02286nas a2200337 4500008004100000022001400041245008400055210006900139260001300208300001000221490000700231520139500238653000901633653001101642653001801653653001801671653001101689653001401700653000901714653001701723653001801740100001901758700002101777700002001798700002101818700001501839700001501854700002201869700002101891856003601912 2010 eng d a1522-964500aHip fractures and heart failure: findings from the Cardiovascular Health Study.0 aHip fractures and heart failure findings from the Cardiovascular c2010 Jan a77-840 v313 a

AIMS: The aim of the study was to find the epidemiology of hip fractures in heart failure. The increasing survival rate for patients with heart failure places them at risk for other diseases of ageing, including osteoporosis.

METHODS AND RESULTS: We included 5613 persons from the Cardiovascular Health Study (CHS) with an average of 11.5 year follow-up. We determined incidence rates and hazard ratios (HRs) in persons with heart failure compared with persons without heart failure and mortality hazards following these fractures. Annualized incidence rates for hip fractures were 14 per 1000 person-years in heart failure and 6.8 per 1000 person-years without heart failure. Unadjusted and multivariable adjusted HRs for hip fracture associated with heart failure in men were 1.87 (95% CI 1.2-2.93) and 1.59 (95% CI 0.93-2.72), respectively. Respective HRs for women were 1.75 (95% CI 1.27-2.4) and 1.41 (95% CI 0.98-2.03). Mortality hazard was approximately 2-fold greater in patients with heart failure and hip fracture compared with those having heart failure alone.

CONCLUSION: Persons with heart failure are at high risk for hip fractures. However, much of the association between hip fractures and heart failure is explained by shared risk factors. Hip fractures are a substantial contributor to mortality in men and women with heart failure.

10aAged10aFemale10aHeart Failure10aHip Fractures10aHumans10aIncidence10aMale10aRisk Factors10aUnited States1 aCarbone, Laura1 aBůzková, Petra1 aFink, Howard, A1 aLee, Jennifer, S1 aChen, Zhao1 aAhmed, Ali1 aParashar, Susmita1 aRobbins, John, R uhttps://chs-nhlbi.org/node/114303251nas a2200445 4500008004100000022001400041245007900055210006900134260001600203300001200219490000800231520205700239653000902296653001102305653002202316653001802338653001102356653002002367653001902387653001402406653000902420653002602429653003202455653002402487653001702511653002102528653001602549653001802565100002102583700002102604700002002625700001502645700001902660700001502679700001702694700001902711700002102730700001802751856003602769 2010 eng d a1538-367900aSubclinical thyroid dysfunction and incident hip fracture in older adults.0 aSubclinical thyroid dysfunction and incident hip fracture in old c2010 Nov 22 a1876-830 v1703 a

BACKGROUND: Subclinical thyroid dysfunction is common in older adults and affects bone metabolism, but its effects on fracture risk have not been reported. We sought to determine prospectively whether older men and women with subclinical hyperthyroidism or hypothyroidism have an increased risk of hip fracture.

METHODS: Prospective cohort of 3567 US community-dwelling adults, 65 years or older, with biochemically defined subclinical thyroid dysfunction or euthyroidism was enrolled from June 10, 1989, through May 30, 1990, and followed up through 2004. Main outcome measures included incidence and hazard ratios (HRs), with 95% confidence intervals (CIs), of confirmed incident hip fractures for groups with subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroidism as defined at baseline.

RESULTS: During 39 952 person-years (median follow-up, 13 years), hip fracture incidence (per 1000 men-years) was 13.65 in men with subclinical hyperthyroidism (n = 29) and 10.27 in men with subclinical hypothyroidism (n = 184), both greater than 5.0 in men with euthyroidism (n = 1159). Men with subclinical hypothyroidism had a multivariable-adjusted HR of 2.31 (95% CI, 1.25-4.27); those with subclinical hyperthyroidism, 3.27 (0.99-11.30). After excluding those with baseline use of thyroid-altering medications, men with endogenous subclinical hyperthyroidism had a higher HR of 4.91 (95% CI, 1.13-21.27), as did men with endogenous subclinical hypothyroidism (2.45, 1.27-4.73). Hip fracture incidence (per 1000 women-years) was 8.93 in women with subclinical hypothyroidism (n = 359) and 10.90 in women with subclinical hyperthyroidism (n = 142) compared with 10.18 in women with euthyroidism (n = 1694). No clear association between subclinical dysfunction and fracture was observed in women.

CONCLUSIONS: Older men with subclinical hyperthyroidism or hypothyroidism are at increased risk for hip fracture. Whether treatment of the subclinical syndrome reduces this risk is unknown.

10aAged10aFemale10aFollow-Up Studies10aHip Fractures10aHumans10aHyperthyroidism10aHypothyroidism10aIncidence10aMale10aMultivariate Analysis10aProportional Hazards Models10aProspective Studies10aRisk Factors10aSex Distribution10aThyrotropin10aUnited States1 aLee, Jennifer, S1 aBůzková, Petra1 aFink, Howard, A1 aVu, Joseph1 aCarbone, Laura1 aChen, Zhao1 aCauley, Jane1 aBauer, Doug, C1 aCappola, Anne, R1 aRobbins, John uhttps://chs-nhlbi.org/node/124603280nas a2200469 4500008004100000022001400041245013300055210006900188260001300257300001200270490000700282520195800289653000902247653002202256653001702278653001102295653003002306653001802336653001102354653002502365653000902390653001602399653002402415653000902439653002102448100002102469700002102490700002102511700001802532700002002550700002002570700002202590700001602612700001902628700001802647700002202665700002402687700002002711700002402731700001902755856003602774 2013 eng d a1945-719700aFibroblast growth factor 23, bone mineral density, and risk of hip fracture among older adults: the cardiovascular health study.0 aFibroblast growth factor 23 bone mineral density and risk of hip c2013 Aug a3323-310 v983 a

CONTEXT: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that also inhibits calcitriol synthesis.

OBJECTIVE: Our objective was to evaluate the relationships of plasma FGF23 concentrations with bone mineral density (BMD) and hip fracture in community-dwelling older adults.

DESIGN AND SETTING: Linear regression and Cox proportional hazard models were used to examine the associations of plasma FGF23 concentrations with BMD and incident hip fracture, respectively. Analyses were also stratified by chronic kidney disease.

PARTICIPANTS: Participants included 2008 women and 1329 men ≥65 years from the 1996 to 1997 Cardiovascular Health Study visit.

MAIN OUTCOME MEASURES: Dual x-ray absorptiometry measured total hip (TH) and lumbar spine (LS) BMD in 1291 participants. Hip fracture incidence was assessed prospectively through June 30, 2008 by hospitalization records in all participants.

RESULTS: Women had higher plasma FGF23 concentrations than men (75 [56-107] vs 66 [interquartile range = 52-92] relative units/mL; P < .001). After adjustment, higher FGF23 concentrations were associated with greater total hip and lumbar spine BMD in men only (β per doubling of FGF23 = 0.02, with 95% confidence interval [CI] = 0.001-0.04 g/cm(2), and 0.03 with 95% CI = 0.01-0.06 g/cm(2)). During 9.6 ± 5.1-11.0 years of follow-up, 328 hip fractures occurred. Higher FGF23 concentrations were not associated with hip fracture risk in women or men (adjusted hazard ratio = 0.95, with 95% CI = 0.78-1.15, and 1.09 with 95% CI = 0.82-1.46 per doubling of FGF23). Results did not differ by chronic kidney disease status (P > .4 for interactions).

CONCLUSIONS: In this large prospective cohort of community-dwelling older adults, higher FGF23 concentrations were weakly associated with greater lumbar spine and total hip BMD but not with hip fracture risk.

10aAged10aAged, 80 and over10aBone Density10aFemale10aFibroblast Growth Factors10aHip Fractures10aHumans10aLongitudinal Studies10aMale10aMiddle Aged10aProspective Studies10aRisk10aSpinal Fractures1 aJovanovich, Anna1 aBůzková, Petra1 aChonchol, Michel1 aRobbins, John1 aFink, Howard, A1 ade Boer, Ian, H1 aKestenbaum, Bryan1 aKatz, Ronit1 aCarbone, Laura1 aLee, Jennifer1 aLaughlin, Gail, A1 aMukamal, Kenneth, J1 aFried, Linda, F1 aShlipak, Michael, G1 aIx, Joachim, H uhttps://chs-nhlbi.org/node/599603107nas a2200361 4500008004100000022001400041245010900055210006900164260001500233300000800248490000700256520206700263653000902330653002902339653001102368653001502379653001802394653001102412653001702423653003202440100002202472700002102494700002002515700002102535700002402556700002002580700001902600700001702619700002302636700002602659700002402685856003602709 2021 eng d a1862-351400aCardiovascular autonomic nervous system function and hip fracture risk: the Cardiovascular Health Study.0 aCardiovascular autonomic nervous system function and hip fractur c2021 10 31 a1630 v163 a

Among 1299 older adults with 24-h Holter monitoring data at baseline, followed for approximately 15 years, 190 incident hip fractures occurred. Increased heart rate variability was independently associated with reduced risk of hip fracture among female participants.

PURPOSE: Autonomic nervous system function modulates bone remodeling in rodent osteoporosis models. We tested whether cardiovascular autonomic function is associated with hip fracture risk in humans.

METHODS: Participants were 1299 subjects from the Cardiovascular Health Study (mean age 72.8 years). Eight heart rate variability (HRV) measures (time and frequency domains, detrended fluctuation analysis variables, and heart rate turbulence) were derived from 24-h Holter monitor scans in sinus rhythm. Median follow-up for incident hip fracture was 14.7 years [IQR 9.1, 20.2]. Cox proportional hazards models were used to calculate hazard ratios (95% confidence intervals, CI).

RESULTS: There were 144 hip fractures among 714 women (1.31 [1.06, 1.61] per 100-person years) and 46 among 585 men (0.62 [0.43, 0.90] per 100 person-years). From among HRV variables examined, a one standard deviation (SD) higher variation between normal heart beats over 24 h (the SD of NN intervals [SDNN]) was associated with a multivariable-adjusted lower hip fracture risk (HR [Formula: see text] 0.80; 95% CI 0.65-0.99; p = 0.04) in women. The adjusted association between very low frequency power, and hip fracture was borderline statistically significant in women (HR [Formula: see text] 0.82; 95% CI, 0.66-1.00; p = 0.06). When the 8 HRV variables were considered conjointly and adjusted for each other's association with hip fracture risk, a 1 SD higher SDNN value was significantly associated with reduced hip fracture risk in women (HR 0.74; 95% CI, 0.50-0.99; p = 0.05). No HRV variables were associated with hip fracture in men.

CONCLUSIONS: In older women, increased heart rate variation is associated with hip fracture risk.

10aAged10aAutonomic Nervous System10aFemale10aHeart Rate10aHip Fractures10aHumans10aOsteoporosis10aProportional Hazards Models1 aStein, Phyllis, K1 aBůzková, Petra1 aFink, Howard, A1 aRobbins, John, A1 aMukamal, Kenneth, J1 aCauley, Jane, A1 aCarbone, Laura1 aElam, Rachel1 aMcMillan, David, W1 aValderrabano, Rodrigo1 aBarzilay, Joshua, I uhttps://chs-nhlbi.org/node/900402430nas a2200241 4500008004100000022001400041245012600055210006900181260001600250520166100266100001401927700001801941700002401959700002201983700002002005700002002025700001902045700002302064700002202087700002302109700002002132856003602152 2022 eng d a1532-541500aSex- and race-specific associations of bone mineral density with incident heart failure and its subtypes in older adults.0 aSex and racespecific associations of bone mineral density with i c2022 Nov 053 a

BACKGROUND: Previous studies have suggested an association between bone mineral density (BMD) and heart failure (HF) risk that may be race-dependent.

METHODS: We evaluated the relationship between BMD and incident HF in a cohort of older adults, the Health, Aging, and Body Composition (Health ABC) study (n = 2835), and next performed a pooled analysis involving a second older cohort, the Cardiovascular Health Study (n = 1268). Hip BMD was measured by dual-energy X-ray absorptiometry in both cohorts and spine BMD by computed tomography in a subset from Health ABC.

RESULTS: In Health ABC, lower BMD at the total hip was associated with higher incident HF in Black women after multivariable adjustment. Similar associations were found for BMD at the femoral neck and spine. In both cohorts, pooled analysis again revealed an association between lower total hip BMD and increased risk of HF in Black women (HR = 1.41 per 0.1-g/cm decrement [95% CI = 1.23-1.62]), and showed the same to be true for White men (HR = 1.12 [1.03-1.21]). There was a decreased risk of HF in Black men (HR 0.80 [0.70-0.91]), but no relationship in White women. The associations were numerically stronger with HFpEF for Black women and White men, and with HFrEF for Black men. Findings were similar for femoral neck BMD. Sensitivity analyses delaying HF follow-up by 2 years eliminated the association in Black men.

CONCLUSIONS: Lower BMD was associated with higher risk of HF and especially HFpEF in older Black women and White men, highlighting the need for additional investigation into underlying mechanisms.

1 aGao, Hans1 aPatel, Sheena1 aFohtung, Raymond, B1 aCawthon, Peggy, M1 aNewman, Anne, B1 aCauley, Jane, A1 aCarbone, Laura1 aChaves, Paulo, H M1 aStein, Phyllis, K1 aCivitelli, Roberto1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/924802513nas a2200217 4500008004100000022001400041245016600055210006900221260001300290300001100303490000600314520179500320100001902115700002102134700002002155700002102175700002402196700002002220700001902240856003602259 2023 eng d a2473-403900aThe Association of Tryptophan and Its Metabolites With Incident Hip Fractures, Mortality, and Prevalent Frailty in Older Adults: The Cardiovascular Health Study.0 aAssociation of Tryptophan and Its Metabolites With Incident Hip  c2023 Oct ae108010 v73 a

Amino acids are the building blocks of proteins, and sufficient protein intake is important for skeletal health. We utilized stored serum from the Cardiovascular Health Study in 1992-1993 to examine the relationship between levels of the essential amino acid tryptophan (trp) and its oxidized and nonoxidized metabolites to risk for incident hip fractures and mortality over 12 years of follow-up. We included 131 persons who sustained a hip fracture during this time period and 131 without a hip fracture over these same 12 years of follow-up; 58% female and 95% White. Weighted multivariable Cox hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of incident hip fracture associated with a one standard deviation (SD) higher trp or its metabolites exposure. Relative risk regression was used to evaluate the cross-sectional association of trp and its metabolites with frailty. Higher serum levels of trp were significantly associated with lower risk of incident hip fractures (HR = 0.75 per SD of trp (95% CI 0.57-0.99) but were not significantly associated with mortality or frailty status by Freid's frailty index. There were no statistically significant associations between any of the oxidized or nonoxidized products of trp with incident hip fractures ( ≥ 0.64), mortality ( ≥ 0.20), or cross-sectional frailty status ( ≥ 0.13) after multiple testing adjustment. Randomized clinical trials examining whether increasing trp intake is beneficial for osteoporosis are needed. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

1 aCarbone, Laura1 aBůzková, Petra1 aFink, Howard, A1 aRobbins, John, A1 aBarzilay, Joshua, I1 aElam, Rachel, E1 aIsales, Carlos uhttps://chs-nhlbi.org/node/949902924nas a2200337 4500008004100000022001400041245008300055210006900138260001600207300000700223490000700230520199400237653000902231653001202240653001802252653001102270653002702281653002202308100002402330700002102354700002002375700002002395700001902415700001702434700002102451700001902472700001802491700001702509700002402526856003602550 2023 eng d a1862-351400aThe associations of markers of endothelial dysfunction with hip fracture risk.0 aassociations of markers of endothelial dysfunction with hip frac c2023 Mar 02 a390 v183 a

UNLABELLED: Endothelial dysfunction underlies the development of atherosclerotic vascular disease, which in turn is associated with osteoporotic fractures. Here, we examined the association of two markers of endothelial dysfunction with incident hip fracture risk in older adults but found no statistically significant associations between them.

PURPOSE/INTRODUCTION: Endothelial dysfunction underlies the development of atherosclerotic vascular disease. Vascular disease, in turn, is associated with the risk of osteoporotic fractures, such as hip fractures. Here, we examine whether two measures of endothelial dysfunction are related to hip fracture risk.

METHODS: Participants for this study were 2792 individuals (mean age 78.6 years) who had flow-mediated dilation (FMD) measured after ischemia in the forearm and 2255 adults (mean age 73.3 years) with measured soluble intercellular adhesion molecule (siCAM) levels, a constitutive endothelial cell membrane protein associated with the initiation of atherosclerosis. Mean follow-up was 9.7 and 11.7 years, respectively. There were 375 and 265 incident hip fractures, respectively, in each group.

RESULTS: In Cox proportional hazards models, there was no significant association between FMD response and incident hip fracture (HR per 1% higher FMD was 0.98 [0.93, 1.04]; p = 0.44). In exploratory analyses, when data were examined dichotomously, participants in the lowest 80% of FMD (≤ 4.5%) had an adjusted 1.29 (0.98, 1.68; p = 0.067) higher hazard of hip fracture compared to participants in the upper 20% of FMD change. There were no significant associations between siCAM and incident hip fracture whether examined as a continuous or dichotomized variable.

CONCLUSIONS: Among older adults, two measures of endothelial dysfunction were not significantly associated with hip fracture risk. There was a trend for higher fracture risk with lower FMD.

10aAged10aForearm10aHip Fractures10aHumans10aOsteoporotic Fractures10aVascular Diseases1 aBarzilay, Joshua, I1 aBůzková, Petra1 aFink, Howard, A1 aCauley, Jane, A1 aCarbone, Laura1 aElam, Rachel1 aRobbins, John, A1 aStein, Phyllis1 aSheets, Kerry1 aJalal, Diana1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/931602552nas a2200217 4500008004100000022001400041245011900055210006900174260001600243520184600259100001902105700002102124700002002145700002102165700002402186700002002210700001902230700002502249700002402274856003602298 2023 eng d a1945-719700aPlasma Levels of Branched Chain Amino Acids, Incident Hip Fractures and Bone Mineral Density of the Hip and Spine.0 aPlasma Levels of Branched Chain Amino Acids Incident Hip Fractur c2023 May 183 a

OBJECTIVE: Branched chain amino acids (BCAA) are building blocks for protein, an essential component of bone. However, the association of plasma levels of BCAA with fractures in populations outside of Hong Kong or with hip fractures in particular is not known. The purpose of these analyses was to determine the relationship of BCAA including valine, leucine and isoleucine and total BCAA (standard deviation of the sum of Z-scores for each BCAA) with incident hip fractures and bone mineral density (BMD) of the hip and lumbar spine in older African American and Caucasian men and women in the Cardiovascular Health Study (CHS).

DESIGN: Longitudinal analyses of association of plasma levels of BCAA with incident hip fractures and cross-sectional BMD of the hip and lumbar spine from the CHS.

SETTING: Community.

PARTICIPANTS: 1850 men (38% of cohort) and women; mean age 73.

MAIN OUTCOME MEASURES: Incident hip fractures and cross-sectional BMD of the total hip, femoral neck and lumbar spine.

RESULTS: In fully adjusted models, over 12 years of follow-up, we observed no significant association between incident hip fracture and plasma values of valine, leucine, isoleucine or total BCAA per 1 standard deviation higher of each BCAA. Plasma values of leucine but not valine, isoleucine or total BCAA, were positively and significantly associated with BMD of the total hip (p = 0.03) and femoral neck (p = 0.02), but not the lumbar spine (p = 0.07).

CONCLUSIONS: Plasma levels of the BCAA leucine may be associated with higher BMD in older men and women. However, given lack of a significant association with hip fracture risk, further information is needed to determine whether BCAAs would be novel targets for osteoporosis therapies.

1 aCarbone, Laura1 aBůzková, Petra1 aFink, Howard, A1 aRobbins, John, A1 aBarzilay, Joshua, I1 aElam, Rachel, E1 aIsales, Carlos1 aConnelly, Margery, A1 aMukamal, Kenneth, J uhttps://chs-nhlbi.org/node/937503396nas a2200433 4500008004100000022001400041245015600055210006900211260001600280520204800296100002202344700002002366700002002386700002402406700002102430700002402451700001702475700001902492700002602511700002102537700002002558700002402578700002002602700002302622700002402645700002402669700002102693700002002714700002102734700001602755700002602771700002602797700003002823700001502853700002002868700001902888700001902907856003602926 2024 eng d a1523-468100aLarge-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures.0 aLargescale circulating proteome association study CPAS metaanaly c2024 Jan 043 a

Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Trøndelag Health Study) with circulating proteomics data (aptamer-based 5 K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P < 1.0 × 10-5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets.

1 aAustin, Thomas, R1 aFink, Howard, A1 aJalal, Diana, I1 aTörnqvist, Anna, E1 aBůzková, Petra1 aBarzilay, Joshua, I1 aLu, Tianyuan1 aCarbone, Laura1 aGabrielsen, Maiken, E1 aGrahnemo, Louise1 aHveem, Kristian1 aJonasson, Christian1 aKizer, Jorge, R1 aLanghammer, Arnulf1 aMukamal, Kenneth, J1 aGerszten, Robert, E1 aNethander, Maria1 aPsaty, Bruce, M1 aRobbins, John, A1 aSun, Yan, V1 aSkogholt, Anne, Heidi1 aÅsvold, Bjørn, Olav1 aValderrábano, Rodrigo, J1 aZheng, Jie1 aRichards, Brent1 aCoward, Eivind1 aOhlsson, Claes uhttps://chs-nhlbi.org/node/9635