ORCID Profile
0000-0003-2950-1944
Current Organisations
Garvan Institute of Medical Research
,
Medical College of Wisconsin
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2020
DOI: 10.1097/BOT.0000000000001743
Abstract: Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fractureamong people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, andsubcutaneous pharmacotherapies are efficaciousandcanreduce risk of future fracture.Patientsneededucation,however, about thebenefitsandrisks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive butmay be beneficial for selected patients at high risk.Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the earlypost-fractureperiod,prompt treatment is recommended.Adequate dietary or supplemental vitaminDand calciumintake shouldbe assured. In iduals beingtreatedfor osteoporosis shouldbe reevaluated for fracture risk routinely, includingvia patienteducationabout osteoporosisandfracturesandmonitoringfor adverse treatment effects.Patients shouldbestronglyencouraged to avoid tobacco, consume alcohol inmoderation atmost, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for in iduals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease).©2019American Society for Bone andMineral Research.
Publisher: Wiley
Date: 08-12-2021
DOI: 10.1002/JBMR.4483
Abstract: Muscle strength and physical performance are associated with fracture risk in men. However, it is not known whether these measurements enhance fracture prediction beyond Garvan and FRAX tools. A total of 5665 community‐dwelling men, aged ≥65 years, from the Osteoporotic Fractures in Men (MrOS) Study, who had data on muscle strength (grip strength) and physical performance (gait speed and chair stand tests), were followed from 2000 to 2019 for any fracture, major osteoporotic fracture (MOF), initial hip, and any hip fracture. The contributions to different fracture outcomes were assessed using Cox's proportional hazard models. Tool‐specific analysis approaches and outcome definitions were used. The added predictive values of muscle strength and physical performance beyond Garvan and FRAX were assessed using categorical net reclassification improvement (NRI) and relative importance analyses. During a median follow‐up of 13 (interquartile range 7–17) years, there were 1014 fractures, 536 MOFs, 215 initial hip, and 274 any hip fractures. Grip strength and chair stand improved prediction of any fracture (NRI for grip strength 3.9% and for chair stand 3.2%) and MOF (5.2% and 6.1%). Gait speed improved prediction of initial hip (5.7%) and any hip (7.0%) fracture. Combining grip strength and the relevant performance test further improved the models (5.7%, 8.9%, 9.4%, and 7.0% for any, MOF, initial, and any hip fractures, respectively). The improvements were predominantly driven by reclassification of those with fracture to higher risk categories. Apart from age and femoral neck bone mineral density, muscle strength and performance were ranked equal to or better than the other risk factors included in fracture models, including prior fractures, falls, smoking, alcohol, and glucocorticoid use. Muscle strength and performance measurements improved fracture risk prediction in men beyond Garvan and FRAX. They were as or more important than other established risk factors. These measures should be considered for inclusion in fracture risk assessment tools. © 2021 American Society for Bone and Mineral Research (ASBMR).
Publisher: Springer Science and Business Media LLC
Date: 07-10-2005
DOI: 10.1007/S00223-004-0073-5
Abstract: Dual energy X ray absorptiometry (DXA) has become a popular analytical technique in mice and other small animals. Comparative study of bone properties at different anatomical sites is an active area of study in model organisms. Such investigations require that site-specific data be generated and interpreted. There are no published data addressing the degree to which contralateral mouse bones resemble each other in the absence of an experimental intervention, nor are there data addressing the correlation of bone densitometry measurements between anatomically distant sites. To address these gaps in our knowledge, we used DXA to compare excised mouse femora and humeri. At the population level, left bones were slightly but significantly denser than right bones, with an overall adjusted bone mineral density (BMD) difference of 0.7 +/- 0.3 and 0.5 +/- 0.2 mg/cm2 at the femur and humerus, respectively. At the level of bone pairs from a single animal, absolute adjusted BMD disparities between the right and left sides were 2.3 +/- 1.9 mg/cm2 at the femur and 1.7 +/- 1.4 mg/cm2 at the humerus. Correlation coefficients between left and right sides were 0.78 for adjusted BMD at both sites. The correlation coefficient between side-averaged femoral and humeral BMD was 0.81, but ranged between 0.70 and 0.75 when limited to ipsilateral or contralateral femur-humerus pairs. Our findings suggest the desirability of randomizing limbs for treatment in studies using contralateral limb controls. These observations may represent the densitometric manifestation of behavioral and neuroanatomical lateralization in laboratory mice.
Publisher: American College of Physicians
Date: 05-1998
DOI: 10.7326/0003-4819-128-9-199805010-00029
Abstract: Neuro-inflammation induced by microglia is crucial in the pathogenesis of sepsis-associated encephalopathy (SAE). The endogenous lipid mediator, Resolvin D1 (RvD1), which is synthesized from docosahexaenoic acid, has been extensively reported to attenuate inflammation in various diseases by its anti-inflammation and pro-resolving functions. However, the effect of RvD1 on SAE remains unclear. In this study, we aimed to ex the function and mechanism of RvD1 on SAE mice. In our study, the SAE mice model was established by the method of cecal ligation and perforation (CLP). C57BL/6J mice were randomly ided into three groups: the Sham group, the CLP group and the CLP+RvD1 group. Cognitive impairment of the mice was assessed by Morris water maze. Iba1 immunohistochemistry was conducted to observe the activation of microglia in hippoc us of the mice from different groups. The production of cytokines, including TNF-α, IL-6 and IL-1β, and their mRNA levels were evaluated by ELISA and Q-PCR. The expression of the molecules from inflammatory signaling pathways was assessed by Western blot. xaRvD1 treatment significantly improved the learning and cognitive ability of SAE mice. The activation of microglia and the production of inflammatory cytokines in hippoc al tissues were inhibited in CLP+RvD1 group. We also found that the inflammation of microglia was attenuated by RvD1 treatment both RvD1 could improve the learning and cognitive ability of SAE mice by inhibiting the systemic and local inflammation. It could attenuate the inflammation in microglia by inhibiting the activation of inflammatory signaling pathways and then decreasing the production of cytokines. These findings are helpful to better understand the pathophysiology of SAE, which also provide a novel therapeutic method in clinic.
Publisher: American College of Physicians
Date: 20-03-2001
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.4158/EP.12.4.406
Publisher: Elsevier BV
Date: 07-2013
Publisher: Wiley
Date: 04-2009
DOI: 10.1002/JOR.20885
Publisher: Wiley
Date: 28-09-2005
DOI: 10.1111/J.1399-0004.2005.00520.X
Abstract: An analysis of PAX1 in the development of vertebral malformations. Due to the sporadic occurrence of congenital vertebral malformations, traditional linkage approaches to identify genes associated with human vertebral development are not possible. We therefore identified PAX1 as a candidate gene in vertebral malformations and congenital scoliosis due to its mutation in the undulated mouse. We performed DNA sequence analysis of the PAX1 gene in a series of 48 patients with congenital vertebral malformations, collectively spanning the entire vertebral column length. DNA sequence coding variants were identified in the heterozygous state in exon 4 in two male patients with thoracic vertebral malformations. One patient had T9 hypoplasia, T12 hemivertebrae and absent T10 pedicle, incomplete fusion of T7 posterior elements, ventricular septal defect, and polydactyly. This patient had a CCC (Pro)-->CTC (Leu) change at amino acid 410. This variant was not observed in 180 chromosomes tested in the National Institute of Environmental Health Sciences (NIEHS) single nucleotide polymorphism (SNP) database and occurred at a frequency of 0.3% in a ersity panel of 1066 human s les. The second patient had a T11 wedge vertebra and a missense mutation at amino acid 413 corresponding to CCA (Pro)-->CTA (Leu). This particular variant has been reported to occur in one of 164 chromosomes in the NIEHS SNP database and was found to occur with a similar frequency of 0.8% in a ersity panel of 1066 human s les. Although each patient's mother was clinically asymptomatic and heterozygous for the respective variant allele, the possibility that these sequence variants have clinical significance is not excluded.
Publisher: Springer Science and Business Media LLC
Date: 08-2017
DOI: 10.1038/548153A
Publisher: Elsevier BV
Date: 2010
Publisher: Informa UK Limited
Date: 2003
DOI: 10.1080/03008200390223918
Abstract: Whole bone strength can be partitioned into structural and material components. In three-point bending tests of 6-month-old female humeri from the HcB/Dem recombinant congenic series, strains HcB/8 and HcB/23 differed markedly in calculated failure stress but not ash percentage. Fourier transform infrared spectroscopic imaging was used to determine whether differences in the ratio of pyridinoline (pyr nonreducible) to dehydrodihydroxynorleucine (de-DHLNL reducible) collagen cross-links (XLR), mineral crystallinity, or spatial ordering could account for the strains' differing biomechanical performance. HcB/8 had significantly higher XLR and significantly higher crystallinity than HcB/23. XLR and crystallinity were highly and similarly correlated in both strains. There were no significant differences between the strains' one-dimensional spatial correlation functions, suggesting no difference in short-range order between them. The strong correlation between XLR and crystallinity reflects the interdependence of the protein and mineral elements of bone. The data illustrate the importance of material properties in addition to mineral quantity to bone tissue strength.
Publisher: American College of Physicians
Date: 17-08-1999
Publisher: Elsevier BV
Date: 04-2015
Publisher: BMJ
Date: 10-04-2014
DOI: 10.1136/JMEDGENET-2013-102067
Abstract: Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.31 LBX1 gene (OMIM #604255) was originally identified by a GWAS of Japanese subjects and replicated in additional Asian populations. To extend this result, and to create larger AIS cohorts for the purpose of large-scale meta-analyses in multiple ethnicities, we formed a collaborative group called the International Consortium for Scoliosis Genetics (ICSG). Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts. We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven cohorts containing both genders yielded P=1.22×10-43 for rs11190870, and P=2.94×10-48 for females in all nine cohorts. Comparing the regional haplotype structures for three populations, we refined the boundaries of association to a ∼25 kb block encompassing the LBX1 gene. The LBX1 protein, a homeobox transcription factor that is orthologous to the Drosophila ladybird late gene, is involved in proper migration of muscle precursor cells, specification of cardiac neural crest cells, and neuronal determination in developing neural tubes. Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.JOCD.2011.05.015
Abstract: Osteoporosis is a serious worldwide epidemic. Increased risk of fractures is the hallmark of the disease and is associated with increased morbidity, mortality and economic burden. FRAX® is a web-based tool developed by the Sheffield WHO Collaborating Center team, that integrates clinical risk factors, femoral neck BMD, country specific mortality and fracture data and calculates the 10 year fracture probability in order to help health care professionals identify patients who need treatment. However, only 31 countries have a FRAX® calculator at the time paper was accepted for publication. In the absence of a FRAX® model for a particular country, it has been suggested to use a surrogate country for which the epidemiology of osteoporosis most closely approximates the index country. More specific recommendations for clinicians in these countries are not available. In North America, concerns have also been raised regarding the assumptions used to construct the US ethnic specific FRAX® calculators with respect to the correction factors applied to derive fracture probabilities in Blacks, Asians and Hispanics in comparison to Whites. In addition, questions were raised about calculating fracture risk in other ethnic groups e.g., Native Americans and First Canadians. In order to provide additional guidance to clinicians, a FRAX® International Task Force was formed to address specific questions raised by physicians in countries without FRAX® calculators and seeking to integrate FRAX® into their clinical practice. The main questions that the task force tried to answer were the following: The Task Force members conducted appropriate literature reviews and developed preliminary statements that were discussed and graded by a panel of experts at the ISCD-IOF joint conference. The statements approved by the panel of experts are discussed in the current paper.
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.JOCD.2011.05.014
Abstract: Given the significant impact the use of glucocorticoids can have on fracture risk independent of bone density, their use has been incorporated as one of the clinical risk factors for calculating the 10-year fracture risk in the World Health Organization's Fracture Risk Assessment Tool (FRAX(®)). Like the other clinical risk factors, the use of glucocorticoids is included as a dichotomous variable with use of steroids defined as past or present exposure of 3 months or more of use of a daily dose of 5 mg or more of prednisolone or equivalent. The purpose of this report is to give clinicians guidance on adjustments which should be made to the 10-year risk based on the dose, duration of use and mode of delivery of glucocorticoids preparations. A subcommittee of the International Society for Clinical Densitometry and International Osteoporosis Foundation joint Position Development Conference presented its findings to an expert panel and the following recommendations were selected. 1) There is a dose relationship between glucocorticoid use of greater than 3 months and fracture risk. The average dose exposure captured within FRAX(®) is likely to be a prednisone dose of 2.5-7.5 mg/day or its equivalent. Fracture probability is under-estimated when prednisone dose is greater than 7.5 mg/day and is over-estimated when the prednisone dose is less than 2.5 mg/day. 2) Frequent intermittent use of higher doses of glucocorticoids increases fracture risk. Because of the variability in dose and dosing schedule, quantification of this risk is not possible. 3) High dose inhaled glucocorticoids may be a risk factor for fracture. FRAX(®) may underestimate fracture probability in users of high dose inhaled glucocorticoids. 4) Appropriate glucocorticoid replacement in in iduals with adrenal insufficiency has not been found to increase fracture risk. In such patients, use of glucocorticoids should not be included in FRAX(®) calculations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2000
Publisher: Springer Science and Business Media LLC
Date: 13-05-2010
DOI: 10.1007/S00198-010-1269-3
Abstract: Low trauma fractures are the cardinal manifestation of osteoporosis. Their occurrence supersedes bone mineral density in deciding whether specific therapy is warranted. We therefore disagree with the notion that a densitometric threshold for treatment should be applied to patients over age 50 who suffer low trauma distal radius fracture.
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.JOCD.2011.05.013
Abstract: The World Health Organization fracture risk assessment tool, FRAX(®), is an advance in clinical care that can assist in clinical decision-making. However, with increasing clinical utilization, numerous questions have arisen regarding how to best estimate fracture risk in an in idual patient. Recognizing the need to assist clinicians in optimal use of FRAX(®), the International Osteoporosis Foundation (IOF) in conjunction with the International Society for Clinical Densitometry (ISCD) assembled an international panel of experts that ultimately developed joint Official Positions of the ISCD and IOF advising clinicians regarding FRAX(®) usage. As part of the process, the charge of the FRAX(®) Clinical Task Force was to review and synthesize data surrounding a number of recognized clinical risk factors including rheumatoid arthritis, smoking, alcohol, prior fracture, falls, bone turnover markers and glucocorticoid use. This synthesis was presented to the expert panel and constitutes the data on which the subsequent Official Positions are predicated. A summary of the Clinical Task Force composition and charge is presented here.
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.JOCD.2011.05.012
Abstract: Rheumatoid arthritis is the only secondary cause of osteoporosis that is considered independent of bone density in the FRAX(®) algorithm. Although input for rheumatoid arthritis in FRAX(®) is a dichotomous variable, intuitively, one would expect that more severe or active disease would be associated with a greater risk for fracture. We reviewed the literature to determine if specific disease parameters or medication use could be used to better characterize fracture risk in in iduals with rheumatoid arthritis. Although many studies document a correlation between various parameters of disease activity or severity and decreased bone density, fewer have associated these variables with fracture risk. We reviewed these studies in detail and concluded that disability measures such as HAQ (Health Assessment Questionnaire) and functional class do correlate with clinical fractures but not morphometric vertebral fractures. One large study found a strong correlation with duration of disease and fracture risk but additional studies are needed to confirm this. There was little evidence to correlate other measures of disease such as DAS (disease activity score), VAS (visual analogue scale), acute phase reactants, use of non-glucocorticoid medications and increased fracture risk. We concluded that FRAX(®) calculations may underestimate fracture probability in patients with impaired functional status from rheumatoid arthritis but that this could not be quantified at this time. At this time, other disease measures cannot be used for fracture prediction. However only a few, mostly small studies addressed other disease parameters and further research is needed. Additional questions for future research are suggested.
Publisher: Wiley
Date: 03-1999
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.JOCD.2011.05.018
Abstract: FRAX(®) is a fracture risk assessment algorithm developed by the World Health Organization in cooperation with other medical organizations and societies. Using easily available clinical information and femoral neck bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA), when available, FRAX(®) is used to predict the 10-year probability of hip fracture and major osteoporotic fracture. These values may be included in country specific guidelines to aid clinicians in determining when fracture risk is sufficiently high that the patient is likely to benefit from pharmacological therapy to reduce that risk. Since the introduction of FRAX(®) into clinical practice, many practical clinical questions have arisen regarding its use. To address such questions, the International Society for Clinical Densitometry (ISCD) and International Osteoporosis Foundations (IOF) assigned task forces to review the best available medical evidence and make recommendations for optimal use of FRAX(®) in clinical practice. Questions were identified and ided into three general categories. A task force was assigned to investigating the medical evidence in each category and developing clinically useful recommendations. The BMD Task Force addressed issues that included the potential use of skeletal sites other than the femoral neck, the use of technologies other than DXA, and the deletion or addition of clinical data for FRAX(®) input. The evidence and recommendations were presented to a panel of experts at the ISCD-IOF FRAX(®) Position Development Conference, resulting in the development of ISCD-IOF Official Positions addressing FRAX(®)-related issues.
Publisher: Springer Science and Business Media LLC
Date: 03-1991
DOI: 10.1007/BF00656486
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.JOCD.2011.05.016
Abstract: Osteoporosis is a serious worldwide epidemic. FRAX® is a web-based tool developed by the Sheffield WHO Collaborating Center team, that integrates clinical risk factors and femoral neck BMD and calculates the 10 year fracture probability in order to help health care professionals identify patients who need treatment. However, only 31 countries have a FRAX® calculator. In the absence of a FRAX® model for a particular country, it has been suggested to use a surrogate country for which the epidemiology of osteoporosis most closely approximates the index country. More specific recommendations for clinicians in these countries are not available. In North America, concerns have also been raised regarding the assumptions used to construct the US ethnic specific FRAX® calculators with respect to the correction factors applied to derive fracture probabilities in Blacks, Asians and Hispanics in comparison to Whites. In addition, questions were raised about calculating fracture risk in other ethnic groups e.g., Native Americans and First Canadians. The International Society for Clinical Densitometry (ISCD) in conjunction with the International Osteoporosis Foundation (IOF) assembled an international panel of experts that ultimately developed joint Official Positions of the ISCD and IOF advising clinicians regarding FRAX® usage. As part of the process, the charge of the FRAX® International Task Force was to review and synthesize data regarding geographic and race/ethnic variability in hip fractures, non-hip osteoporotic fractures, and make recommendations about the use of FRAX® in ethnic groups and countries without a FRAX® calculator. This synthesis was presented to the expert panel and constitutes the data on which the subsequent Official Positions are predicated. A summary of the International Task Force composition and charge is presented here.
Publisher: Defense Technical Information Center
Date: 04-2001
DOI: 10.21236/ADA400522
Publisher: Informa UK Limited
Date: 10-2008
DOI: 10.1517/17530059.2.10.1107
Abstract: Vertebral malformations contribute substantially to the pathophysiology of kyphosis and scoliosis, common health problems associated with back and neck pain, disability, cosmetic disfigurement and functional distress. To provide an overview of the current understanding of vertebral malformations, at both the clinical level and the molecular level, and factors that contribute to their occurrence. The literature related to the following was reviewed: recent advances in the understanding of the molecular embryology underlying vertebral development and relevance to elucidation of etiologies of several known human vertebral malformation syndromes outcomes of molecular studies elucidating genetic contributions to congenital and sporadic vertebral malformations and complex interrelationships between genetic and environmental factors that contribute to the pathogenesis of isolated syndromic and non-syndromic congenital vertebral malformations. Expert opinions extend to discussion of the importance of establishing improved classification systems for vertebral malformation, future directions in molecular and genetic research approaches to vertebral malformation and translational value of research efforts to clinical management and genetic counseling of affected in iduals and their families.
Publisher: Wiley
Date: 04-03-2009
DOI: 10.1096/FJ.08-118679
Abstract: Despite steady progress in identifying quantitative trait loci (QTLs) for bone phenotypes, relatively little progress has been made in moving from QTLs to identifying the relevant gene. We exploited the genetic structure of recombinant congenic mouse strains by performing a reciprocal intercross of the strains HcB-8 and HcB-23, phenotyped for body size, femoral biomechanical performance, and femoral diaphyseal geometry and mapped with R/qtl and QTL Cartographer. Significant QTLs are present on chromosomes 1, 2, 3, 4, 6, and 10. We found significant sex x QTL and cross-direction x QTL interactions. The chromosome 4 QTL affects multiple femoral anatomic features and biomechanical properties. The known segregating segment of chromosome 4 contains only 18 genes, among which Ece1, encoding endothelin-converting enzyme 1, stands out as a candidate. Endothelin signaling has been shown to promote the growth of osteoblastic metastases and to potentiate signaling via the Wnt pathway. The colocalizing chromosome 4 QTL Bmd7 (for bone mineral density 7) increases responsiveness to mechanical loading. By exploiting the short informative segment of chromosome 4 and the known biology, we propose that Ece1 is the gene responsible for Bmd7 and that it acts by increasing responsiveness to mechanical loading through modulation of Wnt signaling.
Publisher: Elsevier BV
Date: 03-2011
Publisher: Springer Science and Business Media LLC
Date: 02-2021
DOI: 10.1007/S11914-021-00659-X
Abstract: To critically assess recent evidence concerning osteoporosis fracture risk. Robust instruments exist for predicting factures incorporating well-documented risk factors especially prior fracture whose magnitude varies with site, occurrence time, and age. Stratifying time-since-prior fracture has resulted in the concept of imminent fracture risk and increased focus on secondary fracture prevention. Secondary fracture prevention recommendations include fracture liaison service, pharmacologic and non-pharmacologic multidisciplinary intervention, and communicating that fractures in older adults are the predictable consequence of underlying osteoporosis rather than unfortunate accidents. Quality improvement in osteoporosis care includes diagnosing osteoporosis on the basis of clinical fractures rather than exclusively relying on bone density testing applying diagnostic rather than screening approaches to patients with prior fractures regularly updating fall and fracture histories performing a physical exam focused on spinal curvature, posture, and musculoskeletal function reviewing images to identify prevalent fractures that may have been missed and general use of fracture risk algorithms at all stages of osteoporosis management. Communicating effectively with patients about osteoporosis and fractures, their consequences, and pharmacological and non-pharmacological management is the cornerstone of high-value care.
Publisher: Wiley
Date: 26-09-2023
DOI: 10.1002/JBMR.4907
Abstract: Goeffrey Rose postulated that a population‐based measure bringing a small benefit to each in idual can yield large benefits to the community. We aimed to test this axiom by quantifying the relationship between change in bone mineral density (BMD) and hip fracture incidence between two prospective cohorts separated by ~10 years. In this prospective population‐based Dubbo Osteoporosis Epidemiology Study (DOES), the participants aged 60+ were recruited in two waves: the initial cohort (1311 women, 842 men) in 1989‐1992, and the second cohort (974 women, 544 men) in 1999‐2001. The incident hip fracture was radiologically ascertained. Femoral neck BMD was measured biannually. Multivariable‐adjusted Cox's proportional hazards models were adjusted for the predefined covariates such as age, BMI, lifestyle factors, falls, and prior fracture. Compared with the initial cohort, the second cohort had a higher femoral neck BMD by ~ 0.04 g/cm 2 in women and 0.03 g/cm 2 in men. However, the prevalence of osteoporosis in the second cohort was halved (prevalence ratio 0.51, 95% CI 0.36‐0.73 in women 0.45, 0.24‐0.84 in men), and its hip fracture incidence was significantly reduced (hazard ratio 0.54, 95% CI, 0.38‐0.78 in women 0.39, 0.19‐0.80 in men). Sensitivity analyses indicated that the “effect” was unlikely due to unmeasured confounders. These findings suggest that a population‐wide strategy aiming at enhancing BMD across the entire population could lead to a substantial decrease in the incidence of hip fractures. This article is protected by copyright. All rights reserved.
Publisher: The Endocrine Society
Date: 11-2015
DOI: 10.1210/JC.2015-2729
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.JOCD.2011.05.011
Abstract: The worldwide prevalence of smoking has been estimated at about 50% in men, and 10% in women, with larger variations among different populations studied. Smoking has been shown to affect many organ systems resulting in severe morbidity and increased mortality. In addition, smoking has been identified as a predictor of ten-year fracture risk in men and women, largely independent of an in idual's bone mineral density. This finding has eventually lead to incorporation of this risk factor into FRAX®, an algorithm that has been developed to calculate an in idual's ten-year fracture risk. However, only little, or conflicting data is available on a possible association between smoking dose, duration, length of time after cessation, type of tobacco and fracture risk, limiting this risk factor's applicability in the context of FRAX®.
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.JOCD.2011.05.010
Abstract: Risk factors for fracture can be purely skeletal, e.g., bone mass, microarchitecture or geometry, or a combination of bone and falls risk related factors such as age and functional status. The remit of this Task Force was to review the evidence and consider if falls should be incorporated into the FRAX® model or, alternatively, to provide guidance to assist clinicians in clinical decision-making for patients with a falls history. It is clear that falls are a risk factor for fracture. Fracture probability may be underestimated by FRAX® in in iduals with a history of frequent falls. The substantial evidence that various interventions are effective in reducing falls risk was reviewed. Targeting falls risk reduction strategies towards frail older people at high risk for indoor falls is appropriate. This Task Force believes that further fracture reduction requires measures to reduce falls risk in addition to bone directed therapy. Clinicians should recognize that patients with frequent falls are at higher fracture risk than currently estimated by FRAX® and include this in decision-making. However, quantitative adjustment of the FRAX® estimated risk based on falls history is not currently possible. In the long term, incorporation of falls as a risk factor in the FRAX® model would be ideal.
Publisher: Elsevier BV
Date: 09-2004
DOI: 10.1385/JCD:7:3:326
Abstract: Many densitometric studies in mice assess bone mineral density (BMD) at specified regions of interest, often using ex vivo specimens. In the present study, we sought to determine the precision and accuracy of ex vivo densitometry of mouse bones, comparing two software versions and two data acquisition techniques. The newer software allows manual adjustment of the threshold value for bone, improving the ability to analyze bone edges correctly. Root mean square standard deviations were 2-3 mg/cm2, with coefficients of variation ranging between 3% and 5% for femora and humeri and between 6% and 7% for radii. The regression coefficients for bone mineral content as a function of ash mass were near 1 for femora and humeri, but considerably lower for radii. Coefficients of determination were inversely related to bone size, with R2 values exceeding 0.9 at the femur, 0.8 at the humerus, and ranging between 0.3 and 0.6 at the radius. We found that our instrument has a position artifact, with BMD and bone mineral content dependent on the specimen's coordinates in the scanned field. Our findings establish the limitations of ex vivo densitometry with the PIXImus and support our recommendation that investigators seek position artifacts in their instruments.
Publisher: Elsevier BV
Date: 05-2009
Publisher: Elsevier BV
Date: 03-2017
Publisher: SAGE Publications
Date: 06-1999
DOI: 10.1177/096120339900800505
Abstract: Genetic predisposition contributes to scoliosis in humans. Two syndromes of primary scoliosis occur — congenital scoliosis, which presents at birth, often associated with other abnormalities, and idiopathic scoliosis which becomes apparent between infancy and adolescence. Little is known regarding the genetic transmission of scoliosis risk. Data gleaned from mouse mutations provide a valuable supplement to human family studies. More than 50 mouse mutations include scoliosis, kyphosis, or tail kinks as a phenotype the locations of the human homologues for 28 of these can be predicted on the basis of synteny conservation. Some mouse mutations are either more penetrant or more fully expressed in one sex. The mouse data provide a basis both for optimism and for caution in understanding human scoliosis. Mouse models provide insight into mechanisms underlying spinal curvature and help direct searches for genes important in human disease. Four types of defects account for most mouse scoliosis: defects of cell–cell communication, intracellular signal transduction, matrix protein synthesis, and matrix protein metabolism. Mouse data suggest that at least two types of heterogeneity complicate genetic analysis: locus heterogeneity, in which lesions of distinct genes lead to a similar phenotype, and allelic heterogeneity, in which the phenotypes arising from alleles of a single gene differ. By focusing initial studies on multiplex families with apparent simple Mendelian inheritance the effect of heterogeneity is minimized.
Publisher: American College of Physicians
Date: 12-1997
Publisher: Springer Science and Business Media LLC
Date: 18-02-2014
DOI: 10.1007/S12018-014-9159-4
Abstract: Bone and muscle mass are highly correlated. In part, this is a consequence of both tissues sharing common genetic determinants. In addition, both tissues are responsive to their mechanical environments. New genetic tools in mice will allow genes of interest to be inactivated in experimentally defined contexts, thus allowing investigators to distinguish direct effects on each tissue from physiological responses to a primary phenotype in the other.
Publisher: Springer Science and Business Media LLC
Date: 20-08-2022
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.JOCD.2011.05.008
Abstract: The best indirect evidence that increased bone turnover contributes to fracture risk is the fact that most of the proven therapies for osteoporosis are inhibitors of bone turnover. The evidence base that we can use biochemical markers of bone turnover in the assessment of fracture risk is somewhat less convincing. This relates to natural variability in the markers, problems with the assays, disparity in the statistical analyses of relevant studies and the independence of their contribution to fracture risk. More research is clearly required to address these deficiencies before biochemical markers might contribute a useful independent risk factor for inclusion in FRAX(®).
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.JOCD.2011.05.007
Abstract: The International Society for Clinical Densitometry (ISCD) and the International Osteoporosis Foundation (IOF) convened the FRAX(®) Position Development Conference (PDC) in Bucharest, Romania, on November 14, 2010, following a two-day joint meeting of the ISCD and IOF on the "Interpretation and Use of FRAX(®) in Clinical Practice." These three days of critical discussion and debate, led by a panel of international experts from the ISCD, IOF and dedicated task forces, have clarified a number of important issues pertaining to the interpretation and implementation of FRAX(®) in clinical practice. The Official Positions resulting from the PDC are intended to enhance the quality and clinical utility of fracture risk assessment worldwide. Since the field of skeletal assessment is still evolving rapidly, some clinically important issues addressed at the PDCs are not associated with robust medical evidence. Accordingly, some Official Positions are based largely on expert opinion. Despite limitations inherent in such a process, the ISCD and IOF believe it is important to provide clinicians and technologists with the best distillation of current knowledge in the discipline of bone densitometry and provide an important focus for the scientific community to consider. This report describes the methodology and results of the ISCD-IOF PDC dedicated to FRAX(®).
Publisher: Elsevier BV
Date: 07-2011
Publisher: Elsevier BV
Date: 04-2016
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1016/J.JOCD.2007.08.003
Abstract: Coexisting conditions such as osteoarthritis and compression fracture may spuriously elevate the dual-energy X-ray absorptiometry (DXA)-measured lumbar spine bone mass. To improve the diagnostic utility of lumbar spine DXA to diagnose osteoporosis, the International Society for Clinical Densitometry (ISCD) suggests excluding vertebrae affected by focal structural anomalies or unusual T-score discrepancies. However, we previously demonstrated only moderate agreement between physicians regarding vertebral body exclusion. We hypothesized that an atlas containing ex les of vertebrae to exclude would improve interobserver agreement. Subsequently, we developed an interactive web-based atlas of lumbar spine DXA images with options to exclude vertebrae and compare one's answers to those derived by group consensus. Before and after review of the atlas, 5 ISCD-certified physicians applied the exclusion criteria to 90 DXA scans, recording the indications for vertebral exclusion on a standardized worksheet. After development and review of the atlas, interobserver agreement regarding vertebral body exclusion improved significantly (p<0.0001). We plotted the deviation of each physician's reported T-score vs the mean T-score for each of 90 scans, and demonstrated that the scatter from the mean is decreased after atlas review. Furthermore, correlations in T-score improved in 7 of 10 physician pairs after atlas review. We conclude that an interactive atlas promotes uniform lumbar spine DXA interpretation.
Publisher: Springer Science and Business Media LLC
Date: 1993
DOI: 10.1007/BF00360830
Publisher: SAGE Publications
Date: 11-2006
DOI: 10.1177/154405910608501111
Abstract: Mice harboring the Col1a2 oim mutation ( oim) express dentinogenesis imperfecta. To determine the effect of Col1a2 genotype on tissue mechanical properties, we compared Young’s modulus and hardness of dentin in the 3 Col1a2 genotypes. Upper incisors were tested by nanoindentation. Genotype had a significant effect on Young’s modulus, but there was not a simple mutant allele dosage relationship. The effect of genotype on hardness did not reach significance. Hardness and Young’s modulus were greater near the dento-enamel junction than near the pulp chamber. Greater hardness and Young’s modulus values near the dento-enamel junction reflected continued mineralization of the dentin following its initial synthesis. Analysis showed the mechanical data to be consistent with Fourier transform infrared and backscattered electron microscopy studies that revealed increased mineralization in oim bone. Analysis of the data suggests that clinical fragility of teeth in oim mice is not due to deficiencies of hardness or Young’s modulus, but may be due to defects in post-yield behavior or resistance to fatigue damage.
Publisher: Springer Science and Business Media LLC
Date: 12-2007
Abstract: Prior investigations have not identified a major locus for vertebral malformations, providing evidence that there is genetic heterogeneity for this condition. WNT3A has recently been identified as a negative regulator of Notch signaling and somitogenesis. Mice with mutations in Wnt3a develop caudal vertebral malformations. Because congenital vertebral malformations represent a sporadic occurrence, linkage approaches to identify genes associated with human vertebral development are not feasible. We hypothesized that WNT3A mutations might account for a subset of congenital vertebral malformations. A pilot study was performed using a cohort of patients with congenital vertebral malformations spanning the entire vertebral column was characterized. DNA sequence analysis of the WNT3A gene in these 50 patients with congenital vertebral malformations was performed. A female patient of African ancestry with congenital scoliosis and a T12-L1 hemivertebrae was found to be heterozygous for a missense variant resulting in the substitution of alanine by threonine at codon 134 in highly conserved exon 3 of the WNT3A gene. This variant was found at a very low prevalence (0.35%) in a control population of 443 anonymized subjects and 1.1% in an African population. These data suggest that WNT3A does not contribute towards the development of congenital vertebral malformations. Factors such as phenotypic and genetic heterogeneity may underlie our inability to detect mutations in WNT3A in our patient s le.
Publisher: Wiley
Date: 06-07-2022
DOI: 10.1002/JBMR.4619
Abstract: Muscle strength and physical performance are associated with incident fractures and mortality. However, their role in the risk of subsequent fracture and postfracture mortality is not clear. We assessed the association between muscle strength (grip strength) and performance (gait speed and chair stands time) and the risk of subsequent fracture and mortality in 830 men with low‐trauma index fracture, who participated in the Osteoporotic Fractures in Men (MrOS) USA Study and had their index measurements assessed within 5 years prior to the index fracture. The annual decline in muscle strength and performance following index fracture, estimated using linear mixed‐effects regression, was also examined in relation to mortality. The associations were assessed using Cox proportional hazards models adjusted for age, femoral neck bone mineral density (FN BMD), prior fractures, falls, body mass index (BMI), index fracture site, lifestyle factors, and comorbidities. Over a median follow‐up of 3.7 (interquartile range [IQR], 1.3–8.1) years from index fracture to subsequent fracture, 201 (24%) men had a subsequent fracture and over 5.1 (IQR, 1.8–9.6) years to death, and 536 (65%) men died. Index measurements were not associated with subsequent fracture (hazard ratios [HRs] ranging from 0.97 to 1.07). However, they were associated with postfracture mortality. HR (95% confidence interval [CI]) per 1 standard deviation (1‐SD) decrement in grip strength: HR 1.12 (95% CI, 1.01–1.25) and gait speed: HR 1.14 (95% CI, 1.02–1.27), and 1‐SD increment in chair stands time: HR 1.08 (95% CI, 0.97–1.21). Greater annual declines in these measurements were associated with higher mortality risk, independent of the index values and other covariates. HR (95% CI) per 1‐SD annual decrement in change in grip strength: HR 1.15 (95% CI, 1.01–1.33) and in gait speed: HR 1.38 (95% CI, 1.13–1.68), and 1‐SD annual increment in chair stands time: HR 1.28 (95% CI, 1.07–1.54). Men who were unable to complete one or multiple tests had greater risk of postfracture mortality (24%–109%) compared to those performed all tests. It remains to be seen whether improvement in these modifiable factors can reduce postfracture mortality. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Publisher: Elsevier BV
Date: 07-2019
Publisher: Springer Science and Business Media LLC
Date: 22-05-2014
Publisher: Wiley
Date: 26-10-2006
DOI: 10.1002/AJMG.A.31509
Abstract: Investigations have not identified a major locus for congenital vertebral malformations. Based on observations in mice, we hypothesized that mutations in DLL3, a member of the notch-signaling pathway, might contribute to human vertebral malformations. We sequenced the DLL3 gene in 50 patients with congenital vertebral malformations. A Caucasian male patient with VACTERL manifestations including a T5-T6 block vertebrae was heterozygous for a "G" to "A" missense mutation changing glycine to arginine at codon 269. This residue is conserved in mammals, including chimpanzee, mouse, dog, and rat. Additional testing in the patient did not show evidence of chromosome abnormalities. The patient's asymptomatic mother was also heterozygous for the missense mutation. Since this mutation was not observed in a control population and leads to an amino acid change, it may be clinically significant. The mutation was not found in a control population of 87 anonymous in iduals. Several established mechanisms could explain the mutation in both the patient and his asymptomatic mother (susceptibility allele requiring additional environmental factors, somatic mosaicism, multigenic inheritance). Documenting the absence of the mutation in a larger control population or the presence of the mutation in additional affected patients, or documenting a functional difference in DLL3 would provide further evidence supporting its causal role.
Publisher: American College of Physicians
Date: 19-12-2017
DOI: 10.7326/L17-0487
Publisher: Elsevier BV
Date: 05-2010
Publisher: Elsevier BV
Date: 03-2013
Publisher: Elsevier BV
Date: 03-2004
DOI: 10.4158/EP.10.2.149
Publisher: Elsevier BV
Date: 06-2019
Publisher: Springer Science and Business Media LLC
Date: 09-01-2015
Publisher: Public Library of Science (PLoS)
Date: 05-02-2016
Publisher: The Endocrine Society
Date: 12-09-2023
Publisher: Public Library of Science (PLoS)
Date: 10-05-2013
Publisher: Wiley
Date: 12-2019
DOI: 10.1002/JBMR.3877
Abstract: Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fracture among people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, and subcutaneous pharmacotherapies are efficacious and can reduce risk of future fracture. Patients need education, however, about the benefits and risks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive but may be beneficial for selected patients at high risk. Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the early post-fracture period, prompt treatment is recommended. Adequate dietary or supplemental vitamin D and calcium intake should be assured. In iduals being treated for osteoporosis should be reevaluated for fracture risk routinely, including via patient education about osteoporosis and fractures and monitoring for adverse treatment effects. Patients should be strongly encouraged to avoid tobacco, consume alcohol in moderation at most, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for in iduals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease). © 2019 American Society for Bone and Mineral Research.
Publisher: Wiley
Date: 03-2005
DOI: 10.1359/JBMR.041134
Publisher: Wiley
Date: 23-12-2008
DOI: 10.1111/J.1749-6632.2008.03452.X
Abstract: Vertebral malformations contribute substantially to the pathophysiology of kyphosis and scoliosis, common health problems associated with back and neck pain, disability, cosmetic disfigurement, and functional distress. This review explores (1) recent advances in the understanding of the molecular embryology underlying vertebral development and relevance to elucidation of etiologies of several known human vertebral malformation syndromes (2) outcomes of molecular studies elucidating genetic contributions to congenital and sporadic vertebral malformation and (3) complex interrelationships between genetic and environmental factors that contribute to the pathogenesis of isolated syndromic and nonsyndromic congenital vertebral malformation. Discussion includes exploration of the importance of establishing improved classification systems for vertebral malformation, future directions in molecular and genetic research approaches to vertebral malformation, and translational value of research efforts to clinical management and genetic counseling of affected in iduals and their families.
Publisher: Wiley
Date: 19-03-1999
DOI: 10.1002/(SICI)1096-8628(19990319)83:3<164::AID-AJMG5>3.0.CO;2-D
Publisher: Wiley
Date: 18-07-2013
DOI: 10.1002/JBMR.1970
Publisher: Wiley
Date: 10-2009
DOI: 10.1359/JBMR.090818
Publisher: Wiley
Date: 18-12-2013
DOI: 10.1002/JBMR.1738
Publisher: Elsevier BV
Date: 05-1982
Publisher: Informa UK Limited
Date: 15-08-2014
Publisher: Springer Science and Business Media LLC
Date: 16-09-2010
Publisher: Springer Science and Business Media LLC
Date: 25-01-2006
DOI: 10.1007/S00198-005-0050-5
Abstract: Changes in bone mineral density are used to monitor osteoporosis therapy. To determine whether a change in bone mass is clinically significant, the precision of bone mineral density measurements must be known. We therefore measured the impact of vertebral body exclusion on dual energy X-ray absorptiometry (DXA) precision. At one university and one Veterans Affairs DXA center, three radiology technologists each scanned 30 participants twice, with repositioning between scans, to estimate DXA precision. Three International Society for Clinical Densitometry-certified physicians reviewed all lumbar spinal scans to note the presence of focal structural defects. We calculated precision for subsets of vertebrae, and for virtual s les of patients with and without physician-identified vertebral focal structural defects. We graphed the reciprocal of least significant change versus bone area to determine the dependence of precision on interpreted scan area. Within each s le, greater interpretable bone area improved precision. The contribution of interpreted bone area to precision differed among the s les, ranging from 57 to 94%. Greater population bone mineral density heterogeneity and presence of focal structural defects each decreased precision. All bone densitometry centers must determine precision using a s le representative of their served populations. Failure to do so may lead to incorrect determination of least significant change. Population heterogeneity, vertebral body exclusion and presence of focal structural defects each decreases precision.
Publisher: Springer Science and Business Media LLC
Date: 08-07-2021
DOI: 10.1038/S41586-021-03767-X
Abstract: The genetic make-up of an in idual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Publisher: Wiley
Date: 10-2008
DOI: 10.1359/JBMR.080503
Abstract: No major susceptibility genes for sporadically occurring congenital vertebral malformations (CVM) in humans have been identified to date. Body patterning genes whose mutants cause axial skeletal anomalies in mice are candidates for human CVM susceptibility. T (also known as Brachyury) and TBX6 are critical genes needed to establish mesodermal identity. We hypothesized that mutations in T and/or TBX6 contribute to the pathogenesis of human CVMs. The complete T and TBX6 coding regions, splice junctions, and proximal 500 bp of the promoters were sequenced in 50 phenotyped patients with CVM. Three unrelated patients with sacral agenesis, Klippel-Feil syndrome, and multiple cervical and thoracic vertebral malformations were heterozygous for a c.1013C>T substitution, resulting in a predicted Ala338Val missense alteration in exon 8. A clinically unaffected parent of each patient also harbored the substitution, but the variant did not occur in an ethnically erse, 443-person reference population. The c.1013C>T variant is significantly associated with CVM (p T variant in intron 7. This previously unreported variant was tested in 347 normal control subjects, and 11 heterozygotes and 2 T/T in iduals were found. No TBX6 variants were identified. We infer that the c.1013C>T substitution is pathogenic and represents the first report of an association between a missense mutation in the T gene and the occurrence of sporadic CVMs in humans. It is uncertain whether the splice junction variant increases CVM risk. TBX6 mutations do not seem to be associated with CVM. We hypothesize that epistatic interactions between T and other developmental genes and the environment modulate the phenotypic consequences of T variants.
Publisher: Oxford University Press (OUP)
Date: 15-11-2021
DOI: 10.1093/HMG/DDAA258
Abstract: The genetic causes of multiple congenital anomalies are incompletely understood. Here, we report novel heterozygous predicted loss-of-function (LoF) and predicted damaging missense variants in the WW domain binding protein 11 (WBP11) gene in seven unrelated families with a variety of overlapping congenital malformations, including cardiac, vertebral, tracheo-esophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-messenger RNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and esophagus, similar to the affected in iduals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. LoF WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or esophageal atresia.
Publisher: Elsevier BV
Date: 09-2000
Publisher: ASME International
Date: 09-05-2013
DOI: 10.1115/1.4024161
Abstract: The recombinant congenic mouse strains HcB-8 and HcB-23 differ in femoral shape, size, and strength, with HcB-8 femora being more gracile, more cylindrical, weaker, and having higher Young's modulus. In previous work, we mapped a robust, pleiotropic quantitative trait locus for these bone traits. Ece1, encoding endothelin converting enzyme 1, is a positional candidate gene for this locus, and was less expressed in HcB-8 bone. We hypothesized that the same genetic factors would impose analogous developmental trajectories on arteries to those in bones. Cardiovascular hemodynamics and biomechanics of carotids were measured in adult HcB-8 and HcB-23 mice. Biological differences in heart and arteries were examined at mRNA and protein levels. As in bone, Ece1 expression was higher in HcB-23 heart and arteries (p 0.05), and its expression was correlated with that of the endothelin B type receptor target Nos3, encoding endothelial nitric oxide synthase. HcB-8 mice had higher ambulatory blood pressure (p 0.005) than HcB-23 mice. Ex vivo, at identical pressures, HcB-8 carotid arteries had smaller diameters and lower compliance (p 0.05), but the same elastic modulus compared to HcB-23 carotid arteries. HcB-8 hearts were heavier than HcB-23 hearts (p 0.01). HcB-8 has both small, stiff bones and small, stiff arteries, lower expression of Ece1 and Nos3, associated in each case with less favorable function. These findings suggest that endothelin signaling could serve as a nexus for the convergence of skeletal and vascular modeling, providing a potential mechanism for the epidemiologic association between skeletal fragility and atherosclerosis.
Publisher: Elsevier BV
Date: 05-2019
Publisher: Portico
Date: 07-2004
DOI: 10.1138/20040131
Publisher: Wiley
Date: 15-06-2017
DOI: 10.1002/JBMR.3182
Abstract: A crisis in osteoporosis treatment exists the majority of those who sustain fracture do not receive treatment to reduce future fracture risk. This crisis presents an opportunity to focus the field from osteoporosis to fracture, the outcome of consequence. Proposed here is a change in focus suggesting that 1) attempts to define the level of trauma leading to fracture are counterproductive and that all fractures in older adults merit consideration of evaluation and 2) bone loss is not the entire problem but rather part of a broader syndrome including osteoporosis, sarcopenia, and other factors leading to fracture. With this approach, all fractures in older adults should be evaluated for potential lifestyle, non-pharmacological, and pharmacological interventions that could be implemented to reduce the risk of fracture recurrence. © 2017 American Society for Bone and Mineral Research.
Publisher: S. Karger AG
Date: 15-11-2013
DOI: 10.1159/000345329
Abstract: Congenital vertebral malformations (CVM) pose a significant health problem because they can be associated with spinal deformities, such as congenital scoliosis and kyphosis, in addition to various syndromes and other congenital malformations. Additional information remains to be learned regarding the natural history of congenital scoliosis and related health problems. Although significant progress has been made in understanding the process of somite formation, which gives rise to vertebral bodies, there is a wide gap in our understanding of how genetic factors contribute to CVM development. Maternal diabetes during pregnancy most commonly contributes to the occurrence of CVM, followed by other factors such as hypoxia and anticonvulsant medications. This review highlights several emerging clinical issues related to CVM, including pulmonary and orthopedic outcome in congenital scoliosis. Recent breakthroughs in genetics related to gene and environment interactions associated with CVM development are discussed. The Klippel-Feil syndrome which is associated with cervical segmentation abnormalities is illustrated as an ex le in which animal models, such as the zebrafish, can be utilized to provide functional evidence of pathogenicity of identified mutations.
Publisher: Oxford University Press (OUP)
Date: 12-01-2014
DOI: 10.1093/HMG/DDU013
Publisher: Wiley
Date: 06-2001
DOI: 10.1359/JBMR.2001.16.6.992
Abstract: Fracture susceptibility depends jointly on bone mineral content (BMC), gross bone anatomy, and bone microarchitecture and quality. Overall, it has been estimated that 50-70% of bone strength is determined genetically. Because of the difficulty of performing studies of the genetics of bone strength in humans, we have used the HcB/Dem series of recombinant congenic (RC) mice to investigate this phenotype. We performed a comprehensive phenotypic analysis of the HcB/Dem strains including morphological analysis of long bones, measurement of ash percentage, and biomechanical testing. Body mass, ash percentage, and moment of inertia each correlated moderately but imperfectly with biomechanical performance. Several chromosome regions, on chromosomes 1, 2, 8, 10, 11, and 12, show sufficient evidence of linkage to warrant closer examination in further crosses. These studies support the view that mineral content, diaphyseal diameter, and additional nonmineral material properties contributing to overall bone strength are controlled by distinct sets of genes. Moreover, the mapping data are consistent with the existence of pleiotropic loci for bone strength-related phenotypes. These findings show the importance of factors other than mineral content in determining skeletal performance and that these factors can be dissected genetically.
Publisher: Elsevier BV
Date: 12-1999
DOI: 10.1016/S1094-6950(06)60409-5
Abstract: As the population ages, fragility fractures grow in importance as a public health problem. The principal goal of osteoporosis therapy is primary and secondary fracture prevention. A growing choice of therapies is now available for the treatment of osteoporosis. In this article, we review their efficacy using fracture prevention as an end point. The considerable heterogeneity among studies with regard to patient age, past fracture history, fracture site, and analytical methods precludes the possibility of performing a meaningful meta-analysis. Fracture outcomes have been reported in clinical trials with calcium supplementation, vitamin D supplementation, estrogen replacement therapy (ERT), calcitonin, etidronate, alendronate, sodium fluoride (NaF), parathyroid hormone (PTH), and raloxifene. Compelling evidence for fracture prevention has been provided for calcium and vitamin D supplementation and alendronate treatment. Evidence of fracture prevention exists for ERT, raloxifene, calcitonin, etidronate, and PTH. Data on NaF are inconsistent. Across agents, there is a trend toward greater efficacy for patients at greatest risk of fracture.
Publisher: Elsevier BV
Date: 2019
Publisher: Wiley
Date: 27-10-2014
DOI: 10.1002/AJMG.A.36799
Abstract: We report on a father and his two daughters diagnosed with Klippel-Feil syndrome (KFS) but with craniofacial differences (zygomatic and mandibular hypoplasia and cleft palate) and external ear abnormalities suggestive of Treacher Collins syndrome (TCS). The diagnosis of KFS was favored, given that the neck anomalies were the predominant manifestations, and that the diagnosis predated later recognition of the association between spinal segmentation abnormalities and TCS. Genetic heterogeneity and the rarity of large families with KFS have limited the ability to identify mutations by traditional methods. Whole exome sequencing identified a nonsynonymous mutation in POLR1D (subunit of RNA polymerase I and II): exon2:c.T332C:p.L111P. Mutations in POLR1D are present in about 5% of in iduals diagnosed with TCS. We propose that this mutation is causal in this family, suggesting a pathogenetic link between KFS and TCS.
Publisher: Marshfield Clinic Research Institute
Date: 04-2003
DOI: 10.3121/CMR.1.2.111
Abstract: Development of a systematic mutation detection assay strategy for denaturing high performance liquid chromatography (DHPLC). Adaptation of Guanine and Cytosine (GC)-cl ing from denaturing gradient gel electrophoresis (DGGE) to DHPLC. Three target sequences harboring known allelic variants were studied to develop a general DHPLC assay design strategy. These were exon 10 of the human RET (REarranged during Transfection) gene, exon 52 of the mouse Col1a2 gene, and exon 9 of the human FAS (APO-1, CD-95) gene. Available software was used to analyze melting curves and determine assay conditions. GC cl s of 20 bp or 36 bp were added to polymerase chain reaction (PCR) primers to introduce a high melting temperature (T(m)) domain to each of the target molecules. DHPLC was performed under partially denaturing conditions. DHPLC assays of PCR- lified sequences can be developed using a personal computer. The following three steps allowed for mutation detection in all three targets. The target sequence should have a uniform T(m)GC cl s of length sufficient to introduce a second melting domain with a T(m) > or = 8 degrees above that of the target sequence should be appended to one of the primers. The DHPLC assay should be performed at the highest temperature at which the target sequence is predicted to be > or = 90% double stranded Addition of GC-cl s to primers facilitates mutation detection by DHPLC. The theoretical basis for this observation is identical to that underlying the utility of GC-cl s in DGGE.
Publisher: Elsevier BV
Date: 12-2002
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000324774
Abstract: Bone biomechanical performance is a complex trait or, more properly, an ensemble of complex traits. Biomechanical performance incorporates flexibility under loading, yield and failure load, and energy to failure all are important measures of bone function. To date, the vast majority of work has focused on yield and failure load and its surrogate, bone mineral density. We performed a reciprocal intercross of the mouse strains HcB-8 and HcB-23 to map and ultimately identify genes that contribute to differences in biomechanical performance. Mechanical testing was performed by 3-point bending of the femora. We measured femoral diaphysis cross-sectional anatomy from photographs of the fracture surfaces. We used beam equations to calculate material level mechanical properties. We performed a principal component (PC) analysis of normalized whole bone phenotypes (17 input traits). We measured distances separating mandibular landmarks from calibrated digital photographs and performed linkage analysis. Experiment-wide α = 0.05 significance thresholds were established by permutation testing. Three quantitative trait loci (QTLs) identified in these studies illustrate the advantages of the comprehensive phenotyping approach. A pleiotropic QTL on chromosome 4 affected multiple whole bone phenotypes with LOD scores as large as 17.5, encompassing size, cross-sectional ellipticity, stiffness, yield and failure load, and bone mineral density. This locus was linked to 3 of the PCs but unlinked to any of the tissue level phenotypes. From this pattern, we infer that the QTL operates by modulating the proliferative response to mechanical loading. On this basis, we successfully predicted that this locus also affects the length of a specific region of the mandible. A pleiotropic locus on chromosome 10 with LOD scores displays opposite effects on failure load and toughness with LOD scores of 4.5 and 5.5, respectively, so that the allele that increases failure load decreases toughness. A chromosome 19 QTL for PC2 with an LOD score of 4.8 was not detected with either the whole bone or tissue level phenotypes. We conclude that first, comprehensive, system-oriented phenotyping provides much information that could not be obtained by focusing on bone mineral density alone. Second, mechanical performance includes inherent trade-offs between strength and brittleness. Third, considering the aggregate phenotypic data allows prediction of novel QTLs.
Publisher: BMJ
Date: 20-02-2014
Publisher: Elsevier BV
Date: 07-2023
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1016/S0945-053X(01)00116-0
Abstract: Differentiating chick limb-bud mesenchymal cell micro-mass cultures routinely mineralize in the presence of 10% fetal calf serum, antibiotics, 4 mM inorganic phosphate (or 2.5 mM beta-glycerophosphate), 0.3 mg/ml glutamine and either 25 microg/ml vitamin C or 5-12 microg/ml vitamin C-sulfate. The failure of these cultures to produce a mineralized matrix (assessed by electron microscopy, 45Ca uptake and Fourier transform infrared microscopy) led to the evaluation of each of these additives. We report here that the "stable" vitamin C-sulfate (ascorbic acid-2-sulfate) causes increased sulfate incorporation into the cartilage matrix. Furthermore, the release of sulfate from the vitamin C derivative appears to be responsible for the inhibition of mineral deposition, as demonstrated in cultures with equimolar amounts of vitamin C and sodium sulfate.
Publisher: Springer Science and Business Media LLC
Date: 1992
DOI: 10.1007/BF00648422
Publisher: Wiley
Date: 08-06-2023
DOI: 10.1002/JBM4.10780
Abstract: Type 2 diabetes (T2D) may be associated with increased risk of fractures, despite preserved bone mineral density (BMD). Obesity and insulin resistance (IR) may have separate effects on bone turnover and bone strength, which contribute to skeletal fragility. We characterized and assessed the relative associations of obesity, body composition, IR, and T2D on bone turnover markers (BTMs), BMD, and advanced hip analysis (AHA). In this cross‐sectional analysis of Dubbo Osteoporosis Epidemiology Study, 525 (61.3% women) participants were grouped according to T2D, IR (homeostasis model assessment insulin resistance [HOMA‐IR] /≥2.5), and BMI ( /≥25 kg/m 2 ): insulin‐sensitive lean (IS‐L), insulin‐sensitive overweight/obese (IS‐O), insulin‐resistant (IR), and T2D. BMD, AHA, and body composition, including visceral adipose tissue (VAT) (on dual‐energy x‐ray absorptiometry scan) and fasting BTMs, were assessed. Analyses performed using Bayesian model averaging and principal component analysis. T2D was associated with low BTMs (by 26%–30% [95% confidence interval [CI] 11%–46%] in women, 35% [95% CI 18%–48%] in men compared to IS‐L), which persisted after adjustment for VAT. BTMs were similar among IR/IS‐O/IS‐L. BMD was similar among T2D/IR/IS‐O BMD was low only in IS‐L. All groups were similar after adjustment for BMI. Similarly, AHA components were lowest in IS‐L (attenuated following adjustment). On multivariate analysis, T2D was independently associated with BTMs. IR was also associated with C‐terminal telopeptide of type 1 collagen in men. Age and body size were the strongest independent contributors to BMD and AHA. VAT was inversely associated with section modulus, cross‐sectional area, cross‐sectional moment of inertia in women, and hip axis length in men. Low bone turnover is associated with T2D and IR (in men), while BMD and hip strength/geometry are predominantly associated with body size. VAT, indicative of dysglycemia, is also associated with impaired bone geometry. Establishing the role of BTMs and AHA fracture risk may improve skeletal assessment in T2D people. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Publisher: Wiley
Date: 07-2001
Publisher: Springer Science and Business Media LLC
Date: 13-04-2017
Publisher: Elsevier BV
Date: 06-2015
Publisher: The Endocrine Society
Date: 21-11-2022
Abstract: Bisphosphonates have been reported to be cardioprotective in some, but not all, studies. It is unknown whether denosumab (Dmab) use protects against cardiovascular events (CVEs). To determine whether oral bisphosphonate (oBP) or Dmab use is associated with CVEs in persons with incident fracture. Participants with an incident minimal trauma fracture from the Sax Institute’s 45 and Up Study, a population-based cohort from NSW, Australia, were followed between 2005/2009 and 2017. Questionnaire data were linked to hospital admissions (Admitted Patients Data Collection [APDC]) by the Centre for Health Record Linkage). Medicare Benefit Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) data sets were provided by Services Australia. Data was stored in a secure computing environment (Secure Unified Research Environment). Fractures, CVEs, and comorbidities were identified from the APDC and oBP and Dmab medication from the PBS. oBP and Dmab users were matched to never users (NoRx) by propensity scores. The main outcome measures were association between oBP and Dmab with CVE (acute myocardial infarction, unstable angina, cerebrovascular accident, and transient ischemic attack) and were determined using a stratified Cox's proportional hazards model. There were 880 pairs of oBP and NoRx (616 women) and 770 pairs of Dmab and NoRx (615 women) followed for ∼4.3 years. CVE risk was similar for oBP and NoRx Hazard Ratios (HR) women, 0.88 [95% CI 0.65-1.18] men, 1.07 [95% CI 0.72-1.57]). Similar findings were obtained for Dmab (Hazard Ratios (HR) women, 1.08 [95% CI 0.78-1.50] men, 1.55 [95% CI 0.96-2.48]). oBP and Dmab use was not associated with CVEs.
Publisher: Elsevier BV
Date: 09-2004
DOI: 10.4158/EP.10.5.445
Publisher: Elsevier BV
Date: 10-2015
Publisher: Elsevier BV
Date: 1999
DOI: 10.1385/JCD:2:1:59
Abstract: Most medical genetic studies seek to answer one of two questions: What genes are important in determining disease risk? and What alleles of a candidate gene confer excess risk? This article seeks to provide physicians with a practical approach to assessing articles on genetic topics, using ex les from bone mineral density and related areas. First, this article reviews the essential features of meiosis, crossing over, and allele detection. Second, mapping strategies are described and illustrated. Third, this article considers studies of the association between alleles of specific candidate genes and bone phenotypes. Linkage without association and association without linkage are both possible. Fourth, the ability of studies using inbred mice to establish both linkage and association is explained. Fifth, the transmission disequilibrium test is proposed as a superior design for investigating the association of alleles with bone phenotypes. Sixth and last, a systematic approach to reading medical genetic studies critically is developed. Common shortcomings in published articles include insufficient evidence for candidate choice, confusion between functionally significant alleles and markers, and failure to distinguish between identity by descent and identity by state.
Publisher: Public Library of Science (PLoS)
Date: 17-01-2023
DOI: 10.1371/JOURNAL.PMED.1004142
Abstract: Multimorbidity is common among fracture patients. However, its association with osteoporosis investigation and treatment to prevent future fractures is unclear. This limited knowledge impedes optimal patient care. This study investigated the association between multimorbidity and osteoporosis investigation and treatment in persons at high risk following an osteoporotic fracture. The Sax Institute’s 45 and Up Study is a prospective population-based cohort of 267,153 people in New South Wales, Australia, recruited between 2005 and 2009. This analysis followed up participants until 2017 for a median of 6 years (IQR: 4 to 8). Questionnaire data were linked to hospital admissions (Admitted Patients Data Collection (APDC)), emergency presentations (Emergency Department Data Collection (EDDC)), Pharmaceutical Benefits Scheme (PBS), and Medicare Benefits Schedule (MBS). Data were linked by the Centre for Health Record Linkage and stored in a secured computing environment. Fractures were identified from APDC and EDDC, Charlson Comorbidity Index (CCI) from APDC, Dual-energy X-ray absorptiometry (DXA) investigation from MBS, and osteoporosis treatment from PBS. Out of 25,280 persons with index fracture, 10,540 were classified as high-risk based on 10-year Garvan Fracture Risk (age, sex, weight, prior fracture and falls) threshold ≥20%. The association of CCI with likelihood of investigation and treatment initiation was determined by logistic regression adjusted for education, socioeconomic and lifestyle factors). The high-risk females and males averaged 77 ± 10 and 86 ± 5 years, respectively % had a CCI ≥2. Only 17% of females and 7% of males received a DXA referral, and 22% of females and 14% males received osteoporosis medication following fracture. A higher CCI was associated with a lower probability of being investigated [adjusted OR, females: 0.73 (95% CI, 0.61 to 0.87) and 0.43 (95% CI, 0.30 to 0.62) males: 0.47 (95% CI, 0.33 to 0.68) and 0.52 (0.31 to 0.85) for CCI: 2 to 3, and ≥4 versus 0 to 1, respectively] and of receiving osteoporosis medication [adjusted OR, females: 0.85 (95% CI, 0.74 to 0.98) and 0.78 (95% CI, 0.61 to 0.99) males: 0.75 (95% CI, 0.59 to 0.94) and 0.37 (95% CI, 0.23 to 0.53) for CCI: 2 to 3, and ≥4 versus 0 to 1, respectively]. The cohort is relatively healthy therefore, the impact of multimorbidity on osteoporosis management may have been underestimated. Multimorbidity contributed significantly to osteoporosis treatment gap. This suggests that fracture risk is either underestimated or underprioritized in the context of multimorbidity and highlights the need for extra vigilance and improved fracture care in this setting.
Publisher: The Endocrine Society
Date: 15-07-2019
Abstract: We previously found that variation in a quantitative trait locus, including the gene-encoding endothelin-converting enzyme 1 (Ece1), accounted for 40% of the variance in bone biomechanics and bone mineral density (BMD) in an intercross of recombinant congenic mouse strains. We hypothesized that single nucleotide polymorphisms (SNPs) within the human ECE1 isoform b promoters, at ECE1 b −338(G/T) and ECE1 b −839(A/C), would associate with osteoporosis in postmenopausal women. We genotyped DNA for the ECE1 −338(G/T) and −839(A/C) SNPs. A community medical center. Postmenopausal women (3564) with ≥1 dual-energy X-ray absorptiometry scan ≥60 years of age. BMD, osteoporosis, and clinical fractures. In multivariate models controlling for age, weight, healthcare duration, and tobacco, the CC genotype reduced the odds of lifetime fracture (OR 0.33, 95% CI 0.12, 0.87) and fracture ≥50 years of age (OR 0.31, 95% CI 0.11, 0.87), whereas the AC genotype increased odds of osteoporosis (OR 1.34, 95% CI 1.02 1.78) relative to the AA genotype. However, when controlling the false-discovery rate, findings were no longer significant. We found no consistent relationship between the ECE1 b −338(G/T) and study outcomes. The CC genotype was associated with fewer fractures, whereas the AC genotype was associated with osteoporosis. Our small s le size and few minorities are study limitations. Findings should be tested in another cohort to confirm a link between the ECE1 −839(A/C) SNPs and osteoporosis.
Publisher: Wiley
Date: 05-05-2020
DOI: 10.1002/AJMG.A.61607
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.FERTNSTERT.2019.09.038
Abstract: Fractures and their consequences are the clinically important manifestation of osteoporosis preventing fractures is the primary goal of management. Effective management is achievable given present knowledge and tools but is seldom prescribed. This review will cover the in idual and social burden of fracture, essential information about fracture risk and its estimation, an approach to patient care emphasizing specific information to elicit and therapeutic strategies to pursue, and existing gaps in knowledge and important questions for future research.
Publisher: American College of Physicians
Date: 05-2001
Publisher: American Medical Association (AMA)
Date: 10-10-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2014
Publisher: Wiley
Date: 02-2017
DOI: 10.14814/PHY2.13088
Publisher: Springer Science and Business Media LLC
Date: 11-05-2019
DOI: 10.1007/S00198-019-04998-5
Abstract: We report a 46-yr-old woman with a history of breast cancer who presented with diffuse myalgias, bone pain, and osteosclerosis. She was found to have recurrent breast cancer producing endothelin-1. Acquired osteosclerosis can be caused by various disorders. Endothelin -1 is believed to contribute to osteosclerosis caused by breast cancer. Although the bone marrow biopsy did not reveal breast cancer, she developed skin lesions consistent with metastatic breast cancer. She ultimately died from progressive disease. At autopsy immunohistochemistry for endothelin-1 was performed on a section from the L5 vertebral body. The section from the L5 vertebral body showed small foci of cells consistent with metastatic carcinoma and a prominent sclerotic response. Immunohistochemistry for endothelin-1 was strongly positive. Recurrent breast cancer may present with diffuse osteosclerosis. Endothelin-1 may be a paracrine factor responsible for increased bone formation and osteosclerosis.
Publisher: Wiley
Date: 11-05-2006
DOI: 10.1002/AJMG.A.31307
Publisher: Springer Science and Business Media LLC
Date: 26-05-2011
DOI: 10.1007/S00774-010-0194-Z
Abstract: The G171V mutation (high bone mass, HBM) is autosomal dominant and is responsible for high bone mass in humans. Transgenic HBM mice in which the human LRP5 G171V gene is inserted also show a similar phenotype with greater bone mass and biomechanical performance than wild-type mice, as determined by whole bone testing. Whole bone mechanics, however, depend jointly on bone mass, architecture, and intrinsic bone tissue mechanical properties. To determine whether the HBM mutation affects tissue-level biomechanical performance, we performed nano-indentation testing of unembedded cortical bone from HBM mice and their nontransgenic (NTG) littermates. Femora from 17-week-old mice (female, 8 mice/genotype) were subjected to nano-indentation using a Triboscope (Hysitron, Minneapolis, MN, USA). For each femoral specimen, approximately 10 indentations were made on the midshaft anterior surface with a target force of either 3 or 9 mN at a constant loading rate of 400 mN/s. The load-displacement data from each test were used to calculate indentation modulus and hardness for bone tissue. The intrinsic material property that reflected the bone modulus was greater (48%) in the HBM as compared to the NTG mice. Our results of intrinsic properties are consistent with the published structural and material properties of the midshaft femur in HBM and NTG mice. The greater intrinsic modulus in HBM reflects greater bone mineral content as compared to NTG (wild-type, WT) mice. This study suggests that the greater intrinsic property of cortical bone is derived from the greater bone mineral content and BMD, resulting in greater bone strength in HBM as compared to NTG (WT) mice.
Publisher: Elsevier BV
Date: 06-2005
DOI: 10.1016/J.BONE.2005.03.004
Abstract: Dentinogenesis imperfecta (DI) is a common but variable feature of osteogenesis imperfecta (OI). The Col1a2(oim) mutation (oim) is a well-studied mouse model of chain deficiency OI. Heterozygous oim/+ mice have subtle skeletal fragility, while homozygous oim/oim mice have marked skeletal fragility. To further define the consequences of oim mutation, we examined teeth by light and scanning electron microscopy (SEM). The dental phenotype in Col1a2(oim) (oim) mice is more severe in incisors than in molars and includes changes in pulp chamber size, tooth shape, and dentin ultrastructure. Teeth in oim/oim animals are clinically fragile, while oim/+ teeth are grossly normal. Incisor pulp chamber areas (in mum(2)) are: upper +/+ = 358 +/- 75, lower +/+ = 671 +/- 162, upper oim/+ = 161 +/- 54, lower oim/+ = 156 +/- 19, upper oim/oim = 6900 +/- 1040, and lower oim/oim = 66 +/- 62 (P < 10(-5)). Incisor non-pulp chamber cross-sectional areas (in mum(2)), reflecting dentin areas, are: upper +/+ = 39,000 +/- 1670, lower +/+ = 35,600 +/- 1980, upper oim/+ = 47,500 +/- 2510, lower oim/+ = 26,000 +/- 1830, upper oim/oim = 29,800 + 315, and lower oim/oim = 36,800 +/- 3450 (P < 10(-5)). Ultrastructural abnormalities are more pronounced in incisors than in molars and depend on dosage of the mutant allele. These include reduction in the number and regularity of spacing of the dentinal tubules, lesser mineralization, and blurring of the boundary between peritubular and intertubular dentin. Our findings demonstrate that both oim/oim and oim/+ mice suffer from DI. The more severe incisor phenotype may reflect incisors' continuous growth.
Publisher: Marshfield Clinic Research Institute
Date: 04-2003
DOI: 10.3121/CMR.1.2.125
Abstract: Genetic and environmental factors influencing spinal development in lower vertebrates are likely to play a role in the abnormalities associated with human congenital scoliosis (CS) and idiopathic scoliosis (IS). An overview of the molecular embryology of spinal development and the clinical and genetic aspects of CS and IS are presented. Utilizing synteny analysis of the mouse and human genetic databases, likely candidate genes for human CS and IS were identified. Review and synteny analysis. A search of the Mouse Genome Database was performed for "genes," "markers" and "phenotypes" in the categories Neurological and neuromuscular, Skeleton, and Tail and other appendages. The Online Mendelian Inheritance in Man was used to determine whether each mouse locus had a known human homologue. If so, the human homologue was assigned candidate gene status. Linkage maps of the chromosomes carrying loci with possibly relevant phenotypes, but without known human homologues, were examined and regions of documented synteny between the mouse and human genomes were identified. Searching the Mouse Genome Database by phenotypic category yielded 100 mutants of which 66 had been mapped. The descriptions of each of these 66 loci were retrieved to determine which among these included phenotypes of scoliosis, kinky or bent tails, other vertebral abnormalities, or disturbances of axial skeletal development. Forty-five loci of interest remained, and for 27 of these the comparative linkage maps of mouse and human were used to identify human syntenic regions to which plausible candidate genes had been mapped. Synteny analysis of mouse candidate genes for CS and IS holds promise due to the close evolutionary relationship between mice and human beings. With the identification of additional genes in animal model systems that contribute to different stages of spine development, the list of candidate genes for CS and IS will continue to grow.
Publisher: Public Library of Science (PLoS)
Date: 18-09-2012
Publisher: Wiley
Date: 19-07-2013
Publisher: Portico
Date: 27-03-2013
Location: United States of America
Location: United States of America
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
Location: United States of America
No related grants have been discovered for Robert Daniel Blank.