Jilmen Quintiens, Walter Coudyzer, Melissa Bevers, Evie Vereecke, Joop P van den Bergh, Sarah L Manske, G Harry van Lenthe
High-Resolution peripheral quantitative CT (HR-pQCT) has become standard practice when quantifying volumetric bone mineral density (vBMD) in vivo. Yet, it is only accessible to peripheral sites, with small fields of view and lengthy scanning times. This limits general applicability in clinical workflows. The goal of this study was to assess the potential of Photon Counting CT (PCCT) in quantitative bone imaging. Using the European Forearm Phantom, PCCT was calibrated to hydroxy-apatite (HA) density. Eight cadaveric forearms were scanned twice with PCCT, and once with HR-pQCT. The dominant forearm of two volunteers was scanned twice with PCCT. In each scan the carpals were delineated. At bone-level, accuracy was assessed with a paired measurement of total vBMD (Tt.vBMD) calculated with PCCT and HR-pQCT. At voxel-level, repeatability was assessed by image registration and voxel-wise subtraction of the ex vivo PCCT scans. In an ideal scenario, this difference would be zero; any deviation was interpreted as falsely detected remodelling. For clinical usage, the least detectable remodelling was determined by finding a threshold in the PCCT difference image that resulted in a classification of bone formation and resorption below acceptable noise levels (<0.5%). The paired measurement of Tt.vBMD had a Pearson correlation of 0.986. Compared to HR-pQCT, PCCT showed a bias of 7.46 mgHA/cm3. At voxel-level, the repeated PCCT scans showed a bias of 17.66 mgHA/cm3 and standard error of 96.23 mgHA/cm3. Least detectable remodelling was found to be 250 mgHA/cm3, for which 0.37% of the voxels was incorrectly classified as newly added or resorbed bone. In vivo, this volume increased to 0.97%. Based on the cadaver data we conclude that PCCT can be used to quantify vBMD and bone turnover. We provided proof of principle that this technique is also accurate in vivo, hence, that it has high potential for clinical applications.
{"title":"The Quantification of Bone Mineral Density Using Photon Counting Computed Tomography and its Implications for Detecting Bone Remodelling.","authors":"Jilmen Quintiens, Walter Coudyzer, Melissa Bevers, Evie Vereecke, Joop P van den Bergh, Sarah L Manske, G Harry van Lenthe","doi":"10.1093/jbmr/zjae163","DOIUrl":"https://doi.org/10.1093/jbmr/zjae163","url":null,"abstract":"<p><p>High-Resolution peripheral quantitative CT (HR-pQCT) has become standard practice when quantifying volumetric bone mineral density (vBMD) in vivo. Yet, it is only accessible to peripheral sites, with small fields of view and lengthy scanning times. This limits general applicability in clinical workflows. The goal of this study was to assess the potential of Photon Counting CT (PCCT) in quantitative bone imaging. Using the European Forearm Phantom, PCCT was calibrated to hydroxy-apatite (HA) density. Eight cadaveric forearms were scanned twice with PCCT, and once with HR-pQCT. The dominant forearm of two volunteers was scanned twice with PCCT. In each scan the carpals were delineated. At bone-level, accuracy was assessed with a paired measurement of total vBMD (Tt.vBMD) calculated with PCCT and HR-pQCT. At voxel-level, repeatability was assessed by image registration and voxel-wise subtraction of the ex vivo PCCT scans. In an ideal scenario, this difference would be zero; any deviation was interpreted as falsely detected remodelling. For clinical usage, the least detectable remodelling was determined by finding a threshold in the PCCT difference image that resulted in a classification of bone formation and resorption below acceptable noise levels (<0.5%). The paired measurement of Tt.vBMD had a Pearson correlation of 0.986. Compared to HR-pQCT, PCCT showed a bias of 7.46 mgHA/cm3. At voxel-level, the repeated PCCT scans showed a bias of 17.66 mgHA/cm3 and standard error of 96.23 mgHA/cm3. Least detectable remodelling was found to be 250 mgHA/cm3, for which 0.37% of the voxels was incorrectly classified as newly added or resorbed bone. In vivo, this volume increased to 0.97%. Based on the cadaver data we conclude that PCCT can be used to quantify vBMD and bone turnover. We provided proof of principle that this technique is also accurate in vivo, hence, that it has high potential for clinical applications.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lieke Maas, Mickaël Hiligsmann, Caroline E Wyers, Sandrine Bours, Trudy van der Weijden, Joop P van den Bergh, Marsha van Oostwaard, Sander M J van Kuijk, Annelies Boonen
Shared decision making (SDM) aims to improve patients' experiences with care, treatment adherence and health outcomes. However, the effectiveness of SDM in patients with a recent fracture who require anti-osteoporosis medication (AOM) is unclear. The objective of this study was to assess the effectiveness of a multi-component adherence intervention (MCAI) including a patient decision aid (PDA) and motivational interviewing at fracture liaison services (FLS) on multiple outcomes compared to usual care (UC). This pre-post superiority study included patients with a recent fracture attending the FLS and with AOM treatment indication. The primary outcome was one-year AOM persistence measured by pharmacy records. Secondary outcomes included treatment initiation, AOM adherence (measured by medication possession ratio, MPR), decision quality (SDM process (0-100; best) and decisional conflict (0-100, highest conflict), subsequent fractures, and mortality. Outcomes were tested in MCAI and UC groups at the first FLS visit and 4- and 12-months after. Multiple imputation, uni- and multi-variable analyses were performed. Post-hoc analyses assessed the role of health literacy level. In total, 245 patients (MCAI: n = 136, UC: n = 109) were included. AOM persistence was 80.4% in the MCAI and 76.7% in the UC group (P=.626). SDM process scores were significantly better in MCAI (60.4 vs 55.1, P=.003). AOM initiation (97.8% vs 97.5%), MPR (90.9% vs 88.3%, P=.582), and decisional conflict (21.7 vs 23.0, P=.314) did not differ between groups. Results did not change importantly after adjustment. Stratified analyses by health literacy showed a better effect on MPR and SDM in those with adequate health literacy. This study showed no significant effect on AOM persistence however demonstrated a significant positive effect of MCAI on SDM process in FLS attenders.
共同决策(SDM)旨在改善患者的护理体验、治疗依从性和健康结果。然而,对于需要服用抗骨质疏松症药物(AOM)的近期骨折患者来说,SDM 的效果尚不明确。本研究旨在评估骨折联络服务机构(FLS)与常规护理(UC)相比,包括患者决策辅助工具(PDA)和动机访谈在内的多成分依从性干预(MCAI)对多种结果的有效性。这项前-后优越性研究的对象包括近期在FLS就诊并有AOM治疗指征的骨折患者。主要结果是通过药房记录测量 AOM 一年的持续性。次要结果包括治疗启动、AOM依从性(以药物持有率(MPR)衡量)、决策质量(SDM过程(0-100;最佳)和决策冲突(0-100,冲突最大))、后续骨折和死亡率。在 FLS 首次就诊时以及之后的 4 个月和 12 个月,对 MCAI 组和 UC 组的结果进行了测试。进行了多重归因、单变量和多变量分析。事后分析评估了健康素养水平的作用。共纳入 245 名患者(MCAI:n = 136;UC:n = 109)。MCAI组的AOM持续率为80.4%,UC组为76.7%(P=.626)。MCAI组的SDM过程得分明显更高(60.4 vs 55.1,P=.003)。AOM启动(97.8% vs 97.5%)、MPR(90.9% vs 88.3%,P=.582)和决策冲突(21.7 vs 23.0,P=.314)在组间无差异。经过调整后,结果没有重要变化。按健康素养进行的分层分析表明,健康素养充足的人群对 MPR 和 SDM 的效果更好。这项研究表明,MCAI 对 AOM 的持续性没有明显影响,但对 FLS 参与者的 SDM 过程有明显的积极影响。
{"title":"A quasi-experimental study about shared decision-making and motivational interviewing on patients with a recent fracture attending a fracture liaison services.","authors":"Lieke Maas, Mickaël Hiligsmann, Caroline E Wyers, Sandrine Bours, Trudy van der Weijden, Joop P van den Bergh, Marsha van Oostwaard, Sander M J van Kuijk, Annelies Boonen","doi":"10.1093/jbmr/zjae161","DOIUrl":"https://doi.org/10.1093/jbmr/zjae161","url":null,"abstract":"<p><p>Shared decision making (SDM) aims to improve patients' experiences with care, treatment adherence and health outcomes. However, the effectiveness of SDM in patients with a recent fracture who require anti-osteoporosis medication (AOM) is unclear. The objective of this study was to assess the effectiveness of a multi-component adherence intervention (MCAI) including a patient decision aid (PDA) and motivational interviewing at fracture liaison services (FLS) on multiple outcomes compared to usual care (UC). This pre-post superiority study included patients with a recent fracture attending the FLS and with AOM treatment indication. The primary outcome was one-year AOM persistence measured by pharmacy records. Secondary outcomes included treatment initiation, AOM adherence (measured by medication possession ratio, MPR), decision quality (SDM process (0-100; best) and decisional conflict (0-100, highest conflict), subsequent fractures, and mortality. Outcomes were tested in MCAI and UC groups at the first FLS visit and 4- and 12-months after. Multiple imputation, uni- and multi-variable analyses were performed. Post-hoc analyses assessed the role of health literacy level. In total, 245 patients (MCAI: n = 136, UC: n = 109) were included. AOM persistence was 80.4% in the MCAI and 76.7% in the UC group (P=.626). SDM process scores were significantly better in MCAI (60.4 vs 55.1, P=.003). AOM initiation (97.8% vs 97.5%), MPR (90.9% vs 88.3%, P=.582), and decisional conflict (21.7 vs 23.0, P=.314) did not differ between groups. Results did not change importantly after adjustment. Stratified analyses by health literacy showed a better effect on MPR and SDM in those with adequate health literacy. This study showed no significant effect on AOM persistence however demonstrated a significant positive effect of MCAI on SDM process in FLS attenders.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lauren S Roe, Elsa S Strotmeyer, Peggy M Cawthon, Nancy W Glynn, Yan Ma, Sonia Ancoli-Israel, Kristine Ensrud, Susan Redline, Katie L Stone, Kelley Pettee Gabriel, Jane A Cauley
Physical activity (PA), sedentary behavior (SB), and sleep are each individually associated with falls and fractures, but often are not examined simultaneously. Compositional data analysis examined the combined prospective associations between the proportion of time in PA, SB, and sleep relative to the remaining behaviors with recurrent falls (2+ falls in any year), any fractures, and major osteoporotic fracture (MOF) from tri-annual questionnaires, with adjudication for fractures, in 2918 older men aged 78.9 ± 5.1 years in the Osteoporotic Fractures in Men (MrOS) Study. Accelerometers were worn on the right tricep for seven consecutive 24-hour periods and measured PA (>1.5 METs), SB (≤1.5 METs), and sleep. Generalized Estimating Equations evaluated associations with recurrent falls. Cox proportional hazards regression estimated any incident fracture and MOF risk separately. Over four years of follow-up 1025 (35.2%) experienced recurrent falls; over 10 ± 4 years of follow-up, 669 (22.9%) experienced incident fractures and 370 (12.7%) experienced a MOF. Higher proportions of PA relative to SB and sleep were associated with a lower odds of recurrent falls [Odds Ratio (OR): 0.87, 95% CI: 0.76-0.99]. Higher proportions of SB relative to PA and sleep were associated with a higher odds of recurrent falls (OR: 1.38, 95% CI: 1.06-1.81) and higher risk of any fracture [Hazard Ratio (HR): 1.42, 95% CI: 1.05-1.92]. Higher proportions of sleep relative to PA and SB were associated with a lower risk of fracture (HR: 0.74, 95% CI: 0.54-0.99). No associations of activity composition with MOF were observed. When accounting for the co-dependence of daily activities, higher proportions of SB relative to the proportion of PA and sleep were associated with higher odds of recurrent falls and fracture risk. Results suggest reducing SB (and increasing PA) may lower fall and fracture risk in older men, which could inform future interventions.
{"title":"24-Hour Activity Composition is Associated with Lower Fall and Fracture Risk in Older Men.","authors":"Lauren S Roe, Elsa S Strotmeyer, Peggy M Cawthon, Nancy W Glynn, Yan Ma, Sonia Ancoli-Israel, Kristine Ensrud, Susan Redline, Katie L Stone, Kelley Pettee Gabriel, Jane A Cauley","doi":"10.1093/jbmr/zjae160","DOIUrl":"https://doi.org/10.1093/jbmr/zjae160","url":null,"abstract":"<p><p>Physical activity (PA), sedentary behavior (SB), and sleep are each individually associated with falls and fractures, but often are not examined simultaneously. Compositional data analysis examined the combined prospective associations between the proportion of time in PA, SB, and sleep relative to the remaining behaviors with recurrent falls (2+ falls in any year), any fractures, and major osteoporotic fracture (MOF) from tri-annual questionnaires, with adjudication for fractures, in 2918 older men aged 78.9 ± 5.1 years in the Osteoporotic Fractures in Men (MrOS) Study. Accelerometers were worn on the right tricep for seven consecutive 24-hour periods and measured PA (>1.5 METs), SB (≤1.5 METs), and sleep. Generalized Estimating Equations evaluated associations with recurrent falls. Cox proportional hazards regression estimated any incident fracture and MOF risk separately. Over four years of follow-up 1025 (35.2%) experienced recurrent falls; over 10 ± 4 years of follow-up, 669 (22.9%) experienced incident fractures and 370 (12.7%) experienced a MOF. Higher proportions of PA relative to SB and sleep were associated with a lower odds of recurrent falls [Odds Ratio (OR): 0.87, 95% CI: 0.76-0.99]. Higher proportions of SB relative to PA and sleep were associated with a higher odds of recurrent falls (OR: 1.38, 95% CI: 1.06-1.81) and higher risk of any fracture [Hazard Ratio (HR): 1.42, 95% CI: 1.05-1.92]. Higher proportions of sleep relative to PA and SB were associated with a lower risk of fracture (HR: 0.74, 95% CI: 0.54-0.99). No associations of activity composition with MOF were observed. When accounting for the co-dependence of daily activities, higher proportions of SB relative to the proportion of PA and sleep were associated with higher odds of recurrent falls and fracture risk. Results suggest reducing SB (and increasing PA) may lower fall and fracture risk in older men, which could inform future interventions.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chongshan Liu, Erika L Cyphert, Sam J Stephen, Bowen Wang, Angie L Morales, Jacob C Nixon, Nicholas R Natsoulas, Matthew Garcia, Pablo Blazquez Carmona, Albert C Vill, Eve Donnelly, Ilana L Brito, Deepak Vashishth, Christopher J Hernandez
Recent studies in mice have indicated that the gut microbiome can regulate bone tissue strength. However, prior work involved modifications to the gut microbiome in growing animals and it is unclear if the same changes in the microbiome, applied later in life, would change matrix strength. Here we changed the composition of the gut microbiome before and/or after skeletal maturity (16 weeks of age) using oral antibiotics (ampicillin + neomycin). Male and female mice (n = 143 total, n = 12-17/group/sex) were allocated into five study groups:1) Unaltered, 2) Continuous (dosing 4-24 weeks of age), 3) Delayed (dosing only 16-24 weeks of age), 4) Initial (dosing 4-16 weeks of age, suspended at 16 weeks), and 5) Reconstituted (dosing from 4-16 weeks following by fecal microbiota transplant from Unaltered donors). Animals were euthanized at 24 weeks of age. In males, bone matrix strength in the femur was 25-35% less than expected by geometry in mice from the Continuous (P=.001), Delayed (P=.005), and Initial (P=.040) groups as compared to Unaltered. Reconstitution of the gut microbiota led to a bone matrix strength similar to Unaltered animals (P=.929). In females, microbiome-induced changes in bone matrix strength followed the same trend as males but were not significantly different, demonstrating a sex-dependent response of bone matrix to the gut microbiota. Minor differences in chemical composition of bone matrix were observed with Raman spectroscopy. Our findings indicate that microbiome-induced impairment of bone matrix in males can be initiated and/or reversed after skeletal maturity. The portion of the femoral cortical bone formed after skeletal maturity (16 weeks) was small; suggesting that microbiome-induced changes in bone matrix occurred without osteoblast/osteoclast turnover through a yet unidentified mechanism. These findings provide evidence that the mechanical properties of bone matrix can be altered in the adult skeleton.
{"title":"Microbiome-induced Increases and Decreases in Bone Matrix Strength can be Initiated After Skeletal Maturity.","authors":"Chongshan Liu, Erika L Cyphert, Sam J Stephen, Bowen Wang, Angie L Morales, Jacob C Nixon, Nicholas R Natsoulas, Matthew Garcia, Pablo Blazquez Carmona, Albert C Vill, Eve Donnelly, Ilana L Brito, Deepak Vashishth, Christopher J Hernandez","doi":"10.1093/jbmr/zjae157","DOIUrl":"https://doi.org/10.1093/jbmr/zjae157","url":null,"abstract":"<p><p>Recent studies in mice have indicated that the gut microbiome can regulate bone tissue strength. However, prior work involved modifications to the gut microbiome in growing animals and it is unclear if the same changes in the microbiome, applied later in life, would change matrix strength. Here we changed the composition of the gut microbiome before and/or after skeletal maturity (16 weeks of age) using oral antibiotics (ampicillin + neomycin). Male and female mice (n = 143 total, n = 12-17/group/sex) were allocated into five study groups:1) Unaltered, 2) Continuous (dosing 4-24 weeks of age), 3) Delayed (dosing only 16-24 weeks of age), 4) Initial (dosing 4-16 weeks of age, suspended at 16 weeks), and 5) Reconstituted (dosing from 4-16 weeks following by fecal microbiota transplant from Unaltered donors). Animals were euthanized at 24 weeks of age. In males, bone matrix strength in the femur was 25-35% less than expected by geometry in mice from the Continuous (P=.001), Delayed (P=.005), and Initial (P=.040) groups as compared to Unaltered. Reconstitution of the gut microbiota led to a bone matrix strength similar to Unaltered animals (P=.929). In females, microbiome-induced changes in bone matrix strength followed the same trend as males but were not significantly different, demonstrating a sex-dependent response of bone matrix to the gut microbiota. Minor differences in chemical composition of bone matrix were observed with Raman spectroscopy. Our findings indicate that microbiome-induced impairment of bone matrix in males can be initiated and/or reversed after skeletal maturity. The portion of the femoral cortical bone formed after skeletal maturity (16 weeks) was small; suggesting that microbiome-induced changes in bone matrix occurred without osteoblast/osteoclast turnover through a yet unidentified mechanism. These findings provide evidence that the mechanical properties of bone matrix can be altered in the adult skeleton.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lucy Collins, Alec Ronan, Evelyn Hutcheon, Peter R Ebeling, Vivian Grill, Hanh H Nguyen
Background: Osteoporosis is common, affecting more than 20% of women and 6% of men globally over the age of 50 (1). Anti-resorptive drugs, bisphosphonates and denosumab, have been effective treatments for osteoporosis for more than 30 years. Rare complications of anti-resorptive therapy include medication-related osteonecrosis of the jaw and atypical femur fractures (AFF). The American Society for Bone and Mineral Research (ASBMR) proposed a case definition for these atypical femoral fractures in 2010, which was updated in 2013. However, atypical fractures at non-classical sites have been increasingly described.
Aims: We aimed to systematically identify atypical fracture cases, excluded from the ASBMR AFF case definition in patients receiving anti-resorptive medication for longer than three years.
Methods: A structured search of electronic databases, including PubMed, Medline (Ovid), Embase (Ovid), Cochrane and Web of Sciences, and hand-searching of conference abstracts was undertaken. All full-text articles written in English describing an atypical fracture in patients (aged >18 years) and receiving anti-resorptive medication for >3 years were included, with data extracted and analysed by two independent reviewers.
Results: Sixty-six articles were identified, describing 151 cases of atypical fractures in 114 individuals. The most frequent fracture site was the ulna, followed by the tibia. All patients were taking anti-resorptive treatment prior to or at the time of fracture, most frequently alendronate monotherapy (44%). Most commonly, fractures were transverse in nature (95%), following minimal or no trauma (96%), non-comminuted (98%) with cortical thickening of the surrounding bone (69%). Anti-resorptive treatment was ceased following atypical fracture in the majority (89%).
Conclusions: Atypical fractures are rare and should not deter physicians from appropriate anti-resorptive therapy for osteoporosis. However, clinicians should be alert to their presence, at additional sites to the femur. An update of the current ASBMR AFF case definition to include other skeletal sites could be timely.
{"title":"Atypical fractures at non-classical sites associated with anti-resorptive therapy: A Systematic Review.","authors":"Lucy Collins, Alec Ronan, Evelyn Hutcheon, Peter R Ebeling, Vivian Grill, Hanh H Nguyen","doi":"10.1093/jbmr/zjae159","DOIUrl":"https://doi.org/10.1093/jbmr/zjae159","url":null,"abstract":"<p><strong>Background: </strong>Osteoporosis is common, affecting more than 20% of women and 6% of men globally over the age of 50 (1). Anti-resorptive drugs, bisphosphonates and denosumab, have been effective treatments for osteoporosis for more than 30 years. Rare complications of anti-resorptive therapy include medication-related osteonecrosis of the jaw and atypical femur fractures (AFF). The American Society for Bone and Mineral Research (ASBMR) proposed a case definition for these atypical femoral fractures in 2010, which was updated in 2013. However, atypical fractures at non-classical sites have been increasingly described.</p><p><strong>Aims: </strong>We aimed to systematically identify atypical fracture cases, excluded from the ASBMR AFF case definition in patients receiving anti-resorptive medication for longer than three years.</p><p><strong>Methods: </strong>A structured search of electronic databases, including PubMed, Medline (Ovid), Embase (Ovid), Cochrane and Web of Sciences, and hand-searching of conference abstracts was undertaken. All full-text articles written in English describing an atypical fracture in patients (aged >18 years) and receiving anti-resorptive medication for >3 years were included, with data extracted and analysed by two independent reviewers.</p><p><strong>Results: </strong>Sixty-six articles were identified, describing 151 cases of atypical fractures in 114 individuals. The most frequent fracture site was the ulna, followed by the tibia. All patients were taking anti-resorptive treatment prior to or at the time of fracture, most frequently alendronate monotherapy (44%). Most commonly, fractures were transverse in nature (95%), following minimal or no trauma (96%), non-comminuted (98%) with cortical thickening of the surrounding bone (69%). Anti-resorptive treatment was ceased following atypical fracture in the majority (89%).</p><p><strong>Conclusions: </strong>Atypical fractures are rare and should not deter physicians from appropriate anti-resorptive therapy for osteoporosis. However, clinicians should be alert to their presence, at additional sites to the femur. An update of the current ASBMR AFF case definition to include other skeletal sites could be timely.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Huifeng Yun, Ye Liu, Jeffrey R Curtis, Kenneth Saag, Gia D'Erasmo, Katherine Haseltine, Emily M Stein
Epidural steroid injections (ESIs) are a common and often effective treatment for radicular back pain. While oral glucocorticoids increase fracture incidence, little is known regarding fracture risk after ESI. This study investigated the incidence of fractures among individuals who received ESI and those who did not. We hypothesized that ESI exposure would be associated with an increased incidence of osteoporotic fracture and specifically vertebral fractures. Using 2005-2018 5% Medicare data, individuals with radicular pain who had ≥1 ESI and those who did not (non-ESI) were matched 1:10 by age, sex, and month of radicular pain diagnosis using exposure density sampling (EDS). Using a high-dimensional propensity score (HDPS) calculated based on the top 500 covariates across multiple data dimensions, ESI and non-ESI individuals were matched 1:1. Fractures were identified using validated ICD-9/10 diagnosis codes. Fracture incidence rate (IR) was calculated by group, and hazard ratios (HR) compared using Cox regression. 25 062 ESI patients and 221 735 non-ESI patients who met eligibility criteria were identified using EDS. Mean age was 76 years (74% female). Among ESI-treated individuals, there were 2296 fractures, IR 49.1 (95% CI: 47.2-51.2) per 1000 person years. For non-ESI individuals, there were 11 917 fractures, IR 35.2 (95% CI: 34.5-35.8). Individuals who received ESI had a greater hazard of fracture at typical osteoporotic sites, HR 1.39 (95% CI 1.33-1.46) by EDS and 1.32 (1.12-1.54) by HDPS, and greater hazard of vertebral fracture, 1.54 (1.45-1.64) by EDS and 1.69 (1.38-2.07) by HDPS. Patients who received greater cumulative ESI doses (≥3 in 1 year) had a higher risk of fractures within the first six months of follow-up. ESI exposure in older individuals is associated with an increased risk of fracture, suggesting there may be lasting detrimental skeletal effects of ESI. Further research into strategies to reduce fracture risk in this population is warranted.
硬膜外类固醇注射(ESI)是治疗根性背痛的一种常见且通常有效的方法。虽然口服糖皮质激素会增加骨折的发生率,但人们对ESI后的骨折风险知之甚少。本研究调查了接受过 ESI 和没有接受过 ESI 的人的骨折发生率。我们假设,接受 ESI 会增加骨质疏松性骨折,尤其是椎体骨折的发生率。我们使用 2005-2018 年 5% 的医疗保险数据,通过暴露密度采样(EDS),按照年龄、性别和根性疼痛诊断月份,将接受过≥1 次 ESI 的根性疼痛患者与未接受过 ESI 的患者(非 ESI)进行 1:10 匹配。根据多个数据维度的前 500 个协变量计算出的高维倾向得分 (HDPS),ESI 和非 ESI 患者进行了 1:1 匹配。骨折是通过有效的 ICD-9/10 诊断代码确定的。按组别计算骨折发生率(IR),并使用 Cox 回归法比较危险比(HR)。通过 EDS 确定了符合资格标准的 25 062 名 ESI 患者和 221 735 名非 ESI 患者。平均年龄为 76 岁(74% 为女性)。在接受过 ESI 治疗的患者中,有 2296 例骨折,IR 为 49.1(95% CI:47.2-51.2)/1000 人年。在未接受ESI治疗的患者中,有11 917人发生骨折,IR值为35.2(95% CI:34.5-35.8)。接受ESI治疗的患者在典型的骨质疏松部位发生骨折的风险更大,根据EDS计算,HR为1.39(95% CI为1.33-1.46),根据HDPS计算,HR为1.32(1.12-1.54);发生脊椎骨折的风险更大,根据EDS计算,HR为1.54(1.45-1.64),根据HDPS计算,HR为1.69(1.38-2.07)。接受较多累积 ESI 剂量(1 年内≥3 次)的患者在随访的前 6 个月内发生骨折的风险较高。老年人接触 ESI 会增加骨折风险,这表明 ESI 可能会对骨骼产生持久的有害影响。有必要进一步研究降低这一人群骨折风险的策略。
{"title":"Epidural Steroid Injections and Fracture Incidence Among Older Individuals with Radiculopathy.","authors":"Huifeng Yun, Ye Liu, Jeffrey R Curtis, Kenneth Saag, Gia D'Erasmo, Katherine Haseltine, Emily M Stein","doi":"10.1093/jbmr/zjae162","DOIUrl":"https://doi.org/10.1093/jbmr/zjae162","url":null,"abstract":"<p><p>Epidural steroid injections (ESIs) are a common and often effective treatment for radicular back pain. While oral glucocorticoids increase fracture incidence, little is known regarding fracture risk after ESI. This study investigated the incidence of fractures among individuals who received ESI and those who did not. We hypothesized that ESI exposure would be associated with an increased incidence of osteoporotic fracture and specifically vertebral fractures. Using 2005-2018 5% Medicare data, individuals with radicular pain who had ≥1 ESI and those who did not (non-ESI) were matched 1:10 by age, sex, and month of radicular pain diagnosis using exposure density sampling (EDS). Using a high-dimensional propensity score (HDPS) calculated based on the top 500 covariates across multiple data dimensions, ESI and non-ESI individuals were matched 1:1. Fractures were identified using validated ICD-9/10 diagnosis codes. Fracture incidence rate (IR) was calculated by group, and hazard ratios (HR) compared using Cox regression. 25 062 ESI patients and 221 735 non-ESI patients who met eligibility criteria were identified using EDS. Mean age was 76 years (74% female). Among ESI-treated individuals, there were 2296 fractures, IR 49.1 (95% CI: 47.2-51.2) per 1000 person years. For non-ESI individuals, there were 11 917 fractures, IR 35.2 (95% CI: 34.5-35.8). Individuals who received ESI had a greater hazard of fracture at typical osteoporotic sites, HR 1.39 (95% CI 1.33-1.46) by EDS and 1.32 (1.12-1.54) by HDPS, and greater hazard of vertebral fracture, 1.54 (1.45-1.64) by EDS and 1.69 (1.38-2.07) by HDPS. Patients who received greater cumulative ESI doses (≥3 in 1 year) had a higher risk of fractures within the first six months of follow-up. ESI exposure in older individuals is associated with an increased risk of fracture, suggesting there may be lasting detrimental skeletal effects of ESI. Further research into strategies to reduce fracture risk in this population is warranted.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The CAGS-snorkel mouse: a game changer in the identification of extracellular vesicles originating from cells of the osteogenic lineage.","authors":"Colin Farquharson","doi":"10.1093/jbmr/zjae155","DOIUrl":"https://doi.org/10.1093/jbmr/zjae155","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Timur A Yorgan, Yihao Zhu, Philip Wiedemann, Kenneth Schöneck, Sandra Pohl, Michaela Schweizer, Michael Amling, Florian Barvencik, Ralf Oheim, Thorsten Schinke
Spermine synthase, encoded by the SMS gene, is involved in polyamine metabolism, as it is required for the synthesis of spermine from its precursor molecule spermidine. Pathogenic variants of SMS are known to cause Snyder-Robinson syndrome (SRS), an X-linked recessive disorder causing various symptoms, including intellectual disability, muscular hypotonia, infertility, but also skeletal abnormalities, such as facial dysmorphisms and osteoporosis. Since the impact of a murine SMS deficiency has so far only been analysed in Gy mice, where a large genomic deletion also includes the neighbouring Phex gene, there is only limited knowledge about the potential role of SMS in bone cell regulation. In the present manuscript we describe two patients carrying distinct SMS variants, both diagnosed with osteoporosis. Whereas the first patient displayed all characteristic hallmarks of SRS, the second patient was initially diagnosed, based on laboratory findings, as a case of adult-onset hypophosphatasia. In order to study the impact of SMS inactivation on bone remodelling we took advantage of a newly developed mouse model carrying a pathogenic SMS variant (p.G56S). Compared to their wildtype littermates 12-week-old male SmsG56S/0 mice displayed reduced trabecular bone mass and cortical thickness, as assessed by μCT analysis of the femur. This phenotype was histologically confirmed by the analysis of spine and tibia sections, where we also observed a moderate enrichment of non-mineralized osteoid in SmsG56S/0 mice. Cellular and dynamic histomorphometry further identified a reduced bone formation rate as a main cause of the low bone mass phenotype. Likewise, primary bone marrow cells from SmsG56S/0 mice displayed reduced capacity to form a mineralized matrix ex vivo, thereby suggesting a cell-autonomous mechanism. Taken together, our data identify SMS as an enzyme with physiological relevance for osteoblast activity, thereby demonstrating an important role of polyamine metabolism in the control of bone remodeling.
{"title":"Inactivation of spermine synthase in mice causes osteopenia due to reduced osteoblast activity.","authors":"Timur A Yorgan, Yihao Zhu, Philip Wiedemann, Kenneth Schöneck, Sandra Pohl, Michaela Schweizer, Michael Amling, Florian Barvencik, Ralf Oheim, Thorsten Schinke","doi":"10.1093/jbmr/zjae156","DOIUrl":"https://doi.org/10.1093/jbmr/zjae156","url":null,"abstract":"<p><p>Spermine synthase, encoded by the SMS gene, is involved in polyamine metabolism, as it is required for the synthesis of spermine from its precursor molecule spermidine. Pathogenic variants of SMS are known to cause Snyder-Robinson syndrome (SRS), an X-linked recessive disorder causing various symptoms, including intellectual disability, muscular hypotonia, infertility, but also skeletal abnormalities, such as facial dysmorphisms and osteoporosis. Since the impact of a murine SMS deficiency has so far only been analysed in Gy mice, where a large genomic deletion also includes the neighbouring Phex gene, there is only limited knowledge about the potential role of SMS in bone cell regulation. In the present manuscript we describe two patients carrying distinct SMS variants, both diagnosed with osteoporosis. Whereas the first patient displayed all characteristic hallmarks of SRS, the second patient was initially diagnosed, based on laboratory findings, as a case of adult-onset hypophosphatasia. In order to study the impact of SMS inactivation on bone remodelling we took advantage of a newly developed mouse model carrying a pathogenic SMS variant (p.G56S). Compared to their wildtype littermates 12-week-old male SmsG56S/0 mice displayed reduced trabecular bone mass and cortical thickness, as assessed by μCT analysis of the femur. This phenotype was histologically confirmed by the analysis of spine and tibia sections, where we also observed a moderate enrichment of non-mineralized osteoid in SmsG56S/0 mice. Cellular and dynamic histomorphometry further identified a reduced bone formation rate as a main cause of the low bone mass phenotype. Likewise, primary bone marrow cells from SmsG56S/0 mice displayed reduced capacity to form a mineralized matrix ex vivo, thereby suggesting a cell-autonomous mechanism. Taken together, our data identify SMS as an enzyme with physiological relevance for osteoblast activity, thereby demonstrating an important role of polyamine metabolism in the control of bone remodeling.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sashank Lekkala, Lynn M Johnson, Kendall F Moseley, Eve Donnelly
{"title":"Response to letter to the editor regarding \"increased advanced glycation endproducts, stiffness, and hardness in iliac crest bone from postmenopausal women with type 2 diabetes mellitus on insulin\".","authors":"Sashank Lekkala, Lynn M Johnson, Kendall F Moseley, Eve Donnelly","doi":"10.1093/jbmr/zjae158","DOIUrl":"https://doi.org/10.1093/jbmr/zjae158","url":null,"abstract":"","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kathryn M Dahir, Amy Shannon, Derek Dunn, Walter Voegtli, Qunming Dong, Jawad Hasan, Rajendra Pradhan, Ryan Pelto, Wei-Jian Pan
Hypophosphatasia (HPP) is a rare, inherited metabolic disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Efzimfotase alfa (ALXN1850) is a second-generation TNSALP enzyme replacement therapy in development for HPP. This first-in-human open-label, dose-escalating phase 1 trial evaluated efzimfotase alfa safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. Fifteen adults (5/cohort) with HPP received efzimfotase alfa in doses of 15 mg (cohort 1), 45 mg (cohort 2), or 90 mg (cohort 3) as one intravenous (i.v.) dose followed by 3 weekly subcutaneous (s.c.) doses. The primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics of ALP substrates known to be biomarkers of disease (inorganic pyrophosphate [PPi] and pyridoxal 5'-phosphate [PLP]) and immunogenicity. Treatment-emergent adverse events (TEAEs) occurred in 12 (80%) participants. Eight (53%) participants had injection site reactions (ISRs), observed after 10 of 41 (24%) s.c. injections. Most ISR TEAEs were mild and resolved within 1-2 d. Peak and total exposures of efzimfotase alfa increased in a greater-than-dose proportional manner over the range of 15-90 mg after i.v. and s.c. dosing. The arithmetic mean elimination half-life was approximately 6 d; absolute bioavailability was 28.6%-36.8% over the s.c. dose range of 15-90 mg. Dose-dependent reductions in plasma concentrations of PPi and PLP relative to baseline reached nadir in the first week after i.v. dosing and were sustained for 3-4 wk after the last s.c. dose. Four (27%) participants tested positive for antidrug antibodies (ADAs), 3 of whom were ADA positive before the first dose of efzimfotase alfa. ADAs had no apparent effect on efzimfotase alfa pharmacokinetics/pharmacodynamics. No participants had neutralizing antibodies. Efzimfotase alfa demonstrated acceptable safety, tolerability, and pharmacokinetic profiles and was associated with sustained reductions in biomarkers of disease in adults with HPP, supporting further evaluation in adult and pediatric patients. Registration: ClinicalTrials.gov NCT04980248 (https://clinicaltrials.gov/study/NCT04980248).
{"title":"Safety, pharmacokinetics, and pharmacodynamics of efzimfotase alfa, a second-generation enzyme replacement therapy: phase 1, dose-escalation study in adults with hypophosphatasia.","authors":"Kathryn M Dahir, Amy Shannon, Derek Dunn, Walter Voegtli, Qunming Dong, Jawad Hasan, Rajendra Pradhan, Ryan Pelto, Wei-Jian Pan","doi":"10.1093/jbmr/zjae128","DOIUrl":"10.1093/jbmr/zjae128","url":null,"abstract":"<p><p>Hypophosphatasia (HPP) is a rare, inherited metabolic disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Efzimfotase alfa (ALXN1850) is a second-generation TNSALP enzyme replacement therapy in development for HPP. This first-in-human open-label, dose-escalating phase 1 trial evaluated efzimfotase alfa safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. Fifteen adults (5/cohort) with HPP received efzimfotase alfa in doses of 15 mg (cohort 1), 45 mg (cohort 2), or 90 mg (cohort 3) as one intravenous (i.v.) dose followed by 3 weekly subcutaneous (s.c.) doses. The primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics of ALP substrates known to be biomarkers of disease (inorganic pyrophosphate [PPi] and pyridoxal 5'-phosphate [PLP]) and immunogenicity. Treatment-emergent adverse events (TEAEs) occurred in 12 (80%) participants. Eight (53%) participants had injection site reactions (ISRs), observed after 10 of 41 (24%) s.c. injections. Most ISR TEAEs were mild and resolved within 1-2 d. Peak and total exposures of efzimfotase alfa increased in a greater-than-dose proportional manner over the range of 15-90 mg after i.v. and s.c. dosing. The arithmetic mean elimination half-life was approximately 6 d; absolute bioavailability was 28.6%-36.8% over the s.c. dose range of 15-90 mg. Dose-dependent reductions in plasma concentrations of PPi and PLP relative to baseline reached nadir in the first week after i.v. dosing and were sustained for 3-4 wk after the last s.c. dose. Four (27%) participants tested positive for antidrug antibodies (ADAs), 3 of whom were ADA positive before the first dose of efzimfotase alfa. ADAs had no apparent effect on efzimfotase alfa pharmacokinetics/pharmacodynamics. No participants had neutralizing antibodies. Efzimfotase alfa demonstrated acceptable safety, tolerability, and pharmacokinetic profiles and was associated with sustained reductions in biomarkers of disease in adults with HPP, supporting further evaluation in adult and pediatric patients. Registration: ClinicalTrials.gov NCT04980248 (https://clinicaltrials.gov/study/NCT04980248).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11425692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}