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HubLE MY MENTOR & I Perspective: Mendelian randomization: evaluation of causality between risk factors and outcomes
Abstract
Mendelian randomization (MR) is a powerful approach that evaluates the causal association between a risk factor and an outcome. It makes use of the random allocation of genetic variants to mimic randomizers in randomized controlled trials (RCTs), providing quality evidence that is less susceptible to unmeasured confounding and reverse causality, when compared to conventional observational studies. Currently, MR has been applied in osteoporosis-related research to begin to unravel the causal risk factors that predispose to low bone mineral density (BMD) and increased susceptibility of fracture. Some MR studies made use of serum level measurement as a surrogate to mimic the role of supplementation, such as vitamin D and calcium, and evaluate the effects of the supplements in bone metabolism. From clinical perspective, MR studies enable identification of diagnostic markers and therapeutic targets. They provide evidence on the efficacy and adverse effects of drugs, contributing to discovery and repurposing of drugs.
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Several epidemiological studies have reported a relationship between statin treatment and increased bone mineral density (BMD) and reduced fracture risk, but the mechanism underlying the purported relationship is unclear. We used Mendelian randomization (MR) to assess whether this relationship is explained by a specific effect in response to statin use or by a general effect of lipid lowering. We utilized 400 single‐nucleotide polymorphisms (SNPs) robustly associated with plasma lipid levels as exposure. The outcome results were obtained from a heel estimated BMD (eBMD) genomewide association study (GWAS) from the UK Biobank and dual‐energy X‐ray absorptiometry (DXA) BMD at four body sites and fracture GWAS from the GEFOS consortium. We performed univariate and multivariable MR analyses of low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), and triglyceride levels on BMD and fracture. Univariate MR analyses suggested a causal effect of LDL‐C on eBMD (β = −0.06; standard deviation change in eBMD per standard deviation change in LDL‐C, 95% confidence interval [CI] = –0.08 to −0.04; p = 4 × 10−6), total body BMD (β = −0.05, 95% CI = –0.08 to −0.01, p = 6 × 10−3) and potentially on lumbar spine BMD. Multivariable MR suggested that the effects of LDL‐C on eBMD and total body BMD were independent of HDL‐C and triglycerides. Sensitivity MR analyses suggested that the LDL‐C results were robust to pleiotropy. MR analyses of LDL‐C restricted to SNPs in the HMGCR region showed similar effects on eBMD (β = −0.083; −0.132 to −0.034; p = 0.001) to those excluding these SNPs (β = −0.063; −0.090 to −0.036; p = 8 × 10−6). Bidirectional MR analyses provided some evidence for a causal effect of eBMD on plasma LDL‐C levels. Our results suggest that effects of statins on eBMD and total body BMD are at least partly due to their LDL‐C lowering effect. Further studies are required to examine the potential role of modifying plasma lipid levels in treating osteoporosis. © 2020 American Society for Bone and Mineral Research.
In bone, sclerostin is mainly osteocyte‐derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two sample Mendelian Randomisation (MR). A genetic instrument for circulating sclerostin, derived from a genome wide association study (GWAS) meta‐analysis of serum sclerostin in 10,584 European‐descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n= 32,744) in GEFOS, and estimated BMD by heel ultrasound (eBMD; n=426,824), and fracture risk (n=426,795), in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation (SD)) change in sclerostin per A allele (β=0.20, P=4.6x10‐49), and GALNT1 (β=0.11 per G allele, P=4.4x10‐11). B4GALNT3 is an N‐acetyl‐galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin‐type O‐linked glycosylation. Using these two SNPs as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β= ‐0.12, 95%CI= ‐0.20 to ‐0.05) and eBMD (β= ‐0.12, 95%CI= ‐0.14 to ‐0.10), and a positive relationship with fracture risk (β= 0.11,95%CI= 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (Probability>99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis. This article is protected by copyright. All rights reserved.
Bone mineral density (BMD) and lipid levels are two of the most extensively studied risk factors for common diseases of aging, such as cardiovascular disease (CVD) and osteoporosis (OP). These two risk factors are also correlated with each other, but little is known about the molecular mechanisms behind this correlation. Recent studies revealed that circulating levels of several metabolites involved in the biosynthesis of androsterone correlate significantly with BMD and have the capacity to affect cholesterol and lipids levels. A main aim of the present study was to investigate the hypothesis that androsterone-related metabolites could provide a link between CVD and OP, as a common cause of lipid levels and BMD. The present study employed data from the NIHR BRC TwinsUK BioResource, comprising 1909 and 1994 monozygotic and dizygotic twin pairs, respectively, to address the causal relationships among BMD and lipids, and their associated metabolites, using reciprocal causation twin modelling, as well as Mendelian randomization (MR) using large publicly-available GWAS datasets on lipids and BMD, in conjunction with TwinsUK metabolite data. While results involving the twin modelling and MR analyses with metabolites were unable to establish a causal link between metabolite levels and either lipids or BMD, MR analyses of BMD and lipids suggest that lipid levels have a causal impact on BMD, which is consistent with findings from clinical trials of lipid-lowering drugs, which have also increased BMD.
Mendelian randomisation uses genetic variation as a natural experiment to investigate the causal relations between potentially modifiable risk factors and health outcomes in observational data. As with all epidemiological approaches, findings from Mendelian randomisation studies depend on specific assumptions. We provide explanations of the information typically reported in Mendelian randomisation studies that can be used to assess the plausibility of these assumptions and guidance on how to interpret findings from Mendelian randomisation studies in the context of other sources of evidence. © Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to.
Context
Osteoporosis is a metabolic bone disease. The impact of blood metabolites on the development of osteoporosis remains elusive now.
Objective
To explore the relationship between blood metabolites and osteoporosis.
Design and Methods
We used 2,286 unrelated Caucasian subjects as discovery samples and 3,143 unrelated Caucasian subjects from the Framingham heart study (FHS) as replication samples. Bone mineral density (BMD) were measured using dual-energy X-ray absorptiometry. Genome-wide SNP genotyping was performed using Affymetrix Human SNP Array 6.0 (for discovery samples) and Affymetrix SNP 500K and 50K array (for FHS replication samples). The SNP sets significantly associated with blood metabolites were obtained from a published whole-genome sequencing study. For each subject, the genetic risk score (GRS) of metabolite was calculated from the genotype data of metabolite associated SNP sets. Pearson correlation analysis was conducted to evaluate the potential impact of blood metabolites on the variations bone phenotypes. 10,000 permutations were conducted to calculate the empirical P value and false discovery rate (FDR).
Results
481 blood metabolites were analyzed in this study. We identified multiple blood metabolites associated with hip BMD, such as 1,5-anhydroglucitol(1,5-AG) (Pdiscovery < 0.0001, Preplication = 0.0361), inosine (Pdiscovery = 0.0018, Preplication = 0.0256), theophylline (Pdiscovery = 0.0048, Preplication = 0.0433, gamma-glutamylmethionine (Pdiscovery = 0.0047, Preplication = 0.0471), 1-linoleoyl-2-arachidonoyl-GPC (18:2/20:4n6) (Pdiscovery = 0.0018, Preplication=0.0390) and X-12127 (Pdiscovery = 0.0002, Preplication = 0.0249).
Conclusions
Our results suggest the modest impact of blood metabolites on the variations of BMD, and identified several candidate blood metabolites for osteoporosis.
Context
Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability. No genome-wide association study (GWAS) of estrogen levels has been performed in men of European origin.
Objective
To investigate the genetic regulation of serum E2 and E1 in men.
Design, setting and participants
GWAS in 11,097 men of European origin from nine epidemiological cohorts.
Main Outcome Measures
Genetic determinants of serum E2 and E1 levels.
Results
Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAM9B, rs5934505 (p-value 3.4 x 10⁻⁸) and Xq27.3, rs5951794 (p-value 3.1 x 10⁻¹⁰). E1 signals were found in CYP19A1 (rs2899472, p-value 5.5 x 10⁻²³), in TRIM4 (rs17277546, p = 5.8 x 10⁻¹⁴) and in CYP11B1/B2 (rs10093796, p-value 1.2 x 10⁻⁸).
E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian Randomization analysis suggested a causal effect of serum E2 on BMD in men. 1 pg/ml genetically increased E2 was associated with a 0.048 SD increase in lumbar spine BMD (p-value 2.8 x 10⁻¹²).
In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.
Conclusions
Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels, and strengthen the causal importance of E2 for bone health in men. We also report 2 new independent loci on the X-chromosome for E2, one new locus each in TRIM4 and CYP11B1/B2, for E1.
The metabolic state of the body can be a major determinant of bone health. We used a Mendelian Randomization approach to identify metabolites causally associated with bone mass to better understand the biological mechanisms of osteoporosis. We tested bone phenotypes (femoral neck, total hip, and lumbar spine BMD) for association with 280 fasting blood metabolites in 6055 women from TwinsUK cohort with genome-wide genotyping scans. Causal associations between metabolites and bone phenotypes were further assessed in a bidirectional Mendelian Randomization study using genetic markers/scores as instrumental variables. Significant associations were replicated in 624 participants from Hong Kong Osteoporosis Study (HKOS). 15 metabolites showed direct associations with bone phenotypes after adjusting for covariates and multiple testing. Using genetic instruments, 4 of these metabolites were found to be causally associated with hip or spine BMD. These included androsterone sulfate, epiandrosterone sulfate, 5alpha-androstan-3beta17beta-diol disulfate (encoded by CYP3A5), and 4-androsten-3beta17beta-diol disulfate (encoded by SULT2A1). In the HKOS population, all four metabolites showed significant associations with hip and spine BMD in the expected directions. No causal reverse association between BMD and any of the metabolites were found. In the first metabolome-genome-wide Mendelian randomization study of human bone mineral density, we identified 4 novel biomarkers causally associated with BMD. Our findings reveal novel biological pathways involved in the pathogenesis of osteoporosis. This article is protected by copyright. All rights reserved
Objective:
To determine whether increasing calcium intake from dietary sources affects bone mineral density (BMD) and, if so, whether the effects are similar to those of calcium supplements.
Design:
Random effects meta-analysis of randomised controlled trials.
Data sources:
Ovid Medline, Embase, Pubmed, and references from relevant systematic reviews. Initial searches were undertaken in July 2013 and updated in September 2014.
Eligibility criteria for selecting studies:
Randomised controlled trials of dietary sources of calcium or calcium supplements (with or without vitamin D) in participants aged over 50 with BMD at the lumbar spine, total hip, femoral neck, total body, or forearm as an outcome.
Results:
We identified 59 eligible randomised controlled trials: 15 studied dietary sources of calcium (n=1533) and 51 studied calcium supplements (n=12,257). Increasing calcium intake from dietary sources increased BMD by 0.6-1.0% at the total hip and total body at one year and by 0.7-1.8% at these sites and the lumbar spine and femoral neck at two years. There was no effect on BMD in the forearm. Calcium supplements increased BMD by 0.7-1.8% at all five skeletal sites at one, two, and over two and a half years, but the size of the increase in BMD at later time points was similar to the increase at one year. Increases in BMD were similar in trials of dietary sources of calcium and calcium supplements (except at the forearm), in trials of calcium monotherapy versus co-administered calcium and vitamin D, in trials with calcium doses of ≥ 1000 versus <1000 mg/day and ≤ 500 versus >500 mg/day, and in trials where the baseline dietary calcium intake was <800 versus ≥ 800 mg/day.
Conclusions:
Increasing calcium intake from dietary sources or by taking calcium supplements produces small non-progressive increases in BMD, which are unlikely to lead to a clinically significant reduction in risk of fracture.
Vascular endothelial growth factor (VEGF) is important for bone formation and has been associated with osteoporosis in humans. Therefore, we conducted a two‐sample Mendelian randomization study to test whether genetically decreased circulating VEGF was associated with decreased bone mineral density (BMD) and increased risk of fracture. Summary statistics from a genome‐wide association study (GWAS) meta‐analysis of circulating VEGF level (N = 16,112) were used to identify 10 genetic variants explaining up to 52% of the variance in circulating VEGF levels. GWAS meta‐analyses on dual X‐ray absorptiometry‐derived BMD of forearm, lumbar spine, and femoral neck (N = up to 32,735), and BMD estimated from heel calcaneus ultrasound (eBMD) (N = 426,824) were used to assess the effect of genetically lowered circulating VEGF levels on BMD. A GWAS meta‐analysis including a total of 76,549 cases and 470,164 controls was used to assess the effect of genetically lowered circulating VEGF levels on risk of fracture. A natural log‐transformed pg/mL decrease in circulating VEGF levels was not associated with a decrease in forearm BMD (0.02 standard deviations (SD), 95% CI: [−0.024, 0.064], p = 0.38), lumbar spine BMD (−0.005 SD, 95% CI: [−0.03, 0.019], p = 0.67), femoral neck BMD (0.004 SD, 95% CI: [−0.017, 0.026], p = 0.68), eBMD (−0.006 SD, 95% CI: [−0.012, −0.001], p = 0.031) or risk of fracture (odds ratio: 0.99, 95% CI: [0.98, 1.0], p = 0.37) in inverse‐variance weighted Mendelian randomization analyses. Sensitivity analyses did not provide evidence that our results were influenced by pleiotropy. Genetically lowered circulating VEGF was not associated with a decrease in BMD or increased risk of fracture, suggesting that efforts to influence circulating VEGF level are unlikely to have beneficial effects on osteoporosis outcomes and that previous observational associations of circulating VEGF with BMD were influenced by confounding or reverse causation. This article is protected by copyright. All rights reserved.
Background:
The relationship between lipids and the risk of fracture is currently controversial and whether such association is causal remains elusive.
Methods:
We performed two-sample inverse variance weighted (IVW) Mendelian randomization (MR) analyses to evaluate causal effects of four lipids (i.e. high-density lipoprotein cholesterol [HDL], low-density lipoprotein cholesterol [LDL], total cholesterol [TC] and triglyceride [TG]) on fracture or bone mineral density (BMD) with summary statistics from large scale genome-wide association studies (up to ~190,000 for lipids, ~66,628 for BMD and ~53,000 for fracture). We validated our MR results with extensive sensitive analyses including MR-PRESSO and MR-Egger regression. Multivariable analyses were implemented to investigate whether other lipids (i.e. LDL and TG) may confound the causal effect of HDL on fracture and mediation analyses were conducted to assess indirect effects of lipids on fracture mediated by BMD.
Results:
The IVW MR showed there existed a statistically significant association between HDL and fracture, with the odd ratio (OR) per standard deviation change of HDL on fracture being 1.12 (95% CI: 1.02-1.22, p = 1.20E-02). HDL was also detected to be causally associated with BMD (beta = -0.116; 95% CI: -0.182 ~ -0.050, p = 5.47E-04). These associations were further confirmed by the weighted median and maximum likelihood methods, with the MR-Egger regression removing the possibility of pleiotropy and the multivariable analysis excluding the confounding effect of other lipids on HDL. Negative associations of HDL with BMD among the elderly and with BMD at the lumbar spine were also discovered. However, no causal associations were detected between other lipids (OR = 0.87, 95% CI: 0.74-1.03, p = .107 for LDL; OR = 1.03; 95% CI: 0.88-1.21, p = .696 for TC and OR = 1.04; 95% CI: 0.90-1.20, p = .610 for TG) and fracture; whereas TG was positively associated BMD (beta = 0.184; 95% CI: 0.048-0.319, p = 7.93E-03). Finally, the mediation effect of BMD was estimated to be -0.116 (95% CI: -0.182 to -0.05, p = 5.47E-04) for HDL or 0.184 (95% CI: 0.048-0.319, p = 7.93E-03) for TG, implying HDL and TG could be indirectly associated with fracture risk via the pathway of BMD.
Conclusion:
Our study is supportive of the causal relationship between HDL and fracture but offers little direct evidence for causal associations between other lipids and fracture, and further reveals HDL and TG may have an indirect influence on fracture mediated by BMD.
Background:
Low-density lipoprotein cholesterol (LDL-C) is suggested to play a role in osteoporosis but its association with bone metabolism remains unclear. Effects of LDL-C-lowering drugs on bone are also controversial. We aim to determine whether LDL-C is linked causally to bone mineral density (BMD) and assess the effects of LDL-C-lowering drugs on BMD.
Methods:
Association between blood lipid levels and BMD was examined by epidemiological observation analyses in a US representative cohort NHANES III (n = 3638) and the Hong Kong Osteoporosis Study (HKOS; n = 1128). Two-sample Mendelian randomization (MR), employing genetic data from a large-scale genome-wide association study (GWAS) of blood lipids (n = 188 577), total body BMD (TB-BMD) (n = 66 628) and estimated BMD (eBMD) (n= 142 487), was performed to infer causality between LDL-C and BMD. Genetic proxies for LDL-C-lowering drugs were used to examine the drugs' effects on BMD.
Results:
In the NHANES III cohort, each standard deviation (SD) decrease in LDL-C was associated with a 0.045 SD increase in femoral neck BMD (95% CI: 0.009 - 0.081; P = 0.015). A similar increase in BMD was observed in the HKOS at femoral neck and lumbar spine. In MR analysis, a decrease in genetically predicted LDL-C was associated with an increase in TB-BMD {estimate per SD decrease, 0.038 [95% confidence interval (CI): 0.002 - 0.074]; P = 0.038} and eBMD [0.076 (0.042 - 0.111); P = 1.20x10-5]. Reduction in TB-BMD was causally associated with increased LDL-C [0.035 (0.033 - 0.066); P = 0.034]. Statins' LDL-C-lowering proxies were associated with increased TB-BMD [0.18 (0.044 - 0.316); P = 9.600x10-3] and eBMD [0.143 (0.062 - 0.223); P = 5.165x10-4].
Conclusions:
Negative causal association exists between LDL-C level and BMD. Statins' LDL-C-lowering effect increases BMD, suggesting their protective effect on bone.
The level of serum lipids is associated with bone mineral density (BMD), an important skeletal trait. Yet the causality has not been determined. Here we performed a Mendelian randomization (MR) analysis to test potential causal links between BMD and lipid profile, i.e., low-density lipoprotein cholesterol (LDC-c), total cholesterol (TC), triglyceride (TG) and high-density lipoprotein cholesterol (HDL-c). We observed causal effect of LDL-c, TC and TG to BMD, and reversely the effect of BMD to HDL-c. We further explored the effect of body mass index (BMI) in these causalities and found that the effect of LDL-c, TC and TG to BMD is independent of BMI. Our findings provided useful information in the clinical relevance of blood lipids on BMD variation and osteoporosis risk.
Leptin, a small polypeptide hormone secreted by the adipocytes, controls body weight and gonadal function by binding to a special receptor located in the hypothalamus. Observational studies have demonstrated a controversial association between leptin and bone mineral density (BMD), and functional studies of the relationship between leptin and BMD still largely vary by different studies. Using SNPs strongly associated with leptin levels in 52,140 individuals, we conducted a two-sample Mendelian randomization study to identify whether genetically lowered leptin levels were associated with BMD by using an inverse-variance weighted method, a weighted median method, MR-Egger and Robust Adjusted Profile Score. We found that circulating leptin levels may causally decrease lumbar spine BMD (effect size = -0.45, 95% CI: -0.82, -0.083; p value = 0.016). The association estimates of circulating leptin levels on femoral neck, forearm and total body BMD were not significant. Our study suggests that genetically predicted higher circulating leptin was associated with lower LS-BMD.
This part of the work was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR). This work was supported by the Medical Research Council (Programme Grant MC_UU_12013/4 to D.M.E.), the Wellcome Trust (Strategic Award grant number 101123; project grant 094134; to G.R.W., J.H.D.B. and P.I.C.), the Netherlands Organization for Health Research and Development ZonMw VIDI 016.136.367 (funding to F.R., C.M.-G. and K.T.), the mobility stimuli plan of the European Union Erasmus Mundus Action 2: ERAWEB (programme funding to K.T.), NIAMS, NIH (AR060981 and AR060234 to C.L.A.-B.), the National Health and Medical Research Council (Early Career Fellowship APP1104818 to N.M.W.), the Swedish Research Council (funding to E.G.), the Réseau de Médecine Génétique Appliquée (RMGA; J.A.M.), the Fonds de Recherche du Québec–Santé (FRQS; J.A.M. and J.B.R.), the Natural Sciences and Engineering Research Council of Canada (C.M.T.G.), the J. Gibson and the Ernest Heine Family Foundation (P.I.C.), Arthritis Research UK (ref. 20000; to C.L.G.), the Canadian Institutes of Health Research (J.B.R.), the Jewish General Hospital (J.B.R.), and the Australian Research Council (Future Fellowship FT130101709 to D.M.E.). This research was conducted using the UK Biobank Resource (application number 12703). Access to the UK Biobank study data was funded by the University of Queensland (Early Career Researcher Grant 2014002959 to N.M.W.).
Context
Observational studies indicate that serum estradiol (E2) is more strongly associated with bone mineral density (BMD) than serum testosterone (T) while both E2 and T associate with fracture risk in men.
Objective
To evaluate the possible causal effect of serum E2 and T on fracture risk in men.
Design, Setting, and Participants
A Mendelian Randomization (MR) approach was undertaken using individual-level data of genotypes, BMD as estimated by quantitative ultrasound of the heel (eBMD), fractures (n=17,650), and relevant covariates of 175,583 unrelated men of European origin from the UK Biobank. The genetic instruments for serum E2 and T were taken from the most recent large scale GWAS meta-analyses on these hormones in men.
Results
MR analyses demonstrated a causal effect of serum E2 on eBMD and fracture risk. A 1 SD (or 9.6 pg/ml) genetically instrumented decrease in serum E2 was associated with a 0.38 SD decrease in eBMD (p-value 9.7 x 10⁻⁷⁴) and an increased risk of any fracture (OR 1.35, 95% CI, 1.18-1.55), non-vertebral major osteoporotic fractures (OR 1.75, 95% CI, 1.35-2.27) and wrist fractures (OR 2.27, 95% CI, 1.62-3.16). These causal effects of serum E2 on fracture risk were robust in sensitivity analyses and remained unchanged in stratified analyses for age, BMI, eBMD, smoking status, and physical activity. MR analyses revealed no evidence of a causal effect of T levels on fracture risk.
Conclusion
Our findings provide the first evidence of a robust causal effect of serum E2, but not T, on fracture risk in men.
The relationship between bone quantitative ultrasound (QUS) and fracture risk was estimated in an individual level data meta-analysis of 9 prospective studies of 46,124 individuals and 3018 incident fractures. Low QUS is associated with an increase in fracture risk, including hip fracture. The association with osteoporotic fracture decreases with time.
The aim of this meta-analysis was to investigate the association between parameters of QUS and risk of fracture.
In an individual-level analysis, we studied participants in nine prospective cohorts from Asia, Europe and North America. Heel broadband ultrasonic attenuation (BUA dB/MHz) and speed of sound (SOS m/s) were measured at baseline. Fractures during follow-up were collected by self-report and in some cohorts confirmed by radiography. An extension of Poisson regression was used to examine the gradient of risk (GR, hazard ratio per 1 SD decrease) between QUS and fracture risk adjusted for age and time since baseline in each cohort. Interactions between QUS and age and time since baseline were explored.
Baseline measurements were available in 46,124 men and women, mean age 70 years (range 20-100). Three thousand and eighteen osteoporotic fractures (787 hip fractures) occurred during follow-up of 214,000 person-years. The summary GR for osteoporotic fracture was similar for both BUA (1.45, 95 % confidence intervals (CI) 1.40-1.51) and SOS (1.42, 95 % CI 1.36-1.47). For hip fracture, the respective GRs were 1.69 (95 % CI, 1.56-1.82) and 1.60 (95 % CI, 1.48-1.72). However, the GR was significantly higher for both fracture outcomes at lower baseline BUA and SOS (p < 0.001). The predictive value of QUS was the same for men and women and for all ages (p > 0.20), but the predictive value of both BUA and SOS for osteoporotic fracture decreased with time (p = 0.018 and p = 0.010, respectively). For example, the GR of BUA for osteoporotic fracture, adjusted for age, was 1.51 (95 % CI 1.42-1.61) at 1 year after baseline, but at 5 years, it was 1.36 (95 % CI 1.27-1.46).
Our results confirm that quantitative ultrasound is an independent predictor of fracture for men and women particularly at low QUS values.
Findings from recent meta-analyses of vitamin D supplementation without co-administration of calcium have not shown fracture prevention, possibly because of insufficient power or inappropriate doses, or because the intervention was not targeted to deficient populations. Despite these data, almost half of older adults (older than 50 years) continue to use these supplements. Bone mineral density can be used to detect biologically significant effects in much smaller cohorts. We investigated whether vitamin D supplementation affects bone mineral density.
Observational epidemiological studies suffer from many potential biases, from confounding and from reverse causation, and this limits their ability to robustly identify causal associations. Several high-profile situations exist in which randomized controlled trials of precisely the same intervention that has been examined in observational studies have produced markedly different findings. In other observational sciences, the use of instrumental variable (IV) approaches has been one approach to strengthening causal inferences in non-experimental situations. The use of germline genetic variants that proxy for environmentally modifiable exposures as instruments for these exposures is one form of IV analysis that can be implemented within observational epidemiological studies. The method has been referred to as 'Mendelian randomization', and can be considered as analogous to randomized controlled trials. This paper outlines Mendelian randomization, draws parallels with IV methods, provides examples of implementation of the approach and discusses limitations of the approach and some methods for dealing with these.
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