Journal of Bone and Mineral Research最新文献

{"title":"3D Finite Element Models Reconstructed From 2D Dual-Energy X-Ray Absorptiometry (DXA) Images Improve Hip Fracture Prediction Compared to Areal BMD in Osteoporotic Fractures in Men (MrOS) Sweden Cohort","authors":"Lorenzo Grassi,&nbsp;Sami P. V??n?nen,&nbsp;Lars Jehpsson,&nbsp;?sten Ljunggren,&nbsp;Bj?rn E. Rosengren,&nbsp;Magnus K. Karlsson,&nbsp;Hanna Isaksson","doi":"10.1002/jbmr.4878","DOIUrl":"https://doi.org/10.1002/jbmr.4878","url":null,"abstract":"<p>Bone strength is an important contributor to fracture risk. Areal bone mineral density (aBMD) derived from dual-energy X-ray absorptiometry (DXA) is used as a surrogate for bone strength in fracture risk prediction tools. 3D finite element (FE) models predict bone strength better than aBMD, but their clinical use is limited by the need for 3D computed tomography and lack of automation. We have earlier developed a method to reconstruct the 3D hip anatomy from a 2D DXA image, followed by subject-specific FE-based prediction of proximal femoral strength. In the current study, we aim to evaluate the method's ability to predict incident hip fractures in a population-based cohort (Osteoporotic Fractures in Men [MrOS] Sweden). We defined two subcohorts: (i) hip fracture cases and controls cohort: 120 men with a hip fracture (&lt;10 years from baseline) and two controls to each hip fracture case, matched by age, height, and body mass index; and (ii) fallers cohort: 86 men who had fallen the year before their hip DXA scan was acquired, 15 of which sustained a hip fracture during the following 10 years. For each participant, we reconstructed the 3D hip anatomy and predicted proximal femoral strength in 10 sideways fall configurations using FE analysis. The FE-predicted proximal femoral strength was a better predictor of incident hip fractures than aBMD for both hip fracture cases and controls (difference in area under the receiver operating characteristics curve, ΔAUROC = 0.06) and fallers (ΔAUROC = 0.22) cohorts. This is the first time that FE models outperformed aBMD in predicting incident hip fractures in a population-based prospectively followed cohort based on 3D FE models obtained from a 2D DXA scan. Our approach has potential to notably improve the accuracy of fracture risk predictions in a clinically feasible manner (only one single DXA image is needed) and without additional costs compared to the current clinical approach. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 9","pages":"1258-1267"},"PeriodicalIF":6.2,"publicationDate":"2023-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4878","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41081504","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}

{"title":"Efficacy and Safety of Transdermal Abaloparatide in Postmenopausal Women with Osteoporosis: A Randomized Study","authors":"E. Michael Lewiecki,&nbsp;Edward Czerwinski,&nbsp;Chris Recknor,&nbsp;Anna Strzelecka,&nbsp;Guillermo Valenzuela,&nbsp;Mary Lawrence,&nbsp;Stuart Silverman,&nbsp;Jose Cardona,&nbsp;Susan M. Nattrass,&nbsp;Neil Binkley,&nbsp;Miriam Annett,&nbsp;Leny Pearman,&nbsp;Bruce Mitlak","doi":"10.1002/jbmr.4877","DOIUrl":"10.1002/jbmr.4877","url":null,"abstract":"<p>Anabolic therapies, recommended for patients at very high fracture risk, are administered subcutaneously (SC). The objective of this study was to evaluate the efficacy and safety of the abaloparatide microstructured transdermal system (abaloparatide-sMTS) as an alternative to the SC formulation. This phase 3, noninferiority study (NCT04064411) randomly assigned postmenopausal women with osteoporosis (<i>N</i> = 511) 1:1 to open-label abaloparatide administered daily via abaloparatide-sMTS or SC injection for 12 months. The primary comparison between treatment groups was the percentage change in lumbar spine bone mineral density (BMD) at 12 months, with a noninferiority margin of 2.0%. Secondary endpoints included percentage change in total hip and femoral neck BMD, bone turnover markers, dermatologic safety, and new clinical fracture incidence. At 12 months, percentage increase from baseline in lumbar spine BMD was 7.14% (SE: 0.46%) for abaloparatide-sMTS and 10.86% (SE: 0.48%) for abaloparatide-SC (treatment difference: −3.72% [95% confidence interval: −5.01%, −2.43%]). Percentage change in total hip BMD was 1.97% for abaloparatide-sMTS and 3.70% for abaloparatide-SC. Median changes from baseline at 12 months in serum procollagen type I N-terminal propeptide (s-PINP) were 52.6% for abaloparatide-sMTS and 74.5% for abaloparatide-SC. Administration site reactions were the most frequently reported adverse events (abaloparatide-sMTS, 94.4%; abaloparatide-SC, 70.5%). Incidence of serious adverse events was similar between groups. Mild or moderate skin reactions occurred with abaloparatide-sMTS with no identifiable risk factors for sensitization reactions. Few new clinical fractures occurred in either group. Noninferiority of abaloparatide-sMTS to abaloparatide-SC for percentage change in spine BMD at 12 months was not demonstrated; however, clinically meaningful increases from baseline in lumbar spine and total hip BMD were observed in both treatment groups. © 2023 Radius Health, Inc and The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 10","pages":"1404-1414"},"PeriodicalIF":6.2,"publicationDate":"2023-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4877","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10239959","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}

{"title":"Measurements of the Vitamin D Metabolome in the Calgary Vitamin D Study: Relationship of Vitamin D Metabolites to Bone Loss","authors":"Lauren A. Burt,&nbsp;Martin Kaufmann,&nbsp;Marianne S. Rose,&nbsp;Glenville Jones,&nbsp;Emma O. Billington,&nbsp;Steven K. Boyd,&nbsp;David A. Hanley","doi":"10.1002/jbmr.4876","DOIUrl":"https://doi.org/10.1002/jbmr.4876","url":null,"abstract":"<p>In a 36-month randomized controlled trial examining the effect of high-dose vitamin D₃ on radial and tibial total bone mineral density (TtBMD), measured by high-resolution peripheral quantitative tomography (HR-pQCT), participants (311 healthy males and females aged 55–70 years with dual-energy X-ray absorptiometry T-scores &gt; −2.5 without vitamin D deficiency) were randomized to receive 400 IU (<i>N</i> = 109), 4000 IU (<i>N</i> = 100), or 10,000 IU (<i>N</i> = 102) daily. Participants had HR-pQCT radius and tibia scans and blood sampling at baseline, 6, 12, 24, and 36 months. This secondary analysis examined the effect of vitamin D dose on plasma measurements of the vitamin D metabolome by liquid chromatography–tandem mass spectrometry (LC-MS/MS), exploring whether the observed decline in TtBMD was associated with changes in four key metabolites [25-(OH)D₃; 24,25-(OH)₂D₃; 1,25-(OH)₂D₃; and 1,24,25-(OH)₃D₃]. The relationship between peak values in vitamin D metabolites and changes in TtBMD over 36 months was assessed using linear regression, controlling for sex. Increasing vitamin D dose was associated with a marked increase in 25-(OH)D₃, 24,25-(OH)₂D₃ and 1,24,25-(OH)₃D₃, but no dose-related change in plasma 1,25-(OH)₂D₃ was observed. There was a significant negative slope for radius TtBMD and 1,24,25-(OH)₃D₃ (−0.05, 95% confidence interval [CI] −0.08, −0.03, <i>p</i> &lt; 0.001) after controlling for sex. A significant interaction between TtBMD and sex was seen for 25-(OH)D₃ (female: −0.01, 95% CI −0.12, −0.07; male: −0.04, 95% CI −0.06, −0.01, <i>p</i> = 0.001) and 24,25-(OH)₂D₃ (female: −0.75, 95% CI −0.98, −0.52; male: −0.35, 95% CI −0.59, −0.11, <i>p</i> &lt; 0.001). For the tibia there was a significant negative slope for 25-(OH)D₃ (−0.03, 95% CI −0.05, −0.01, <i>p</i> &lt; 0.001), 24,25-(OH)₂D₃ (−0.30, 95% CI −0.44, −0.16, <i>p</i> &lt; 0.001), and 1,24,25-(OH)₃D₃ (−0.03, 95% CI −0.05, −0.01, <i>p</i> = 0.01) after controlling for sex. These results suggest vitamin D metabolites other than 1,25-(OH)₂D₃ may be responsible for the bone loss seen in the Calgary Vitamin D Study. Although plasma 1,25-(OH)₂D₃ did not change with vitamin D dose, it is possible rapid catabolism to 1,24,25-(OH)₃D₃ prevented the detection of a dose-related rise in plasma 1,25-(OH)₂D₃. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 9","pages":"1312-1321"},"PeriodicalIF":6.2,"publicationDate":"2023-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4876","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41081858","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}

{"title":"Cortical and Trabecular Bone Deficit in Middle-Aged Men Living with HIV","authors":"Namki Hong,&nbsp;Jung Ho Kim,&nbsp;Graham Treece,&nbsp;Hyeon Chang Kim,&nbsp;Jun Yong Choi,&nbsp;Yumie Rhee","doi":"10.1002/jbmr.4873","DOIUrl":"https://doi.org/10.1002/jbmr.4873","url":null,"abstract":"<div>\u0000 \u0000 <p>A significant increase in the risk of hip fracture was observed in middle-aged men living with human immunodeficiency virus (MLWH), almost a decade earlier than those without infection. Data regarding cortical and trabecular bone deficit of hip, an important determinant of bone strength, in MLWH are limited. Quantitative CT was performed in consecutive MLWH aged ≥30 years between November 2017 and October 2018 at Severance Hospital, Seoul, Korea. Volumetric bone mineral density (vBMD) and cortical bone mapping parameters of hip (cortical thickness [CTh], cortical bone vBMD [CBMD], cortical mass surface density [CMSD], endocortical trabecular density [ECTD]) were compared to age-matched and body mass index (BMI)-matched controls (1:2) using a community-based healthy adults cohort. Among 83 MLWH and 166 controls (mean age: 47.2 years; BMI: 23.6 kg/m²), MLWH had lower total hip vBMD (280 ± 41 versus 296 ± 41 mg/cm³), CMSD (155 versus 160 mg/cm²), and ECTD (158 versus 175 mg/cm³) than controls that remained robust after adjustment for covariates (adjusted β: total hip vBMD, −18.8; CMSD, −7.3; ECTD, −18.0; <i>p</i> &lt; 0.05 for all). Cortical bone mapping revealed localized deficit of CTh, CBMD, and CMSD in the anterolateral trochanteric region and femoral neck in MLWH compared to controls, with a more extensive ECTD deficit. In MLWH, lower CD4 T-cell count (/100 cells/mm³ decrement) and protease inhibitor (PI)-based regimen (versus non-PI regimen) at the time of antiretroviral treatment initiation were associated with lower total hip vBMD (adjusted β −7.5 for lower CD4 count; −28.3 for PI-based regimen) and CMSD (adjusted β −2.6 for lower CD4 count; −12.7 for PI-based regimen; <i>p</i> &lt; 0.05 for all) after adjustment for covariates including age, BMI, smoking, alcohol use, hepatitis C virus co-infection, tenofovir exposure, and CT scanner types. MLWH had lower hip bone density with cortical and trabecular bone deficit compared to community-dwelling controls. © 2023 American Society for Bone and Mineral Research (ASBMR).</p>\u0000 </div>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 9","pages":"1288-1295"},"PeriodicalIF":6.2,"publicationDate":"2023-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41081714","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":"Interactions Between HR-pQCT Bone Density and D3Cr Muscle Mass (or HR-pQCT Bone Structure and HR-pQCT Muscle Density) in Predicting Fractures: The Osteoporotic Fractures in Men Study","authors":"Ben Kirk,&nbsp;Stephanie L Harrison,&nbsp;Jesse Zanker,&nbsp;Andrew J Burghardt,&nbsp;Eric Orwoll,&nbsp;Gustavo Duque,&nbsp;Peggy M Cawthon","doi":"10.1002/jbmr.4874","DOIUrl":"https://doi.org/10.1002/jbmr.4874","url":null,"abstract":"<p>We examined if an interaction exists between bone and muscle in predicting fractures in older men. Prospective data from the Osteoporotic Fractures in Men study was used to build Cox proportional hazards models. Predictors included HR-pQCT total volumetric BMD (Tt.BMD), trabecular BMD (Tb.BMD), cortical BMD (Ct.BMD) and cortical area (Ct.Ar) at distal radius/tibia, HR-pQCT muscle volume and density (diaphyseal tibia), D₃-creatine dilution (D₃Cr) muscle mass, and grip strength and leg force, analyzed as continuous variables and as quartiles. Incident fractures were self-reported every 4 months via questionnaires and centrally adjudicated by physician review of radiology reports. Potential confounders (demographics, comorbidities, lifestyle factors, etc.) were considered. A total of 1353 men (mean age 84.2 ± 4.0 years, 92.7% white) were followed for 6.03 ± 2.11 years. In the unadjusted (continuous) model, there were no interactions (<i>p</i> &gt; 0.05) between any muscle variable (D₃Cr muscle mass, muscle volume, muscle density, grip strength or leg force) and Tt.BMD at distal radius/tibia for fractures (all: <i>n</i> = 182–302; nonvertebral: <i>n</i> = 149–254; vertebral: <i>n</i> = 27–45). No consistent interactions were observed when interchanging Tt.BMD for Tb.BMD/Ct.BMD or for Ct.Ar (bone structure) at the distal radius/tibia in the unadjusted (continuous) models. Compared with men in quartiles (Q) 2–4 of D₃Cr muscle mass and Q2–4 of distal tibia Tt.BMD, men in Q1 of both had increased risk for all fractures (hazard ratio (HR) = 2.00; 95% confidence interval [CI] 1.24–3.23, <i>p</i> = 0.005) and nonvertebral fractures (HR = 2.10; 95% CI 1.25–3.52, <i>p</i> &lt; 0.001) in the multivariable-adjusted model. Confidence intervals overlapped (<i>p</i> &gt; 0.05) when visually inspecting other quartile groups in the multivariable-adjusted model. In this prospective cohort study of older men, there was no consistent interactions between bone and muscle variables on fracture risk. Larger sample sizes and longer follow-up may be needed to clarify if there is an interaction between bone and muscle on fracture risk in men. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 9","pages":"1245-1257"},"PeriodicalIF":6.2,"publicationDate":"2023-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4874","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41081920","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}

{"title":"Exposure to Multiple Air Pollutants and the Risk of Fractures: A Large Prospective Population-Based Study","authors":"Wenhao Qi,&nbsp;Zhendong Mei,&nbsp;Zhonghan Sun,&nbsp;Chenhao Lin,&nbsp;Jinran Lin,&nbsp;Jialin Li,&nbsp;John S. Ji,&nbsp;Yan Zheng","doi":"10.1002/jbmr.4872","DOIUrl":"10.1002/jbmr.4872","url":null,"abstract":"<div>\u0000 \u0000 <p>Atmospheric chemistry studies suggest air pollution impedes ultraviolet B photons and thus reduces cutaneous vitamin D₃ synthesis. Biological evidence shows that inhaled pollutants disrupt circulating 25-hydroxyvitamin D (25[OH]D) metabolism and ultimately impact bone health. The hypothesis is that higher air pollution concentrations are associated with a higher risk of fractures, mediated by lower circulating 25(OH)D. The study included participants of the UK Biobank who were free of fracture history at enrollment (2006 to 2010) and analyzed their environmental exposure data (2007 to 2010). Air pollution measurements included the annual averages of air particulate matter (PM_2.5, PM_2.5–10, and PM₁₀), nitrogen oxides (NO₂ and NO_x), and a composite air pollution score. Multivariable Cox proportional hazard models were used to assess the associations of the individual pollutants and the score with fracture risks. Mediation analyses were conducted to assess the underlying role of serum 25(OH)D in such associations. Among 446,395 participants with a median of 8-year follow-up, 12,288 incident fractures were documented. Participants living in places with the highest quintile of air pollution score had a 15.3% increased risk of fractures (hazard ratio [95%CI]: 1.15[1.09,1.22]) compared to those in the lowest, and 5.49% of this association was mediated through serum 25(OH)D (<i>p</i>_mediation &lt; 0.05). Pollutant-specific hazard of top-to-bottom quintiles was 16% for PM_2.5, 4% for PM_2.5–10, 5% for PM₁₀, 20% for NO₂, and 17% for NO_x, with a 4% to 6% mediation effect of serum 25(OH)D concentrations. The associations of the air pollution score with fracture risks were weaker among female participants, those who drank less alcohol, and consumed more fresh fruit than their counterparts (<i>p</i>_interaction &lt; 0.05). © 2023 American Society for Bone and Mineral Research (ASBMR).</p>\u0000 </div>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 11","pages":"1549-1559"},"PeriodicalIF":6.2,"publicationDate":"2023-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10175477","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":"Risk of Fractures in Thyroid Cancer Patients With Postoperative Hypoparathyroidism: A Nationwide Cohort Study in Korea","authors":"Seong Hee Ahn,&nbsp;You Jin Lee,&nbsp;Seongbin Hong,&nbsp;Jung Wee Park,&nbsp;Ye Jhin Jeon,&nbsp;Bit-Na Yoo,&nbsp;Yong-Chan Ha,&nbsp;Jean Kyung Bak,&nbsp;Ha Young Kim,&nbsp;Young-Kyun Lee","doi":"10.1002/jbmr.4871","DOIUrl":"https://doi.org/10.1002/jbmr.4871","url":null,"abstract":"<div>\u0000 \u0000 <p>Postoperative hypoparathyroidism (PO-hypoPT) is an uncommon complication of total thyroidectomy in thyroid cancer patients. Although long-term hypoPT causes characteristic changes in bone metabolism, the risk of fractures in hypoPT remains inconclusive. We investigated the risk of fractures in Korean thyroid cancer patients with PO-hypoPT. This was a retrospective cohort study using data from the Korea Central Cancer Registry and Korean National Health Insurance Service. We analyzed 115,821 thyroid cancer patients aged ≥18 years, who underwent total thyroidectomy between 2008 and 2016. The risk of any fractures, including vertebral, hip, humerus, and wrist fractures, according to parathyroid function after total thyroidectomy, was analyzed using the multivariable Cox proportional hazard model. The PO-hypoPT and preserved parathyroid function groups included 8789 (7.6%) and 107,032 (92.4%) patients, respectively. Over a mean follow-up duration of 4.8 years, 159 (1.8%) and 2390 (2.2%) fractures occurred in the PO-hypoPT and preserved parathyroid function groups, respectively. The risk of any fractures was significantly lower in the PO-hypoPT group than in the preserved parathyroid function group (hazard ratio [HR] = 0.83; 95% confidence interval [CI] 0.70–0.98; <i>p</i> = 0.037) after adjusting for confounders. Regarding the fracture site, only the risk of vertebral fractures was significantly lower in the PO-hypoPT group compared with the preserved parathyroid function group (HR = 0.67; 95% CI 0.47–0.96; <i>p</i> = 0.028) after adjusting for confounders. Subgroup analyses showed that bone mineral density measurements and calcium supplementation interacted with the relationship between PO-hypoPT and the risk of any fractures (<i>p</i> for interactions = 0.010 and 0.017, respectively). PO-hypoPT was associated with a lower risk of fractures in thyroid cancer patients, especially at the vertebra. The relatively low bone turnover caused by PO-hypoPT and appropriate management for PO-hypoPT with active vitamin D and calcium may prevent the deterioration of skeletal health in thyroid cancer patients who can easily be exposed to long-term overtreatment with levothyroxine. © 2023 American Society for Bone and Mineral Research (ASBMR).</p>\u0000 </div>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 9","pages":"1268-1277"},"PeriodicalIF":6.2,"publicationDate":"2023-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41082072","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":"Reduced GS Domain Serine/Threonine Requirements of Fibrodysplasia Ossificans Progressiva Mutant Type I BMP Receptor ACVR1 in the Zebrafish","authors":"Robyn S. Allen,&nbsp;William D. Jones,&nbsp;Maya Hale,&nbsp;Bailey N. Warder,&nbsp;Eileen M. Shore,&nbsp;Mary C. Mullins","doi":"10.1002/jbmr.4869","DOIUrl":"https://doi.org/10.1002/jbmr.4869","url":null,"abstract":"<div>\u0000 \u0000 <p>Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic condition characterized by altered skeletal development and extraskeletal bone formation. All cases of FOP are caused by mutations in the type I bone morphogenetic protein (BMP) receptor gene <i>ACVR1</i> that result in overactivation of the BMP signaling pathway. Activation of the wild-type ACVR1 kinase requires assembly of a tetrameric type I and II BMP receptor complex followed by phosphorylation of the ACVR1 GS domain by type II BMP receptors. Previous studies showed that the FOP-mutant ACVR1-R206H required type II BMP receptors and presumptive glycine/serine-rich (GS) domain phosphorylation for overactive signaling. Structural modeling of the ACVR1-R206H mutant kinase domain supports the idea that FOP mutations alter the conformation of the GS domain, but it is unclear how this leads to overactive signaling. Here we show, using a developing zebrafish embryo BMP signaling assay, that the FOP-mutant receptors ACVR1-R206H and -G328R have reduced requirements for GS domain phosphorylatable sites to signal compared to wild-type ACVR1. Further, ligand-independent and ligand-dependent signaling through the FOP-mutant ACVR1 receptors have distinct GS domain phosphorylatable site requirements. ACVR1-G328R showed increased GS domain serine/threonine requirements for ligand-independent signaling compared to ACVR1-R206H, whereas it exhibited reduced serine/threonine requirements for ligand-dependent signaling. Remarkably, while ACVR1-R206H does not require the type I BMP receptor partner, Bmpr1, to signal, a ligand-dependent GS domain mutant of ACVR1-R206H could signal independently of Bmpr1 only when Bmp7 ligand was overexpressed. Of note, unlike human ACVR1-R206H, the zebrafish paralog Acvr1l-R203H does not show increased signaling activity. However, in domain-swapping studies, the human kinase domain, but not the human GS domain, was sufficient to confer overactive signaling to the Acvr1l-R203H receptor. Together these results reflect the importance of GS domain activation and kinase domain functions in regulating ACVR1 signaling and identify mechanisms of reduced regulatory constraints conferred by FOP mutations. © 2023 American Society for Bone and Mineral Research (ASBMR).</p>\u0000 </div>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 9","pages":"1364-1385"},"PeriodicalIF":6.2,"publicationDate":"2023-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41081892","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":"Reductions in Bone Mineral Density Are Apparent Early in Children With Prevalent Osteonecrosis Lesions Following Leukemia Therapy","authors":"Jacqueline M. Halton,&nbsp;Jinui Ma,&nbsp;Paul Babyn,&nbsp;Mary Ann Matzinger,&nbsp;Sue C. Kaste,&nbsp;Maya Scharke,&nbsp;Conrad V. Fernandez,&nbsp;Paivi Miettunen,&nbsp;Josephine Ho,&nbsp;Nathalie Alos,&nbsp;Sharon Abish,&nbsp;Ronald Barr,&nbsp;Elizabeth Cairney,&nbsp;David B. Dix,&nbsp;Ronald M. Grant,&nbsp;Sara Israels,&nbsp;Victor Lewis,&nbsp;Beverly Wilson,&nbsp;Stephanie Atkinson,&nbsp;David Cabral,&nbsp;Elizabeth Cummings,&nbsp;Celia Rodd,&nbsp;Robert Stein,&nbsp;Anne Marie Sbrocchi,&nbsp;Jacob L. Jaremko,&nbsp;Khaldoun Koujok,&nbsp;Nazih Shenouda,&nbsp;Frank Rauch,&nbsp;Kerry Siminoski,&nbsp;Leanne M. Ward,&nbsp;the Canadian STOPP Consortium","doi":"10.1002/jbmr.4870","DOIUrl":"https://doi.org/10.1002/jbmr.4870","url":null,"abstract":"<p>Osteonecrosis (ON) is a serious complication of childhood acute lymphoblastic leukemia. We determined the prevalence of osteonecrotic lesions in our patient population by a one-time multisite magnetic resonance imaging (MRI) more than 1 year following leukemia therapy. MRI findings were evaluated in relationship to clinical factors (including longitudinal changes in bone mineral density [BMD]). Eighty-six children enrolled in the Steroid Associated Osteoporosis in the Pediatric Population (STOPP) study were evaluated for ON at 3.1 ± 1.3 years following therapy. Thirty children had a total of 150 confirmed ON lesions (35%). Lumbar spine (LS) BMD <i>Z</i>-scores (mean ± SD) were low at diagnosis and similar between patients with and without ON (−1.09 ± 1.53 versus −1.27 ± 1.25, <i>p</i> = 0.549). LS BMD <i>Z</i>-scores declined from baseline to 12 months in children with ON (−0.31 ± 1.02) but not in those without (0.13 ± 0.82, <i>p</i> = 0.035); the hip BMD <i>Z</i>-scores from baseline to 24 months declined in both groups, but to a greater extent in those with ON (−1.77 ± 1.22) compared to those without (−1.03 ± 1.07, <i>p</i> = 0.045). At the time of the MRI, mean total hip and total body (TB) BMD <i>Z</i>-scores were lower in children with ON (hip −0.98 ± 0.95 versus −0.28 ± 1.06, <i>p</i> = 0.010; TB −1.36 ± 1.10 versus −0.48 ± 1.50, <i>p</i> = 0.018). Pain occurred in 11/30 (37%) with ON versus 20/56 (36%) without, <i>p</i> = 0.841. In multivariable models, older age at diagnosis (odds ratio [OR] 1.57; 95% confidence interval [CI], 1.15–2.13; <i>p</i> = 0.004), and hip BMD <i>Z</i>-score at MRI (OR 2.23; 95% CI, 1.02–4.87; <i>p</i> = 0.046) were independently associated with ON. Overall, one-third of children demonstrated ON after leukemia therapy. Those with ON had greater reductions in spine and hip BMD <i>Z</i>-scores in the first 1 and 2 years of therapy, respectively. Older age and lower hip BMD <i>Z</i>-scores at MRI were significantly associated with prevalent, off-therapy ON. These data assist in identifying children at risk of ON. © 2023 The Authors. <i>Journal of Bone and Mineral Research</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 8","pages":"1104-1115"},"PeriodicalIF":6.2,"publicationDate":"2023-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4870","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5881213","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}

{"title":"Issue Information - Declaration of Helsinki","authors":"","doi":"10.1002/jbmr.4592","DOIUrl":"https://doi.org/10.1002/jbmr.4592","url":null,"abstract":"1. The World Medical Association has developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects. Medical research involving human subjects includes research on identifiable human material or identifiable data. 2. It is the duty of the physician to promote and safeguard the health of the people. The physician’s knowledge and conscience are dedicated to the fulfillment of this duty. 3. The Declaration of Geneva of the World Medical Association binds the physician with the words, “The health of my patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act only in the patient’s interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient.” 4. Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects. 5. In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society. 6. The primary purpose of medical research involving human subjects is to improve prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology and pathogenesis of disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research for their effectiveness, efficiency, accessibility and quality. 7. In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic procedures involve risks and burdens. 8. Medical research is subject to ethical standards that promote respect for all human beings and protect their health and rights. Some research populations are vulnerable and need special protection. The particular needs of the economically and medically disadvantaged must be recognized. Special attention is also required for those who cannot give or refuse consent for themselves, for those who may be subject to giving consent under duress, for those who will not benefit personally from the research and for those for whom the research is combined with care. 9. Research investigators should be aware of the ethical, legal and regulatory requirements for research on human subjects in their own countries as well as applicable international requirements. No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration.","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":"38 6","pages":"BMi-BMii"},"PeriodicalIF":6.2,"publicationDate":"2023-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4592","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5653714","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}