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This study aimed to evaluate femoral perfusion using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for two weeks after the simultaneous initiation of electrical stimulation (ES) and steroid treatment in a steroid-induced osteonecrosis (ON) model. A single dose of methylprednisolone was injected into 14 rabbits. Seven rabbits underwent ES (ES group), and seven rabbits did not (control group). DCE-MRI was performed before steroid administration and 1, 5, 10, and 14 days after steroid administration. Regions of interest were set in the bilateral proximal femora. The enhancement ratio, initial slope, and area under the curve were analyzed. These parameters were evaluated after steroid administration in each group and between the two groups, and the ratios of ON in both groups were compared. In the control group, the minimum values of all parameters decreased significantly after steroid administration (P < 0.05), but in the ES group, the parameters did not decrease. In the ES group, all parameter values were significantly increased on the 10th and 14th days (P < 0.05). All parameter values in the ES group were significantly higher than those in the control group on the 14th day (P < 0.05). In the control group, ON was detected in three of five rabbits (in three of ten femora). In the ES group, ON was not detected. These results suggest that increased femoral blood flow elicited by ES may be related to ON prevention after steroid administration.

This study was designed to evaluate femoral perfusion after pulsed electromagnetic field (PEMF) stimulation in a steroid-induced osteonecrosis rabbit model by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Steroid-induced osteonecrosis was produced by single intramuscular injection of methylprednisolone in 15 rabbits. Eight rabbits underwent PEMF stimulation (PEMF group) and seven did not (control group). DCE-MRI was performed before PEMF stimulation, immediately before steroid administration, and 1, 5, 10, and 14 days after steroid administration. Regions of interest were set in the bilateral proximal femora. Enhancement ratio (ER), initial slope (IS), and area under the curve (AUC) were analyzed. ER, IS, and AUC in the control group significantly decreased after steroid administration compared with before administration (P<0.05). In PEMF group, IS significantly decreased; however, ER and AUC showed no significant differences after steroid administration compared with before. ER and IS in PEMF group were higher than in control group until 10th day, and AUC was higher until 5th day after steroid administration (P<0.05). PEMF stimulation restrains the decrease in blood flow after steroid administration., (© 2015 Wiley Periodicals, Inc.)

Purpose: To evaluate perfusion during the early phase after steroid administration in vivo using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with a high magnetic field MRI system. The main pathogenesis of steroid-induced osteonecrosis is considered to be ischemia., Materials and Methods: A single dose of methylprednisolone (MPSL) was injected into nine rabbits. DCE-MRI was performed for these rabbits before MPSL administration and 1, 5, 10, and 14 days after administration. Time-signal intensity curves were created for each femur based on the signal intensity to evaluate perfusion. Enhancement ratio (ER), initial slope (IS), and area under the curve (AUC) were calculated and the value before MPSL administration and the minimal value after administration were compared statistically., Results: ER, IS, and AUC values after MPSL administration significantly decreased (P < 0.05, P < 0.01, and P < 0.01, respectively). All of them decreased by the 5th day in 56% of the femora and by the 14th day in 83%, and some femora even showed a decrease from the 1st day., Conclusion: In this study, decreased perfusion in the femora after steroid administration was proven. Additionally, we could show that it occurred from the early days after steroid administration., (© 2014 Wiley Periodicals, Inc.)

Background and Purpose: It has been suggested that avascular osteonecrosis (AVN) of the femoral head occurs early after systemic steroid administration. The purpose of this study was to investigate the risks regarding development of AVN at a very early stage after renal transplantation., Methods: The presence or absence of AVN was determined by MRI at 4 weeks, at 6-12 weeks, at 24 weeks, and at 12 months after renal transplantation in 286 patients (183 males) with a mean age of 39 (16-65) years. The relationship between AVN and age, sex, absence or presence of acute rejection (AR), type of transplanted kidney (living or cadaveric), type of immune suppressor, and total dose of orally administered steroids given in the 2-week period after transplantation was investigated., Results: There were no statistically significant correlations between the development of AVN and age, sex, absence or presence of AR, type of transplanted kidney, or type of immune suppressor. A significant dose-response relationship was found between development of AVN and the total dose of steroid administered in the first 2 weeks after surgery., Interpretation: We found a relationship between AVN development and steroid dose in the early postoperative period, and we also showed a dose-response relationship.

We evaluated the preoperative errors in the pelvic tilt of 249 hips before total hip arthroplasty using fluoroscopic imaging while the patients were in the lateral decubitus position. The mean absolute value errors of the pelvic tilt were 2.94° (SD, 2.92°), 2.49° (SD, 2.68°), and 5.92° (SD, 5.20°) in the coronal, transverse, and sagittal planes, respectively. Such preoperative errors in the pelvic tilt contribute to malpositioning of the acetabular component, as is frequently observed on postoperative radiographs. We reduced the incidence of malpositioning by correcting the errors in the pelvic tilt through repositioning of the operating table using fluoroscopic imaging before surgery. The new technique using fluoroscopic imaging described in this article can be performed within a short time without a navigation system., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Although numerous studies describe the clinical characteristics of idiopathic osteonecrosis of the femoral head (ONFH) in specific study populations, these have not been confirmed in countrywide studies., Questions/purposes: We therefore determined: (1) the annual number of patients seeking medical care and number of patients newly diagnosed; and (2) the distribution of the age and gender of the patients, potential causative factors, severity of the disease, and operative procedures performed., Patients and Methods: We conducted a nationwide epidemiologic survey in 2005. The survey included all orthopaedic departments in Japan by stratified random sampling according to the number of beds., Results: The number of patients who sought medical care for idiopathic ONFH during 2004 was estimated to be 11,400 (95% confidence interval, 10,100-12,800). We obtained clinical information from 1502 of these patients. The peak in age distribution occurred in the 40s. Potential causative factors were systemic steroid administration (51%) and habitual alcohol use (31%). Hip replacement was the most frequently performed procedure (65%). Among patients with a history of systemic steroid administration, systemic lupus erythematosus was reported most frequently (31%) as the underlying disease. Among patients younger than 40 years, steroid use was the most prominent potential causative factor (60%), and hip replacement frequently was performed (45%). A greater proportion of patients with no history of steroid or alcohol use was observed among patients 65 years or older (41%)., Conclusions: In addition to the disease burden of idiopathic ONFH in Japan, our results confirmed the importance of developing preventive and treatment strategies, especially among the younger population., Level of Evidence: Level IV, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Background: Pulsed electromagnetic field (PEMF) therapy has been widely used in clinical practice for bone fracture healing. However, the mechanism of its action remains to be elucidated. Our object was to investigate the mechanism by which PEMF accelerates bone fracture healing., Methods: We used 20 mice in this study. Ten mice received PEMF for 10 h/day for 1 week via the coils of a PEMF stimulation device (PEMF group), while the remaining 10 mice did not (control group). The femurs were harvested immediately after euthanasia to examine the proteins included in the bone marrow. The proteins examined by Western blotting were growth factors with angiogenetic activities, including tunica interna endothelial cell kinase-2, angiopoietin-1, angiopoietin-2, fibroblast growth factor-2, and vascular endothelial growth factor. The expression levels of angiogenesis-related proteins extracted from the bone marrow of each mouse were compared., Results: The expression levels of angiopoietin-2 and fibroblast growth factor-2 were significantly higher in the PEMF group than in the control group. This difference suggests that PEMF may induce an angiogenesis-prone environment in the bone marrow. Such angiogenesis acceleration represents one possible mechanism for the acceleration of bone fracture healing by PEMF. There were no significant differences between the two groups for the expression levels of tunica interna endothelial cell kinase-2, angiopoietin-1, and vascular endothelial growth factor. The lack of increase in tunica interna endothelial cell kinase-2 expression may indicate that PEMF does not unnecessarily increase blood vessels in normal bone marrow. The lack of an increase in the expression level of vascular endothelial growth factor suggests that PEMF does not have invasive effects including the induction of hypoxic conditions and inflammation on the bone marrow., Conclusion: The angiogenesis-promoting function of PEMF may contribute to its mechanism to noninvasively accelerate bone fracture healing.

Background: The Japanese Orthopaedic Association (JOA) hip score has been widely used in Japan as a method to assess hip joint diseases. The JOA hip score consists of four subcategories: pain (Pain), range of motion (ROM), ability to walk (Gait), and activities of daily life (ADL). We present the first report to verify the reliability and validity of the JOA hip score., Methods: A total of 123 patients with osteoarthritis of a unilateral hip and 29 patients with osteonecrosis of a unilateral hip were investigated. The JOA hip score was recorded by orthopedic surgeons in their offices. On the same day, each patient answered a Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) (Japanese version 1.2) by himself or herself. The SF-36 survey measures eight subscales. The internal-consistency reliability of the JOA hip score was evaluated by Cronbach's coefficient alpha. The validity of the JOA hip score was tested by Spearman's correlation coefficients between the four subcategories of the JOA hip score and the eight SF-36 subscales., Results: When patients with osteoarthritis with conservative treatment were assessed by the JOA hip score, Cronbach's coefficient alpha was 0.70, demonstrating internal-consistency reliability. However, when the JOA hip score was used for other groups, Cronbach's coefficient alpha was <0.70, demonstrating the lack of internal-consistency reliability. Significant correlations were observed between Pain and bodily pain (r = 0.63), between Gait and physical functioning (PF) (r = 0.70), and between ADL and PF (r = 0.81), but not in any other combinations., Conclusions: We found that the JOA hip score is a reliable system only for patients with osteoarthritis of the hip with conservative treatment. The JOA hip score is a scaling system with convergent and discriminant validity for the assessment of physical function and pain.

The clinical results of total hip arthroplasty using the Richards Modular Hip System prosthesis were evaluated in 41 patients (44 joints). The mean Harris hip score improved from 42 points before surgery to 82 after 1 year, 85 at 5 years, and 79 at the final examination. The average polyethylene wear rate was 0.09 +/- 0.07 mm/y. Forty joints (90.9%) achieved press fit in either of the proximal or the distal stem portion, and only 4 joints (9.1%) failed to achieve press fit in both the proximal and distal stem portions. Although the 10-year survival of the stem was 94.5% and no revisions of the stem were performed, osteolysis was found at high frequency at a distal stem. The high incidence of osteolysis has been the limiting factor in the long-term success of Richards Modular Hip System. Achievement of good canal fill in both the proximal and distal stem portions did not contribute to the good long-term result of the stem., ((c) 2010 Elsevier Inc. All rights reserved.)

Background and Purpose: Prevention of osteonecrosis after corticosteroid administration would be important. We examined the potential of vitamin E (alpha-tocopherol) to reduce the incidence of corticosteroid-induced osteonecrosis in an animal model., Methods: Japanese white rabbits were divided into 2 groups; the control group was fed a normal diet and the experimental group was fed alpha-tocopherol-supplemented diet in which alpha-tocopherol (600 mg/kg diet) was added to the normal diet. To induce osteonecrosis, high-dose methylprednisolone acetate (MPSL) (20 mg/kg body weight) was injected once into the right gluteus medius muscle of all rabbits. 4 weeks after the injection of MPSL, the presence or absence of osteonecrosis of bilateral femurs was examined histopathologically. The tocopherol/cholesterol ratios were calculated. The plasma levels of thiobarbituric acid-reactive substances (TBARS) were measured., Results: Alpha-tocopherol-supplemented diet reduced the incidence of osteonecrosis, which developed in 14 of 20 rabbits in the control group and 5 of 21 rabbits in the experimental group (p = 0.004). The tocopherol/cholesterol ratio was higher in the experimental group than in the control group after the alpha-tocopherol administration. The plasma TBARS level was lower in the experimental group than in the control group at 4 weeks after the MPSL administration., Interpretation: Our findings may offer a new approach for the prevention of corticosteroid-induced osteonecrosis.

The S-ROM-A femoral prosthesis (DePuy, Warsaw, IN) is a modular cementless femoral stem system that was developed to adapt to hip joint disorders of Asian patients. Clinical results of total hip arthroplasties using the S-ROM-A femoral prosthesis were evaluated in 68 hips. The average age at the time of surgery was 57.1 years. The mean follow-up period was 27.8 months. The Harris hip score improved from 47.1 points preoperatively to 91.4 points at final follow-up. No dislocations were observed. Implant fixation was good without any evidence of osteolysis or loosening. The S-ROM-A femoral prosthesis fitted well for Asian patients who often have osteoarthritis secondary to developmental dysplasia of the hip, by providing a shorter stem and greater variety in the neck shape of the stem with a smaller diameter.

Aim: The purpose of this study was to investigate risk factors for hip fracture in 169 Japanese elderly women., Methods: Patients were divided into three groups: 53 patients had osteoporosis with hip fractures (FX-G), 59 patients had osteoporosis without hip fractures (NFX-G) and 57 patients had low back pain with neither osteoporosis nor hip fracture (NOP-G). Bone mineral density (BMD) of lumbar spine, bone-specific alkaline phosphatase (BAP) and deoxypyridinoline (DPD) were compared among the three groups., Results: The mean BMD of FX-G and NFX-G was lower than that of NOP-G, but there was no significant difference between FX-G and NFX-G. Although the mean BAP of FX-G was similar to that of NOP-G, both were lower than NFX-G (P < 0.05). However, the mean DPD of FX-G was higher than the other groups (P < 0.05, vs NFX-G, P < 0.001, vs NOP-G). The percentage of patients who showed BAP levels less than 35 IU/L and DPD levels of 7.5 nmoL/mmol-Cr or more, was highest in FX-G (72.7%). This percentage was lower for NFX-G (30.9%) and NOP-G (16.4%). The odds ratio of hip fracture occurring was 5.77 (95% confidence interval, 2.25-14.66)., Conclusion: Bone turnover consisting of increase in bone resorption and decrease in bone formation apart from BMD of lumbar spine resulted in a higher incidence of hip fracture for Japanese elderly women with osteoporosis.

Background and Purpose: It has been suggested that avascular osteonecrosis (AVN) of the femoral head develops early after renal transplantation. We evaluated the relationship between risk of AVN and dose of steroids administered in different time periods., Methods: Development of AVN was determined using MRI at 3-6 weeks, 9-12 weeks, 24 weeks, and 12 months after transplantation in 150 patients (96 males). We investigated possible associations between acute rejection reactions, the dose of cyclosporine, tacrolimus use, total steroid dose by the second, fourth, sixth, or eighth weeks after transplantation, and incidence of AVN., Results: There was no statistically significant difference between incidence of AVN and presence or absence of an acute rejection reaction. We found a statistically significant association between AVN incidence and the total dose of steroids administered during the first 2 months after transplantation, and there was a doseresponse relationship. No other statistically significant associations were found., Interpretation: Our findings confirm that the total dose of steroids given within the first 2 months after renal transplantation has a great influence on the incidence of AVN.

Background: Osteonecrosis of the femoral head (ONF) often develops following corticosteroid administration. We previously investigated the genetic background for the development of corticosteroid-induced ONF and found relations between ONF development and genetic polymorphisms in the ATP binding cassette B1 (ABCB1) gene (C3435T), apolipoprotein B (ApoB) gene (C7623T), and cAMP-response element binding protein-binding protein (CBP) gene (rs3751845). In the present study, we examined whether combined information regarding these three single nucleotide polymorphisms (SNPs) in the ABCB1, ApoB, and CBP genes is useful for predicting ONF development., Methods: A case-control study was performed to study the development of corticosteroid-induced ONF. The cases were 34 patients who developed ONF, and the references were 123 patients who did not develop ONF. To evaluate the presence of interactions among the ABCB1, ApoB, and CBP genes, a synergistic index was calculated using an additive model., Results: The synergistic index between the ABCB1 and CBP genes was >1.00 (1.99), revealing the presence of an interaction., Conclusions: Through analysis of multiple genes that may affect ONF development, we have shown a possible relation among genes encoding completely different proteins. We believe that analysis of the interactions among these genes can contribute to elucidating the mechanism of ONF development in addition to enabling identification of high-risk patients for ONF development.

Establishing a means to prevent osteonecrosis after corticosteroid administration is an important theme. We asked whether pulsed electromagnetic field stimulation, a noninvasive treatment, could prevent osteonecrosis. Ninety rabbits were divided into four treatment groups: (1) exposure of 10 hours per day to electromagnetic stimulation for 1 week, followed by injection of methylprednisolone (20 mg/kg), and exposure of 10 hours per day to electromagnetism for a further 4 weeks (n = 40); (2) methylprednisolone injection only (n = 40); (3) no treatment (n = 5); and (4) exposure of 10 hours per day to electromagnetism for 5 weeks (n = 5). After 5 weeks, we harvested and histologically examined femurs bilaterally. The frequency of osteonecrosis was lower in the steroid-electromagnetism group (15/40) than in the steroid-only group (26/40). No necrotic lesions were found in the two control groups. We observed no clear effects of electromagnetism on the number, location, extent, and repair of necrotic lesions and intramedullary fat cell size in affected rabbits. Pulsed electromagnetic field stimulation reportedly augments angiogenesis factors and dilates blood vessels; these effects may lower the frequency of osteonecrosis. Exposure to pulsed electromagnetic field stimulation before corticosteroid administration could be an effective means to reduce the risk of osteonecrosis.

Background: The aim of this study was to clarify the significance of subchondral bone in the pathology of osteoarthritis (OA) by investigating the expression of inflammatory cytokines, proteases, and receptor activator of NF-kappaB ligand (RANKL)/receptor activator of NF-kappaB (RANK)/osteoprotegerin (OPG) involved in cartilage degeneration., Methods: Subchondral bone was obtained from 19 patients diagnosed with knee OA and 4 patients diagnosed with femoral neck fracture. Subchondral bone osteoblasts (SBOs) were isolated, and total RNA was extracted. Messenger RNA expression of inflammatory cytokines, proteases, and RANKL/RANK/OPG were analyzed using a real-time reverse transcription-polymerase chain reaction (RT-PCR)., Results: Real-time RT-PCR showed that mRNA expressions of interleukin-6 (IL-6), matrix metalloproteinase-13 (MMP-13), and RANKL were significantly enhanced in OA SBOs compared to SBOs without OA. The expressions of these genes was greater in patients with severe cartilage damage than in those with mild cartilage damage. A high correlation between mRNA expression of IL-6 and that of MMP-13 was found in OA SBOs., Conclusion: The increases in IL-6, MMP-13, and RANKL expression in OA SBOs suggest that in subchondral bone OA progression involves abnormal osseous tissue remodeling, which induces mechanical property changes. Cartilage degeneration in OA may also be due, at least in part, to IL-6 and MMP-13 produced by SBOs. Comprehensive research on these pathological features may lead to the development of more effective therapies for OA by administration of molecules that affect bone remodeling and metabolism.

Steroid-induced osteonecrosis of the femoral head (steroid-induced ONF) is an aseptic and ischemic disease developing after steroid therapy. Functions of hip joint are markedly disturbed when collapse is developed on the femoral head. Steroid-induced ONF accounted for the majority of the ONF. The occurrence mechanism is unknown, and prevention methods and fundamental remedies remain to be established. The timing of the occurrence of steroid-induced ONF is within several months after steroid administration. During the continuous steroid administration, no expansion of necrotic area was found. Recurrence was not also noticed. Patients have no symptoms when steroid-induced ONF occurs due to the establishment of ischemic conditions, and pain appears when the collapse of femoral head develops. There is an interval of several months or years between the occurrence of ONF and the onset of symptoms. Generally, conservative treatment is chosen during the asymptomatic period, and surgical treatment is considered after the symptoms appear. Appropriate screening and early detection are important to rational remedy for steroid-induced ONF.

Idiopathic osteonecrosis of the femoral head (ION) is caused by disruption of blood flow. This disease often occurs in association with steroid treatment. The pathology of corticosteroid-induced ION is unclear, although abnormalities in the coagulation and fibrinolytic systems or in the lipid metabolism have been reported to be involved. We found the differences of gene polymorphism frequencies of ATP-binding casette, sub-family B, member 1 (ABCB1) C3435T, Apolipoprotein B (ApoB) C7623T and cAMP-response element binding protein-binding protein (CBP) (rs3751845) between ION cases and referent patients among those who were subjected to renal transplantation. For the prediction of ION, it is useful to analyze ABCB1 C3435T, ApoB C7623T and CBP (rs3751845) before the administration of steroids.

Background: Nontraumatic osteonecrosis of the femoral head (ONFH) is caused by disruption of blood flow. This disease often occurs in association with steroid treatment. The pathology of steroid-induced ONFH remains unclear, although abnormalities in lipid metabolism have been reported to be involved. In this study, we examined the differences of gene polymorphism frequencies of apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1), which are important proteins for lipid transport, as well as of lipid parameters, between ONFH cases and referent patients among those who were subjected to renal transplantation., Methods: Subjects were 158 cases who had undergone renal transplant, including 34 cases that were diagnosed as ONFH after renal transplantation and 124 cases that were not. Four single nucleotide polymorphisms including C7623T and G12619A for the ApoB gene and G75A and C83T for the ApoA1 gene were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and Taqman real-time PCR chemistry. Also, serum levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), ApoB, and ApoA1 were measured. Their relationship to ONFH was statistically evaluated., Results: A higher frequency of 7623TT or CT of the ApoB gene was observed in ONFH cases than in referent patients (P = 0.033), resulting in an elevated odds ratio that was statistically significant (adjusted odds ratio = 6.37, 95% CI = 1.53-26.5, P = 0.011). No significant relationship was observed between other genes and ONFH. Regarding lipid parameters, a higher value of ApoB/ApoA1 ratio was observed in cases (P = 0.045)., Conclusion: For the prediction of ONFH, it is useful to analyze ApoB C7623T and plasma ApoB/ApoA1 ratio before the administration of steroids.

Osteoarthritis (MIM 165720), characterized by degeneration of articular cartilage, is the most common form of human arthritis and a major concern for aging societies worldwide. Epidemiological and genetic studies have shown that osteoarthritis is a polygenic disease. Here, we report that the gene encoding growth differentiation factor 5 (GDF5) is associated with osteoarthritis in Asian populations. A SNP in the 5' UTR of GDF5 (+104T/C; rs143383) showed significant association (P = 1.8 x 10(-13)) with hip osteoarthritis in two independent Japanese populations. This association was replicated for knee osteoarthritis in Japanese (P = 0.0021) and Han Chinese (P = 0.00028) populations. This SNP, located in the GDF5 core promoter, exerts allelic differences on transcriptional activity in chondrogenic cells, with the susceptibility allele showing reduced activity. Our findings implicate GDF5 as a susceptibility gene for osteoarthritis and suggest that decreased GDF5 expression is involved in the pathogenesis of osteoarthritis.

Objective: Osteonecrosis of the femoral head (ONF) is a necrosis due to disruption of the blood flow. The disease often occurs in association with corticosteroid treatment. The pathology of corticosteroid-induced ONF is unclear, although abnormalities in the coagulation and fibrinolytic systems or in the lipid metabolism have been reported to be involved. We examined the relationships between development of ONF and genetic variations and plasma level of lipoprotein(a) (Lp(a)), which is closely involved in the coagulation and fibrinolytic systems and lipid metabolism., Methods: The study population consisted of 112 renal transplant patients undergoing corticosteroid treatment. Their apolipoprotein (a) [apo(a)] isoform was determined by Western blotting, and patients were classified into low molecular weight (LMW) or high molecular weight (HMW) groups. The plasma Lp(a) level was measured. Patients were also examined for 3 single-nucleotide polymorphisms (SNP), -773 (G/A), +93 (C/T), and +121 (G/A). Relationships between these 3 genetic factors of Lp(a) and ONF development were examined using statistical methods including multivariate analysis., Results: A strong relationship was observed between the apo(a) molecular weight phenotype and ONF development, with an increased risk of ONF development for the LMW group (adjusted odds ratio 5.75, 95% CI 1.76-18.74, p = 0.0038). No significant relationships were observed between ONF and plasma Lp(a) level and SNP., Conclusion: Apo(a) molecular weight phenotype would be a useful predictor of ONF that develops after corticosteroid treatment.

Nontraumatic osteonecrosis (ON) of the femoral head is known to be one of the major complications after organ transplantations. Although the precise mechanism is still uncertain, the administration of glucocorticoid (GC) has been considered to play an important role in the occurrence of ON. To elucidate the genetic factors involved in this pathogenesis, we analyzed single nucleotide polymorphisms (SNP) in the genes for the GC receptor (GR), CYP3A4, cAMP-responsive element binding protein-binding protein (CBP), and nuclear receptor co-activator 2 (NCoA2). Among the patients examined, A/G alleles of the CBP gene were demonstrated in 32.4% of those with ON, but in only 14.6% of those without ON (P = 0.018). No relationships were observed between the SNPs of GR, CYP3A4, and NCoA2 genes and the occurrence of ON. These results indicate that the genetic polymorphism of the CBP, which is one of the essential factors exerting the biological effects of GC, may affect susceptibility to steroid-induced ON in patients after renal transplantation.

Objective: The aim of this study was to investigate the relationship between abnormal acetabular labrum depicted by radial magnetic resonance and progressive joint space narrowing (JSN) of hip dysplasia., Methods: Subjects were 23 joints [21 patients; mean age: 35.1 years (16-53 years)] that had acetabular dysplasia with lateral center-edge angle of Wiberg (CE angle) greater than 5 degrees and smaller than 25 degrees (mean, 16.4 degrees ), which did not show any arthrotic changes on plain radiograms and were followed up for 3 years or longer. Radial images of acetabular labrum were classified into three stages., Results: Progression of JSN was not significantly related to CE angle but to progression of MRI stage (P=.006). In multivariate analysis, one rank progression of MRI stage was significantly associated with progression of JSN (adjusted OR=11.41, 95% CI: 1.51-86.24, P=.018)., Conclusion: Our findings showed that in patients whose acetabular dysplasia has 5-25 degrees CE angle, MRI staging based on radial MRI is a better factor for prediction of progression of JSN than CE angle.

Objectives: To identify whether differences exist in the outcomes between patients undergoing hemodialysis and elderly nonhemodialysis patients with a femoral neck fracture., Design: Retrospective review., Setting: Level 1 trauma center., Patients/interventions: A total of 71 femoral neck fractures in 62 patients undergoing hemodialysis treated nonoperatively or operatively., Main Outcome Measurements: Clinical outcomes were analyzed to identify factors that may be correlated with life expectancy and functional prognosis., Results: The overall survival rates in this study at 1-year and 5-years postfracture were found to be 89.8% and 51.5%, respectively. There were significant correlations among the survival rate, patients' age, type of treatment, prefracture ambulation status, and prefracture activities of daily living status. However, using multivariate analysis, the only significant predictor of life expectancy was prefracture ambulation status. As for functional prognosis, the rates of total ambulation recovery and total activities of daily living recovery at 1-year postfracture were 50.0% and 71.2%, respectively. Both patients' age and age at the onset of hemodialysis may contribute considerably to functional prognosis in patients undergoing hemodialysis after femoral neck fracture., Conclusions: The present study suggests that the clinical outcomes of patients with femoral neck fractures who undergo hemodialysis are considerably superior to those of previous studies. In addition, when those fractures are treated surgically with specific management in patients undergoing hemodialysis, it may be possible to expect a life expectancy and functional prognosis similar to elderly nonhemodialysis patients with hip fractures.

Although epidemiological studies on epiphyseal injury have been reported, such studies have not been made systematically in Japan. In this study, we examined the incidence of epiphyseal injury in paediatric patients treated at five general hospitals and three private clinics. We treated the patients with limb injuries between January 1992 and December 1997, and reviewed them at least 18 months after the original injuries. The original radiograms and the completed case records were classified according to age and sex of the injured children, site of the fracture, type of treatment, and its complications. Epiphyseal injuries accounted for 17.9% of all paediatric fractures. The most frequently injured epiphysis was the phalanges of hands, 21.9% of all physeal injuries. Salter-Harris type I accounted for 28.6% of physeal injuries; type II (60.9%) revealed the largest number of cases in this study, compared with type III (6.7%) and type IV (3.7%). Type V was not recognized. Most physeal injuries were treated conservatively. Either weight-bearing joints or elbow joints were treated surgically. Complications of physeal injuries were seen in seven cases. Five cases involved the upper limb, and the other two cases involve the lower limb. Although deformity or malfunction caused by physeal injuries was remained, only one case needed a corrective osteotomy. Other six cases revealed a fair prognosis.

Objective: The femoral head is reported to be in a markedly hypoemic state as compared with other tissues even under normal conditions, and it is therefore necessary to understand its hemodynamics to investigate the pathogenesis of hip disorders. It is known that aspects of intraosseous hemodynamics including blood flow and blood pool can be evaluated soon after radioisotope administration. In this study, hemodynamic changes in the femoral head according to gender and age were examined by investigating accumulation of radioisotope in the tissue during the early phase of bone scintigraphy., Methods: The subjects of this study consisted of 58 joints of 31 men and 75 joints of 41 women, whose ages ranged from 15 to 87 years (average age: 67.9 years). Images of bone scintigraphy were obtained for 15 to 20 minutes at 5 minutes and at 3 hours after radioisotope administration. The ratio of accumulation in the femoral head to that in the diaphysis (head-to-diaphysis ratio, HD ratio) was calculated., Results: HD ratios obtained 15-20 minutes later ranged from 0.01 to 7.35 (1.88 +/- 0.91, mean +/- SD). HD ratios decreased with age, and a significant inverse correlation was observed between age and HD ratio, demonstrating a correlation coefficient of -0.27 (p = 0.001). The HD ratio among men was 0.01-3.57 (1.66 +/- 0.71), while that among women was 0.53-7.35 (2.05 +/- 1.01), and a significant difference was observed in HD ratio between men and women (p = 0.02). There was a significant difference in HD ratios between men and women in their teens to forties (p = 0.03), while no significant differences was observed in the other age groups.. HD ratios obtained 3 hours later ranged from 0.44 to 6.32 (1.95 +/- 0.79, mean +/- SD), and no significant correlation was observed between age and HD ratio, demonstrating a correlation coefficient of -0.14., Conclusion: The present study demonstrated that blood flow and blood pool of the femoral head decrease with aging particularly in women. This hemodynamic deterioration of the femoral head caused by aging may have an effect on the onset and progression of hip disorders by influencing bone metabolism.

Objective: To investigate the therapeutic effects of basic fibroblast growth factor (bFGF) contained in gelatin hydrogel microspheres on osteoarthritis (OA) development in rabbit knee joints., Methods: (125)I-labeled bFGF contained in gelatin hydrogel microspheres was administered to the knee joints of normal rabbits to confirm the sustained-release kinetics of bFGF in the knee joint. In addition, the expression of proteoglycan core protein messenger RNA was examined using real-time polymerase chain reaction to confirm the anabolic effects on the cartilage treated with the sustained release of bFGF. The bFGF in gelatin hydrogel microspheres was administered to the knee joint once every 3 weeks (a total of twice) from 4 weeks after anterior cruciate ligament transection (ACLT). Ten weeks after ACLT, gross morphologic and histologic examinations were performed., Results: Sustained release of bFGF in the knee joint continued for >7 days and induced the anabolic effects on the cartilage. Intraarticular injections of bFGF contained in gelatin hydrogel microspheres suppressed the progression of OA in the ACLT rabbit model., Conclusion: Our findings demonstrated that sustained release of bFGF into the joint had therapeutic effects on OA development in a rabbit model. Our results suggest the potential feasibility of a new conservative treatment for OA.

Objective: Non-traumatic osteonecrosis of the femoral head (ONF) is considered to be a disease that occurs primarily due to ischemia of the femoral head, while its etiology and pathology are not fully understood. It is therefore necessary to identify the characteristics of the hemodynamics of the femoral head. In this study, the hemodynamics in the ilium and proximal regions of the femur, including the femoral head, was investigated using positron emission tomography (PET)., Methods: The subjects of this study consisted of 8 hip joints of four healthy male adults and 3 hip joints on the contralateral side of a femoral neck fracture, avulsion fracture of the greater trochanter and coxarthrosis (1 case each, all females) for a total of 11 hip joints of 7 subjects. The ages of the subjects ranged from 25 to 87 years (average age: 54 years). Blood flow was measured by means of the H215O dynamic study method and blood volume was measured by means of the 15O-labeled carbon monoxide bolus inhalation method., Results: Blood flow was determined to be 9.1 +/- 4.8 ml/min/100 g in the ilium and among proximal regions of the femur (femoral head, neck and intertrochanteric region), 1.8 +/- 0.7 ml/min/100 g in the femoral head, 2.1 +/- 0.6 ml/min/100 g in the femoral neck, and 2.6 +/- 0.7 ml/min/100 g in the intertrochanteric region. In addition, blood volume was 4.7 +/- 1.3 ml/100 g in the ilium, and among proximal regions of the femur, 1.1 +/- 0.5 ml/100 g in the femoral head, 2.1 +/- 0.7 ml/100 g in the femoral neck, and 2.6 +/- 0.9 ml/100 g in the intertrochanteric region. The results showed that both blood flow and volume were lowest in the femoral head. Blood flow and volume were significantly lower in the proximal regions of the femur (femoral head, neck and intertrochanteric region) than in the ilium (p < 0.01)., Conclusion: The present study demonstrated that the femoral head is in a hypoemic state as compared with other osseous tissue, indicating that even the slightest exacerbation of hemodynamics in the femoral head can trigger an ischemic condition culminating in ONF.

Limb lengthening by the callotasis method has been clinically applied to patients who suffered from limb length inequality, micromelia, angular deformation and partial bone defect on long bones. However, this technique was time consuming and led to various complications, such as infection at the pin insertion sites, limitation of the range of motion in adjacent joints, muscular weakness and peripheral neuroparalysis. This study was undertaken to investigate whether alternating current electric (AC) stimulation could shorten the maturation period during callotasis. The tibiae of 20 immature male Japanese white rabbits were osteotomized and fixed with external lengthener (Orthofix M100; Orthofix Srl, Bussolengo, Italy). The experimental schedule lasted 5 weeks consisting of 1 week for the latency period, 2 weeks for distraction and 2 weeks for maturation. Twenty rabbits were equally divided into two groups: the control group and the electrical stimulation (ES) group. The control group was not stimulated with an AC stimulator. The ES group was stimulated for 5 weeks just after osteotomy. The obtained results revealed radiologically, electrophysiologically and histologically that AC stimulation accelerated the maturation of lengthened callus and that it could shorten the time course of callus lengthening.

Objective: Conventional methods of quantitative Na18F positron emission tomography require multiple arterial blood sampling in order to obtain the input function, and the procedures are invasive and complicated. This study aims to establish a simplified and reliable technique for obtaining the input function., Methods: Multiple arterial blood sampling was performed on 12 persons. The time point for one-point sampling was determined as the time when (1) the plasma radioactivity obtained showed the highest correlation to the real integrated value, which was calculated from the input function, and (2) the coefficient of variation of the real integrated value divided by plasma radioactivity obtained at each time point became the minimum. Scaling factors were obtained in order to estimate the plasma radioactivity at each time point, and a reference table was produced in order to estimate the input function., Results: The optimal timing for one-point sampling was 12 min after intravenous injection of Na18F. The estimated integrated value obtained from arterial blood sampling at 12 min and the reference table was highly correlated with the real integrated value (P<0.001). Levels of plasma radioactivity of arterial blood and venous blood were almost the same at 12 and 40 min after Na18F injection. Percentage errors in the estimation of the integrated value were 2.63% (n=12) for the arterial blood collected at 12 min and 4.14% (n=12) for the venous blood collected at 30 min., Conclusions: This simplified method is clinically applicable and would replace traditional methods that require multiple blood sampling.

Osteoarthritis (OA), a common skeletal disease, is a leading cause of disability among the elderly populations. OA is characterized by gradual loss of articular cartilage, but the etiology and pathogenesis of OA are largely unknown. Epidemiological and genetic studies have demonstrated that genetic factors play an important role in OA. To identify susceptibility genes for OA, we performed a large-scale, case-control association study using gene-based single nucleotide polymorphisms (SNPs). In two independent case-control populations, we found significant association (P=9.8x10(-7)) between hip OA and a SNP (IVS3-293C>T) located in intron 3 of the calmodulin (CaM) 1 gene (CALM1). CALM1 was expressed in cultured chondrocytes and articular cartilage, and its expression was increased in OA. Subsequent linkage-disequilibrium mapping identified five SNPs showing significant association equivalent to IVS3-293C>T. One of these (-16C>T) is located in the core promoter region of CALM1. Functional analyses indicate that the susceptibility -16T allele decreases CALM1 transcription in vitro and in vivo. Inhibition of CaM in chondrogenic cells reduced the expression of the major cartilage matrix genes Col2a1 and Agc1. These results suggest that the transcriptional level of CALM1 is associated with susceptibility for hip OA through modulation of chondrogenic activity. Our findings reveal the CALM1-mediated signaling pathway in chondrocytes as a novel potential target for treatment of OA.

To investigate the usefulness of epiphyseal quotient (EQ) measurement for outcome prediction in patients with Legg-Calve-Perthes disease (LCPD), magnetic resonance (MR) imaging was performed in 26 patients with unilateral LCPD within 6 months of the disease onset and subsequently once every 3 months. All the patients were treated conservatively in our institute between 1990 and 1999. The mean follow-up period was 80 months. Clinical outcome was evaluated based on the plain radiograms of the femoral head at the final examination according to Stulberg's classification: the patients whose outcome was class I were regarded as 'excellent' (excellent group), class II as 'good' (good group), and classes III, IV and V as 'poor' (poor group). The excellent group consisted of 10 patients, the good group of 12, and the poor group of four. The EQ measured on MR images (MR-EQ) decreased remarkably in the poor group chronologically, whereas there was no decrease in the excellent group and a slow decrease in the good group. The mean MR-EQ at or before the sixth month (range, 2-6 months; mean, 4.9 months) was 86.2 (range, 76.8-94.8) in the excellent group, 78.3 (57.0-93.4) in the good group, and 67.4 (57.8-74.5) in the poor group (P<0.05 among the three groups). According to our results, because all patients having an MR-EQ at or before the sixth month of 75 or higher were classified in the excellent or good groups, it is thought that the ongoing method of treatment can be continued. On the other hand, since half of the patients having an MR-EQ at or before the sixth month of lower than 75 were classified in the poor group and had a high potential for a poor outcome, it is thought that these patients require strict containment therapy, and altering the surgical procedure could be considered depending on the particular patient. It was thought that the MR-EQ is a useful predictive factor of LCPD prognosis.

Background: Nontraumatic osteonecrosis of the femoral head (ONFH) is one of the complications that may occur after renal transplantation. We investigated the relationship between the incidence of ONFH and polymorphisms in the genes for plasminogen activator inhibitor (PAI)-1, which is one of the major regulatory proteins of the fibrinolytic system, and 5,10-methylenetetrahydrofolate reductase (MTHFR), which is associated with the plasma levels of homocysteine in Japanese subjects., Methods: Thirty-one patients with postrenal transplant ONFH and 106 patients without ONFH were selected. Genotypes of PAI-1 4G/5G and MTHFR C677T were determined by direct sequencing of genomic DNA. In addition, plasma PAI-1 antigen (Ag) levels and plasma total homocysteine (tHcy) levels at the steady state were measured. The relationships between the incidence of ONFH and these genotypes, as well as plasma levels of the gene products, were investigated., Results: Plasma PAI-1 Ag levels were the highest in patients with the 4G/4G genotype, and plasma tHcy levels were the highest in patients with TT genotypes of MTHFR C677T. However, the relationship between the incidence of ONFHH and PAI-1 4G/5G or MTHFR C677T was not observed. The relationship between the incidence of ONFH and plasma levels of PAI-1 Ag or tHcy was not observed., Conclusions: Genotypes of PAI-1 4G/5G and MTHFR C677T or plasma concentrations of PAI-1 Ag and tHcy had no effect on the incidence of ONFH in Japanese subjects, unlike the results of studies performed in white subjects. The effect of genetic background on the pathologic conditions that developed in patients with postrenal transplant ONFH may differ according to race.

We report the case of a 29-year-old Japanese man with transient osteoporosis of the left hip (TOH) following contralateral TOH, paying special attention to the initial changes on MRI. MR images showed no abnormal findings 6 weeks before the clinical manifestation, but the images just after the onset depicted a linear abnormality equivalent to a subchondral insufficiency fracture. Both radiological findings and clinical symptoms disappeared completely without any surgical intervention within 10 months.

Advances in transplantation technology have brought about great benefits to patients suffering from organ failure, but the problem still remains of complications induced by steroids used for post-transplant immunosuppression. Among the side-effects caused by steroids, non-traumatic osteonecrosis of the femoral head (ONF) constitutes a serious problem. The same protocol for steroid administration induces ONF in some patients, but not in others, indicating the presence of individual difference in steroid sensitivity. We hypothesized that this difference might be mediated by the drug-transport protein, P-glycoprotein (P-gp), and investigated the relationship between single nucleotide polymorphisms in the multidrug resistance gene 1 (ABCB1, MDR1) encoding P-gp and ONF. Subjects comprised 136 patients receiving kidney transplantation. Thirty patients developed post-transplant ONF. Genomic DNA was extracted from peripheral blood, and genotypes of ABCB1 C3435T (exon 26) and G2677T/A (exon 21) were determined by direct sequencing. Multivariate analyses based on clinical information were performed to determine the relationship between ABCB1 genotypes and ONF. The dose/concentration (D/C) ratios of tacrolimus were also determined to estimate the activity of P-gp in patients with different genotypes of ABCB1 C3435T (CC, CT, TT), and in those who did and did not develop ONF. The ABCB1 3435TT genotype showed a significantly lower incidence of ONF (adjusted odds ratio = 0.10, P = 0.034). The D/C ratio in the 3435TT genotype was significantly higher than that in the 3435CC genotype. The D/C ratio in patients developing ONF was significantly higher than in those patients who did not develop ONF. The results suggest increased activity of P-gp in patients with the 3435TT genotype and in those who did not develop ONF. The ABCB1 2677 homozygous variant type also showed a lower incidence of ONF (adjusted odds ratio = 0.26, P = 0.056). The 3435T and 3435C alleles were in linkage disequilibrium with the 2677T and the 2677G alleles, respectively, in the study population. An assessment of C3435T and G2677T/A polymorphisms preceding steroid treatment could be useful for predicting the resistance to ONF development., (Copyright 2003 Lippincott Williams & Wilkins)

We investigated risk factors for osteonecrosis of the femoral head (ONF) in renal transplant recipients, who are susceptible to the disease. Among 287 renal transplant recipients, 18 ONF patients with enough data were included, and 18 age- and sex-matched recipients without ONF were nominated as reference cases. Risk factors were analyzed using a conditional logistic regression method. There were no differences between the ONF patients and the reference cases regarding the types of immunosuppressant or the donor (living or cadaveric, father or mother, matching blood type and human leukocyte antigens). The daily oral steroid dosage (prednisolone 25.0 mg/day or more) and blood urea nitrogen level 2 months after transplantation were the only factors with relevance to the occurrence of ONF. We propose that oral steroid dosages should be low or reduced after renal transplantation, and acute rejection should be controlled with pulsed therapy.

With advanced organ transplantation technology, steroid-induced osteonecrosis of the femoral head (ONF) is one of the most troublesome complications. Steroid sensitivity varies among individuals, and the involvement of polymorphism of various genes relating to steroid metabolism is suggested. The present study investigated the relation between single nucleotide polymorphism (SNP) on the DNA sequence of cytochrome p(450) and ONF development. The subjects were 80 renal transplant patients. Genome DNA was obtained from the peripheral blood, and SNP analyses for CYP3A4, CYP2D6, and CYP2C19 were conducted using various methods: direct sequencing, polymerase chain reaction restriction fragment length polymorphism, and DNA Chip. The relation between ONF development and SNP was statistically analyzed. It is useful if the generating risk judged according to SNPs to prevention of steroid-induced ONF is possible. This time, SNPs, which are clearly related to ONF, were not accepted, although the possibility that SNP related to steroid metabolism is involved in ONF development is important. We think that it is necessary to examine this area more closely.

We radiographically investigated 36 hips in 34 patients with osteoarthritis of the hip who had undergone total hip arthroplasty. Their mean age was 59.2 years (range 36-79 years), and the mean follow-up period was 11.2 years (range 10-14 years). The long-term outcome and the chronological changes in the bulk autograft were examined. The acetabular component of the prosthesis was a Lord-type threaded cup with a smooth surface. At follow-up, bone absorption was minor in 17 joints, moderate in 11, and major in 8. The hips with graft coverage of >==20% (group A) had a significantly higher loosening rate than hips with coverage of <<20% (group B) ( P << 0.05). The cup position changed markedly in group A. Our findings indicate that graft coverage should be less than 20% when a bulk graft is used together with a smooth-surfaced cementless cup.

Thermotherapy has been applied to various joint diseases and injuries, but its direct effects on articular cartilage have remained unclear. The present study examined the effects on cell viability and metabolism by using the chondrocyte-like cell line HCS-2/8. The temperatures and durations of heat stimulation were 39 degrees, 41 degrees, 43 degrees, and 45 degrees C for 15 or 30 min. After heat stimulation of 41 degrees C or lower for 15 or 30 min, cell viability increased and proteoglycan metabolism was accelerated, whereas after stimulation at 43 degrees C or higher for 30 min the viability and metabolism decreased. These results indicate that appropriate heat stimulation positively affects cell viability and the proteoglycan metabolism of articular cartilage, whereas too much heat stimulation produces negative effects. Clinical efficacy is therefore determined by the overall thermal dose. When the appropriate combination of temperature and duration is found, thermotherapy for diseases and injury of articular cartilage can be highly useful in clinical practice.

Ischemic bone necrosis following talar fractures is a problematic complication and its early diagnosis is important. Patients with Hawkins Type II and III talar fractures received internal fixation using titanium alloy screws, and chronological bone changes were observed with Magnetic Resonance Imaging (MRI). With the Type II patient, Hawkins' sign was radiographically confirmed 2 months after the surgery. Furthermore, there were no changes of MR images for 2 years and a good clinical outcome was obtained. However, in the Type III patient, Hawkins' sign was negative and MRI revealed a low signal-intensity band on the talus 2 months after the surgery and then necrosis was radiographically confirmed; pain appeared 10 months later. These 2 cases suggest that MRI is a useful means for detecting bone necrosis with talar fractures in the early post-operative period.