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1.
J Am Geriatr Soc ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31580488

RESUMO

OBJECTIVES: Bisphosphonates are effective at preventing hip fractures among older adults, yet many patients still fracture while on treatment and may benefit from additional preventive interventions. Little data are specifically available to target such efforts among bisphosphonate users. We aimed to identify predictors of hip fracture unique to frail older adults initiating pharmacologic treatment for osteoporosis. DESIGN: Retrospective cohort using 2008-2013 linked national Minimum Data Set assessments, Medicare claims, and nursing home (NH) facility data. SETTING: NHs in the United States. PARTICIPANTS: Long-stay NH residents 65 years or older who initiated treatment with a bisphosphonate (N = 17 753). Estimates for bisphosphonate initiators were contrasted with those for calcitonin initiators (control group; N = 5348). MEASUREMENTS: Hospitalized hip fracture outcomes were measured using Part A claims. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for 36 a priori selected potential predictors. RESULTS: The mean (SD) age of the study population was 84 (8) years, 85% were women, and 51% had moderate to severe cognitive impairment. Predictors associated with a higher risk of hip fracture despite bisphosphonate use included age 75 years or older to 85 years (vs ≥65 to <75 y; HR = 1.25; 95% CI = 1.02-1.55), female sex (HR = 1.33; 95% CI = 1.06-1.67), white race (vs black race (HR = 1.87; 95% CI = 1.36-2.58), and body mass index = 18.5-24.9 (vs ≥30; HR = 1.93; 95% CI = 1.53-2.42). Independent ability to transfer (vs total dependence; HR = 3.11; 95% CI = 1.83-5.30) and occasional urinary incontinence (vs frequent; HR = 1.45; 95% CI = 1.18-1.78) were also important predictors. Dementia, diabetes, psychoactive drug use, and other characteristics were not associated with post-prescribing hip fracture. Predictors did not differ between bisphosphonate and calcitonin users. CONCLUSION: Predictors of hip fracture among frail older adults did not differ between those who were new users of bisphosphonates vs calcitonin. Given the absence of risk factors unique to bisphosphonate users, targeting of fracture prevention efforts should extend beyond pharmacologic therapy to include existing nonpharmacologic therapies, particularly fall prevention strategies.

2.
Epigenetics ; : 1-13, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31506003

RESUMO

DNA methylation (DNAm) has a well-established association with age in many tissues, including peripheral blood mononuclear cells (PBMCs). Compared to DNAm, the closely related epigenetic modification known as DNA hydroxymethylation (DNAhm) was much more recently discovered in mammals. Preliminary investigations have observed a positive correlation between gene body DNAhm and cis-gene expression. While some of these studies have observed an association between age and global DNAhm, none have investigated region-specific age-related DNAhm in human blood samples. In this study, we investigated DNAhm and gene expression in PBMCs of 10 young and 10 old, healthy female volunteers. Thousands of regions were differentially hydroxymethylated in the old vs. young individuals in gene bodies, exonic regions, enhancers, and promoters. Consistent with previous work, we observed directional consistency between age-related differences in DNAhm and gene expression. Further, age-related DNAhm and genes with high levels of DNAhm were enriched for immune system processes which may support a role of age-related DNAhm in immunosenescence.

3.
Bone ; 128: 115050, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31472301

RESUMO

OBJECTIVE: Tools were unavailable to assess fracture risk in nursing homes (NH); therefore, we developed the Fracture Risk Assessment in Long term care (FRAiL) model. The objective of this validation study was to assess the performance of the FRAiL model to predict 2-year risk of non-vertebral and hip fractures in a separate large cohort of NH residents. METHODS: This retrospective cohort study included most long-stay NH residents in the United States (N = 896,840). Hip and non-vertebral fractures were identified using Medicare claims. The Minimum Data Set (MDS) was used to identify characteristics from the original FRAiL model. Multivariable competing risk regression was used to model risk of fracture. RESULTS: Mean age was 83.8 years (±8.2 years) and 70.7% were women. Over a mean follow-up of 1.52 years (SD 0.65), 41,531 residents (4.6%) were hospitalized with non-vertebral fracture (n = 30,356 hip fractures). In the fully adjusted model, 14/15 model characteristics remained significant predictors of non-vertebral fracture. Female sex (HR = 1.55, 95% CI 1.52, 1.59), wandering (HR = 1.30, 95% CI 1.26, 1.34), and falls (HR = 1.28, 95% CI 1.26, 1.31) were strongly associated with non-vertebral fracture rate. Total dependence in ADLs (versus independence) was associated with a decrease in non-vertebral fracture rate (HR = 0.57, 95% CI 0.52, 0.64). Discrimination was moderate in men (C-index = 0.68 for hip, 0.66 for non-vertebral) and women (C-index = 0.68 for hip, 0.65 for non-vertebral), and calibration was excellent. CONCLUSIONS: Our model comprised entirely from routinely collected data was able to identify NH residents at greatest risk for non-vertebral fracture.

4.
J Bone Miner Res ; 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31310354

RESUMO

Although a relationship between vascular disease and osteoporosis has been recognized, its clinical importance for fracture risk evaluation remains uncertain. Abdominal aortic calcification (AAC), a recognized measure of vascular disease detected on single-energy images performed for vertebral fracture assessment, may also identify increased osteoporosis risk. In a prospective 10-year study of 1024 older predominantly white women (mean age 75.0 ± 2.6 years) from the Perth Longitudinal Study of Aging cohort, we evaluated the association between AAC, skeletal structure, and fractures. AAC and spine fracture were assessed at the time of hip densitometry and heel quantitative ultrasound. AAC was scored 0 to 24 (AAC24) and categorized into low AAC (score 0 and 1, n = 459), moderate AAC (score 2 to 5, n = 373), and severe AAC (score >6, n = 192). Prevalent vertebral fractures were calculated using the Genant semiquantitative method. AAC24 scores were inversely related to hip BMD (rs = -0.077, p = 0.013), heel broadband ultrasound attenuation (rs = -0.074, p = 0.020), and the Stiffness Index (rs = -0.073, p = 0.022). In cross-sectional analyses, women with moderate to severe AAC were more likely to have prevalent fracture and lumbar spine imaging-detected lumbar spine fractures, but not thoracic spine fractures (Mantel-Haenszel test of trend p < 0.05). For 10-year incident clinical fractures and fracture-related hospitalizations, women with moderate to severe AAC (AAC24 score >1) had increased fracture risk (HR 1.48; 95% CI, 1.15 to 1.91; p = 0.002; HR 1.46; 95% CI, 1.07 to 1.99; p = 0.019, respectively) compared with women with low AAC. This relationship remained significant after adjusting for age and hip BMD for clinical fractures (HR 1.40; 95% CI, 1.08 to 1.81; p = 0.010), but was attenuated for fracture-related hospitalizations (HR 1.33; 95% CI, 0.98 to 1.83; p = 0.073). In conclusion, older women with more marked AAC are at higher risk of fracture, not completely captured by bone structural predictors. These findings further support the concept that vascular calcification and bone pathology may share similar mechanisms of causation that remain to be fully elucidated © 2019 American Society for Bone and Mineral Research.

6.
Am J Clin Nutr ; 110(2): 437-450, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31165884

RESUMO

BACKGROUND: Folate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans. OBJECTIVE: The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes. METHODS: A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes. RESULTS: The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs. CONCLUSIONS: We identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies.

7.
J Bone Miner Res ; 34(9): 1549-1551, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31237962

RESUMO

The public health implications of osteoporosis are enormous but the disease remains underdiagnosed and undertreated. In October 2018, the National Institutes of Health (NIH) convened a Pathways to Prevention (P2P) Workshop entitled "Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention" designed to identify research gaps, suggest future research opportunities, and advance the field through an evidence-based assessment. By design, the P2P report focused on "gaps" in our knowledge base. Unfortunately, however, the report did not sufficiently acknowledge the current evidence that unequivocally demonstrates the therapeutic efficacy of existing pharmacologic therapies for osteoporosis, which has the potential to exacerbate the current crises in osteoporosis diagnosis and treatment. © 2019 American Society for Bone and Mineral Research.

10.
Bone ; 126: 1, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31136830
12.
Bone ; 123: 204-210, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30951886

RESUMO

OBJECTIVES: To compare the standardized incidence rates (IRs) of hip fracture for Native Americans versus other racial groups in U.S. nursing homes (NHs). METHODS: We studied Medicare fee-for-service NH residents aged ≥65 years who became long-stay (index date) between 1/1/2008 and 12/31/2009 (n = 1,136,544). Residents were followed from the index date until occurrence of hip fracture, death, Medicare disenrollment, or study end (12/31/2013). We calculated hip fracture IRs by race and used inverse probability weighting to standardize the rates for baseline demographic and clinical characteristics collected from the Minimum Data Set and Medicare claims data. We compared characteristics of NHs used by residents of different races using Online Survey, Certification and Reporting (OSCAR) data. RESULTS: Among long-stay U.S. NH residents, the standardized IR of hip fracture per 100 person-years was highest in Native Americans [2.16; 95% confidence interval (CI) 1.91-2.44] and white residents (2.05; 2.03-2.06), and lowest in black residents (0.82; 0.79-0.85). NHs caring for Native American residents were more likely to be rurally located as compared to other racial group. CONCLUSIONS: In U.S. NHs, Native Americans and whites have the highest standardized IR of hip fracture and should receive particular attention in fracture prevention efforts.

14.
BMJ Open ; 9(4): e026232, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30944137

RESUMO

INTRODUCTION: Abdominal aortic calcification (AAC) is associated with low bone mass and increased fracture risk. Two previous meta-analyses have investigated the association between AAC and fracture. However, these meta-analyses only identified articles until December 2016, undertook limited searches and did not explore potential sources of between-study heterogeneity. We aim to undertake a sensitive and comprehensive assessment of the relationship between AAC, bone mineral density (BMD) as well as prevalent and incident fractures. METHODS: We will search MEDLINE, EMBASE, Web of Science core collection and Google Scholar (top 200 articles sorted by relevance) from their inception to 1 June 2018. Reference lists of included studies and previous systematic reviews will be hand searched for additional eligible studies. Retrospective and prospective cohort studies (cross-sectional, case-control and longitudinal) reporting the association between AAC, BMD and fracture at any site will be included. At least two investigators will independently: (A) evaluate study eligibility and extract data, with a third investigator to adjudicate when discrepancies occur, (B) assess study quality by the Newcastle-Ottawa Scale for each cohort/study. The meta-analysis will be reported in adherence to the Meta-analysis of Observational Studies in Epidemiology criteria. AAC will be grouped as either: (1) AAC present or absent, (2) AAC categorised as 'low' (referent-lowest reported group) versus 'high' (all other groups) or (3) dose-response when AAC was assessed in ≥3 groups. Where primary event data were reported in individual studies, pooled risk differences and risk ratios with 95% CI will be calculated, from which, a summary estimate will be determined using DerSimonian-Laird random effects models. For the AAC and BMD pooled analyses, estimates will be expressed as standardised mean difference with 95% CI. We will examine the likelihood of publication bias and where possible, investigate potential reasons for between-study heterogeneity using subgroup analyses and meta-regression. ETHICS AND DISSEMINATION: The study will be submitted to a peer- reviewed journal and disseminated via research presentations. PROSPERO REGISTRATION NUMBER: CRD42018088019.

15.
Artigo em Inglês | MEDLINE | ID: mdl-30869772

RESUMO

BACKGROUND: Lack of consensus on how to diagnose sarcopenia has limited the ability to diagnose this condition and hindered drug development. The Sarcopenia Definitions and Outcomes Consortium (SDOC) was formed to develop evidence-based diagnostic cut-points for lean mass and/or muscle strength that identify people at increased risk of mobility disability. We describe here the proceedings of a meeting of SDOC and other experts to discuss strategic considerations in the development of evidence-based sarcopenia definition. METHODS: Presentations and panel discussions reviewed the usefulness of sarcopenia as a biomarker, the analytical approach used by SDOC to establish cut-points, preliminary findings, and provided strategic direction to develop an evidence-based definition of sarcopenia. RESULTS: The SDOC assembled data from 8 Epidemiologic Cohorts consisting of 18,831 participants; clinical populations from 10 randomized trials and observational studies; and 2 nationally representative cohorts. In preliminary assessments, grip strength or grip strength/body mass index (BMI) were identified as discriminators of risk for mobility disability (walking speed<0.8 m/sec), while DXA-derived lean mass measures were not good discriminators of mobility disability. Candidate definitions based on grip strength variables were associated with increased risk of mortality, falls, mobility disability and instrumental activities of daily living (IADL) disability. The prevalence of low grip strength increased with age. The attendees recommended the establishment of an International Expert panel to review a series of position statements on sarcopenia definition that are informed by the findings of the SDOC analyses and synthesis of literature. CONCLUSIONS: International consensus on an evidence-based definition of sarcopenia is needed. Grip strength - absolute or adjusted for BMI - is an important discriminator of mobility disability and other endpoints. Additional research is needed to develop a predictive risk model that takes into account sarcopenia components as well as age, sex, and race, and comorbidities.

16.
Curr Osteoporos Rep ; 17(2): 86-95, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30820831

RESUMO

PURPOSE OF REVIEW: To summarize the evidence from recent studies on the shared genetics between bone and muscle in humans. RECENT FINDINGS: Genome-wide association studies (GWAS) have successfully identified a multitude of loci influencing the variability of different bone or muscle parameters, with multiple loci overlapping between the traits. In addition, joint analyses of multiple correlated musculoskeletal traits (i.e., multivariate GWAS) have underscored several genes with possible pleiotropic effects on both bone and muscle including MEF2C and SREBF1. Notably, several of the proposed pleiotropic genes have been validated using human cells or animal models. It is clear that the study of pleiotropy may provide novel insights into disease pathophysiology potentially leading to the identification of new treatment strategies that simultaneously prevent or treat both osteoporosis and sarcopenia. However, the role of muscle factors (myokines) that stimulate bone metabolism, as well as osteokines that affect muscles, is in its earliest stage of understanding.

17.
Nat Genet ; 51(2): 258-266, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30598549

RESUMO

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.


Assuntos
Densidade Óssea/genética , Predisposição Genética para Doença/genética , Osteoporose/genética , Adulto , Idoso , Animais , Feminino , Fraturas Ósseas/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
18.
J Am Geriatr Soc ; 67(4): 768-776, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30575958

RESUMO

BACKGROUND: Bisphosphonates are seldom used in frail, older adults, in part due to lack of direct evidence of efficacy in this population and increasing concerns about safety. OBJECTIVE: We estimated the effects of bisphosphonates on hip fractures, nonvertebral fractures, and severe esophagitis among frail, older adults. DESIGN: Population-based retrospective cohort using 2008 to 2013 linked national Minimum Data Set assessments; Online Survey Certification and Reporting System records; and Medicare claims. SETTING: US nursing homes (NHs). PARTICIPANTS: Long-stay NH residents 65 years and older without recent osteoporosis medication use (N = 24,571). Bisphosphonate initiators were 1:1 propensity score matched to calcitonin initiators (active comparator). MEASUREMENTS: Hospitalized hip fracture, nonvertebral fracture, and esophagitis outcomes were measured using part A claims. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated, controlling for over 100 baseline characteristics. RESULTS: The matched cohort included 5209 new bisphosphonate users and an equal number of calcitonin users (mean age [SD] = 85 [8] years; 87% female; 52% moderate-severe cognitive impairment). Over a mean follow-up of 2.5 (SD = 1.7) years, 568 residents (5.5%) had a hip fracture, 874 (8.4%) had a nonvertebral fracture, and 199 (1.9%) had a hospitalized esophagitis event. Users of bisphosphonates were less likely than calcitonin users to experience hip fracture (HR = 0.83; 95% CI = 0.71-0.98), with an average gain in time without fracture of 28.4 days (95% CI = 6.0-50.8 days). Bisphosphonate and calcitonin users had similar rates of nonvertebral fracture (HR = 0.91; 95% CI = 0.80-1.03) and esophagitis events (HR = 1.11; 95% CI = 0.84-1.47). The effects of bisphosphonates on fractures and esophagitis were generally homogeneous across subgroups, including those defined by age, sex, history of prior fracture, and baseline fracture risk. CONCLUSIONS: Use of bisphosphonates is associated with a meaningful reduction in hip fracture among frail, older adults, but little difference in nonvertebral fracture or severe esophagitis. J Am Geriatr Soc 67:768-776, 2019.

19.
Artigo em Inglês | MEDLINE | ID: mdl-30503163

RESUMO

BACKGROUND: Although areal bone mineral density (aBMD) assessed by dual-energy x-ray absorptiometry (DXA) is the clinical standard for determining fracture risk, most older adults who sustain a fracture have T scores greater than -2·5 and thus do not meet the clinical criteria for osteoporosis. Importantly, bone fragility is due to low BMD and deterioration in bone structure. We assessed whether indices of high-resolution peripheral quantitative CT (HR-pQCT) were associated with fracture risk independently of femoral neck aBMD and the Fracture Risk Assessment Tool (FRAX) score. METHODS: We assessed participants in eight cohorts from the USA (Framingham, Mayo Clinic), France (QUALYOR, STRAMBO, OFELY), Switzerland (GERICO), Canada (CaMos), and Sweden (MrOS). We used Cox proportional hazard ratios (HRs) to estimate the association between HR-pQCT bone indices (per 1 SD of deficit) and incident fracture, adjusting for age, sex, height, weight, and cohort, and then additionally for femoral neck DXA aBMD or FRAX. FINDINGS: 7254 individuals (66% women and 34% men) were assessed. Mean baseline age was 69 years (SD 9, range 40-96). Over a mean follow-up of 4·63 years (SD 2·41) years, 765 (11%) participants had incident fractures, of whom 633 (86%) had femoral neck T scores greater than -2·5. After adjustment for age, sex, cohort, height, and weight, peripheral skeleton failure load had the greatest association with risk of fracture: tibia HR 2·40 (95% CI 1·98-2·91) and radius 2·13 (1·77-2·56) per 1 SD decrease. HRs for other bone indices ranged from 1·12 (95% CI 1·03-1·23) per 1 SD increase in tibia cortical porosity to 1·58 (1·45-1·72) per 1 SD decrease in radius trabecular volumetric bone density. After further adjustment for femoral neck aBMD or FRAX score, the associations were reduced but remained significant for most bone parameters. A model including cortical volumetric bone density, trabecular number, and trabecular thickness at the distal radius and a model including these indices plus cortical area at the tibia were the best predictors of fracture. INTERPRETATION: HR-pQCT indices and failure load improved prediction of fracture beyond femoral neck aBMD or FRAX scores alone. Our findings from a large international cohort of men and women support previous reports that deficits in trabecular and cortical bone density and structure independently contribute to fracture risk. These measurements and morphological assessment of the peripheral skeleton might improve identification of people at the highest risk of fracture. FUNDING: National Institutes of Health National Institute of Arthritis Musculoskeletal and Skin Diseases.

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