Shigeo Hagiwara

Distribution of hip pain in patients with idiopathic osteonecrosis of the femoral head

Abstract Objective: To determine the distribution of referred hip pain in patients with idiopathic osteonecrosis of the femoral head (ION). Methods: We prospectively documented 119 hips in 90 patients with ION (mean age 51 years). Patients identified the location of pain originating in their hip on a drawing of the body. Osteoarthritis of the hip (OA) was used as a historical cohort. Results: Referral of pain originating from the hip in patients with ION was 93% (111 hips) to the groin, 68% (81 hips) to the knee, 36% (43 hips) to the anterior thigh, 34% (40 hips) to the buttock, 18% (22 hips) to the lower leg, 9% (11 hips) to the greater trochanter, and 8% (9 hips) to the low back. About 97% (115 hips) of pain was located in the hip region (groin, buttock, and greater trochanter) and 77% (92 hips) showed referred pain (anterior thigh, knee, lower leg, and low back). Pain from ION was significantly more frequent in the knee and lower leg, but significantly less frequent in the lower back than pain from OA. Conclusion: We should be aware of ION masquerading as pain in the knee or anterior thigh.

A novel rat model of hip pain by intra-articular injection of nerve growth factor-characteristics of sensory innervation and inflammatory arthritis.

Objectives. To determine the direct effects of intra-articular injection of nerve growth factor (NGF) into normal rat hips and the time course of pain-related mediator appearance. Methods. Using 36 numbers of 8-week-old male Sprague–Dawley rats, 30 μl of 1% Fluoro-Gold solution (FG) (Sham-operated group; n = 12), 30 μl of 1% FG with 50 μg/ml NGF (NGF50 group; n = 12), and 30 μl of 1% FG with 100 μg/ml NGF (NGF100 group; n = 12) were injected into the left hip joints. Neurons in the dorsal root ganglion (DRG) labeled with FG, and FG and calcitonin gene-related peptide-immunoreactivity (CGRP-IR) were counted. The synovia in the left hip joint was examined histologically. Results. The NGF50 and NGF100 groups showed evidence of synovitis without cartilage degeneration compared with the Sham-operated group. At 7 days, the proportions of CGRP-IR FG-labeled to total FG-labeled neurons were 12%, 18%, and 36% in the Sham-operated, NGF50, and NGF100 groups, respectively. At 14 days, the proportions were 13%, 22%, and 35% in the Sham-operated, NGF50, and NGF100 groups, respectively. At 7 and 14 days, the NGF50 and NGF100 groups showed a significantly higher proportion of CGRP-IR FG-labeled neurons than the Sham-operated group. Conclusions. Intra-articular administration of NGF into the hip joint produces a novel rat model for hip pain.

Pain‐related behavior and the characteristics of dorsal‐root ganglia in a rat model of hip osteoarthritis induced by mono‐iodoacetate

The principal aim of this study was to clarify the time course of pain‐related behavior and pain‐related sensory innervation in a rat model of hip osteoarthritis (OA) induced by intra‐articular injection of mono‐iodoacetate (MIA). Using 6‐week‐old male Sprague Dawley rats, 25 μl of sterile saline of 1% Fluoro‐Gold solution (FG) (control group; n = 30) and 25 μl of sterile saline of 1% FG with 2 mg of MIA (MIA group; n = 30) was injected into the right hip joints. Gait function was evaluated using a CatWalk system after 7, 14, 28, 42, and 56 days (n = 5, respectively). Neurons in the dorsal root ganglion (DRG) between L1 and L5 were immunostained for calcitonin gene‐related peptide (CGRP) and activating transcription factor‐3 (ATF3). Gait analysis revealed the mean six parameters of hind paws at all time points were significantly lower in the MIA group (p = 0.05). The number of CGRP‐immunoreactive (‐IR) DRG neurons was significantly increased on days 7, 14, 28, and 42 peaking at 14 days in the MIA group. By contrast, expression of ATF3‐IR in FG‐labeled DRG neurons was significantly increased on days 42 and 57. The FG‐labeled DRG neurons were distributed between L1 and L5, mainly at the L4 level. Pain‐related behavior indicated by gait disturbance was observed in a MIA model of hip OA in rat. Early elevation of CGRP expression and late expression of ATF‐3 were demonstrated in DRG neurons, possibly reflecting inflammatory pain and neuropathic pain in hip OA.

Outcome of patients with Legg-Calvé-Perthes onset before 6 years of age.

Background: The prognosis of Legg-Calvé-Perthes disease (LCPD) in young patients has been accepted as favorable. The purpose of this study was to clarify the outcome of LCPD patients with onset before 6 years of age. Methods: From 1989 to 2007, of 332 LCPD patients, 114 hips (in 100 patients) were diagnosed before 6 years of age (mean age, 4.5 y old) with subsequent repair of the epiphysis in all cases. Waldenström classification at presentation was initial stage in 76 hips and fragmentation stage in 38 hips. Lateral pillar classification was group A in 17 hips, group B in 22 hips, group B/C in 24 hips, and group C in 51 hips. Treatment methods were observation with restriction of activity alone in 42 hips and several containment treatments in 72 hips. Results: At the mean age of 14, Stulberg classification was class I in 26 hips, II in 46 hips, III in 28 hips, and IV in 14 hips. These data show an acceptable outcome in 72 of 114 hips (63%). Logistic regression analysis revealed that lateral pillar classification (odds ratio, 3.6) and good range of abduction without treatment (odds ratio, 4.0) were prognostic factors. Conclusions: Poor outcome was observed even in patients before 6 years of age with large necrotic area. Lateral pillar classification and good range of abduction were prognostic factors. Level of Evidence: Level IV. Therapeutic studies—investigating the results of treatment. Case series.

Corticosteroids and low bone mineral density affect hip cartilage in systemic lupus erythematosus patients: Quantitative T2 mapping.

The purpose of this diagnostic study was to quantify the effect of high‐dose corticosteroid treatment on hip joint cartilage degeneration in patients with systemic lupus erythematosus (SLE), with and without osteonecrosis, using magnetic resonance imaging (MRI).

Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head

Idiopathic osteonecrosis of the femoral head (IONFH) is an ischemic disorder that causes bone necrosis of the femoral head, resulting in hip joint dysfunction. IONFH is a polygenic disease and steroid and alcohol have already known to increase its risk; however, the mechanism of IONFH remains to be elucidated. We performed a genome-wide association study using ~60,000 subjects and found two novel loci on chromosome 20q12 and 12q24. Big data analyses identified LINC01370 as a candidate susceptibility gene in the 20q12 locus. Stratified analysis by IONFH risk factors suggested that the 12q24 locus was associated with IONFH through drinking capacity. Our findings would shed new light on pathophysiology of IONFH.

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.

Osteoporotic Pain is Associated with Increased Transient Receptor Vanilloid 4 Expression in the Dorsal Root Ganglia of Ovariectomized Osteoporotic Rats: A Pilot Basic Study

Introduction Osteoporosis can produce a persistent state of pain known as osteoporotic pain. One proposed mechanism of this pathology is increased calcitonin gene-related peptide (CGRP; a marker related to inflammatory pain) expression in the dorsal root ganglia (DRG) innervating osteoporotic vertebrae. Alternatively, a previous study revealed that axial loading caused osteoporotic pain in a rodent model of coccygeal vertebrae compression. Because this compression model is associated with trauma, additional mechanistic studies of osteoporotic pain in the absence of trauma are required. The current study aimedto evaluate the expression and relative distribution of transient receptor potential vanilloid 4 (TRPV4), a pain-related mechanoreceptor, in ovariectomized (OVX) osteoporotic rats. Methods CGRP-immunoreactive (-ir) and TRPV4-ir DRG neurons innervating the L3 vertebrae of Sprague-Dawley rats were labeled with a neurotracer, FluoroGold. Intravertebral pH was also measured during the neurotracer procedure. TRPV4-ir/CGRP-ir FluoroGold-positive DRG neurons were quantified in sham control and OVX rats (n = 10, ea). The threshold for statistical significance was set at P < 0.05. Results There was no statistical difference in the number of FluoroGold-positive DRG neurons between groups; however, there were significantly more CGRP-ir/TRPV4-ir FluoroGold-positive DRG neurons in the OVX group compared with the sham control group (P < 0.05) as well as the significantly increased molecular production of each peptide. Intravertebral pH was also lower in the OVX group compared with the sham control group (P < 0.05). Conclusion Sensory neurons innervating osteoporotic vertebrae exhibited increased expression of co-localized CGRP and TRPV4 in OVX osteoporotic rats. Additionally, intravertebral pH was low in the vicinity osteoporotic vertebrae. Considering that TRPV4 is a mechanosensitive nociceptor that is activated in acidic environments, its upregulation may be associated with the pathology of osteoporotic pain derived from microinflammation involved in osteoporosis.

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.