Yuya Kawarai

Vertebral compression exacerbates osteoporotic pain in an ovariectomy-induced osteoporosis rat model.

Study Design. Basic pain study using osteoporotic rodent models. Objective. To examine alterations in distribution of pain-related neuropeptides after compressive force on osteoporotic vertebrae and their chronic pain-related properties. Summary of Background Data. We previously reported significantly increased production of calcitonin gene-related peptide (CGRP), a marker of inflammatory pain, in the dorsal root ganglia (DRG) of vertebrae in osteoporosis-model ovariectomized (OVX) rats. Here, we hypothesized that longitudinal compressive force on vertebrae can affect osteoporotic pain properties, which has not been examined yet. Methods. OVX rats were used as the osteoporosis model. Female Sprague-Dawley rats were prepared and Fluoro-Gold (FG) neurotracer was applied to the periosteal surface of the Co5 vertebra. After FG labeling, the animals were divided into 4 groups: Control, Control + compression, OVX, and OVX + compression. The Control groups were not ovariectomized. In the compression groups, K-wires were stabbed transversely through Co4 and Co6 with Co5 compressed longitudinally by rubber bands bridged between the 2. One, 2, 4, and 8 weeks after surgery, bilateral S1 to S3 DRGs were excised for immunofluorescence assays. Expression of CGRP and activating transcription factor 3, a marker of neuronal injury, were compared among the 4 groups. Results. Sustained upregulation of CGRP in DRG neurons was observed after compression of the Co5 vertebra, and Co5 compression caused significant increase in CGRP production in DRG neurons, whereas a greater level of activating transcription factor 3 upregulation was observed in DRGs in OVX rats after dynamic vertebral compression 8 weeks after surgery, implying potential neuropathic pain. Conclusion. There was sustained upregulation of CGRP and activating transcription factor 3 in DRGs in osteoporotic model rats compared with controls, and levels were further enhanced by dynamic vertebral compression. These findings imply that dynamic compression stress on vertebrae can exacerbate osteoporotic pain by inducing both inflammatory and neuropathic pain mediators. Level of Evidence: N/A

Increase of TRPV1-Immunoreactivity in Dorsal Root Ganglia Neurons Innervating the Femur in a Rat Model of Osteoporosis

Purpose Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel, which can be activated by capsaicin and other noxious stimuli. Recently, an association between bone pain and TRPV1 has been reported. However, the influence of osteoporosis on TRPV1 in the sensory system innervating the femur has not been reported. Materials and Methods TRPV1-immunoreactive (ir) in dorsal root ganglia (DRG) neurons labeled with neurotracer [Fluoro-Gold (FG)] innervating the femurs of Sprague Dawley rats were examined in control, sham, and ovariectomized (OVX) rats. We evaluated osteoporosis in the femurs and compared the proportion of TRPV1-ir DRG neurons innervating femur between the 3 groups of rats. Results OVX rats showed osteoporotic cancellous bone in the femur. FG labeled neurons were distributed from L1 to L6 DRG, but there was no significant difference in the proportion of labeled neurons between the 3 groups (p>0.05). The proportions of FG labeled TRPV1-ir DRG neurons were 1.7%, 1.7%, and 2.8% of DRG neurons innervating the femur, in control, sham-operated, and OVX rats, respectively. The proportion of TRPV1-ir neurons in DRG innervating the femur in OVX rats was significantly higher than that in control and sham-operated rats (p<0.05). Conclusion Under physiological conditions, DRG neurons innervating femurs in rats contain TRPV1. Osteoporosis increases the numbers of TRPV1-ir neurons in DRG innervating osteoporotic femurs in rats. These findings suggest that TRPV1 may have a role in sensory perception of osteoporotic femurs.

Transient Receptor Potential Vanilloid 1-Immunoreactive Innervation Increases in Fractured Rat Femur

Purpose Pain from vertebral or femoral neck fractures is a particularly important problem in clinical orthopaedics. Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel, and there are recent reports on an association between bone pain and TRPV1. However, an increase in TRPV1 activity has not been reported following femoral fracture. Materials and Methods We applied a neurotracer [Fluoro-gold (FG)] onto femur to detect dorsal root ganglia (DRGs) innervating the cortex of the femur in 30 Sprague Dawley rats. Seven days after application, a closed mid-diaphyseal fracture of the femur was performed. FG labeled TRPV1-immunoreactive (ir) DRGs innervating the femur were examined in nonfractured controls, and 3 days, 1 week, 2 weeks, and 4 weeks after fracture. We evaluated bone healing of the femur and compared the ratio of TRPV1-ir DRG neurons innervating the femur at the time points. Results Four weeks after fracture, complete bone union was observed. There was no significant difference in the ratio of FG labeled DRG neurons to total DRG neurons at each time point. The percentages of TRPV1-ir neurons in DRGs innervating the femur at 3 days and 1 week after fracture were significantly higher than those in control, 2 weeks, and 4 weeks after fracture (p<0.05). Conclusion Fracture induced an increase of TRPV1-ir neurons in DRGs innervating the fractured femur within 3 days, and decreased during bone healing over 4 weeks. These findings show that TRPV1 may play a role in sensory sensation of bone fracture pain.

Prediction of fracture load and stiffness of the proximal femur by CT-based specimen specific finite element analysis: cadaveric validation study

BackgroundFinite element analysis (FEA) of the proximal femur has been previously validated with large mesh size, but these were insufficient to simulate the model with small implants in recent studies. This study aimed to validate the proximal femoral computed tomography (CT)-based specimen-specific FEA model with smaller mesh size using fresh frozen cadavers.MethodsTwenty proximal femora from 10 cadavers (mean age, 87.1 years) were examined. CT was performed on all specimens with a calibration phantom. Nonlinear FEA prediction with stance configuration was performed using Mechanical Finder (mesh,1.5 mm tetrahedral elements; shell thickness, 0.2 mm; Poisson’s coefficient, 0.3), in comparison with mechanical testing. Force was applied at a fixed vertical displacement rate, and the magnitude of the applied load and displacement were continuously recorded. The fracture load and stiffness were calculated from force–displacement curve, and the correlation between mechanical testing and FEA prediction was examined.ResultsA pilot study with one femur revealed that the equations proposed by Keller for vertebra were the most reproducible for calculating Young’s modulus and the yield stress of elements of the proximal femur. There was a good linear correlation between fracture loads of mechanical testing and FEA prediction (R2 = 0.6187) and between the stiffness of mechanical testing and FEA prediction (R2 = 0.5499). There was a good linear correlation between fracture load and stiffness (R2 = 0.6345) in mechanical testing and an excellent correlation between these (R2 = 0.9240) in FEA prediction.ConclusionsCT-based specimen-specific FEA model of the proximal femur with small element size was validated using fresh frozen cadavers. The equations proposed by Keller for vertebra were found to be the most reproducible for the proximal femur in elderly people.

Transitional changes in the incidence of osteonecrosis in systemic lupus erythematosus patients: focus on immunosuppressant agents and glucocorticoids

Objective The purpose of this study was to investigate transitional changes in the incidence of glucocorticoid-associated osteonecrosis in SLE patients, with a focus on immunosuppressive agent and glucocorticoid consumption. Methods We retrospectively registered 185 SLE patients with 740 joints, who were newly diagnosed and hospitalized for initial high-dose glucocorticoid therapy from 1986 to 2015. Immunosuppressive agent, glucocorticoid dose, age, sex, organ lesion at hospitalization, complement (C3, C4, CH50) and anti-DNA antibody before initial glucocorticoid therapy, the frequency of use of anticoagulant and antilipidemic drugs, and incidence of osteonecrosis were documented. Results Based on trends in immunosuppressive agent use, 116 patients treated from 1986 to 1999, before calcineurin inhibitors were introduced, comprised the past group, and 69 patients treated from 2000 to 2015 comprised the recent group. Patient characteristics (age, sex and organ lesion at hospitalization, complement, anti-DNA antibody, the frequency of use of anticoagulant and antilipidemic drugs) were similar between groups. Glucocorticoid doses were significantly lower in the recent group than in the past group (highest daily glucocorticoid dose, 45.7 vs 59.0 mg/day, respectively; dose per weight, 0.88 vs 1.16 mg/day/kg, respectively; and cumulative dose at 3 months, 3118 vs 3985 mg). The incidence of osteonecrosis was significantly lower in the recent group than in the past group (26.4 vs 41.0%, respectively), particularly in the knee (25.4 vs 46.6%, respectively). Conclusion The incidence of glucocorticoid-associated osteonecrosis in SLE patients decreased in association with a decrease in glucocorticoid administration after introduction of immunosuppressant agents.

Diffusion tensor imaging of the sciatic and femoral nerves in unilateral osteoarthritis of the hip and osteonecrosis of femoral head: Comparison of the affected and normal sides

Abstract Objective: The aim was to compare the fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of the sciatic and femoral nerves in patients with unilateral osteoarthritis of the hip (OA) and osteonecrosis of the femoral head (ONFH) using diffusion tensor imaging (DTI) and to investigate the mechanism of hip pain. Methods: Forty-four patients (22 OA and 22 ONFH) underwent DTI of the sciatic and femoral nerves at the level of the hip joint and the S1 roots to visualize the tractography and quantify the FA and ADC values. Results: The tractography of the femoral and the sciatic nerves on the affected side with OA and ONFH were similar to those on the normal side. The mean FA values of the sciatic and femoral nerves, and the S1 roots were 0.542, 0.551, and 0.316 with OA, 0.568, 0.560, and 0.318 with ONFH on the affected side, and 0.559, 0.560, and 0.315 on the normal side, respectively, and did not show significant differences. The FA values of the sciatic nerve on the affected side with OA decreased with longer pain duration. Conclusion: The FA and ADC values of the sciatic and femoral nerves in patients with unilateral OA and ONFH showed no significant differences between the affected and normal sides.

Changes in proinflammatory cytokines, neuropeptides, and microglia in an animal model of monosodium iodoacetate-induced hip osteoarthritis: PAIN IN INDUCED HIP OSTEOARTHRITIS

The aim of this study was to investigate the local production of proinflammatory cytokines, pain‐related sensory innervation of dorsal‐root ganglia (DRG), and spinal changes in a rat model of induced hip osteoarthritis (OA). Seventy‐five Sprague–Dawley rats were used, including 25 controls and 50 injected into the right hip joints (sham group, injected with 25 µl of sterile saline: N = 25; and monosodium iodoacetate (MIA) group, injected with 25 µl of sterile saline with 2 mg of MIA: N = 25). We measured the local production of TNF‐α, immunoreactive (‐ir) neurons for calcitonin gene‐related peptide (CGRP), and growth associated protein‐43 (GAP‐43) in DRG, and immunoreactive neurons for ionized‐calcium‐binding adaptor molecule‐1 (Iba‐1) in the dorsal horn of spinal cord, on post‐induction days 7, 14, 28, 42, and 56 (N = 5 rats/group/time point). For post‐induction days 7–42, the MIA group presented significantly elevated concentrations of TNF‐α than the other groups (p < 0.01), and a higher expression of CGRP‐ir in FG‐labeled DRG neurons than the sham group (p < 0.01). MIA rats also presented significantly more FG‐labeled GAP‐43‐ir DRG neurons than the sham group on post‐induction days 28, 42, and 56 (p < 0.05), and a significantly higher number of Iba‐1‐ir microglia in the ipsilateral dorsal horn than the other groups, on post‐induction days 28, 42, and 56. The results suggest that in rat models, pain‐related pathologies due to MIA‐induced hip OA, originate from inflammation caused by cytokines, which leads to progressive, chronic neuronal damage that may cause neuropathic pain.

Interobserver and Intraobserver Reliability of Computed Tomography–Based Three-Dimensional Preoperative Planning for Primary Total Knee Arthroplasty

BACKGROUND Preoperative planning is an important factor for total knee arthroplasty (TKA). The aim of this study is to document the interobserver and intraobserver reliability of computed tomography (CT)-based 3-dimensional (3D) preoperative planning for primary TKA. METHODS Twenty knees (10 with osteoarthritis and 10 with rheumatoid arthritis) were studied independently by 6 orthopedic surgeons using a CT-based 3D planning system. The measurements were made twice at more than 3-week intervals without any knowledge of their own previous measurements or those of the others. We assessed the femoral and tibial component sizes and the alignment of the femoral component. RESULTS The interobserver and intraobserver agreements for femoral component size were 44.3% and 62.5% with exact size, and increased to 90.7% and 99.2% within one size difference; the intraclass correlation coefficients (ICCs) were 0.919 and 0.936, respectively. The interobserver and intraobserver agreements for tibial component size were 57.0% and 66.7% with exact size, and increased to 87.3% and 90.0% within one size difference; the ICCs were 0.909 and 0.924, respectively. The ICCs for femoral and tibial size were better in rheumatoid arthritis than in osteoarthritis. Interobserver ICC for femoral valgus angle was 0.807, and 0.893 for intraobserver reliability. Interobserver ICC of the femoral external rotation angle was 0.463, and 0.622 for intraobserver reliability. CONCLUSION CT-based 3D preoperative planning for primary TKA has clinical implications for predicting appropriate size and alignment of the component in patients with osteoarthritis and rheumatoid arthritis.