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ABSTRACT Long‐duration spaceflight is associated with an increased risk of urolithiasis, and the pain caused by urinary calculi could result in loss of human performance and mission objectives. The present study investigated the risk of urolithiasis in astronauts during 6 months on the International Space Station, and evaluated whether the suppression of bone resorption by the bisphosphonate, alendronate (ALN), can reduce the risk. A total of 17 astronauts were included into the analysis: exercise using the advanced resistive exercise device (ARED) plus weekly oral 70 mg alendronate (ARED+ALN group, n = 7) was compared to resistive exercise alone (ARED group, n = 10). Urine volume decreased in both groups during spaceflight but recovered after return. The ARED group showed increased urinary calcium excretion from the 15th to 30th day of spaceflight, whereas urinary calcium was slightly decreased in the ARED+ALN group. Urinary N‐terminal telopeptide (NTX) and helical peptide (HP) of type I collagen, as bone resorption markers, were elevated in the ARED group during and until 0 days after spaceflight, while there was no elevation in these parameters in the ARED+ALN group. Urinary oxalate and uric acid excretion tended to be higher in the ARED group than in the ARED+ALN group during spaceflight. These results demonstrate that astronauts on long‐duration spaceflights may be at high risk for the formation of urinary calcium oxalate and calcium phosphate stones through increased urinary excretion of oxalate and uric acid, from degraded type I collagen, as well as of calcium from enhanced bone resorption. Our findings suggest that increased bone resorption during spaceflight, as a risk factor for urinary calculus formation, could be effectively prevented by an inhibitor of bone resorption. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Post traumatic osteoarthritis (PTOA) is a form of secondary osteoarthritis (OA) that develops in ~50% of cases of severe articular joint injuries and leads to chronic and progressive degradation of articular cartilage and other joint tissues. PTOA progression can be exacerbated by repeated injury and systemic inflammation. Few studies have examined approaches for blunting or slowing down PTOA progression with emphasis on systemic inflammation; most arthritis studies focused on the immune system have been in the context of rheumatoid arthritis. To examine how the gut microbiome affects systemic inflammation during PTOA development, we used a chronic antibiotic treatment regimen starting at weaning for 6 weeks before anterior cruciate ligament (ACL) rupture in STR/ort mice combined with lipopolysaccharide (LPS)‐induced systemic inflammation. STR/ort mice develop spontaneous OA as well as a more severe PTOA phenotype than C57Bl/6J mice. By 6 weeks post injury, histological examination showed a more robust cartilage staining in the antibiotic‐treated (AB) STR/ort mice than in the untreated STR/ort controls. Furthermore, we also examined the effects of AB treatment on systemic inflammation and found that the effects of LPS administration before injury are also blunted by AB treatment in STR/ort mice. The AB‐ or AB+LPS‐treated STR/ort injured joints more closely resembled the C57Bl/6J VEH OA phenotypes than the vehicle‐ or LPS‐treated STR/ort, suggesting that antibiotic treatment has the potential to slow disease progression and should be further explored therapeutically as prophylactic post injury. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Osteoclasts are multinucleated cells that are characterized by their unique ability to resorb large quantities of bone. Therefore, they are frequently the target of therapeutic interventions to ameliorate bone loss. In an adult organism, osteoclasts derive from hematopoietic stem cells and differentiate into osteoclasts within a multistep process under the influence of macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL). Historically, the osteoclast life cycle has been defined as linear, whereby lineage‐committed mononuclear precursors fuse to generate multinucleated highly specialized and localized bone phagocytic cells, which then undergo apoptosis within weeks. Recent advances through lineage tracing, single cell RNA sequencing, parabiosis, and intravital imaging approaches have challenged this dogma, revealing they have greater longevity and the capacity to circulate and undergo cell recycling. Indeed, these new insights highlight that under homeostatic conditions very few incidences of osteoclast apoptosis occur. More importantly, as we revisit the formation and fate of the osteoclast, novel methods to target osteoclast biology in bone pathology and regeneration are emerging. This review briefly summarizes the historical life cycle of osteoclasts and highlights recent discoveries made through advanced methodologies, which have led to a paradigm shift in osteoclast biology. These findings are discussed in light of both existing and emerging bone targeted therapeutics, bone pathologies, and communication between osteoclasts and cells resident in bone or at distant sites. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ABSTRACT Osteoporosis and its precursor osteopenia are common metabolic bone diseases in postmenopausal women. A growing body of evidence suggests that the gut microbiota is involved in the regulation of bone metabolism; however, there are few studies examining how gut microbiomes in osteoporosis and osteopenia may differ from those in healthy individuals. The aim of this study was to characterize the diversity, composition, and functional gene potential of the gut microbiota of healthy, osteopenic, and osteoporotic women. Body composition, bone density, and fecal metagenomes were analyzed in 86 postmenopausal women. The women were classified as healthy, osteopenic, or osteoporotic based on T‐scores. The taxonomic and functional gene compositions of the microbiome were analyzed using shotgun metagenomic sequencing. Both osteoporotic and osteopenic taxonomic compositions were found to be significantly different from healthy participants. Linear discriminant‐analysis effect‐size analyses identified that healthy participants had more unclassified Clostridia and methanogenic archaea (Methanobacteriaceae) than in both osteoporotic and osteopenic participants. Bacteroides was found to be more abundant in osteoporosis and osteopenia groups. Some KEGG pathways, including carbohydrate metabolism, biosynthesis of secondary metabolites, and cyanoamino acid metabolism, were found to be more abundant in both osteoporosis and osteopenia. These results show that osteoporosis and osteopenia alter the gut microbiome of postmenopausal women and identify potential microbial taxonomic and functional pathways that may be involved in this disease. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

ABSTRACT We are currently in the midst of a sleep crisis. Our current work and lifestyle environments are normalizing poor sleep with substantial negative impact on our health. Research on sleep has linked sleep deprivation to poorer mental health, obesity, cancer, diabetes, heart disease, and a myriad of other health conditions. Sleep deprivation is an even greater issues for people with musculoskeletal conditions and chronic pain. Between 67% and 88% of individuals with chronic pain experience sleep disruption and insomnia, and at least 50% of people with insomnia report chronic pain. The link between sleep and pain is well documented. Experimental, cohort, and longitudinal studies have all demonstrated that restricted sleep is linked to greater pain. Poor sleep therefore not only affects general health but has a direct impact on inflammation, pain response, and experience. Improving sleep in people living with musculoskeletal conditions and with chronic pain has the potential to deliver great benefit to many. This article describes the evidence base that can underpin such work, including research about the link between pain and sleep as well as theories and approaches to intervention that may help. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Children with hemato-oncological diseases may have significant skeletal morbidity, not only during and after treatment but also at the time of diagnosis before cancer treatment. This study was designed to evaluate the vitamin D status and circulating bone metabolic markers and their determinants in children at the time of diagnostic evaluation for hemato-oncological disease. This cross-sectional study included 165 children (91 males, median age 6.9 yr range 0.2–17.7 yr). Of them, 76 patients were diagnosed with extracranial or intracranial solid tumors, 83 with leukemia, and 6 with bone marrow failure. Bone metabolism was assessed by measuring serum 25OHD, PTH, bone alkaline phosphatase, intact N-terminal propeptide of type I procollagen, and C-terminal cross-linked telopeptide of type I collagen. Vitamin D deficiency was found in 30.9% of children. Lower 25OHD levels were associated with older age, lack of vitamin D supplementation, season outside summer, and a country of parental origin located between latitudes −45° and 45°. Children diagnosed with leukemia had lower levels of markers of bone formation and bone resorption than those who had solid tumors or bone marrow failure. In conclusion, vitamin D deficiency was observed in one-third of children with newly diagnosed cancer. Bone turnover markers were decreased in children with leukemia, possibly because of the suppression of osteoblasts and osteoclasts by leukemic cells. The identification of patients with suboptimal vitamin D status and compromised bone remodeling at cancer diagnosis may aid in the development of supportive treatment to reduce the adverse effects of cancer and its treatment. Lay Summary This study was designed to evaluate the vitamin D status and circulating bone metabolic markers in children with hemato-oncological diseases. Vitamin D deficiency was found in one-third of children. Lower vitamin D levels were associated with older age, lack of vitamin D supplementation, season outside summer, and a country of parental origin located between latitudes −45° and 45°. Children diagnosed with leukemia had lower levels of markers of bone formation and bone resorption than those who had solid tumors or bone marrow failure. The identification of patients with suboptimal vitamin D status and compromised bone remodeling may aid in the development of supportive treatment to reduce the adverse effects of cancer and its treatment. Graphical Abstract Graphical Abstract

ABSTRACT Medication‐related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse effect of antiresorptive medications administered for control of osseous malignancy, osteoporosis, or other bone metabolic diseases. Despite being reported in the literature two decades ago, MRONJ etiology, pathophysiology, and progression remain largely unknown, and current nonoperative or operative treatment strategies are mostly empirical. Several hypotheses that attempt to explain the mechanisms of MRONJ pathogenesis have been proposed. However, none of these hypotheses alone is able to capture the complex mechanistic underpinnings of the disease. In this minireview, we aim to highlight key findings from clinical and translational studies and propose a unifying model for the pathogenesis and progression of MRONJ. We also identify aspects of the disease process that require further investigation and suggest areas for future research efforts toward calibrating methodologic approaches and validating experimental findings. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. The etiology of medication‐related osteonecrosis of the jaw (MRONJ), a rare but serious adverse effect of antiresorptive medications, remains largely elusive. This minireview highlights key findings from clinical and translational studies and proposes a unifying model for the pathogenesis and progression of MRONJ.

Histomorphometric analysis of undecalcified bone biopsy images provides quantitative assessment of bone turnover, volume, and mineralization using static and dynamic parameters. Traditionally, quantification has relied on manual annotation and tracing of relevant tissue structures, a process that is time-intensive and subject to inter-operator variability. We developed ADAM, an automated pipeline for digital phenotyping, to quantify tissue and cellular components pertinent to static histomorphometric parameters such as bone and osteoid area, osteoclast and osteoblast count, and bone marrow adipose tissue (BMAT) area. The pipeline allowed rapid generation of delineated tissue and cell maps for up to 20 images in less than a minute. Comparing deep learning-generated annotation pixels with manual annotations, we observed Spearman correlation coefficients of ρ = 0.99 for both mineralized bone and osteoid, and ρ = 0.94 for BMAT. For osteoclast and osteoblast cell counts, which are subject to morphologic heterogeneity, using only brightfield microscopic images and without additional staining, we noted ρ = 0.60 and 0.69, respectively (inter-operator correlation was ρ = 0.62 for osteoclast and 0.84 for osteoblast count). The study also explored the application of morphological texture analysis (MTA), measuring relative pixel patterns that potentially vary with diverse tissue conditions. Notably, MTA from mineralized bone, osteoid, and BMAT showed differentiating potential to identify common pixel characteristics between images labeled as low or high bone turnover based upon the final diagnostic report of the bone biopsy. The Area Under the Receiver Operating Characteristic Curve (AUC-ROC) obtained for BMAT MTA features as a classifier for bone turnover, was 0.87, suggesting that computer-extracted features, not discernable to the human eye, hold potential in classifying tissue states. With additional evaluation, ADAM could be potentially integrated into existing clinical routines to improve pathology workflows and contribute to diagnostic insights into bone biopsy evaluation and reporting. Lay Summary Bone biopsies are used to study bone diseases at a microscopic level. For precise measurements, detailed tracings of tissue and cell structures are hand-drawn on images, a process that is time-consuming and prone to variability between observers. Advances in artificial intelligence, particularly deep learning, enable automatic identification of tissue and cell parts using their shape, color, texture, and location. We developed ADAM, the first automated deep learning-based pipeline to trace tissue and cellular structures, and extract texture patterns embedded in images of undecalcified bone samples. These automated tracings allow quicker and easier processing of bone biopsy images for diagnostic reporting. Graphical Abstract Graphical Abstract

ABSTRACT 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. Astronauts have an increased risk of back pain and disc herniation upon returning to Earth, so it is imperative to understand the effects of spaceflight and readaptation to gravity on the musculoskeletal tissues of the spine. Spaceflight‐induced declines in astronauts’ vertebral 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 regions remained significantly below preflight levels (−4.66%, p = 0.0094). Bone loss in the transverse vertebral body and incomplete recovery even after a year of readaptation on Earth may contribute to spinal pathology in long‐duration astronauts.

As osteoporosis therapy options have expanded, and clinical guidelines have begun to embrace the concept of limited treatment courses and \"drug holidays,\" the choices that physicians must make when initiating, electing to continue, or switching therapies have become more complex. As a result, one of the fundamental issues that must be carefully considered is whether, when, and in what sequence anabolic therapies should be utilized. This review evaluates the current evidence supporting the optimal sequence for the use of anabolic and antiresorptive drugs and assesses the expanding number of clinical trials favoring the initial use of anabolic therapy followed by an antiresorptive agent. This review also explores the evidence suggesting that the effectiveness of anabolic medications are diminished when used in patients that have been previously treated with specific antiresorptive drugs for prolonged periods. Finally, the recent advances in designing combination antiresorptive/anabolic treatment approaches are detailed, with a focus on combined denosumab/teriparatide regimens, which appear to provide the most substantial and clinically relevant skeletal benefits to patients with established osteoporosis. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.