B. Hadzimuratovic, J. Haschka, M. Hackl, A. Diendorfer, Andreas Mittelbach, J. Feurstein, J. Zwerina, H. Resch, R. Kocijan
Hypophosphatasia (HPP) is a rare genetic bone disease characterized by low activity of tissue non-specific alkaline phosphatase (TNSALP). The enzyme replacement therapy asfotase alfa has been approved for childhood-onset forms of HPP. MicroRNAs (miRNAs) have emerged recently as a novel disease biomarker, with potential application in therapy monitoring. Circulating miRNAs were analyzed at baseline, months 1, 2, 4 and 16 in a 49-year-old woman with childhood-onset HPP, chronic musculoskeletal pain and multiple non-traumatic fractures prior to enzyme replacement therapy. Serum RNA was extracted and sequenced using miRNeasy Mini Kit (Qiagen, Germany), RealSeq Biosciences Kit (Santa Cruz, US) together with miND spike-in control kit (TAmiRNA, Austria) and Illumina NovaSeq 6000 SP1 flow cell (San Diego, US). Brief Pain Inventory Severity and Interference scores (BPI-S/BPI-I), fatigue severity scale (FSS), Patient Global Impression of Improvement (PGI-I), Western Ontario and McMaster university hip disability and osteoarthritis outcome score (WOMAC) and fibromyalgia impact questionnaire (FIQ), 6-Minute Walking Test (6-MWT), chair-rise-test (CRT) and handgrip dynamometry (HD) were performed at baseline and different timepoints during the therapy. Out of >800 screened, 84 miRNAs were selected based on differences in expression profiles between 24 HPP patients and 24 healthy controls (Haschka et al. 2024). Six miRNAs showed a clear graphic trend and were up- or downregulated by ≥50% reads per million (rpm). These included hsa-let-7i-5p (+50%), hsa-miR-1-3p (-66.66%), hsa-miR-1294 (+63.63%), hsa-miR-206 (-85.57%), hsa-miR-375-3p (-71.43%) and hsa-miR-624-5p (+69,44%). hsa-miR-1-3p and hsa-miR-206 were identified as muscle-specific miRNAs. hsa-mir-375-3p, which negatively regulates osteogenesis, was significantly downregulated. In terms of patient-reported outcomes, BPI-S, BPI-I, FSS, PGI-I, WOMAC and FIQ showed a reduction by -58.62%, -68.29%, -33,33%, -75.00%, -63.29% and -43.02%, respectively. 6-MWT improved by +33,89% and CRT by -44.46%. Mean hand grip strength of the right/left hand measured by HD improved by +12.50% and + 23.53%, respectively. miRNA profile changes during the therapy with asfotase alfa, accompanying improvements in functionality tests and quality of life scores.
{"title":"Longitudinal Course of Circulating miRNAs in a Patient with Hypophosphatasia and Asfotase alfa Treatment: a Case Report","authors":"B. Hadzimuratovic, J. Haschka, M. Hackl, A. Diendorfer, Andreas Mittelbach, J. Feurstein, J. Zwerina, H. Resch, R. Kocijan","doi":"10.1093/jbmrpl/ziae107","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae107","url":null,"abstract":"\u0000 Hypophosphatasia (HPP) is a rare genetic bone disease characterized by low activity of tissue non-specific alkaline phosphatase (TNSALP). The enzyme replacement therapy asfotase alfa has been approved for childhood-onset forms of HPP. MicroRNAs (miRNAs) have emerged recently as a novel disease biomarker, with potential application in therapy monitoring. Circulating miRNAs were analyzed at baseline, months 1, 2, 4 and 16 in a 49-year-old woman with childhood-onset HPP, chronic musculoskeletal pain and multiple non-traumatic fractures prior to enzyme replacement therapy. Serum RNA was extracted and sequenced using miRNeasy Mini Kit (Qiagen, Germany), RealSeq Biosciences Kit (Santa Cruz, US) together with miND spike-in control kit (TAmiRNA, Austria) and Illumina NovaSeq 6000 SP1 flow cell (San Diego, US). Brief Pain Inventory Severity and Interference scores (BPI-S/BPI-I), fatigue severity scale (FSS), Patient Global Impression of Improvement (PGI-I), Western Ontario and McMaster university hip disability and osteoarthritis outcome score (WOMAC) and fibromyalgia impact questionnaire (FIQ), 6-Minute Walking Test (6-MWT), chair-rise-test (CRT) and handgrip dynamometry (HD) were performed at baseline and different timepoints during the therapy. Out of >800 screened, 84 miRNAs were selected based on differences in expression profiles between 24 HPP patients and 24 healthy controls (Haschka et al. 2024). Six miRNAs showed a clear graphic trend and were up- or downregulated by ≥50% reads per million (rpm). These included hsa-let-7i-5p (+50%), hsa-miR-1-3p (-66.66%), hsa-miR-1294 (+63.63%), hsa-miR-206 (-85.57%), hsa-miR-375-3p (-71.43%) and hsa-miR-624-5p (+69,44%). hsa-miR-1-3p and hsa-miR-206 were identified as muscle-specific miRNAs. hsa-mir-375-3p, which negatively regulates osteogenesis, was significantly downregulated. In terms of patient-reported outcomes, BPI-S, BPI-I, FSS, PGI-I, WOMAC and FIQ showed a reduction by -58.62%, -68.29%, -33,33%, -75.00%, -63.29% and -43.02%, respectively. 6-MWT improved by +33,89% and CRT by -44.46%. Mean hand grip strength of the right/left hand measured by HD improved by +12.50% and + 23.53%, respectively. miRNA profile changes during the therapy with asfotase alfa, accompanying improvements in functionality tests and quality of life scores.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141919865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08eCollection Date: 2024-09-01DOI: 10.1093/jbmrpl/ziae103
Ernst J Reichenberger, Kevin O'Brien, Ayano Hatori, Thomas O Carpenter, Koen van de Wetering, Lisa Flaman, Jennifer Howe, Daniel Ortiz, Yves Sabbagh, I-Ping Chen
Craniometaphyseal dysplasia (CMD) is a rare genetic bone disorder, characterized by progressive thickening of craniofacial bones and flared metaphyses of long bones. Craniofacial hyperostosis leads to the obstruction of neural foramina and neurological symptoms such as facial palsy, blindness, deafness, or severe headache. Mutations in ANKH (mouse ortholog ANK), a transporter of small molecules such as citrate and ATP, are responsible for autosomal dominant CMD. Knock-in (KI) mice carrying an ANKF377del mutation (AnkKI/KI ) replicate many features of human CMD. Pyrophosphate (PPi) levels in plasma are significantly reduced in AnkKI/KI mice. PPi is a potent inhibitor of mineralization. To examine the extent to which restoration of circulating PPi levels may prevent the development of a CMD-like phenotype, we treated AnkKI/KI mice with the recombinant human ENPP1-Fc protein IMA2a. ENPP1 hydrolyzes ATP into AMP and PPi. Male and female Ank+/+ and AnkKI/KI mice (n ≥ 6/group) were subcutaneously injected with IMA2a or vehicle weekly for 12 wk, starting at the age of 1 wk. Plasma ENPP1 activity significantly increased in AnkKI/KI mice injected with IMA2a (Vehicle/IMA2a: 28.15 ± 1.65/482.7 ± 331.2 mOD/min; p <.01), which resulted in the successful restoration of plasma PPi levels (Ank+/+ /AnkKI/KI vehicle treatment/AnkKI/KI IMA2a: 0.94 ± 0.5/0.43 ± 0.2/1.29 ± 0.8 μM; p <.01). We examined the skeletal phenotype by X-Ray imaging and μCT. IMA2a treatment of AnkKI/KI mice did not significantly correct CMD features such as the abnormal shape of femurs, increased bone mass of mandibles, hyperostotic craniofacial bones, or the narrowed foramen magnum. However, μCT imaging showed ectopic calcification near basioccipital bones at the level of the foramen magnum and on joints of AnkKI/KI mice. Interestingly, IMA2a treatment significantly reduced the volume of calcified nodules at both sites. Our data demonstrate that IMA2a is sufficient to restore plasma PPi levels and reduce ectopic calcification but fails to rescue skeletal abnormalities in AnkKI/KI mice under our treatment conditions.
{"title":"ENPP1 enzyme replacement therapy improves ectopic calcification but does not rescue skeletal phenotype in a mouse model for craniometaphyseal dysplasia.","authors":"Ernst J Reichenberger, Kevin O'Brien, Ayano Hatori, Thomas O Carpenter, Koen van de Wetering, Lisa Flaman, Jennifer Howe, Daniel Ortiz, Yves Sabbagh, I-Ping Chen","doi":"10.1093/jbmrpl/ziae103","DOIUrl":"10.1093/jbmrpl/ziae103","url":null,"abstract":"<p><p>Craniometaphyseal dysplasia (CMD) is a rare genetic bone disorder, characterized by progressive thickening of craniofacial bones and flared metaphyses of long bones. Craniofacial hyperostosis leads to the obstruction of neural foramina and neurological symptoms such as facial palsy, blindness, deafness, or severe headache. Mutations in <i>ANKH</i> (mouse ortholog <i>ANK</i>), a transporter of small molecules such as citrate and ATP, are responsible for autosomal dominant CMD. Knock-in (KI) mice carrying an ANK<sub>F377del</sub> mutation (<i>Ank<sup>KI/KI</sup></i> ) replicate many features of human CMD. Pyrophosphate (PPi) levels in plasma are significantly reduced in <i>Ank<sup>KI/KI</sup></i> mice. PPi is a potent inhibitor of mineralization. To examine the extent to which restoration of circulating PPi levels may prevent the development of a CMD-like phenotype, we treated <i>Ank<sup>KI/KI</sup></i> mice with the recombinant human ENPP1-Fc protein IMA2a. ENPP1 hydrolyzes ATP into AMP and PPi. Male and female <i>Ank<sup>+/+</sup></i> and <i>Ank<sup>KI/KI</sup></i> mice (<i>n</i> ≥ 6/group) were subcutaneously injected with IMA2a or vehicle weekly for 12 wk, starting at the age of 1 wk. Plasma ENPP1 activity significantly increased in <i>Ank<sup>KI/KI</sup></i> mice injected with IMA2a (Vehicle/IMA2a: 28.15 ± 1.65/482.7 ± 331.2 mOD/min; <i>p</i> <.01), which resulted in the successful restoration of plasma PPi levels (<i>Ank<sup>+/+</sup></i> /<i>Ank<sup>KI/KI</sup></i> vehicle treatment/<i>Ank<sup>KI/KI</sup></i> IMA2a: 0.94 ± 0.5/0.43 ± 0.2/1.29 ± 0.8 μM; <i>p</i> <.01). We examined the skeletal phenotype by X-Ray imaging and μCT. IMA2a treatment of <i>Ank<sup>KI/KI</sup></i> mice did not significantly correct CMD features such as the abnormal shape of femurs, increased bone mass of mandibles, hyperostotic craniofacial bones, or the narrowed foramen magnum. However, μCT imaging showed ectopic calcification near basioccipital bones at the level of the foramen magnum and on joints of <i>Ank<sup>KI/KI</sup></i> mice. Interestingly, IMA2a treatment significantly reduced the volume of calcified nodules at both sites. Our data demonstrate that IMA2a is sufficient to restore plasma PPi levels and reduce ectopic calcification but fails to rescue skeletal abnormalities in <i>Ank<sup>KI/KI</sup></i> mice under our treatment conditions.</p>","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11334334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Metabolic syndromes (e.g., obesity, type 2 diabetes (T2D), atherosclerosis, and neurodegenerative diseases) and aging, they all have a strong component of carbonyl and reductive-oxidative (redox) stress. Reactive carbonyl (RCS) and oxidant (ROS) stress species are commonly generated as products or byproducts of cellular metabolism or are derived from the environment. RCS and ROS can play a dual role in living organisms. Some RCS and ROS function as signaling molecules which control cellular defenses against biological and environmental assaults. However, due to their high reactivity, RCS and ROS inadvertently interact with different cellular and extracellular components, and for example, lead to the formation of undesired posttranslational modifications of bone matrix proteins. These are advanced glycation (AGEs) and glycoxidation (AGOEs) end products generated in vivo by non-enzymatic amino-carbonyl reactions. In this review, metabolic processes involved in generation of AGEs and AGOEs within and on protein surfaces including extracellular bone matrix are discussed from the perspective of cellular metabolism and biochemistry of certain metabolic syndromes. The impact of AGEs and AGOEs on some characteristics of mineral is also discussed. Different therapeutic approaches with potential to prevent formation of RCS, ROS and driven by these chemicals formation of AGEs and AGOEs are also briefly reviewed. These are antioxidants, scavenging agents of reactive species, and newly emerging technologies for the development of synthetic detoxifying systems. Further research in the area of in vivo glycation and glycoxidation should lead to the development of diverse new strategies for halting the progression of metabolic complications before irreversible damage to body tissues materializes.
{"title":"In Vivo Glycation – Interplay between Oxidant and Carbonyl Stress in Bone","authors":"G. Sroga, Deepak Vashishth","doi":"10.1093/jbmrpl/ziae110","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae110","url":null,"abstract":"\u0000 Metabolic syndromes (e.g., obesity, type 2 diabetes (T2D), atherosclerosis, and neurodegenerative diseases) and aging, they all have a strong component of carbonyl and reductive-oxidative (redox) stress. Reactive carbonyl (RCS) and oxidant (ROS) stress species are commonly generated as products or byproducts of cellular metabolism or are derived from the environment. RCS and ROS can play a dual role in living organisms. Some RCS and ROS function as signaling molecules which control cellular defenses against biological and environmental assaults. However, due to their high reactivity, RCS and ROS inadvertently interact with different cellular and extracellular components, and for example, lead to the formation of undesired posttranslational modifications of bone matrix proteins. These are advanced glycation (AGEs) and glycoxidation (AGOEs) end products generated in vivo by non-enzymatic amino-carbonyl reactions. In this review, metabolic processes involved in generation of AGEs and AGOEs within and on protein surfaces including extracellular bone matrix are discussed from the perspective of cellular metabolism and biochemistry of certain metabolic syndromes. The impact of AGEs and AGOEs on some characteristics of mineral is also discussed. Different therapeutic approaches with potential to prevent formation of RCS, ROS and driven by these chemicals formation of AGEs and AGOEs are also briefly reviewed. These are antioxidants, scavenging agents of reactive species, and newly emerging technologies for the development of synthetic detoxifying systems. Further research in the area of in vivo glycation and glycoxidation should lead to the development of diverse new strategies for halting the progression of metabolic complications before irreversible damage to body tissues materializes.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141929527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gabriella Johnson, Lanny V Griffin, Shijing Qiu, S. Rao
Atypical femur fractures (AFF) are a well-established complication of long-term bisphosphonate (BP) therapy, but their pathogenesis is not fully understood. Although many patients on long-term BP therapy have severe suppression of bone turnover (SSBT), not all such patients AFF even though SSBT is a major contributor to AFF. Accordingly, we evaluated tissue level properties using nano-scratch testing of trans-iliac bone biopsy specimens in 12 women (6 with and 6 without AFF matched for age and race). Nano-scratch data were analyzed using a mixed model ANOVA with volume normalized scratch energy as a function of AFF (Yes or No), region (periosteal or endosteal), and a first-order interaction between region and AFF. Tukey Post-hoc analyses of the differences of least squared means of scratch energy were performed and reported as significant if P<.05. The volume normalized scratch energy was 10.6% higher in AFF than in non-AFF patients (P=.003) and 17.9 % higher in the periosteal than in the endosteal region (P=.004). The differences in normalized scratch energy are consistent with a higher hardness of the bone tissue after long-term BP therapy. The results of this study are consistent with other studies in the literature and demonstrate the efficacy of using Nano-Scratch technique to evaluate bone tissue that exhibits SSBT and AFF. Further studies using nano-scratch may help quantify and elucidate underlying mechanisms for the pathogenesis of AFF.
{"title":"Differences in tissue-Level Properties as Assessed by Nano-Scratching in Patients With and Without Atypical Femur Fractures on Long-Term Bisphosphonate Therapy: A Proof-of-Concept Pilot Study","authors":"Gabriella Johnson, Lanny V Griffin, Shijing Qiu, S. Rao","doi":"10.1093/jbmrpl/ziae097","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae097","url":null,"abstract":"\u0000 Atypical femur fractures (AFF) are a well-established complication of long-term bisphosphonate (BP) therapy, but their pathogenesis is not fully understood. Although many patients on long-term BP therapy have severe suppression of bone turnover (SSBT), not all such patients AFF even though SSBT is a major contributor to AFF. Accordingly, we evaluated tissue level properties using nano-scratch testing of trans-iliac bone biopsy specimens in 12 women (6 with and 6 without AFF matched for age and race). Nano-scratch data were analyzed using a mixed model ANOVA with volume normalized scratch energy as a function of AFF (Yes or No), region (periosteal or endosteal), and a first-order interaction between region and AFF. Tukey Post-hoc analyses of the differences of least squared means of scratch energy were performed and reported as significant if P<.05. The volume normalized scratch energy was 10.6% higher in AFF than in non-AFF patients (P=.003) and 17.9 % higher in the periosteal than in the endosteal region (P=.004). The differences in normalized scratch energy are consistent with a higher hardness of the bone tissue after long-term BP therapy. The results of this study are consistent with other studies in the literature and demonstrate the efficacy of using Nano-Scratch technique to evaluate bone tissue that exhibits SSBT and AFF. Further studies using nano-scratch may help quantify and elucidate underlying mechanisms for the pathogenesis of AFF.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141803950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. M. Naqvi, L. O’Sullivan, H. Allison, Vincent J Casey, Jessica Schiavi-Tritz, L. M. McNamara
Osteoporosis is primarily associated with bone loss, but changes in bone tissue matrix composition and osteocyte mechanotransduction have also been identified. However, the molecular mechanisms underlying these changes and their relation to bone loss are not fully understood. The objectives of this study were to (1) conduct comprehensive temporal gene expression analyses on cortical bone tissue from ovariectomized rats, with a specific focus on genes known to govern matrix degradation, matrix production, and mechanotransduction, and (2) correlate these findings with bone mass, trabecular microarchitecture and mineral and matrix composition. Microarray data revealed 35 differentially expressed genes in the cortical bone tissue of the ovariectomized cohort. We report that catabolic gene expression abates after the initial accelerated bone loss period, which occurs within the first 4 weeks of estrogen deficiency. However, in long-term estrogen deficiency we report increased expression of genes associated with extracellular matrix deposition (Spp1, COL1A1, COL1A2, OCN) and mechanotransduction (Cx43) compared to age-matched controls and short-term estrogen deficiency. These changes coincided with increased heterogeneity of mineral-matrix ratio and collagen maturity, to which extracellular matrix markers COL1A1 and COL1A2 were positively correlated. Interestingly, mineral heterogeneity and collagen maturity exhibited a negative correlation with PHEX and IFT88, associated with mechanosensory cilia formation and Hedgehog (Hh) signaling. This study provides the first insight into the underlying mechanisms governing secondary mineralisation and heterogeneity of matrix composition of bone tissue in long-term estrogen deficiency. We propose that altered mechanobiological responses in long-term estrogen deficiency may play a role in these changes.
{"title":"Altered extracellular matrix and mechanotransduction gene expression in rat bone tissue following long-term estrogen deficiency","authors":"S. M. Naqvi, L. O’Sullivan, H. Allison, Vincent J Casey, Jessica Schiavi-Tritz, L. M. McNamara","doi":"10.1093/jbmrpl/ziae098","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae098","url":null,"abstract":"\u0000 Osteoporosis is primarily associated with bone loss, but changes in bone tissue matrix composition and osteocyte mechanotransduction have also been identified. However, the molecular mechanisms underlying these changes and their relation to bone loss are not fully understood. The objectives of this study were to (1) conduct comprehensive temporal gene expression analyses on cortical bone tissue from ovariectomized rats, with a specific focus on genes known to govern matrix degradation, matrix production, and mechanotransduction, and (2) correlate these findings with bone mass, trabecular microarchitecture and mineral and matrix composition. Microarray data revealed 35 differentially expressed genes in the cortical bone tissue of the ovariectomized cohort. We report that catabolic gene expression abates after the initial accelerated bone loss period, which occurs within the first 4 weeks of estrogen deficiency. However, in long-term estrogen deficiency we report increased expression of genes associated with extracellular matrix deposition (Spp1, COL1A1, COL1A2, OCN) and mechanotransduction (Cx43) compared to age-matched controls and short-term estrogen deficiency. These changes coincided with increased heterogeneity of mineral-matrix ratio and collagen maturity, to which extracellular matrix markers COL1A1 and COL1A2 were positively correlated. Interestingly, mineral heterogeneity and collagen maturity exhibited a negative correlation with PHEX and IFT88, associated with mechanosensory cilia formation and Hedgehog (Hh) signaling. This study provides the first insight into the underlying mechanisms governing secondary mineralisation and heterogeneity of matrix composition of bone tissue in long-term estrogen deficiency. We propose that altered mechanobiological responses in long-term estrogen deficiency may play a role in these changes.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141808164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alice Dudle, Michael Ith, Rainer Egli, Johannes Heverhagen, Yvan Gugler, Christina Wapp, Daniela A Frauchiger, Kurt Lippuner, Christian Jackowski, Philippe Zysset
The estimation of bone mineral density (BMD) with CT scans requires a calibration method, usually based on a phantom. In asynchronous calibration, the phantom is scanned separately from the patient. A standardized acquisition protocol must be used to avoid variations between patient and phantom. However, variations can still be induced, e.g. by temporal fluctuations or patient characteristics. Based on the further use of 739 forensic and 111 clinical CT scans, this study uses the proximal femur BMD value (“total hip”) to assess asynchronous calibration accuracy, using in-scan calibration as ground truth. It identifies the parameters affecting the calibration accuracy and quantifies their impact. For time interval and table height, the impact was measured by calibrating the CT scan twice (once using the phantom scan with closest acquisition parameters and once using a phantom scan with standard values) and comparing the calibration accuracy. For other parameters such as body weight, the impact was measured by computing a linear regression between parameter values and calibration accuracy. Finally, this study proposes correction methods to reduce the effect of these parameters and improve the calibration accuracy. The BMD error of the asynchronous calibration, using the phantom scan with the closest acquisition parameters, was −1.2 ± 1.7% for the forensic and − 1.6 ± 3.5% for the clinical dataset. Among the parameters studied, time interval and body weight were identified as the main sources of error for asynchronous calibration, followed by table height and reconstruction kernel. Based on these results, a correction method was proposed to improve the calibration accuracy.
{"title":"Asynchronous calibration of a CT scanner for bone mineral density estimation: sources of error and correction","authors":"Alice Dudle, Michael Ith, Rainer Egli, Johannes Heverhagen, Yvan Gugler, Christina Wapp, Daniela A Frauchiger, Kurt Lippuner, Christian Jackowski, Philippe Zysset","doi":"10.1093/jbmrpl/ziae096","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae096","url":null,"abstract":"\u0000 The estimation of bone mineral density (BMD) with CT scans requires a calibration method, usually based on a phantom. In asynchronous calibration, the phantom is scanned separately from the patient. A standardized acquisition protocol must be used to avoid variations between patient and phantom. However, variations can still be induced, e.g. by temporal fluctuations or patient characteristics. Based on the further use of 739 forensic and 111 clinical CT scans, this study uses the proximal femur BMD value (“total hip”) to assess asynchronous calibration accuracy, using in-scan calibration as ground truth. It identifies the parameters affecting the calibration accuracy and quantifies their impact. For time interval and table height, the impact was measured by calibrating the CT scan twice (once using the phantom scan with closest acquisition parameters and once using a phantom scan with standard values) and comparing the calibration accuracy. For other parameters such as body weight, the impact was measured by computing a linear regression between parameter values and calibration accuracy. Finally, this study proposes correction methods to reduce the effect of these parameters and improve the calibration accuracy. The BMD error of the asynchronous calibration, using the phantom scan with the closest acquisition parameters, was −1.2 ± 1.7% for the forensic and − 1.6 ± 3.5% for the clinical dataset. Among the parameters studied, time interval and body weight were identified as the main sources of error for asynchronous calibration, followed by table height and reconstruction kernel. Based on these results, a correction method was proposed to improve the calibration accuracy.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141812996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jack Boylan, Jane Turton, Zoe Hicks, Julia Cottam, Michael Stone
The Metabolic Bone Health Department, Cardiff and Vale University Health Board, serves a local population of approximately 445 000 people. A retrospective audit of attendance data regarding the Denosumab treatment clinic (the traditional treatment pathway) and the Denosumab Self Injection Programme (SIP) was conducted to determine whether the Self Injection Programme is both cost effective and environmentally beneficial, compared to the traditional treatment pathway. Cost analysis was then conducted by the Finance Department. The audit was conducted over 3 years following the implementation of the service development; 233 patients had enrolled in the program at the time of the audit and 69 had completed 3 years of self- injected treatment. A control group of 497 patients were identified by the service. This group remained on the historical pathway and had consistent attendance activity over the three-year period from 2017 to 2019. Pre and post period activity of all patients on the program was compared, together with the activity for the independent control group. The SIP resulted in a reduction in clinical contacts, with financial analysis showing a total opportunity cost saving per patient of £420 per annum. There were obvious benefits to the patient of a reduced number of visits to a clinical site, which also resulted in an estimated carbon footprint reduction of 59 KG CO2 per patient per annum. The cost analysis is based on our organisation’s 2022 charges. The SIP demonstrates that through focusing on care “closer to home”, it is possible to maximise resources, improve the patient experience through reduced travel and reduce the environmental impact of healthcare.
{"title":"A Retrospective Audit with Subsequent Cost and Environmental Analysis of a Denosumab Self Injection Programme","authors":"Jack Boylan, Jane Turton, Zoe Hicks, Julia Cottam, Michael Stone","doi":"10.1093/jbmrpl/ziae092","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae092","url":null,"abstract":"\u0000 The Metabolic Bone Health Department, Cardiff and Vale University Health Board, serves a local population of approximately 445 000 people. A retrospective audit of attendance data regarding the Denosumab treatment clinic (the traditional treatment pathway) and the Denosumab Self Injection Programme (SIP) was conducted to determine whether the Self Injection Programme is both cost effective and environmentally beneficial, compared to the traditional treatment pathway. Cost analysis was then conducted by the Finance Department.\u0000 The audit was conducted over 3 years following the implementation of the service development; 233 patients had enrolled in the program at the time of the audit and 69 had completed 3 years of self- injected treatment.\u0000 A control group of 497 patients were identified by the service. This group remained on the historical pathway and had consistent attendance activity over the three-year period from 2017 to 2019. Pre and post period activity of all patients on the program was compared, together with the activity for the independent control group.\u0000 The SIP resulted in a reduction in clinical contacts, with financial analysis showing a total opportunity cost saving per patient of £420 per annum. There were obvious benefits to the patient of a reduced number of visits to a clinical site, which also resulted in an estimated carbon footprint reduction of 59 KG CO2 per patient per annum.\u0000 The cost analysis is based on our organisation’s 2022 charges. The SIP demonstrates that through focusing on care “closer to home”, it is possible to maximise resources, improve the patient experience through reduced travel and reduce the environmental impact of healthcare.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141828221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Holly Evans, Rebecca Andrews, Fatma Ali Abedi, Alexandria Sprules, Jacob Trend, Goran Lovric, Alanna Green, Andrew Chantry, Claire Clarkin, Janet Brown, Michelle Lawson
Myeloma bone disease (MBD) affects approximately 90% of multiple myeloma patients but current treatment options are suboptimal. Therefore, to successfully develop new therapies or optimize current ones, we must improve our fundamental knowledge of how myeloma affects bone microstructure and function. Here we have investigated the osteocyte lacuno-canalicular network (LCN) in MBD, as bone porosity affects bone quality and resilience. We used the syngeneic 5TGM1-C57BL-Kalwrij and the xenograft U266-NSG models at end stage and compared them to healthy controls (naïve). Micro-computed tomography (μCT) and histomorphometry indicated the 5TGM1 and U266 models developed mild and extensive MBD respectively, with the U266 model producing large osteolytic lesions. High-resolution synchrotron micro-CT (SR-μCT) revealed significant osteocyte lacunae changes in U266 bones but not 5TGM1, with a reduction in lacunae number and sphericity, and an increase in lacunae volume compared to naïve. Canalicular length, visualized using histological Ploton silver staining, appeared significantly shorter in 5TGM1 and U266 bones compared to naïve. Canalicular area as a proportion of the bone was also decreased by 24.2% in the U266 model. We observed significant upregulation of genes implicated in peri-lacunar remodeling (PLR), but immunohistochemistry confirmed that the osteocyte-specific protein sclerostin, a known driver of PLR, was unchanged between MBD and naïve bones. In summary, we have demonstrated evidence of PLR and altered organization of the osteocyte LCN in MBD mouse models. The next step would be to further understand the drivers and implications of PLR in MBD, and whether treatments to manipulate PLR and the LCN may improve patient outcomes.
{"title":"Evidence for peri-lacunar remodeling and altered osteocyte lacuno-canalicular network in mouse models of myeloma-induced bone disease","authors":"Holly Evans, Rebecca Andrews, Fatma Ali Abedi, Alexandria Sprules, Jacob Trend, Goran Lovric, Alanna Green, Andrew Chantry, Claire Clarkin, Janet Brown, Michelle Lawson","doi":"10.1093/jbmrpl/ziae093","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae093","url":null,"abstract":"\u0000 Myeloma bone disease (MBD) affects approximately 90% of multiple myeloma patients but current treatment options are suboptimal. Therefore, to successfully develop new therapies or optimize current ones, we must improve our fundamental knowledge of how myeloma affects bone microstructure and function. Here we have investigated the osteocyte lacuno-canalicular network (LCN) in MBD, as bone porosity affects bone quality and resilience. We used the syngeneic 5TGM1-C57BL-Kalwrij and the xenograft U266-NSG models at end stage and compared them to healthy controls (naïve). Micro-computed tomography (μCT) and histomorphometry indicated the 5TGM1 and U266 models developed mild and extensive MBD respectively, with the U266 model producing large osteolytic lesions. High-resolution synchrotron micro-CT (SR-μCT) revealed significant osteocyte lacunae changes in U266 bones but not 5TGM1, with a reduction in lacunae number and sphericity, and an increase in lacunae volume compared to naïve. Canalicular length, visualized using histological Ploton silver staining, appeared significantly shorter in 5TGM1 and U266 bones compared to naïve. Canalicular area as a proportion of the bone was also decreased by 24.2% in the U266 model. We observed significant upregulation of genes implicated in peri-lacunar remodeling (PLR), but immunohistochemistry confirmed that the osteocyte-specific protein sclerostin, a known driver of PLR, was unchanged between MBD and naïve bones. In summary, we have demonstrated evidence of PLR and altered organization of the osteocyte LCN in MBD mouse models. The next step would be to further understand the drivers and implications of PLR in MBD, and whether treatments to manipulate PLR and the LCN may improve patient outcomes.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141652137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maximilian M Delsmann, Leon-Gordian Leonhardt, Assil-Ramin Alimy, T. Hoenig, F. Timo Beil, Klaus Püschel, Felix N von Brackel, Michael Amling, Lennart Viezens, Darius M Thiesen, Tim Rolvien
Sacral insufficiency fractures are known to occur primarily in older women without adequate trauma. While an association with low bone mineral density (i.e., osteoporosis) has been reported, more detailed information on local bone quality properties in affected patients is not available. In the present study, core biopsies were obtained from the S1 sacral ala in patients with a bilateral sacral insufficiency fracture (type IV according to the fragility fractures of the pelvis (FFP) classification) who required surgical stabilization. Dual energy X-ray absorptiometry (DXA) and laboratory bone metabolism analyses were performed. For comparison, control biopsies were acquired from skeletally intact age- and sex-matched donors during autopsy. A total of 31 biopsies (fracture: n = 19; control: n = 12) were evaluated by micro-computed tomography (μ-CT), histomorphometry on undecalcified sections, and quantitative backscattered electron imaging (qBEI). DXA measurements showed mean T-scores in the range of osteoporosis in the fracture cohort (T-scoremin -2.6 ± 0.8). Biochemical analysis of bone metabolism parameters revealed high serum alkaline phosphatase and urinary deoxypyridinoline/creatinine levels. In the biopsies, a loss of trabecular microstructure along with increased osteoid values were detected in the fracture patients compared to controls (osteoid volume per bone volume 5.9 ± 3.5 vs. 0.9 ± 0.5%, p < 0.001). We also found evidence of microfractures with chronic healing processes (i.e., microcallus) as well as pronounced hypomineralization in the biopsies of the fracture cohort compared to the controls as evidenced by lower CaMean measured by qBEI (22.5 ± 1.6 vs. 24.2 ± 0.5 wt%, p = 0.003). In conclusion, this high-resolution biopsy study provides evidence of local hypomineralization in patients with sacral insufficiency fractures, pointing to reduced fracture resistance but also a distinct phenotype other than the predominant loss of trabeculae as in postmenopausal osteoporosis. Our data highlight the importance of therapies that promote bone mineralization to optimally treat and prevent sacral insufficiency fractures.
众所周知，骶骨发育不全骨折主要发生在没有足够创伤的老年妇女身上。虽然有报道称这种骨折与低骨矿物质密度（即骨质疏松症）有关，但目前还没有关于受影响患者局部骨质特性的更详细资料。在本研究中，我们从需要手术稳定的双侧骶骨发育不全骨折（根据骨盆脆性骨折（FFP）分类为 IV 型）患者的 S1 骶骨椎弓处获取了核心活检组织。研究人员进行了双能 X 射线吸收测量（DXA）和实验室骨代谢分析。为了进行比较，在尸体解剖时从骨骼完整、年龄和性别匹配的捐献者身上采集了对照组活检样本。通过微型计算机断层扫描（μ-CT）、未钙化切片组织形态测量法和定量反向散射电子成像（qBEI）对总共 31 份活检样本（骨折：19 份；对照：12 份）进行了评估。DXA 测量显示，骨折队列中的平均 T 值在骨质疏松症范围内（T-scoremin -2.6 ± 0.8）。骨代谢参数的生化分析表明，血清碱性磷酸酶和尿脱氧吡啶啉/肌酐水平较高。与对照组相比，在活检中发现骨折患者骨小梁微结构缺失，骨质含量增加（单位骨量骨质含量为 5.9 ± 3.5 vs. 0.9 ± 0.5%，p < 0.001）。我们还发现，与对照组相比，骨折组群的活检组织中存在慢性愈合过程的微骨折（即微胼胝体）以及明显的低矿化现象，qBEI 测量的 CaMean 值较低就是证明（22.5 ± 1.6 vs. 24.2 ± 0.5 wt%，p = 0.003）。总之，这项高分辨率活检研究提供了骶骨功能不全骨折患者局部矿化不足的证据，表明骨折抵抗力降低，但除了绝经后骨质疏松症中占主导地位的骨小梁缺失外，还有一种独特的表型。我们的数据凸显了促进骨矿化的疗法对最佳治疗和预防骶骨功能不全骨折的重要性。
{"title":"Biopsies from patients with sacral insufficiency fracture are characterized by low bone matrix mineralization and high turnover","authors":"Maximilian M Delsmann, Leon-Gordian Leonhardt, Assil-Ramin Alimy, T. Hoenig, F. Timo Beil, Klaus Püschel, Felix N von Brackel, Michael Amling, Lennart Viezens, Darius M Thiesen, Tim Rolvien","doi":"10.1093/jbmrpl/ziae094","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae094","url":null,"abstract":"\u0000 Sacral insufficiency fractures are known to occur primarily in older women without adequate trauma. While an association with low bone mineral density (i.e., osteoporosis) has been reported, more detailed information on local bone quality properties in affected patients is not available. In the present study, core biopsies were obtained from the S1 sacral ala in patients with a bilateral sacral insufficiency fracture (type IV according to the fragility fractures of the pelvis (FFP) classification) who required surgical stabilization. Dual energy X-ray absorptiometry (DXA) and laboratory bone metabolism analyses were performed. For comparison, control biopsies were acquired from skeletally intact age- and sex-matched donors during autopsy. A total of 31 biopsies (fracture: n = 19; control: n = 12) were evaluated by micro-computed tomography (μ-CT), histomorphometry on undecalcified sections, and quantitative backscattered electron imaging (qBEI). DXA measurements showed mean T-scores in the range of osteoporosis in the fracture cohort (T-scoremin -2.6 ± 0.8). Biochemical analysis of bone metabolism parameters revealed high serum alkaline phosphatase and urinary deoxypyridinoline/creatinine levels. In the biopsies, a loss of trabecular microstructure along with increased osteoid values were detected in the fracture patients compared to controls (osteoid volume per bone volume 5.9 ± 3.5 vs. 0.9 ± 0.5%, p < 0.001). We also found evidence of microfractures with chronic healing processes (i.e., microcallus) as well as pronounced hypomineralization in the biopsies of the fracture cohort compared to the controls as evidenced by lower CaMean measured by qBEI (22.5 ± 1.6 vs. 24.2 ± 0.5 wt%, p = 0.003). In conclusion, this high-resolution biopsy study provides evidence of local hypomineralization in patients with sacral insufficiency fractures, pointing to reduced fracture resistance but also a distinct phenotype other than the predominant loss of trabeculae as in postmenopausal osteoporosis. Our data highlight the importance of therapies that promote bone mineralization to optimally treat and prevent sacral insufficiency fractures.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141654379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fiona Obiezu, M. T. M. D. Q. Costa, Laryssa A. Huryn, Kristen Pan, K. Almpani, Anisha Ninan, KL Roszko, Lee S Weinstein, R. Gafni, Carlos R Ferreira, Janice Lee, Michael T Collins, Smita Jha
Jansen Metaphyseal Chondrodysplasia (JMC) is an ultra-rare disorder caused by germline heterozygous PTHR1 variants resulting in constitutive activation of parathyroid hormone type 1 receptor (PTHR1) with only 30 patients identified globally. A description of ocular manifestations of the disease is lacking. Six patients with JMC underwent a detailed ophthalmic evaluation, spectral-domain optical coherence tomography (OCT), visual field testing and craniofacial CT scans. Five of six patients had good visual acuity. All patients had widely spaced eyes; 5/6 had downslanted palpebral fissures. One patient had proptosis, and another had bilateral ptosis. Two patients had incomplete closure of the eyelids (lagophthalmos), one had a history of progressive right facial nerve palsy with profuse epiphora while the second had advanced optic nerve atrophy with corresponding retinal nerve fiber layer (RNFL) thinning on OCT and significant bilateral optic canal narrowing on CT scan. Additionally, this patient also had central visual field defects, and abnormal color vision. A third patient had normal visual acuity, subtle temporal pallor of the optic nerve head, normal average RNFL, but decreased temporal RNFL and retinal ganglion cell layer analysis (GCA) on OCT. GCA was decreased in 4/6 patients indicating a subclinical optic nerve atrophic process. None of the patients had glaucoma or high myopia. These data represent the first comprehensive report of ophthalmic findings in JMC. Patients with JMC have significant eye findings associated with optic canal narrowing due to extensive skull base dysplastic bone overgrowth that appear to be more prevalent and pronounced with age. Progressive optic neuropathy from optic canal narrowing may be a feature of JMC and OCT GCA can serve as a useful biomarker for progression in the setting of optic canal narrowing. We suggest that patients with JMC should undergo regular ophthalmic examination including color vision, OCT, visual field testing, orbital and craniofacial imaging.
{"title":"Ocular Findings in Jansen Metaphyseal Chondrodysplasia","authors":"Fiona Obiezu, M. T. M. D. Q. Costa, Laryssa A. Huryn, Kristen Pan, K. Almpani, Anisha Ninan, KL Roszko, Lee S Weinstein, R. Gafni, Carlos R Ferreira, Janice Lee, Michael T Collins, Smita Jha","doi":"10.1093/jbmrpl/ziae089","DOIUrl":"https://doi.org/10.1093/jbmrpl/ziae089","url":null,"abstract":"\u0000 Jansen Metaphyseal Chondrodysplasia (JMC) is an ultra-rare disorder caused by germline heterozygous PTHR1 variants resulting in constitutive activation of parathyroid hormone type 1 receptor (PTHR1) with only 30 patients identified globally. A description of ocular manifestations of the disease is lacking. Six patients with JMC underwent a detailed ophthalmic evaluation, spectral-domain optical coherence tomography (OCT), visual field testing and craniofacial CT scans. Five of six patients had good visual acuity. All patients had widely spaced eyes; 5/6 had downslanted palpebral fissures. One patient had proptosis, and another had bilateral ptosis. Two patients had incomplete closure of the eyelids (lagophthalmos), one had a history of progressive right facial nerve palsy with profuse epiphora while the second had advanced optic nerve atrophy with corresponding retinal nerve fiber layer (RNFL) thinning on OCT and significant bilateral optic canal narrowing on CT scan. Additionally, this patient also had central visual field defects, and abnormal color vision. A third patient had normal visual acuity, subtle temporal pallor of the optic nerve head, normal average RNFL, but decreased temporal RNFL and retinal ganglion cell layer analysis (GCA) on OCT. GCA was decreased in 4/6 patients indicating a subclinical optic nerve atrophic process. None of the patients had glaucoma or high myopia. These data represent the first comprehensive report of ophthalmic findings in JMC. Patients with JMC have significant eye findings associated with optic canal narrowing due to extensive skull base dysplastic bone overgrowth that appear to be more prevalent and pronounced with age. Progressive optic neuropathy from optic canal narrowing may be a feature of JMC and OCT GCA can serve as a useful biomarker for progression in the setting of optic canal narrowing. We suggest that patients with JMC should undergo regular ophthalmic examination including color vision, OCT, visual field testing, orbital and craniofacial imaging.","PeriodicalId":14611,"journal":{"name":"JBMR Plus","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141653002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：