Gut Clostridium sporogenes-derived indole propionic acid suppresses osteoclast formation by activating pregnane X receptor.

Bone homeostasis is maintained by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. A dramatic decrease in estrogen levels in postmenopausal women leads to osteoclast overactivation, impaired bone homeostasis, and subsequent bone loss. Changes in the gut microbiome affect bone mineral density. However, the role of the gut microbiome in estrogen deficiency-induced bone loss and its underlying mechanism remain unknown. In this study, we found that the abundance of Clostridium sporogenes (C. spor.) and its derived metabolite, indole propionic acid (IPA), were decreased in ovariectomized (OVX) mice. In vitro assays suggested that IPA suppressed osteoclast differentiation and function. At the molecular level, IPA suppressed receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced pregnane X receptor (PXR) ubiquitination and degradation, leading to increased binding of remaining PXR with P65. In vivo daily IPA administration or repeated C. spor. colonization protected against OVX-induced bone loss. To protect live bacteria from the harsh gastric environment and delay the emptying of orally administered C. spor. from the intestine, a C. spor.-encapsulated silk fibroin (SF) hydrogel system was developed, which achieved bone protection in OVX mice comparable to that achieved with repeated germ transplantation or daily IPA administration. Overall, we found that gut C. spor.-derived IPA was involved in estrogen deficiency-induced osteoclast overactivation by regulating the PXR/P65 complex. The C. spor.-encapsulated SF hydrogel system is a promising tool for combating postmenopausal osteoporosis without the disadvantages of repeated germ transplantation.

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.

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.

Inhibition of PFKFB3 suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss.

Osteoclasts are multinucleated cells derived from the monocyte/macrophage cell lineage under the regulation of receptor activator of nuclear factor-κB ligand (RANKL). In previous studies, stimulation by RANKL during osteoclastogenesis was shown to induce a metabolic switch to enhanced glycolytic metabolism. Thus, we hypothesized that blockage of glycolysis might serve as a novel strategy to treat osteoclast-related diseases. In the present study, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), an essential regulator of glycolysis, was up-regulated during osteoclast differentiation. Genetic and pharmacological inhibition of PFKFB3 in bone marrow-derived macrophages suppressed the differentiation and function of osteoclasts. Moreover, intraperitoneal administration of the PFKFB3 inhibitor PFK15 prevented ovariectomy-induced bone loss. In addition, glycolytic activity characterized by lactate accumulation and glucose consumption in growth medium was reduced by PFKFB3 inhibition. Further investigation indicated that the administration of L-lactate partially reversed the repression of osteoclastogenesis caused by PFKFB3 inhibition and abrogated the inhibitory effect of PFK15 on the activation of NF-κB and MAPK pathways. In conclusion, the results of this study suggest that blockage of glycolysis by targeting PFKFB3 represents a potential therapeutic strategy for osteoclast-related disorders.

Fine-tuning of FOXO3A in cHL as a survival mechanism and a hallmark of abortive plasma cell differentiation.

We recently found that FOXO1 repression contributes to the oncogenic program of classical Hodgkin lymphoma (cHL). Interestingly, FOXO3A, another member of the FOXO family, was reported to be expressed in the malignant Hodgkin and Reed-Sternberg cells of cHL at higher levels than in non-Hodgkin lymphoma subtypes. We thus aimed to investigate mechanisms responsible for the maintenance of FOXO3A as well as the potential role of FOXO3A in cHL. Here, we show that high FOXO3A levels in cHL reflect a B-cell-differentiation-specific pattern. In B cells, FOXO3A expression increases during the process of centroblast to plasma cell (PC) differentiation. FOXO3A levels in cHL were found higher than in germinal center B cells, but lower than in terminally differentiated PCs. This intermediate FOXO3A expression in cHL might manifest the "abortive PC differentiation" phenotype. This assumption was further corroborated by the finding that overexpression of FOXO3A in cHL cell lines induced activation of the master PC transcription factor PRDM1α. As factors attenuating FOXO3A expression in cHL, we identified MIR155 and constitutive activation of extracellular signal-regulated kinase. Finally, we demonstrate the importance of FOXO3A expression in cHL using an RNA interference approach. We conclude that tightly regulated expression of FOXO3A contributes to the oncogenic program and to the specific phenotype of cHL.

REV-ERB agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation.

REV-ERBs (REV-ERBα and REV-ERBß) are transcription repressors and circadian regulators. Previous investigations have shown that REV-ERBs repress the expression of target genes, including MMP9 and CX3CR1, in macrophages. Because MMP9 and CX3CR1 reportedly participate in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, we inferred that REV-ERBs might play a role in osteoclastogenesis. In the present study, we found that the REV-ERBα level decreased significantly during RANKL-induced osteoclast differentiation from primary bone marrow-derived macrophages (BMMs). REV-ERBα knockdown by small interfering RNA in BMMs resulted in the enhanced formation of osteoclasts, whereas REV-ERBß knockdown showed no effect on osteoclast differentiation. Moreover, the REV-ERB agonist SR9009 inhibited osteoclast differentiation and bone resorption. Intraperitoneal SR9009 administration prevented ovariectomy-induced bone loss; this effect was accompanied by decreased serum RANKL and C-terminal telopeptide of type I collagen levels and increased osteoprotegerin levels. Further investigation revealed that NF-κB and MAPK activation and nuclear factor of activated T cells, cytoplasmic 1, and c-fos expression were suppressed by SR9009. The level of reactive oxygen species was also decreased by SR9009, with NADPH oxidase subunits also being down-regulated. In addition, an expression microarray showed that FABP4, an intracellular lipid-binding protein, was up-regulated by REV-ERB agonism. BMS309403, an inhibitor of FABP4, partially prevented the suppression of osteoclastogenesis by SR9009 through stabilizing phosphorylation of p65. To summarize, our results proved that the REV-ERB agonism inhibited osteoclastogenesis partially via FABP4 up-regulation.-Song, C., Tan, P., Zhang, Z., Wu, W., Dong, Y., Zhao, L., Liu, H., Guan, H., Li, F. REV-ERB agonism suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss partially via FABP4 upregulation.

Lipoxin A4 suppresses osteoclastogenesis in RAW264.7 cells and prevents ovariectomy-induced bone loss.

Lipoxin A4 (LXA4; 5S, 6R, 15Strihydroxy- 7,9,13-trans-11-eicosatetraenoic acid) is a metabolic product of arachidonic acid under the action of lipoxidase. This lipid molecule plays important roles in several biological functions, especially inflammatory processes. In vivo, LXA4 regulates the inflammatory response through several signaling pathways. Its mechanism suggests that it might have an effect on osteoclastogenesis and bone loss. Using both in vitro and in vivo studies, it was here observed that LXA4 could significantly inhibit the formation and function of osteoclasts and these effects could be blocked by Boc-2, the specific inhibitor of FPR2/ALX (the receptor of LXA4). Meanwhile, LXA4 reduce the amount of ovariectomy-induced bone loss. These protective effects was found to be associated with inhibition of nuclear factor-κB (NF-κB), activator protein-1 (AP-1), PI3K-AKT, and p-38, ERK, and JNK in MAPKs. The expression of the receptor activator of the NF-κB ligand RANKL:osteoprotegerin ratio and serum levels of TNF-α, IL-1ß, and IL-6 were decreased by LXA4. Moreover, LXA4 prevented the production of reactive oxygen species (ROS), the expression of osteoclast-specific genes, including tartrate-resistant acid phosphatase (TRAP), cathepsin K (CK), matrix metalloproteinase (MMP)-9, RANK, and osteoclastic related transcription factors of c-Fos, NFATc1 could also be significantly inhibited by LXA4 in a dose-dependent manner. Studies have demonstrated that LXA4 can inhibit the formation and function of osteoclasts through modulation of several pathways both upstream and downstream of RANKL signaling and FPR2/ALX was involved in the procedures. This shows that LXA4 may be used as a new strategy for the treatment of osteoclast-related diseases.

FOXO1 repression contributes to block of plasma cell differentiation in classical Hodgkin lymphoma.

The survival of classical Hodgkin lymphoma (cHL) cells depends on activation of NF-κB, JAK/STAT, and IRF4. Whereas these factors typically induce the master regulator of plasma cell (PC) differentiation PRDM1/BLIMP-1, levels of PRDM1 remain low in cHL. FOXO1, playing a critical role in normal B-cell development, acts as a tumor suppressor in cHL, but has never been associated with induction of PC differentiation. Here we show that FOXO1 directly upregulates the full-length isoform PRDM1α in cHL cell lines. We also observed a positive correlation between FOXO1 and PRDM1 expression levels in primary Hodgkin-Reed-Sternberg cells. Further, we show that PRDM1α acts as a tumor suppressor in cHL at least partially by blocking MYC. Here we provide a link between FOXO1 repression and PRDM1α downregulation in cHL and identify PRDM1α as a tumor suppressor in cHL. The data support a potential role for FOXO transcription factors in normal PC differentiation.

Epoxyeicosanoids suppress osteoclastogenesis and prevent ovariectomy-induced bone loss.

Epoxyeicosatrienoic acids (EETs) are products of arachidonic acid metabolism catalyzed by cytochrome P450 epoxygenases. These small molecules are autocrine and paracrine lipid mediators with important roles in inflammation, cardiovascular function, and angiogenesis. Recent evidence has highlighted EETs as potent promoters of organ regeneration and malignant metastasis. We speculated that EETs might impact osteoclastogenesis and bone loss. Using both in vitro and in vivo studies, we observed that EETs significantly attenuated bone loss and inhibited osteoclast formation and activity, which were associated with a decreased receptor activator of NF-κB ligand (RANKL):osteoprotegerin ratio and serum levels of TNF-α and IL-1ß. At the molecular level, EETs abrogated RANKL-induced activation of NF-κB, activator protein-1 (AP-1), and MAPKs, including ERK and JNK, but not p38, during osteoclast formation. EETs also prevented the production of reactive oxygen species (ROS) following RANKL stimulation. As a result, EETs suppressed osteoclast-specific gene expression, including tartrate resistant acid phosphatase (TRAP), cathepsin K (CK), matrix metalloproteinase (MMP)-9, and receptor activator of NF-κB (RANK). In conclusion, our findings demonstrate that EETs inhibit osteoclastogenesis through modulation of multiple pathways both upstream and downstream of RANKL signaling. The administration or stabilized endogenous levels of EETs could represent a novel therapeutic strategy for osteoclast-related disorders, such as rheumatoid arthritis and postmenopausal osteoporosis.

FOXO1 is a tumor suppressor in classical Hodgkin lymphoma.

The FOXO transcription factors control proliferation and apoptosis in different cell types. Their activity is regulated by posttranslational modifications, mainly by the PI3K-PKB pathway, which controls nuclear export and degradation. We show that FOXO1 is highly expressed in normal germinal center B cells as well as in non-Hodgkin lymphomas, including follicular lymphoma, diffuse large B-cell lymphoma, mucosa-associated lymphoid tissue non-Hodgkin lymphoma, B-cell chronic lymphocytic leukemia, and mantle cell lymphoma. In contrast, in 31 of 32 classical Hodgkin lymphoma (cHL) cases, Hodgkin and Reed-Sternberg cells were FOXO1 negative. Neoplastic cells of nodular lymphocyte-predominant Hodgkin lymphoma were negative in 14 of 20 cases. FOXO1 was down-regulated in cHL cell lines, whereas it was expressed in non-Hodgkin lymphoma cell lines at levels comparable with normal B cells. Ectopic expression of a constitutively active FOXO1 induced apoptosis in cHL cell lines and blocked proliferation, accompanied with cell-cycle arrest in the G(0)/G(1) phase. We found that, in cHL cell lines, FOXO1 is inactivated by multiple mechanisms, including constitutive activation of AKT/PKB and MAPK/ERK kinases and up-regulation of microRNAs miR-96, miR-182, and miR-183. These results suggest that FOXO1 repression contributes to cHL lymphomagenesis.

Decitabine represses translocated MYC oncogene in Burkitt lymphoma.

Burkitt lymphoma (BL) is caused by translocation of the MYC gene to an immunoglobulin locus resulting in its constitutive expression depending on the activity of the immunoglobulin (Ig) enhancer elements. Treatment of BL cell lines with epigenetic modifiers is known to repress B-cell-specific genes and to up-regulate B-cell-inappropriate genes including the transcription repressor ID2 expression. We found that the DNA methyltransferase inhibitor decitabine/5-aza-2-deoxycytidine (5-aza-dC) represses the MYC oncogene on RNA and protein levels by inducing ID2. Down-regulation of MYC was associated with repression of transcriptional activity of the Ig locus and with inhibition of proliferation. The induction of ID2 can be in part explained by activation of the transcription factor NF-κB. We conclude that up-regulation of ID2 contributes to anti-tumour activity of 5-aza-dC via repression of Ig locus activity and consequently MYC expression.

The Research on Spinopelvic Parameters and Clinical Outcomes of Oblique Lumbar Interbody Fusion and Transforaminal Lumbar Interbody Fusion in the Treatment of Complex Degenerative Lumbar Spondylolisthesis.

OBJECTIVE: To investigate the improvement of spinopelvic parameters and therapeutic efficacy in the treatment of complex degenerative lumbar spondylolisthesis (CDLS) after oblique lumbar interbody fusion (OLIF) and transforaminal lumbar interbody fusion (TLIF). METHODS: From January 2018 to December 2020, 71 patients with CDLS underwent OLIF or TLIF at the same hospital: 31 in the OLIF group and 40 in the TLIF group. The spinopelvic parameters, perioperative data, and clinical outcomes were elected and compared between the 2 groups. RESULTS: There were no statistic differences in demographic perioperative complication rates and preoperative spinopelvic parameters between the two groups. OLIF group showed lower serum C-reactive protein in the early postoperative stage, shorter length of stay, less estimated blood loss and larger slippage correction rate (88.05 vs. 62.37%) (all P ＜ 0.05). There was no significant difference in the visual analog scale and Oswestry disability index scores before operation and three and six months after surgery, but OLIF group was better in the long-term with visual analog scale and Oswestry disability index (1.7/13.2 vs. 2.3/16.5). And it was significantly different in the lumbar lordosis angle, segmental lordosis angle, pelvic tilt, sacral slope (46.0°/9.3°/18.2°/35.9° vs. 40.4°/7.2°/23.9°/31.1°), and sagittal vertical axis (21.6 vs. 31.7mm) after surgery between OLIF and TLIF groups (all P ＜ 0.05). CONCLUSIONS: In the therapy of CDLS, OLIF can better reduce pelvic tilt, L1 axis S1 distance, and sagittal vertical axis, and increase lumbar lordosis angle and sacral slope, showing advantages over TLIF in improving and maintaining spinopelvic parameters. Although there was no difference in complication rates between OLIF and TLIF, OLIF was more minimally invasive, had less tissue damage, had faster recovery, and had better long-term outcomes.

Total spondylectomy of C2 and circumferential reconstruction via combined anterior and posterior approach to cervical spine for axis tumor surgery.

As a result of the complex anatomy in upper cervical spine, the operative treatment of axis neoplasms is always complicated. Although the procedure for the second cervical vertebra (C2) surgery had been described previously in diverse approaches and reconstruction forms, each has its own limitations and restrictions that usually result in less satisfactory conclusions. The purpose of this study was to evaluate the operation efficacy for axis tumors by using a combined anterior (retropharyngeal) cervical and posterior approach in achieving total resection of C2 and circumferential reconstruction. Eight consecutive C2 tumor patients with mean age of 47.6 years in our institute sequentially underwent vertebra resection and fixation through aforementioned approach from Jan. 2006 to Dec. 2010. No surgical mortality or severe morbidity occurred in our group. In terms of complications, 2 cases developed transient difficulty in swallowing liquids (one of them experienced dysphonia) and 1 developed cerebrospinal fluid leakage (CSFL) that was resolved later. During a mean follow-up period of 31.9 months, the visual analogue scale (VAS) and Japanese orthopedic association (JOA) score revealed that the pain level and neurological function in all patients were improved postoperatively, and there was no evidence of fixation failure and local recurrence. It is concluded that the anterior cervical retropharyngeal approach permits a visible exposure to facilitate the C2 vertebra resection and perform an effective anterior reconstruction at the same time. The custom-made mesh cage applied in our cases can be acted as a firm and convenient implant in circumferential fixation.

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.

KLF4 is a tumor suppressor in B-cell non-Hodgkin lymphoma and in classic Hodgkin lymphoma.

The transcription factor KLF4 may act both as an oncogene and a tumor suppressor in a tissue-depending manner. In T- and pre-B-cell lymphoma, KLF4 was found to act as tumor suppressor. We found the KLF4 promoter methylated in B-cell lymphoma cell lines and in primary cases of B-cell lymphomas, namely, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, and in classic Hodgkin lymphoma (cHL) cases. Promoter hypermethylation was associated with silencing of KLF4 expression. Conditional overexpression of KLF4 in Burkitt lymphoma cell lines moderately retarded proliferation, via cell-cycle arrest in G(0)/G(1). In the cHL cell lines, KLF4 induced massive cell death that could partially be inhibited with Z-VAD.fmk. A quantitative reverse-transcribed polymerase chain reaction array revealed KLF4 target genes, including the proapoptotic gene BAK1. Using an shRNA-mediated knock-down approach, we found that BAK1 is largely responsible for KLF4-induced apoptosis. In addition, we found that KLF4 negatively regulates CXCL10, CD86, and MSC/ABF-1 genes. These genes are specifically up-regulated in HRS cells of cHL and known to be involved in establishing the cHL phenotype. We conclude that epigenetic silencing of KLF4 in B-cell lymphomas and particularly in cHL may favor lymphoma survival by loosening cell-cycle control and protecting from apoptosis.

Synthesis and characterization of UPPE-PLGA-rhBMP2 scaffolds for bone regeneration.

A novel unsaturated polyphosphoester (UPPE) was devised in our previous research, which is a kind of promising scaffold for improving bone regeneration. However, the polymerization process of UPPE scaffolds was unfavorable, which may adversely affect the bioactivity of osteoinductive molecules added if necessary, such as recombinant human bone morphogenetic protein-2 (rhBMP2). The purpose of this study was to build a kind of optimal scaffold named UPPE-PLGA-rhBMP2 (UPB) and to investigate the bioactivity of rhBMP2 in this scaffold. Furthermore, the cytotoxicity and biocompatibility of UPB scaffold was assessed in vitro. A W1/O/W2 method was used to fabricate PLGA-rhBMP2 microspheres, and then the microspheres were added to UPPE for synthesizing UPB scaffold. The morphological characters of PLGA-rhBMP2 microspheres and UPB scaffolds were observed under the scanning electron microscopy and laser scanning confocal microscopy. The cumulative release of UPB scaffolds was detected by using ELISA. The cytotoxicity and biocompatibility of UPB scaffolds were evaluated through examining the adsorption and apoptosis of bone marrow stromal cells (bMSCs) seeded on the surface of UPB scaffolds. The bioactivity of rhBMP2 in UPB scaffolds was assessed through measuring the alkaline phosphates (ALP) activity in bMSCs seeded. The results showed that UPB scaffolds sequentially exhibited burst and sustained release of rhBMP2. The cytotoxicity was greatly reduced when the scaffolds were immersed in buffer solution for 2 h. bMSCs attached and grew on the surface of soaked UPB scaffolds, exerting well biocompatibility. The ALP activity of bMSCs seeded was significantly enhanced, indicating that the bioactivity of rhBMP2 remained and still took effect after the unfavorable polymerization process of scaffolds. It was concluded that UPB scaffolds have low cytotoxicity, good biocompatibility and preserve bioactivity of rhBMP2. UPB scaffolds are promising in improving bone regeneration.

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.

Clinical and Radiological Outcomes of Two Modified Open-door Laminoplasties Based on a Novel Paraspinal Approach for Treatment of Multilevel Cervical Spondylotic Myelopathy.

STUDY DESIGN: A case-control study. OBJECTIVES: The aim of this study was to evaluate the outcomes of two modified laminoplasties (LPs) based on a novel paraspinal approach for treating multilevel cervical spondylotic myelopathy. SUMMARY OF BACKGROUND DATA: No laminoplasty through a natural intermuscular plane mimicking Wiltse approach to minimize intraoperative injury to extensor muscles has ever been developed and studied. METHODS: Ninety-two patients were enrolled, including patients treated with either modified LP and patients treated with concurrent conventional LP. Operation time, blood loss, and complications were recorded. Clinical outcomes were evaluated by VAS, JOA scores, and recovery rate. Cervical sagittal alignment was measured on cervical radiographs. Spinal canal expansion was assessed on CT scans. Cross-sectional area (CSA) and atrophy rate (AR) of cervical deep extensors were evaluated on MRI. RESULTS: The average follow-up duration was 33.05, 31.55, 33.02, and 32.52 months, respectively in each group. Compared to concurrent conventional procedure, unilateral muscle-preserving procedure displayed similar, whereas bilateral muscle-preserving procedure showed significantly increased operation time and blood loss; each modified procedure resulted in comparable and satisfied perioperative clinical scores, spinal canal expansion while achieving significantly lower axial pain incidence, better cervical lordosis maintenance, and better deep extensor preservation. AR of deep extensors on the open side was significantly lower than that on the hinge side. Bilateral paraspinal approach demonstrated significantly better muscle-preservation on the open side and increased operation duration, with similar clinical scores, axial pain incidence, cervical lordosis maintenance, and spinal canal expansion compared to unilateral paraspinal approach. Loss of cervical lordosis was strongly correlated with AR of deep extensors. CONCLUSION: Paraspinal approach is a good manner to protect deep extensor muscles; the two modified LPs have similar effects on clinical outcomes.Level of Evidence: 3.

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.

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.