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An understanding of the risk of gene deletion and mutation posed by endocrine-disrupting chemicals (EDCs) is necessary for the identification of etiological reagents for many human diseases. Therefore, the characterization of the genetic traits caused by developmental exposure to EDCs is an important research subject. A new regenerative approach using embryonic stem cells (ESCs) holds promise for the development of stem-cell-based therapies and the identification of novel therapeutic agents against human diseases. Here, we focused on the characterization of the genetic traits and alterations in pluripotency/stemness triggered by phthalate ester derivatives. Regarding their in vitro effects, we reported the abilities of ESCs regarding proliferation, cell - cycle control, and neural ectoderm differentiation. The expression of their stemness-related genes and their genetic changes toward neural differentiation were examined, which led to the observation that the tumor suppressor gene product p53/retinoblastoma protein 1 and its related cascades play critical functions in cell-cycle progression, cell death, and neural differentiation. In addition, the expression of neurogenic differentiation 1 was affected by exposure to di- n -butyl phthalate in the context of cell differentiation into neural lineages. The nervous system is one of the most sensitive tissues to exposure to phthalate ester derivatives. The present screening system provides a good tool for studying the mechanisms underlying the effects of EDCs on the developmental regulation of humans and rodents, especially on the neuronal development of ESCs. [Display omitted] • Phthalate ester derivatives (PEDs) promote cell-cycle exit and neural differentiation. • Phthalate ester derivatives (PEDs) activate Trp53/Rb/E2F1 axis. • PEDs activate p21Cip1 promoter via p53-responsive elements. • Di-n-butyl phthalate induces neural differentiation through NeuroD1. [ABSTRACT FROM AUTHOR]

• Pre-existing immunity against recent SARS-CoV-2 strains in Vietnam was determined. • Pre-COVID-19 samples neutralize Wuhan and Alpha strains but not newer variants. • Limited cellular immunity to SARS-CoV-2 suggests a lack of cross-immunity among newer variants of concern. • Pre-COVID-19 immunity may influence low transmission in the early phase of a pandemic. SARS-CoV-2 transmission and epidemic potential is related to the population's immunity levels. As such, assessing different regions' preexisting immune responses to SARS-CoV-2 is important to understand the transmission potential of emerging SARS-CoV-2 variants. In 975 serum samples from Vietnam (2014 to 2019), anti-SARS-CoV-2 Immunoglobulin G levels were determined by enzyme-linked immunosorbent assay. Plaque reduction neutralization test (PRNT) was performed using Wuhan strain and variants of concern (VOCs). Cross-reactivity was confirmed by analyzing B-cell receptor (BCR) repertoire sequences and identifying BCR repertoire sequences-derived T-cell epitopes. Overall, 20.9% (n = 76/364) and 9.2% (n = 7) demonstrated SARS-CoV-2 neutralizing activity (PRNT 50) against the Wuhan and Alpha strain, respectively. Neutralizing activity against Beta, Gamma, and Delta strains was absent (PRNT 50 <5) in all samples. Cross-reactive epitopes against SARS-CoV-2 and other coronavirus spike proteins were detected in the N-terminal domain, S2, and receptor-binding domain regions. Following BCR and major histocompatibility complex analysis, T-cell receptor-recognized epitope motif (TREM) among pathogenic coronaviruses and coronaviruses spike proteins were the top TREM peptide, suggesting that pre-existing immunity against SARS-CoV-2 in Vietnam was due to exposure to common cold coronaviruses. With limited immunity against emerging VOCs, further monitoring, and control of the epidemic, along with COVID-19 vaccine programs against VOCs, are necessary. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate if differences in leg positioning affect spinal bone mineral density (BMD) measurements and the detection of low bone mass. Subjects included 1039 Japanese patients, 878 women and 161 men (mean ages: 67 and 71 years, respectively). Spinal BMD (L1–4) was measured using dual-energy X-ray absorptiometry (DXA) with patients lying in 2 different positions: (1) supine on the scanning table with hips flexed and knees flexed over a 90° support pad (the standard position) and (2) simply supine (the supine position). Predictive indices were calculated for spinal DXA acquired with patients in the supine position. A BMD T -score of −2.5 or lower was set as the threshold for low bone mass. For the standard and the supine positions during scanning in women, BMDs were 0.911 and 0.915 g/cm 2 , respectively; in men, they were 1.117  and 1.124 g/cm 2 , respectively. The estimated systematic bias in BMD between the positions was 0.42% (95% confidence interval: 0.24, 0.59; p  = 0.009). Random errors in the densitometry measurements for the standard and supine positions were 0.66% and 0.84%, respectively. There was no significant difference between the errors ( p   =  0.164). The likelihood ratios of a positive and negative test for the detection of low bone mass following supine DXA were 121.0 and 0.066, respectively, compared with results acquired using the standard position. In conclusion, DXA measurements acquired with patients in the supine position slightly overestimated BMD vs the standard position. However, the clinical equivalency between the positioning methods for DXA is preserved to the extent that low bone mass can be reliably detected in the supine position. [ABSTRACT FROM AUTHOR]

Objective: Osteoarthritis (OA) and rheumatoid arthritis (RA) are widespread disabling joint disorders that are considered to be polygenic in nature. This study investigated the spatial expression patterns of all six known human CCN genes using end-stage OA and RA joint samples. Design: We performed in situ hybridization and histological analysis to investigate the spatial expression patterns of human CCN genes using joint tissues obtained during total knee and hip joint replacement procedures on patients with advanced OA or RA. Normal joint tissues taken while performing bipolar hip replacement surgeries were used as controls. Results: All CCN genes were expressed at higher levels in OA and RA synovial samples as compared with normal controls. Whereas CCN3 and CCN6 were undetectable in control, OA, and RA cartilage, CCN1, CCN2, CCN4, and CCN5 were expressed to a greater extent in OA and RA knee cartilage. Conclusions: Our results indicate an involvement of several CCN genes in the pathophysiology of OA and RA. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to examine and compare the areas of brain blood flow in patients with chronic low back pain (CLBP) without structural abnormality and acute low back pain (ALBP) with lumber disc herniation (LDH). Functional neuroimaging studies provide evidence of abnormalities in the regional cerebral blood flow during low back pain. Recent studies have shown that CLBP is associated with plastic, pathophysiological changes in the brain. However, there has been no report yet statistically or by neuro-images on the compared brain single photon-emission computed tomography (SPECT) findings between CLBP and ALBP patients. Methods: The subjects comprised 14 patients, 7 CLBP and 7 ALBP patients. The CLBP group included the patients who had no or minor structural abnormality in the lumbar spine on magnetic resonance imaging (MRI) and met the criteria for a classification of 'pain disorder' (chronic) according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. The ALBP group included the patients who had symptoms within 3 months of onset and LDH revealed by MRI. All patients were assessed using brain SPECT. We then performed a two-tailed view analysis using the easy Z score imaging system, determined the mean Z scores, and performed vBSEE software (Fujifilm RI Pharma, Tokyo, Japan) for both CLBP and ALBP patients. Results: The CLBP group showed significantly reduced blood flow in the bilateral prefrontal cortex of the frontal lobe and increased blood flow in the bilateral posterior lobe of the cerebellum. Conclusions: SPECT images and statistical analyses revealed the brain blood flow alterations in the patients with ALBP and CLBP. These results may suggest that the dysfunction of the prefrontal cortex could lead to the appearance of unconscious pain behavior controlled by the cerebellum in the patients with CLBP. [ABSTRACT FROM AUTHOR]

Background: We examined whether the data obtained by monitoring central venous oxygen saturation (ScvO2) and/or stroke volume variation (SVV) during hepatectomy, as measured with the FloTrac/Vigileo system, can predict postoperative liver dysfunction. Methods: This study included 33 patients with normal liver function who underwent hepatectomy between December 2007 and August 2010. Baseline ScvO2 and baseline SVV, as control values, were defined as the mean of ScvO2 and SVV, respectively, measured with the FloTrac/Vigileo system before hepatectomy. ScvO2 decrease (ΔScvO2) was defined as the difference between the baseline ScvO2 and the lowest intraoperative ScvO2 and SVV increase (ΔSVV) was defined as the difference between the baseline SVV and the highest intraoperative SVV. Moreover, mean ScvO2 and mean SVV were defined as the means of all ScvO2 and SVV values measured during surgery, respectively. We examined correlations of the new parameters with the highest postoperative values of total bilirubin (T. Bil). Results: The cutoff values for ΔScvO2 and mean SVV for predicting the highest postoperative T. Bil level to be ≥3.0 mg/dL with the highest sensitivity and specificity were found to be 10.2% and 13.6%, respectively. The areas under curve in receiver-operating-characteristic analysis of ΔScvO2 and mean SVV were 0.797 and 0.757, respectively, showing significant differences. Conclusion: Our results suggest that ΔScvO2 and mean SVV can predict postoperative liver dysfunction. When ΔScvO2 and mean SVV exceed 10.2% and 13.6%, respectively, we advocate that adequate attention be paid to postoperative liver dysfunction, and that early intraoperative general circulatory management measures be implemented as needed. [Copyright &y& Elsevier]

Background: Cluster analysis is used for dividing many prognostic indicators, including liver function, tumor progression, and operative variables, into specific clusters. The albumin (ALB), hepatocyte growth factor (HGF), and branched chain amino-acid to tyrosine ratio (BTR) may represent the severity of liver disease and function of the hepatic reserve. We developed the ALB-BTR and HGF-BTR classifications depending on each level to find specific unique subgroups. Our aim was to identify specific subgroups destined for favorable and poor prognoses after initial hepatectomy. Methods: Between 2002 and 2008, 165 patients were analyzed retrospectively. Liver function indicators, including BTR, tumor-related factors, and operative variables, were evaluated by cluster analysis with Ward’s criterion. The ALB-BTR classification was divided into 4 groups depending on ALB (cutoff value, 4.0 g/dL) and BTR (cutoff value, 6.0). The HGF-BTR classification was also divided into 4 groups depending on HGF (cutoff value, 0.35 ng/mL) and BTR (cutoff value, 6.0). The prognoses of the subgroups were compared by the log-rank test. Results: Cluster analysis divided multiple indicators into 5 different clusters. In each cluster, we further analyzed subgroups using the ALB-BTR and HGF-BTR classification. Mean recurrence-free survival times in ALB-GI (19.1 ± 2.4 months) and HGF-GIII (29.4 ± 3.8 months) were less than their mean overall survival times. Conclusion: Cluster analysis is useful to find similar and different indicators. Even though liver function was well preserved, low BTR could identify early recurrence in hepatocellular carcinoma patients after resection. [ABSTRACT FROM AUTHOR]

Introduction: The branched-chain amino acid/tyrosine ratio (BTR) reflects the amino acid balance and the severity of liver disease. The aim of the present study was to determine the relationship between BTR and liver function in patients with hepatocellular carcinoma (HCC). Furthermore, we evaluated the clinical usefulness of BTR as a prognostic indicator of disease-free and overall patient survival after initial hepatectomy.Methods: Between January 2004 and December 2008, 105 consecutive HCC patients who underwent initial hepatectomy were enrolled in this study. The correlation between BTR and preoperative liver functional indicators was evaluated. The cutoff levels of BTR for 2-year survival prediction were evaluated using a dot blot diagram. The patients were divided into high BTR (4.5 or higher) and low BTR (4.4 or lower) groups and these were compared in terms of clinical variables such as liver functional indicators, operative variables, and tumor characteristics.Results: The preoperative BTR level decreased according to the severity of liver disease. BTR was correlated with the albumin, bilirubin, and prealbumin levels, as well as the prothrombin time. Although the preoperative liver function was significantly different between the high BTR and low BTR groups, the operative variables and tumor-related variables were not found to be significantly different. Postoperative complications in the high BTR group were significantly less frequent than in the low BTR group (p = 0.003). Disease-free and overall patient survival in the high BTR group were significantly longer than in the low BTR group (p < 0.001 and p = 0.021, respectively).Conclusions: BTR reflected the pathological liver background with a high correlation to the other liver functional indicators. BTR is thus considered to be a useful marker to predict postoperative complications, disease-free survival, and overall survival of HCC patients after initial hepatectomy. It is, therefore, a useful indicator of liver function and a predictor for the risk of cancer recurrence and overall survival in HCC patients. [ABSTRACT FROM AUTHOR]

Abstract: Homoplasy is a phenomenon in which organisms in different phylogenetic groups independently acquire similar traits. However, it is largely unknown how developmental mechanisms are altered to give rise to homoplasy. In the genus Drosophila, all species of the subgenus Sophophora, including Drosophila (D.) melanogaster, have eggshells with two dorsal appendages (DAs); most species in the subgenus Drosophila, including D. virilis, and in the subgenus Dorsilopha, have four-DAs. D. melanica belongs to the Drosophila subgenus, but has two-DAs, and phylogenetic analyses suggest that it acquired this characteristic independently. The patterning of the DAs is tightly regulated by epidermal growth factor receptor (EGFR) signaling in D. melanogaster. Previous studies suggested that a change in the EGFR signal activation pattern could have led to the divergence in DA number between D. melanogaster and D. virilis. Here, we compared the patterns of EGFR signal activation across the Drosophila subgenera by immunostaining for anti-activated MAP kinase (MAPK). Our analysis revealed distinct patterns of EGFR signal activation in each subgenus that was consistent with their phylogenetic relationship. In addition, the number of DAs always corresponded to the number of EGFR signaling activation domains in two, three, and four-DA species. Despite their common two-DA characteristic, the EGFR signaling activation pattern in D. melanica diverged significantly from that of species in the subgenus Sophophora. Our results suggest that acquisition of the homoplastic two-DA characteristic could be explained by modifications of the EGFR signaling system in the genus Drosophila that occurred independently and at least twice during evolution. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to determine the localization of bone morphogenetic protein-2 (BMP-2), BMP receptors (BMPRs) and Noggin in mouse spinal tissues. The coordinate expression of these positive and negative regulators of BMP signaling may elucidate regulatory mechanisms for bone induction in the spine. Whole spines from 3-week-old mice were used and the spatial expression profiles of BMP-2, BMPR-1a, -1b, -2 and Noggin were examined using in situ hybridization. BMP-2, BMPR-1b and -2 were observed in bone marrow cells in the vertebrae, chondrocytes, hyaline cartilage cells and fibrous cells in the intervertebral discs and neurons of the spinal cord in the entire spine. BMPR-1a was also observed in these cells, but only in the cervical spine. Noggin was expressed in bone marrow cells in the vertebrae, chondrocytes and hyaline cartilage cells and fibrous cells in the intervertebral discs in the entire spine and in neurons in the spinal cord in the cervical and thoracic regions. Noggin was also expressed in the anterior longitudinal, posterior longitudinal and yellow ligaments in the cervical spine, and in the fibrous cells in the anterior longitudinal and yellow ligaments of the lumbar spine. [Copyright &y& Elsevier]

Summary: Objective and importance:: Meningioma arising in Werner syndrome has been described previously, but never in association with a mutation analysis. We present the first reported case of meningioma in a patient with Werner syndrome and a confirmed major mutation. In addition, we review 27 previously reported patients with meningioma associated with Werner syndrome. Clinical presentation:: We report a 56-year-old Japanese woman with Werner syndrome and a meningioma. She presented with pain and redness of the right eye and a headache. Cranial CT revealed a tumor the in right frontal and temporal lobes. Pathological examination after surgical removal confirmed meningioma. She displayed typical features of Werner syndrome including juvenile cataract, short stature and low weight, a bird-like face, a hoarse voice, and dry, atrophic, pigmented skin. Investigation:: To confirm the clinical diagnosis, a mutation analysis based on the mutant allele-specific amplification (MASA) method was performed. Conclusion:: Mutation analysis of peripheral blood leukocyte DNA showed amplification of the mutation 4/4. There were 22 patients with Werner syndrome and meningioma reported from Japan and 5 from outside Japan. There was only one malignant meningioma. Meningiomas in Werner syndrome have a higher frequency in males and occur at a younger age than those of the general population. [Copyright &y& Elsevier]

Abstract: To examine how fibroblast growth factor-2 (FGF-2) affects the BMP signaling pathway during bone morphogenetic protein-2 (BMP-2)-induced ectopic bone formation, we implanted type I collagen disks containing constant amounts of BMP-2 (5 μg) and varying amounts of FGF-2 onto the back muscles of adult male mice. We then performed histological analyses and histomorphometry, and measured bone mineral density and radiopaque area on the discs 1, 2, and 3 weeks after implantation. We also determined the expression profiles of several genes involved in bone formation and the BMP signaling pathway in the muscle that had been adjacent to the implanted disc and in muscle-derived primary culture cells that had similarly been treated with a constant concentration of BMP-2 and a varying concentration of FGF-2. In the presence of a constant amount of BMP-2, we confirmed that low doses of FGF-2 increased ectopic bone formation in vivo and high doses inhibited bone formation. Northern and/or Western blots of recovered muscle from the in vivo experiment and treated muscle-derived primary culture cells from the in vitro experiment revealed that low doses of FGF-2, but not high doses, increased the expression BMP receptor (BMPR)-1B, phosphorylated Smad1, Noggin, and Osteocalcin. Our results indicate that low-dose FGF-2 may facilitate BMP-2-induced ectopic bone formation by altering the expression of BMPRs on the surface of bone forming progenitor cells. They also indicate that the inhibitory effect of high-dose FGF-2 is not mediated via increased expression of the BMP inhibitor Noggin. [Copyright &y& Elsevier]

In Drosophila melanogaster, the patterning of dorsal appendages on the eggshell is strictly controlled by EGFR signaling. However, the number of dorsal appendages is remarkably diverse among Drosophila species. For example, D. melanogaster and D. virilis have two and four dorsal appendages, respectively. Here we show that during oogenesis the expression patterns of rhomboid (rho) and argos (aos), positive and negative regulators of EGFR signaling, respectively, were substantially different between D. melanogaster and D. virilis. Importantly, the number and position of both the rho expression and MAPK activation were consistent with those of the dorsal appendages in each species. Despite the differences in the spatial expression, these results suggest that the function of EGFR signaling in dorsal appendage formation is largely conserved between these two species. Thus, our results link the species-specific activation of EGFR signaling and the evolution of eggshell morphology in Drosophila. [Copyright &y& Elsevier]

In-line 4 engines have many merits when compared to engines with more cylinders, such as low cost, excellent gas mileage, low weight and compactness. However, one disadvantage is a vibration at 2nd order frequency. This vibration can be canceled by applying a 2nd order balance shaft. For the 2AZ-FE engine, a world class balance shaft system was achieved using resin gears for the first time ever. Reliability was achieved by developing a high-strength resin optimal impact absorption characteristics. Cost, friction and weight of the balance shaft system were lowered 50% when compared to the Toyota 5S-FE engine. [Copyright &y& Elsevier]

Although associations among obesity, adipocytokines, and bone mineral density have been reported, the influence of adipocytokines on osteoporotic fractures remains unclear. This study aimed to assess the impact of the adipocytokines leptin and adiponectin on the risk of incident vertebral and long-bone fractures in postmenopausal women. Clinical data were obtained from the retrospective Nagano Cohort Study of outpatients followed at a single primary care institute in Nagano Prefecture, Japan, between 1993 and 2018. The primary outcome was the occurrence of incident vertebral or long-bone fractures. In total, 1167 Japanese postmenopausal women (mean age: 65.9 years) completed the follow-up and the average observation period was 7.2 years. The subjects were divided into 4 groups (quartile 1 to 4) based respective leptin and adiponectin values. Kaplan–Meier analysis demonstrated a significantly lower incident long-bone fracture rate in the higher quartiles of serum leptin levels (p = 0.002). A significantly higher and more rapid occurrence of incident vertebral fractures, but not long-bone fractures, was found in the highest adiponectin quartile (p < 0.001). A Cox proportional hazards model adjusted for confounders including age, body weight, and either leptin or adiponectin revealed lower leptin levels and higher adiponectin levels as significant independent risk factors for incident long-bone fractures (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.50–0.96; p = 0.03) and vertebral fractures (HR 1.18, 95% CI 1.02–1.37; p = 0.02), respectively. Therefore, serum leptin and adiponectin may be independent risk factors for osteoporotic fractures affecting different bone types and sites. Determining patient adipocytokine levels may help predict the occurrence of specific osteoporotic fractures, thereby enabling optimal treatment for osteoporosis and improving quality of life. • The influence of adipocytokines on osteoporotic fractures remains controversial. • Serum leptin and adiponectin are independent osteoporotic fracture risk factors. • Serum adipocytokine levels may predict the occurrence of osteoporotic fractures. [ABSTRACT FROM AUTHOR]

Abstract: In the Sonoda-Tajima Cell Collection, one of the cell bank of RIKEN BioResource Center, DNA samples from an Amerindian ethnic minority group (Wayuu) in Colombia analysed for 21 autosomal STRs, 17 Y-STRs and HV-I and -II regions in mtDNA to select the kinships among those samples in order to study on how the kinships influence population genetic analysis. As a result, totally 17 kinships including 4 mother–child, 6 one-parent-two-child, 3 sibling relationships, and 4 kinds of complicated kinships were selected. All the paternal linages were confirmed by the Y-STR haplotypes. The sequence data of almost the maternal linages were concordant with each relationship. When compared between the 98-samples population and the 78-samples population in which the first degree of parentage relationships were removed, no significant difference was observed at allele frequency distributions, and the topology in a NJ-tree with the data from the other 20 ethnic groups in South America was not different. It suggested that about one-fifth of parentage relationship in such population size does not influence population genetic analysis. [Copyright &y& Elsevier]

Highlights ● Thirty-seven progenitor cell lines were established from a common cell source. ● The time required for establishment of the cell lines varied greatly. ● The enucleation efficiency differed among the progenitor cell lines. ● An adult type of cell line with mild karyotype abnormality was generated. ● The methods reported here are important for establishing erythroid progenitors. Immortalized erythroid progenitor cell lines, which exhibit potential for enucleated red blood cell (RBC) production, are expected to serve as an in vitro source of RBCs. These erythroid progenitor cell lines have previously been established from a variety of sources; however, large numbers of cell lines have not been established, characterized, and compared from a common cell source. In the present study, 37 cell lines were established from human bone marrow cells from a single donor. The time required for the establishment of each cell line varied greatly from 46 to 246 days. Of these lines, five were selected and their characteristics were analyzed. The cell lines established at the earliest time point showed better results in terms of both karyotype and differentiation potential than those established the latest. Moreover, obvious differences were noted even when cell lines were established at the earliest time point from the same source. These results suggest that it is important to select the best cell lines from ones established at the earliest time point for generating cell lines with low genomic abnormality and high differentiation ability. We have successfully generated an adult type of cell line with 50% cells carrying a normal karyotype and with 25% enucleation efficiency. These findings could be valuable in the development of an optimal method for establishing cell lines. [ABSTRACT FROM AUTHOR]

Romosozumab is a potent drug for treating postmenopausal osteoporosis but has a limited dosing period of 12 months. Bone mineral density (BMD) decreases soon after romosozumab discontinuation, thus emphasizing the importance of appropriate sequential treatment. The present VICTOR randomized controlled study compared the efficacy of ibandronate and denosumab as sequential therapy options following 12-month romosozumab treatment. Subjects completing 12 months of romosozumab administration for severe postmenopausal osteoporosis were randomly assigned to receive either ibandronate or denosumab for an additional 12 months. The primary outcome of interest was the percentage changes in BMD at the lumbar spine, total hip, and femoral neck from 12 months (completion of romosozumab) to 18 and 24 months of total treatment (6 and 12 months, respectively, after the conversion to sequential therapy). Secondary outcomes included alterations in serum bone turnover markers and the incidence of adverse events. Sixty-two subjects each in the ibandronate and denosumab groups completed the sequential therapy. The respective percentage changes in BMD at the lumbar spine from 12 months to 24 months were 2.5 % in the ibandronate group and 5.4 % in the denosumab group. At 24 months, we observed significant differences versus 12 months for both groups as well as between the groups (all P < 0.01), showing a superior ability to increase BMD at the lumbar spine for denosumab over ibandronate. BMD gains at the total hip and femoral neck exhibited comparably favorable trends. P1NP and TRACP-5b were significantly decreased from 12 to 24 months (−64.9 % and − 26.8 % in the ibandronate group and − 67.4 % and − 36.3 % in the denosumab group, respectively; all P < 0.001 versus 12 months). Several minor adverse events were recorded in both groups, none of which led to the discontinuation of the trial. The VICTOR study revealed that denosumab could be considered more effective than ibandronate, with few severe adverse events, for the enhancement of BMD as a sequential agent after romosozumab in postmenopausal osteoporosis patients. • Ibandronate or denosumab was given after 12-month romosozumab for osteoporosis. • In 12-month sequential therapy, both agents provided benefits in BMD improvement. • Denosumab was superior in increasing lumbar spine BMD over ibandronate. • A treatment-naïve status prior to Romo showed higher increases in BMD with Dmab. [ABSTRACT FROM AUTHOR]

Bisphosphonates are effective in increasing bone mineral density (BMD), but fragility fractures can still occur despite bisphosphonate treatment. The purpose of this study was to determine if long-term bisphosphonate users have characteristic findings in the musculoskeletal system, which could put them at risk of developing typical or atypical femoral fractures. We recruited 40 female patients who had taken bisphosphonates for more than 3 years. The control group included 60 volunteers who were matched by age, body mass index, and dual-energy X-ray absorptiometry-derived BMDs. We measured the skeletal muscle cross sectional area around the proximal thigh and buckling ratio of the femoral neck using quantitative computed tomography (qCT) and several biochemical markers of bone metabolism. Those parameters were compared between the groups. While no significant differences of buckling ratio derived from qCT were detected, the skeletal muscle cross sectional area was significantly smaller in the long-term bisphosphonate users than in the controls. Furthermore, the serum pentosidine level was significantly higher in the bisphosphonate users than in the controls. To determine if those differences were attributable to bisphosphonate treatment, we further compared those parameters between before and after 3 years of bisphosphonate treatment in 32 patients. After 3 years of bisphosphonate treatment, the BMD of the femoral neck and serum pentosidine level increased but not the skeletal muscle cross sectional area. In the present study, the skeletal muscle mass did not match the bone mass in long-term bisphosphonate users, thus suggesting that increases in BMD by bisphosphonates are unlikely to have secondary positive effects on the surrounding skeletal muscles. Also, serum pentosidine levels were greater in the long-term bisphosphonate users. Further study is necessary to test if such patients are prone to develop typical or atypical femoral fractures. [ABSTRACT FROM AUTHOR]