Effect of romosozumab in premenopausal women with severe osteoporosis and anorexia nervosa

Kazuki Fujimoto,Narumi Maki,Daisuke Hashiba,Toshifumi Maeyama,Ryosuke Nakagawa,Hajime Arai,Seiji Ohtori 대한골다공증학회 2023 Osteoporosis and Sarcopenia Vol.9 No.4

Objectives: This study aims to investigate the effects of romosozumab on bone mineral density (BMD) and bone metabolism. Methods: In this retrospective case series, romosozumab was administered to 5 premenopausal female patients with osteoporosis and anorexia nervosa with fragility fractures. BMD and bone turnover marker changes were investigated at 6 months and 1 year after administering romosozumab. Results: BMD increased and high-turnover bone metabolism decreased 6 months and 1 year after administering romosozumab. Conclusions: Romosozumab is useful for treating osteoporosis in patients with anorexia nervosa.

Use of Bioelectrical Impedance Analysis for the Measurement of Appendicular Skeletal Muscle Mass/Whole Fat Mass and Its Relevance in Assessing Osteoporosis among Patients with Low Back Pain: A Comparative Analysis Using Dual X-ray Absorptiometry

Kazuki Fujimoto,Kazuhide Inage,Yawara Eguchi,Sumihisa Orita,Miyako Suzuki,Go Kubota,Takeshi Sainoh,Jun Sato,Yasuhiro Shiga,Koki Abe,Hirohito Kanamoto,Masahiro Inoue,Hideyuki Kinoshita,Masaki Norimoto 대한척추외과학회 2018 Asian Spine Journal Vol.12 No.5

Study Design: Cross-sectional observational study. Purpose: To compare measurements of appendicular skeletal muscle mass (ASMM) and whole fat mass (WFM) obtained using dualenergy X-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA) among patients with low back pain (LBP). Moreover, the study investigated the correlation between BIA-based ASMM and DXA-based bone mineral density (BMD). Overview of the Literature: If reliable, BIA may be a useful alternative to DXA as a screening tool for sarcopenia and osteoporosis among patients with LBP. Methods: Measurements were performed in 130 patients, including BMD of the lumbar spine and femoral neck. The correlation between DXA and BIA as well as between BIA-ASMM and BMD were evaluated. Results: BIA and DXA were highly correlated in both male and female patients (r =0.73–0.90, p <0.0001). However, BIA consistently overestimated ASMM by 1.5–2.5 kg on an average (p <0.0001) and underestimated WFM (−4.0 to −2.7 kg) on an average (p <0.0001). BIA-based ASMM correlated with BMD of the lumbar spine in both male and female patients (r =0.28–0.37, p ≤0.02) and that of the femoral neck (r =0.34–0.51, p ≤0.005). Regarding the calculated skeletal muscle index (SMI: ASMM/height [m2]) used as a criterion for sarcopenia, BIA-based SMI correlated with BMD of the lumbar spine in male patients (r =0.44, p =0.0004) and that of the femoral neck in female patients (r =0.33, p =0.009). Conclusions: BIA may be a favorable alternative to DXA as a screening tool for sarcopenia and osteoporosis among patients with LBP. Considering the overestimation of BIA-based ASMM and SMI, we recommend using the cutoff values for sarcopenia of 7.9 kg/m2 for males and 6.1 kg/m2 for females.

Angiopoietin-Like Protein 2 Induces Synovial Inflammation in the Facet Joint Leading to Degenerative Changes via Interleukin-6 Secretion

Kazuki Sugimoto,Takayuki Nakamura,Takuya Tokunaga,Yusuke Uehara,Tatsuya Okada,Takuya Taniwaki,Toru Fujimoto,Yuichi Oike,Eiichi Nakamura 대한척추외과학회 2019 Asian Spine Journal Vol.13 No.3

Study Design: Experimental human study. Purpose: To determine whether angiopoietin-like protein 2 (ANGPTL2) is highly expressed in the hyperplastic facet joint (FJ) synovium and whether it activates interleukin-6 (IL-6) secretion in FJ synoviocytes. Overview of Literature: Mechanical stress-induced synovitis is partially, but significantly, responsible for degenerative and subsequently osteoarthritic changes in the FJ tissues in patients with lumbar spinal stenosis (LSS). However, the underlying molecular mechanism remains unclear. IL-6 is highly expressed in degenerative FJ synovial tissue and is responsible for local chronic inflammation. ANGPTL2, an inflammatory and mechanically induced mediator, promotes the expression of IL-6 in many cells. Methods: FJ tissues were harvested from five patients who had undergone lumbar surgery. Immunohistochemistry for ANGPTL2, IL-6, and cell markers was performed in the FJ tissue samples. After cultured synoviocytes from the FJ tissues were subjected to mechanical stress, ANGPTL2 expression and secretion were measured quantitatively using real-time quantitative reverse-transcription–polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA), respectively. Following ANGPTL2 administration in the FJ synoviocytes, anti-nuclear factor-κB (NF-κB) activation was investigated using immunocytochemistry, and IL-6 expression and secretion were assayed quantitatively with or without NF-κB inhibitor. Moreover, we assessed whether ANGPTL2-induced IL-6 modulates leucocyte recruitment in the degenerative process by focusing on the monocyte chemoattractant protein-1 (MCP-1) expression. Results: ANGPTL2 and IL-6 were highly expressed in the hyperplastic FJ synovium samples. ANGPTL2 was co-expressed in both, fibroblast-like and macrophage-like synoviocytes. Further, the expression and secretion of ANGPTL2 in the FJ synoviocytes increased in response to stimulation by mechanical stretching. ANGPTL2 protein promoted the nuclear translocation of NF-κB and induced IL-6 expression and secretion in the FJ synoviocytes. This effect was reversed following treatment with NF-κB inhibitor. Furthermore, ANGPTL2-induced IL-6 upregulated the MCP-1 expression in the FJ synoviocytes. Conclusions: Mechanical stress-induced ANGPTL2 promotes chronic inflammation in the FJ synovium by activating IL-6 secretion, leading to FJ degeneration and subsequent LSS.

Elevated Levels of Serum Pentosidine Are Associated with Dropped Head Syndrome in Older Women

Yawara Eguchi,Toru Toyoguchi,Kazuhide Inage,Kazuki Fujimoto,Sumihisa Orita,Kazuyo Yamauchi,Miyako Suzuki,Hirohito Kanamoto,Koki Abe,Masaki Norimoto,Tomotaka Umimura,Masao Koda,Takeo Furuya,Yasuchika A 대한척추외과학회 2019 Asian Spine Journal Vol.13 No.1

Study Design: A retrospective observational study was performed. Purpose: We investigated the prevalence of sarcopenia in dropped head syndrome (DHS), and the relationship between biochemical markers, including major advanced glycation end products (AGEs), pentosidine, and DHS in older women. Overview of Literature: AGEs have been implicated in the pathogenesis of sarcopenia. Methods: We studied 13 elderly women with idiopathic DHS (mean age, 77.2 years) and 20 healthy volunteers (mean age, 74.8 years). We used a bioelectrical impedance analyzer to analyze body composition, including appendicular skeletal muscle mass index (SMI; appendicular lean mass [kg]/[height (m)]2). Cervical sagittal plane alignment, including C2–C7 sagittal vertical axis (C2–C7SVA), C2–C7 angle, and C2 slope (C2S), was measured. Biochemical markers, such as serum and urinary pentosidine, serum homocysteine, 1, 25-dihydroxyvitamin D, and 25-hydroxyvitamin D, were measured. The level of each variable was compared between DHS and controls. The relationship between biochemical markers and DHS was examined. Results: Sarcopenia (SMI <5.75) was observed at a high prevalence in participants with DHS (77% compared to 22% of healthy controls). Height, weight, femoral bone mineral density, appendicular lean mass, total lean mass, and SMI all had significantly lower values in the DHS group. Serum and urinary pentosidine, and serum homocysteine were significantly higher in the DHS group compared to controls. Analysis of cervical alignment revealed a significant positive correlation of serum pentosidine with C2–C7SVA and C2S. Conclusions: Sarcopenia was involved in DHS, and high serum pentosidine levels are associated with severity of DHS in older women.

Freeze-Dried Platelet-Rich Plasma Induces Osteoblast Proliferation via Platelet-Derived Growth Factor Receptor-Mediated Signal Transduction

Hideyuki Kinoshita,Sumihisa Orita,Kazuhide Inage,Kazuki Fujimoto,Yasuhiro Shiga,Koki Abe,Masahiro Inoue,Masaki Norimoto,Tomotaka Umimura,Takeshi Ishii,Tsukasa Yonemoto,Hiroto Kamoda,Toshinori Tsukanis 대한척추외과학회 2020 Asian Spine Journal Vol.14 No.1

Study Design: Controlled laboratory study. Purpose: This study aimed to evaluate the in vitro pharmacological activity of growth factors (GFs) in freeze-dried platelet-rich plasma (FD-PRP) after storage for 4 weeks. Overview of Literature: Freshly prepared PRP is a rich source of many GFs. We reported that FD-PRP stored for 8 weeks accelerated bone union in a rat posterolateral fusion model equally well as fresh-PRP. However, the pharmacological activity of FD-PRP after long-term storage has not been shown in vitro. Methods: Immediately after preparation, as well as 4 weeks after freeze-dried storage, the platelet count was measured. Human osteoblasts were treated with fresh-PRP and FD-PRP, respectively. Western blotting was used to assess the phosphorylation of the platelet-derived growth factor (PDGF) receptor (PDGFR) and its downstream target, extracellular signal-regulated kinase (ERK). The proliferation rates of osteoblasts were investigated by immunocytochemistry and MTT cell viability assays. Furthermore, we used western blotting to evaluate the effect of PDGFR knockdown on the phosphorylation of ERK stimulated with fresh-PRP and FD-PRP. Results: Platelet counts in both the fresh-PRP and FD-PRP samples were approximately 10-fold higher than in peripheral blood samples. The phosphorylation and activation of the PDGFR and ERK were evenly induced by fresh-PRP and FD-PRP stimulation. Both fresh-PRP and FD-PRP significantly induced osteoblast proliferation in MTT cell viability assays. Furthermore, osteoblast PDGFR knockdown attenuated the downstream ERK activation by fresh PRP and FD-PRP. Conclusions: We demonstrated the pharmacological activity of PDGF in FD-PRP in vitro after 4 weeks of storage.

Influence of Skeletal Muscle Mass and Spinal Alignment on Surgical Outcomes for Lumbar Spinal Stenosis

Yawara Eguchi,Munetaka Suzuki,Hajime Yamanaka,Hiroshi Tamai,Tatsuya Kobayashi,Sumihisa Orita,Kazuyo Yamauchi,Miyako Suzuki,Kazuhide Inage,Kazuki Fujimoto,Hirohito Kanamoto,Koki Abe,Masaki Norimoto,Tom 대한척추외과학회 2018 Asian Spine Journal Vol.12 No.3

Study Design: Retrospective observational study. Purpose: We considered the relationship between spinal alignment and skeletal muscle mass on clinical outcomes following a surgery for lumbar spinal stenosis (LSS). Overview of Literature: There are no reports of preoperative factors predicting residual low back pain following surgery for LSS. Methods: Our target population included 34 women (mean age, 74.4 years) who underwent surgery for LSS. Prior to and 6 months after the surgery, systemic bone mineral density and lean soft tissue mass were measured using dual-energy X-ray absorptiometry. Skeletal muscle mass index (SMI) was calculated as the sum of the arm and leg lean mass in kilograms divided by height in meters squared. The spinal alignment was also measured. Clinical outcomes were evaluated using the Japanese Orthopedic Association scoring system, leg and low back pain Visual Analog Scale, and Roland–Morris Disability Questionnaire (RDQ). Additionally, we examined the bone mineral density, skeletal muscle mass, and spinal alignment before and after the surgery. We used the Spearman correlation coefficient to examine the associations among clinical outcomes, preoperative muscle mass, and spinal alignment. Results: Sarcopenia (SMI <5.46) was observed in nine subjects (26.5%). Compared with normal subjects (SMI >6.12), RDQ was significantly higher in subjects with sarcopenia (p =0.04). RDQ was significantly negatively correlated with SMI (r =−0.42, p <0.05). There was a significant positive correlation between postoperative RDQ and pelvic tilt (PT; r =0.41, p <0.05). SMI and PT were significantly negatively correlated (r =−0.39, r <0.05). Conclusions: Good postoperative outcomes were negatively correlated with low preoperative appendicular muscle mass, suggesting that postoperative outcomes were inferior in cases of decreased appendicular muscle mass (sarcopenia). Posterior PT due to decreased limb muscle mass may contribute to postoperative back pain, showing that preoperatively reduced limb muscle mass and posterior PT are predictive factors in the persistence of postoperative low back pain.

The Time Course Changes in Bone Metabolic Markers after Administering the Anti-Receptor Activator of Nuclear Factor-Kappa B Ligand Antibody and Drug Compliance among Patients with Osteoporosis

Kazuhide Inage,Sumihisa Orita,Kazuyo Yamauchi,Yoshihiro Sakuma,Go Kubota,Yasuhiro Oikawa,Takeshi Sainoh,Jun Sato,Kazuki Fujimoto,Yasuhiro Shiga,Kazuhisa Takahashi,Seiji Ohtori 대한척추외과학회 2015 Asian Spine Journal Vol.9 No.3

Study Design: Retrospective study. Purpose: We conducted a study to investigate the time course changes in bone metabolic markers after the administration of the anti-receptor activator of nuclear factor-kappa B ligand (RANKL) antibody and to assess drug compliance among osteoporotic patients. Overview of Literature: The anti-RANKL antibody is expected to provide an improvement in those with a bone metabolism disorder. However there are only a few clinical reports available on the effect of treatment. Methods: We included 40 post-menopausal osteoporotic patients who received the anti-RANKL antibody. To determine the time course changes in the bone metabolic markers, we measured the serum tartrate-resistant acid phosphatase 5b (TRACP 5b; a bone resorption marker) and the serum N-terminal propeptide of type 1 collagen (P1NP; a bone formation marker) levels prior to and 1 month after administrating the anti-RANKL antibody. To evaluable drug compliance, we assessed the dropout rate during treatment and at 6 months after treatment. Results: The average TRACP 5b level significantly decreased from 574.8 mU/dL before treatment to 153.2 mU/dL 1 month after treatment (p <0.05). There was no significant difference in the average P1NP level, which was 56.9 μG/L and 35.1 μG/L before and 1 month after treatment, respectively (p >0.05). As for drug compliance, we did not have any dropouts during the treatment or after 6 months (dropout rate: 0%). Conclusions: Our study suggests that anti-RANKL antibody treatment suppresses bone resorption and maintains bone formation.

Long-Term Outcomes of In Situ Fusion for Treating Dysplastic Spondylolisthesis

Kazuhide Inage,Sumihisa Orita,Kazuyo Yamauchi,Miyako Suzuki,Yoshihiro Sakuma,Go Kubota,Yasuhiro Oikawa,Takeshi Sainoh,Jun Sato,Kazuki Fujimoto,Yasuhiro Shiga,Koki Abe,Hirohito Kanamoto,Masahiro Inoue 대한척추외과학회 2017 Asian Spine Journal Vol.11 No.2

Study Design: Retrospective, observational, single-center study. Purpose: To investigate the long-term outcomes of in situ fusion procedures for treating dysplastic spondylolisthesis. Overview of Literature: In situ fusion performed in patients with dysplastic spondylolisthesis avoids the development of nerve complications. Methods: In total, 12 of 28 patients who underwent in situ fusion for treating dysplastic spondylolisthesis at Chiba University Hospital from 1974 to 2004 were followed up in August 2013. Surgical complications were evaluated. Low back pain and leg pain were assessed using a visual analog scale (VAS). Vertebral alignment, including the lumbosacral angle and lumbar lordosis angle measurement on radiographic images (profile view in the neutral standing position), was evaluated during preoperative, postoperative, and final examinations. Results: The mean follow-up duration, patient age at the final examination, and patient age at operation were 20.0±7.2, 42.3±13.3, and 22.3±11.4 years, respectively. No complications were reported. Mean VAS scores for low back pain and leg pain were significantly lower at the final examination than at the preoperative examination (p <0.05). At the preoperative, postoperative, and final examinations, the mean lumbosacral angle was 32.3°±14.2°, 33.7°±11.8°, and 36.5°±16.4°, while the mean lumbar lordosis angle was 51.0°±14.8°, 48.6°±18.8°, and 49.6°±15.5°, respectively. No significant differences were noted among these values across the different time periods (p <0.05). Conclusions: In situ fusion performed in patients with dysplastic spondylolisthesis avoids the development of nerve complications such as nerve paralysis that may occur after repositioning operation and maintains appropriate long-term sagittal alignment, even 20 years after operation.

Improvements in Intractable Lumbar and LowerExtremity Symptoms after Systemic Administration of Tocilizumab, an Anti-interleukin-6 Receptor Antibody

Sainoh Takeshi,Orita Sumihisa,Miyagi Masayuki,Suzuki-Narita Miyako,Sakuma Yoshihiro,Oikawa Yasuhiro,Kubota Go,Sato Jun,Shiga Yasuhiro,Fujimoto Kazuki,Eguchi Yawara,Koda Masao,Aoki Yasuchika,Akazawa Ts 대한척추외과학회 2022 Asian Spine Journal Vol.16 No.1

Study Design: Prospective cohort study (open-label, single-arm, and non-blinded).Purpose: This study aims to determine the effects of systemic administration of tocilizumab, an anti-interleukin-6 (IL-6) receptor antibody on refractory low back pain and leg symptoms.Overview of Literature: IL-6 overexpression is associated with neuropathic pain pathogenesis, which is potentially followed by chronic low back pain, including leg pain and numbness. This finding suggest that inhibition of IL-6 at the site of pain or in the transmission pathway could provide novel therapeutic targets for chronic low back pain.Methods: This prospective, single-arm study included 11 patients (eight men; mean age, 62.7 years) with ≥3-months’ chronic pain history due to lumbar disease. Subcutaneous TCZ injections were administered twice, at a 2-week interval. We evaluated low back pain, leg pain, and leg numbness using numeric rating scales and the Oswestry Disability Index (ODI; baseline and 6 months postinjection); serum IL-6 and tumor necrosis factor-α levels (baseline and 1 month postinjection); and clinical adverse events.Results: Intractable symptoms reduced after TCZ administration. Low back pain improved for 6 months. Improvements in leg pain and numbness peaked at 4 and 1 month, respectively. Improvements in ODI were significant at 1 month and peaked at 4 months. Serum IL-6 was increased at 1 month. IL-6 responders (i.e., patients with IL-6 increases >10 pg/mL) showed particularly significant improvements in leg pain at 2 weeks, 1 month, and 2 months compared with nonresponders. We observed no apparent adverse events.Conclusions: Systemic TCZ administration improved symptoms effectively for 6 months, with peak improvements at 1–4 months and no adverse events. Changing serum IL-6 levels correlated with leg pain improvements; further studies are warranted to elucidate the mechanistic connections between lumbar disorders and inflammatory cytokines.

Change of Lumbar Ligamentum Flavum after Indirect Decompression Using Anterior Lumbar Interbody Fusion

Seiji Ohtori,Sumihisa Orita,Kazuyo Yamauchi,Yawara Eguchi,Yasuchika Aoki,Junichi Nakamura,Masayuki Miyagi,Miyako Suzuki,Gou Kubota,Kazuhide Inage,Takeshi Sainoh,Jun Sato,Kazuki Fujimoto,Yasuhiro Shiga 대한척추외과학회 2017 Asian Spine Journal Vol.11 No.1

Study Design: Retrospective case series. Purpose: The purpose of this study was to examine changes in the ligamentum flavum thickness and remodeling of the spinal canal after anterior fusion during a 10-year follow-up. Overview of Literature: Extreme lateral interbody fusion provides minimally invasive treatment of the lumbar spine; this anterior fusion without direct posterior decompression, so-called indirect decompression, can achieve pain relief. Anterior fusion may restore disc height, stretch the flexure of the ligamentum flavum, and increase the spinal canal diameter. However, changes in the ligamentum flavum thickness and remodeling of the spinal canal after anterior fusion during a long follow-up have not yet been reported. Methods: We evaluated 10 patients with L4 spondylolisthesis who underwent stand-alone anterior interbody fusion using the iliac crest bone. Magnetic resonance imaging was performed 10 years after surgery. The cross-sectional area (CSA) of the dural sac and the ligamentum flavum at L1–2 to L5–S1 was calculated using a Picture Archiving and Communication System. Results: Spinal fusion with correction loss (average, 4.75 mm anterior slip) was achieved in all patients 10 years postsurgery. The average CSAs of the dural sac and the ligamentum flavum at L1–2 to L5–S1 were 150 mm2 and 78 mm2, respectively. The average CSA of the ligamentum flavum at L4–5 (30 mm2) (fusion level) was significantly less than that at L1–2 to L3–4 or L5–S1. Although patients had an average anterior slip of 4.75 mm, the average CSA of the dural sac at L4–5 was significantly larger than at the other levels. Conclusions: Spinal stability induced a lumbar ligamentum flavum change and a sustained remodeling of the spinal canal, which may explain the long-term pain relief after indirect decompression fusion surgery.