Serum non-esterified fatty acid levels and hip fracture risk: The Cardiovascular Health Study.

Among elderly participants from the Cardiovascular Health Study, we found that non-esterified trans fatty acid levels had a significant prospective association with hip fracture risk. Other non-esterified fatty acid classes were not associated with hip fracture risk. INTRODUCTION: Serum non-esterified fatty acids (NEFAs) are bioactive metabolic intermediates that can be taken up by bone tissue. Their associations with hip fracture risk have not been previously examined. METHODS: Thirty-five individual NEFAs in five classes (saturated [SFA], mono-un-saturated [MUFA], poly-unsaturated n-6 and n-3 [PUFA], and trans-FA) were measured in Cardiovascular Health Study participants (n = 2139, mean age 77.8 years) without known diabetes. The multivariable associations of NEFA levels with hip fracture risk were evaluated in Cox hazards models. RESULTS: We documented 303 incident hip fractures during 11.1 years of follow-up. Among the five NEFA classes, total trans FA levels were positively associated with higher hip fracture risk (HR 1.17 [95% CI, 1.04, 1.31; p = 0.01] per one standard deviation higher level). The SFA lignoceric acid (24:0) was positively associated with higher risk (HR 1.09 [1.04, 1.1]; p < 0.001), while behenic (22:0) and docosatetraenoic (22:4 n6) acids were associated with lower risk (HR 0.76 [0.61, 0.94]; p = 0.01; 0.84 [0.70, 1.00]; p = 0.05, respectively). CONCLUSION: Total plasma trans NEFA levels are related to hip fracture risk, suggesting an unrecognized benefit of their systematic removal from food. Novel associations of individual NEFAs with hip fracture risk require confirmation in other cohort studies.

Associations of hemoglobin and change in hemoglobin with risk of incident hip fracture in older men and women: the cardiovascular health study.

In a multi-site longitudinal cohort study, decreasing hemoglobin was associated with increased hip fracture risk in men. Anemia was associated with hip fracture in men and in African American women. Decreasing hemoglobin may be a marker of progressing bone fragility, making its serial measurement useful for fracture risk stratification. INTRODUCTION: Hematopoiesis and bone health are interdependent. Anemia has been associated with risk of fracture in humans. To further elucidate this relationship, we hypothesized that decreasing hemoglobin could indicate defective hematopoiesis and would also predict fracture risk. METHODS: We performed a prospective analysis from study baseline (1992) of the Cardiovascular Health Study, a multi-site longitudinal cohort study. A total of 4670 men and women, ages >65 years, who were able to consent and not institutionalized or wheelchair bound, had hemoglobin (Hb) measured in 1992. For 4006 subjects, Hb change from 1989 to 1992 was annualized and divided into sex-specific quartiles. Incident hip fractures were verified against Medicare claims data during a median follow-up of 11.8 years. RESULTS: Nested Cox proportional-hazard models estimated association of hip fracture with anemia (men Hb <13 g/dL, women Hb <12 g/dL) and separately, greatest Hb decrease (versus others). Anemia was associated with increased hip fracture risk in all men (HR 1.59; 95% CI 1.01-2.50) and African American women (HR 3.21; 95% CI 1.07-9.63). In men, an annualized Hb loss of >0.36 g/dL/year was associated with a higher risk of hip fracture (HR 1.67; 95% CI 1.10-2.54), which was lessened by anemia at the start of fracture follow-up (HR 1.53; 95% CI 0.99-2.39). CONCLUSIONS: Decreasing Hb may be an early marker for subsequent hip fracture risk in men, which may be less informative once an anemia threshold is crossed. Only African American women with anemia had increased hip fracture risk, suggesting a race difference in this relationship.

Assessing risk factors of non-fatal outcomes amid a competing risk of mortality: the example of hip fracture.

The Fine-Gray method is often used instead of Cox regression to account for competing risks of death in time-to-event analyses for non-fatal outcomes. A series of examples using well-known risk factors of hip fracture in an older cohort with substantial competing mortality demonstrates that the Fine-Gray approach can yield estimates that implausibly contradict long-established associations, while Cox regression preserves them. Cox regression is generally preferred for risk factor-outcome associations even in the presence of competing risk of death. INTRODUCTION: Factors like age, sex, and race are associated not only with risk of hip fracture but also with mortality. Substantial misunderstanding remains regarding the appropriate statistical approach to account for the competing risk of mortality. METHODS: In the Cardiovascular Health Study, an ongoing cohort study of 5888 older adults, we followed participants for incident hip fracture from their 1992-1993 visit through June 2014. We contrasted the conventional cause-specific Cox analysis, which censors individuals at the time of death, with the Fine-Gray (FG) approach, which extends participant follow-up even after death, to estimate the association of well-established demographic and clinical factors with incident hip fracture. RESULTS: For age, current smoking and sex, Cox and FG methods yielded directionally concordant but quantitatively different strengths of association. For example, the Cox hazard ratio (HR) for a 5-year increment in age was 1.74 (95% CI, 1.61-1.87), while the corresponding FG HR was 1.16 (1.09-1.24). In contrast, the FG approach estimated a stronger association of hip fracture with sex. The two approaches yielded nearly identical results for race. For diabetes and kidney function, the estimates were discordant in direction, and the FG HRs suggested effects that were in the opposite direction of well-understood and widely accepted associations. CONCLUSIONS: Cause-specific Cox models provide appropriate estimates of hazard for non-fatal outcomes like hip fracture even in the presence of competing risk of mortality. The Cox approach estimates hazard in the population of individuals who have not yet had an incident hip fracture and remain alive, which is typically the group of clinical interest. The Fine-Gray method estimates hazard in a hypothetical population that can yield misleading inferences about risk factors in populations of clinical interest.

The associations of subclinical atherosclerotic cardiovascular disease with hip fracture risk and bone mineral density in elderly adults.

In the absence of clinically recognized cardiovascular disease, increased carotid artery intimal medial thickness was associated with higher hip fracture risk in older adults, despite its association with higher bone mineral density (BMD). Low ankle brachial index and aortic wall thickness were not associated with fracture risk or BMD. INTRODUCTION: Clinically recognized cardiovascular disease (CVD) is associated with osteoporosis and hip fracture risk, but the relationship of subclinical atherosclerosis to bone health is not certain. METHODS: We followed 3385 participants from the Cardiovascular Health Study (mean age 74.7 ± 5.3 years) with a median time to fracture of 12.1 years who underwent baseline carotid artery and aortic wall ultrasound scanning and ankle brachial blood pressure index (ABI) determinations. A subset underwent bone mineral density (BMD) testing. RESULTS: There were 494 hip fractures during follow-up. Among persons without clinical CVD, an average standard-deviation increase in a composite score of maximal common and internal carotid artery intimal medial thickness (cIMT) was associated with increased risk of hip fracture [(HR 1.18 [1.04, 1.35]), even though cIMT was positively associated with BMD. Neither aortic wall thickness nor ABI were associated with hip fracture risk or BMD. Among participants with clinical CVD, cIMT and aortic wall thickness, but not ABI, were associated with increased hip fracture risk. CONCLUSION: Subclinical cIMT is associated with an increased risk of hip fractures despite being associated with increased BMD. This finding suggests that vascular health, even in its early stages, is linked to bone health, by pathways other than BMD.

Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI.

OBJECTIVE: Body mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population. SUBJECTS: Using eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models. RESULTS: We replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P<2.5 × 10-7). Bioinformatic functional investigation of SNPs at these loci suggests a possible impact on pathways that regulate metabolism and adipose tissue. CONCLUSION: Conducting studies in genetically diverse populations continues to be a valuable strategy for replicating known loci and uncovering novel BMI associations.

Association of DPP-4 activity with BMD, body composition, and incident hip fracture: the Cardiovascular Health Study.

There was no association of plasma DPP-4 activity levels with bone mineral density (BMD), body composition, or incident hip fractures in a cohort of elderly community-dwelling adults. INTRODUCTION: Dipeptidyl peptidase IV (DPP-4) inactivates several key hormones including those that stimulate postprandial insulin secretion, and DPP-4 inhibitors (gliptins) are approved to treat diabetes. While DPP-4 is known to modulate osteogenesis, the relationship between DPP-4 activity and skeletal health is uncertain. The purpose of the present study was to examine possible associations between DPP-4 activity in elderly subjects enrolled in the Cardiovascular Health Study (CHS) and BMD, body composition measurements, and incident hip fractures. METHODS: All 1536 male and female CHS participants who had evaluable DXA scans and plasma for DPP-4 activity were included in the analyses. The association between (1) BMD of the total hip, femoral neck, lumbar spine, and total body; (2) body composition measurements (% lean, % fat, and total body mass); and (3) incident hip fractures and plasma levels of DPP-4 activity were determined. RESULTS: Mean plasma levels of DPP-4 activity were significantly higher in blacks (227 ± 78) compared with whites (216 ± 89) (p = 0.04). However, there was no significant association of DPP-4 activity with age or gender (p ≥ 0.14 for both). In multivariable adjusted models, there was no association of plasma DPP-4 activity with BMD overall (p ≥ 0.55 for all) or in gender stratified analyses (p ≥ 0.23). There was also no association of DPP-4 levels and incident hip fractures overall (p ≥ 0.24) or in gender stratified analyses (p ≥ 0.39). CONCLUSION: Plasma DPP-4 activity, within the endogenous physiological range, was significantly associated with race, but not with BMD, body composition, or incident hip fractures in elderly community-dwelling subjects.

Incident atrial fibrillation and the risk of fracture in the cardiovascular health study.

In this prospective cohort of 4462 older adults, incident atrial fibrillation (AF) was not statistically significantly associated with subsequent risk of incident fracture. INTRODUCTION: AF is associated with stroke, heart failure, dementia, and death, but its association with fracture is unknown. Therefore, we examined the association of incident AF with the risk of subsequent fracture in the Cardiovascular Health Study (CHS) cohort. METHODS: Of the CHS participants aged ≥65 years, 4462 were followed between 1991 and 2009, mean follow-up 8.8 years. Incident AF was identified by annual study electrocardiogram (ECG), hospital discharge diagnosis codes, or Medicare claims. Fractures of the hip, distal forearm, humerus, or pelvis were identified using hospital discharge diagnosis codes or Medicare claims. We used Cox proportional hazard models to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for the association between incident AF (time-varying) and the risk of subsequent fracture. We also evaluated whether AF was associated with risk of sustaining a fall. RESULTS: Crude incident fracture rate was 22.9 per 1000 person-years in participants with AF and 17.7 per 1000 person-years in participants without AF. Individuals with incident AF were not at significantly higher risk of hip fracture (adjusted HR = 1.09, 95 % CI 0.83-1.42) or fracture at any selected site (adjusted HR = 0.97, 95 % CI 0.77-1.22) or risk of sustaining a fall (adjusted HR = 1.00, 95 % CI = 0.87-1.16) compared with those without AF. CONCLUSION: In this cohort of older, community-dwelling adults, incident AF was not shown to be associated with falls or hip or other fractures.

Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations.

BACKGROUND/OBJECTIVES: Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition. SUBJECTS/METHODS: To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants. RESULTS: Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses. CONCLUSIONS: Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

Systemic markers of microvascular disease and bone mineral density in older adults : The cardiovascular health study.

Here we report that abnormal brain white matter and, to a lesser extent, albuminuria are associated with reduced bone mineral density in the hip, spine, and total body in men and women. These findings may explain the increased hip fracture risk reported in some studies in association with microvascular disorders. INTRODUCTION: Markers of microvascular disease have been individually associated with increased risk of osteoporotic fractures in some studies. Here, we examine whether these markers are associated with reduced bone mineral density (BMD) individually and together. METHODS: BMD testing using dual x-ray absorptiometry of the hip, lumbar spine, and total body was performed in 1473 participants from the Cardiovascular Health Study (mean age ~ 78 years): 1215 were assessed for urinary albumin-creatinine ratio, 944 for abnormal white matter disease (AWMD) by brain MRI, and 541 for retinal vascular disease with fundus photographs. Linear regression models were used to evaluate the cross-sectional association of each marker with BMD accounting for potentially confounding factors. RESULTS: AWMD was associated with lower hip, spine, and total body BMD in women (ß -3.08 to -4.53; p < 0.01 for all) and lower hip and total body BMD in men (ß -2.90 to -4.24; p = 0.01-0.03). Albuminuria was associated with lower hip (ß -3.37; p = .05) and total body (ß -3.21; p = .02) BMD in men, but not in women. The associations of AWMD and albuminuria with BMD persisted with mutual adjustment and appeared to be additive to each other. Retinal vascular disease was not associated with BMD in men or women. CONCLUSION: AWMD and, to a lesser extent, albuminuria were independently associated with lower BMD, suggesting that microvascular disease may play a role in the pathogenesis of reduced BMD. These findings need to be confirmed by longitudinal studies.

Soluble CD14 and fracture risk.

UNLABELLED: Soluble CD14 (sCD14) is an inflammatory marker associated with osteoclasts. Using Cox proportional hazards models, we found a positive association between plasma levels of sCD14 and risk of incident fracture among participants in the Cardiovascular Health Study. sCD14 may be useful in identifying those at risk for fracture. INTRODUCTION: Soluble CD14, a proinflammatory cytokine, is primarily derived from macrophages/monocytes that can differentiate into osteoclasts. The purpose of this study was to examine the relationship between sCD14 levels and osteoporotic fractures. METHODS: In the Cardiovascular Health Study, 5462 men and women had sCD14 levels measured at baseline. Incident hip fractures (median follow-up time 12.5 years) and incident composite fractures (defined as the first hip, pelvis, humerus, or distal radius fracture, median follow-up 8.6 years) were identified from hospital discharge summaries and/or Medicare claims data. Cox proportional hazards models were used to model the association between sCD14 levels and time to incident hip or composite fracture, overall and as a function of race and gender. RESULTS: In unadjusted models, there was a positive association between sCD14 levels (per 1 standard deviation increase, i.e., 361.6 ng/mL) and incident hip (HR, 1.26; 95 % CI, 1.17, 1.36) and composite (HR, 1.20; 95 % CI, 1.12, 1.28) fractures. When models were fully adjusted for demographics, lifestyle factors, and medication use, these associations were no longer significant. However, in whites, the association of sCD14 levels with hip fractures remained significant in fully adjusted models (HR, 1.11; 95 % CI, 1.01-1.23). Associations of sCD14 levels with hip and composite fracture did not differ between men and women. CONCLUSIONS: In this large cohort of community-dwelling older adults, higher sCD14 levels were associated with an increased risk of incident hip fractures in whites.

Fibrosis markers, hip fracture risk, and bone density in older adults.

UNLABELLED: We examined whether blood levels of two markers of fibrosis (transforming growth factor beta one (TGF-ß1) and procollagen type III N-terminal propeptide (PIIINP)) are related to hip fracture risk and to bone mineral density (BMD). TGF-ß1 levels were associated with lower hip fracture risk in women and with lower BMD in men. PIIINP levels were not associated with either outcome. INTRODUCTION: TGF-ß1 serves several roles in bone formation and resorption. A consequence of TGF-ß1 activation is the production of PIIINP, a marker of collagen III deposition. Here, we explore whether these two biomarkers are related to incident hip fracture and bone mineral density (BMD) and whether their associations are modified by systemic inflammation, as measured by C-reactive protein (CRP) levels. METHODS: Participants were from the Cardiovascular Health Study (mean age 78 years; mean follow-up 8.3 years). We included 1681 persons with measured levels of TGF-ß1 (149 hip fractures) and 3226 persons with measured levels of PIIINP (310 hip fractures). RESULTS: Among women, higher TGF-ß1 levels were associated with lower hip fracture risk (HR, per doubling, 0.78 [95 % CI 0.61, 0.91]). Among men, TGF-ß1 levels were associated with hip fracture risk in a non-linear manner, but among those with elevated CRP levels, doubling was associated with increased risk of fracture (HR 2.22 [1.20, 4.08]) (p = 0.02, interaction between low and high CRP and TGF-ß1 on fracture risk). TGF-ß1 levels had no significant association with total hip or total body BMD in women but were significantly associated with lower BMD in men. There were no associations of PIIINP levels with hip fracture risk or BMD in men or women. CONCLUSIONS: TGF-ß1 levels appear to be associated with bone-related phenotypes in a sex-specific manner. The reasons for these differences between men and women regarding TGF-ß1 levels and hip fracture risk and bone density require further investigation.

Albuminuria is associated with hip fracture risk in older adults: the cardiovascular health study.

UNLABELLED: The microcirculation plays an important role in bone health. Here, we examine whether albuminuria, a marker of renal microvascular disease, is associated with the risk of hip fracture in older adults (age, 78 years). We find a small independent association in women but not in men. INTRODUCTION: The microvascular circulation plays an important role in bone physiology. Two studies of middle-aged adults have found that albuminuria (>30 mg albumin/g creatinine), a disorder of the renal microvasculature, is associated with fracture risk. Here, we examine whether albuminuria is related to hip fracture risk and reduced hip bone mineral density (BMD) in older adults with a mean age of 78 years. METHODS: From the Cardiovascular Health Study (41 % male), 3,110 adults with albuminuria testing were followed up for incident hip fracture for up to 9.5 years. BMD was performed in a subset of 1,208 participants. RESULTS: There were 313 hip fractures during follow-up (7.7 % of men; 11.7 % of women). The incidence rate for men, with and without albuminuria, was 1.43 and 0.93/100 person-years of follow-up (p = 0.02); for women, 1.84 and 1.33 (p = 0.04). After adjustment for osteoporosis-related factors, frailty and falling, a doubling of albuminuria was significantly associated with hip fracture risk in women (hazard ratio, 1.12, 95 % CI, 1.001-1.25), but not in men. In the subcohort with BMD measurement, increased urine albumin levels were significantly associated with decreased total hip BMD in men (-0.009 g calcium/cm(2) (-0.017, -0.001); p = 0.04), but not in women. CONCLUSIONS: In older women, albuminuria is associated with a small, but statistically significant, increased risk of hip fracture independent of other explanatory factors. No such risk appears to be present in men, although their total hip BMD is lower in association with albuminuria.