these techniques to investigate changes in intracortical vessels in aging and disease.Recent findingsUltra-short echo time MRI (UTE MRI), dynamic contrast-enhanced MRI (DCE-MRI), and susceptibility-weighted MRI techniques are able to probe intracortical vasculature. Applied to patients with type 2 diabetes, DCE-MRI was able to find significantly larger intracortical vessels compared to nondiabetic controls. Using the same technique, a significantly larger number of smaller vessels was observed in patients with microvascular disease compared to those without. Preliminary data on perfusion MRI showed decreased cortical perfusion with age.SummaryDevelopment of in vivo techniques for intracortical vessel visualization and characterization will enable the exploration of interactions between the vascular and skeletal systems, and further our understanding of drivers of cortical pore expansion. As we investigate potential pathways of cortical pore expansion, appropriate treatment and prevention strategies will be clarified.

Birds use their legs and wings when transitioning from aerial to ground locomotion during landing. To improve our understanding of the effects of footpad dermatitis (FPD) and keel bone fracture (KBF) upon landing biomechanics in laying hens, we measured ground-reaction forces generated by hens (n = 37) as they landed on force plates (Bertec Corporation, Columbus, OH) from a 30 cm drop or 170 cm jump in a single-blinded placebo-controlled trial using a cross-over design where birds received an anti-inflammatory (meloxicam, 5 mg/kg body mass) or placebo treatment beforehand. We used generalized linear mixed models to test for effects of health status, treatment and their interaction on landing velocity (m/s), maximum resultant force (N), and impulse (force integrated with respect to time [N s]). Birds with FPD and KBF tended to show divergent alterations to their landing biomechanics when landing from a 30 cm drop, with a higher landing velocity and maximum force in KBF compared to FPD birds, potentially indicative of efforts to either reduce the use of their wings or impacts on inflamed footpads. In contrast, at 170 cm jumps fewer differences between birds of different health statuses were observed likely due to laying hens being poor flyers already at their maximum power output. Our results indicate that orthopedic injuries, apart from being welfare issues on their own, may have subtle influences on bird mobility through altered landing biomechanics that should be considered.

Human skeletal stem cells (hSSCs) hold tremendous therapeutic potential for developing new clinical strategies to effectively combat congenital and age-related musculoskeletal disorders. Unfortunately, refined methodologies for the proper isolation of bona fide hSSCs and the development of functional assays that accurately recapitulate their physiology within the skeleton have been lacking. Bone marrow-derived mesenchymal stromal cells (BMSCs), commonly used to describe the source of precursors for osteoblasts, chondrocytes, adipocytes and stroma, have held great promise as the basis of various approaches for cell therapy. However, the reproducibility and clinical efficacy of these attempts have been obscured by the heterogeneous nature of BMSCs due to their isolation by plastic adherence techniques. To address these limitations, our group has refined the purity of individual progenitor populations that are encompassed by BMSCs by identifying defined populations of bona fide hSSCs and their downstream progenitors that strictly give rise to skeletally restricted cell lineages. Here, we describe an advanced flow cytometric approach that utilizes an extensive panel of eight cell surface markers to define hSSCs; bone, cartilage and stromal progenitors; and more differentiated unipotent subtypes, including an osteogenic subset and three chondroprogenitors. We provide detailed instructions for the FACS-based isolation of hSSCs from various tissue sources, in vitro and in vivo skeletogenic functional assays, human xenograft mouse models and single-cell RNA sequencing analysis. This application of hSSC isolation can be performed by any researcher with basic skills in biology and flow cytometry within 1-2 days. The downstream functional assays can be performed within a range of 1-2 months.

Normal bone remodeling depends of a balance between bone forming cells, osteoblasts and bone resorbing cells, the osteoclasts. In chronic arthritides and some inflammatory and autoimmune diseases such as rheumatoid arthritis, there is a great constellation of cytokines produced by pannus that impair bone formation and stimulate bone resorption by inducing osteoclast differentiation and inhibiting osteoblast maturation. Patients with chronic inflammation have multiple causes that lead to low bone mineral density, osteoporosis and a high risk of fracture including circulating cytokines, impaired mobility, chronic administration of glucocorticoids, low vitamin D levels and post-menopausal status in women, among others. Biologic agents and other therapeutic measures to reach prompt remission might ameliorate these deleterious effects. In many cases, bone acting agents need to be added to conventional treatment to reduce the risk of fractures and to preserve articular integrity and independency for daily living activities. A limited number of studies related to fractures in chronic arthritides were published, and future investigation is needed to determine the risk of fractures and the protective effects of different treatments to reduce this risk.

Estradiol (E2) affects both reproductive and non-reproductive tissues, and the sensitivity to different doses of E2 varies between tissues. Membrane estrogen receptor α (mERα)-initiated signaling plays a tissue-specific role in mediating E2 effects, however, it is unclear if mERα signaling modulates E2 sensitivity. To determine this, we treated ovariectomized C451A females, lacking mERα signaling, and wildtype (WT) littermates with physiological (0.05 μg/mouse/day (low); 0.6 μg/mouse/day (medium)) or supraphysiological (6 μg/mouse/day (high)) doses of E2 (17β-estradiol-3-benzoate) for three weeks. Low-dose treatment increased uterus weight in WT, but not C451A mice, while non-reproductive tissues (gonadal fat, thymus, trabecular and cortical bone) were unaffected in both genotypes. Medium-dose treatment increased uterus weight and bone mass and decreased thymus and gonadal fat weights in WT mice. Uterus weight was also increased in C451A mice, but the response was significantly attenuated (- 85%) compared to WT mice, and no effects were triggered in non-reproductive tissues. High-dose treatment effects in thymus and trabecular bone were significantly blunted (- 34% and - 64%, respectively) in C451A compared to WT mice, and responses in cortical bone and gonadal fat were similar between genotypes. Interestingly, the high dose effect in uterus was enhanced (+ 26%) in C451A compared to WT mice. In conclusion, loss of mERα signaling reduces the sensitivity to physiological E2 treatment in both non-reproductive tissues and uterus. Furthermore, the E2 effect after high-dose treatment in uterus is enhanced in the absence of mERα, suggesting a protective effect of mERα signaling in this tissue against supraphysiological E2 levels.

Osteoporosis is the most common metabolic bone disease. With special respect to the aging population, it is very common, not only due to changes in lifestyle and diet but as a result of the aging process there is low-grade inflammation and immune system activation that directly affects bone strength and quality. This article provides a review of the incidence, etiology, and approach to screening and management of osteoporosis in the aging population. A thorough screening of lifestyle, environmental, and clinical conditions will be reviewed which identifies appropriate candidates for screening and treatment.

The development of Wnt-based osteoanabolic agents has progressed rapidly in recent years, given the potent effects of Wnt modulation on bone homeostasis. Simultaneous pharmacologic inhibition of the Wnt antagonists sclerostin and Dkk1 can be optimized to create potentiated effects in the cancellous bone compartment. We looked for other candidates that might be co-inhibited along with sclerostin to potentiate the effects in the cortical compartment. Sostdc1 (Wise), like sclerostin and Dkk1, also binds and inhibits Lrp5/6 coreceptors to impair canonical Wnt signaling, but Sostdc1 has greater effects in the cortical bone. To test this concept, we deleted Sostdc1 and Sost from mice and measured the skeletal effects in cortical and cancellous compartments individually. Sost deletion alone produced high bone mass in all compartments, whereas Sostdc1 deletion alone had no measurable effects on either envelope. Mice with codeletion of Sostdc1 and Sost had high bone mass and increased cortical properties (bone mass, formation rates, mechanical properties), but only among males. Combined administration of sclerostin antibody and Sostdc1 antibody in wild-type female mice produced potentiation of cortical bone gain despite no effect of Sostdc1 antibody alone. In conclusion, Sostdc1 inhibition/deletion can work in concert with sclerostin deficiency to improve cortical bone properties. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Patients with bone metastases may experience debilitating pain, neurological conditions, increased risk of pathological fractures, and death. A deeper understanding of the bone microenvironment, the molecular biology of cancer types prone to metastasis, and how bone physiology promotes cancer growth, may help to uncover targeted treatment options. The purpose of this paper is to outline the current concepts relevant to topics including bone remodeling, angiogenesis, and immunomodulation as it relates to metastatic bone disease.

Ultrashort echo time (UTE) MRI can image and consequently enable quantitative assessment of cortical bone. UTE-MRI-based evaluation of bone is largely underutilized due to the high cost and time demands of MRI in general. The signal ratio in dual-echo UTE imaging, known as porosity index (PI), as well as the signal ratio between UTE and inversion recovery UTE (IR-UTE) imaging, known as the suppression ratio (SR), are two rapid UTE-based bone evaluation techniques (∼ 5 mins scan time each), which can potentially reduce the time demand and cost in future clinical studies. This study aimed to investigate the correlations of PI and SR measures with cortical bone microstructural and mechanical properties. Cortical bone strips (n = 135) from tibial and femoral midshafts of 37 donors (61 ± 24 years old) were scanned using a dual-echo 3D Cones UTE sequence and a 3D Cones IR-UTE sequence for PI and SR calculations, respectively. Average bone mineral density, porosity, and pore size were measured using microcomputed tomography (μCT). Bone mechanical properties were measured using 4-point bending tests. The μCT measures showed significant correlations with PI (moderate to strong, R = 0.68-0.71) and SR (moderate, R = 0.58-0.68). Young's modulus, yield stress, and ultimate stress demonstrated significant moderate correlations with PI and SR (R = 0.52-0.62) while significant strong correlations with μCT measures (R > 0.7). PI and SR can potentially serve as fast and noninvasive (non-ionizing radiation) biomarkers for evaluating cortical bone in various bone diseases.

BACKGROUND: Although T1ρ and T2 have emerged as early indicators for hip osteoarthritis (OA), there is little information regarding longitudinal changes across the cartilage in the early stages of this disease. PURPOSE: To characterize the variability in 2-year hip cartilage T1ρ and T2 changes and investigate associations between these patterns of change and common indicators of hip OA. STUDY TYPE: Prospective. POPULATION: A total of 25 women (age: 51.9 ± 16.3 years old; BMI: 22.6 ± 2.0 kg/m2 ) and 17 men (age: 55.8 ± 14.9 years old; body mass index (BMI): 24.4 ± 3.8 kg/m2 ) who were healthy or with early-to-moderate hip OA. FIELD STRENGTH/SEQUENCE: A 3 T MRI (GE), 3D combined T1ρ /T2 magnetization-prepared angle-modulated partitioned k-space spoiled gradient echo snapshots. ASSESSMENT: Principal component (PC) analysis of Z-score difference maps of 2-year changes in hip cartilage T1ρ and T2 relaxation times, participant hip disability and osteoarthritis outcome scores (HOOS) and functional tests at 2-year follow-up. STATISTICAL TESTS: Shapiro-Wilk test, unpaired t-tests, Kruskal Wallis tests, Pearson or Spearman (ρ) correlations. Significance was set at P

Extracellular vesicles have received a great interest as safe biocarriers in biomedical engineering. There is a need to develop more efficient delivery strategies to improve localized therapeutic efficacy and minimize off-target adverse effects. Here, exosome mimetics (EMs) are reported for bone targeting involving the introduction of hydroxyapatite-binding moieties through bioorthogonal functionalization. Bone-binding ability of the engineered EMs is verified with hydroxyapatite-coated scaffolds and an ex vivo bone-binding assay. The EM-bound construct provided a biocompatible substrate for cell adhesion, proliferation, and osteogenic differentiation. Particularly, the incorporation of Smoothened agonist (SAG) into EMs greatly increased the osteogenic capacity through the activation of hedgehog signaling. Furthermore, the scaffold integrated with EM/SAG significantly improved in vivo reossification. Lastly, biodistribution studies confirmed the accumulation of systemically administered EMs in bone tissue. This facile engineering strategy could be a versatile tool to promote bone regeneration, offering a promising nanomedicine approach to the sophisticated treatment of bone diseases.

Zebrafish (Danio rerio) are aquatic vertebrates with significant homology to their terrestrial counterparts. While zebrafish have a centuries-long track record in developmental and regenerative biology, their utility has grown exponentially with the onset of modern genetics. This is exemplified in studies focused on skeletal development and repair. Herein, the numerous contributions of zebrafish to our understanding of the basic science of cartilage, bone, tendon/ligament, and other skeletal tissues are described, with a particular focus on applications to development and regeneration. We summarize the genetic strengths that have made the zebrafish a powerful model to understand skeletal biology. We also highlight the large body of existing tools and techniques available to understand skeletal development and repair in the zebrafish and introduce emerging methods that will aid in novel discoveries in skeletal biology. Finally, we review the unique contributions of zebrafish to our understanding of regeneration and highlight diverse routes of repair in different contexts of injury. We conclude that zebrafish will continue to fill a niche of increasing breadth and depth in the study of basic cellular mechanisms of skeletal biology.

Obtaining frozen sections of bone tissue for intraoperative examination is challenging. To identify the bony edge of resection, orthopaedic oncologists therefore rely on pre-operative X-ray computed tomography or magnetic resonance imaging. However, these techniques do not allow for accurate diagnosis or for intraoperative confirmation of the tumour margins, and in bony sarcomas, they can lead to bone margins up to 10-fold wider (1,000-fold volumetrically) than necessary. Here, we show that real-time three-dimensional contour-scanning of tissue via ultraviolet photoacoustic microscopy in reflection mode can be used to intraoperatively evaluate undecalcified and decalcified thick bone specimens, without the need for tissue sectioning. We validate the technique with gold-standard haematoxylin-and-eosin histology images acquired via a traditional optical microscope, and also show that an unsupervised generative adversarial network can virtually stain the ultraviolet-photoacoustic-microscopy images, allowing pathologists to readily identify cancerous features. Label-free and slide-free histology via ultraviolet photoacoustic microscopy may allow for rapid diagnoses of bone-tissue pathologies and aid the intraoperative determination of tumour margins.

Mechanical unloading causes rapid loss of bone structure and strength, which gradually recovers after resuming normal loading. However, it is not well established how this adaptation to unloading and reloading changes with age. Clinically, elderly patients are more prone to musculoskeletal injury and longer periods of bedrest, therefore it is important to understand how periods of disuse will affect overall skeletal health of aged subjects. Bone also undergoes an age-related decrease in osteocyte density, which may impair mechanoresponsiveness. In this study, we examined bone adaptation during unloading and subsequent reloading in mice. Specifically, we examined the differences in bone adaptation between young mice (3-month-old), old mice (18-month-old), and transgenic mice that exhibit diminished osteocyte density at a young age (3-month-old BCL-2 transgenic mice). Mice underwent 14 days of hindlimb unloading followed by up to 14 days of reloading. We analyzed trabecular and cortical bone structure in the femur, mechanical properties of the femoral cortical diaphysis, osteocyte density and cell death in cortical bone, and serum levels of inflammatory cytokines. We found that young mice lost ~10% cortical bone volume and 27-42% trabecular bone volume during unloading and early reloading, with modest recovery of metaphyseal trabecular bone and near total recovery of epiphyseal trabecular bone, but no recovery of cortical bone after 14 days of reloading. Old mice lost 12-14% cortical bone volume and 35-50% trabecular bone volume during unloading and early reloading but had diminished recovery of trabecular bone during reloading and no recovery of cortical bone. In BCL-2 transgenic mice, no cortical bone loss was observed during unloading or reloading, but 28-31% trabecular bone loss occurred during unloading and early reloading, with little to no recovery during reloading. No significant differences in circulating inflammatory cytokine levels were observed due to unloading and reloading in any of the experimental groups. These results illustrate important differences in bone adaptation in older and osteocyte deficient mice, suggesting a possible period of vulnerability in skeletal health in older subjects during and following a period of disuse that may affect skeletal health in elderly patients.

We previously showed that the NO/cGMP/protein kinase G (PKG) signaling pathway positively regulates osteoblast proliferation, differentiation, and survival in vitro, and that cGMP-elevating agents have bone-anabolic effects in mice. Here, we generated mice with an osteoblast-specific (OB) knockout (KO) of type 2 PKG (gene name Prkg2) using a Col1a1(2.3 kb)-Cre driver. Compared to wild type (WT) littermates, 8-week-old male OB Prkg2-KO mice had fewer osteoblasts, reduced bone formation rates, and lower trabecular and cortical bone volumes. Female OB Prkg2-KO littermates showed no bone abnormalities, despite the same degree of PKG2 deficiency in bone. Expression of osteoblast differentiation- and Wnt/β-catenin-related genes was lower in primary osteoblasts and bones of male KO but not female KO mice compared to WT littermates. Osteoclast parameters were unaffected in both sexes. Since PKG2 is part of a mechano-sensitive complex in osteoblast membranes, we examined its role during mechanical loading. Cyclical compression of the tibia increased cortical thickness and induced mechanosensitive and Wnt/β-catenin-related genes to a similar extent in male and female WT mice and female OB Prkg2-KO mice, but loading had a minimal effect in male KO mice. We conclude that PKG2 drives bone acquisition and adaptation to mechanical loading via the Wnt/β-catenin pathway in male mice. The striking sexual dimorphism of OB Prkg2-KO mice suggests that current U.S. Food and Drug Administration-approved cGMP-elevating agents may represent novel effective treatment options for male osteoporosis. © 2022 American Society for Bone and Mineral Research (ASBMR).

While formation and regeneration of the skeleton have been studied for a long period of time, significant scientific advances in this field continue to emerge based on an unmet clinical need to improve options to promote bone repair. In this review, we discuss the relationship between mechanisms of bone formation and bone regeneration. Data clearly show that regeneration is not simply a reinduction of the molecular and cellular programs that were used for development. Instead, the mechanical environment exerts a strong influence on the mode of repair, while during development, cell-intrinsic processes drive the mode of skeletal formation. A major advance in the field has shown that cell fate is flexible, rather than terminal, and that chondrocytes are able to differentiate into osteoblasts and other cell types during development and regeneration. This is discussed in a larger context of regeneration in vertebrates as well as the clinical implication that this shift in understanding presents.

IntroductionUltrashort echo time (UTE) MRI enables quantitative assessment of cortical bone. The signal ratio in dual-echo UTE imaging, known as porosity index (PI), as well as the signal ratio between UTE and inversion recovery UTE (IR-UTE) imaging, known as the suppression ratio (SR), are two rapid UTE-based bone evaluation techniques developed to reduce the time demand and cost in future clinical studies. The goal of this study was to investigate the performance of PI and SR in detecting bone quality differences between subjects with osteoporosis (OPo), osteopenia (OPe), and normal bone (Normal).MethodsTibial midshaft of fourteen OPe (72 ± 6 years old), thirty-one OPo (72 ± 6 years old), and thirty-seven Normal (36 ± 19 years old) subjects were scanned using dual-echo UTE and IR-UTE sequences on a clinical 3T scanner. Measured PI, SR, and bone thickness were compared between OPo, OPe, and normal bone (Normal) subjects using the Kruskal-Wallis test by ranks. Spearman's rank correlation coefficients were calculated between dual-energy x-ray absorptiometry (DEXA) T-score and UTE-MRI results.ResultsPI was significantly higher in the OPo group compared with the Normal (24.1%) and OPe (16.3%) groups. SR was significantly higher in the OPo group compared with the Normal (41.5%) and OPe (21.8%) groups. SR differences between the OPe and Normal groups were also statistically significant (16.2%). Cortical bone was significantly thinner in the OPo group compared with the Normal (22.0%) and OPe (13.0%) groups. DEXA T-scores in subjects were significantly correlated with PI (R=-0.32), SR (R=-0.50), and bone thickness (R=0.51).DiscussionPI and SR, as rapid UTE-MRI-based techniques, may be useful tools to detect and monitor bone quality changes, in addition to bone morphology, in individuals affected by osteoporosis.

Focal bone lesions are often found prior to clinically relevant stress-fractures. Lesions are characterized by low bone volume fraction, low mineral density, and high levels of microdamage and are hypothesized to develop when bone tissue cannot sufficiently respond to damaging loading. It is difficult to determine how exercise drives the formation of these lesions because bone responds to mechanical loading and repairs damage. In this study, we derive steady-state rate constants for a compartment model of bone turnover using morphometric data from fractured and non-fractured racehorse proximal sesamoid bones (PSBs) and relate rate constants to racing-speed exercise data. Fractured PSBs had a subchondral focus of bone turnover and microdamage typical of lesions that develop prior to fracture. We determined steady-state model rate constants at the lesion site and an internal region without microdamage using bone volume fraction, tissue mineral density, and microdamage area fraction measurements. The derived undamaged bone resorption rate, damage formation rate, and osteoid formation rate had significant robust regression relationships to exercise intensity (rate) variables, layup (time out of exercise), and exercise 2-10 months before death. However, the direction of these relationships varied between the damaged (lesion) and non-damaged regions, reflecting that the biological response to damaging-loading differs from the response to non-damaging loading.

Phosphorus is an essential micromineral with a key role in cellular metabolism and tissue structure. Serum phosphorus is maintained in a homeostatic range by the intestines, bones, and kidneys. This process is coordinated by the endocrine system through the highly integrated actions of several hormones, including FGF23, PTH, Klotho, and 1,25D. The excretion kinetics of the kidney after diet phosphorus load or the serum phosphorus kinetics during hemodialysis support that there is a "pool" for temporary phosphorus storage, leading to the maintenance of stable serum phosphorus levels. Phosphorus overload refers to a state where the phosphorus load is higher than is physiologically necessary. It can be caused by a persistently high-phosphorus diet, renal function decline, bone disease, insufficient dialysis, and inappropriate medications, and includes but is not limited to hyperphosphatemia. Serum phosphorus is still the most commonly used indicator of phosphorus overload. Trending phosphorus levels to see if they are chronically elevated is recommended instead of a single test when judging phosphorus overload. Future studies are needed to validate the prognostic role of a new marker or markers of phosphorus overload.

ABSTRACT Purpose: To evaluate collagen fibers during the bone repair process in critical defects created in the tibias of rats, treated with zoledronic acid (AZ) associated with low-level laser therapy (LLLT). Methods: Ten rats were distributed according to treatment: group 1) saline solution; group 2) LLLT; group 3) AZ; group 4) AZ and LLLT. AZ was administered at the dose of 0.035 mg/kg at fortnightly intervals over eight weeks. Next, 2-mm bone defects were created in the tibias of all animals. The bone defects in groups 2 and 4 were irradiated LLLT in the immediate postoperative period. After periods 14 and 28 of application, the animals were euthanized, and birefringence analysis was performed. Results: Approximately 90% of the total area was occupied by collagen fibers within the red color spectrum, this area being statistically larger in relation to the area occupied by collagen fibers within the green and yellow spectrum, in the four groups. Over the 14-day period, there was no statistically significant difference between the groups. In the 28-day period, group 2 (14.02 ± 15.9%) was superior in quantifying green birefringent fibers compared to group 1 (3.06 ± 3.24%), with p = 0.009. Conclusions: LLLT associated with ZA is effective in stimulating the neoformation of collagen fibers. The LLLT group without the association with ZA showed a greater amount of immature and less organized matrix over a period of 28 days.

OBJECTIVES: To compare the value of zero echo time (ZTE) and gradient echo black bone (BB) MRI sequences for bone assessment of the sacroiliac joint (SI) using computed tomography (CT) as the reference standard. MATERIALS AND METHODS: Between May 2019 and January 2021, 79 patients prospectively underwent clinically indicated 3-T MRI including ZTE and BB imaging. Additionally, all patients underwent a CT scan covering the SI joints within 12 months of the MRI examination. Two blinded readers performed bone assessment by grading each side of each SI joint qualitatively in terms of seven features (osteophytes, subchondral sclerosis, erosions, ankylosis, joint irregularity, joint widening, and gas in the SI joint) using a 4-point Likert scale (0 = no changes-3 = marked changes). Scores were compared between all three imaging modalities. RESULTS: Interreader agreement was largely good (k values: 0.5-0.83). Except for the feature gas in SI joint where ZTE exhibited significantly lower scores than CT (p  0.52) with inter-modality agreement being substantial to almost perfect (Krippendorffs alpha coefficients: 0.724-0.983). When combining the data from all features except for gas in the SI joint and when binarizing grading scores, combined sensitivity/specificity was 76.7%/98.6% for ZTE and 80.8%/99.1% for BB, respectively, compared to CT. CONCLUSIONS: The performance of ZTE and BB sequences was comparable to CT for bone assessment of the SI joint. These sequences may potentially serve as an alternative to CT yet without involving exposure to ionizing radiation.

The development and progression of tumor is closely associated with the microenvironment in which the tumor is located. In the process of bone metastasis, the numerous immune cells in bone marrow microenvironment play an important role in the colonization of tumor cells and the formation of metastases, and in particular, they can assist tumor cells with immune escape. Therefore, it is especially important to explore effective interventions to suppress the immune escape of tumor. This article reviews the role of macrophages, myeloid-derived suppressor cells, and lymphocytes in bone metastasis, so as to provide a refe-rence for the basic research on tumor immunotherapy and clinical treatment.

Abstract Background The growing prevalence of musculoskeletal diseases increases radiologic workload, highlighting the need for optimized workflow management and automated metadata classification systems. We developed a large-scale, well-characterized dataset of musculoskeletal radiographs and trained deep learning neural networks to classify radiographic projection and body side. Methods In this IRB-approved retrospective single-center study, a dataset of musculoskeletal radiographs from 2011 to 2019 was retrieved and manually labeled for one of 45 possible radiographic projections and the depicted body side. Two classification networks were trained for the respective tasks using the Xception architecture with a custom network top and pretrained weights. Performance was evaluated on a hold-out test sample, and gradient-weighted class activation mapping (Grad-CAM) heatmaps were computed to visualize the influential image regions for network predictions. Results A total of 13,098 studies comprising 23,663 radiographs were included with a patient-level dataset split, resulting in 19,183 training, 2,145 validation, and 2,335 test images. Focusing on paired body regions, training for side detection included 16,319 radiographs (13,284 training, 1,443 validation, and 1,592 test images). The models achieved an overall accuracy of 0.975 for projection and 0.976 for body-side classification on the respective hold-out test sample. Errors were primarily observed in projections with seamless anatomical transitions or non-orthograde adjustment techniques. Conclusions The deep learning neural networks demonstrated excellent performance in classifying radiographic projection and body side across a wide range of musculoskeletal radiographs. These networks have the potential to serve as presorting algorithms, optimizing radiologic workflow and enhancing patient care. Relevance statement The developed networks excel at classifying musculoskeletal radiographs, providing valuable tools for research data extraction, standardized image sorting, and minimizing misclassifications in artificial intelligence systems, ultimately enhancing radiology workflow efficiency and patient care. Key points • A large-scale, well-characterized dataset was developed, covering a broad spectrum of musculoskeletal radiographs. • Deep learning neural networks achieved high accuracy in classifying radiographic projection and body side. • Grad-CAM heatmaps provided insight into network decisions, contributing to their interpretability and trustworthiness. • The trained models can help optimize radiologic workflow and manage large amounts of data. Graphical Abstract

OBJECTIVE: To qualitatively evaluate the utility of zero echo-time (ZTE) MRI sequences in identifying osseous findings and to compare ZTE with optimized spoiled gradient echo (SPGR) sequences in detecting knee osseous abnormalities. MATERIALS AND METHODS: ZTE and standard knee MRI sequences were acquired at 3T in 100 consecutive patients. Three radiologists rated confidence in evaluating osseous abnormalities and image quality on a 5-grade Likert scale in ZTE compared to standard sequences. In a subset of knees (n = 57) SPGR sequences were also obtained, and diagnostic confidence in identifying osseous structures was assessed, comparing ZTE and SPGR sequences. Statistical significance of using ZTE over SPGR was characterized with a paired t-test. RESULTS: Image quality of the ZTE sequences was rated high by all reviewers with 278 out of 299 (100 studies, 3 radiologists) scores ≥ 4 on the Likert scale. Diagnostic confidence in using ZTE sequences was rated very high confidence in 97%, 85%, 71%, and 73% of the cases for osteophytosis, subchondral cysts, fractures, and soft tissue calcifications/ossifications, respectively. In 74% of cases with osseous findings, reviewer scores indicated confidence levels (score ≥ 3) that ZTE sequences improved diagnostic certainty over standard sequences. The diagnostic confidence in using ZTE over SPGR sequences for osseous structures as well as abnormalities was favorable and statistically significant (p

BackgroundMetaphyseal sclerosis secondary to canine distemper virus has been described histopathologically, but its radiographic appearance has not been described.ObjectivesDescribe the radiographic appearance of metaphyseal sclerosis secondary to canine distemper virus in juvenile dogs as distinct from metaphyseal osteopathy (formerly called hypertrophic osteodystrophy).AnimalsFour dogs (2 intact females and 2 intact males) between 2.5 and 4 months of age presented to 2 different veterinary teaching hospitals.MethodsRetrospective case series in which definitive diagnosis of canine distemper virus based on antemortem positive reverse transcription-polymerase chain reaction (RT-PCR) result or necropsy was required.ResultsAll 4 dogs were presented for evaluation of neurologic abnormalities, respiratory signs, and lethargy; 2 dogs had gastrointestinal signs and ocular abnormalities. Radiographs on all patients featured multifocal, symmetric, metaphyseal sclerosis, with no evidence of lysis or changes to the adjacent growth plate. The metaphyseal sclerosis was most apparent at the proximal humeral diaphyses and other included long bones. Diagnosis of distemper was confirmed by necropsy (2 of 4 dogs) or positive RT-PCR results (2 of 4 dogs). Three dogs were euthanized because of progressive illness, and 1 dog was lost to follow-up.Conclusion and clinical importanceIdentification of metaphyseal sclerosis on radiographs during diagnostic evaluation of young dogs should lead to a clinical suspicion of canine distemper virus infection. Sclerosis identified secondary to canine distemper virus is distinct from the necrosis and inflammation of metaphyseal osteopathy.

Purpose: Re-irradiation for bulky recurrent sarcoma carries significant risks. Pulsed low-dose rate radiotherapy (PLDR) is an attractive option for re-irradiation due to inherent radiobiological advantages. Materials and Methods: We present two patients who underwent re-irradiation using PLDR technique, followed by a literature review. Results: The first case is that of a 76-year-old male who developed an in-field recurrence of a bulky pelvic bone high-grade chondrosarcoma after he was treated with definitive radiotherapy using helical TomoTherapy with a total dose of 66 Gy. The patient was re-irradiated using PLDR with a shrinking field technique; 50 Gy in 2 Gy fractions followed by a boost of 20 Gy in 2 Gy fractions. The patient remains disease-free without significant toxicity 60 months post-irradiation. The second case is that of an 82-year-old female who was treated with a definitive irradiation of 66 Gy in 33 fractions for a right shoulder grade II chondrosarcoma. She developed an in-field recurrence 28 months later and presented with bulky disease causing brachial plexopathy and lymphedema. The patient was re-irradiated with a palliative intent to a total dose of 50 Gy in 2 Gy fractions over 5 weeks using PLDR. Brachial plexopathy resolved shortly after re-irradiation, but local progression near the surface was evident 8 months later. She passed away from unrelated causes 11 months later. Conclusion: We present two cases highlighting our early experience with PLDR, which was effective in the re-irradiation of recurrent bony sarcoma. Our study highlights PLDR as an option for re-irradiation in recurrent unresectable tumors. [ABSTRACT FROM AUTHOR]

When large amounts of Fluoride are consumed produces insulin resistance, but exercise can reverse insulin resistance in rats, because of a high fluoride uptake by bone tissue. However, bone quality has not been studied in those experiments. Therefore, the aim of this work was to evaluate bone quality in rats treated with fluoride when performing exercise. Sprague-Dawley rats were divided into 3 groups (n=6 per group): Control (drinking water without fluoride), Fluoride (drinking water with fluoride 15 mg/L for 30 days) and Exercise (daily running on a treadmill and drinking water with fluoride 15 mg/L for 30 days). Then, bone mineral density, mechanical and histological properties and bone fluoride level were measured. No effect of treatment on any bone parameters were observed. These results indicate that exercise normalizes glucose metabolism in insulin-resistant rats by bone fluoride uptake; however, this increase in bone fluoride does not manifest in bone deterioration.

ObjectivesThe lack of standardized X-ray imaging remains a challenge for comparative studies on spatial scans acquired from different clinic-specific X-ray scanners. The central objectives of this study are: 1) to delineate mineral density (MD) values, and 2) generate spatial MD maps of various physiologic and pathologic biominerals, and 3) propose a standardization protocol within the safe-operating zone of a CT scanner that underpins normalization of absorbed dose to shape and density of tissues.MethodsA systematic approach to propose a standardization protocol for CT imaging in vivo included: 1) estimation of pathologic MD ranges by performing a comparative meta-analysis on 2009-2019 data from the PubMed database; 2) calibration of cone-beam CT (CBCT) and micro-CT scanners with phantoms of known mineral densities (0, 250, 500, 750 and 3000 mg/cc) and shapes (cylinders and polyhedrons); 3) scanning craniofacial bones (N = 5) and dental tissues (N = 5), and ectopic minerals from humans (N = 3 each, pulp, salivary gland, kidney and prostrate stones, and penile and vascular plaques); 4) underscoring the effect of shape-factor (surface area-to-volume ratio) on MD of biominerals.ResultsHigher MDs of physiologic and pathologic cortical bones (504-1009 mg/cc) compared to trabecular bone (82-212 mg/cc) were observed. An increase in shape-factor increased the CBCT error in MD measurement and revealed that the scanner resolution is dependent on the absorbed dose and shape-factor of detectable features.SignificanceCT scanners should be calibrated with phantoms containing segments of known shape-factors and mineral densities to identify safe-operating zones. The calibrated approach will narrow the gap between length-scale dependent measurements, and will permit spatiotemporal quantitative and reliable detection of pathologies.

Areal bone mineral density (aBMD) from dual-energy x-ray absorptiometry (DEXA) and volumetric bone mineral density (vBMD) have demonstrated limited capabilities in the evaluation of bone mechanical competence and prediction of bone fracture. Predicting the macroscopic mechanical behavior of the bone structure has been challenging because of the heterogeneous and anisotropic nature of bone, such as the dependencies on loading direction, anatomical location, and sample dimensions. Magnetic resonance imaging (MRI) has been introduced as a promising modality that can be coupled with finite element analysis (FEA) for the assessment of bone mechanical competence. This review article describes studies investigating MRI-based micro-FEA as a potential non-invasive method to predict bone mechanical competence and facilitate bone fracture risk estimation without exposure to ionizing radiation. Specifically, the steps, applications, and future potential of FEA using indirect and direct bone imaging are discussed.

Abstract Objective To reproduce in an animal model the surgical technique of Masquelet used in the treatment of critical bone defects and to analyze the characteristics of the membrane formed around the bone cement. Methods A 10mm critical defect was created in the femoral shaft of 21 Sprague-Dawley rats. After resection of the central portion of the diaphysis, the defect was stabilized with a Kirschner wire introduced through the medullary canal and with the interposition of a bone cement spacer. After 2, 4, and 6 weeks of the surgical procedure, the animals were euthanized and evaluated on radiographs of the posterior limb regarding the size of the defect, alignment and stability of the osteosynthesis. The membranes formed around the spacer were subjected to histological analysis to assess thickness, connective tissue maturation and vascular density. Results Over time, the membranes initially made up of loose connective tissue were replaced by membranes represented by dense connective tissue, rich in thick collagen fibers. At six weeks, membrane thickness was greater (565 ± 208μm) than at four (186.9 ± 70.21μm, p = 0.0002) and two weeks (252.2 ± 55.1μm, p = 0.001). All membranes from the initial time showed foci of osteogenic differentiation that progressively reduced over time. Conclusion In addition to the structural and protective function of the membrane, its intrinsic biological characteristics can actively contribute to bone regeneration. The biological activity attributed by the presence of foci of osteogenesis confers to the membrane the potential of osteoinduction that favors the local conditions for the integration of the bone graft.

Bone and bone marrow are vital to mammalian structure, movement, and immunity. These tissues are also commonly subjected to molecular alterations giving rise to debilitating diseases like rheumatoid arthritis and osteomyelitis. Technologies such as matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) facilitate the discovery of spatially resolved chemical information in biological tissue samples to help elucidate the complex molecular processes underlying pathology. Traditionally, preparation of osseous tissue for MALDI IMS has been difficult due to its mineralized composition and heterogeneous morphology, and compensation for these challenges with decalcification and fixation protocols can remove or delocalize molecular species. Here, sample preparation methods were advanced to enable multimodal MALDI IMS of undecalcified, fresh-frozen murine femurs, allowing the distribution of endogenous lipids to be linked to tissue structures and cell types. Adhesive-bound bone sections were mounted onto conductive glass slides with microscopy-compatible glue and freeze-dried to minimize artificial bone marrow damage. High spatial resolution (10 μm) MALDI IMS was employed to characterize lipid distributions, and use of complementary microscopy modalities aided tissue and cell assignments. For example, various phosphatidylcholines localize to the bone marrow, adipose tissue, marrow adipose tissue, and muscle. Further, sphingomyelin(42:1) was abundant in megakaryocytes, whereas sphingomyelin(42:2) was diminished in this cell type. These data reflect the vast molecular and cellular heterogeneity indicative of the bone marrow and the soft tissue surrounding the femur. Multimodal MALDI IMS has the potential to advance bone-related biomedical research by offering deep molecular coverage with spatial relevance in a preserved native bone microenvironment.

Bone marrow niches (endosteal and perivascular) play important roles in both normal bone marrow function and pathological processes such as cancer cell dormancy. Unraveling the mechanisms underlying these events in humans has been severely limited by models that cannot dissect dynamic events at the niche level. Utilizing microfluidic and stem cell technologies, we present a 3D in vitro model of human bone marrow that contains both the perivascular and endosteal niches, complete with dynamic, perfusable vascular networks. We demonstrate that our model can replicate in vivo bone marrow function, including maintenance and differentiation of CD34+ hematopoietic stem/progenitor cells, egress of neutrophils (CD66b+), and niche-specific responses to doxorubicin and granulocyte-colony stimulating factor. Our platform provides opportunities to accelerate current understanding of human bone marrow function and drug response with high spatial and temporal resolution.

The Lake Titicaca basin was one of the major centers for cultural development in the ancient world. This lacustrine environment is unique in the high, dry Andean altiplano, and its aquatic and terrestrial resources are thought to have contributed to the florescence of complex societies in this region. Nevertheless, it remains unclear to what extent local aquatic resources, particularly fish, and the introduced crop, maize, which can be grown in regions along the lakeshores, contributed to facilitating sustained food production and population growth, which underpinned increasing social political complexity starting in the Formative Period (1400 BCE to 500 CE) and culminating with the Tiwanaku state (500 to 1100 CE). Here, we present direct dietary evidence from stable isotope analysis of human skeletal remains spanning over two millennia, together with faunal and floral reference materials, to reconstruct foodways and ecological interactions in southern Lake Titicaca over time. Bulk stable isotope analysis, coupled with compound-specific amino acid stable isotope analysis, allows better discrimination between resources consumed across aquatic and terrestrial environments. Together, this evidence demonstrates that human diets predominantly relied on C3 plants, particularly quinoa and tubers, along with terrestrial animals, notably domestic camelids. Surprisingly, fish were not a significant source of animal protein, but a slight increase in C4 plant consumption verifies the increasing importance of maize in the Middle Horizon. These results underscore the primary role of local terrestrial food resources in securing a nutritious diet that allowed for sustained population growth, even in the face of documented climate and political change across these periods.

Physiological loading of knee cartilage is highly dynamic and may contribute to the progression of osteoarthritis. Thus, an understanding of cartilage's dynamic mechanical properties is crucial in cartilage research. In this study, vibrometry was used as a fast (2 h), noncontact and novel alternative to the slower (30 h), traditional mechanical and biochemical assays for characterization of cartilage from the condyle, patella, trochlear groove and meniscus. Finite-element models predicted tissue resonant frequencies and bending modes, which strongly correlated with experiments (R2 = 0.93). Vibrometry-based viscoelastic properties significantly correlated with moduli from stress relaxation and creep tests, with correlation strengths reaching up to 0.78. Loss modulus also strongly correlated with glycosoaminoglycan (GAG) content. Dynamic properties measured by vibrometry significantly differed among various knee cartilages, ranging between 6.1 and 56.4 MPa. Interestingly, meniscus viscoelastic properties suggest that contrary to common belief, it may lack shock absorption abilities; instead, condylar hyaline cartilage may be a better shock absorber. These data demonstrate for the first time that vibrometry is a noncontact approach to dynamic mechanical characterization of hyaline and fibrocartilage cartilage with concrete relationships to standard quasi-static mechanical testing and biochemical composition. Thus, with a single tool, vibrometry greatly facilitates meeting multiple regulatory recommendations for mechanical characterization of cartilage replacements.

Abstract Background The collection and annotation of medical images are hindered by data scarcity, privacy, and ethical reasons or limited resources, negatively affecting deep learning approaches. Data augmentation is often used to mitigate this problem, by generating synthetic images from training sets to improve the efficiency and generalization of deep learning models. Methods We propose the novel use of statistical shape and intensity models (SSIM) to generate augmented images with variety in both shape and intensity of imaged structures and surroundings. The SSIM uses segmentations from training images to create co-registered tetrahedral meshes of the structures and to efficiently encode image intensity in their interior with Bernstein polynomials. In the context of segmentation of hip joint (pathological) bones from retrospective computed tomography images of 232 patients, we compared the impact of SSIM-based and basic augmentations on the performance of a U-Net model. Results In a fivefold cross-validation, the SSIM augmentation improved segmentation robustness and accuracy. In particular, the combination of basic and SSIM augmentation outperformed trained models not using any augmentation, or relying exclusively on a simple form of augmentation, achieving Dice similarity coefficient and Hausdorff distance of 0.95 [0.93–0.96] and 6.16 [4.90–8.08] mm (median [25th–75th percentiles]), comparable to previous work on pathological hip segmentation. Conclusions We proposed a novel augmentation varying both the shape and appearance of structures in generated images. Tested on bone segmentation, our approach is generalizable to other structures or tasks such as classification, as long as SSIM can be built from training data. Relevance statement Our data augmentation approach produces realistic shape and appearance variations of structures in generated images, which supports the clinical adoption of AI in radiology by alleviating the collection of clinical imaging data and by improving the performance of AI applications. Key points • Data augmentation generally improves the accuracy and generalization of deep learning models. • Traditional data augmentation does not consider the appearance of imaged structures. • Statistical shape and intensity models (SSIM) synthetically generate variations of imaged structures. • SSIM support novel augmentation approaches, demonstrated with computed tomography bone segmentation. Graphical abstract