Effects of metformin on knee joint capsule fibrosis in a diabetic mouse model.

Aims: The antidiabetic agent metformin inhibits fibrosis in various organs. This study aims to elucidate the effects of hyperglycaemia and metformin on knee joint capsule fibrosis in mice. Methods: Eight-week-old wild-type (WT) and type 2 diabetic (db/db) mice were divided into four groups without or with metformin treatment (WT met(-/+), Db met(-/+)). Mice received daily intraperitoneal administration of metformin and were killed at 12 and 14 weeks of age. Fibrosis morphology and its related genes and proteins were evaluated. Fibroblasts were extracted from the capsules of 14-week-old mice, and the expression of fibrosis-related genes in response to glucose and metformin was evaluated in vitro. Results: The expression of all fibrosis-related genes was higher in Db met(-) than in WT met(-) and was suppressed by metformin. Increased levels of fibrosis-related genes, posterior capsule thickness, and collagen density were observed in the capsules of db/db mice compared with those in WT mice; these effects were suppressed by metformin. Glucose addition increased fibrosis-related gene expression in both groups of mice in vitro. When glucose was added, metformin inhibited the expression of fibrosis-related genes other than cellular communication network factor 2 (Ccn2) in WT mouse cells. Conclusion: Hyperglycaemia promotes fibrosis in the mouse knee joint capsule, which is inhibited by metformin. These findings can help inform the development of novel strategies for treating knee joint capsule fibrosis.

Prevalent morphometric vertebral fractures as a risk factor for subsequent clinical vertebral fractures after shortfusion surgery in older Japanese women with degenerative spondylolisthesis.

STUDY DESIGN: A retrospective cohort study using the Kaplan-Meier method with propensity-score matching. PURPOSE: To evaluate whether the presence of prevalent morphometric vertebral fractures (VFs) poses a risk for subsequent clinical VFs after short-fusion surgery in women aged ≥60 years with degenerative spondylolisthesis. OVERVIEW OF LITERATURE: VFs are common osteoporotic fractures and are associated with a low quality of life. Subsequent VFs are a complication of instrumented fusion in patients with degenerative lumbar disorders. Thus, risk factors for subsequent VFs after fusion surgery must be analyzed. Population-based studies have suggested that prevalent morphometric VFs led to a higher incidence of subsequent VFs in postmenopausal women; however, no studies have investigated whether prevalent morphometric VFs are a risk factor for subsequent VFs after fusion surgery in patients with degenerative spondylolisthesis. METHODS: The study enrolled a total of 237 older female patients: 50 and 187 patients had prevalent morphometric VFs (VF [+] group) and nonprevalent morphometric VFs (VF [-] group), respectively. The time to subsequent clinical VFs after fusion surgery was compared between the two groups using the Kaplan-Meier method. Moreover, 40 and 80 patients in the VF (+) and VF (-) groups, respectively, were analyzed and matched by propensity scores for age, follow-up duration, surgical procedure, number of fused segments, body mass index, and number of patients treated for osteoporosis. RESULTS: Kaplan-Meier analysis indicated that the VF (+) group had a higher incidence of subsequent clinical VFs than the VF (-) group, and Cox regression analysis showed that the presence of prevalent morphometric VFs was an independent risk factor for subsequent clinical VFs before matching. Kaplan-Meier analysis demonstrated comparable results after matching. CONCLUSIONS: The presence of prevalent morphometric VFs may be a risk factor for subsequent clinical VFs in older women with degenerative spondylolisthesis who underwent short-fusion surgery.

Association between ligamentous stenosis at spondylolisthetic segments before fusion surgery and symptomatic adjacent canal stenosis at follow-up in patients with degenerative spondylolisthesis.

STUDY DESIGN: A retrospective case-control propensity score-matching study. PURPOSE: This study aimed to longitudinally evaluate whether preoperative ligamentous stenosis at the spondylolisthetic segments could affect the incidence of symptomatic adjacent canal stenosis following one-segment fusion surgery. OVERVIEW OF LITERATURE: Several risk factors for symptomatic adjacent canal stenosis following fusion surgery have been assessed. Patients with lumbar canal stenosis mainly due to ligamentum flavum (LF) hypertrophy (ligamentous stenosis) also have LF hypertrophy in other segments. METHODS: In total, 76 patients participated in this case-control study (neurologically symptomatic adjacent canal stenosis, n=33; neurologically asymptomatic cases at follow-up, n=43). Their risk factors during surgery and magnetic resonance (MR) images before the surgery and at follow-up were evaluated. Data from the two groups (n=25 each) were matched using propensity scores for age, sex, time to MR imaging at follow-up, surgical procedure, and LF hypertrophy in adjacent segments before the surgery and analyzed. RESULTS: Compared with the asymptomatic group, the symptomatic adjacent canal stenosis group had a significantly larger LF area/spinal canal area in the spondylolisthetic segments before the surgery. During the follow-up periods (in months), they had a larger LF area/ spinal canal area in the adjacent segments: the two values were significantly correlated. The sensitivity, specificity, and positive and negative predictive values for determining symptomatic adjacent canal stenosis were high compared with on the cutoff value for the LF area/spinal canal area at the spondylolisthetic segments before the surgery. These results were the same after matching. CONCLUSIONS: Symptomatic adjacent canal stenosis is mainly caused by LF hypertrophy. Ligamentous stenosis at the spondylolisthetic segments before fusion surgery might be strongly associated with symptomatic adjacent canal stenosis at follow-up.

Delayed cortical bone healing due to impaired nuclear Nrf2 translocation in COPD mice.

The effect of the pathogenesis of chronic obstructive pulmonary disease (COPD) on bone fracture healing is unknown. Oxidative stress has been implicated in the systemic complications of COPD, and decreased activity of Nrf2 signaling, a central component of the in vivo antioxidant mechanism, has been reported. We investigated the process of cortical bone repair in a mouse model of elastase-induced emphysema by creating a drill hole and focusing on Nrf2 and found that the amount of new bone in the drill hole was reduced and bone formation capacity was decreased in the model mice. Furthermore, nuclear Nrf2 expression in osteoblasts was reduced in model mice. Sulforaphane, an Nrf2 activator, improved delayed cortical bone healing in model mice. This study indicates that bone healing is delayed in COPD mice and that impaired nuclear translocation of Nrf2 is involved in delayed cortical bone healing, suggesting that Nrf2 may be a novel target for bone fracture treatment in COPD patients.

Validation of foot plantar pressure sensor data used to estimate standing, sitting, and moving durations in one working day.

BACKGROUND: Maintaining immovable postures for long durations might be a cause of low back pain. However, the relation between low back pain and the maintenance of postures for long durations has been unclear. Therefore, the durations of several postures in one working day should be measured to evaluate the risk of low back pain, although the available measuring methods are limited. To the best of our knowledge, no study has reported the development and investigation of a foot plantar pressure sensor for measurement of standing, sitting, and moving durations in daily work routines. Thus, in this study, we aimed to develop a foot plantar pressure sensor that could withstand long-term loads in the workplace. Furthermore, we aimed to evaluate the estimated results of standing, sitting, and moving durations among factory workers using the developed foot plantar pressure sensor. METHODS: The developed foot plantar pressure sensor obtained a percentage difference within ±5% to estimate standing, sitting, and moving durations in the laboratory. We measured foot plantar pressures of 20 factory workers to estimate standing, sitting, and moving activity in one working day using data obtained by the foot plantar pressure sensor. The estimated standing, sitting, and moving durations were compared with the human estimation of photo data obtained by a wearable camera. RESULTS: The agreement rate (Cohen's kappa coefficient) was 0.75 between the evaluation using the foot plantar pressure sensor data and human estimation using a wearable camera. Cohen's kappa coefficient was 0.81 in subjects who sat for ≥30% during daily work and 0.68 in subjects who sat for <30%. CONCLUSION: Our foot plantar pressure sensor effectively measured the standing, sitting, and moving durations in daily work that requires various movements and assumption of postures.

Comparison of gender differences in health-related quality of life between patients with hand disease and those with other musculoskeletal disorders of the knee and lumbar spine.

BACKGROUND: Musculoskeletal diseases are a major public health concern among older adults. There has been an increase in the number of studies on pain between men and women, such as knee and lumbar pain. However, there is a dearth of research on pain between men and women in hand disease. This study compared health-related quality of life (HRQOL) between patients with musculoskeletal disorders of the hand and those with disorders of the knee and the lumbar spine. METHODS: From 2014 to 2018, 5595 adult patients completed a questionnaire on HRQOL. Among these patients, we identified patients with hand disease (n = 1038), knee disease (n = 680), and lumbar spine disease (n = 2021) resulting in a total sample of 3739 patients (1749 men and 1992 women). Patients' responses to the EuroQol (EQ-5D), the Short Form 12-item Survey (SF-12), and three visual analogue scales (VAS), as different measures of the HRQOL, were evaluated. RESULTS: It was found that the EQ-5D index was lowest in the lumbar spine patients, followed by knee and hand patients. The VAS scores were negatively affected in all groups. The EQ-5D index was significantly lower in women than in men only in the hand disease group. Multivariate analysis revealed that for the EQ-5D index, age, gender, and VAS scores for job and activities of daily living were explanatory factors in the hand disease group. Gender was not a significant predictor in the other groups. CONCLUSIONS: This study demonstrated that pain negatively affected HRQOL, and gender differences in HRQOL were found only in patients with hand disease. Gender differences in HRQOL in patients with hand disease warrant appropriate clinical attention.

Oxidative stress causes muscle structural alterations via p38 MAPK signaling in COPD mouse model.

INTRODUCTION: Sarcopenia is a complication of Chronic Obstructive Pulmonary Disease (COPD) that negatively affects physical activity and quality of life. However, the underlying mechanism by which COPD affects skeletal muscles remains to be elucidated. Therefore, we investigated the association between oxidative stress and structural alterations in muscles in elastase-induced emphysema mouse models. MATERIALS AND METHODS: Twelve-week-old male C57BL/6J mice were treated with either intratracheal porcine pancreatic elastase (PPE) dissolved in saline, or saline alone. The mice were euthanized 12 weeks after treatment, and the lungs and limb muscles were used for protein analysis of oxidative stress, p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway and muscle atrophy signaling pathway related with oxidative stress. Furthermore, C57BL/6J mice treated with PPE or saline were analyzed for the effects of oral administration of astaxanthin or p38 inhibitor. RESULTS: The weight of the soleus muscle, proportion of type I muscle fibers, and cross-sectional areas of muscle fibers in the PPE group were lower than those in the control group. Oxidative stress marker levels in the PPE group were elevated in skeletal muscles. The p38 MAPK signaling pathway was activated in the soleus muscles, leading to the activation of the ubiquitin-proteasome system and autophagy. Astaxanthin and p38 inhibitors attenuated alterations in muscle structure through the deactivation of the p38 MAPK signaling pathway. CONCLUSIONS: This study provides first evidence in COPD mouse model that oxidative stress trigger a series of muscle structural changes. Our findings suggest a novel target for sarcopenia in COPD.

Vertebral Osteomyelitis and Infective Endocarditis Co-Infection.

Many cases of vertebral osteomyelitis (VO) and infective endocarditis (IE) co-infection have been reported, and it has been recognized that attention should be paid to the possibility of both diseases co-existing during diagnosis and treatment. However, the incidence, clinical status, and outcomes of IE in patients with VO remain unclear. For this study, the eligibility criteria for patient recruitment included all cases of VO at the five medical university hospitals. Patients with a history of spinal surgery were excluded from this study. Echocardiography was routinely performed for all patients with VO. IE was diagnosed according to the modified Duke criteria for definite endocarditis. We analyzed demographic data, underlying conditions, clinical features, laboratory data, echocardiography, radiologic images, treatments, and outcomes. VO was diagnosed in 59 patients and IE was diagnosed in seven patients (12%). There were no significant differences in the clinical features, microorganisms, or radiographic status between the VO-IE co-infection and VO-only groups. In this study, using routine echocardiography for VO, the IE prevalence was 12%. The lack of specific clinical features and laboratory findings may hamper the diagnosis of IE. Therefore, clinicians are always required to suspect IE in patients with VO.

Development of a novel knee contracture mouse model by immobilization using external fixation.

AIMS: Several studies have used animal models to examine knee joint contracture; however, few reports detail the construction process of a knee joint contracture model in a mouse. The use of mouse models is beneficial, as genetically modified mice can be used to investigate the pathogenesis of joint contracture. Compared to others, mouse models are associated with a lower cost to evaluate therapeutic effects. Here, we describe a novel knee contracture mouse model by immobilization using external fixation. METHODS: The knee joints of mice were immobilized by external fixation using a splint and tape. The passive extension range of motion (ROM), histological and immunohistochemical changes, and expression levels of fibrosis-related genes at 2 and 4 weeks were compared between the immobilized (Im group) and non-immobilized (Non-Im group) groups. RESULTS: The extension ROM at 4 weeks was significantly lower in the Im group than in the Non-Im group (p < 0.01). At 2 and 4 weeks, the thickness and area of the joint capsule were significantly greater in the Im group than in the Non-Im group (p < 0.01 in all cases). At 2 weeks, the mRNA expression levels of the fibrosis-related genes, except for the transforming growth factor-ß1, and the protein levels of cellular communication network factor 2 and vimentin in the joint capsule were significantly higher in the Im group (p < 0.01 in all cases). CONCLUSION: This mouse model may serve as a useful tool to investigate the etiology of joint contracture and establish new treatment methods.

Effect of metformin treatment and its time of administration on joint capsular fibrosis induced by mouse knee immobilization.

Joint contracture leads to major patient discomfort. Metformin, one of the most extensively used oral drugs against type 2 diabetes has recently been found to suppress tissue fibrosis as well. However, its role in suppressing tissue fibrosis in joint contractures remains unknown. In this study, we examined the role of metformin treatment in suppressing joint capsular fibrosis and the most effective time of its administration. Joint capsular fibrosis was induced by immobilizing the knee joints of mice using splints and tapes. Metformin was administered intraperitoneally every alternate day after immobilization. Histological and immunohistochemical changes and expression of fibrosis-related genes were evaluated. Metformin treatment significantly suppressed fibrosis in joint capsules based on histological and immunohistochemical evaluation. Joint capsular tissue from metformin-treated mice also showed decreased expression of fibrosis-related genes. Early, but not late, metformin administration showed the same effect on fibrosis suppression in joint capsule as the whole treatment period. The expression of fibrosis-related genes was most suppressed in mice administered with metformin early. These studies demonstrated that metformin treatment can suppress joint capsular fibrosis and the most effective time to administer it is early after joint immobilization; a delay of more than 2 weeks of administration is less effective.

Longitudinal study of risk factors for decreased cross-sectional area of psoas major and paraspinal muscle in 1849 individuals.

This 10-year retrospective observational study investigated longitudinal losses in psoas major and paraspinal muscle area in 1849 healthy individuals (1690 male, 159 female) screened using computed tomography. Logistic regression analysis revealed significant decreases in psoas major and paraspinal muscle area at 10 years relative to the baseline area regardless of age or sex, starting at 30 years of age. Only aging [≥ 50 s (odds ratio [OR]: 1.72; 95% confidence interval [CI] 1.05-2.84; p = 0.03) and ≥ 60 s (OR: 2.67; 95% CI 1.55-4.60; p < 0.001)] was a risk factor for decreases in psoas major area. Age ≥ 60 years (OR: 2.05; 95% CI 1.24-3.39; p = 0.005), body mass index ≥ 25 kg/m2 (OR: 1.32; 95% CI 1.01-1.73; p = 0.04), and visceral fat ≥ 100 cm2 (OR: 1.61; 95% CI 1.20-2.15; p = 0.001) were risk factors for decreases in paraspinal muscle area. Physical activity ≥ 900 kcal/week (OR: 0.68; 95% CI 0.50-0.94; p = 0.02) attenuated paraspinal muscle area loss in male. Our study demonstrated that walking > 45 min daily (Calories = METs (walking: 3.0) × duration of time (h) × weight (60 kg) × 1.05) can reduce paraspinal muscle loss, which may in turn decrease the risk of falls, low-back pain, and sarcopenia.

Is Arthroscopic Hip Labral Repair/Reconstruction Surgery Effective for Treating Femoroacetabular Impingement in the Presence of Osteoarthritis?

OBJECTIVE: To investigate clinical outcomes after arthroscopic labral preservation surgery for femoroacetabular impingement (FAI) in the presence of osteoarthritis (OA) compared with FAI without significant OA. DESIGN: Retrospective case-control study. SETTING: Department of Orthopaedic Surgery and Sports Medicine, Hospital of Academic Institute. PATIENTS: Femoroacetabular impingement patients (n = 97; ≥35 years) undergoing arthroscopic FAI correction with labral preservation surgery from March 2009 to April 2014 were enrolled in this study. INTERVENTIONS: Patients were divided into 2 groups: FAI group (79 patients), with Tonnis grade 0 or 1, and FAI + OA group (18 patients), with Tonnis grade 2 or 3. MAIN OUTCOME MEASURES: We examined the clinical outcomes using the Modified Harris Hip Score (MHHS), Nonarthritic Hip Score (NAHS), and the conversion rate to total hip arthroplasty (THA). RESULTS: No significant differences existed between the 2 groups with respect to age, sex, follow-up period, or preoperative MHHS or NAHS. The mean MHHS and NAHS at the final follow-up were significantly lower in the FAI + OA group than in the FAI group. There was a significant difference in the rate of conversion to THA and failure between the 2 groups (THA 5% vs 50%) (failure 15% vs 67%). CONCLUSION: Patients with FAI in the presence of OA did not improve after arthroscopic labral preservation surgery and had a high conversion rate to THA. LEVEL OF EVIDENCE: Level III.

Performance of two bone substitutes of novel cotton-like ß-TCP/PDLGA and granular ß-TCP on bone regeneration in the femoral bone defect of the Beagle dogs.

This study aimed to clarify whether novel cotton-like composite made of ß-tricalcium phosphate (ß-TCP) and poly(Dl-lactide-co-glycolide) (PDLGA) has a different effect on in vivo bone regeneration after bone defect than that of granular ß-TCP. Five male Beagle dogs served as subjects. Cortical and medullary bone defect as non-through holes were made at the diaphysis of the bilateral femurs. One side was implanted with ß-TCP/PDLGA (ß-TCP/PDLGA group) and the other side was implanted with granular ß-TCP (ß-TCP group). At 4 weeks after implantation, we found no significant differences in the percentages of newly formed bone area and fibrous tissue area in the bone defect between the two groups. The ß-TCP/PDLGA group showed more uniform filling on the surface and earlier disappearance of the material in the medullary region, and there were fewer inflammatory cells and osteoclasts in the bone defect in the ß-TCP/PDLGA group. In conclusion, ß-TCP/PDLGA performs better at filling the bone defect uniformly and disappears earlier at the cortical and medullary regions while causing less inflammation and bone resorption. Although bone formation activity of the ß-TCP/PDLGA group in the cortical region was lower, the newly formed bone volume in bone defect of the ß-TCP/PDLGA group was equal to that of the ß-TCP group.

A Diagnostic Approach to Myelopathy Based on Prognostic Factors in Patients With Lower Extremity Symptoms.

STUDY DESIGN: Case-control study. OBJECTIVE: We aimed to identify predictors for latent myelopathy and to develop a diagnostic protocol based on these factors. SUMMARY OF BACKGROUND DATA: There is no diagnostic protocol for latent myelopathy to avoid misdiagnosis in patients complaining only of lower extremity symptoms. METHODS: This case-control study identified 791 patients discussed at conferences from April 2006 to August 2012. Overall, 460 patients complaining only of lower extremity symptoms and who underwent spine surgery were included as participants; 54 underwent surgery involving the cervical and thoracic vertebrae and were assigned to the cervical-thoracic group (C-T group); 406 underwent lumbar surgery and were assigned to the lumbar group (L group). RESULTS: By univariate analysis, age ≥67 years, patellar tendon (PT) hyperreflexia, Achilles tendon (AT) hyperreflexia, spastic gait, and gait inability were more common in the C-T group than in the L group. By multivariate analysis, age ≥67 years (OR, 8; P = 0.001), AT hyperreflexia (OR, 20.5; P < 0.001), spastic gait (OR, 225; P < 0.001), and gait inability (OR, 64; P < 0.001) were significant predictive factors. In patients with age ≥67 years, PT hyperreflexia, and/or AT hyperreflexia, the sensitivity for myelopathy diagnosis was 98%. In patients with spastic gait or gait inability, the specificity of myelopathy diagnosis was 96%. CONCLUSIONS: We analyzed factors that predict latent myelopathy in patients complaining only of lower extremity symptoms. We believe a diagnostic protocol based on the predictors shown in this study would contribute to the accurate diagnosis of latent myelopathy. LEVEL OF EVIDENCE: 4.

Presence or absence of adjacent vertebral fractures has no effect on long-term global alignment and quality of life in patients with osteoporotic vertebral fractures treated with balloon kyphoplasty.

BACKGROUND: Global sagittal malalignment after osteoporotic vertebral fracture is correlated with decreased quality of life. Balloon kyphoplasty promotes short-term global alignment, but long-term correction is difficult in patients with such fractures. Adjacent vertebral fracture is one of the major complications of balloon kyphoplasty. We investigated the correlation of the incidence of adjacent vertebral fracture with the loss of global alignment correction after balloon kyphoplasty. METHODS: Forty patients were enrolled in this retrospective study. Adjacent vertebral fracture occurred in 17 patients. Sagittal vertical axis, the angle between the two vertebrae above and below the balloon kyphoplasty site (local alignment angle), and the vertebral kyphotic angle at the kyphoplasty site were measured pre- and post-operatively. Clinical results were assessed. RESULTS: There were no significant differences between the sagittal vertical axis before and after balloon kyphoplasty in groups with (+) or without (-) adjacent vertebral fracture. Local alignment angles decreased soon after balloon kyphoplasty, but increased during follow-up in both groups. Vertebral kyphotic angles decreased significantly soon after balloon kyphoplasty in both groups; although this increased significantly in the adjacent vertebral fracture (-) group, but not in the adjacent vertebral fracture (+) group, during follow-up. Correction loss of alignment was found in both adjacent vertebral fracture (+) and (-) groups, attributed to adjacent vertebral fracture in the former and re-collapse of the balloon kyphoplasty site in the latter. No significant differences in clinical results were observed between the groups, although these were strongly correlated with sagittal vertical axis before balloon kyphoplasty. CONCLUSIONS: The adjacent vertebral fracture (+) and (-) groups exhibited similar correction loss of alignment and improved quality of life. The presence or absence of adjacent vertebral fractures had no effect on long-term global alignment and patient quality of life.

Chronic obstructive pulmonary disease severity in middle-aged and older men with osteoporosis associates with decreased bone formation.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a risk factor for osteoporosis. Nevertheless, much remains unclear regarding the bone metabolism dynamics associated with COPD. The present study focuses on the associations between the COPD severity and serum bone metabolism biomarkers. METHODS: We enrolled 40 patients who visited the orthopedics departments at our institutions and underwent dual-energy X-ray absorptiometry between September 2015 and December 2017. Only male osteoporosis patients over 45 years of age were included, and 5 patients were excluded due to disease or use of internal medicines affecting bone metabolism. All subjects underwent lung function testing, spine radiography, and blood tests. We measured percent forced expiratory volume in 1 second (%FEV1), which reflects COPD severity, and we examined the relationships between %FEV1 and serum levels of bone metabolism biomarkers. RESULTS: All subjects were diagnosed with osteoporosis based on T-scores. %FEV1 correlated with body weight, body mass index (BMI), and Z-score/T-scores. %FEV1 moderately correlated with serum levels of alkaline phosphatase (ALP), procollagen type 1 N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase 5b in the partial correlation analysis adjusted for BMI or T-score in the lumbar vertebrae. We performed a hierarchical multiple regression analysis to identify that serum ALP and P1NP were the independent explanatory variables to %FEV1 independent of other factors. CONCLUSIONS: The data suggest that the COPD severity in middle-aged and older men with osteoporosis associates with decreased bone formation. COPD patients may exhibit bone metabolism dynamics characterized by low bone turnover with osteogenesis dysfunction as COPD becomes severe.

Comparison of once-weekly teriparatide and alendronate against new osteoporotic vertebral fractures at week 12.

The objective of the present multicenter randomized study was to compare weekly teriparatide with alendronate in their inhibition of vertebral collapse, effects on delayed union, pain relief, and improvement of quality of life (QOL) in women with new osteoporotic vertebral fractures within 1 week after onset of the fracture. Patients were randomly allocated to the teriparatide and alendronate groups. Vertebral collapse, low back pain assessed by a visual analog scale, and QOL assessed by EuroQol 5 dimension at weeks 1, 2, 4, 8, and 12 after the start of the treatment were compared between the groups. Lumbar bone mineral density (BMD) at baseline and week 12 and the rate of delayed union at week 12 were also compared. Each group consisted of 48 subjects. Vertebral collapse progressed over time in both groups, with no significant difference between the groups. Pain on rising up from lying position, turning over in bed, and resting in the lying position improved over time in both groups, with no significant difference between the groups. There were no significant differences in increase in BMD and delayed union. QOL in the teriparatide group showed significant improvement in comparison with that in the alendronate group at week 12. The weekly formulation of teriparatide showed comparable inhibition of vertebral collapse, increase in BMD, promotion of bone union, and improvement of pain and significant improvement of QOL at week 12 in comparison with alendronate in patients with a new osteoporotic vertebral fracture within 1 week after onset of the fracture. The weekly formulation of teriparatide may have improved components of QOL other than pain at week 12.

Attenuation of Post-Traumatic Osteoarthritis After Anterior Cruciate Ligament Injury Via Inhibition of Hedgehog Signaling.

We aimed to investigate whether post-traumatic osteoarthritis (PTOA) progression is appropriately represented by a PTOA mouse model using a unique climbing cage to add mechanical loading after anterior cruciate ligament (ACL) transection and to determine how Hedgehog signaling inhibition prevents PTOA progression by observing time-dependent morphological changes. This controlled laboratory study histologically compared mice with surgically-induced ACL transection (ACLT) and those with voluntary increased activity in a climbing cage from 1 week postoperatively (ACLT + climbing). We generated conditional knockout (cKO) mice with a deleted Smoothened (Smo) gene. Time-dependent histopathological, immunohistochemical, and gene expression analyses were performed. The ACLT + climbing group showed more severe cartilage defects and massive osteophyte formation than the ACLT group. Smo deletion significantly suppressed PTOA progression. The time-dependent assessment revealed cartilaginous processes of equivalent size at the posterior tibial margin in the Smo cKO and control mice at 4 weeks postoperatively. However, at 8 weeks postoperatively, mature ossifying lesions were detected in the controls but not in Smo cKO mice. In the articular cartilage, ADAMTS5 and RUNX2 expression were observed in hypertrophic chondrocytes near the defective cartilage in controls but not in Smo cKO mice. Climbing exercise after ACLT accelerated PTOA progression more severely not only through increasing joint instability induced by ACLT but also through mechanical loading force induced by climbing exercise. Hedgehog signaling inhibition attenuated PTOA progression by suppressing chondrocyte hypertrophy induced by mechanical loads, to which ACL-deficient athletes are usually exposed. Thus, Hedgehog signaling inhibition may be a therapeutic option to prevent arthritic changes in athletes. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:609-619, 2020.

Lower lumbar osteoporotic vertebral fractures with neurological symptoms might have two different pathogeneses according to early magnetic resonance images.

BACKGROUND: Most osteoporotic vertebral fractures (OVFs) occur in the thoracolumbar area without neurological symptoms. The pathogenesis and clinical results of symptomatic lower lumbar OVFs have not been analysed. We aimed to retrospectively investigate the risk factors for the occurrence of neurological symptoms in patients with lower lumbar OVFs and to assess the clinical results of these symptoms using magnetic resonance (MR) images. METHODS: Of the 104 patients enrolled, 21% reported neurological symptoms. We divided OVFs with neurological symptoms into various types using early MR images and investigated the risk factors for each type. Clinical results of symptomatic patients were also evaluated. RESULTS: Symptomatic patients with lower lumbar OVFs mainly had one of two fracture types, indicated by total low and superior/inferior low-intensity signals on T1-weighted images. A multivariate logistic regression analysis showed that a smaller canal area and longer disease duration were risk factors for all patients. For patients with OVFs indicated by total low intensity, symptomatic patients had a significantly smaller canal area than non-symptomatic patients. For patients with OVFs indicated by superior/inferior low intensity, symptomatic patients had a significantly higher frequency of L4 and L5 vertebral fractures, longer disease duration, smaller canal area, smaller angle between the facets, and higher frequency of coexisting degenerative spondylolisthesis than non-symptomatic patients. Symptomatic patients with OVFs indicated by total low intensity had poorer clinical results regarding walking ability than symptomatic patients with OVFs indicated by superior/inferior low intensity. CONCLUSIONS: Lower lumbar OVFs with neurological symptoms might have two different pathogeneses according to early MR images. Compared with symptomatic patients with OVFs indicated by superior/inferior low intensity, symptomatic patients with OVFs indicated by total low intensity may require different treatment strategies to avoid symptoms.

Findings as a starting point to unravel the underlying mechanisms of in vivo interactions involving Wnt10a in bone, fat and muscle.

Wnt10a is a member of the WNT family. Although deficiency of this gene causes symptoms related to teeth, hair, nails, and skin, we recently demonstrated a new phenotype of Wnt10a knockout (KO) mice involving bone and fat. The in vivo effect of the Wnt10a gene on bone and fat is unclear, and the relationship between bone/fat and muscle in Wnt10a signaling is also interesting. We aimed to evaluate the tissue changes in Wnt10a KO mice compared to wild-type mice and show the findings as a starting point to unravel the underlying mechanisms of in vivo interactions involving Wnt10a in bone, fat and muscle. Trabecular bone loss in the lower limbs of Wnt10a mice and decreased bone mineralization were observed. The adipose tissue in bone marrow was also decreased, and adipocyte differentiation was reduced. The body fat mass in Wnt10a KO mice was decreased, and white adipocytes in subcutaneous fat were converted to beige adipocytes. The muscle weight of the lower limbs was not decreased despite trabecular bone loss, but Gdf8/myostatin expression was reduced in the subcutaneous fat and gastrocnemius muscles of Wnt10a KO mice. Thus, in vivo deletion of Wnt10a inhibited osteogenic activity, promoted beige adipogenesis of white adipocytes and maintained muscle mass. These results suggest that regulation of Gdf8 by Wnt10a may help maintain the muscle mass of Wnt10a KO mice. This study was the first to histologically evaluate the bone, fat and muscle phenotypes of Wnt10a KO mice. The results of this study, which were obtained by investigating the three tissues together, could influence the understanding of in vivo interactions involving the Wnt10a gene.