A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis.

Activating Nrf2 by small molecules is a promising strategy to treat postmenopausal osteoporosis. However, there is currently no Nrf2 activator approved for treating chronic diseases, and the downstream mechanism underlying the regulation of Nrf2 on osteoclast differentiation remains unclear. Here, we found that bitopertin, a clinical-stage glycine uptake inhibitor, suppresses osteoclast differentiation and ameliorates ovariectomy-induced bone loss by activating Nrf2. Mechanistically, bitopertin interacts with the Keap1 Kelch domain and decreases Keap1-Nrf2 binding, leading to reduced Nrf2 ubiquitination and degradation. Bitopertin is associated with less adverse events than clinically approved Nrf2 activators in both mice and human subjects. Furthermore, Nrf2 transcriptionally activates ferroportin-coding gene Slc40a1 to reduce intracellular iron levels in osteoclasts. Loss of Nrf2 or iron supplementation upregulates ornithine-metabolizing enzyme Odc1, which decreases ornithine levels and thereby promotes osteoclast differentiation. Collectively, our findings identify a novel clinical-stage Nrf2 activator and propose a novel Nrf2-iron-ornithine metabolic axis in osteoclasts.

IL-17 promotes osteoclast-induced bone loss by regulating glutamine-dependent energy metabolism.

Osteoclasts consume an amount of adenosine triphosphate (ATP) to perform their bone resorption function in the development of osteoporosis. However, the mechanism underlying osteoclast energy metabolism has not been fully elucidated. In addition to glucose, glutamine (Glu) is another major energy carrier to produce ATP. However, the role of Glu metabolism in osteoclasts and the related molecular mechanisms has been poorly elucidated. Here we show that Glu is required for osteoclast differentiation and function, and that Glu deprivation or pharmacological inhibition of Glu transporter ASCT2 by V9302 suppresses osteoclast differentiation and their bone resorptive function. In vivo treatment with V9302 improved OVX-induced bone loss. Mechanistically, RNA-seq combined with in vitro and in vivo experiments suggested that Glu mediates the role of IL-17 in promoting osteoclast differentiation and in regulating energy metabolism. In vivo IL-17 treatment exacerbated OVX-induced bone loss, and this effect requires the participation of Glu or its downstream metabolite α-KG. Taken together, this study revealed a previously unappreciated regulation of IL-17 on energy metabolism, and this regulation is Glu-dependent. Targeting the IL-17-Glu-energy metabolism axis may be a potential therapeutic strategy for the treatment of osteoporosis and other IL-17 related diseases.

Metagenomic analysis of the microbial communities and associated network of nitrogen metabolism genes in the Ryukyu limestone aquifer.

While microbial biogeochemical activities such as those involving denitrification and sulfate reduction have been considered to play important roles in material cycling in various aquatic ecosystems, our current understanding of the microbial community in groundwater ecosystems is remarkably insufficient. To assess the groundwater in the Ryukyu limestone aquifer of Okinawa Island, which is located in the southernmost region of Japan, we performed metagenomic analysis on the microbial communities at the three sites and screened for functional genes associated with nitrogen metabolism. 16S rRNA amplicon analysis showed that bacteria accounted for 94-98% of the microbial communities, which included archaea at all three sites. The bacterial communities associated with nitrogen metabolism shifted by month at each site, indicating that this metabolism was accomplished by the bacterial community as a whole. Interestingly, site 3 contained much higher levels of the denitrification genes such as narG and napA than the other two sites. This site was thought to have undergone denitrification that was driven by high quantities of dissolved organic carbon (DOC). In contrast, site 2 was characterized by a high nitrate-nitrogen (NO3-N) content and a low amount of DOC, and this site yielded a moderate amount of denitrification genes. Site 1 showed markedly low amounts of all nitrogen metabolism genes. Overall, nitrogen metabolism in the Ryukyu limestone aquifer was found to change based on environmental factors.

Higher Risk of Rheumatoid Arthritis in Patients With Chronic Rhinosinusitis: Prospective Association in the U.K. Biobank and Genetic Evidence by Mendelian Randomization Analysis.

BACKGROUND: Previous studies have shown that respiratory diseases are associated with an increased risk of rheumatoid arthritis (RA). However, whether there is a correlation between chronic rhinosinusitis (CRS) and RA is not known. Due to the high incidence of CRS, it remains to be clarified whether we should pay additional attention to RA risk in the huge population of CRS. METHODS: We used a 2-sample Mendelian randomization (MR) analysis to explore the causal effects of CRS on the incidence of RA. The inverse variance weighted (IVW) approach was used as the main analysis in the MR randomization study. Then, we used the data from the U.K. Biobank to examine the association between RA and CRS at the individual level in a prospective cohort. We identified patients with CRS at the time of recruitment and further followed the incidence of RA until 2021. The risk of developing RA in patients with CRS was determined by a multivariate Cox regression model. We used 3 multivariate Cox models to adjust for individual characteristics, lifestyle factors and concomitant diseases, respectively. RESULTS: The MR analysis by the IVW model suggested that the odds ratio of RA associated with genetically predicted CRS was 2.39 (95% CI [1.08-5.30]; p = .032). In the first multivariate model adjusting for individual characteristics, CRS was associated with a 47% increase of risk of developing RA (hazard ratio [HR] = 1.47; 95% CI [1.12-1.90]). In the second multivariate model adjusting for lifestyle factors, the HR of RA associated with CRS was 1.48 (95% CI [1.15-1.90]). In the third multivariate model, chronic sinusitis was associated with a 32% increase in RA risk (HR = 1.32; 95% CI [1.03-1.70]). CONCLUSION: CRS has a genetically causal effect on the incidence of RA, and the risk of RA is greatly higher in CRS at the individual level. This is the first study to reveal an association between CRS and RA. Due to the high incidence of CRS, it is recommended that additional attention should be paid to the increased RA risk in patients with CRS compared to that in common people.

Higher risk of osteoporosis in adult-onset asthma than childhood-onset asthma: from genetic and prospective evidence.

Both COA and AOA have a genetically causal effect on osteoporosis. COA and AOA were independently associated with incident osteoporosis, and the risk was greatly higher in AOA. Besides corticosteroids, the increased risk of osteoporosis among asthma patients should be attributed to genetic susceptibility and other asthma medications. PURPOSE/INTRODUCTION: Childhood-onset asthma (COA) differs with adult-onset asthma (AOA) on genetic susceptibility, severity, and co-morbidities. Whether COA or AOA is independently associated with osteoporosis is unexplored. We aimed to determine the effects of COA and AOA on osteoporosis at genetic and individual level. METHODS: We used two-sample Mendelian randomization analysis to explore the causal effects of COA and AOA on osteoporosis. In the UK Biobank cohort, we included 478,289 osteoporosis-free participants at baseline (2006-2010). Participants were classified as non-asthma, COA, and AOA at recruitment. Multivariate Cox regression analysis was used to evaluate the effects of COA, AOA, and multiple asthma medications on incident osteoporosis risk. RESULTS: COA and AOA were causally related to osteoporosis, with odds ratio of 1.007 (95% confidence interval (CI), 1.0003-1.0132) and 1.012 (95% CI, 1.002-1.023), respectively. Multivariate Cox regression analysis suggested that COA (hazard ratio (HR), 1.46; 95% CI, 1.32-1.61) and AOA (HR, 1.70; 95% CI, 1.61-1.80) were independently associated with incident osteoporosis, and the risk was greatly higher in AOA (HR, 1.51; 95% CI, 1.34-1.70). In addition to corticosteroids, monotherapy with leukotriene modifiers (HR, 1.70; 95% CI, 1.20-2.42), long-acting beta agonists (HR, 1.49; 95% CI, 1.18-1.87), and short-acting beta agonists (HR, 1.72; 95% CI1.01-2.93) were independently associated with a higher risk of osteoporosis. CONCLUSIONS: Both COA and AOA have a genetically causal effect on osteoporosis, and the risk of osteoporosis is greatly higher in AOA. Besides corticosteroids, the increased risk of osteoporosis among asthma patients should be attributed to genetic susceptibility and other asthma medications.

Mechanism of denitrification in subsurface-dammed Ryukyu limestone aquifer, southern Okinawa Island, Japan.

Denitrification crucially regulates the attenuation of groundwater nitrate and is unlikely to occur in a fast-flowing aquifer such as the Ryukyu limestone aquifer in southern Okinawa Island, Japan. However, evidences of denitrification have been observed in several wells within this region. This study analyzed environmental isotopes (δ15NNO3 and ẟ18ONO3) to derive the rationale for denitrification at this site. Additionally, the presence of two subsurface dams in the study area may influence the processes involved in nitrate attenuation. Herein, we analyzed 150 groundwater samples collected spatially and seasonally to characterize the variations in the groundwater chemistry and stable isotopes during denitrification. The values of δ15NNO3 and δ18ONO3 displayed a progressive trend up to +59.7 ‰ and + 21 ‰, respectively, whereas the concentrations of NO3--N decreased to 0.1 mg L-1. In several wells, the enrichment factors of δ15NNO3 ranged from -6.6 to -2.1, indicating rapid denitrification, and the δ15NNO3 to δ18ONO3 ratios varied from 1.3:1 to 2:1, confirming the occurrence of denitrification. Denitrification intensively proceeds under conditions of depleted dissolved oxygen concentrations (<2 mg L-1), sluggish groundwater flow with longer residence times, high concentrations of dissolved organic carbon (>1.2 mg L-1), and low groundwater levels during the dry season with precipitation rates of <100 mm per month (Jun-Sep). SF6 analysis indicated the exclusive occurrence of denitrification in specific wells with groundwater residence times exceeding 30 years. These wells are located in close proximity to the major NE-SW fault system in the Komesu area, where the hydraulic gradient was below 0.005. Detailed geological and lithological investigations based on borehole data revealed that subsurface dams did not cause denitrification while the major NE-SW fault system uplifted the impermeable basement rock of the Shimajiri Group, creating a lithological gap at an equivalent depth that ultimately formed a sluggish groundwater area, promoting denitrification.

Cancer-Erythrocyte Membrane-Mimicking Fe3O4 Nanoparticles and DHJS for Ferroptosis/Immunotherapy Synergism in Tumors.

Ferroptosis is characterized by iron accumulation and lipid peroxidation. However, a clinical dose of Fe3O4 nanoparticles could not cause effective ferroptosis in tumors, and the mechanism is yet to be completely understood. In this study, using RNA-seq data, we found that tumor cells could feedback-activate the antioxidant system by upregulating Nrf-2 expression, thus avoiding ferroptosis caused by Fe3O4 nanoparticles. We also found that DHJS (a probe for ROS generation) can antagonize Nrf-2 expression when it synergizes with Fe3O4 nanoparticles, thus inducing ferroptosis in tumor cells. Considering these findings, we created a biomimetic hybrid cell membrane camouflaged by PLGA-loaded Fe3O4 and DHJS to treat osteosarcoma. The hybrid cell membrane endowed the core nanoparticle with the extension of blood circulation life and enhanced homologous targeting ability. In addition, DHJS and Fe3O4 in nanoparticles prompted synergistically lethal ferroptosis in cancer cells and induced macrophage M1 polarization as well as the infiltration of CD8(+) T cells and dendritic cells in tumors. In summary, this study provides novel mechanistic insights and practical strategies for ferroptosis induction of Fe3O4 nanoparticles. Meanwhile, the synthesized biomimetic nanoparticles exhibited synergistic ferroptosis/immunotherapy against osteosarcoma.

Inhibition of FAAH suppresses RANKL-induced osteoclastogenesis and attenuates ovariectomy-induced bone loss partially through repressing the IL17 pathway.

Fatty amide hydrolase (FAAH) is a key degradation enzyme of the endocannabinoid system, mainly responsible for the hydrolysis of arachidonic acid ethanolamine (AEA). Previous investigations have shown that FAAH is involved in a series of biological processes, such as inflammation, immune regulation, and transmembrane signal transduction of neurons. Endogenous cannabinoids and cannabinoid receptors have been reported to participate in the regulation of bone homeostasis by regulating the differentiation of osteoblasts and osteoclasts. We hypothesized that FAAH may play an important role in osteoclastogenesis based on the above evidence. The present study found that the FAAH expression was increased at both mRNA and protein levels during RANKL-induced osteoclastogenesis. Pharmacological and genetic inhibition of FAAH in bone marrow-derived macrophages (BMMs) inhibited osteoclastogenesis, F-actin ring formation, bone resorption, and osteoclast-specific gene expression in vitro. Moreover, intragastric administration of the FAAH inhibitor PF-04457845(PF) ameliorated ovariectomy (OVX)-induced bone loss in mice. Further investigation revealed that nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were inhibited by PF treatment and FAAH knockdown. RNAseq indicated that the IL17 pathway was blocked by PF, and administration of recombinant murine IL17 protein could partially restore osteoclastogenesis and activate NF-κB and MAPK pathways. To sum up, our findings demonstrate that targeting FAAH could be a promising candidate strategy for treating osteoclast-related diseases, especially osteoporosis.

What was the Epidemiology and Global Burden of Disease of Hip Fractures From 1990 to 2019? Results From and Additional Analysis of the Global Burden of Disease Study 2019.

BACKGROUND: Hip fractures are associated with a high risk of death; among those who survive a hip fracture, many experience substantial decreases in quality of life. A comprehensive understanding of the epidemiology and burden of hip fractures by country, age, gender, and sociodemographic factors would provide valuable information for healthcare policymaking and clinical practice. The Global Burden of Disease (GBD) study 2019 was a global-level study estimating the burden of 369 diseases and injuries in 204 countries and territories. An exploration and additional analysis of the GBD 2019 would provide a clearer picture of the incidence and burden of hip fractures. QUESTIONS/PURPOSES: Using data from the GBD 2019, we asked, (1) What are the global, regional, and national incidences of hip fractures, and how did they change over a recent 30-year span? (2) What is the global, regional, and national burden of hip fractures in terms of years lived with disability, and how did it change over that same period? (3) What is the leading cause of hip fractures? (4) How did the incidence and years lived with disability of patients with hip fractures change with age, gender, and sociodemographic factors? METHODS: This was a cross-sectional study. Participant data were obtained from the GBD 2019 ( http://ghdx.healthdata.org/gbd-results-tool ). The GBD study is managed by the WHO, coordinated by the Institute of Health Metrics and Evaluation, and funded by the Bill and Melinda Gates Foundation. It estimates the burden of disease and injury for 204 countries by age, gender, and sociodemographic factors, and can serve as a valuable reference for health policymaking. All estimates and their 95% uncertainty interval (UI) were produced using DisMod-MR 2.1, a Bayesian meta-regression tool in the GBD 2019. In this study, we directly pulled the age-standardized incidence rate and years lived with disability rate of hip fractures by location, age, gender, and cause from the GBD 2019. Based on these data, we analyzed the association between the incidence rate and latitude of each country. Then, we calculated the estimated annual percentage change to represent trends from 1990 to 2019. We also used the Spearman rank-order correlation analysis to determine the correlation between the incidence or burden of hip fractures and the sociodemographic index, a composite index of the income per capita, average years of educational attainment, and fertility rates in a country. RESULTS: Globally, hip fracture incidences were estimated to be 14.2 million (95% UI 11.1 to 18.1), and the associated years lived with disability were 2.9 million (95% UI 2.0 to 4.0) in 2019, with an incidence of 182 (95% UI 142 to 231) and 37 (95% UI 25 to 50) per 100,000, respectively. A strong, positive correlation was observed between the incidence rate and the latitude of each country (rho = 0.65; p < 0.001). From 1990 to 2019, the global incidence rate for both genders remained unchanged (estimated annual percentage change 0.01 [95% confidence interval -0.08 to 0.11]), but was slightly increased in men (estimated annual percentage change 0.11 [95% CI 0.01 to 0.2]). The years lived with disability rate decreased slightly (estimated annual percentage change 0.66 [95% CI -0.73 to -0.6]). These rates were standardized by age. Falls were the leading cause of hip fractures, accounting for 66% of all patients and 55% of the total years lived with disability. The incidence of hip fractures was tightly and positively correlated with the sociodemographic index (rho 0.624; p < 0.001), while the years lived with disability rate was slightly negatively correlated (rho -0.247; p < 0.001). Most hip fractures occurred in people older than 70 years, and women had higher incidence rate (189.7 [95% UI 144.2 to 247.2] versus 166.2 [95% UI 133.2 to 205.8] per 100,000) and years lived with disability (38.4 [95% UI 26.9 to 51.6] versus 33.7 [95% UI 23.1 to 45.5] per 100,000) than men. CONCLUSION: Hip fractures are common, devastating to patients, and economically burdensome to healthcare systems globally, with falls being the leading cause. The age-standardized incidence rate has slightly increased in men. Many low-latitude countries have lower incidences, possibly because of prolonged sunlight exposure. Policies should be directed to promoting public health education about maintaining bone-protective lifestyles, enhancing the knowledge of osteoporosis management in young resident physicians and those in practice, increasing the awareness of osteoporosis screening and treatment in men, and developing more effective antiosteoporosis drugs for clinical use. LEVEL OF EVIDENCE: Level III, prognostic study.

Blocking the cytohesin-2/ARF1 axis by SecinH3 ameliorates osteoclast-induced bone loss via attenuating JNK-mediated IRE1 endoribonuclease activity.

cytohesin-2 is a guanine nucleotide exchange factor to activate ARF1 and ARF6, which are involved in various biological processes, including signal transduction, cell differentiation, cell structure organization, and survival. Nevertheless, there is a lack of evidence revealing the role of cytohesin-2 in osteoclast differentiation and in the development of osteoporosis. In this study, we find cytohesin-2 and ARF1 positively regulate osteoclast differentiation and function. Blocking the cytohesin-2 /ARF1 axis with SecinH3 or by genetic silencing of cytohesin-2 inhibits osteoclast formation and function in vitro. In vivo treatment with SecinH3 ameliorates ovariectomy-induced osteoporosis. Mechanistically, RNA-sequencing combined with molecular biological methodologies reveal that the regulatory function of cythohesin-2/ARF1 axis in osteoclast differentiation is mainly dependent on activating the JNK pathway. Further, in addition to the common viewpoint that JNK is activated by IRE1 via its kinase activity, we found that JNK can act upstream and regulate the endoribonuclease activity of IRE1 to promote XBP1 splicing. Both SecinH3 and silencing of cytohesin-2 inhibit JNK activation and IRE1 endoribonuclease activity, leading to the suppression of osteoclast differentiation. Taken together, our findings add new insights into the regulation between JNK and IRE1, and reveal that inhibiting the cytohesin-2/ARF1/JNK/IRE1 axis might represent a potential new strategy for the treatment of post-menopause osteoporosis.

Global, Regional, and National Burden of Low Bone Mineral Density From 1990 to 2019: Results From the Global Burden of Disease Study 2019.

Objective: We aim to explore the global spatial prevalence and temporal trends of the burden of low bone mineral density (LBMD) worldwide, due to a lack of related studies. Design: Cross-sectional study. Methods: We used data from the Global Burden of Disease Study 2019 to conduct this study. LBMD in the GBD study includes both osteopenia and osteoporosis. The estimation for the prevalence, measured by the summary exposure value (SEV), and burden of LBMD was made in DisMod-MR 2.1, a Bayesian meta-regression tool. Correlation analysis was performed using the Spearman rank order correlation methods. The temporal trends were represented by the estimated annual percentage change (EAPC). Results: In 2019, there were 438 thousand deaths and 16.6 million DALYs attributable to LBMD, increasing by 111.1% and 93.8% respectively, compared to that in 1990. From 1990 to 2019, the prevalence of LBMD has decreased worldwide, but has increased in high-income North America. Some countries, such as the United States, Australia, Canada, and China had increased disability and mortality rates of LBMD with time. Countries with low socio-demographic index (SDI) had higher incidence and mortality rate than those with high SDI. The prevalence of LBMD was lower in males, but the attributable disability and mortality were higher in males in all years from 1990 to 2019. Conclusion: With population aging, countries worldwide, especially those with low-SDI, will face increasing challenges in reducing the burden attributable to LBMD and osteoporosis. The treatment of osteoporosis has been overlooked in men for a long time. Effective measures are warranted to control the prevalence and burden of LBMD.

Impact of Limb Salvage on Prognosis of Patients Diagnosed With Extremity Bone and Soft Tissue Sarcomas.

Background: Although clinicians and patients with extremity bone and soft tissue (EBST) are increasingly interested in limb salvage surgery (LSS), because of the minimal damage to physical appearance and function, however, there is still a lack of large-scale population studies on whether LSS improves the prognosis of patients. Purpose: The aim of this study was to compare the survival of patients with EBST sarcomas after receiving LSS and amputation. Methods: To conduct the population-based study, we identified 6,717 patients with a histologically diagnosed bone sarcoma and 24,378 patients with a histologically diagnosed soft tissue sarcoma from the Surveillance, Epidemiology, and End Results database. We analyzed overall survival (OS), cancer-specific survival (CSS), and non-sarcoma survival (NSS) using the Kaplan-Meier method, log-rank test or Gray test, Cox regression model, propensity score-matched analysis, and landmark analysis. Results: LSS could improve the prognosis in patients with most EBST subtypes, except for Ewing sarcomas and MPNST. However, in the subgroup without distant metastases, limb salvage increased CSS only for patients with osteosarcoma, Ewing sarcoma, and leiomyosarcoma, as well as NSS for patients with chondrosarcoma and synovial sarcoma. Landmark analysis further demonstrated that sarcoma survivors surviving <10 years could benefit from LSS but not for long-term survivors ≥10 years. Moreover, for patients with distant metastases, LSS could improve survival of osteosarcoma patients but worsen CSS among patients with MPNST. Landmark analysis further demonstrated that LSS improved survival among osteosarcomas patients with distant metastases only within 1 year after surgery. Moreover, patients receiving LSS and those receiving amputation had a high risk of dying from different non-sarcoma diseases during the postoperative follow-up. Conclusions: The impact of limb salvage on the prognosis of patients depends on the pathological subtype and stage of EBST sarcomas.

Inhibition of MAT2A suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss.

Methionine adenosyltransferase II alpha (MAT2A) is the key enzyme to transform methionine and adenosine-triphosphate (ATP) to S-adenosylmethionine (SAM), a general methyl-group donor in vitro. MAT2A has been reported to participate in the NF-κB pathway and maintain the methylated modification, which also affects osteoclastogenesis. In this study, we found the expression of MAT2A was increased upon RANKL stimulation. Pharmacological inhibition of MAT2A by its selective inhibitor AG-270 or genetic silencing by MAT2A-shRNA suppressed osteoclast formation and function in vitro. In vivo treatment with the inhibitor AG-270 also prevented OVX-induced bone loss. Further study revealed that the inhibition of MAT2A affected osteoclast differentiation mainly by suppressing crucial transcription factors and reactive oxygen species induced by RANKL. A quasi-targeted metabolomics assay performed by LC-MS/MS indicated that SAM was reduced by MAT2A knockdown, and the administration of SAM partly rescued the effects of MAT2A inhibition on osteoclastogenesis. These findings revealed that MAT2A is crucial for osteoclastogenesis and might be a potential target for the treatment of osteoporosis attributed to osteoclast dysfunction.

Inhibition of IRE1 suppresses the catabolic effect of IL-1ß on nucleus pulposus cell and prevents intervertebral disc degeneration in vivo.

Neck pain and low back pain are two of the major diseases, which causes patients a low quantify of life and a heavy economic burden, intervertebral disc degeneration (IDD) contributes to them, and the mechanism is not totally clear. The increased inflammatory cytokines including interleukin (IL)-1ß and tumor necrosis factor (TNF)α and downstream signaling pathways are involved. Inositol requiring enzyme 1 (IRE1) is a crucial enzyme that regulates endoplasmic reticulum (ER) stress. It is reported that IRE1 plays an important role in the activation of NF-κB, PI3K/Akt and MAPK signaling pathways. Considering this, we performed a series of experiments in vitro and in vivo to evaluate the role of IRE1 in the progress of IDD. We demonstrated that IRE1 pathway was induced by IL-1ß, inhibition of IRE1 suppressed the matrix degeneration of NP cells and ameliorated IDD grade in the punctured rat model. Further results indicated that inhibition of IRE1 suppressed H2O2 induced cell senescence, IL-1ß-induced cellular reactive oxygen species (ROS) level and the activation of NF-κB, PI3K/Akt and MAPK signaling pathways. It also played a crucial role in the apoptosis of NP cells and the progress of macrophage polarization. Our findings demonstrated that inhibition of IRE1 could suppress the degeneration of NP cells and prevent IDD in vivo. IRE1 may be a potential target for IDD treatment.

Global incidence, prevalence, and disability of vertebral fractures: a systematic analysis of the global burden of disease study 2019.

BACKGROUND CONTEXT: In the context of the population growing and aging worldwide, the epidemiology, and burden of vertebral fracture have not been comprehensively analyzed. PURPOSE: To delineate the global number and rate of incidence, prevalence and burden of vertebral fracture in 2019, and the temporal trends from 1990 to 2019 by location, age, sex, and the socio-demographic index (SDI). STUDY DESIGN/SETTING: A cross-sectional study using data from the Global Burden of Disease Study 2019 (GBD study 2019). PATIENT SAMPLE: Patients with vertebral fracture documented in medical records or registrations and included in the GBD study 2019 from different countries worldwide. OUTCOME MEASURES: Age standardized incidence rate (ASIR), age standardized prevalence rate (ASPR), and age standardized years lived with disability (YLDs). METHODS: The GBD study 2019 was used to obtain data for this analysis. The incidence, prevalence and disability were analyzed by location, year, sex, age, and SDI. DisMod-MR 2.1, a Bayesian meta-regression tool, was used to produce the estimates for each value after adjustment for age, sex, and other variables. Estimated annual percentage change (EAPC) was calculated to represent the temporal trends from 1990 to 2019. Spearman's rank order correlation was used to determine the correlation between SDI and the incidence and burden of vertebral fracture. This work was supported by the Key Research and Development Program of Hubei Province of China (No. 2020BCB049), and no conflicts of interest-associated biases existed in this study. RESULTS: Globally, there were 8.6 million (95% uncertainty interval [UI], 6,6-11,3 million) incident cases, 5.3 million (95% UI, 4.6-6.2 million) prevalent cases, and 0.55 million (95% UI, 0.37-0.77 million) YLDs of vertebral fracture. Compared with 1990, the number of incident cases and YLDs in 2019 increased by 38% (95% UI, 23%-48%) and 75% (95% UI, 65%-85%), respectively, while the ASIR (EAPC, -0.28; 95% CI, -0.41 to -0.14), ASPR (EAPC, -0.12; 95% CI, -0.22 to -0.02) and age standardized YLD rate (ASYR) (EAPC, -0.13; 95% CI, -0.23 to -0.04) decreased during this period. High ASIR, ASPR and ASYR were commonly seen in high-SDI countries, such as high-income North America, Australia, Central and Eastern Europe. In the country level, positive correlations were observed between SDI and ASIR (rho, 0.596; p<.001) and ASYR (rho, 0.413; p<.001). Males had higher ASIR and ASYR worldwide in each year from 1990 to 2019. However, the incidence, and YLD rates in females surpassed that in males after 65 years of age. Increasing trends were observed for both incidence and YLD rates with age. Falls were the leading cause for vertebral fracture across all ages. CONCLUSIONS: The past thirty years have seen increasing numbers but decreasing rates of global incidence, prevalence, and disability of vertebral fractures, resulting from the growing population worldwide. With population aging, efforts are still in urgent need to address vertebral fracture related health outcomes.

A Competing Risk-based Prognostic Model to Predict Cancer-specific Death of Patients with Spinal and Pelvic Chondrosarcoma.

STUDY DESIGN: Retrospective analysis. OBJECTIVE: The aim of this study was to develop and validate a competing-risk-based prognostic model and a nomogram for predicting the three- and five-year probability of cancer-specific death (CSD) in patients with spinal and pelvic chondrosarcoma. SUMMARY OF BACKGROUND DATA: The issue of competing risk has rarely been addressed and discussed in survival analysis of bone sarcoma. In addition, the Fine and Gray model, a more accurate method for survival analysis in the context of competing risk, has also been less reported in prognostic study of chondrosarcoma. METHODS: A total of 623 patients with spinal or pelvic chondrosarcoma were identified from the SEER database and were divided into a training and a validation cohort. These two cohorts were used to develop and validate a prognostic model to predict the 3- and 5-year probability of CSD, considering non-CSD as competing risk. The C-index, calibration plot, and decision curve analysis were used to assess the predictive performance and clinical utility of the model. RESULTS: Older age (subdistribution hazards ratio [SHR]: 1.02, 95% confidence interval [CI]: 1.01∼1.03; P = 0.013), high grade (SHR: 2.68, 95% CI: 1.80∼3.99; P < 0.001), regional involvement (SHR: 1.66, 95% CI: 1.06∼2.58; P = 0.026), distant metastasis (SHR: 5.18, 95% CI: 3.11∼8.62; P < 0.001) and radical resection (SHR: 0.38, 95% CI: 0.24∼0.60; P < 0.001) were significantly associated with the incidence of CSD. These factors were used to build a competing-risk-based model and a nomogram to predict CSD. The C-index, calibration plot, and decision curve analysis indicated that the nomogram performs well in predicting CSD and is suitable for clinical use. CONCLUSION: A competing-risk based prognostic model is developed to predict the probability of CSD of patients with spinal and pelvic chondrosarcoma. This nomogram performs well and is suitable for clinical use.Level of Evidence: 4.

Suicide and accidental deaths among patients with primary malignant bone tumors.

BACKGROUND: It has been recognized that cancer is associated with a higher risk of suicide or accidental death. Earlier studies have evidenced that patients with malignant bone tumors usually experience psychological dysfunction and physical disability following surgery, which are shared risk factors between suicidal and accidental deaths. To our knowledge, there is no large population-based study on the risk of suicide or accidental death among patients with malignant bone tumors. QUESTIONS/PURPOSES: This study aimed to determine whether patients with primary malignant bone tumors are at a higher risk of suicide and accidental death than the general population and to identify the demographic and tumour-related characteristics and type of surgery associated with a higher risk of suicide and accidental death among these patients. METHODS: Overall, 50,817 patients diagnosed with primary malignant bone tumors between 1973 and 1975 were identified from the Surveillance, Epidemiology, and End Results database. The standardised mortality ratio (SMR) was calculated based on the general population's mortality data, gathered by the National Center for Health Statistics. The Cox regression model was developed to determine risk factors associated with a higher risk of suicide and accidental death. RESULTS: Patients with primary malignant bone tumors had a higher risk of suicide and accidental death than the general population in the United States (US) (SMR = 2.17; 95% confidence interval (CI) [1.80-2.62] and SMR = 1.73; 95% CI [1.54-1.95]). Compared with limb salvage, amputation significantly increased the risk of suicide (SMR = 3.99; 95% CI [2.52-6.34], hazard ratio (HR) = 2.32; 95% CI [1.31-4.09]; P < 0.01) but did not increase the risk of accidental death (SMR = 1.61; 95% CI [1.07-2.42], HR = 1.11; 95% CI [0.71-1.74]; P = 0.65). Higher suicide risk was observed among older patients whose age at diagnosis was more than 60 years (HR = 4.04; 95% CI [1.98-8.26]; P < 0.001), males (HR = 3.48; 95% CI [2.16-5.62]; P < 0.001), and whites (HR = 3.71; 95% CI [1.17-11.73]; P < 0.001). The risk of suicide and accidental death was highest in the first year after diagnosis (SMR = 2.95; 95% CI [1.86-4.69] and SMR = 2.02; 95% CI [1.48-2.74]). CONCLUSION: We first reported that patients with primary malignant bone tumors had a higher risk of suicide and accidental death than the general US population. Therefore, clinicians should pay more attention to the psychological status, physical function, and cognitive level of these survivors.

Individualized model for predicting COVID-19 deterioration in patients with cancer: A multicenter retrospective study.

The 2019 novel coronavirus has spread rapidly around the world. Cancer patients seem to be more susceptible to infection and disease deterioration, but the factors affecting the deterioration remain unclear. We aimed to develop an individualized model for prediction of coronavirus disease (COVID-19) deterioration in cancer patients. The clinical data of 276 cancer patients diagnosed with COVID-19 in 33 designated hospitals of Hubei, China from December 21, 2019 to March 18, 2020, were collected and randomly divided into a training and a validation cohort by a ratio of 2:1. Cox stepwise regression analysis was carried out to select prognostic factors. The prediction model was developed in the training cohort. The predictive accuracy of the model was quantified by C-index and time-dependent area under the receiver operating characteristic curve (t-AUC). Internal validation was assessed by the validation cohort. Risk stratification based on the model was carried out. Decision curve analysis (DCA) were used to evaluate the clinical usefulness of the model. We found age, cancer type, computed tomography baseline image features (ground glass opacity and consolidation), laboratory findings (lymphocyte count, serum levels of C-reactive protein, aspartate aminotransferase, direct bilirubin, urea, and d-dimer) were significantly associated with symptomatic deterioration. The C-index of the model was 0.755 in the training cohort and 0.779 in the validation cohort. The t-AUC values were above 0.7 within 8 weeks both in the training and validation cohorts. Patients were divided into two risk groups based on the nomogram: low-risk (total points ≤ 9.98) and high-risk (total points > 9.98) group. The Kaplan-Meier deterioration-free survival of COVID-19 curves presented significant discrimination between the two risk groups in both training and validation cohorts. The model indicated good clinical applicability by DCA curves. This study presents an individualized nomogram model to individually predict the possibility of symptomatic deterioration of COVID-19 in patients with cancer.

Characteristics, incidence, and risk factors for death from fatal pneumonia among patients with primary malignant bone tumors: a SEER-based observational study.

BACKGROUND: (I) To determine whether patients with malignant bone tumors had a higher risk of dying from pneumonia compared with the general US population; (II) to identify the independent risk factor associated with fatal pneumonia among these patients. METHODS: We identified 18,583 patients diagnosed with primary malignant bone tumors between 1973 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database. Standardized mortality ratios (SMRs) were calculated based on the mortality data of the general population gathered by the National Center for Health Statistics, which provided the risk of death from pneumonia among cancer patients relative to that of the general population. Given that other causes of death were considered as competing events, we also designed the Fine-Gray model to identify demographic and tumor-related characteristics associated with a higher risk of dying from pneumonia among these patients. RESULTS: Patients with primary malignant bone tumors had a higher risk of dying from pneumonia than the general population after adjusting the distribution difference of age, sex, and race among them (SMR =2.79; 95% CI: 2.17-3.59). The older age, Black and earlier period of diagnosis were found to be the independent prognostic factor for a higher risk of death from pneumonia for these patients. Additionally, amputation due to malignant bone tumors significantly increased the risk of death from pneumonia compared with non-surgery. The highest mortality rate of pneumonia was observed among patients with chordoma. Interaction tests demonstrated that amputation only increased the relative risk of fatal pneumonia among patients with osteosarcoma. Throughout the follow-up period, the mortality rate of fatal pneumonia was the highest within the first year after diagnosis, and the highest relative suicide risks persisted over time in patients with osteosarcoma. CONCLUSIONS: To mitigate the risk of fatal pneumonia among patients with bone tumors, we call for long-term clinical monitoring of the lung condition among these patients, especially for those after amputation for bone tumors.