Inhibiting Vascular Endothelial Growth Factor in Injured Intervertebral Discs Attenuates Pain-Related Neuropeptide Expression in Dorsal Root Ganglia in Rats

Jun Sato,Kazuhide Inage,Masayuki Miyagi,Yoshihiro Sakuma,Kazuyo Yamauchi,Masao Koda,Takeo Furuya,Junichi Nakamura,Miyako Suzuki,Go Kubota,Yasuhiro Oikawa,Takeshi Sainoh,Kazuki Fujimoto,Yasuhiro Shiga 대한척추외과학회 2017 Asian Spine Journal Vol.11 No.4

Study Design: An experimental animal study. Purpose: To evaluate effects of anti-vascular endothelial growth factor (VEGF) on the content and distribution of the calcitonin generelated peptide (CGRP) in the dorsal ganglia in a rat model. Overview of Literature: Increased expression of VEGF in degenerative disc disease increases the levels of inflammatory cytokines and nerve ingrowth into the damaged discs. In animal models, increased levels of VEGF can persist for up to 2 weeks after an injury. Methods: Through abdominal surgery, the dorsal root ganglia (DRG) innervating L5/L6 intervertebral disc were labeled (FluoroGold neurotracer) in 24, 8-week old Sprague Dawley rats. The rats were randomly allocated to three groups of eight rats each. The anti- VEGF group underwent L5/6 intervertebral disc puncture using a 26-gauge needle, intradiscal injection of 33.3 μg of the pegaptanib sodium, a VEGF165 aptamer. The control-puncture group underwent disc puncture and intradiscal injection of 10 μL saline solution, and the sham-surgery group underwent labeling but no disc puncture. Two rats in each group were sacrificed on postoperative days 1, 7, 14, and 28 after surgery. L1–L6 DRGs were harvested, sectioned, and immunostained to detect the content and distribution of CGRP. Results: Compared with the control, the percentage of CGRP-positive cells was lower in the anti-VEGF group (p <0.05; 40.6% and 58.1% on postoperative day 1, 44.3% and 55.4% on day 7, and 42.4% and 59.3% on day 14). The percentage was higher in the control group compared with that of the sham group (p <0.05; sham group, 34.1%, 40.7%, and 33.7% on postoperative days 1, 7, and 14, respectively). Conclusions: Decreasing CGRP-positive cells using anti-VEGF therapy provides fundamental evidence for a possible therapeutic role of anti-VEGF in patients with discogenic lower back pain.

Comparison of Effects of Alendronate and Raloxifene on Lumbar Bone Mineral Density, Bone Turnover, and Lipid Metabolism in Elderly Women with Osteoporosis

Jun Iwamoto,Yoshihiro Sato,Mitsuyoshi Uzawa,Tsuyoshi Takeda,Hideo Matsumoto 연세대학교의과대학 2008 Yonsei medical journal Vol.49 No.1

Purpose: To compare the effects of alendronate and raloxifene on lumbar bone mineral density (BMD), bone turnover, and lipid metabolism in elderly women with osteoporosis. Subjects and Methods: One hundred twenty- two postmenopausal women with osteoporosis (mean age: 69.4 years) were randomly divided into 2 groups of 61 patients: the alendronate group and the raloxifene group. BMD of the lumbar spine, urinary level of cross-linked N-terminal telopeptides of type I collagen (NTX), and serum levels of alkaline phosphatase (ALP), total cholesterol (TC), high and low density lipoprotein cholesterols (LDL-C and HDL-C, respectively), and triglycerides (TG) were measured during the 12-month-treatment period. Results: The trial in 50 patients in the alendronate group and 52 patients in the raloxifene group could be completed. Both alendronate and raloxifene increased lumbar BMD (+8.0% and +2.4% at 12 months, respectively), followed by reductions of urinary NTX level and serum ALP level; however, the effects of alendronate were more pronounced than those of raloxifene. Only raloxifene reduced the serum levels of TC and LDL-C (-3.9% and -7.7% at 12 months, respectively), without any significant effect on the serum HDL-C and TG levels. Conclusion: The present study confirmed the efficacy of alendronate greater than raloxifene in increasing lumbar BMD through its effect on marked reduction of the bone turnover more than by raloxifene, and some beneficial effects of raloxifene on lipid metabolism in elderly women with osteoporosis.

Comparison of the Effects of Alendronate and Alfacalcidol on Hip Bone Mineral Density and Bone Turnover in Japanese Men Having Osteoporosis or Osteopenia with Clinical Risk Factors for Fractures

Jun Iwamoto,Yoshihiro Sato,Mitsuyoshi Uzawa,Tsuyoshi Takeda,Hideo Matsumoto 연세대학교의과대학 2009 Yonsei medical journal Vol.50 No.4

Purpose: The comparative effects of alendronate and alfacalcidol on bone mineral density (BMD) and bone turnover have already been established in postmenopausal women with osteoporosis. An open-labeled prospective study was conducted to compare the treatment effects of alendronate and alfacalcidol on hip BMD and bone turnover in Japanese men with osteoporosis or osteopenia with clinical risk factors for fractures. Materials and Methods: One hundred twelve men with osteoporosis or osteopenia with clinical risk factors for fractures (mean age: 71.4 years) were randomly divided into two groups of 56 patients each: the alendronate (5 mg daily) and alfacalcidol (1 μg daily) groups. The BMD of the total hip, urinary level of cross-linked N-terminal telopeptides of type I collagen (NTX), and serum levels of bone-specific alkaline phosphatase (BSAP) were measured during the 12-month-treatment period. Results: Forty-five patients in the alendronate group and 42 patients in the alfacalcidol group completed the trial. Alendronate increased BMD (+2.3% at 12 months) following reductions in the urinary level of NTX (-46.4% at 3 months) and serum level of BSAP (-34.1% at 12 months), while alfacalcidol sustained BMD (-1.9% at 12 months) as well as the urinary level of NTX (+13.2% at 3 months) and serum level of BSAP (+1.8% at 12 months). Conclusion: The present study confirmed that alendronate has better efficacy than alfacalcidol (active control) in increasing hip BMD and reducing bone turnover in Japanese men with osteoporosis or osteopenia with clinical risk factors for fractures. Purpose: The comparative effects of alendronate and alfacalcidol on bone mineral density (BMD) and bone turnover have already been established in postmenopausal women with osteoporosis. An open-labeled prospective study was conducted to compare the treatment effects of alendronate and alfacalcidol on hip BMD and bone turnover in Japanese men with osteoporosis or osteopenia with clinical risk factors for fractures. Materials and Methods: One hundred twelve men with osteoporosis or osteopenia with clinical risk factors for fractures (mean age: 71.4 years) were randomly divided into two groups of 56 patients each: the alendronate (5 mg daily) and alfacalcidol (1 μg daily) groups. The BMD of the total hip, urinary level of cross-linked N-terminal telopeptides of type I collagen (NTX), and serum levels of bone-specific alkaline phosphatase (BSAP) were measured during the 12-month-treatment period. Results: Forty-five patients in the alendronate group and 42 patients in the alfacalcidol group completed the trial. Alendronate increased BMD (+2.3% at 12 months) following reductions in the urinary level of NTX (-46.4% at 3 months) and serum level of BSAP (-34.1% at 12 months), while alfacalcidol sustained BMD (-1.9% at 12 months) as well as the urinary level of NTX (+13.2% at 3 months) and serum level of BSAP (+1.8% at 12 months). Conclusion: The present study confirmed that alendronate has better efficacy than alfacalcidol (active control) in increasing hip BMD and reducing bone turnover in Japanese men with osteoporosis or osteopenia with clinical risk factors for fractures.

Retraction: Paper “Comparison of the Effects of Alendronate and Alfacalcidol on Hip Bone Mineral Density and Bone Turnover in Japanese Men Having Osteoporosis or Osteopenia with Clinical Risk Factors for Fractures” by Iwamoto J, et al. [Yonsei Med J 20

Jun Iwamoto,Yoshihiro Sato,Mitsuyoshi Uzawa,Tsuyoshi Takeda,Hideo Matsumoto 연세대학교의과대학 2023 Yonsei medical journal Vol.64 No.3

We have decided to retract the paper entitled “Comparison of the Effects of Alendronate and Alfacalcidol on Hip Bone Mineral Density and Bone Turnover in Japanese Men Having Osteoporosis or Osteopenia with Clinical Risk Factors for Fractures” [Yonsei Med J 2009 Aug;50(4):474-481] by Iwamoto J, Sato Y, Uzawa M, Takeda T, Matsumoto H. From information obtained after publication, we have recently become aware of a number of issues related to scientific misconduct.

Determinants of One-year Response of Lumbar Bone Mineral Density to Alendronate Treatment in Elderly Japanese Women with Osteoporosis

Jun Iwamoto,Tsuyoshi Takeda,Yoshihiro Sato,Mitsuyoshi Uzawa 연세대학교의과대학 2004 Yonsei medical journal Vol.45 No.4

Retraction: Paper “Efficacy of Oral Etidronate for Skeletal Diseases in Japan” by Iwamoto J, et al. [Yonsei Med J 2005 Jun;46(3):313-320]

Jun Iwamoto,Tsuyoshi Takeda,Yoshihiro Sato 연세대학교의과대학 2023 Yonsei medical journal Vol.64 No.5

We have decided to retract the paper entitled “Efficacy of Oral Etidronate for Skeletal Diseases in Japan” [Yonsei Med J 2005 Jun;46(3):313-320.] by Iwamoto J, Takeda T, Sato Y. From information obtained after publication, we have recently become aware of a number of issues related to scientific misconduct.

Comparison of Effect of Treatment with Etidronate and Alendronate on Lumbar Bone Mineral Density in Elderly Women with Osteoporosis

Jun Iwamoto,Tsuyoshi Takeda,Yoshihiro Sato,Mitsuyoshi Uzawa 연세대학교의과대학 2005 Yonsei medical journal Vol.46 No.6

The purpose of this open-labeled prospective study was to compare the treatment effects of cyclical etidronate and alendronate on the lumbar bone mineral density (BMD), bone resorption, and back pain in elderly women with osteoporosis. Fifty postmenopausal women with osteoporosis, age ranging from 55 to 86 years (mean: 70.7 years), were randomly divided into two groups with 25 patients in each group: the cyclical etidronate group (etidronate 200mg daily for 2 weeks every 3 months) and the alendronate group (5mg daily). The BMD of the lumbar spine (L1-L4) measured by DXA, the urinary cross-linked N-terminal telopeptides of type I collagen (NTX) level measured by the enzyme-linked immunosorbent assay, and back pain evaluated by the face scale score were assessed at baseline, 6 months, and 12 months. There were no significant differences in baseline characteristics including age, body mass index, years since menopause, lumbar BMD, urinary NTX level, and face scale score between the two treatment groups. Etidronate treatment sustained the lumbar BMD following a reduction in the urinary NTX level and improved back pain, while alendronate treatment reduced the urinary NTX level more significantly, resulting in an increase in the lumbar BMD, and similarly improved back pain. No serious adverse events were observed in either group. This study confirmed that alendronate treatment had a greater efficacy than etidronate treatment in increasing the lumbar BMD through the reduction of bone resorption in elderly women with osteoporosis.

Evaluation of Histological Changes in Back Muscle Injuries in Rats over Time

Koki Abe,Kazuhide Inage,Yoshihiro Sakuma,Sumihisa Orita,Kazuyo Yamauchi,Miyako Suzuki,Go Kubota,Yasuhiro Oikawa,Takeshi Sainoh,Jun Sato,Kazuki Fujimoto,Yasuhiro Shiga,Hirohito Kanamoto,Kazuhisa Takaha 대한척추외과학회 2017 Asian Spine Journal Vol.11 No.1

Study Design: Animal model study. Purpose: The purpose of this study was to evaluate the histological variation in the injured muscle and production of calcitonin generelated peptide in rats over time. Overview of Literature: Vertebral surgery has been reported to cause atrophy of the back muscles, which may result in pain. However, few reports have described the time series histological variation in the injured muscle and changes in the dominant nerve. Methods: We used 30 male, 8-week-old Sprague-Dawley rats. The right and left sides of the paravertebral muscle were considered as the injured and uninjured sides, respectively. A 115 g weight was dropped from a height of 1 m on the right paravertebral muscle. Hematoxylin and eosin (H&E) staining of the muscle was performed 1–3 weeks after injury for histological evaluation. Fluoro-Gold (FG) was injected into the paravertebral muscle. The L2 dorsal root ganglia on both sides were resected 1, 2, and 3 weeks after injury, and immunohistochemical staining for calcitonin gene-related peptide was performed. Results: H&E staining of the paravertebral muscle showed infiltration of inflammatory cells and the presence of granulation tissue in the injured part on the ipsilateral side 1 week after injury. Muscle atrophy occurred 3 weeks after injury, but was repaired via spontaneous replacement of muscle cells/fibers. In contrast, compared with the uninjured side, the percentage of cells double-labeled with FG and calcitonin gene-related peptide in FG-positive cells in the dorsal root ganglia of the injured side was significantly increased at each time point throughout the study period. Conclusions: These results suggest that sensitization of the dominant nerve in the dorsal root ganglia, which may be caused by cicatrix formation, can protract injured muscle pain. This information may be helpful in elucidating the underlying mechanism of persistent pain after back muscle injury.

Productivity and Quality of Mulberry Leaves under Cattle Grazing in a Wasted Mulberry Plantation

Shin-ichiro Ogura,Shusuke Sato,Shigefumi Tanaka,Shin Matsumoto,Kunihiro Abe,Toshio Shimizu,Yoshihiro Takahashi,Hiroshi Yoshida 한국초지조사료학회 2009 한국초지조사료학회 학술대회논문집 Vol.2009 No.08

Mulberry (Morus sp.) plantations have been deteriorating in Japan due to decline of silk industry. In mountainous areas, large part of the mulberry plantations has been wasted. Cattle grazing in the wasted mulberry plantations is a practical system to reuse the wasted areas for food production, because mulberry leaves are highly nutritive (Ezenwa and Kitahara, 2001), productive (Kitahara et al., 2002) and palatable to cattle (Ogura et al., 2008). In this study, the productivity and quality of mulberry leaves were investigated for 3 years in a wasted mulberry plantation grazed with beef cows, in Minamisanriku town, Miyagi, Japan. Cattle grazing started in September 2005 (paddock A, 44 a) and June 2006 (paddock B, 96 a). For each paddock, two pregnant cows were grazed from June to August-October in 2006-2008. In the paddocks A and B, four mulberry trees were chosen and the leaf mass and chemical composition were measured in mid-June and late August (pre-grazing leaf mass) during 2006-2008. A non-grazed paddock was also measured in 2007-2008. Leaf productivity of mulberry trees significantly decreased with cattle grazing; pre-grazing leaf mass changed from 246.8 g to 10.4 g DM/tree and 286.2 g to 17.6 g DM/tree in the paddock A and B, respectively (Fig 1). In contrast, 149.2-365.1 g DM/tree of leaves was produced in the non-grazed paddock. Chemical composition was stable during the three years in all paddocks. It is concluded that cattle grazing gives severe damage to leaf production of mulberry trees in three years.

Prevention and Treatment of Corticosteroid-Induced Osteoporosis

Jun Iwamoto,Tsuyoshi Takeda,Yoshihiro Sato 연세대학교의과대학 2005 Yonsei medical journal Vol.46 No.4

Osteoporosis is one of the most serious complications of corticosteroid treatment. Loss of bone mineral density (BMD) and fractures occur early in the course of corticosteroid treatment, and thus early recognition of fracture risk and effective intervention based on evidence-based-medicine (EBM) are needed. A study of meta-analysis representing the highest level in a hierarchy of evidence showed that when the outcome measure of interest was limited to changes in lumbar spine BMD, bisphosphonates were the most effective of the agents studied in comparison with no therapy or treatment with calcium, and were also more efficacious than either vitamin D or calcitonin; the efficacy of bisphosphonates was enhanced when used in combination with vitamin D. Randomized controlled trials (RCTs) representing the second level in a hierarchy of evidence showed that bisphosphonates stabilized BMD not only in the lumbar spine, but also in the hip, and that parathyroid hormone (PTH) markedly increased lumbar spine BMD. According to the EBM, bisphosphonates and possibly PTH are suggested to be the most efficacious for preserving BMD. The efficacy of these agents in reducing the incidence of vertebral fractures in patients exposed to corticosteroids remains to be established in meta-analysis studies, although some RCTs have demonstrated the anti-fracture effects of etidronate, alendronate, and risedronate in the spine. Further RCTs of fracture prevention conducted on a large number of patients and their meta-analysis are needed to confirm the efficacy of bisphosphonates, PTH, or other agents in preventing vertebral and nonvertebral fractures.