稲毛 一秀

INTRODUCTION: Although muscle injury is a common source of pain, the mechanism causing such pain is not completely known. We have previously reported nerve growth factor (NGF) as a proinflammatory mediator involved in acute pain, and clinical trials have shown the effectiveness of anti-NGF antibodies for management of low back pain. Here, we aim to examine the effects of anti-NGF antibodies on muscle-derived pain by studying their effects on sensory innervation in a rat muscle injury model. METHODS: A nervous system tracer, Fluoro-Gold, was applied to both gastrocnemius muscles of 24 male Sprague Dawley rats to stain the sensory nerves. Then, the drop-mass method was used to damage the right gastrocnemius muscle of the posterior limb. Anti-NGF antibodies (50μL) were injected into the injured muscles in 12 rats. Tissues were evaluated 1, 3, and 7 days post-injury by performing haematoxylin-and-eosin (HE) staining. The percentage of the total number of FG-positive cells that were also positive for a pain-related neuropeptide, calcitonin gene-related peptide (CGRP), was determined for the bilateral dorsal root ganglia from L1 to L6 7 days post-injury. RESULTS: HE staining showed active inflammation, indicated by increased basophil and eosinophil accumulation, at the injury site 1 and 3 days post-injury, as well as scar tissue formation 7 days post-injury. Injection of anti-NGF reduced muscle necrosis 1 and 3 days post-injury, and resulted in replacement of granulation tissue and muscle fibre regeneration 7 days post-injury. Anti-NGF also significantly inhibited CGRP among FG-positive cells (treatment group 38.2%, control group 49.6%; P<0.05). DISCUSSION: This study found active inflammation induced by NGF, which may contribute to pain after muscle injury. Anti-NGF antibodies successfully suppressed the pain mediator NGF and inhibited inflammation, suggesting NGF as a target for control in pain management.

ビスホスホネートによる骨粗鬆症に対する治療効果と除痛効果との関連について検討した。対象は腰痛を呈するも骨折のない骨粗鬆症患者113例(男性9例、女性104例、平均年齢73.8±8.0歳)で、ミノドロン酸水和物50mgを平均5.6ヵ月間投与した。その結果、1)痛みに関する経時的評価では腰痛平均NRSは安静時では開始前2.85±2.10、1ヵ月後2.64±2.31、2ヵ月後2.30±2.14、3ヵ月2.02±2.11、4〜6ヵ月後2.20±2.11と、投与2ヵ月後で開始時と比較し有意な低下が認められた。2)体動時腰痛NRSでは開始時4.67±2.84、1ヵ月後4.22±2.67、2ヵ月4.13±2.64、3ヵ月3.94±2.74、4〜6ヵ月3.81±2.71と経時的に軽減し、投与1ヵ月で開始時に比較し有意な低下がみられた。3)骨粗鬆症の治療効果に関する経時的評価では腰椎平均骨密度は開始時0.62±0.20g/cm2、4〜6ヵ月後0.64±0.20g/cm2と有意差は認められなかった。4)骨代謝マーカーの経時的変化では平均TRACP-5b値は開始時504.2±218.5から1ヵ月後306.0±135.7mu/dlと有意に低下(平均改善率36.5%)した。5)安静時NRS改善率とTRACP-5b改善率は有意な正の相関が認められたものの、体動時NRS改善率とTRACP-5b改善率は有意な相関はみられなかった。

【はじめに，目的】我が国では今日，超高齢社会を迎え，高齢者のQOL（quality of life）の向上は，必須の課題と考える。近年では，高齢者におけるQOL低下を招く原因として，サルコペニアによる筋量減少と骨粗鬆症による骨密度低下が注目されている。また，サルコペニアによる筋量減少は転倒などのリスクを増大させ，骨粗鬆症では骨折などのリスクを増大させることで，QOLの低下の原因になると考える。骨粗鬆症とサルコペニアにおいて様々な研究がなされているが，年代別にみた研究は数少ない。そこで本研究では，対象者全体と年代別にみた骨密度と筋量の関係について明らかにすることを目的とした。【方法】対象は2015年4月15日から10月2日までに当院に来院した60歳以上で椎体骨折，側弯変形，卵巣摘出手術など骨密度に影響を与えない，閉経女性394例（年齢74±7.09，身長158±5.85cm，体重51±9.44kg）とした。そのうち，60代121例（年齢65±2.74歳，身長154±5.33cm，体重52±10.76kg），70代187例（年齢75±2.90歳，身長151±5.13cm，体重51±9.20kg），80代86例（年齢83±2.60歳，身長148±6.04cm，体重49±7.31kg）と3群に群分けを行った。骨密度は，DXA法（GE社製DPX-BRAV）を用い，腰椎・大腿骨全体・大腿骨頸部の各骨密度を測定した。筋量は，インピーダンス法（InBody720，BIOSPACE社製）を用い，両上肢・両下肢の骨格筋量を体重比で正規化した骨格筋量指標（skeletal muscle mass index以下，SMI）を算出した。統計学的分析として，それぞれ年代別の腰椎・大腿骨全体・大腿骨頚部の各骨密度とSMIの相関にはspearmanの順位相関係数を用い，有意水準は1％未満とした。【結果】対象全体での骨密度とSMIは，各測定部位ともに正の相関関係を示した（相関係数：腰椎0.29，大腿骨全体0.39，大腿骨頸部0.40，すべてP＜0.01）。年代別（60代→70代→80代）にみると，加齢とともに全ての測定部位において相関係数は低下していた（相関係数：腰椎0.49→0.30→0.18，大腿骨全体0.46→0.40→0.29，大腿骨頸部0.41→0.40→0.15，80代の腰椎，大腿骨頸部のみP＞0.01，他はすべてP＜0.01）。DXA測定部位別にみると，大腿骨全体のみ全年代にわたり有意な相関関係を示していた（P＜0.01）。【結論】本研究では，対象全体での骨密度とSMIは相関するという結果を得た。すなわち，筋量の増加が骨密度の維持に繋がる可能性が示唆された。一方で，各年代別にみると加齢とともに，骨密度とSMIの相関度は低下していた。このことは，高齢になればなるほど，様々な運動器疾患（変形性膝関節症や変形性脊椎症など）が合併する頻度が高まるためと推測された。そのため，80歳以前の骨粗鬆症，サルコペニアの早期治療が必要である可能性も考えられる。今後は，骨粗鬆症，サルコペニアに対して，運動療法の介入方法を検討し，治療・予防効果を明確にしていく。

OBJECTIVE: To examine the analgesic effect of intradiscal administration of a tumor necrosis factor-αα (TNF-α) inhibitor in patients with discogenic low back pain (LBP). DESIGN: Prospective, randomized study. SETTING: Department of Orthopaedic Surgery, Chiba (Japan) University Hospital. SUBJECTS: Seventy-seven patients diagnosed with discogenic LBP. METHODS: Discogenic LBP patients were randomly assigned to the etanercept (n = 38; bupivacaine [2 mL] with etanercept [10 mg]) or control (n = 39; bupivacaine [2 mL]) groups. Patients received a single intradiscal injection. Numerical rating scale (NRS) scores for LBP at baseline, 1 day, and 1, 2, 4, and 8 weeks after the injection were recorded. The Oswestry disability index (ODI) scores at baseline and at 4 and 8 weeks after injection were evaluated. Postinjection complications were recorded and evaluated. RESULTS: In the etanercept group, the NRS scores were significantly lower than in the control group at every time point after the injection for 8 weeks (P < 0.05). Similarly, 4 weeks after the injection, the ODI score was lower in the etanercept group than in the control group (P < 0.05). However, the ODI scores were not significantly different at 8 weeks. Complications were not observed. CONCLUSIONS: Single intradiscal administration of a TNF-α inhibitor can alleviate intractable discogenic LBP for up to 8 weeks. TNF-α may be involved in discogenic pain pathogenesis. This procedure is a novel potential treatment; longer-term effectiveness trials are required in the future.

BACKGROUND: Inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α, are gaining attention as important etiologic factors associated with discogenic low back pain. We conducted a prospective cohort study to evaluate the efficacy and safety of intradiscal injection of the interleukin-6 receptor antibody tocilizumab in patients with discogenic low back pain. METHODS: Thirty-two consecutive patients were intradiscally injected with 2 mL of 0.5% bupivacaine (control group). Another 31 consecutive patients were intradiscally injected with 40 mg tocilizumab and 1-2 mL of 0.5% bupivacaine (tocilizumab group) at the same time. Prior to treatment, the vertebral origin of low back pain was confirmed in all patients based on pain provocation during discography and pain relief with 1 mL of 1% xylocaine. Numeric rating scale and Oswestry disability index scores were used to evaluate pain level before and after treatment between the 2 groups. The association between pain relief with tocilizumab and intervertebral disc degeneration grade was also determined. RESULTS: At the end of the study (8 weeks after treatment), 30 patients in each group were evaluable. In the tocilizumab group, numeric rating scale and Oswestry disability index scores improved significantly at 2 and 4 weeks after treatment, respectively. Intervertebral disc degeneration was not associated with improvement of numeric rating scale score in the tocilizumab group. Local infection (i.e., discitis) was observed in 1 patient in the tocilizumab group. CONCLUSIONS: The results demonstrate the clinical relevance of interleukin-6 in discogenic low back pain. Intradiscal tocilizumab injection was shown to exert a short-term analgesic effect in patients with discogenic low back pain. Further research is required to determine the long-term effects of intradiscal tocilizumab therapy in patients with discogenic low back pain.

[This corrects the article on p. 338 in vol. 9, PMID: 26097648.].

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA)-caused pyogenic spondylitis is a serious complication associated with lumbar fusion surgery. Often, anti-MRSA drugs are not used properly or patients discontinue drug use because of side effects including renal failure. CASE PRESENTATION: We report a case at our hospital of a 54-year-old male renal-transplant patient who developed MRSA vertebral osteomyelitis after spinal fusion and was treated effectively with linezolid. After diagnosis of post-fusion surgery osteomyelitis, we conducted emergency flushing and debridement and began linezolid treatment (1200 mg/day, divided) immediately after the surgery. The level of C-reactive protein gradually decreased and became negative 4 weeks after the initiation of linezolid treatment. Serum creatinine level was approximately 1.3 mg/dL throughout the treatment period, indicating no deterioration in renal function. CONCLUSION: These results suggest that early flushing and debridement together with linezolid administration is an effective treatment for MRSA vertebral osteomyelitis in renal-transplant patients.

Recently several authors have reported that diffusion tensor imaging (DTI) might provide a new understanding of sciatica. The purpose of this study was to investigate the clinical feasibility of DTI for the evaluation of lumbar spinal nerve of patients with sciatica associated with lumbar degenerative disorders. Thirty-four patients (25men, mean age63. 3years) with degenerated lumbar disease, 14 patients with lumbar spinal stenosis with foraminal stenosis, 12 with lumbar spinal stenosis without foraminal stenosis, five with lumbar disc herniation, two with discogenic low back pain, and one with spondylolysis who underwent 3.0T magnetic resonance (MR) imaging and surgical treatment were included in the present study. Fractional anisotropy (FA) was calculated from an FA map, and tractography was investigated. In asymptomatic nerves, tractography showed all L3-S1 spinal nerve roots clearly. Abnormalities of tractography were classified into three types by shape; "Disrupted", "Narrowing", and "Tapering". More abnormalities of tractography were found in patients with lumbar spinal stenosis, and especially in patients with foraminal stenosis. The disrupted type was the most common. The mean FA of entrapped symptomatic nerves was less than seen on the intact side. This study demonstrates that tractography shows abnormal findings for nerve roots in lumbar spinal degeneration and that FA decreases in symptomatic roots. DTI may offer not only morphological evaluation, but also quantitative evaluation. We believe that DTI can be used as a tool for the diagnosis of lumbar spinal degenerative disease.

The pathological mechanism of intractable low back pain is unclear. However, intervertebral disc (IVD) degeneration is a primary cause of low back pain, and pain-related mediators, such as interleukin-6 (IL-6), have been correlated with discogenic pain. The objective of this study is to elucidate the mechanism of local IL-6 and IL-6 receptor (IL-6R) expression after IVD injury as well as determine the involvement of IL-6/IL-6 signaling in discogenic pain. To do this, quantitative and immunohistological analyses in a mouse model of IVD injury were performed. Firstly, we measured the local expression levels of IL-6 and IL-6R in IVDs by enzyme-linked immunosorbent assay (ELISA). Secondly, we immunohistochemically confirmed their localization in injured IVDs. Lastly, we evaluated the effects of intradiscal injection of an IL-6 inhibitor by evaluating pain-related protein, calcitonin gene-related peptide (CGRP), expression in dorsal root ganglia (DRG) neurons that innervate IVDs. Injured IVDs showed increased production of IL-6 and IL-6R. IL-6 and IL-6R expression in the injured IVD were predominantly localized in the annulus fibrosus and endplate, and intradiscal injection of the IL-6 inhibitor suppressed CGRP expression in the DRG neurons. These results show that IL-6 and IL-6R expression levels are responsive to IVD injury and that inhibition of IL-6/IL-6R signaling may be a promising analgesic treatment for degenerative disc diseases.

椎間板性腰痛の病態と今後の展望について、1)innervation:感覚神経支配が存在すること、2)inflammation:その感覚神経を感作する因子が存在すること、3)hypermobility:不安定性があること、に分けて述べた。現時点では、術前の痛みや術後残存する痺れと術前拡散テンソル画像での障害の程度が相関しており、基礎、臨床的に認められた椎間板内への神経発芽を可視化することが現実化できると期待される。

PURPOSE: Nuclear factor-κB (NF-κB), receptor activator of NF-κB (RANK), and RANK ligand (RANKL) are transcriptional regulators of inflammatory cytokines. RANKL expression in dorsal root ganglion (DRG) neurons is elevated in animal models of pain or intervertebral disc herniation. We sought to evaluate the effect of anti-RANKL antibodies on sensory nerves innervating injured intervertebral discs. METHOD: We labeled DRG neurons innervating L5-6 discs with FluoroGold (FG). The L5-6 discs of 36 rats were punctured using a 23-gage needle and 18 rats underwent sham surgery without disc puncture. The puncture group was evenly subdivided into a group in which 10 μl saline was administered to the injured disc and a group in which 10 μl of anti-RANKL antibody was administered. Seven and 14 days postsurgery, DRGs at L2 level were harvested, sectioned, and immunostained for calcitonin gene-related peptide (CGRP). The proportion of CGRP-immunoreactive (IR) DRG neurons of all FG-positive neurons was determined. Amount of tumor necrosis factor (TNF)-α and interleukin(IL)-6 was measured within the intervertebral discs in each group at 7 and 14 days after surgery using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The proportion of CGRP-IR DRG neurons to total FG-labeled neurons innervating injured intervertebral discs and amount of TNF-α and IL-6 in the injured discs in the saline control group was significantly increased compared with that found in rats from the sham surgery group (P < 0.05). However, application of anti-RANKL antibody to the injured discs significantly decreased the proportion of CGRP-IR DRG neurons to total FG-labeled neurons and amount of TNF-α and IL-6 in the injured discs (P < 0.05). CONCLUSIONS: TNF-α and IL-6 in the injured discs increased and CGRP expression increased in DRG neurons innervating injured discs, and antibodies to RANKL could suppress this increased TNF-α, IL-6, and CGRP expression. RANKL may be a therapeutic target for pain control in patients with lumbar disc degeneration.

PURPOSE: Osteoarthritic (OA) pain is largely considered to be inflammatory pain. However, during the last stage of knee OA, sensory nerve fibers in the knee are shown to be significantly damaged when the subchondral bone junction is destroyed, and this can induce neuropathic pain. Several authors have reported that tumor necrosis factor-α (TNFα) in a knee joint plays a crucial role in pain modulation. The purpose of the current study was to evaluate the efficacy of etanercept, a TNFα inhibitor, for pain in knee OA. MATERIALS AND METHODS: Thirty-nine patients with knee OA and a 2-4 Kellgren-Lawrence grading were evaluated in this prospective study. Patients were divided into two groups; hyaluronic acid (HA) and etanercept injection. All patients received a single injection into the knee. Pain scores were evaluated before and 4 weeks after injection using a visual analogue scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and they were compared between the groups. RESULTS: Before injection, VAS and WOMAC scores were not significantly different between the groups (p>0.05). Significant pain relief was found in the etanercept group at 1 and 2 weeks by VAS, and at 4 weeks by WOMAC score, compared with the HA group (p<0.05). No adverse events were observed in either group. CONCLUSION: Direct injection of etanercept into OA knee joints was an effective treatment for pain in moderate and severe OA patients. Furthermore, this finding suggests that TNFα is one factor that induces OA pain.

STUDY DESIGN: Prospective case series. PURPOSE: To examine the clinical efficacy of mini-open anterior retroperitoneal lumbar interbody fusion: oblique lateral interbody fusion (OLIF) for degenerated lumbar spinal kyphoscoliosis. OVERVIEW OF LITERATURE: The existing surgical procedures for the treatment of spinal kyphotic deformity, including Smith-Petersen osteotomy, pedicle subtraction osteotomy, and vertebral column resection procedures, are invasive in nature. Extreme lateral interbody fusion to provide less invasive treatment of the deformity has been reported, but complications including spinal nerve and psoas muscle injury have been noted. In the current study, we examined the clinical efficacy and complications of OLIF for degenerated lumbar spinal kyphoscoliosis. METHODS: Twelve patients with degenerated lumbar spinal kyphoscoliosis were examined. All patients underwent OLIF surgery (using a cage and bone graft from the iliac crest) with open pedicle screws or percutaneous pedicle screws, without real-time monitoring by electromyography. Visual analog scale score and Oswestry disability index were evaluated before and 12 months after surgery, and fusion rate at OLIF cage, correction of the deformity, total blood loss, and surgical complications were also evaluated. RESULTS: Pain scores significantly improved after surgery (p<0.05). Fusion rate was found to be 90%, balance parameters also improved after surgery (p<0.05), and average total blood loss was less than 350 mL. There was no spinal nerve, major vessel, peritoneal, or urinary injury, or breakage of instrumentation. CONCLUSIONS: OLIF surgery for degenerated lumbar spinal kyphoscoliosis is less invasive than other procedures and good surgical results were produced without major complications.

STUDY DESIGN: Retrospective case series. PURPOSE: To examine the most effective duration of teriparatide use for spinal fusion in women with postmenopausal osteoporosis. OVERVIEW OF LITERATURE: We reported that daily subcutaneous injection of teriparatide (parathyroid hormone) significantly improved bone union after instrumented lumbar posterolateral fusion (PLF) in women with postmenopausal osteoporosis when compared with oral administration of bisphosphonate. However, the most effective duration of teriparatide use for spinal fusion has not been explored. METHODS: Forty-five women with osteoporosis diagnosed with degenerative spondylolisthesis from one of the three treatment groups were evaluated based on: short-duration treatment (average, 5.5 months; n=15; daily subcutaneous injection of 20 µg teriparatide), long-duration treatment (average, 13.0 months; n=15; daily subcutaneous injection of 20 µg teriparatide), and bisphosphonate treatment (average, 13.0 months; n=15; weekly oral administration of 17.5 mg risedronate). All patients underwent PLF with a local bone graft. Fusion rate and duration of bone union were evaluated 1.5 years after surgery. RESULTS: Bone union rate and average duration for bone union were 92% and 7.5 months in the long-duration treatment group, 80% and 8.5 months in the short-duration treatment group, and 70% and 10.0 months in the bisphosphonate treatment group, respectively. Results of bone union rate and average duration for bone union in the teriparatide treatment groups were significantly superior to those in the bisphosphonate treatment group (p<0.05); whereas, significantly superior results were observed in long-duration treatment group when compared with short-duration treatment group (p<0.05). CONCLUSIONS: Daily injection of teriparatide for bone union was more effective than oral administration of bisphosphonate. Furthermore, a longer period of teriparatide treatment for bone union was more effective than a shorter period of same treatment.