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Osteoporosis and bone fractures are a severe problem for the welfare of laying hens, with genetics and environment, such as housing system, each making substantial contributions to bone strength. In this work, we performed genetic analyses of bone strength, bone mineral density, and bone composition, as well as body weight, in 860 commercial crossbred laying hens from 2 different companies, kept in either furnished cages or floor pens. We compared bone traits between housing systems and crossbreds and performed a genome-wide association study of bone properties and body weight. As expected, the 2 housing systems produced a large difference in bone strength, with layers housed in floor pens having stronger bones. These differences were accompanied by differences in bone geometry, mineralization, and chemical composition. Genome scans either combining or independently analyzing the 2 housing systems revealed no genome-wide significant loci for bone breaking strength. We detected 3 loci for body weight that were shared between the housing systems on chromosomes 4, 6, and 27 (either genome-wide significant or suggestive) and these coincide with associations for bone length. In summary, we found substantial differences in bone strength, content, and composition between hens kept in floor pens and furnished cages that could be attributed to greater physical activity in pen housing. We found little evidence for large-effect loci for bone strength in commercial crossbred hens, consistent with a highly polygenic architecture for bone strength in the production environment. The lack of consistent genetic associations between housing systems in combination with the differences in bone phenotypes could be due to gene-by-environment interactions with housing system or a lack of power to detect shared associations for bone strength.
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Pollos , Tibia , Animales , Femenino , Pollos/genética , Estudio de Asociación del Genoma Completo , Vivienda para Animales , Peso CorporalRESUMEN
Results from real-world evidence (RWE) from the largest healthcare region in Sweden show low uptake of antiresorptive (AR) treatment, but beneficial effect in those receiving treatment, especially for the composite outcome of hip fracture or death. For RWE studies, Sweden is unique, with virtually complete coverage of electronic medical records (EMRs) and both regional and national registries, in a universal publicly funded healthcare system. To our knowledge, there is no previous RWE study evaluating the efficacy of AR treatment compared to no AR treatment after fragility fracture, including data on parenteral treatments administered in hospital settings. The Stockholm Real World Management (STORM) study cohort was established in the healthcare region of Stockholm to retrospectively assess the effectiveness of AR treatment after first fragility fracture using the regional EMR system for both hospital and primary care. Between 2012 and 2018, we identified 69,577 fragility fracture episodes among 59,078 patients, men and women, 50 years and older. Of those, 21,141 patients met inclusion and exclusion criteria (eligible cohort). From these, the final matched study cohort comprised 9840 fragility fractures (cases receiving AR treatment [n = 1640] and controls not receiving AR treatment [n = 8200]). Propensity scores were estimated using logistic regression models with AR treatment as outcome and confounders as independent variables followed by analysis using Cox proportional hazard models. Real world evidence from Sweden's largest healthcare region, comprising a quarter of the Swedish population, show that only 10% of patients receive AR treatment within 1 year after a fragility fracture. Factors associated with not receiving treatment include having a diagnosis of cardiovascular disease. In those treated, AR have positive effects particularly on the composite of fracture and death (any fracture/death and hip fracture/death) in individuals matched for all major confounders. © 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).
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Fracturas de Cadera , Fracturas Osteoporóticas , Estudios de Cohortes , Femenino , Fracturas de Cadera/tratamiento farmacológico , Fracturas de Cadera/epidemiología , Humanos , Masculino , Fracturas Osteoporóticas/tratamiento farmacológico , Fracturas Osteoporóticas/epidemiología , Estudios Retrospectivos , Suecia/epidemiologíaRESUMEN
The Klotho (KL) gene is involved in phosphate homeostasis. Polymorphisms in this gene have been reported to be associated with the risk of cardiovascular disease. Here we used computational tools to predict the damage-associated single nucleotide polymorphisms (SNPs) in the human KL gene. We further investigated the association of SNPs in the KL gene and mortality in the Swedish multicenter prospective Osteoporotic Fractures in Men (MrOS) cohort. This study included 2921 men (aged 69-81 years) with mean 4.49 ± 1.03 years follow-up. 18 SNPs in the KL gene were genotyped using Sequenom. These SNPs were identified by in silico tools for the coding and noncoding genome to predict the damaging SNPs. After quality analyses, SNPs were analyzed for mortality risk using two steps approach on logistic regression model screening and then Cox regression model confirmation. Two non-synonymous SNPs rs9536314 and rs9527025 were found to be potentially damaging SNPs that affect KL protein stability and expression. However, these two SNPs were not statistically significantly associated with all-cause mortality (crude Hazard ratio [HR] 1.72, 95% confidence interval [CI] 0.96-3.07 in rs9536314; crude HR 1.82, 95% CI 0.998-3.33 in rs9527025) or cardiovascular mortality (crude HR 1.52, 95% CI 0.56-4.14 in rs9536314; crude HR 1.54, 95% CI 0.55-4.33 in rs9527025) in additive model using Cox regression analysis. In conclusion, these two potentially damaging SNPs (rs9536314 and rs9527025) in the KL gene were not associated with all-cause mortality or cardiovascular mortality in MrOs cohort. Larger scales studies and meta-analysis are needed to confirm the correlation between polymorphisms of the KL gene and mortality.
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Glucuronidasa/genética , Fracturas Osteoporóticas/mortalidad , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Causas de Muerte , Simulación por Computador , Humanos , Proteínas Klotho , Masculino , Fracturas Osteoporóticas/genética , Estudios Prospectivos , Suecia/epidemiologíaRESUMEN
Gaucher disease (GD) is a rare, genetic lysosomal disorder leading to lipid accumulation and dysfunction in multiple organs. Involvement of the skeleton is one of the most prevalent aspects of GD and a major cause of pain, disability, and reduced quality of life. Uniform recommendations for contemporary evaluation and management are needed. To develop practical clinical recommendations, an international group of experienced physicians conducted a comprehensive review of 20 years' of the literature, defining terms according to pathophysiological understanding and pointing out best practice and unmet needs related to the skeletal features of this disorder. Abnormalities of bone modeling, reduced bone density, bone infarction, and plasma cell dyscrasias accompany the displacement of healthy adipocytes in adult marrow. Exposure to excess bioactive glycosphingolipids appears to affect hematopoiesis and the balance of osteoblast and osteoclast numbers and activity. Imbalance between bone formation and breakdown induces disordered trabecular and cortical bone modeling, cortical bone thinning, fragility fractures, and osteolytic lesions. Regular assessment of bone mineral density, marrow infiltration, the axial skeleton and searching for potential malignancy are recommended. MRI is valuable for monitoring skeletal involvement: It provides semiquantitative assessment of marrow infiltration and the degree of bone infarction. When MRI is not available, monitoring of painful acute bone crises and osteonecrosis by plain X-ray has limited value. In adult patients, we recommend DXA of the lumbar spine and left and right hips, with careful protocols designed to exclude focal disease; serial follow-up should be done using the same standardized instrument. Skeletal health may be improved by common measures, including adequate calcium and vitamin D and management of pain and orthopedic complications. Prompt initiation of specific therapy for GD is crucial to optimizing outcomes and preventing irreversible skeletal complications. Investing in safe, clinically useful, and better predictive methods for determining bone integrity and fracture risk remains a need. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
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Huesos/fisiopatología , Enfermedad de Gaucher/fisiopatología , Pautas de la Práctica en Medicina , Enfermedades Óseas/complicaciones , Enfermedades Óseas/diagnóstico por imagen , Enfermedades Óseas/fisiopatología , Médula Ósea/patología , Médula Ósea/fisiopatología , Remodelación Ósea , Huesos/diagnóstico por imagen , Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/diagnóstico , Enfermedad de Gaucher/terapia , HumanosRESUMEN
BACKGROUND: Osteogenesis imperfecta (OI) is a clinical and genetic heterogeneous group of connective tissue disorders, characterized by bone fragility and a propensity to fracture. METHODS: In this report we describe the clinical phenotype of two patients, a 28-year-old woman and her mother (54 years old), both with a history of short stature and multiple fractures. RESULTS: Exome sequencing revealed the recurring IFITM5:c.-14 C>T variant causing OI type V. Both patients had several fractures during childhood. CT-scan and scintigraphy showed ossification of the origin and attachment of muscles and hypertrophic callus formation. CONCLUSION: Ossification of the origin and attachment of muscles seems to be part of the phenotype in patients with OI type V.
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Proteínas de la Membrana/genética , Osificación Heterotópica/patología , Osteogénesis Imperfecta/genética , Adulto , Femenino , Fracturas Óseas/etiología , Humanos , Persona de Mediana Edad , Músculos/fisiología , Osteogénesis Imperfecta/patología , Fenotipo , Polimorfismo de Nucleótido Simple , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVE: Polymorphisms in the CYP2R1 gene encoding Vitamin D 25-hydroxylase have been reported to correlate with circulating levels of 25-OH vitamin D3 (25(OH)D). It is unknown whether these variations also affect overall bone metabolism. In order to elucidate the overall associations of polymorphisms in the CYP2R1, we studied haplotype tagging single nucleotide polymorphisms (SNPs) in the gene and serum levels of 25(OH)D, calcium, phosphate, parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23), as well as bone mineral density (BMD). METHODS: Baseline data on serum parameters and BMD from MrOS Sweden, a prospective population-based cohort study of elderly men (mean age 75 years, range 69-81), were analyzed. Genotyping was performed for eight SNPs covering the CYP2R1 gene in 2868 men with available samples of DNA. Subjects were followed up concerning incidence of fracture during five years. RESULTS: There was a significant genetic association with circulating levels of 25(OH)D (4.6-18.5% difference in mean values between SNP alleles), but there were no correlations with levels of calcium, phosphate, PTH or FGF23 for any genetic variant. No differences were found in fracture incidence between the variants. There was an inverse relationship between lower BMD and concomitant higher 25(OH)D for three of the haplotypes (p < 0.005). CONCLUSIONS: Common variants in the CYP2R1 gene encoding Vitamin D 25-hydroxylase correlate with levels of circulating 25(OH)D but do not otherwise associate with measures of calcium and phosphate homeostasis. Presence of the specific haplotypes may be an indicator of risk for low 25(OH)D levels, and may in addition be correlated to bone mineral density.
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Densidad Ósea/genética , Calcifediol/sangre , Colestanotriol 26-Monooxigenasa/genética , Familia 2 del Citocromo P450/genética , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Calcio/sangre , Estudios de Cohortes , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Fracturas Óseas/sangre , Fracturas Óseas/genética , Haplotipos , Humanos , Masculino , Hormona Paratiroidea/sangre , Fosfatos/sangre , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , SueciaRESUMEN
BACKGROUND: Mutations of the endoplasmic reticulum (ER)-stress transducer OASIS (encoded by CREB3L1), cause severe recessive osteogenesis imperfecta (OI) not compatible with surviving the neonatal period, as has been shown in two unrelated families through a whole gene deletion vs. a qualitative alteration of OASIS. Heterozygous carriers in the described families have exhibited a mild phenotype. OASIS is a transcription factor highly expressed in osteoblasts, and OASIS-/- mice exhibit severe osteopenia and spontaneous fractures. Here, we expand the clinical spectrum by a detailed phenotypic characterization of the first case of OASIS-associated OI surviving the neonatal period, with heterozygous family members being unaffected. METHODS: All OI-associated genes were sequenced. Primary human osteoblast-like cell (hOB) and fibroblast (FB) cultures were obtained for qPCR, and steady-state collagen biochemistry. FB, hOB and skin biopsies were ultrastructurally analyzed. Bone was analyzed by µCT, histomorphometry, quantitative backscattered electron imaging (qBEI), and Raman microspectroscopy. RESULTS: The proband, a boy with severe OI, had blue sclera and tooth agenesis. A homozygous CREB3L1 stop codon mutation was detected by sequencing, while several family members were heterozygotes. Markedly low levels of CREB3L1 mRNA were confirmed by qPCR in hOBs (16%) and FB (21%); however, collagen I levels were only reduced in hOBs (5-10%). Electron microscopy of hOBs showed pronounced alterations, with numerous myelin figures and diminished RER vs. normal ultrastructure of FB. Bone histomorphometry and qBEI were similar to collagen I OI, with low trabecular thickness and mineral apposition rate, and increased bone matrix mineralization. Raman microspectroscopy revealed low level of glycosaminoglycans. Clinical response to life-long bisphosphonate treatment was as expected in severe OI with steadily increasing bone mineral density, but despite this the boy suffered repeated childhood fractures. CONCLUSIONS: Deficiency of OASIS can cause severe OI compatible with surviving the neonatal period. A marked decrease of collagen type I transcription was noted in bone tissue, but not in skin, and ultrastructure of hOBs was pathological. Results also suggested OASIS involvement in glycosaminoglycan secretion in bone.
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Codón sin Sentido/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Homocigoto , Proteínas del Tejido Nervioso/genética , Osteogénesis Imperfecta/diagnóstico por imagen , Osteogénesis Imperfecta/genética , Sobrevivientes , Adulto , Células Cultivadas , Niño , Humanos , Masculino , Osteoblastos/patología , Osteoblastos/fisiología , Osteoblastos/ultraestructuraRESUMEN
Osteogenesis imperfecta (OI) is a heterogeneous group of disorders of connective tissue, caused mainly by mutations in the collagen I genes (COL1A1 and COL1A2). Dentinogenesis imperfecta (DGI) and other dental aberrations are common features of OI. We investigated the association between collagen I mutations and DGI, taurodontism, and retention of permanent second molars in a retrospective cohort of 152 unrelated children and adolescents with OI. The clinical examination included radiographic evaluations. Teeth from 81 individuals were available for histopathological evaluation. COL1A1/2 mutations were found in 104 individuals by nucleotide sequencing. DGI was diagnosed clinically and radiographically in 29% of the individuals (44/152) and through isolated histological findings in another 19% (29/152). In the individuals with a COL1A1 mutation, 70% (7/10) of those with a glycine substitution located C-terminal of p.Gly305 exhibited DGI in both dentitions while no individual (0/7) with a mutation N-terminal of this point exhibited DGI in either dentition (p = 0.01). In the individuals with a COL1A2 mutation, 80% (8/10) of those with a glycine substitution located C terminal of p.Gly211 exhibited DGI in both dentitions while no individual (0/5) with a mutation N-terminal of this point (p = 0.007) exhibited DGI in either dentition. DGI was restricted to the deciduous dentition in 20 individuals. Seventeen had missense mutations where glycine to serine was the most prevalent substitution (53%). Taurodontism occurred in 18% and retention of permanent second molars in 31% of the adolescents. Dental aberrations are strongly associated with qualitatively changed collagen I. The varying expressivity of DGI is related to the location of the collagen I mutation. Genotype information may be helpful in identifying individuals with OI who have an increased risk of dental aberrations.
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Colágeno Tipo I/genética , Dentinogénesis Imperfecta/etiología , Mutación/genética , Osteogénesis Imperfecta/complicaciones , Osteogénesis Imperfecta/genética , Adolescente , Adulto , Niño , Preescolar , Cadena alfa 1 del Colágeno Tipo I , Cavidad Pulpar/anomalías , Dentinogénesis Imperfecta/genética , Femenino , Genotipo , Humanos , Lactante , Masculino , Mutación Missense/genética , Fenotipo , Estudios Retrospectivos , Anomalías Dentarias/genética , Adulto JovenRESUMEN
The adrenal-derived hormones dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are the most abundant circulating hormones and their levels decline substantially with age. DHEAS is considered an inactive precursor, which is converted into androgens and estrogens via local metabolism in peripheral target tissues. The predictive value of serum DHEAS for fracture risk is unknown. The aim of this study was, therefore, to assess the associations between baseline DHEAS levels and incident fractures in a large cohort of older men. Serum DHEAS levels were analyzed with mass spectrometry in the population-based Osteoporotic Fractures in Men study in Sweden (n = 2568, aged 69 to 81 years). Incident X-ray validated fractures (all, n = 594; non-vertebral major osteoporotic, n = 255; hip, n = 175; clinical vertebral, n = 206) were ascertained during a median follow-up of 10.6 years. DHEAS levels were inversely associated with the risk of any fracture (hazard ratio [HR] per SD decrease = 1.14, 95% confidence interval [CI] 1.05-1.24), non-vertebral major osteoporotic fractures (HR = 1.31, 95% CI 1.16-1.48), and hip fractures (HR = 1.18, 95% CI 1.02-1.37) but not clinical vertebral fractures (HR = 1.09, 95% CI 0.95-1.26) in Cox regression models adjusted for age, body mass index (BMI) and prevalent fractures. Further adjustment for traditional risk factors for fracture, bone mineral density (BMD), and/or physical performance variables as well as serum sex steroid levels only slightly attenuated the associations between serum DHEAS and fracture risk. Similarly, the point estimates were only marginally reduced after adjustment for FRAX estimates with BMD. The inverse association between serum DHEAS and all fractures or major osteoporotic fractures was nonlinear, with a substantial increase in fracture risk (all fractures 22%, major osteoporotic fractures 33%) for those participants with serum DHEAS levels below the median (0.60 µg/mL). In conclusion, low serum DHEAS levels are a risk marker of mainly non-vertebral fractures in older men, of whom those with DHEAS levels below 0.60 µg/mL are at highest risk. © The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
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Envejecimiento/sangre , Deshidroepiandrosterona/sangre , Fracturas Óseas , Osteoporosis , Anciano , Anciano de 80 o más Años , Fracturas Óseas/sangre , Fracturas Óseas/diagnóstico por imagen , Fracturas Óseas/epidemiología , Humanos , Incidencia , Masculino , Osteoporosis/sangre , Osteoporosis/diagnóstico por imagen , Osteoporosis/epidemiología , Suecia/epidemiologíaRESUMEN
Measurement of serum testosterone (T) levels is recommended in the evaluation of osteoporosis in older men and estradiol (E2) and sex hormone binding globulin (SHBG) levels are associated with the rate of bone loss and fractures, but the clinical utility of sex steroid and SHBG measurements for the evaluation of osteoporosis in men has not been examined. To evaluate whether measurements of T, E2, and/or SHBG are useful for the prediction of fracture risk or the rate of bone loss in older men, we analyzed longitudinal data from 5487 community-based men participating in the Osteoporotic Fractures in Men (MrOS) study in the United States, Sweden, and Hong Kong. Serum T, E2, and SHBG levels were assessed at baseline; incident fractures were self-reported at 4-month intervals with radiographic verification (US), or ascertained via national health records (Sweden, Hong Kong). Rate of bone loss was assessed by serial measures of hip bone mineral density (BMD). We used receiver operating characteristic (ROC) curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) to assess improvement in prediction. Mean age at baseline was 72 to 75 years and the prevalence of low T levels (<300 ng/dL) was 7.6% to 21.3% in the three cohorts. There were 619 incident major osteoporotic and 266 hip fractures during follow-up of approximately 10 years. Based on ROC curves, there were no improvements in fracture risk discrimination for any biochemical measure when added to models, including the Fracture Risk Assessment Tool (FRAX) with BMD. Although minor improvements in NRI were observed for the dichotomous parameters low bioavailable E2 (BioE2) (<11.4 pg/mL) and high SHBG (>59.1 nM), neither sex steroids nor SHBG provided clinically useful improvement in fracture risk discrimination. Similarly, they did not contribute to the prediction of BMD change. In conclusion, there is limited clinical utility of serum E2, T, and SHBG measures for the evaluation of osteoporosis risk in elderly men. © 2016 American Society for Bone and Mineral Research.
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Resorción Ósea/diagnóstico , Estradiol/sangre , Fracturas Óseas/diagnóstico , Fracturas Óseas/epidemiología , Globulina de Unión a Hormona Sexual/metabolismo , Testosterona/sangre , Anciano , Resorción Ósea/sangre , Estudios de Cohortes , Fracturas Óseas/sangre , Fracturas de Cadera/sangre , Fracturas de Cadera/diagnóstico , Fracturas de Cadera/epidemiología , Humanos , Masculino , Curva ROC , Factores de RiesgoRESUMEN
MicroRNAs (miRNAs) are a family of small, non-coding RNAs (17-24 nucleotides), which regulate gene expression either by the degradation of the target mRNAs or inhibiting the translation of genes. Recent studies have indicated that miRNA plays an important role in regulating osteoblast differentiation. In this study, we identified miR-203 and miR-320b as important miRNAs modulating osteoblast differentiation. We identified Dlx5 as potential common target by prediction algorithms and confirmed this by knock-down and over expression of the miRNAs and assessing Dlx5 at mRNA and protein levels and specificity was verified by luciferase reporter assays. We examined the effect of miR-203 and miR-320b on osteoblast differentiation by transfecting with pre- and anti-miRs. Over-expression of miR-203 and miR-320b inhibited osteoblast differentiation, whereas inhibition of miR-203 and miR-320b stimulated alkaline phosphatase activity and matrix mineralization. We show that miR-203 and miR-320b negatively regulate BMP-2-induced osteoblast differentiation by suppressing Dlx5, which in turn suppresses the downstream osteogenic master transcription factor Runx2 and Osx and together they suppress osteoblast differentiation. Taken together, we propose a role for miR-203 and miR-320b in modulating bone metabolism.
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We investigated the impact of treatment with parathyroid hormone (PTH) and dexamethasone (DEX) for 2 and 24h by RNA sequencing of miRNAs in primary human bone (HOB) cells. A total of 207 million reads were obtained, and normalized absolute expression retrieved for 373 most abundant miRNAs. In naïve control cells, 7 miRNAs were differentially expressed (FDR<0.05) between the two time points. Ten miRNAs exhibited differential expression (FDR <0.05) across two time points and treatments after adjusting for expression in controls and were selected for downstream analyses. Results show significant effects on miRNA expression when comparing PTH with DEX at 2h with even more pronounced effects at 24h. Interestingly, several miRNAs exhibiting differences in expression are predicted to target genes involved in bone metabolism e.g. miR-30c2, miR-203 and miR-205 targeting RUNX2, and miR-320 targeting ß-catenin (CTNNB1) mRNA expression. CTNNB1and RUNX2 levels were decreased after DEX treatment and increased after PTH treatment. Our analysis also identified 2 putative novel miRNAs in PTH and DEX treated cells at 24h. RNA sequencing showed that PTH and DEX treatment affect miRNA expression in HOB cells and that regulated miRNAs in turn are correlated with expression levels of key genes involved in bone metabolism.
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Dexametasona/farmacología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , MicroARNs/genética , Osteocitos/metabolismo , Hormona Paratiroidea/farmacología , Secuencia de Bases , Secuencia Conservada/genética , Evolución Molecular , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , MicroARNs/química , MicroARNs/metabolismo , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteocitos/efectos de los fármacos , Reproducibilidad de los ResultadosRESUMEN
Previous prospective cohort studies have shown that serum levels of sex steroids and sex hormone-binding globulin (SHBG) associate with nonvertebral fracture risk in men. The predictive value of sex hormones and SHBG for vertebral fracture risk specifically is, however, less studied. Elderly men (aged ≥ 65 years) from Sweden and Hong Kong participating in the Osteoporotic Fractures in Men (MrOS) study had baseline estradiol and testosterone analyzed by gas chromatography-mass spectrometry (GC-MS) and SHBG by immunoradiometric assay (IRMA). Incident clinical vertebral fractures (n = 242 cases) were evaluated in 4324 men during an average follow-up of 9.1 years. In a subsample of these men (n = 2256), spine X-rays were obtained at baseline and after an average follow-up of 4.3 years to identify incident radiographic vertebral fractures (n = 157 cases). The likelihood of incident clinical and radiographic vertebral fractures was estimated by Cox proportional hazards models and logistic regression models, respectively. Neither serum estradiol (hazard ratio [HR] per SD increase = 0.93, 95% confidence interval [CI] 0.80-1.08) nor testosterone (1.05, 0.91-1.21) predicted incident clinical vertebral fractures in age-adjusted models in the combined data set. High serum SHBG, however, associated with increased clinical vertebral fracture risk (1.24, 1.12-1.37). This association remained significant after further adjustment for FRAX with or without bone mineral density (BMD). SHBG also associated with increased incident radiographic vertebral fracture risk (combined data set; odds ratio [OR] per SD increase = 1.23, 95% CI 1.05-1.44). This association remained significant after adjustment for FRAX with or without BMD. In conclusion, high SHBG predicts incident clinical and radiographic vertebral fractures in elderly men and adds moderate information beyond FRAX with BMD for vertebral fracture risk prediction.
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Globulina de Unión a Hormona Sexual/metabolismo , Fracturas de la Columna Vertebral/sangre , Anciano , Hueso Esponjoso/patología , Fracturas de Cadera/sangre , Fracturas de Cadera/epidemiología , Humanos , Incidencia , Masculino , Fracturas Osteoporóticas/sangre , Fracturas Osteoporóticas/epidemiología , Prevalencia , Factores de Riesgo , Fracturas de la Columna Vertebral/epidemiología , Estados Unidos/epidemiologíaRESUMEN
Trabecular bone score (TBS) is a gray-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a bone mineral density (BMD)-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual-level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables, and outcomes during follow-up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities, and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% confidence interval [CI] 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR = 1.32, 95% CI 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65-1.87 versus 1.70, 95% CI 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines. © 2015 American Society for Bone and Mineral Research.
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Densidad Ósea , Fracturas de Cadera , Vértebras Lumbares , Modelos Biológicos , Osteoporosis , Fracturas de la Columna Vertebral , Femenino , Fracturas de Cadera/diagnóstico por imagen , Fracturas de Cadera/etiología , Fracturas de Cadera/metabolismo , Humanos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/metabolismo , Masculino , Osteoporosis/complicaciones , Osteoporosis/diagnóstico por imagen , Osteoporosis/metabolismo , Estudios Prospectivos , Factores de Riesgo , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/etiología , Fracturas de la Columna Vertebral/metabolismoRESUMEN
MicroRNAs (miRNAs) are important post-transcriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. The aim of this study was to investigate miRNA-mRNA interactions that may be relevant for bone metabolism by assessing correlations and interindividual variability in miRNA levels as well as global correlations between miRNA and mRNA levels in a large cohort of primary human osteoblasts (HOBs) obtained during orthopedic surgery in otherwise healthy individuals. We identified differential expression (DE) of 24 miRNAs, and found 9 miRNAs exhibiting DE between males and females. We identified hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b and their target genes as important modulators of bone metabolism. Further, we used an integrated analysis of global miRNA-mRNA correlations, mRNA-expression profiling, DE, bioinformatics analysis, and functional studies to identify novel target genes for miRNAs with the potential to regulate osteoblast differentiation and extracellular matrix production. Functional studies by overexpression and knockdown of miRNAs showed that, the differentially expressed miRNAs hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b target genes highly relevant to bone metabolism, e.g., collagen, type I, α1 (COL1A1), osteonectin (SPARC), Runt-related transcription factor 2 (RUNX2), osteocalcin (BGLAP), and frizzled-related protein (FRZB). These miRNAs orchestrate the activities of key regulators of osteoblast differentiation and extracellular matrix proteins by their convergent action on target genes and pathways to control the skeletal gene expression.
Asunto(s)
MicroARNs/genética , MicroARNs/metabolismo , Osteoblastos/citología , Osteogénesis , ARN Mensajero/genética , Células Cultivadas , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Osteoblastos/metabolismo , ARN Mensajero/metabolismoRESUMEN
Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder, caused by collagen I mutations in 90% of cases. There are no comprehensive genotype-phenotype studies on >100 families outside North America, and no population-based studies determining the genetic epidemiology of OI. Here, detailed clinical phenotypes were recorded, and the COL1A1 and COL1A2 genes were analyzed in 164 Swedish OI families (223 individuals). Averages for bone mineral density (BMD), height and yearly fracture rate were calculated and related to OI and mutation type. N-terminal helical mutations in both the α1- and α2-chains were associated with the absence of dentinogenesis imperfecta (P<0.0001 vs 0.0049), while only those in the α1-chain were associated with blue sclera (P=0.0110). Comparing glycine with serine substitutions, α1-alterations were associated with more severe phenotype (P=0.0031). Individuals with type I OI caused by qualitative vs quantitative mutations were shorter (P<0.0001), but did not differ considering fractures or BMD. The children in this cohort were estimated to represent >95% of the complete Swedish pediatric OI population. The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population. Collagen I mutation analysis was performed in the family of 97% of known cases, with causative mutations found in 87%. Qualitative mutations caused 32% of OI type I. The data reported here may be helpful to predict phenotype, and describes for the first time the genetic epidemiology in >95% of an entire OI population.