Kazushi Takayama

Characteristic Radiographic or Magnetic Resonance Images of Fresh Osteoporotic Vertebral Fractures Predicting Potential Risk for Nonunion: A Prospective Multicenter Study

Study Design. Prospective multicenter study. Objective. To identify radiographic or magnetic resonance (MR) images of fresh vertebral fractures that can predict a high risk for delayed union or nonunion of osteoporotic vertebral fractures (OVFs). Summary of Background Data. Vertebral body fractures are the most common fractures in osteoporosis patients. Conservative treatments are typically chosen for OVFs, and associated back pain generally subsides within several weeks with residual persistent deformity of the vertebral body. In some patients, OVF healing is impaired and correlated with prolonged back pain. However, assessments such as plain radiograph or MR images taken during the early phase to predict high risks for nonunions of OVFs and/or poor prognoses have not been identified. Methods. A total of 350 OVF patients from 25 institutes were enrolled in this clinical study. Plain radiograph and MR images of the OVFs were routinely taken at enrollment at the respective institutes. The findings on the plain radiograph and MR images were classified after enrollment in the study. All the patients were treated conservatively without any surgical intervention. After a 6-month follow-up, the patients were classified into two groups, a union group and a nonunion group, depending on the presence of an intravertebral cleft on plain radiograph or MR images. The associations of the images from the first visit with those of the corresponding nonunions at the 6-month follow-up were analyzed by multivariate logistic regression to elucidate specific image characteristics that may predict a high risk for nonunion of OVFs. Results. Forty-eight patients (49 vertebrae) among the 350 patients (363 vertebrae) were classified as nonunions, indicating a nonunion incidence of 13.5% for conventional conservative treatments for OVFs. The statistical analyses revealed that a vertebral fracture in the thoracolumbar spine, presence of a middle-column injury, and a confined high intensity or a diffuse low intensity area in the fractured vertebrae on T2-weighted MR images were significant risk factors for nonunion of OVFs. Conclusion. The results of this study revealed significant relationships between plain radiograph and MR images of acute phase OVFs and the incidence of nonunion. As these risk factors are defined more clearly and further validated, they may become essential assessment tools for determining subsequent OVF treatments. Patients with one or more of the earlier-described risk factors for nonunion should be observed carefully and provided with more intensive treatments.

Local delivery of siRNA using a biodegradable polymer application to enhance BMP-induced bone formation.

Small interfering RNA (siRNA) is useful tool for specific and efficient knockdown of disease-related genes. However, in vivo applications of siRNA are limited due to difficulty in its efficient delivery to target cells. In this study, we investigated the efficacy of a biodegradable hydrogel, poly-d,l-lactic acid-p-dioxanone-polyethylene glycol block co-polymer (PLA-DX-PEG), as a siRNA carrier. PLA-DX-PEG pellets with or without fluorescein-labeled dsRNA were implanted into mouse dosal muscle pouches. The cellular uptake of dsRNA surround the polymer was confirmed by fluorescent microscopy. The fluorescence intensity was dose-dependent of the dsRNA, and exhibited a time-dependent decrease. To investigate its biological efficiency, noggin (antagonoist to BMPs) gene-silencing with siRNA (siRNA/Noggin) was examined by the amount of suppression of BMP-2-induced noggin expression and the level of performance of BMP, indicated by ectopic bone formation. Noggin gene expression induced by BMP-2 was suppressed by addition of siRNA/Noggin to the implant, and the ectopic bone formation induced by implants with both BMP-2 and siRNA/Noggin was significantly greater than those induced by implants with BMP-2 alone. These results indicate the efficacy of local delivery of siRNAs by PLA-DX-PEG polymer, which intensified bone-inducing effects of BMP and promoted new bone formation by suppressing gene expression of Noggin.

Quality of life in patients treated surgically for scoliosis: longer than sixteen-year follow-up.

Study Design. A retrospective study. Objective. To evaluate the long-term quality of life (QOL) of patients treated surgically for scoliosis. Summary of Background Data. Measures of long-term outcome after surgery for scoliosis have focused mainly on radiologic changes. However, QOL issues such as working status and marital status are the subjects of greatest concern for patients who will undergo surgical treatment for scoliosis. Methods. Thirty-two patients treated surgically for scoliosis between 1976 and 1989 were included in this study. The mean duration of follow-up was 21.1 years. Eighteen patients had adolescent idiopathic scoliosis, 8 congenital scoliosis, and 6 symptomatic scoliosis. We evaluated long-term outcome by direct interview with patients. Working status, marital status, and childbearing were determined in addition to clinical and radiologic evaluation. Patients were also asked to fill out the short form (SF)-36 and Scoliosis Research Society (SRS)-22 questionnaires. Results. Twenty-seven patients (84.4%) were or had been engaged in various occupations without marked difficulty. Although none of the male patients was married, 62.5% of the female patients were married. Half of the female patients had delivered babies after surgery, and the mean number of such children was 1.83. On the SF-36, none of the scores for subjects with idiopathic or congenital scoliosis were markedly different from those for age-matched healthy controls. Multivariate logistic regression analysis revealed that marked preoperative Cobb angle and positive sagittal balance at the most recent follow-up were significantly associated with increased odds ratio for poor scores on the SRS-22. Conclusion. We evaluated long-term QOL in patients treated surgically for scoliosis, and found that it was not impaired, particularly in the case of patients with idiopathic or congenital scoliosis. Larger preoperative Cobb angle and positive sagittal balance at the most recent follow-up were related to poor outcome in QOL as assessed by the SRS-22.

Low back pain in patients treated surgically for scoliosis: longer than sixteen-year follow-up.

Study Design. A retrospective study. Objective. To evaluate long-term outcome regarding low back pain (LBP) in patients treated surgically for scoliosis. Summary of Background Data. Measures of long-term outcome after surgery for scoliosis have focused mainly on radiologic changes. However, subjective symptoms such as LBP after surgical treatment are of great concern to patients who undergo surgical treatment for scoliosis. Methods. Thirty-two patients treated surgically for scoliosis between 1976 and 1989 were included in this study. The mean duration of follow-up was 21.1 years. Eighteen patients had adolescent idiopathic scoliosis, 8 had congenital scoliosis, and 6 had symptomatic scoliosis. We evaluated long-term outcome by direct interview. Degree of LBP was evaluated by visual analogue scale score and Moskowitz classification in addition to clinical and radiologic evaluation. Patients were also asked to complete the SF-36 questionnaire. Results. Mean visual analogue scale score at the latest follow-up was 21 (0–80), and 15% of patients had occasional or frequent LBP in Moskowitz classification. On the SF-36, score for bodily pain was not markedly different from that for age-matched controls. Among radiologic findings, level of distal fusion had no effect on the incidence or severity of LBP. Furthermore, preoperative Cobb angle, latest Cobb angle, and degenerative changes of subjacent segment each exhibited no correlation with degree of LBP, either. On the other hand, sagittal balance was a factor affecting LBP following scoliosis surgery. Conclusion. We evaluated long-term outcomes regarding LBP following scoliosis surgery. Regardless of residual back deformity, LBP was found to be no more frequent than in the normal population in Japan. Positive sagittal balance at the latest follow-up was a factor significantly contributing to LBP following scoliosis surgery.

Prognostic Factors for Reduction of Activities of Daily Living Following Osteoporotic Vertebral Fractures

Study Design. Prospective cohort study. Objective. To elucidate the prognostic factors indicating reduced activities of daily living (ADL) at the time of the 6-month follow-up after osteoporotic vertebral fracture (OVF). Summary of Background Data. OVF has severe effects on ADL and quality of life (QOL) in elderly patients and leads to long-term deteriorations in physical condition. Many patients recover ADL with acceleration of bony union and spinal stability, but some experience impaired ADL even months after fracture. Identifying factors predicting reduced ADL after OVF may prove valuable. Methods. Subjects in this prospective study comprised 310 OVF patients from 25 institutes. All patients were treated conservatively without surgery. Pain, ADL, QOL, and other factors were evaluated on enrollment and at 6 months. ADL were evaluated using the criteria of the Japanese long-term care insurance system to evaluate the degree of independence. We defined reduced ADL as a reduction of at least single grade at 6 months after fracture and investigated factors predicting reduced ADL after OVF, using uni- and multivariate regression analysis. Results. ADL were reduced at 6 months after OVF in 66 of 310 patients (21.3%). In univariate analysis, age more than 75 years (P = 0.044), female sex (P = 0.041), 2 or more previous spine fractures (P = 0.009), presence of middle column injury (P = 0.021), and lack of regular exercise before fracture (P = 0.001) were significantly associated with reduced ADL. In multivariate analysis, presence of middle column injury (odds ratio [OR], 2.26; P = 0.022) and lack of regular exercise before fracture (OR, 2.49; P = 0.030) were significantly associated with reduced ADL. Conclusion. These results identified presence of middle column injury of the vertebral body and lack of regular exercise before fracture as prognostic factors for reduced ADL. With clarification and validation, these risk factors may provide crucial tools for determining subsequent OVF treatments. Patients showing these prognostic factors should be observed carefully and treated with more intensive treatment options.

Impact of initial conservative treatment interventions on the outcomes of patients with osteoporotic vertebral fractures.

Study Design. Prospective multicenter study. Objective. To examine whether initial conservative treatment interventions for osteoporotic vertebral fractures (OVF) influence patient outcomes. Summary of Background Data. OVFs have been described as stable spinal injuries and, in most cases, are managed well with conservative treatment. However, systematic treatments for OVF have not been clearly established. Methods. A total of 362 patients with OVF (59 males and 303 females; mean age, 76.3 yr) from 25 institutes were enrolled in this clinical study. All the patients were treated conservatively without any surgical interventions. The patient outcomes were evaluated 6 months after the fractures on the basis of Short Form-36 (SF-36) physical component summary (PCS) and mental component summary (MCS), activities of daily living (the Japanese long-term care insurance system), back pain (visual analogue scale), cognitive status (mini-mental state examination), and vertebral collapse, which were used as response variables. Furthermore, brace type, hospitalization, bisphosphonates after injury, and painkillers after injury were explanatory variables for the treatment interventions. To evaluate the independent effects of treatment interventions on patient outcomes, we performed multivariate logistic regression analyses and obtained odds ratios that were adjusted for the potential confounding effects of age, sex, level of fracture, presence of middle-column injury, pain visual analogue scale at enrollment, mini-mental state examination score at enrollment, and previous use of steroids. Results. There was no significant difference for treatment intervention factors including brace type, hospitalization, bisphosphonates after injury, and painkillers after injury. For adjusting factors, the presence of middle-column injury was significantly associated with SF-36 PCS ⩽ 40, reduced activities of daily living, prolonged back pain, and vertebral collapse. Female sex and advanced age were associated with SF-36 PCS ⩽ 40. Low mini-mental state examination scores at enrollment were associated with SF-36 PCS ⩽ 40 and reduced activities of daily living. The previous use of steroids was associated with SF-36 MCS ⩽ 40, prolonged back pain, and vertebral collapse. No other examined variables were significant risk factors for patient outcomes. Conclusion. These results showed that treatment intervention factors did not affect patient outcomes 6 months after OVF. Middle-column injury was a significant risk factor for both clinical and radiological outcomes. In the future, establishing systematic treatments for cases with middle-column injuries is needed. Level of Evidence: 2

New Predictive Index for Lumbar Paraspinal Muscle Degeneration Associated With Aging.

Study Design. A cross-sectional imaging study of paraspinal muscle degeneration using a new index for easy evaluation. Objective. To examine the natural progression of age-related changes in the lumbar paraspinal muscles and to verify the validity of our new index for evaluating paraspinal muscle degeneration Summary of Background Data. Measurement of paraspinal muscle morphology is an effective method for reflecting atrophy and fat infiltration, but it is complicated to perform. Therefore, we focused on the groove between lumbar paraspinal muscles as a simple index for evaluating paraspinal muscle degeneration. Methods. A total of 160 subjects aged 10 to 88 years (10 male and 10 female subjects in each decade) with lumbar lordosis of more than 20° were included. Body mass index (BMI) was calculated. Sagittal T2-weighted magnetic resonance imaging (MRI) was used to measure lumbar lordosis, while axial T2-weighted MRI was used to measure cross-sectional area (CSA) and fat infiltration rate of the paraspinal muscles at the intervertebral disc level from L1 to L5. To quantify the depth of the groove between the paraspinal muscles, our own image index (lumbar indentation value (LIV): equal to the length of the bulge of the muscle to the attachment of the spinous process), also was measured. We then determined the correlation between LIV and paraspinal muscle degeneration. Results. There were no significant differences in BMI and lumbar lordosis between age groups. CSA of the paraspinal muscles tended to decrease with age, and fat infiltration rate increased with age. There was a negative correlation between CSA and fat infiltration rate at all levels (r = −0.474 to −0.634). LIV decreased significantly with age and strongly correlated with CSA at all levels (r = 0.709–0.789). Conclusion. Our new index is a simple and effective parameter for evaluating paraspinal muscle degeneration associated with aging. Level of Evidence: 4

Expression profiles of phosphodiesterase 4D splicing variants in osteoblastic cells.

The promotion of osteoblastic differentiation by bone morphogenetic proteins (BMPs) is accelerated by chemical compounds that increase the intracellular concentration of cyclic 3′,5′-adenosine monophosphate (cAMP). cAMP is synthesized from adenosine triphosphate (ATP) by adenyl cyclase and degraded by phosphodiesterase (PDE) family enzymes. Inhibition of PDEs leads to prolonged accumulation of cAMP within cells and Camp-mediated reactions. Rolipram, a specific inhibitor of PDE4, is a compound effective in inducing osteoblastic differentiation. Four PDE4 family members are transcribed from four distinct genes (4A, 4B, 4C, and 4D). Expression of PDE4A and PDE4D has been observed in osteoblastic cells. We identified PDE4D splicing variants that expressed in ST2 or primary calvarial osteoblasts by rapid amplification of the 5′-ends of cDNA when they were cultured with BMP. PDE4D9 mRNA was identified from ST2, and PDE4D1 and −4D2 mRNAs were identified from primary calvarial osteoblasts. Expression of these three variants of PDE4D mRNA was found in ST2, MC3T3-E1, C3H10T1/2, C2C12, and primary calvarial osteoblasts by RT-PCR, but not PDE4D1 or −4D2 in ST2 or PDE4D2 in MC3T3-E1. Expression of these three variants was detectable in brain, heart, lung, liver, kidney, placenta, and femur, and was thus ubiquitous. Purified recombinant PDE4D9 protein exhibited phosphodiesterase activity, which degraded cAMP to AMP, and this activity was inhibited by rolipram. These findings suggest that PDE4D1, −2, and −9 play some roles in bone formation.

Risk factors for cognitive decline following osteoporotic vertebral fractures: A multicenter cohort study

BACKGROUND Osteoporotic vertebral fractures (OVFs) are the most common cause of intractable back pain and reduced activities of daily living (ADL), which may affect cognitive function. However, no previous studies have reported a change in cognitive function after OVFs. The purpose was to reveal cognitive function changes after OVFs and investigate the risk factors for cognitive decline. METHODS Consecutive patients with symptomatic OVFs were enrolled in a prospective multicenter cohort study. The inclusion criteria were age >65 years, diagnosis of acute or subacute OVF, and back pain onset within 2 months prior to presentation. Cognitive function was assessed with the mini-mental state examination. Medical history, radiological findings, and ADL were investigated as risk factors for cognitive decline. RESULTS We recruited a sample of 339 patients (58 men and 281 women) who met the inclusion criteria. Patients underwent examinations and completed questionnaires at both the time of enrollment and at 6-month follow-up. At 6-month follow-up, cognitive decline was observed in 26 (7.7%) patients. Medical history, including comorbidities and sports activities, did not affect odds ratios (ORs). However, elevated ORs were associated with delayed union (OR: 4.67, 95% Confidence interval: 1.22-17.87). In addition, significantly increased ORs were associated with reduced ADL at 6-month follow-up. CONCLUSIONS The current results revealed the incidence of cognitive decline after the onset of OVF. Delayed union and reduced ADL at 6-month follow-up were associated with cognitive decline. Patients with cognitive decline experienced significantly reduced quality of life. These results highlight the importance of preventing cognitive impairment in patients with symptomatic OVF. Physical treatment or early surgical treatment may provide appropriate options, particularly for patients with suspected delayed union.

MRI Features of Psoas Major Muscles in Patients with Paraspinal Muscle Atrophy

Introduction Maintaining both lumbar lordosis and paraspinal muscle function is important for prevention of sagittal imbalance. We previously reported that the cross-sectional area of the paraspinal muscles tends to decrease with age. To quantify the depth of the groove between the paraspinal muscles, we have developed our own parameter, the T-back value, which indicates the length of the bulge of muscle on the attachment of the spinous process. The T-back value is strongly correlated with the CSA of the paraspinal muscles. The occurrence of T-back value of 0 or less shows a marked increase in individuals aged 60 years or older. The CSA of the paraspinal and psoas muscles shows a similar decreasing trend with age, but fat infiltration of the paraspinal muscles is far more prominent than that of the psoas muscles in the elderly. The aims of this study are to investigate the CSA and fat infiltration of the psoas muscles in patients with paraspinal muscle atrophy, and to compare the findings with those in patients having a T-back value above 0. Methods Among 704 patients who underwent MRI of the lumbar spine at our hospital during 2010, 141 patients had a T-back value of 0 or less. Of these 141 patients, there were 120 patients, 40 men and 80 women, aged 60 years or older. We defined these as T-back − group. The control group included 120 age- and sex-matched individuals with a T-back value above0. We defined them as T-back + group. We compared their data from the two groups. The body mass index (BMI) of participants was calculated. Lumbar lordosis was measured on sagittal T2-weighted MR images. Axial T2-weighted MR images and a digital image analysis technique were used to measure the cross-sectional area and the percentage of fat infiltration of the paraspinal and psoas muscles at the intervertebral disc levels from L1/2 to L4/5 bilaterally. Then the mean values of both sides were used as CSA and the percentage of fat respectively Results The T-back − group had a significantly lower BMI than the T-back + group. Lumbar lordosis was significantly smaller in the T-back − group than in the T-back + group. In addition, the CSA of the paraspinal muscles was significantly smaller in the T-back − group than the T-back + group. The %Fat of the paraspinal muscles was significantly higher in the T-back − group than the T-back + group. When the CSA of the psoas muscles was compared across all spinal levels, there was no significant difference between the two groups. The %Fat of the psoas muscles also showed no significant difference between the two groups. Conclusion The patients in this study were divided into two groups according to the T-back value. The T-back − group had a smaller BMI, less lumbar lordosis, and the advanced atrophy of the paraspinal muscles than the T-back + group. However, MRI features of the psoas muscles were similar in the two groups. This study demonstrates that the psoas muscles are less susceptible to atrophy than the paraspinal muscles.