scholarly journals Age-specific effects of body size on fracture risk in later life: A lifecourse Mendelian randomization study

2021 ◽  
Author(s):  
Grace M. Power ◽  
Jon H. Tobias ◽  
Timothy M. Frayling ◽  
Jess Tyrrell ◽  
April Hartley ◽  
...  
Keyword(s):  
Body Size ◽  
Fracture Risk ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Later Life ◽  
Observational Research ◽  
Mineral Density ◽  
Specific Effects ◽  
Inverse Variance ◽  
Using Data

AbstractMusculoskeletal conditions, including fractures, can have severe and long-lasting consequences. Higher body mass index in adulthood is widely acknowledged to be protective for most fracture sites, indicated through previous clinical and epidemiological observational research. However, the association between weight and bone health is complex and sources of bias, induced by confounding factors, may have distorted earlier findings. Employing a lifecourse Mendelian randomization (MR) approach by using genetic instruments to separate effects at different life stages, this investigation aims to explore how prepubertal and adult body size independently influence fracture risk in later life.Using data from a large UK-based prospective cohort, univariable and multivariable MR with inverse variance weighted meta-analysis were conducted to simultaneously estimate the effects of age-specific genetic proxies for body size (n=453,169) on the odds of fracture in later life (n=416,795). A two-step MR framework was additionally applied to elucidate potential mediators. Univariable and multivariable MR indicated strong evidence that higher body size in childhood reduced fracture risk in later life (OR, 95% CI: 0.89, 0.82 to 0.96, P=0.005 and OR, 95% CI: 0.76, 0.69 to 0.85, P=1×10−6, respectively). Conversely, higher body size in adulthood increased fracture risk (OR, 95% CI: 1.08, 1.01 to 1.16, P=0.023 and OR, 95% CI: 1.26, 1.14 to 1.38, P=2×10−6, respectively). Two-step MR analyses suggested that the effect of higher body size in childhood on reduced fracture risk was mediated by its influence on higher estimated bone mineral density (eBMD) in adulthood.This investigation provides novel evidence that higher body size in childhood has a direct effect on reduced fracture risk in later life through its influence on increased eBMD. Results indicate that higher body size in adulthood is a risk factor for fractures, opposing findings from earlier research. Protective effect estimates previously observed are likely attributed to childhood effects.

Comparative Efficacy of Alendronate upon Vertebral Bone Mineral Density and Fracture Rates in East Asians Versus Non-East Asians with Postmenopausal Osteoporosis: A Systematic Review and Meta-Analysis

2018 ◽  
Vol 50 (10) ◽  
pp. 738-746 ◽  
Author(s):  
Yexin Wang ◽  
Gongwei Jia ◽  
Jin Song ◽  
Xiangqing Kong ◽  
Weihong Zhang ◽  
...  
Keyword(s):  
Vertebral Fracture ◽  
Fracture Risk ◽  
Postmenopausal Osteoporosis ◽  
Meta Analysis ◽  
East Asian ◽  
Bisphosphonate Therapy ◽  
Mineral Density ◽  
East Asians ◽  
Vertebral Fracture Risk ◽  
Lumbar Spinal

AbstractBisphosphonates, such as alendronate, have become the most widely used and effective anti-resorptive therapy for postmenopausal osteoporosis. Previous genetic studies suggest that ethnicity may drive differing responses to bisphosphonate therapy in East Asians and non-East Asians. Therefore, the aim of this study was to comparatively evaluate the efficacy of alendronate upon lumbar spinal BMD and vertebral fracture rates in East Asians and non-East Asians with postmenopausal osteoporosis. MEDLINE, EMBASE, and Cochrane CENTRAL were searched for relevant randomized controlled trials (RCTs) comparing the efficacy of alendronate versus placebo (or calcium/mineral and/or Vitamin D or hormone replacement therapy) in primary postmenopausal osteoporotic women. We calculated the weighted mean differences (WMDs) for lumbar spinal BMD and the risk ratios (RRs) for vertebral fracture risk along with their respective 95% confidence intervals (CIs). From an initial set of 445 non-duplicate records, 13 full-text articles were finally included in this meta-analysis consisting of four East Asian RCTs and nine non-East Asian RCTs. Alendronate therapy displayed significant effects in improving lumbar spinal BMD in both East Asians [WMD (95% CI)=5.30 (0.32–10.29), p=0.037] and non-East Asians [WMD (95% CI)=5.73 (3.61–7.85), p=0.000]. Alendronate therapy did not display significant effects upon vertebral fracture risk in East Asians [RR (95% CI)=0.41 (0.06–2.73), p=0.358] but did display a significant effect upon lowering vertebral fracture risk in non-East Asians [RR (95% CI)=0.55 (0.42–0.72), p=0.000]. These findings suggest that ethnicity may affect the efficacy of bisphosphonate therapy in postmenopausal osteoporotic women.

Effect of metabolites levels on type 2 diabetes mellitus and glycemic traits: a Mendelian randomization study

2021 ◽  
Author(s):  
Yue Sun ◽  
Ya-Ke Lu ◽  
Hao-Yu Gao ◽  
Yu-Xiang Yan
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Significance Level ◽  
Inverse Variance ◽  
Meta Analyses

Abstract Objective To assess the causal associations of plasma levels of metabolites with type 2 diabetes mellitus (T2DM) and glycemic traits. Methods Two-sample mendelian randomization (MR) was conducted to assess the causal associations. Genetic variants strongly associated with metabolites at genome-wide significance level (P < 5 × 10 −8) were selected from public GWAS, and SNPs of Outcomes were obtained from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium for T2DM and from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) for the fasting glucose, insulin and HbA1c. The Wald ratio and inverse-variance weighted methods were used for analyses, and MR-Egger was used for sensitivity analysis. Results The β estimates per 1 SD increasement of arachidonic acid (AA) level was 0.16 (95% CI: 0.078, 0.242; P<0.001). Genetic predisposition to higher plasma AA levels were associated with higher FG levels (β 0.10 [95%CI: 0.064, 0.134], P<0.001), higher HbA1c levels (β 0.04 [95%CI: 0.027, 0.061]) and lower FI levels (β -0.025 [95%CI: -0.047, -0.002], P=0.033). Besides, 2-hydroxybutyric acid (2-HBA) might have positive causal effect on glycemic traits. Conclusions Our findings suggest that AA and 2-HBA may have the causal associations on T2DM and glycemic traits. It is beneficial for clarifying the pathogenesis of T2DM, which would be valuable for early identification and prevention for T2DM.

scholarly journals Weight loss since early adulthood, later life risk of fracture hospitalizations, and bone mineral density: a prospective cohort study of 0.5 million Chinese adults

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Zewei Shen ◽  
◽  
Canqing Yu ◽  
Yu Guo ◽  
Zheng Bian ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Weight Loss ◽  
Hip Fracture ◽  
Fracture Risk ◽  
Bone Mineral ◽  
Early Adulthood ◽  
Broadband Ultrasound Attenuation ◽  
Later Life ◽  
Mineral Density

Abstract Summary In a Chinese population from both urban and rural areas, weight loss of ≥ 5 kg from early adulthood to midlife was associated with a higher risk of hip fracture and lower BMD in later life. Introduction This study investigates the association of the long-term weight loss from young adulthood through the middle ages with the subsequent 10-year risk of hospitalized fracture and calcaneus bone mineral density (BMD). Methods China Kadoorie Biobank (CKB) was established during 2004–2008 in ten areas across China. Weight at age 25 years was self-reported at baseline, and weight at baseline and resurvey was measured by the calibrated equipment. Outcomes were hospitalized fracture during follow-up and calcaneus BMD measured at resurvey. Analysis for fracture risk included 411,812 participants who were free of fracture in the last 5 years before baseline, cancer, or stroke at any time before baseline. Analysis for BMD included 21,453 participants who participated in the resurvey of 2013–2014 with the same exclusion criteria as above. Results The mean age was 50.8 at baseline and 58.4 at resurvey. Median weight change from age 25 to baseline was 4.4 kg, with 20.7% losing weight and 58.5% gaining weight. During a median follow-up of 10.1 years, we documented 13,065 cases of first diagnosed fracture hospitalizations, including 1222 hip fracture. Compared with participants whose weight was stable (± 2.4 kg), the adjusted hazard ratios (95% CIs) for those with weight loss of ≥ 5.0 kg from age 25 to baseline was 1.39 (1.17 to 1.66) for hip fracture. Weight loss was not associated with fracture risk at other sites. Those with weight loss from age 25 to resurvey had the lowest BMD measures, with β (95% CIs) of − 4.52 (− 5.08 to − 3.96) for broadband ultrasound attenuation (BUA), − 4.83 (− 6.98, − 2.67) for speed of sound (SOS), and − 4.36 (− 5.22, − 3.49) for stiffness index (SI). Conclusions Weight loss from early adulthood to midlife was associated with a higher risk of hip fracture and lower BMD in later life.

scholarly journals Authors’ Reply: Veganism, vegetarianism, bone mineral density, and fracture risk: a systematic review and meta-analysis

2019 ◽  
Vol 77 (6) ◽  
pp. 452-453
Author(s):  
Isabel Iguacel ◽  
María L Miguel-Berges ◽  
Alejandro Gómez-Bruton ◽  
Luis A Moreno ◽  
Cristina Julian
Keyword(s):  
Bone Mineral Density ◽  
Systematic Review ◽  
Fracture Risk ◽  
Bone Mineral ◽  
Meta Analysis ◽  
Mineral Density

scholarly journals Aspirin and fracture risk: a systematic review and exploratory meta-analysis of observational studies

BMJ Open ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. e026876 ◽  
Author(s):  
A L Barker ◽  
Sze-Ee Soh ◽  
Kerrie M Sanders ◽  
Julie Pasco ◽  
Sundeep Khosla ◽  
...  
Keyword(s):  
Systematic Review ◽  
Fracture Risk ◽  
Observational Studies ◽  
Meta Analysis ◽  
Large Population ◽  
Mineral Density ◽  
Random Effects Models ◽  
Manual Search ◽  
Relative Risks ◽  
Hip Bmd

ObjectivesThis review provides insights into the potential for aspirin to preserve bone mineral density (BMD) and reduce fracture risk, building knowledge of the risk-benefit profile of aspirin.MethodsWe conducted a systematic review and exploratory meta-analysis of observational studies. Electronic searches of MEDLINE and Embase, and a manual search of bibliographies was undertaken for studies published to 28 March 2018. Studies were included if: participants were men or women aged ≥18 years; the exposure of interest was aspirin; and relative risks, ORs and 95% CIs for the risk of fracture or difference (percentage or absolute) in BMD (measured by dual energy X-ray absorptiometry) between aspirin users and non-users were presented. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklists for observational studies. Pooled ORs for any fracture and standardised mean differences (SMDs) for BMD outcomes were calculated using random-effects models.ResultsTwelve studies met the inclusion criteria and were included in the meta-analysis. Aspirin use was associated with a 17% lower odds for any fracture (OR 0.83, 95% CI 0.70 to 0.99; I2=71%; six studies; n=511 390). Aspirin was associated with a higher total hip BMD for women (SMD 0.03, 95% CI −0.02 to 0.07; I2=0%; three studies; n=9686) and men (SMD 0.06, 95% CI −0.02 to 0.13, I2=0%; two studies; n=4137) although these associations were not significant. Similar results were observed for lumbar spine BMD in women (SMD 0.03, 95% CI −0.03 to 0.09; I2=34%; four studies; n=11 330) and men (SMD 0.08; 95% CI −0.01 to 0.18; one study; n=432).ConclusionsWhile the benefits of reduced fracture risk and higher BMD from aspirin use may be modest for individuals, if confirmed in prospective controlled trials, they may confer a large population benefit given the common use of aspirin in older people.

scholarly journals Matrix Metalloproteinases in Relation to Bone Mineral Density: A Two-Sample Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Lv ◽  
Pengfei Wu ◽  
Shipeng Xiao ◽  
Wan Zhang ◽  
Yawei Li ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Lumbar Spine ◽  
Matrix Metalloproteinases ◽  
Femoral Neck ◽  
Bone Mineral ◽  
Mendelian Randomization ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Mineral Density ◽  
Inverse Variance

Background: We aimed at investigating causal associations between matrix metalloproteinases (MMPs) and bone mineral density (BMD) by the Mendelian randomization (MR) analysis.Methods: From genome-wide association studies of European ancestry, we selected instrumental variables for MMP-1, MMP-3, MMP-7, MMP-8, MMP-10, and MMP-12. Accordingly, we retrieved summary statistics of three site-specific BMD, namely, forearm, femoral neck, and lumbar spine. We conducted an inverse variance weighted MR as the primary method to compute overall effects from multiple instruments, while additional MR approaches and sensitivity analyses were implemented. Bonferroni-adjusted significance threshold was set at p < 0.05/18 = 0.003.Results: Totally, there was no evidence for causal effects of genetically-predicted levels of MMPs on BMD measurement at three common sites. MR results indicated that there were no causal associations of circulating MMPs with forearm BMD (all p ≥ 0.023) by the inverse variance weighted method. Similarly, there were no causal effects of MMPs on femoral neck BMD (all p ≥ 0.120) and MR results did not support causal relationships between MMPs and lumbar spine BMD (all p ≥ 0.017). Multiple sensitivity analyses suggested the robustness of MR results, which were less likely to be biased by unbalanced pleiotropy or evident heterogeneity.Conclusion: We found no evidence for the causal relationship between MMPs and BMD in the European population.

scholarly journals High Level of Uromodulin Increases the Risk of Hypertension: A Mendelian Randomization Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Ruilian You ◽  
Lanlan Chen ◽  
Lubin Xu ◽  
Dingding Zhang ◽  
Haitao Li ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Inverse Variance ◽  
The Uk ◽  
High Level

Background: The association of uromodulin and hypertension has been observed in clinical studies, but not proven by a causal relationship. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between uromodulin and blood pressure.Methods: We selected single nucleotide polymorphisms (SNPs) related to urinary uromodulin (uUMOD) and serum uromodulin (sUMOD) from a large Genome-Wide Association Studies (GWAS) meta-analysis study and research in PubMed. Six datasets based on the UK Biobank and the International Consortium for Blood Pressure (ICBP) served as outcomes with a large sample of hypertension (n = 46,188), systolic blood pressure (SBP, n = 1,194,020), and diastolic blood pressure (DBP, n = 1,194,020). The inverse variance weighted (IVW) method was performed in uUMOD MR analysis, while methods of IVW, MR-Egger, Weighted median, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were utilized on sUMOD MR analysis.Results: MR analysis of IVM showed the odds ratio (OR) of the uUMOD to hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.04 (95% Confidence Interval (CI), 1.03-1.04, P < 0.001); the effect sizes of the uUMOD to SBP are 1.10 (Standard error (SE) = 0.25, P = 8.92E-06) and 0.03 (SE = 0.01, P = 2.70E-04) in “ieu-b-38” and “ukb-b-20175”, respectively. The β coefficient of the uUMOD to DBP is 0.88 (SE = 0.19, P = 4.38E-06) in “ieu-b-39” and 0.05 (SE = 0.01, P = 2.13E-10) in “ukb-b-7992”. As for the sUMOD, the OR of hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.01 (95% CI 1.01–1.02, all P < 0.001). The β coefficient of the SBP is 0.37 (SE = 0.07, P = 1.26E-07) in “ieu-b-38” and 0.01 (SE = 0.003, P = 1.04E-04) in “ukb-b-20175”. The sUMOD is causally associated with elevated DBP (“ieu-b-39”: β = 0.313, SE = 0.050, P = 3.43E-10; “ukb-b-7992”: β = 0.018, SE = 0.003, P = 8.41E-09).Conclusion: Our results indicated that high urinary and serum uromodulin levels are potentially detrimental in elevating blood pressure, and serve as a causal risk factor for hypertension.

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