01955nas a2200217 4500008004100000022001400041245014500055210006900200260001300269300001200282490000800294520125300302100002201555700002101577700002001598700002101618700002001639700002101659700002101680856003601701 2017 eng d a1432-082700aAssociation of Plasma SDF-1 with Bone Mineral Density, Body Composition, and Hip Fractures in Older Adults: The Cardiovascular Health Study.0 aAssociation of Plasma SDF1 with Bone Mineral Density Body Compos c2017 Jun a599-6080 v1003 a

Aging is associated with an increase in circulating inflammatory factors. One, the cytokine stromal cell-derived factor 1 (SDF-1 or CXCL12), is critical to stem cell mobilization, migration, and homing as well as to bone marrow stem cell (BMSC), osteoblast, and osteoclast function. SDF-1 has pleiotropic roles in bone formation and BMSC differentiation into osteoblasts/osteocytes, and in osteoprogenitor cell survival. The objective of this study was to examine the association of plasma SDF-1 in participants in the cardiovascular health study (CHS) with bone mineral density (BMD), body composition, and incident hip fractures. In 1536 CHS participants, SDF-1 plasma levels were significantly associated with increasing age (p < 0.01) and male gender (p = 0.04), but not with race (p = 0.63). In multivariable-adjusted models, higher SDF-1 levels were associated with lower total hip BMD (p = 0.02). However, there was no significant association of SDF-1 with hip fractures (p = 0.53). In summary, circulating plasma levels of SDF-1 are associated with increasing age and independently associated with lower total hip BMD in both men and women. These findings suggest that SDF-1 levels are linked to bone homeostasis.

1 aCarbone, Laura, D1 aBůzková, Petra1 aFink, Howard, A1 aRobbins, John, A1 aBethel, Monique1 aHamrick, Mark, W1 aHill, William, D uhttps://chs-nhlbi.org/node/734102469nas a2200241 4500008004100000022001400041245010100055210006900156260001600225490000600241520172300247100002401970700002001994700002202014700002002036700002202056700002302078700002202101700002302123700002502146700002002171856003602191 2017 eng d a2047-998000aBone Mineral Density and Risk of Heart Failure in Older Adults: The Cardiovascular Health Study.0 aBone Mineral Density and Risk of Heart Failure in Older Adults T c2017 Mar 130 v63 a

BACKGROUND: Despite increasing evidence of a common link between bone and heart health, the relationship between bone mineral density (BMD) and heart failure (HF) risk remains insufficiently studied.

METHODS AND RESULTS: We investigated whether BMD measured by dual-energy x-ray absorptiometry was associated with incident HF in an older cohort. Cox models were stratified by sex and interactions of BMD with race assessed. BMD was examined at the total hip and femoral neck separately, both continuously and by World Health Organization categories. Of 1250 participants, 442 (55% women) developed HF during the median follow-up of 10.5 years. In both black and nonblack women, neither total hip nor femoral neck BMD was significantly associated with HF; there was no significant interaction by race. In black and nonblack men, total hip, but not femoral neck, BMD was significantly associated with HF, with evidence of an interaction by race. In nonblack men, lower total hip BMD was associated with higher HF risk (hazard ratio, 1.13 [95% CI, 1.01-1.26] per 0.1 g/cm(2) decrement), whereas in black men, lower total hip BMD was associated with lower HF risk (hazard ratio, 0.74 [95% CI, 0.59-0.94]). There were no black men with total hip osteoporosis. Among nonblack men, total hip osteoporosis was associated with higher HF risk (hazard ratio, 2.83 [95% CI, 1.39-5.74]) compared with normal BMD.

CONCLUSIONS: Among older adults, lower total hip BMD was associated with higher HF risk in nonblack men but lower risk in black men, with no evidence of an association in women. Further research is needed to replicate these findings and to study potential underlying pathways.

1 aFohtung, Raymond, B1 aBrown, David, L1 aKoh, William, J H1 aBartz, Traci, M1 aCarbone, Laura, D1 aCivitelli, Roberto1 aStein, Phyllis, K1 aChaves, Paulo, H M1 aKestenbaum, Bryan, R1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/734403015nas a2200241 4500008004100000022001400041245013700055210006900192260001300261300001200274490000800286520225700294100001402551700002102565700002102586700002002607700002002627700002202647700002202669700002402691700002202715856003602737 2019 eng d a1432-082700aThe Association of Aromatic Amino Acids with Incident Hip Fracture, aBMD, and Body Composition from the Cardiovascular Health Study.0 aAssociation of Aromatic Amino Acids with Incident Hip Fracture a c2019 Aug a161-1720 v1053 a

In 5187 persons from the Cardiovascular Health Study, there was no significant association of dietary intakes of aromatic amino acids (AAA) with areal BMD of the hip or body composition. However, those who had the lowest dietary intakes of AAA were at increased risk for incident hip fractures. Prior studies of the association of protein intake with osteoporosis are conflicting and have not directly examined the relationship of aromatic amino acids (AAA) with fractures, areal bone mineral density (aBMD), and body composition. We sought to determine the relationship of dietary intakes of AAA with osteoporosis parameters in elderly men and women. 5187 men and women aged ≥ 65 years from the Cardiovascular Health Study (CHS) with dietary intakes of AAA (tryptophan, phenylalanine, tyrosine) estimated by food frequency questionnaire (FFQ) were included. We examined the relationship between a one-time estimate of daily dietary AAA intake with risk of incident hip fractures over a median of 13.2 years of fracture follow-up. A subset (n = 1336) who had dual energy X-ray absorptiometry (DXA) performed were included in a cross-sectional analysis of the association of dietary AAA intake with aBMD of the total hip and measurements of body composition. In multivariable models adjusted for demographic and clinical variables, medication use, and diet, higher dietary AAA intake was not significantly associated with incident hip fractures. All hazard ratios (HR) were less than one (tryptophan, HR 0.14, 95% CI 0.01 to 1.89; phenylalanine, HR 0.60, 95% CI 0.23 to 1.55; tyrosine, HR 0.59, 95% CI 0.27 to 1.32), but confidence intervals were wide and included no difference. However, in post hoc analyses, the lowest quartile of intake for each AAA was associated with an increased risk for hip fracture compared to higher quartiles (p ≤ 0.047 for all). Dietary AAA intakes were not significantly associated with total hip aBMD or any measurements of body composition. Overall, there was no significant association of dietary AAA intake with hip fractures, aBMD of the hip, or body composition. However, there may be a subset of elderly individuals with low dietary intakes of AAA who are at increased for hip fractures.

1 aLe, Brian1 aBůzková, Petra1 aRobbins, John, A1 aFink, Howard, A1 aRaiford, Mattie1 aIsales, Carlos, M1 aShikany, James, M1 aCoughlin, Steven, S1 aCarbone, Laura, D uhttps://chs-nhlbi.org/node/810402689nas a2200217 4500008004100000022001400041245012900055210006900184260001600253520198000269100002202249700002102271700002002292700002002312700001402332700002202346700002202368700002402390700002102414856003602435 2019 eng d a1523-468100aAssociation of Dietary Niacin Intake With Incident Hip Fracture, BMD, and Body Composition: The Cardiovascular Health Study.0 aAssociation of Dietary Niacin Intake With Incident Hip Fracture  c2019 Jan 193 a

Interest in niacin has increased in the setting of reports suggesting that niacin plays a role in diseases of aging. No study to date has examined the association of dietary niacin intake with multiple skeletal health parameters including bone mineral density (BMD), hip fractures, and body composition, and none have included both African American and white men and women. Participants included 5187 men and women ≥65 years from the Cardiovascular Health Study (CHS). Mean daily dietary niacin intake was 32.6 mg, with quartiles 1 through 4 defined as 3.6 to 21.8 mg/day, 21.9 to 30.2 mg/day, 30.3 to 40.9 mg/day, and 41.0 to 102.4 mg/day, respectively. Risk of incident hip fracture per 10 mg increment of daily dietary niacin intake was estimated using proportional hazards models. During a median follow-up of 13 years, 725 participants had an incident hip fracture. In models adjusted for demographic and clinical characteristics and diet, dietary niacin intake was significantly associated with an increased risk of hip fractures (hazard ratio [HR] 1.12; 95% CI, 1.01 to 1.24) with spline models suggesting a U-shaped association. In post hoc analyses, both the lowest (HR 1.31; 95% CI, 1.04 to 1.66) and highest (HR 1.53; 95% CI, 1.20 to 1.95) quartiles of niacin intake were associated with an increased risk of incident hip fracture versus quartiles 2 and 3. There was a trend for a significant inverse association of dietary niacin intake with hip BMD (p = 0.06), but no significant association with total body BMD or any body composition measures. In this cohort of elderly, community-dwelling African American and white men and women, both high and low dietary niacin intakes were associated with a significantly increased risk of subsequent hip fracture, suggesting a possible U-shaped association. By comparison, dietary niacin may have an inverse linear association with hip BMD. © 2018 American Society for Bone and Mineral Research.

1 aCarbone, Laura, D1 aBůzková, Petra1 aFink, Howard, A1 aRaiford, Mattie1 aLe, Brian1 aIsales, Carlos, M1 aShikany, James, M1 aCoughlin, Steven, S1 aRobbins, John, A uhttps://chs-nhlbi.org/node/796702302nas a2200229 4500008004100000022001400041245010300055210006900158260001600227520158200243100002401825700002101849700002101870700002001891700002001911700001801931700002101949700002201970700002001992700002402012856003602036 2022 eng d a1555-716200aThe Association of Lipids and Lipoproteins with Hip Fracture Risk the Cardiovascular Health Study.0 aAssociation of Lipids and Lipoproteins with Hip Fracture Risk th c2022 Jun 063 a

BACKGROUND: It is uncertain if lipids or lipoproteins are associated with osteoporotic fractures. In this study, incident hip fracture risk according to conventional lipid levels and lipoprotein levels and sizes was examined.

METHODS: We followed 5832 participants aged ≥65 years from the Cardiovascular Health Study for hip fracture for a mean of 13.5 (SD 5.7) years. Standard enzymatic methods were used to determine lipid levels (HDL-c, LDL-c, triglycerides). Nuclear magnetic resonance spectroscopy was used to measure lipoprotein fractions (VLDL-P, LDL-P, HDL-P) in a subset of 1849 participants.

RESULTS: We documented 755 incident hip fractures among women (1.19 fractures per 100 participant years [95% CI, 1.04, 1.35]) and 197 among men (0.67 fractures per 100 participant years [95% CI, 0.41, 1.10]) over an average follow-up. HDL-c and LDL-c levels had statistically significant non-linear U-shaped relationships with hip fracture risk (HDL-c, p=0.009; LDL-c, p=0.02). Triglyceride levels were not significantly associated with hip fracture risk. In fully adjusted conjoint models, higher VLDL-P concentration [HR per 1-standard (SD) increment 1.47 (1.13, 1.91)] and size [HR per 1-SD increment 1.24 [1.05, 1.46]) and higher HDL-P size (HR per 1-SD increment 1.81 [1.25, 2.62]) were all associated with higher hip fracture risk.

CONCLUSIONS: Lipids and lipoproteins are associated with hip fracture risk in older adults. The associations are complex. Mechanistic studies are needed to understand these findings.

1 aBarzilay, Joshua, I1 aBůzková, Petra1 aKuller, Lewis, H1 aCauley, Jane, A1 aFink, Howard, A1 aSheets, Kerry1 aRobbins, John, A1 aCarbone, Laura, D1 aElam, Rachel, E1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/908703034nas a2200409 4500008004100000022001400041245011900055210006900174260001200243300001100255490000800266520189800274653002702172653000902199653001702208653001102225653001802236653001102254653000902265653001702274653001702291100002002308700002102328700002402349700001702373700001502390700002302405700002002428700002002448700001502468700002102483700001502504700002202519700002502541700002202566856003602588 2022 eng d a1873-276300aTrimethylamine N-oxide and hip fracture and bone mineral density in older adults: The cardiovascular health study.0 aTrimethylamine Noxide and hip fracture and bone mineral density  c2022 08 a1164310 v1613 a

CONTEXT: Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) may adversely affect bone by inducing oxidative stress. Whether this translates into increased fracture risk in older adults is uncertain.

OBJECTIVE: Determine the associations of plasma TMAO with hip fracture and bone mineral density (BMD) in older adults.

DESIGN AND SETTING: Cox hazard models and linear regression stratified by sex examined the associations of TMAO with hip fracture and BMD in the longitudinal cohort of the Cardiovascular Health Study.

PARTICIPANTS: 5019 U.S. adults aged ≥65 years.

EXPOSURE: Plasma TMAO.

MAIN OUTCOME MEASURES: Incident hip fractures; total hip BMD dual x-ray absorptiometry in a subset (n = 1400).

RESULTS: Six hundred sixty-six incident hip fractures occurred during up to 26 years of follow-up (67,574 person-years). After multivariable adjustment, TMAO was not significantly associated with hip fracture (women: hazard ratio (HR) [95% confidence interval (CI)] of 1.00[0.92,1.09] per TMAO doubling; men: 1.12[0.95,1.33]). TMAO was also not associated with total hip BMD (women: BMD difference [95% CI] of 0.42 g/cm*100 [-0.34,1.17] per TMAO doubling; men: 0.19[-1.04,1.42]). In exploratory analyses, we found an interaction between body mass index (BMI) and the association of TMAO with hip fracture (P < 0.01). Higher TMAO was significantly associated with risk of hip fracture in adults with overweight or obesity (BMI ≥ 25) (HR [95% CI]:1.17[1.05,1.31]), but not normal or underweight.

CONCLUSIONS: Among older US men and women, TMAO was not significantly associated with risk of hip fracture or BMD overall. Exploratory analyses suggested a significant association between higher TMAO and hip fracture when BMI was elevated, which merits further study.

10aAbsorptiometry, Photon10aAged10aBone Density10aFemale10aHip Fractures10aHumans10aMale10aMethylamines10aRisk Factors1 aElam, Rachel, E1 aBůzková, Petra1 aBarzilay, Joshua, I1 aWang, Zeneng1 aNemet, Ina1 aBudoff, Matthew, J1 aCauley, Jane, A1 aFink, Howard, A1 aLee, Yujin1 aRobbins, John, A1 aWang, Meng1 aHazen, Stanley, L1 aMozaffarian, Dariush1 aCarbone, Laura, D uhttps://chs-nhlbi.org/node/908903335nas a2200337 4500008004100000022001400041245015100055210006900206260001300275300001000288490000700298520234000305653000902645653002102654653001202675653001802687653001102705653002402716653001702740653001702757100002102774700002102795700001502816700002202831700002002853700002402873700002102897700002302918700002002941856003602961 2023 eng d a1433-296500aAssociation of covert brain infarcts and white matter hyperintensities with risk of hip fracture in older adults: the Cardiovascular Health Study.0 aAssociation of covert brain infarcts and white matter hyperinten c2023 Jan a91-990 v343 a

UNLABELLED: Covert brain infarcts and white matter hyperintensities (WMHs), incidental markers of brain microvascular disease commonly seen on brain MRIs in older adults, have been associated with falls and lower bone mineral density. We found covert infarcts and WMHs may also be associated with an increased risk of future hip fracture.

INTRODUCTION: To determine whether covert infarcts and white matter hyperintensities (WMHs) are associated with increased risk of incident hip fracture.

METHODS: A prospective cohort of 3373 community-dwelling adults aged ≥ 65 years enrolled in the Cardiovascular Health Study with a brain MRI (1992-1993) was analyzed. Covert infarcts were categorized by number of infarcts and largest infarct size. WMH burden was assessed by radiologists and graded qualitatively from 0 (no WMHs) to 9 (extensive).

RESULTS: Participants had 465 incident hip fractures during a mean follow-up of 12.8 years. The demographic-adjusted hazard of incident hip fracture was 32% higher among participants with ≥ 1 covert infarct compared to those without infarcts (hazard ratio (HR) 1.32; 95% CI, 1.08-1.62). The hazard of incident hip fracture was similar after further adjustment for medications and medical history (HR = 1.34; 95% CI, 1.08-1.65), but attenuated following additional adjustment for functional status, frailty, and falls (HR = 1.25; 95% CI, 0.99-1.57). Fully adjusted hazard of incident hip fracture per increase in infarct number was 1.10 (95% CI, 0.98-1.23); risk in individuals whose largest infarct was ≥ 20 mm versus 3 to < 20 mm was similar. Compared with WMH grades 0-1, the demographic-adjusted hazard of hip fracture was 1.34 (95% CI, 1.09-1.66) and 1.83 (95% CI, 1.37-2.46), respectively, for WMH grades 2-3 and 4-9. The hazard was similar following adjustment for medications and medical history (grades 2-3: HR = 1.32; 95% CI, 1.05-1.64; grades 4-9: HR = 1.69; 95% CI, 1.23-2.30), but attenuated following additional adjustment for functional status, frailty, and falls (grades 2-3: HR = 1.24; 95% CI, 0.98-1.56; grades 4-9: HR = 1.34; 95% CI, 0.95-1.90).

CONCLUSION: Older, community-dwelling adults with covert infarcts or WMHs may be at increased risk of hip fracture.

10aAged10aBrain Infarction10aFrailty10aHip Fractures10aHumans10aProspective Studies10aRisk Factors10aWhite Matter1 aSheets, Kerry, M1 aBůzková, Petra1 aChen, Zhao1 aCarbone, Laura, D1 aCauley, Jane, A1 aBarzilay, Joshua, I1 aStarks, Jamie, L1 aMiller, Lindsay, M1 aFink, Howard, A uhttps://chs-nhlbi.org/node/924202665nas a2200313 4500008004100000022001400041245010000055210006900155260001600224520170900240100002001949700002101969700002501990700002002015700002402035700002202059700001502081700002102096700002402117700003002141700002002171700002202191700001902213700002002232700002302252700002002275700002002295856003602315 2023 eng d a1432-082700aAssociation of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study.0 aAssociation of Immune Cell Subsets with Incident Hip Fracture Th c2023 Aug 313 a

In this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998-1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4CD28 T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60-0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01-1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37-0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women.

1 aElam, Rachel, E1 aBůzková, Petra1 aDelaney, Joseph, A C1 aFink, Howard, A1 aBarzilay, Joshua, I1 aCarbone, Laura, D1 aSaha, Rick1 aRobbins, John, A1 aMukamal, Kenneth, J1 aValderrábano, Rodrigo, J1 aPsaty, Bruce, M1 aTracy, Russell, P1 aOlson, Nels, C1 aHuber, Sally, A1 aDoyle, Margaret, F1 aLanday, Alan, L1 aCauley, Jane, A uhttps://chs-nhlbi.org/node/947802472nas a2200241 4500008004100000022001400041245009400055210006900149260001600218520173600234100002101970700002101991700002402012700002002036700002002056700002202076700001502098700002202113700001702135700001802152700002402170856003602194 2023 eng d a1555-716200aMortality Following Hip Fracture in Older Adults With and Without Coronary Heart Disease.0 aMortality Following Hip Fracture in Older Adults With and Withou c2023 Apr 243 a

BACKGROUND: Comorbidities like coronary heart disease are common among older people who sustain an osteoporotic hip fracture. However, their impact on short- and long-term mortality post-hip fracture is not well quantified.

METHODS: We examined 4092 and 1173 older adults without and with prevalent coronary heart disease, respectively. Post-hip fracture mortality rates were computed with Poisson models and hazard ratios with Cox regression. For perspective, we compared mortality rates among participants with prevalent coronary heart disease who had either a hip fracture or incident heart failure (but no hip fracture).

RESULTS: Among participants without prevalent coronary heart disease, the mortality rate post-hip fracture was 21.83 per 100 participant years, including 49.27 per 100 participant years in the first 6 months following hip fracture. Among participants with prevalent coronary heart disease, the corresponding mortality rates were 32.52 and 79.44 per 100 participant years, respectively. Participants with prevalent coronary heart disease and incident heart failure (but no hip fracture) had corresponding post-incident heart failure mortality rates per 100 participant years of 25.62 overall and 46.4 in the first 6 months. In all 3 groups, the hazard ratio for mortality was similarly elevated: 5- to 7-fold at 6 months and 1.7- to 2.5-fold beyond 5 years.

CONCLUSION: As a case study in the absolute effects of a comorbidity on post-hip fracture mortality, hip fracture in a person with coronary heart disease carries an exceedingly high mortality rate, even higher than that following incident heart failure in individuals with coronary heart disease.

1 aRobbins, John, A1 aBůzková, Petra1 aBarzilay, Joshua, I1 aCauley, Jane, A1 aFink, Howard, A1 aCarbone, Laura, D1 aChen, Zhao1 aStein, Phyllis, K1 aElam, Rachel1 aSheets, Kerry1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/9384