The natural trends of C-reactive protein after hip arthroplasty for femoral neck fracture without infection.

ABSTRACT: The aim of this study was to estimate the degree of normalization of C-reactive protein (CRP) at 2-weeks and 4-weeks after hip arthroplasty after femoral neck fracture. We also wished to determine whether the degree of CRP normalization differs after total hip arthroplasty (THA) compared to bipolar hemiarthroplasty (BH). We also wanted to analyze the patient factors that may influence CRP normalization.We conducted a retrospective study of 135 patients who had undergone THA (32 cases) or BH (103 cases) for femoral neck fracture by single surgeon from January 2015 to December 2019. We analyzed CRP levels during the preoperative period, the early postoperative period, the 2-week postoperative period, and the 4-week postoperative period.In THA, CRP was normalized in 4 patients (12.5%) and in 15 patients (46.9%) within 2-weeks and 4-weeks after surgery, respectively. In BH, CRP was normalized in 16 patients (15.5%) and in 52 patients (50.5%) within 2-weeks and 4-weeks after surgery, respectively. There were no statistical differences between THA and BH. Compared to women, men were 3.78 (95% confidence interval, 1.05-13.63) times less likely to have normalized CRP at 2-weeks after surgery (P = .042). Compared to women, men were 3.01 (95% confidence interval, 1.44-6.27) times less likely to have normalized CRP at 4-weeks after surgery (P = .003).Only 50% of patient's CRP level was normalized during 4-week postoperative period. In men, CRP levels were significantly higher than women in whole period. In the case of THA, the CRP level was higher only in early postoperative period compared to BH, and there was no difference since then.

Bone screws of porous silicon carbide coated with tantalum improve osseointegration and osteogenesis in goat femoral neck fractures.

Traditional metal materials, such as stainless steel and titanium (Ti) alloys, are still the gold standards for fracture fixation. However, the elastic moduli of these materials differ from that of human cortical bone, and the stress shielding effect affects fracture healing, leading to secondary fractures. Herein, a new porous Ta coated SiC (pTa-SiC) scaffold using in internal fixation devices with good mechanical and biological properties was prepared based on porous silicon carbide (SiC) scaffold and tantalum (Ta) metal. The osteogenic and osseointegration properties of the pTa-SiC scaffold were investigated by bothin vitroandin vivotests. The results showed that compared with porous titanium (pTi), the pTa-SiC promoted the proliferation, migration, and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. Moreover, the internal fixation tests were carried out in a goat load-bearing femoral neck fracture model. Histological results showed good osseointegration around the pTa-SiC screws. And the acid etching results showed that bone cells grew tightly on the pTa-SiC throughout bone canaliculi, and the growth mode was contact osteogenesis, which indicated good biological fixation effects. Therefore, it is reasonable to be expected that the new pTa-SiC scaffold with excellent mechanical and biological properties could be a promising candidate for bone implant field.

Cell-associated type I collagen in nondegenerate and degenerate human articular cartilage.

Chondrocytes with abnormal morphology are present in nondegenerate human cartilage suggesting dedifferentiation to a fibroblastic phenotype and production of a mechanically-weakened matrix of unknown composition. We determined the relationship between in situ chondrocyte morphology, chondrocyte clusters, and levels of cell-associated collagen type I. Chondrocyte morphology in fresh femoral head cartilage from 19 patients with femoral neck fracture and collagen type I labelling was identified with Cell TrackerTM fluorescence and immunofluorescence, respectively, in axial/coronal orientations using confocal microscopy with images analysed by ImarisTM . In axial images of grade 0 cartilage, 87 ± 8% were normal chondrocytes with a small (10 ± 6%) abnormal population possessing ≥1 cytoplasmic process. More normal chondrocytes (78 ± 11%) were collagen type I negative than those labelling positively (p < 0.001). For abnormal chondrocytes, 81 ± 14% labelled negatively for collagen type I compared to those labelling positively (19 ± 3%; p = 0.007; N(n)=11(3)). Overall, approximately 9% of the cells in normal cartilage labelled for collagen type I. With degeneration, the percentage of normal chondrocytes decreased (p < 0.001) but increased for abnormal cells (p = 0.036) and clusters (p = 0.003). A larger percentage of normal, abnormal and clustered chondrocytes now demonstrated collagen type I labelling (p = 0.004; p = 0.009; p = 0.001 respectively). Coronal images exhibited increased (p = 0.001) collagen type I labelling in the superficial zone of mildly degenerate cartilage with none in the mid or deep zones. These results show that collagen type I was identified around normal and abnormal chondrocytes in nondegenerate cartilage, which increased with degeneration. This suggested the presence of mechanically weak fibro-cartilaginous repair tissue in otherwise macroscopically nondegenerate human cartilage which progressed with degeneration as occurs in osteoarthritis.

MALAT1 knockdown promoted cell viability and migration of LPS-treated MG-63 cells via sponging miR-212.

BACKGROUND: Most fractures could heal after treatment, around 5-10 % of patients still develop delayed union and nonunion. Evidence has increasingly shown that abnormal expression of long noncoding RNAs is closely related to the occurrence and development of various diseases including fracture healing. However, evidence regarding the effect of MALAT1 on fracture healing remains limited. OBJECTIVES: In this study, we attempt to explore the role of MALAT1 during the process of femoral neck fracture healing and elucidate the underlying mechanism of this disease. METHODS: We first detect the expression of lncRNAs in serums from 3 pairs of patients with delayed femoral neck fracture healing and healthy volunteers using lncRNA microarray. And the expression of long noncoding RNA MALAT1 in serums and LPS-treated MG-63 cells was measured using qRT-PCR. CCK-8 assay, cell migration and qRT-PCR were applied to the role of MALAT1 knockdown in LPS-treated MG-63 cells. ELISA was used for the measurement of inflammatory cytokines in serums of patients and healthy volunteers. The bioinformatics analysis and the rescue experiment were devoted to the underlying mechanism. RESULTS: MALAT1 expression was up-regulated in serum of patients with delayed union of femoral neck fracture. MALAT1 knockdown promoted cell viability and migration, reduced inflammation in LPS-treated MG-63 cells. The bioinformatics analysis showed MALAT1 acts as a molecular sponge for miR-212. And SOX6 was a target of miR-212. Besides, MALAT1 knockdown suppressed SOX6 expression via targeting miR-212 in LPS-treated MG-63 cells. CONCLUSIONS: These data suggest MALAT1 knockdown promoted the biological behavior of LPS-treated MG-63 cells via sponging miR-212, which may provide a new therapeutic avenue for delayed union of femoral neck fracture.

HIF/Ca2+/NO/ROS is critical in roxadustat treating bone fracture by stimulating the proliferation and migration of BMSCs.

AIMS: Fracture site is regionally hypoxic resulting from vasculature disruption. HIF-1αplays an essential role in fracture repair. This study aims to investigate the influence of FG4592 on the femur fracture of SD rats and the proliferation, migration of BMSCs. MATERIALS AND METHODS: After the femoral fracture model was established, computed tomography imaging and histological analyses were used to quantify bone healing and the expression of CD90, HIF-1α, VEGF were observed by means of immunohistochemistry method on Day 10 and Day 20. In addition, CCK-8 assay, transwell, flow cytometric analysis, laser confocal microscopy assay, western blot and rT-PCR were performed to text the proliferation and migration of BMSCs using FG4592. KEY FINDINGS: In vivo, FG4592 facilitated the repair of bone fracture by increasing the number of BMSCs and cartilage formation. In vitro, FG4592 markedly improved the proliferation, migration of BMSCs via upregulation of intracellular Ca2+, NO and concomitant decrease of ROS. Gene silencing of HIF-1α resulted in the opposite phenomenon in BMSCs with the treatment of FG4592. SIGNIFICANCE: The transplantation of BMSCs is the most promising candidate for the treatment of fracture non-union. We illustrated that FG4592 promoted the proliferation, migration of BMSCs via the HIF/Ca2+/NO/ROS pathway and further accelerated fracture healing. These results provide a deeper understanding for the mechanism of HIF in promoting fracture healing.

The local concentration of Ca2+ correlates with BMP7 expression and osseointegration in patients with total hip arthroplasty.

BACKGROUND: A successful osseointegration of total hip arthroplasty (THA) relies on the interplay of implant surface and bone marrow microenvironment. This study was undertaken to investigate the impact of perioperative biochemical molecules (Ca2+, Mg2+, Zn2+, VD, PTH) on the bone marrow osteogenetic factors (BMP2, BMP7, Stro-1+ cells) in the metaphyseal region of the femoral head, and further on the bone mineral density (BMD) of Gruen R3. METHODS: Bone marrow aspirates were obtained from the discarded metaphysis region of the femoral head in 51 patients with THA. Flow cytometry was used to measure the Stro-1+ expressing cells. ELISA was used to measure the concentrations of bone morphologic proteins (BMP2 and BMP7) and the content of TRACP5b in serum. TRAP staining was used to detect the osteoclast activity in the hip joint. The perioperative concentrations of the biochemical molecules above were measured by radioimmunoassay. The BMD of Gruen zone R3 was examined at 6 months after THA, using dual-energy X-ray absorptiometry (DEXA). RESULTS: Our data demonstrated that the concentration of Ca2+ was positively correlated with BMP7 expression, and with the postoperative BMD of Gruen zone R3. However, the concentration of Mg2+ had little impact on the R3 BMD, although it was negatively correlated with the expression of BMP7. Osteoclast activity in hip joint tissue of patients with femoral neck fractures was increased. Compared with the patients before THA, the levels of TRACP5b in serum of patients after THA were decreased. The data also suggested that the other biochemical molecules, such as Zn2+, VD, and PTH, were not significantly correlated with any bone marrow osteogenetic factors (BMP2, BMP7, Stro-1+ cells). The postoperative R3 BMD of patients of different gender and age had no significant difference. CONCLUSIONS: These results indicate the local concentration of Ca2+ may be an indicator for the prognosis of THA patients.

LncRNA HAGLR accelerates femoral neck fracture healing through negatively regulating miRNA-19a-3p.

OBJECTIVE: This study aims to uncover the function of long non-coding RNA (lncRNA) HAGLR in the healing process of femoral neck fracture and the underlying mechanism. PATIENTS AND METHODS: Expression levels of HAGLR, microRNA-19a-3p (miRNA-19a-3p) and TGFBR2 in fractured femoral neck tissues and adjacent normal tissues were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Regulatory effects of HAGLR on viability, apoptosis, migration, and protein levels of BALP and Osteocalcin in MC3T3-E1 cells were determined. Dual-Luciferase reporter gene assay was conducted to assess the binding in HAGLR/miRNA-19a-3p/TGFBR2. In addition, relative levels of TGFBR2, p-smad2, p-smad3, and RUNX2 in MSCs influenced by HAGLR were detected. RESULTS: HAGLR was downregulated in fractured femoral neck tissues. Knockdown of HAGLR reduced viability and migration, enhanced apoptotic rate, as well as downregulated BALP and Osteocalcin in MC3T3-E1 cells. HAGLR served as miRNA-19a-3p sponge, and miRNA-19a-3p directly targeted 3'-untranslated region (3'-UTR) of TGFBR2. Knockdown of HAGLR downregulated expressions of TGFBR2, p-smad2, p-smad3, and RUNX2 in MC3T3-E1 cells, indicating the inhibited TGF-ß pathway. CONCLUSIONS: LncRNA HAGLR/miRNA-19a-3p/TGFBR2 regulatory loop accelerates the healing process of femoral neck fracture by inhibiting the TGF-ß pathway.

Altered microRNA profile during fracture healing in rats with diabetes.

BACKGROUND: MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that regulate gene expression. There is increasing evidence that some miRNAs are involved in the pathology of diabetes mellitus (DM) and its complications. We hypothesized that the functions of certain miRNAs and the changes in their patterns of expression may contribute to the pathogenesis of impaired fractures due to DM. METHODS: In this study, 108 male Sprague-Dawley rats were divided into DM and control groups. DM rats were created by a single intravenous injection of streptozotocin. Closed transverse femoral shaft fractures were created in both groups. On post-fracture days 5, 7, 11, 14, 21, and 28, miRNA was extracted from the newly generated tissue at the fracture site. Microarray analysis was conducted with miRNA samples from each group on post-fracture days 5 and 11. The microarray findings were validated by real-time polymerase chain reaction (PCR) analysis at each time point. RESULTS: Microarray analysis revealed that, on days 5 and 11, 368 and 207 miRNAs, respectively, were upregulated in the DM group, compared with the control group. The top four miRNAs on day 5 were miR-339-3p, miR451-5p, miR-532-5p, and miR-551b-3p. The top four miRNAs on day 11 were miR-221-3p, miR376a-3p, miR-379-3p, and miR-379-5p. Among these miRNAs, miR-221-3p, miR-339-3p, miR-376a-3p, miR-379-5p, and miR-451-5p were validated by real-time PCR analysis. Furthermore, PCR analysis revealed that these five miRNAs were differentially expressed with dynamic expression patterns during fracture healing in the DM group, compared with the control group. CONCLUSIONS: Our findings will aid in understanding the pathology of impaired fracture healing in DM and may support the development of molecular therapies using miRNAs for the treatment of impaired fracture healing in patients with DM.

A quantitative biomechanical study of positive buttress techniques for femoral neck fractures: a finite element analysis.

BACKGROUND: Refractory femoral neck fractures cannot be anatomically reduced by closed traction reduction which may affect fracture healing. We evaluated the biomechanical effects of positive, negative, and anatomic reduction of various degrees of displacement in Pauwels I femoral neck fractures by a finite element analysis. METHODS: Five reduction models of Pauwels type I femoral neck fracture were established using the Mimics 17.0 (Materialize, Leuven, Belgia) and Hypermesh 12.0 (Altair Engineering, Troy, MI, USA). According to the degree of fracture displacement, there were three models of positive support, an anatomic reduction model, and a negative 2 mm reduction model. Finite element analysis was conducted using the ABAQUS 6.9 software (Simulia, Suresnes, France). The von Mises stress distribution and the stress peak of internal fixation in different models, the displacement between fracture blocks, and the principal strain of the femoral neck cancellous bone model were recorded under the axial stress of 2100 N. RESULTS: The peak von Mises stress on screw of each model was located at the thread of the screw tip. The peak von Mises stress was the lowest at the tip of the anatomic reduction model screw (261.2 MPa). In the positive 4 mm model, the von Mises stress peak was the highest (916.1 MPa). The anatomic reduction model showed the minimum displacement (0.388 mm) between fracture blocks. The maximum displacement was noted in the positive 4 mm model (0.838 mm). The displacement in the positive 3 mm model (0.721 mm) was smaller than that in the negative 2 mm model (0.786 mm). Among the five models, the strain area of the femoral neck cancellous bone was mainly concentrated around the screw hole, and the area around the screw hole could be easily cut. CONCLUSIONS: Compared with negative buttress for femoral neck fracture, positive buttress can provide better biomechanical stability. In Pauwel type I fracture of femoral neck, the range of positive buttress should be controlled below 3 mm as far as possible.

Performance of FRAX and FRAX-Based Treatment Thresholds in Women Aged 40 Years and Older: The Manitoba BMD Registry.

We examined among women aged ≥40 years the performance of the Fracture Risk Assessment Tool (FRAX) and FRAX-based osteoporosis treatment thresholds under the US National Osteoporosis Foundation (NOF) and UK National Osteoporosis Guideline Group (NOGG) guidelines. We used registry data for all women aged ≥40 years in Manitoba, Canada, with baseline bone mineral density (BMD) testing (n = 54,459). Incident major osteoporotic fracture (MOF), hip fracture, and clinical fracture were assessed from population-based health services data (mean follow-up 10.5 years). Age-stratified hazard ratios (HR) were estimated from Cox regression models. We assessed the sensitivity, specificity, positive predictive value (PPV), number needed to screen (NNS), and number needed to treat (NNT) to prevent a fracture (assuming 20% relative risk reduction on treatment) for osteoporosis treatment thresholds under the NOF and NOGG guidelines. Femoral neck T-score and FRAX (with and without BMD) predicted all fracture outcomes at all ages. There was good calibration in FRAX-predicted versus observed 10-year MOF and hip fracture probability. Overall sensitivity (PPV) for incident MOF was 25.7% (24.0%) for femoral neck T-score ≤ -2.5; 20.3% (26.3%) for FRAX (with BMD)-predicted 10-year MOF risk ≥20% (NOF threshold); 27.3% (22.0%) for FRAX-predicted 10-year MOF risk ≥ age-dependent cut-off (NOGG threshold), 59.4% (19.0%) for the NOF treatment algorithm; and 28.5% (18.4%) for the NOGG treatment algorithm. Sensitivity for identifying incident MOF varied by age, ranging from 0.0% to 26.3% in women 40 to 49 years old and from 49.0% to 93.3% in women aged 80+ years. The gradient of risk for fracture prediction from femoral neck T-score and FRAX (with and without BMD) as continuous measures was strong across the age spectrum. The sensitivity and PPV of the strategies based on dichotomous cut-offs are low, especially among women aged 40 to 49 years (who have lowest incidence rates). Threshold-based approaches should be reassessed, particularly in younger women. © 2019 American Society for Bone and Mineral Research.

Deletion of FOXO1 in chondrocytes rescues the effect of diabetes on mechanical strength in fracture healing.

Diabetes increases the risk of fracture, impairs fracture healing and causes rapid loss of the fracture callus cartilage, which was linked to increased FOXO1 expression in chondrocytes. We recently demonstrated that deletion of FOXO1 in chondrocytes blocked the premature removal of cartilage associated with endochondral bone formation during fracture healing. However, the ultimate impact of this deletion on mechanical strength was not investigated and remains unknown. Closed fractures were induced in Col2α1Cre+.FOXO1L/L mice with lineage specific deletion of FOXO1 in chondrocytes compared to littermate controls. Type 1 diabetes was induced by multiple low dose streptozotocin treatment. Thirty-five days after fracture micro CT analysis showed that diabetes significantly reduced callus volume and bone volume (P < 0.05), both which were reversed by FOXO1 deletion in chondrocytes. Diabetes significantly reduced mechanical strength measured by maximum torque, stiffness, modulus of rigidity and toughness and FOXO1 deletion in diabetic mice rescued each parameter (P < 0.05). Diabetes also reduced both bone volume and mechanical strength in non-fractured femurs. However, FOXO1 deletion did not affect bone volume or strength in non-fractured bone. These results point to the important effect that diabetes has on chondrocytes and show for the first time that the premature removal of cartilage induced by FOXO1 in chondrocytes has a significant impact on the mechanical strength of the healing bone.

Targeted proteomics of hip articular cartilage in OA and fracture patients.

Osteoarthritis (OA) is a common chronic disease, causing joint pain and reduced physical function. OA progresses slowly over a period of several years; to avoid an exacerbation of symptoms, it is critical to able to diagnose the disease as early as possible. The identification of disease-specific biomarkers may enable such an early diagnosis. The aim of this study was to investigate potential biomarkers of cartilage metabolism in OA using a targeted multiplex approach by single reaction monitoring. Intact looking cartilage of femoral heads from patients with OA (n = 9) or femoral neck fractures (n = 12) was examined. Variations and relative quantifications of 35 selected extracellular matrix (ECM) proteins were analyzed using nano-LC coupled to tandem mass spectrometry. Our study showed statistically significantly increased levels of asporin (ASPN), mimecan (MIME), matrilin-3 (MATN3), cartilage intermediate layer protein 2 (CILP-2), collagen VI, collagen II, and collagen III N-propeptide in OA cartilage compared with non-OA cartilage. The other proteins in the protein panel did not appear to be different between the two groups. In conclusion, we identified a number of cartilage matrix proteins which may represent early molecular changes in the OA process and may have potential to predict the development of OA. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Different Kinetics of Perioperative CRP after Hip Arthroplasty for Elderly Femoral Neck Fracture with Elevated Preoperative CRP.

This study aimed to determine the kinetics of four inflammatory markers and to identify the variables that affect the natural kinetics of inflammatory markers in aged patients having hip fractures with and without elevated preoperative CRP. 240 elderly patients who have been operated on for femoral neck fracture with no infectious complications were divided into two groups on elevated preoperative CRP level (>10 mg/L). The temporal values of four inflammatory markers of WBC, neutrophil count (N) (%), ESR, and CRP were assessed eight times every other day until the 14th postoperative day. At 48-60 h postoperatively, mean CRP was markedly higher in patients with preoperatively elevated CRP than in those with nonelevated CRP (122.1 ± 65.9 and 73.7 ± 35.5, p < 0.001). However, the abrupt elevation of CRP in the elevated group was conversely decreased on the 4th-5th postoperative day, demonstrating similar kinetic curves with no significant differences between both groups. For WBC, N (%), and ESR, both groups showed similar patterns of temporal values 14 days after surgery regardless of preoperative CRP level. Our findings could be used as guidelines for patient discharge and during the follow-up period after surgery.

Upregulation of microRNA-320 decreases the risk of developing steroid-induced avascular necrosis of femoral head by inhibiting CYP1A2 both in vivo and in vitro.

Steroid-induced avascular necrosis of femoral head (SANFH) occurs frequently in patients receiving high-dose steroid treatment for these underlying diseases. The target of this study is to investigate the effect of microRNA-320 (miR-320) on SANFH by targeting CYP1A2. CYP1A2 expression was detected using immunohistochemistry. Specimens were collected from patients with SANFH and femoral neck fracture. Seventy rats were assigned into seven groups. The targeting relationship between miR-320 and CYP1A2 was verified by bioinformatics website and dual luciferase reporter gene assay. RT-qPCR and Western blot analysis were used to detect miR-320 and CYP1A2 expressions. The enzymatic activity of CYP1A2 was detected by fluorescence spectrophotometry. Hemorheology and microcirculation were measured in rats. MiR-320 expression decreased and CYP1A2 expression and enzymatic activity increased in SANFH patients compared to those with femoral neck fracture. CYP1A2 was the target gene of miR-320. Hemorheology and microcirculation results showed that up-regulated expression of CYP1A2 promoted the development of SANFH while increased expression of miR-320 inhibited the development of SANFH. Compared with the SANFH group, the SANFH + miR-320 mimic group showed increased miRNA-320 expression, and decreased CYP1A2 expression and enzymatic activity. Opposite results were found in the SANFH + miR-320 inhibitor group. The SANFH + miR-320 inhibitor + pCR-CYP1A2_KO group showed decreased miRNA-320 expression and the SANFH + pCR-CYP1A2_KO group showed decreased CYP1A2 expression and enzymatic activity. Our findings provide evidences that miR-320 might inhibit the development of SANFH by targeting CYP1A2.

FGF2 and FAM201A affect the development of osteonecrosis of the femoral head after femoral neck fracture.

Osteonecrosis of the femoral head (ONFH) is a common orthopedic disease associated with high disability, and femoral neck fracture (FNF) is one of the most common reasons for traumatic ONFH. This study was designed to reveal the mechanisms underlying ONFH. Using fastx_toolkit and prinseq-lite tools, quality control was conducted for the sequencing data. The differentially expressed genes (DEGs, including both mRNAs and lncRNAs) between ONFH and FNF samples were identified using the edgeR package in R, and were then subjected to enrichment analysis using the BioCloud platform. Subsequently, protein-protein interaction (PPI) networks were constructed using Cytoscape software. After the target genes of DE-lncRNAs were predicted based on Spearman's rank correlation coefficient, lncRNA-gene coexpression network was visualized using the Cytoscape software. Furthermore, functional enrichment analysis was carried out for the target genes using the clusterprofiler package in R. Additionally, the key genes were detected by quantitative real-time polymerase chain reaction (qRT-PCR). A total of 2965 DEGs were identified from the ONFH samples, including 602 DE-lncRNAs (such as downregulated FAM201A). In the PPI networks, eight upregulated genes (including FGF2, IGF1, SOX9, and COL2A1) and 11 downregulated genes were among the top 20 genes according to all of the scores, such as degree centrality, closeness centrality, and betweenness centrality scores. Functional enrichment analysis showed that IGF1, SOX9, and COL2A1 were significantly enriched during skeletal system development. Moreover, qRT-PCR experiments detected the upregulation of FGF2 and downregulation of FAM201A in ONFH samples. FGF2 and FAM201A were correlated with the development of ONFH. Besides, IGF1, SOX9, and COL2A1 might also affect the pathogenesis of ONFH.

Increased microRNA-93-5p inhibits osteogenic differentiation by targeting bone morphogenetic protein-2.

BACKGROUND AND PURPOSE: Trauma-induced osteonecrosis of the femoral head (TIONFH) is a major complication of femoral neck fractures. Degeneration and necrosis of subchondral bone can cause collapse, which results in hip joint dysfunction in patients. The destruction of bone metabolism homeostasis is an important factor for osteonecrosis. MicroRNAs (miRNAs) have an important role in regulating osteogenic differentiation, but the mechanisms underlying abnormal bone metabolism of TIONFH are poorly understood. In this study, we screened specific miRNAs in TIONFH by microarray and further explored the mechanism of osteogenic differentiation. DESIGN: Blood samples from patients with TIONFH and patients without necrosis after trauma were compared by microarray, and bone collapse of necrotic bone tissue was evaluated by micro-CT and immunohistochemistry. To confirm the relationship between miRNA and osteogenic differentiation, we conducted cell culture experiments. We found that many miRNAs were significantly different, including miR-93-5p; the increase in this miRNA was verified by Q-PCR. Comparison of the tissue samples showed that miR-93-5p expression increased, and alkaline phosphatase (ALP) and osteopontin (OPN) levels decreased, suggesting miR-93-5p may be involved in osteogenic differentiation. Further bioinformatics analysis indicated that miR-93-5p can target bone morphogenetic protein 2 (BMP-2). A luciferase gene reporter assay was performed to confirm these findings. By simulating and/or inhibiting miR-93-5p expression in human bone marrow mesenchymal stem cells, we confirmed that osteogenic differentiation-related indictors, including BMP-2, Osterix, Runt-related transcription factor, ALP and OPN, were decreased by miR-93-5p. CONCLUSION: Our study showed that increased miR-93-5p in TIONFH patients inhibited osteogenic differentiation, which may be associated with BMP-2 reduction. Therefore, miR-93-5p may be a potential target for prevention of TIONFH.

The Effect of Abaloparatide-SC on Fracture Risk Is Independent of Baseline FRAX Fracture Probability: A Post Hoc Analysis of the ACTIVE Study.

Daily subcutaneous (SC) injections of the investigational drug abaloparatide-SC (80 mcg) for 18 months significantly decrease the risk of vertebral and nonvertebral fracture compared with placebo in postmenopausal women. We examined the efficacy of abaloparatide-SC as a function of baseline fracture risk, assessed using the FRAX tool. Baseline clinical risk factors (age, body mass index [BMI], prior fracture, glucocorticoid use, rheumatoid arthritis, and smoking) were entered into country-specific FRAX models to calculate the 10-year probability of major osteoporotic fractures, with or without femoral neck bone mineral density (BMD). The interaction between probability of a major osteoporotic fracture and treatment efficacy was examined by a Poisson regression. A total of 821 women randomized to placebo and 824 women to abaloparatide-SC, mean age 69 years in both groups, were followed for up to 2 years. At baseline, the 10-year probability of major osteoporotic fractures (with BMD) ranged from 2.3% to 57.5% (mean 13.2%). Treatment with abaloparatide-SC was associated with a 69% (95% confidence interval [CI] 38-85%) decrease in major osteoporotic fracture (MOF) and a 43% (95% CI 9-64%) decrease in any clinical fracture compared with placebo. For all outcomes, hazard ratios tended to decrease (ie, greater efficacy) with increasing fracture probability. Whereas the interaction approached significance for the outcome of any fracture (p = 0.11), there was no statistically significant interaction for any of the fracture outcomes. Similar results were noted when FRAX probability was computed without BMD. Efficacy of abaloparatide-SC to decrease the risk of major osteoporotic fracture or any clinical fracture in postmenopausal women with low BMD and/or prior fracture appears independent of baseline fracture probability. © 2017 American Society for Bone and Mineral Research.

Spatial Differences in the Distribution of Bone Between Femoral Neck and Trochanteric Fractures.

There is little knowledge about the spatial distribution differences in volumetric bone mineral density and cortical bone structure at the proximal femur between femoral neck fractures and trochanteric fractures. In this case-control study, a total of 93 women with fragility hip fractures, 72 with femoral neck fractures (mean ± SD age: 70.6 ± 12.7 years) and 21 with trochanteric fractures (75.6 ± 9.3 years), and 50 control subjects (63.7 ± 7.0 years) were included for the comparisons. Differences in the spatial distributions of volumetric bone mineral density, cortical bone thickness, cortical volumetric bone mineral density, and volumetric bone mineral density in a layer adjacent to the endosteal surface were investigated using voxel-based morphometry (VBM) and surface-based statistical parametric mapping (SPM). We compared these spatial distributions between controls and both types of fracture, and between the two types of fracture. Using VBM, we found spatially heterogeneous volumetric bone mineral density differences between control subjects and subjects with hip fracture that varied by fracture type. Interestingly, femoral neck fracture subjects, but not subjects with trochanteric fracture, showed significantly lower volumetric bone mineral density in the superior aspect of the femoral neck compared with controls. Using surface-based SPM, we found that compared with controls, both fracture types showed thinner cortices in regions in agreement with the type of fracture. Most outcomes of cortical and endocortical volumetric bone mineral density comparisons were consistent with VBM results. Our results suggest: 1) that the spatial distribution of trabecular volumetric bone mineral density might play a significant role in hip fracture; 2) that focal cortical bone thinning might be more relevant in femoral neck fractures; and 3) that areas of reduced cortical and endocortical volumetric bone mineral density might be more relevant for trochanteric fractures in Chinese women. © 2017 American Society for Bone and Mineral Research.

Clinical Utility of Using Lumbar Spine Trabecular Bone Score to Adjust Fracture Probability: The Manitoba BMD Cohort.

Decreased lumbar spine trabecular bone score (TBS), a dual-energy X-ray absorptiometry (DXA)-derived image texture measurement, is a risk factor for major osteoporotic fracture (MOF) and hip fracture (HF) independent of 10-year fracture probability estimated using FRAX. We determined how often applying the TBS adjustment to fracture probability altered treatment qualification. Using a population-based registry containing all clinical DXA results for Manitoba, Canada, we identified 34,316 women with baseline spine and hip DXA, FRAX-based fracture probability measurements (computed with femoral neck bone mineral density), lumbar spine TBS, and minimum 5 years of observation (mean 8.7 years). Population-based health services data were used to identify incident non-traumatic MOF and HF in 3503 and 945 women, respectively. Baseline MOF and HF probabilities were estimated using FRAX before and after applying the TBS adjustment. Risk recategorization was assessed using net reclassification improvement (NRI) for individual FRAX-based intervention criteria and three national clinical practice guidelines (CPGs) (US National Osteoporosis Foundation, Osteoporosis Canada, and UK National Osteoporosis Guideline Group). Overall, proportions of women reclassified with the TBS adjustment to FRAX were small (less than 5%) with more than 90% of the reclassification occurring close to the intervention threshold. For women close to an intervention cut-off reclassification, rates ranged from 9.0% to 17.9% and were <1% otherwise. There was a small but significant improvement in overall NRI for all individual FRAX-based intervention criteria (range 0.007 to 0.018) and all three national CPGs (range 0.008 to 0.011). NRI was larger in women below age 65 years (up to 0.056 for hip fracture). In summary, a small but significant improvement in MOF and HF risk assessment was found by using lumbar spine TBS to adjust FRAX probability. An improvement in risk reclassification was observed for CPGs from three different countries, with almost all of the benefit found in individuals close to an intervention threshold. © 2017 American Society for Bone and Mineral Research. © 2017 American Society for Bone and Mineral Research.