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Central nervous system (CNS) trauma, including traumatic brain injury and spinal cord injury, has a high rate of disability and mortality, and effective treatment is currently lacking. Previous studies have revealed that neural inflammation plays a vital role in CNS trauma. As the initial enzyme in neuroinflammation, cytosolic phospholipase A

Spinal cord injury (SCI) results in a wide range of disabilities. Its complex pathophysiological process limits the effectiveness of many clinical treatments. Betulinic acid (BA) has been shown to be an effective treatment for some neurological diseases, but it has not been studied in SCI. In this study, we assessed the role of BA in SCI and investigated its underlying mechanism. We used a mouse model of SCI, and functional outcomes following injury were assessed. Western blotting, ELISA, and immunofluorescence techniques were employed to analyze levels of autophagy, mitophagy, pyroptosis, and AMPK-related signaling pathways were also examined. Our results showed that BA significantly improved functional recovery following SCI. Furthermore, autophagy, mitophagy, ROS level and pyroptosis were implicated in the mechanism of BA in the treatment of SCI. Specifically, our results suggest that BA restored autophagy flux following injury, which induced mitophagy to eliminate the accumulation of ROS and inhibits pyroptosis. Further mechanistic studies revealed that BA likely regulates autophagy and mitophagy via the AMPK-mTOR-TFEB signaling pathway. Those results showed that BA can significantly promote the recovery following SCI and that it may be a promising therapy for SCI.

Central nervous system (CNS) trauma, including traumatic brain injury (TBI) and spinal cord injury (SCI), remains a leading cause for morbidity and mortality worldwide. Past research has shown that cell death plays a critical role in the pathophysiology of CNS injuries. More recently, pyroptosis has been identified as a form of programmed inflammatory cell death, and it is a unique form of cell death in various aspects. Mechanistically, pyroptosis can be categorized into canonical (mediated by caspase-1) and non-canonical (mediated by caspase-4/5/11). In canonical pyroptosis, Nod-like receptors (NLRs) inflammasomes play a critical role, and their activation promotes the maturation and secretion of the inflammatory cytokines interleukin-1β/18 (IL-1β/18), cleavage of gasdermin D (GSDMD), and ultimately pyroptotic cell death. Despite a plethora of new knowledge regarding pyroptosis, detailed understanding of how pyroptosis is involved in CNS injuries and possible ways to improve clinical outcomes following CNS injuries remain elusive. This review discusses the current knowledge on how pyroptosis is involved in CNS injuries, focusing on new discoveries regarding how pyroptosis activation occurs, differences between CNS cell types following injury, time-course of inflammatory responses, and key regulatory steps of pyroptosis. In addition, we highlight various investigational agents that are capable of regulating key steps in pyroptotic cell death, and we discuss how these agents may be used as therapies to improve outcomes following CNS trauma.

Background Glucocorticoids (GCs) overuse is associated with decreased bone mass and osseous vasculature destruction, leading to severe osteoporosis. Platelet lysates (PL) as a pool of growth factors (GFs) were widely used in local bone repair by its potent pro-regeneration and pro-angiogenesis. However, it is still seldom applied for treating systemic osteopathia due to the lack of a suitable delivery strategy. The non-targeted distribution of GFs might cause tumorigenesis in other organs. Results In this study, PL-derived exosomes (PL-exo) were isolated to enrich the platelet-derived GFs, followed by conjugating with alendronate (ALN) grafted PEGylated phospholipid (DSPE-PEG-ALN) to establish a bone-targeting PL-exo (PL-exo-ALN). The in vitro hydroxyapatite binding affinity and in vivo bone targeting aggregation of PL-exo were significantly enhanced after ALN modification. Besides directly modulating the osteogenic and angiogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and endothelial progenitor cells (EPCs), respectively, PL-exo-ALN also facilitate their coupling under GCs’ stimulation. Additionally, intravenous injection of PL-exo-ALN could successfully rescue GCs induced osteoporosis (GIOP) in vivo. Conclusions PL-exo-ALN may be utilized as a novel nanoplatform for precise infusion of GFs to bone sites and exerts promising therapeutic potential for GIOP. Graphical Abstract

Spinal cord injury (SCI) refers to a major worldwide cause of accidental death and disability. However, the complexity of the pathophysiological mechanism can result in less-effective clinical treatment. Growth differentiation factor 11 (GDF-11), an antiageing factor, was reported to affect the development of neurogenesis and exert a neuroprotective effect after cerebral ischaemic injury. The present work is aimed at investigating the influence of GDF-11 on functional recovery following SCI, in addition to the potential mechanisms involved. We employed a mouse model of spinal cord contusion injury and assessed functional outcomes via the Basso Mouse Scale and footprint analysis following SCI. Using western blot assays and immunofluorescence, we analysed the levels of pyroptosis, autophagy, necroptosis, and molecules related to the AMPK-TRPML1-calcineurin signalling pathway. The results showed that GDF-11 noticeably optimized function-related recovery, increased autophagy, inhibited pyroptosis, and alleviated necroptosis following SCI. Furthermore, the conducive influences exerted by GDF-11 were reversed with the application of 3-methyladenine (3MA), an autophagy suppressor, indicating that autophagy critically impacted the therapeutically related benefits of GDF-11 on recovery after SCI. In the mechanistic study described herein, GDF-11 stimulated autophagy improvement and subsequently inhibited pyroptosis and necroptosis, which were suggested to be mediated by TFE3; this effect resulted from the activity of TFE3 through the AMPK-TRPML1-calcineurin signalling cascade. Together, GDF-11 protects the injured spinal cord by suppressing pyroptosis and necroptosis via TFE3-mediated autophagy augmentation and is a potential agent for SCI therapy.

Objectives There is an increased interest in enhanced recovery after surgery (ERAS) minimizing adverse events after orthopedic surgery. Little consensus supports the effectiveness of these interventions. The purpose of present systematic review and meta-analysis is to comprehensively analyze and evaluate the significance of ERAS interventions for postoperative outcomes after orthopedic surgery. Methods PubMed, EMBASE, and Cochrane databases were totally searched from the inception dates to May 31, 2018. Two reviewers independently extracted the data from the selected articles using a standardized form and assessed the risk of bias. The analysis was performed using STATA 12.0. Results A total of 15 published studies fulfilled the requirements of inclusion criteria. We found that the ERAS group showed a significant association with lower incidence of postoperative complications (OR, 0.70; 95% CI, 0.64 to 0.78). Meanwhile, ERAS was also associated with the decline in 30-day mortality rate and Oswestry Disability Index (ODI). However, no significant differences were identified between the two groups regarding the 30-day readmission rate (P = 0.397). Conclusions Our meta-analysis suggested that the ERAS group had more advantages in reducing incidence of postoperative complications, 30-day mortality rate, and ODI after orthopedic surgery, but not of 30-day readmission rate. However, further research with standardized, unbiased methods and larger sample sizes is required for deeper analysis. Electronic supplementary material The online version of this article (10.1186/s13018-019-1116-y) contains supplementary material, which is available to authorized users.

The anti‐inflammatory effect of sinapic acid (SA) has been reported in several studies. However, whether SA has the same effect on osteoarthritis (OA) has yet to be clearly elucidated. We designed a series of in vitro and in vivo procedures to verify the above conjecture. Compared with controls, SA‐pretreated human chondrocytes showed lower levels of interleukin (IL)‐1β‐induced IL‐6, prostaglandin E2 (PGE2), nitric oxide (NO) and tumour necrosis factor‐α (TNF‐α) in vitro. Meanwhile, SA could also reverse the degradation of type II collage and aggrecan, as well as the overproduction of matrix metalloproteinase‐9 (MMP‐9) and matrix metalloproteinase‐13 (MMP‐13), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)‐2 and a disintegrin and metalloproteinase thrombospondin motifs (ADAMTS)‐5. Furthermore, activation of nuclear factor κB (NF‐κB), which was induced by IL‐1β, was also inhibited by SA through the pathway of nuclear factor‐erythroid 2‐related factor‐2 (Nrf2)/heme oxygenase 1. In vivo, SA could delay the progress of mice OA models. We propose that SA may be applied as a potential therapeutic drug in OA treatment.

Objective: This research aimed at examining the volume of hidden blood loss (HBL) in lumbar fusion surgery with two kinds of screw implanting techniques and evaluating HBL-related factors in the patient population receiving lumbar fusion surgeryMethods: A retrospective study was conducted targeting 104 patients with lumbar degenerative diseases and treated with TLIF from January 2017 to December 2018, and the CBT (cortical bone trajectory) technique and conventional PS (pedicle screw) technique were applied to 45 and 59 patients, respectively. The collected data covered patients’ weight, height, BMI index, and operation time. It was followed by the recording of preoperative and postoperative hematocrit (HCT) of patients, based on which the blood loss was calculated by Gross’s formula. Results: The CBT and PS groups presented no significant difference in demographic characteristics (p > 0. 05), but the average HBL of 280±227 mL and 298±232 mL as well as the average TBL of 603±232 mL and 728±321 mL, respectively. It indicated the difference of the two groups in TBL, but no significant difference in HBL. In addition, an association of HBL of two screw techniques with operation time, concomitant disease and age was found from the data analysis.Conclusion: Large total blood loss incurred in lumbar fusion surgery, specifically with a lower value by the CBT technique than by the PS technique. Nonetheless, HBL occupied a large part of the total blood loss and it was identified in both groups. Thus, a good understanding of HBL will improve postoperative rehabilitation and guarantee patients’ safety.

MicroRNAs (miRNAs) perform a variety of important cellular functions, including regulating the cell cycle, apoptosis and differentiation, amongst others. Recent research has demonstrated an essential function performed by miRNAs in regulating pyroptosis, which is a type of programmed cell death associated with inflammatory responses that plays a critical role in numerous diseases. Through direct or indirect action on proteins associated with the pyroptosis signaling pathway, miRNAs are involved in the pathological processes of cardiovascular, kidney and immune diseases, among others. The present review discusses the maturation process of miRNAs and the process of pyroptosis, with a specific focus on the transport of miRNAs to damaged cells via exosomes, shedding vesicles and protein stabilized complexes, as well as the role of different miRNAs in the regulation of pyroptosis through different gene and protein targets. The aim of the present review was to provide a novel insight into the regulatory role of miRNAs in pyroptosis and new treatment options for pyroptosis‑associated diseases.

Background: Spinal cord injury (SCI) is a serious injury that can lead to irreversible motor dysfunction and subsequently result in disability and even death. Due to its complicated pathogenic mechanism, there are no effective drug treatments. Piperine, a natural active alkaloid extracted from black pepper, suppressed inflammation in a previous study. The aim of this study was to investigate the therapeutic effect of piperine in a spinal cord injury model.Methods: Spinal cord injury was induced in C57BL/6 mice by clamping the spinal cord with a vascular clip (15 g force; Oscar) for 1 min. Eighty mice were divided randomly into the following four groups: The Sham group (n = 20), the SCI+Vehicle group (n = 20), the SCI+ Piperine group (n = 20), and the SCI+ Piperine+3MA group (n = 20). Before SCI and every 2 days post-SCI, evaluations of the Basso mouse scale (BMS) were performed. On day 14 after SCI, inclined plane tests and footprint analyses were performed. On postoperative day 3, the spinal cord was harvested to assess pyroptosis, reactive oxygen species (ROS), inflammation, and autophagy. Qualitative or quantitative analysis of the components of these potential mechanisms was performed by Western blotting (WB), immunofluorescence (IF), quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA).Results: Piperine enhanced the functional recovery of spinal cord injury. Additionally, piperine inhibited inflammation, attenuated oxidative stress and pyroptosis, and activated autophagy. However, the effects of piperine on the functional recovery of SCI, ROS-mediated autophagy, inflammation and pyroptosis were reversed by the inhibition of autophagy.Conclusions: Our experiments demonstrated that piperine facilitated the functional recovery of spinal cord injury by inhibiting the inflammatory response, oxidative stress and pyroptosis, which are mediated by the activation of autophagy.

To analyze the causes of vascular injury occurred in oblique lateral interbody fusion for treating lumbar degenerative diseases, and put forward preventive measures.There were 235 patients analyzed from October 2014 to May 2017 in five hospitals, who were treated with oblique lateral interbody fusion with or without posterior pedicle screw fixation. There were 79 males and 156 females with an average age of (61.9±13.5) years old (ranged from 32 to 83 years). There were 7 cases of vascular injury, including 4 cases of segmental vessel injury, 1 case of left common iliac artery injury, 1 case of left common iliac veininjury and 1 case of ovarian vein injury.The follow up time ranged from 6 to 36 months, averagely (15.6±7.5) months. There was no pedicle screw loosen or fracture. The low back pain VAS decreased from preoperative 6.7±2.3 to 1.4±0.8 at the latest follow-up, which was statistically difference(Oblique lateral interbody fusion technique provides a new method for minimally invasive fusion of lumbar internal fixation. However, it has a risk of vascular injury. In order to effectively prevent the occurrence of vascular injury, the operative indications and careful and meticulous operation should be strictly grasped.

Background Previous studies have confirmed the feasibility of the cortical bone trajectory (CBT) technique. However, there are few reports on spinous process violation and screw penetration during the screw insertion. The purpose of this study was to evaluate the incidence of spinous process violation and screw penetration through the pedicle during CBT screw insertion. Methods Computed tomography (CT) scans with normal lumbar structures were consecutively obtained and three-dimensional (3D) reconstructions of the lumbar spine were created. Bilateral CBT screw placement was simulated on each segment using a screw diameter of 4.5 mm, 5.0 mm, or 5.5 mm. Incidences of these complications were recorded and analyzed. Results A total of 90 patients were enrolled. Spinous process violation was observed in 68.3, 53.3, 25.5, 1.7, and 0% from L1 to L5, respectively, using 4.5 mm screws. A significant difference was found among the five segments but this was unconnected to gender or screw diameter. The incidence of screw penetration through the inner wall decreased from L1 to L4; in turn, L1 (16.7–35.5%), L2 (12.7–34.4%), L3 (2.8–23.8%) and L4 (1.1–6.7%). This trend was reversed in L5 (6.7–16.7%). Moreover, screw penetration through the outer wall was rare. The incidence of screw penetration varied with screw size as well as lumbar level, but not with gender. Conclusions There are more difficulties of CBT screw fixation in upper lumbar spine. The low rate of screw penetration, using 4.5 mm screws, suggests the safety for CBT fixation in the lumbar spine. Larger screws (5.0 mm or 5.5 mm) are more recommended for use in the lower lumbar spine. Moreover, CBT fixation in L5 deserves greater attention because of the unique morphology of the pedicle.

Osteoarthritis (OA) is a degenerative joint disease characterized by destruction of articular cartilage. The inflammatory response is the most important factor affecting the disease process. As interleukin-1β (IL-1β) stimulates several key mediators in the inflammatory response, it plays a major role in the pathogenesis of OA. Maslinic acid (MA) is a natural compound distributed in olive fruit. Previous studies have found that maslinic acid has an inhibitory effect on inflammation, but its specific role in the progression of OA disease has not been studied so far. In this study, we aim to assess the protective effect of MA on OA progression by in vitro and in vivo experiments. Our results indicate that, in IL-1β-induced inflammatory response, MA is effective in attenuating some major inflammatory mediators such as nitric oxide (NO) and prostaglandin E2, and inhibits the expression of IL-6, inducible nitric oxide synthase, cyclooxygenase-2, and tumor necrosis factor-α (TNF-α) in a concentration-dependent manner. Also, MA downregulated the expression levels of thrombospondin motif 5 (ADAMTS5) and matrix metalloproteinase 13 in chondrocytes, resulting in reduced degradation of its extracellular matrix. Mechanistically, MA exhibits an anti-inflammatory effect by inactivating the PI3K/AKT/NF-κB pathway. In vivo, the protective effect of MA on OA development can be detected in a surgically induced mouse OA model. In summary, these findings suggest that MA can be used as a safe and effective potential OA therapeutic strategy.

Purpose: The purpose of this study was to investigate finite element biomechanical properties of the novel transpedicular transdiscal (TPTD) screw fixation with interbody arthrodesis technique in lumbar spine. Methods: An L4–L5 finite element model was established and validated. Then, two fixation models, TPTD screw system and bilateral pedicle screw system (BPSS), were established on the validated L4–L5 finite element model. The inferior surface of the L5 vertebra was set immobilised, and moment of 7.5 Nm was applied on the L4 vertebra to test the range of motion (ROM) and stress at flexion, extension, lateral bending and axial rotation. Results: The intact model was validated for prediction accuracy by comparing two previously published studies. Both of TPTD and BPSS fixation models displayed decreased motion at L4–L5. The ROMs of six moments of flexion, extension, left lateral bending, right lateral bending, left axial rotation and right axial rotation in TPTD model were 1.92, 2.12, 1.10, 1.11, 0.90 and 0.87°, respectively; in BPSS model, they were 1.48, 0.42, 0.35, 0.38, 0.74 and 0.75°, respectively. The screws' peak stress of above six moments in TPTD model was 182.58, 272.75, 133.01, 137.36, 155.48 and 150.50 MPa, respectively; and in BPSS model, it was 103.16, 129.74, 120.28, 134.62, 180.84 and 169.76 MPa, respectively. Conclusion: Both BPSS and TPTD can provide stable biomechanical properties for lumbar spine. The decreased ROM of flexion, extension and lateral bending was slightly more in BPSS model than in TPTD model, but TPTD model had similar ROM of axial rotation with BPSS model. The screws' peak stress of TPTD screw focused on the L4–L5 intervertebral space region, and more caution should be put at this site for the fatigue breakage. The translational potential of this article: Our finite element study provides the biomechanical properties of novel TPTD screw fixation, and promotes this novel transpedicular transdiscal screw fixation with interbody arthrodesis technique be used clinically. Keywords: Bilateral pedicle screw system, Biomechanics, Finite element, Lumbar arthrodesis, Transpedicular transdiscal screw

Objective: The objective of this study is to use 3D digital lumbar models to investigate and simulate the optimal posterior operative approach for safe decompression and insertion of an interbody cage. Methods: Thirty lumbar spine (L3-S1) computed tomography data are collected for 3D reconstruction. We cut medial half part of the superior facet and define the distance between the margin of the operative side of the spinous process and the medial margin of the cut superior facet as “medial distance (MD)”. Then, we cut the total superior facet and define the distance between the margin of the operative side of the spinous process and the lateral side of the junction of the pedicle and the vertebral body as “extend distance (ED)”. The feasible insertion of the current standard width size (10 mm and 12 mm) interbody cages was assessed by the two aforementioned MD and ED approaches. Besides the ED, we also simulate four other extensive options of lateral upper, lateral lower, vertical upper and lower and transmedian contralateral decompression on 3D digital lumbar model. Results: The MD increased from 13.48 ± 1.28 mm at L3/4 to 18.05 ± 1.43 mm at L5/S1, and the ED increased from 16.64 ± 1.34 mm at L3/4 to 21.12 ± 1.62 mm at L5/S1. To insert a 10-mm-wide cage, 16.7% (left) and 13.3% (right) of MD for L3/4 is not enough, 60.0% (left) and 46.7% (right) of MD for L3/4 is subsafe, 13.3% (left) and 16.7% (right) of MD for L4/5 is subsafe and all others are safe. To insert a 12-mm-wide cage, 76.7% (left) and 60.0% (right) of MD for L3/4 is not enough, 20.0% (left) and 30.0% (right) of MD for L3/4 is subsafe, 13.3%% (left) and 16.7% (right) of MD for L4/5 is not enough, 63.3% (left) and 56.7% (right) of MD for L4/5 is subsafe and 6.7% (left) and 10.0% (right) of MD for L5/S1 is subsafe, whereas 33.3%% (left) and 30.0% (right) of ED for L3/4 is subsafe, 3.3% (left) and 3.3% (right) of ED for L4/5 is subsafe and all others are safe. Besides the ED, on 3D models, four other extensive options could be simulated too and may need to be performed for different special individuals. Conclusion: Our 3D digital image study provides a feasible optimal medial transforaminal lumbar interbody fusion approach with five extensive options on lower lumbar region. It can provide safe lumbar decompression and interbody fusion in most population. In addition, surgeons can choose the different extensive options for special individual conditions. The translational potential of this article: Transforminal lumbar interbody fusion is very common used for lumbar degenerative diseases. The optimal medial transforminal lumbar interbody fusion with five options provide a safe and precise approach for surgeons in treatment of lumbar degenerative diseases. Keywords: 3D images, Anatomic, Lumbar spine, Transforaminal lumbar interbody fusion

Rapid development of 3D printing techniques has led to the design of navigation templates to assist with accurate insertion of pedicle screws in last decades. However, there are still without the precise step-by-step methods to design 3D navigation templates from computed tomography (CT) images. Our present article provides a detailed protocol to allow the readers or researchers to obtain the 3D navigation template easily, and assist with pedicle screw insertion in their future research and surgery. Using 3D navigation template-assisted pedicle screw fixation in spine surgery is low cost and can decrease the radiation exposure to both patients and surgeons.

Aim: To compare the outcomes of minimally invasive surgery (MIS) for degenerative spondylolisthesis transforaminal lumbar interbody fusion (TLIF) and oblique lumbar interbody fusion (OLIF). Materials & methods: The clinical and surgical characteristics and outcomes of 38 patients with MIS–OLIF and 55 with MIS–TLIF were retrospectively evaluated. Results: Procedures and hospital stay were shorter and blood loss was less, with MIS–OLIF than with MIS–OLIF. The clinical and radiographic outcomes were similar. Postoperative changes in disk height and foraminal dimension were greater and patient satisfaction was better with MIS–OLIF than with MIS–TLIF. Conclusion: The clinical findings associated with the two procedures were similar; but patients preferred MIS–OLIF, which is less invasive, to MIS–TLIF. Clinical trial registration number: ChiCTR1800019443.

Background/Aims: Osteoarthritis is a degenerative joint disease characterized by cartilage degeneration and a chondrocyte inflammatory response that induces an inflammatory environment closely linked to extracellular matrix (ECM) degradation. Ligustilide (LIG) is a major component of the herb Radix Angelicae Sinensis, with demonstrated anti-inflammatory effects. To confirm whether LIG has an equally inhibitory effect on inflammation in human osteoarthritis chondrocytes, we performed in vivo and in vitro experiments to validate the above conjectures and determine the relevant mechanisms. Methods: Quantitative realtime PCR and western blotting were performed to evaluate the expression of MMP-3, MMP-13, ADAMTS-5, iNOS, and COX-2 at both gene and protein levels. An enzyme-linked immunosorbent assay was used to evaluate the levels of other inflammatory factors (PGE2, TNF-α, and IL-6). The PI3K/AKT and nuclear factor kappa B (NF-κB) signaling pathways were also analyzed by western blotting, whereas immunofluorescence was used to assess the expression of collagen II and aggrecan. The in vitro effect of LIG was evaluated by intraperitoneal injection into a mouse osteoarthritis model induced by destabilization of the medial meniscus. Results: LIG lowered the phosphorylation levels of p65, IκBα, and IKKα/β and suppressed the IL-1β-induced expression of MMP-3, ADAMTS-5, iNOS, and COX-2 and the inflammatory factors PGE2, TNF-α, and IL-6. LIG markedly decreased IL-1β-induced degradation of collagen II and aggrecan. In vivo results showed that LIG-treated mouse cartilage showed less damage than the control group; the Osteoarthritis Research Society International (OARSI) score was also lower. LIG further reduced the thickness of the subchondral bone plate and alleviated the synovitis. Conclusion: LIG may act as a promising therapeutic agent for osteoarthritis by attenuating IL-1β-induced inflammation in chondrocytes and ECM degradation via suppression of NF-κB activation by the PI3K/AKT pathway.

STUDY DESIGN This was a longitudinal cohort study. OBJECTIVE The main objective of this study was to investigate the outcomes of surgery with or without radiotherapy during treatment of patients with chondrosarcoma of the osseous spine. SUMMARY OF BACKGROUND DATA Chondrosarcoma is a primary spinal malignant tumor; chemotherapy and radiotherapy (RT) are generally unsuccessful, and thus, the main treatment of choice is complete en bloc resection. However, even with complete resection, these patients still have a significant rate of recurrence, morbidity, and mortality. Although there have been reports that the addition of RT to surgery may lead to increased survival and better cancer control, the evidence of the efficacy of RT remains controversial. MATERIALS AND METHODS Patients diagnosed with chondrosarcoma who are then treated by surgery alone or surgery+RT were identified and extracted from the SEER (Surveillance, Epidemiology, and End Results) database (1973-2013). Propensity score matched (PSM) analysis was performed to balance patient characteristics between surgery alone and surgery+RT groups. Patients with a different grade and stage were stratified and analyzed. RESULTS A total of 778 patients with chondrosarcoma of the osseous spine treated by surgery alone or surgery+RT were extracted from the SEER database. Before PSM, the unadjusted Kaplan-Meier curve and bivariable Cox proportional hazard regression models showed that the surgery alone group had higher chondrosarcoma cancer-specific survival and overall survival than the surgery+RT group (both P

This study examined the volume of hidden blood loss (HBL) and compared perioperative blood loss between minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) and open transforaminal lumbar interbody fusion (O-TLIF).Forty-eight patients who were treated with MI-TLIF and 59 patients treated with O-TLIF were enrolled in this study. Patients' height, weight, and preoperative and postoperative hematocrit (Hct) were recorded and used to calculate total blood loss (TBL) according to the Gross formula. Each patient's HBL was calculated. The data were further analyzed by the Student t test and the χThe visible blood loss (VBL) was 186 ± 95 mL in the MI-TLIF; however, the HBL (423 ± 233 mL; 66.5 ± 16.1% of TBL) was twice the VBL. The VBL in the O-TLIF group was 471 ± 147 mL, and the HBL was 271 ± 223 mL (31.3 ± 23.9% of TBL). Although TBL in MI-TLIF (602 ± 251 mL) was less than in O-TLIF (742 ± 275 mL), the HBL was significantly higher (P0.01). No difference in postoperative blood loss was observed between the 2 groups. Seven and 10 patients had preoperative anemia in the MI-TLIF group and the O-TLIF group, respectively, and 32 and 45 postoperatively.HBL is seriously underestimated and accounts for a large percentage of TBL in both MI-TLIF and O-TLIF. A correct understanding of HBL can ensure patient safety and improve postoperative rehabilitation.

Steroid-induced avascular necrosis of the femoral head (SANFH) is a major limitation of long-term or excessive clinical administration of glucocorticoids. Fludarabine, which is a compound used to treat various hematological malignancies, such as chronic lymphocytic leukemia, acts by down-regulating signal transducer and activator of transcription 1 (STAT1) by inhibiting STAT1 phosphorylation in both normal and cancer cells. This study assessed the effects of fludarabine in vitro (primary murine osteoblasts) and in vivo (rat SANFH model). In vitro, pretreatment with fludarabine significantly inhibited Dexamethasone (Dex)-induced apoptosis in osteoblasts, which was examined by TUNEL staining. Treatment with Dex caused a remarkable decrease in the expression of Bcl-2; an increase in cytochrome c release; activation of BAX, caspase-9, and caspase-3; and an obvious enhancement in STAT1 phosphorylation. However, treatment resulted in the up-regulation of caspase-3 expression. Enhanced P-STAT1 activity and up-regulation of caspase-3 expression were also observed in osteoblasts. In vivo, the subchondral trabeculae in fludarabine-treated rats exhibited less bone loss and a lower ratio of empty lacunae. Taken together, our results suggest that STAT1-mediated up-regulation of caspase-3 is involved in osteoblast apoptosis induced by Dex and indicates that fludarabine may serve as a potential agent for the treatment of SANFH.

Osteoarthritis (OA) is the most common form of joint disease and is widespread in the elderly population and is characterized by erosion of articular cartilage, subchondral bone sclerosis and synovitis. Oleuropein (OL), a secoiridoid, is considered as the most prevalent phenolic component in olive leaves and seeds, pulp and peel of unripe olives and has been shown to have potent anti-inflammatory effects. However, its effects on OA have not been clearly elucidated. This study aimed to assess the effect of OL on human OA chondrocytes. Human OA chondrocytes were pretreated with OL (10, 50 and 100 μM) for 2 h and subsequently stimulated with IL-1β for 24 h. The production of NO, PGE2, MMP-1, MMP-13, and ADAMTS-5 was evaluated by the Griess reaction and ELISA assays. The messenger RNA (mRNA) expression of COX-2, iNOS, MMP-1, MMP13, ADAMTS-5, aggrecan, and collagen-II was measured by using real-time PCR. The protein expressions of COX-2, iNOS, p65, IκB-α, JNK, p-JNK, ERK, p-ERK, p38, and p-p38 were tested by using western blot. We found that OL significantly inhibited the IL-1β-induced production of NO and PGE2; expression of COX-2, iNOS, MMP-1, MMP-13, and ADAMTS-5; and degradation of aggrecan and collagen-II. Furthermore, OL dramatically suppressed IL-1β-stimulated NF-κB and MAPK activation. Immunofluorescence staining demonstrated that OL could suppress IL-1β-induced phosphorylation of p65 nuclear translocation. These results indicate that the therapeutic effect of OL on OA is accomplished through the inhibition of both NF-κB and MAPK signaling pathways. Altogether, our findings provide the evidence to develop OL as a potential therapeutic agent for patients with OA.

Purpose. To investigate the evidence of minimally invasive (MI) versus open (OP) posterior lumbar fusion in treatment of lumbar spondylolisthesis from current prospective literatures.Methods. The electronic literature database of Pubmed, Embase, and Cochrane library was searched at April 2016. The data of operative time, estimated blood loss and length of hospital stay, visual analog scale (VAS) of both lower back pain and leg pain, Oswestry disability index (ODI), SF-36 PCS (physical component scores) and SF-36 MCS (mental component scores), complications, fusion rate, and secondary surgery were extracted and analyzed by STATA 12.0 software.Results. Five nonrandom prospective comparative studies were included in this meta-analysis. The meta-analysis showed that the MI group had a significantly longer operative time than OP group, less blood loss, and shorter hospital stay. No significant difference was found in back pain, leg pain, ODI, SF-36 PCS, SF-36 MCS, complications, fusion rate, and secondary surgery between MI and OP groups.Conclusion. The prospective evidence suggested that MI posterior fusion for spondylolisthesis had less EBL and hospital stay than OP fusion; however it took more operative time. Both MI and OP fusion had similar results in pain and functional outcomes, complication, fusion rate, and secondary surgery.

ObjectiveInconsistent findings in regard to association between different concentrations of vitamin D, calcium or their combination and the risk of fracture have been reported during the past decade in community-dwelling older people. This study was designed to compare the fracture risk using different concentrations of vitamin D, calcium or their combination.DesignA systematic review and network meta-analysis.Data sourcesRandomised controlled trials in PubMed, Cochrane library and Embase databases were systematically searched from the inception dates to 31 December 2017.OutcomesTotal fracture was defined as the primary outcome. Secondary outcomes were hip fracture and vertebral fracture. Due to the consistency of the original studies, a consistency model was adopted.ResultsA total of 25 randomised controlled trials involving 43 510 participants fulfilled the inclusion criteria. There was no evidence that the risk of total fracture was reduced using different concentrations of vitamin D, calcium or their combination compared with placebo or no treatment. No significant associations were found between calcium, vitamin D, or combined calcium and vitamin D supplements and the incidence of hip or vertebral fractures.ConclusionsThe use of supplements that included calcium, vitamin D or both was not found to be better than placebo or no treatment in terms of risk of fractures among community-dwelling older adults. It means the routine use of these supplements in community-dwelling older people should be treated more carefully.PROSPERO registration numberCRD42017079624.

There is no effective strategy for the treatment of spinal cord injury (SCI), a devastating condition characterized by severe hypoxia and ischemic insults. In this study, we investigated the histology and pathophysiology of the SCI milieu in a rat model and found that areas of hypoxia were unevenly interspersed in compressed SCI. With this new knowledge, we generated embryonic neural stem cells (NSCs) expressing basic fibroblast growth factor (bFGF) under the regulation of five hypoxia‐responsive elements (5HRE) using a lentiviral vector (LV‐5HRE‐bFGF‐NSCs) to specifically target these hypoxic loci. SCI models treated with bFGF expressed by the LV‐5HRE‐bFGF‐NSCs viral vector demonstrated improved recovery, increased neuronal survival, and inhibited autophagy in spinal cord lesions in the rat model due to the reversal of hypoxic conditions at day 42 after injury. Furthermore, improved functional restoration of SCI with neuron regeneration was achieved in vivo, accompanied by glial scar inhibition and the evidence of axon regeneration across the scar boundary. This is the first study to illustrate the presence of hypoxic clusters throughout the injury site of compressed SCI and the first to show that the transplantation of LV‐5HRE‐bFGF‐NSCs to target this hypoxic microenvironment enhanced the recovery of neurological function after SCI in rats; LV‐5HRE‐bFGF‐NSCs may therefore be a good candidate to evaluate cellular SCI therapy in humans., Embryonic neural stem cells (NSCs) expressing basic fibroblast growth factor (bFGF) under the regulation of five hypoxia responsive elements (5HRE) using a lentiviral vector (LV‐5HRE‐bFGF‐NSCs) to specifically target these hypoxic loci. SCI models treated with bFGF expressed by the LV‐5HRE‐bFGF‐NSCs viral vector demonstrated improved recovery, increased the survival of neurons, and inhibited autophagy in spinal cord lesions in the rat model due to a reversal of hypoxic conditions post‐injury. Furthermore, improved functional restoration of SCI with neuron regeneration was achieved in vivo accompanied by glial scar inhibition and evidence of axon regeneration across the scar boundary.

Chordoma is a type of rare bone tumor and is a relatively slow-growing, low-grade malignancy that is locally invasive and aggressive. The nomogram is widely used in the field of cancer because it can provide a clear picture for clinicians to predict the survival rate, which can lead more accurate decisions in clinical treatment.Overall, 875 patients with a primary spinal chordoma were identified and collected from the Surveillance, Epidemiology, and End Results registry databases (1973-2015). The nomogram was established based on 425 patients with complete data. The predictive accuracy and discriminative ability of the nomogram were determined by the concordance index (C-index) and calibration curve.The statistical nomogram was built on 10 independent prognostic factors: age, sex, race, disease stage, surgery, year of diagnosis, marital status, primary site, radiation, and tumor size, with C-indices of 0.76. The calibration curve to determine the probability of survival showed good agreement between the predictions by the nomogram and actual observation. Tumor diameter10 cm (hazard ratio [HR] 2.95, 95% confidence interval [CI] 1.77-4.90, P0.001), regional invasive (HR 1.71, 95% CI 1.16-2.53, P0.01), and distant metastasis (HR 3.44, 95% CI 1.98-5.96, P0.001) were independent risk factors for poor survival. Undergoing subtotal resection or gross total resection (HR 0.37, 95% CI 0.25-0.56, P0.001; HR 0.26, 95% CI 0.17-0.41, respectively) and a primary site located in the sacrum/pelvis (HR 0.51, 95% CI 0.34-0.78, P0.01) were prognostic factors for better survival.The nomogram provided more accurate prognostic predictions for patients with spinal chordoma. Moreover, our study suggests that tumor diameter5 cm, distant metastasis, and not performing resection are major risk factors that can dramatically decrease the survival time of patients with spinal chordoma.

Background: Whether or not the addition of 3D (three-dimension) printed models can enhance the teaching and learning environment for undergraduate students in regard to bone spatial anatomy is still unknown. In this study, we investigated the use of 3D printed models versus radiographic images as a technique for the education of medical students about bone spatial anatomy and fractures. Methods: The computed tomography (CT) data from four patients, each with a different fracture type (one spinal fracture, one pelvic fracture, one upper limb fracture, and one lower limb fracture), were obtained, and 3D models of the fractures were printed. A total of 90 medical students were enrolled in the study and randomly divided into two groups as follows: a traditional radiographic image group (presented by PowerPoint) and a 3D printed model group (combined PowerPoint and 3D models). Each student answered 5 questions about one type of fracture and completed a visual analog scale of satisfaction (0–10 points). Results: No significant differences were found in the upper limb or lower limb test scores between the 3D printed model group and the traditional radiographic image group; however, the scores on the pelvis and spine test for the traditional radiographic image group were significantly lower than the scores for the 3D printed model group (P=0.000). No significant differences were found in the test-taking times for the upper limb or lower limb (P=0.603 and P=0.746, respectively) between the two groups; however, the test-taking times for the pelvis and spine in the traditional radiographic image group were significantly longer than those of the 3D printed model group (P=0.000 and P=0.002, respectively). Conclusions: The 3D printed model may improve medical students’ understanding of bone spatial anatomy and fractures in some anatomically complex sites.

Among metabolic and systemic bone diseases, osteoporosis is known as one of the most progressive disease characterized by bone microstructural deterioration and bone mass reduction. Calcitriol (Cal) is widely accepted as a fat-soluble small molecule drug with reported anti-osteoporotic activity. However, delivery systems capable of local sustained release of small molecule drugs remain a significant challenge. Herein, based on poly(D, L-lactide)-poly(ethylene glycol)-poly(D, L-lactide) (PDLLA-PEG-PDLLA) hydrogels, we developed a thermosensitive and multifunctional sustainable delivery system by doubly integrating with polydopamine modified nano-hydroxyapatite (HA-D) and calcitriol-loaded amino-terminated poly(ethylene glycol)-block-poly(epsilon-caprolactone) (PCL-PEG-NH2) micelles to realize the long-term delivery of small molecule drugs. The sustained release of Cal from the system was associate with triple controlled release effects including the protective screen of the hydrogels over micelles, the reservoir effect of the HA nanoparticles for Cal, and the encapsulation of Cal in micelles. In vitro, results from the present study demonstrated that sustainable delivery system effectively activated osteogenesis, proliferation and migration in these bone mesenchymal stromal cells of ovariectomized rats (OVX-rBMSCs). In vivo, the composite Cal-loaded system was verified to promote bone regeneration in the critical-size femoral epicondyle bone defect model. Meanwhile, little cytotoxicity and appropriate degradation rate of the composite Cal delivery system were revealed. Thus, incorporating Cal into a multifunctional delivery system to perform a long-acting drug delivery in an injectable hydrogel form is a promising therapeutic to improve anti-osteoporotic ability and promote bone regeneration of osteoporosis.

We did a clinical trial to determine whether olfactory mucosa lamina propria (OLP) transplants promote regeneration and functional recovery in chronic human spinal cord injury (SCI). The trial randomized 12 subjects to OLP transplants ( n = 8) or control sham surgery ( n=4). The subjects received magnetic resonance imaging (MRI), electromyography (EMG), urodynamic study (UDS), American Spinal Injury Association impairment scale (AIS), and other functional assessments. OLP-transplanted subjects recovered more motor, sensory, and bladder function compared to sham-operated subjects. At 3 years after OLP transplant, one patient improved from AIS A to C and another recovered from AIS A to B, two recovered more than three segmental sensory levels, two had less spasticity, two had altered H-reflexes and SSEP, two regained bladder and anorectal sensation and had improved bladder compliance on UDS. OLP-treated patients had partial or complete tissue bridges at the injury site compared to cavitary gaps in sham-operated patients. The limited recovery suggests that OLP transplants alone do not have significant benefits but may provide a rationale for larger randomized trials or combination therapies.

Objective To analyze the early complications and causes of oblique lateral interbody fusion, and put forward preventive measures. Methods There were 235 patients (79 males and 156 females) analyzed in our study from October 2014 to May 2017. The average age was 61.9 ± 0.21 years (from 32 to 83 years). Ninety-one cases were treated with oblique lateral interbody fusion (OLIF) alone (OLIF alone group) and 144 with OLIF combined with posterior pedicle screw fixation through the intermuscular space approach (OLIF combined group). In addition, 137/144 cases in the combined group were primarily treated by posterior pedicle screw fixation, while the treatments were postponed in 7 cases. There were 190 cases of single fusion segments, 11 of 2 segments, 21 of 3 segments, and 13 of 4 segments. Intraoperative and postoperative complications were observed. Results Average follow-up time was 15.6 ± 7.5 months (ranged from 6 to 36 months). Five cases were lost to follow-up (2 cases from the OLIF alone group and 3 cases from the OLIF combined group). There were 7 cases of vascular injury, 22 cases of endplate damage, 2 cases of vertebral body fracture, 11 cases of nerve injury, 18 cases of cage sedimentation or cage transverse shifting, 3 cases of iliac crest pain, 1 case of right psoas major hematoma, 2 cases of incomplete ileus, 1 case of acute heart failure, 1 case of cerebral infarction, 3 case of left lower abdominal pain, 9 cases of transient psoas weakness, 3 cases of transient quadriceps weakness, and 8 cases of reoperation. The complication incidence was 32.34%. Thirty-three cases occurred in the OLIF alone group, with a rate of 36.26%, and 43 cases in the group of OLIF combined posterior pedicle screw fixation, with a rate of 29.86%. Fifty-seven cases occurred in single-segment fusion, with a rate of 30.0% (57/190), 4 cases occurred in two-segment fusion, with a rate of 36.36% (4/11), 9 cases occurred in three-segment fusion, with a rate of 42.86% (9/21), and 6 cases occurred in four-segment fusion, with a rate of 46.15% (6/13). Conclusion In summary, OLIF is a relatively safe and very effective technique for minimally invasive lumbar fusion. Nonetheless, it should be noted that OLIF carries the risk of complications, especially in the early stage of development.

Background: To investigate the outcomes of using percutaneous kyphoplasty in the treatment of the secondary osteoporotic vertebral compression fractures. Methods: Eighty-one patients had the secondary single segmental osteoporotic vertebral compression fractures after the initial fractures and treated by percutaneous kyphoplasty were reviewed, 74 of them had minimum 2 years follow-up were included in this study. The 74 patients with primary osteoporotic vertebral compression fractures treated by percutaneous kyphoplasty at the same time period were matched as control group in 1:1 ratio. Visual Analogue Scales (VAS) and Oswestry Disability Index (ODI) were used to assess the back pain and functional outcomes. The kyphotic angulation (KA) and compression ratio (CR) of the fractured vertebra was measured too. Results: Both the secondary fracture group and control group had significantly relieved back pain, improved functional outcomes, corrected KA and restored CR after operation, but no difference was found between two groups. Conclusions: Our findings suggest that percutaneous kyphoplasty is an effective and safe procedure for patients with secondary single segmental osteoporotic vertebral compression fractures; it can achieve similar clinical outcomes to the primary osteoporotic vertebral compression fractures.

Many studies have reported micro RNAs involved in the differentiation of bone marrow mesenchymal stem cells (BMSCs) into neural cells; however, the roles of long non-coding RNAs (lncRNAs) in the differentiation of BMSCs into neural cells remain poorly understood. We used microarray assays to compare the lncRNA and messenger RNA (mRNA) expression profiles in BMSCs and neural-induced BMSCs. We found a total of 24 lncRNAs and 738 mRNAs that were upregulated and 32 lncRNAs and 682 mRNAs that were downregulated in samples induced for 3h; 27 lncRNAs and 864 mRNAs that were upregulated and 37 lncRNAs and 968 mRNAs that were downregulated in 6h samples; and 23 lncRNAs and 1159 mRNAs that were upregulated or downregulated in both the 3h and 6h samples. For 23 differentially lncRNAs and 83 differentially mRNAs, 256 matched lncRNA-mRNA pairs were found. GO (Gene ontology) analysis showed that these lncRNAs were associated with biological processes, cellular components, and molecular functions. Twenty-five pathways were identified by pathway analysis. Then, RT-qPCR validation of the differentially expressed H19, Esco2, Pcdhb18, and RGD1560277 genes confirmed the microarray data. Our study revealed the expression patterns of lncRNAs in the differentiation of BMSCs into neural cells, and many lncRNAs were differentially expressed in induced BMSCs, suggesting that they may play key roles in processes of differentiation. Our findings may promote the use of BMSCs to treat neurodegenerative diseases and trauma.

Transpedicular transdiscal screw fixation is an alternative technique used in lumbar spine fixation; however, it requires an accurate screw trajectory. The aim of this study is to design a novel 3D-printed custom drill guide and investigate its accuracy to guide the trajectory of transpedicular transdiscal (TPTD) lumbar screw fixation. Dicom images of thirty lumbar functional segment units (FSU, two segments) of L1–L4 were acquired from the PACS system in our hospital (patients who underwent a CT scan for other abdomen diseases and had normal spine anatomy) and imported into reverse design software for three-dimensional reconstructions. Images were used to print the 3D lumbar models and were imported into CAD software to design an optimal TPTD screw trajectory and a matched custom drill guide. After both the 3D printed FSU models and 3D-printed custom drill guide were prepared, the TPTD screws will be guided with a 3D-printed custom drill guide and introduced into the 3D printed FSU models. No significant statistical difference in screw trajectory angles was observed between the digital model and the 3D-printed model (P > 0.05). Our present study found that, with the help of CAD software, it is feasible to design a TPTD screw custom drill guide that could guide the accurate TPTD screw trajectory on 3D-printed lumbar models.

Osteoarthritis (OA) is a common degenerative disease characterized by progressive erosion of articular cartilage, subchondral bone sclerosis and synovitis. Cryptotanshinone (CTS), an active component extracted from the root of Salvia miltiorrhiza Bunge, has been shown to have potent anti-inflammatory effects. However, its effects on OA have not been clearly elucidated. This study aimed to assess the effect of CTS on human OA chondrocytes and mice OA models. Human OA chondrocytes were pretreated with CTS (5, 10 and 20μM) for 2h and subsequently stimulated with IL-1β for 24h. Production of NO, PGE2, IL-6, TNF-α was evaluated by the Griess reaction and ELISA. The protein expression of COX-2, iNOs, MMP-3, MMP13, COX-2, ADAMTS-5, JNK, p-JNK, ERK, p-ERK, p38, p-p38, p-IKKα/β, p65, p-p65, IκB-α, and p-IκB-α was tested by Western blot. In vivo, the severity of OA was determined by histological analysis. We found that CTS significantly inhibited the IL-1β-induced production of NO and PGE2; expression of COX-2, iNOS, MMP-3, MMP-13, and ADAMTS-5. Furthermore, CTS in dramatically suppressed IL-1β-stimulated NF-κB and MAPK activation. Immunofluorescence staining demonstrated that CTS could suppress IL-1β-induced phosphorylation of p65 nuclear translocation. In vivo, treatment of CTS prevented the destruction of cartilage and the thickening of subchondral bone in mice OA models. These results indicate that the therapeutic effect of CTS on OA is accomplished through the inhibition of both NF-κB and MAPK signaling pathways. Our findings provide the evidence to develop CTS as a potential therapeutic agent f or patients with OA.

To design and investigate a novel technique of percutaneous posterior transdiscal oblique screw fixation with lateral interbody fusion. CT scans of 45 patients were collected and imported into Mimics software for three-dimensional (3D) reconstruction. Cylinders were drawn to simulate the trajectory of the oblique screw. Six measurements were obtained for each unit to design a right size cage: a the distance between the intersection of the simulated trajectory of the screw with the inferior border of the upper vertebra and its anteroinferior corner; b the distance between the intersection of the simulated trajectory of the screw with the superior border of the inferior vertebra and its anterosuperior corner; h the height of the intervertebral space; θ the angle between simulated trajectory of screw and the upper endplate of inferior vertebra; uw: the width of the inferior endplate of upper vertebra; iw: the width of upper endplate of inferior vertebra. Three intact adult fresh-frozen cadaveric specimens were obtained, percutaneous posterior transdiscal oblique screw fixation was performed under X-ray apparatus, and interbody cage was implanted by assistance with special self-retaining retractor system and endoscope. According to the results of data measured from 3D images, trapezoid shape interbody cages with suitable size were designed. Percutaneous posterior oblique screw fixation with lateral interbody fusion was performed on three cadaveric specimens successfully. Using specially designed trapezoid shape interbody cages, assisted by intra-operative image intensification and endoscope, it is feasible to perform percutaneous posterior transdiscal oblique screw fixation with lateral interbody fusion technique.

Osteoporotic fracture is a significant cause of morbidity and mortality and is a challenging global health problem. Previous reports of the relation between vitamin A intake or blood retinol and risk of fracture were inconsistent. We searched Medline and Embase to assess the effects of vitamin A (or retinol or beta-carotene but not vitamin A metabolites) on risk of hip and total fracture. Only prospective studies were included. We pooled data with a random effects meta-analysis with adjusted relative risk (adj.RR) and 95% confidence interval (CI). We used Q statistic and I2 statistic to assess heterogeneity and Egger's test to assess publication bias. Eight vitamin A (or retinol or beta-carotene) intake studies (283,930 participants) and four blood retinol level prospective studies (8725 participants) were included. High intake of vitamin A and retinol were shown to increase risk of hip fracture (adj.RR [95% CI] = 1.29 [1.07, 1.57] and 1.40 [1.03, 1.91], respectively), whereas beta-carotene intake was not found to increase the risk of hip fracture (adj.RR [95% CI] = 0.82 [0.59, 1.14]). Both high or low level of blood retinol was shown to increase the risk of hip fracture (adj.RR [95% CI] = 1.87 [1.31, 2.65] and 1.56 [1.09, 2.22], respectively). The risk of total fracture does not differ significantly by level of vitamin A (or retinol) intake or by blood retinol level. Dose-response meta-analysis shows a U-shaped relationship between serum retinol level and hip fracture risk. Our meta-analysis suggests that blood retinol level is a double-edged sword for risk of hip fracture. To avoid the risk of hip fracture caused by too low or too high a level of retinol concentration, we suggest that intake of beta-carotene (a provitamin A), which should be converted to retinol in blood, may be better than intake of retinol from meat, which is directly absorbed into blood after intake. © 2014 American Society for Bone and Mineral Research.