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.

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.

Treatment with once-weekly alendronate oral jelly compared with once-weekly alendronate oral tablet for Japanese patients with primary osteoporosis: An open-label, prospective, observational study.

BACKGROUND AND AIMS: Clinical data regarding alendronate jelly are limited. We compared the efficacy and safety of once-weekly alendronate oral jelly with once-weekly alendronate tablet formulations in the context of primary osteoporosis. METHODS: In this 6-month, open-label, prospective, observational study, Japanese patients aged ≥60 years with primary osteoporosis were included from 14 primary care centres in Japan. The effects of once-weekly alendronate oral jelly and tablet formulations on bone mineral density (BMD), bone turnover markers, and quality of life related to gastrointestinal symptoms were assessed at baseline and 6 months. Treatment was allocated by patient preference. This potentially confounding factor was adjusted for statistically. RESULTS: In total, 170 patients were enrolled (jelly, n = 97; tablet, n = 73). Mean percent changes in radius, lumbar spine, femoral neck, and hip BMD were similar in both treatment groups at 6 months. Both formulations decreased tartrate-resistant acid phosphatase 5b (TRACP-5b) and procollagen 1 N-terminal peptide (P1NP) between baseline and 6 months (by about 50% and 60%, respectively); no significant differences in mean changes were noted in these markers between groups. At 6 months, no significant differences were noted in visual analogue scale or EuroQOL five-dimension questionnaire scores between groups. The jelly group had significantly lower scores than the tablet group in the Izumo scale domains of heartburn (-0.81, P = 0.0040), epigastralgia (-0.94, P = 0.0003), and epigastric fullness (-0.49, P = 0.044). During treatment, more patients discontinued for upper gastrointestinal symptoms in the tablet group (n = 4) than the jelly group (n = 1). CONCLUSIONS: Once-weekly alendronate oral jelly 35 mg may be a suitable alternative therapeutic agent for primary osteoporosis in Japan.

Industry-based retrospective cohort study of the risk of prostate cancer among rotating-shift workers.

OBJECTIVES: The risk of prostate cancer among shift workers was examined in the present industry-based retrospective cohort study. METHODS: The study was established based on a health-care database from a Japanese manufacturing corporation. Work schedules of 4995 male workers (mean age = 55.5 years) were followed up retrospectively; mean follow-up period = 25.0 years. Of the subjects, 4168 had previously undertaken only daytime work (daytime workers), whereas 827 had undertaken rotating three-shift work for >80% of their career (shift workers). All subjects had undergone prostate-specific antigen (PSA) testing. Prostate cancer incidence data were obtained from the health insurance records of 13 daytime and four shift workers. Multivariate logistic regression was used to estimate the relative risk of prostate cancer for the two groups with adjustments for age, body mass index, alcohol intake, smoking, exercise and marital status. RESULTS: Compared with daytime workers, shift workers showed a non-significant increase in the risk of prostate cancer (odds ratio = 1.79; 95% confidence interval = 0.57, 5.68; P-value = 0.32). CONCLUSIONS: Some increase in the risk of prostate cancer for shift workers was observed, although the result was not statistically significant as a result of the small number of cases. To identify the prostate cancer risk among shift workers, longer-term follow up, including the period after retirement, is required.

Retrospective cohort study of the risk of obesity among shift workers: findings from the Industry-based Shift Workers' Health study, Japan.

OBJECTIVES: The authors investigated the effect of shift working on the risk of obesity using data from the Industry-based Shift Workers' Health (IbSH) study, a retrospective cohort study based on a health care database system belonging to a manufacturing corporation in Japan. METHODS: The study database contains data on annual health check-ups and work schedules for every worker in the corporation in Japan since 1981. Study subjects consisted of 9912 male employees (8892 daytime workers and 920 rotating three-shift workers; mean age at first check-up was 23.7 years) whose work schedules were consistent during the follow-up period. Obesity was defined as a body mass index ≥ 25.0. RESULTS: 3319 cases of obesity were recorded over the 27.5 years of retrospective follow-up. Kaplan-Meier survival analysis visually demonstrated an increased risk of obesity among shift workers. The risk becomes particularly obvious after 10 years of follow-up. Cox proportional-hazards model analysis revealed a significantly increased risk among shift workers (RR 1.14, 95% CI 1.01 to 1.28). CONCLUSION: The risk of obesity among male shift workers was visually and statistically demonstrated.

Anxiety about starting three-shift work among female workers: findings from the Female Shift Workers' Health Study.

In 1999, the Japanese Law on Equal Employment Opportunity and Conditions was amended and the previous prohibition of the assignment of female workers to night work was abolished. Subsequently, the number of female shift workers has been increasing in Japan, necessitating greater attention to the health care of this population. The aim of the current study is to evaluate the relationship between anxiety expressed about starting three-shift work and background characteristics among female workers who were being assigned to three-shift work for the first time. The subjects were 38 middle-aged female workers (age range: 44 to 59 years) who were working at a chemical plant. The women completed a self-administered questionnaire before starting three-shift work. Levels of anxiety about starting three-shift work were assessed by the question 'Do you feel anxious about starting three-shift work?' The available responses were: 'Very agree', 'Considerably agree', 'Rather agree', 'Slightly agree' and 'Not agree at all', and 63% of the subjects gave one of the first two answers, which were defined as indicating anxiety. We also acquired information regarding lifestyle and occupation for each subject, including the following factors: frequency of breakfast consumption, subjective sleep insufficiency, previous experience of similar work before beginning shift work, previous experience of two-shift work, and responsibility for household duties. In the study, we found a marginally statistically significant trend association between frequent breakfast consumption and anxiety about starting three-shift work (P(trend) = 0.09). Anxiety was also high among subjects with sleep disorders, especially those suffering from subjective sleep insufficiency (P = 0.08). Due to the small study population, these results should be interpreted with caution and confirmed by future studies.

Flt-1 tyrosine kinase-deficient homozygous mice result in decreased trabecular bone volume with reduced osteogenic potential.

To clarify the role of Fms-like tyrosine kinase-1 (Flt-1) signaling in bone dynamics, we examined C57BL/6J mice, aged 6, 9 and 16 weeks, with disruption of the flt1 tyrosine kinase domain gene (flt1(TK-/-)) and compared with age-matched wild-type (flt1(TK+/+)) mice. Dynamic histomorphometric analysis confirmed a significant decrease in the values of mineralizing surface (MS/BS), mineral apposition rate (MAR), and bone formation rate (BFR/BS) in the trabecular bone of the proximal tibiae of flt1(TK-/-) mice compared with those in flt1(TK+/+) mice. The value of trabecular bone volume (BV/TV) was also significantly reduced in flt1(TK-/-) mice compared with that in flt1(TK+/+) mice. The values of osteoclast surface (Oc.S/BS) and osteoclast number (Oc.N/BS) in flt1(TK-/-) mice were somewhat lower than those in flt1(TK+/+) mice. The values of bending load of the femur significantly decreased in flt1(TK-/-) mice. In addition, serum osteocalcin significantly decreased in flt1(TK-/-) mice compared with those in flt1(TK+/+) mice. Furthermore, there was a significant decreased mineralization of bone marrow stromal cultures from flt1(TK-/-) mice. These findings demonstrate that flt1(TK-/-) mice show lower trabecular bone volume than flt1(TK+/+) mice, providing powerful evidence that vascular endothelial growth factor signal pathway through the Flt-1 tyrosine kinase domain could be implicated in osteoblast development.

Cyclooxygenase-2 selective inhibition suppresses restoration of tibial trabecular bone formation in association with restriction of osteoblast maturation in skeletal reloading after hindlimb elevation of mice.

To clarify the role of cyclooxygenase-2 (COX-2) in acute recovery of trabecular bone in reloaded hindlimbs of tail-suspended mice, we administered a COX-2 selective inhibitor in the mice during the reloading period after unloading. Experiments were conducted on 140 male C57BL/6J mice (8 weeks old). They were divided into ground control (GC) and unloading by tail suspension (UL) groups. On day 7, Group GC was divided into Groups GC+Vehicle (Veh) and GC+Celecoxib (Cel), while Group UL mice were fed on the ground [reloading (RL)] after 7-day unloading and were then divided into Groups RL+Veh and RL+Cel. Bone histomorphometry, osteogenic cell development, and mRNA expression of osteogenic molecules were assessed. At 5 days after reloading, the increase of bone formation rate and the ratio of osteocalcin mRNA expression per CFU-f colony in Group RL+Cel were significantly decreased compared with those in Group RL+Veh, while alkaline phosphatase-positive (ALP+) CFU-f formation and the ratios of cbfa-1, osterix, and type 1 collagen mRNA expression per CFU-f colony increased to the same levels in both RL groups. At 14 days after reloading, decreased bone volume by unloading in RL+Veh recovered to the same level as that of GC+Veh, but that in RL+Cel did not recover completely. The increase of c-fos mRNA expression in bone marrow cells at 1, 24, and 48 h after reloading, osteocalcin mRNA at 6 h, and osterix mRNA at 24 h were suppressed by COX-2 inhibitor. These data indicate that the COX-2 selective inhibitor celecoxib suppresses the restoration of tibial trabecular bone formation and the acute recovery of trabecular bone. These actions are closely related to restriction of c-fos and osteocalcin mRNA expressions and osteoblast differentiation in bone marrow cells.

Skeletal unloading alleviates the anabolic action of intermittent PTH(1-34) in mouse tibia in association with inhibition of PTH-induced increase in c-fos mRNA in bone marrow cells.

UNLABELLED: We analyzed the effect of unloading by tail suspension on the anabolic action of intermittent PTH in the tibia of growing mice. Unloading alleviated the PTH-induced increase of bone formation and accelerated bone resorption, consequently reducing bone mass. Reduction of the PTH-induced anabolic actions on bone was associated with unloading, which was apparently related to suppression of c-fos mRNA expression in bone marrow. INTRODUCTION: The effects of intermittent parathyroid hormone (PTH) administration on unloading bone have not been well elucidated at the cellular and molecular levels. We tested the effects of PTH on unloaded tibias of tail-suspended mice. MATERIALS AND METHODS: Eighty male C57BL/6J mice, 8 weeks of age, were divided into four groups with loading or unloading and administration of PTH (40 microg/kg body weight) or vehicle five times per week. Mice were killed at 8 or 15 days, and both tibias were obtained. Bone histomorphometry of the trabecular bone in the proximal tibia, development of osteogenic cells, and mRNA expression of osteogenic molecules in bone marrow cells were assessed. RESULTS AND CONCLUSIONS: At 15 days of unloading, bone volume decreased in PTH-treated mice. The increase in the bone formation rate by PTH was depressed, and the osteoclast surface was thoroughly increased. The increase in alkaline phosphatase-positive colony-forming units-fibroblastic (CFU-f) colonies induced by PTH was maintained and that of TRACP+ multinucleated cells enhanced. The PTH-induced increase in c-fos mRNA was depressed, but the increases in Osterix and RANKL mRNA were maintained. Unloading promoted the PTH-associated osteoclastogenesis and seemed to delay the progression of osteogenic differentiation in association with reduction of the PTH-dependent increase of c-fos mRNA in bone marrow cells.

Regulation of mineral-to-matrix ratio of lumbar trabecular bone in ovariectomized rats treated with risedronate in combination with or without vitamin K2.

The relationship between bone turnover and bone tissue and material properties was examined in ovariectomized (OVX) rats treated with risedronate in combination with or without vitamin K2. Seventy female rats, 18 weeks of age, were assigned to 7 groups (n=10): sham-operated + vehicle control; OVX + vehicle control; OVX + risedronate 0.1, 0.5, or 2.5 mg/kg/day po; OVX + vitamin K2 approximately 30 mg/kg/day po; OVX + vitamin K2 (approximately 30 mg/kg/day) and risedronate (0.5 mg/kg/day). Treatments were given daily for 9 months. To assess bone turnover, we measured serum osteocalcin and urinary deoxypyridinoline at 0, 3, and 9 months. To assess vertebral and femoral tissue and material properties, bone mass, bone mineral density (BMD by DXA), trabecular bone structure (vertebra: 3D-microCT), cortical bone structure (femur: histomorphometry), biomechanical properties, and mineral properties (mineral-to-matrix and carbonate-to-phosphate ratios by Fourier transform infrared microspectroscopy) were measured ex vivo at 9 months. Ovariectomy increased bone turnover and induced significant loss of bone mass/density, structure, mineral properties (mineral-to-matrix ratio), and strength. Risedronate produced dose-dependent inhibition of the ovariectomy-induced increase in turnover and loss of bone mass/density, structure, mineral-to-matrix ratio, and strength, with a lowest effective dose of 0.1-0.5 mg/kg/day. High-dose risedronate (2.5 mg/kg/day) did not induce increases in any parameter above that of sham control. Vitamin K2 had no effects. In the OVX groups, urinary deoxypyridinoline at 3 and 9 months correlated significantly with vertebral BMD, trabecular bone volume, ultimate load, stiffness, and mineral-to-matrix ratio, and with femoral BMD, cortical area, and ultimate load. These results support the concept that changes in bone tissue and material properties can result directly from changes in bone turnover. Different effects among different drugs on material properties, including mineral-to-matrix ratio, may reflect differences in the relative rate and magnitude of osteoclastic bone resorption and osteoblastic primary bone mineralization.

Vascular endothelial growth factor is expressed along with its receptors during the healing process of bone and bone marrow after drill-hole injury in rats.

In this study, we investigated the expression of vascular endothelial growth factor (VEGF) mRNA along with its receptors in the healing process following rat femoral drill-hole injury. The cellular events involved in the differential expression of VEGF were studied by reverse transcription-polymerase chain reaction, immunocytochemistry, and in situ hybridization. Abundant alkaline phosphatase-positive osteoprogenitor cells were present in the bone marrow cavity surrounding the wound region at day 3. Some of the cells were immunoreactive for Flk-1, a marker of angioblasts. At day 5, osteoblasts expressing osteocalcin mRNA actively participated in bone formation. After day 11, medullary bone gradually decreased and hematopoietic cells covered the wound region. The expressions of the VEGF splice variants VEGF120 and VEGF164 were detected at days 1 and 3, and VEGF188 mRNA began to appear from day 5. The expressions of the three VEGF splice variants gradually decreased after day 11. VEGF immunoreactivity and mRNA expression were strongly detected in angioblasts, osteoprogenitor cells, and osteoblasts between days 3 and 7, but gradually decreased after day 11. Immunoreactivity for Flt-1 was also detected in endothelial cells, osteoprogenitor cells, and osteoblasts between days 3 and 7. However, immunoreactivity for Flk-1 was not detected on osteoblasts but rather on endothelial cells. These findings indicate that the differential expression of VEGF splicing isoforms along with its receptors may play an important role in the healing process after rat femoral drill-hole injury.

Effects of 1,25(OH)2D3 on turnover, mineralization, and strength of bone in growing rats with liver cirrhosis induced by administration of carbon tetrachloride.

To clarify the effects of 1 alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) on bone growth, strength, and turnover in growing rats with liver cirrhosis induced by carbon tetrachloride (CCl(4)) injection, groups of 4-week-old male Wistar rats (n = 10, each) were injected intraperitoneally with CCl(4) twice weekly for 7 weeks. One group was treated with the vehicle alone (Group 1). Three CCl(4)-injected groups were orally administered 1,25(OH)(2)D(3) at doses of 0, 0.05, and 0.1 micro g/kg, respectively (Groups 2, 3, and 4). At the end, serum levels of 1,25(OH)(2)D(3), IGF-I, and osteocalcin were reduced in Group 2 compared to Group 1, and the corresponding values in Group 4 were larger than those in Group 2. Urinary deoxypyridinoline levels increased in Group 2 compared to Group 1, and did not significantly differ in Groups 2-4. The values for bone sizes, mineral content (BMC) in the lumbar vertebra and femur, and ultimate bending load in the femur were reduced in Group 2 compared to Group 1, and lumbar BMC in Group 3 and bone sizes in Group 4 were larger than those in Group 2. The values for lumbar trabecular bone volume in Group 2 were reduced compared to Group 1, and the corresponding values in Group 4 were larger than those in Group 2. Bone formation rates, reduced in Group 2 compared to Group 1, did not differ in Groups 2-4. Parameters for trabecular osteoclasts did not differ among all groups. In the proximal tibia, the value of activation frequency (Ac.f) in Group 2 significantly decreased compared to Group 1. Ac.f values in Groups 3 and 4 were larger than that in Group 2. These data demonstrated that retardation of bone growth in CCl(4)-injected rats was associated with reduced serum 1,25(OH)(2)D(3) and IGF-I levels. The trabecular bone in the rats exhibited low turnover osteopenia. 1,25(OH)(2)D(3) administration partially prevented the growth disturbance, but did not substantially affect bone turnover. Factors other than 1,25(OH)(2)D(3) and IGF-I appeared to be critical in the low turnover osteopenia evident in liver cirrhosis.