Weight change, variability, and trajectories and risk of hip fracture among older adults with Dysglycemia: the cardiovascular health study.

BACKGROUND: Type 2 diabetes mellitus and lower weight are both associated with osteoporotic fractures, but the roles of variability and trajectory are less clear.1 The associations of these factors among older adults with dysglycemia, who are at highest risk of fracture, with fracture risk and bone mineral density (BMD) remains uncertain. METHODS: We followed 775 men and 1080 women from the Cardiovascular Health Study (mean age 77.4 years) with abnormal oral glucose tolerance testing in 1989-1990. We measured their weights yearly through 1994-1995 and derived intra-individual mean weight, weight slope, and weight variability. We also used growth mixture modelling to derive four latent body-mass index trajectories over time. We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI) for subsequent hip fracture through 2015 and linear regression models to estimate cross-sectional associations with bone mineral density (BMD) of the hip. RESULTS: Each 10 kg higher mean weight was associated with a lower risk of subsequent hip fracture overall (HR 0.81; CI 0.70-0.94) and among women (HR 0.76; CI 0.64-0.91) and with higher BMD (P-value <0.001). Higher weight variability was directly associated with incident hip fracture among women (HR 1.18; CI: 1.03-1.35). Compared with a stable trajectory, a "progressive overweight" trajectory was associated with lower risk of hip fracture (HR 0.66; CI: 0.44-0.99). An uncommon trajectory of "accelerating obesity" was associated with higher BMD. CONCLUSIONS: Among older adults with dysglycemia at high risk for fracture, lower mean weight is associated with higher fracture risk, but variability and trajectory may also contribute. These results highlight the complex effects of weight in older age.

Older adults with diabetes are susceptible to falls and fractures, but how their weight affects their bone strength and fractures remains uncertain. We followed 1855 men and women age 65 years and older with abnormal glucose in The Cardiovascular Health Study and used yearly measured weights to calculate average weight, change in weight over time, and variability in weight. Higher mean weight was associated with lower risk of hip fracture and higher bone density. Weight variability was associated with higher fracture risk among older women. Using trajectories, a group that slowly gained weight over time had a lower risk of hip fracture compared to a group with stable weight.

Association of serum levels of phenylalanine and tyrosine with hip fractures and frailty in older adults: The cardiovascular health study.

This study examined if the amino acids phenylalanine or tyrosine contribute to risk of hip fracture or frailty in older adults. We determined that neither phenylalanine nor tyrosine are important predictors of hip fracture or frailty. We suggest advice on protein intake for skeletal health consider specific amino acid composition. PURPOSE: Protein is essential for skeletal health, but the specific amino acid compositions of protein may have differential associations with fracture risk. The aim of this study was to determine the association of serum levels of the aromatic amino acids phenylalanine and tyrosine with risk for incident hip fractures over twelve years of follow-up and cross sectional associations with frailty. METHODS: We included 131 older men and women from the Cardiovascular Health Study (CHS) who sustained a hip fracture over twelve years of follow-up and 131 men and women without an incident hip fracture over this same period of time. 42% of this cohort were men and 95% were Caucasian. Weighted multivariable Cox hazards molecules 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 serum level of phenylalanine or tyrosine. Relative risk regression was used to determine the cross-sectional association of these amino acids with Freid's frailty index. RESULTS: Neither serum levels of phenylalanine (HR 0.85 (95% CI 0.62-1.16) or tyrosine (HR 0.82 (95% CI 0.62-1.1) were significantly associated with incident hip fractures or cross sectionally with frailty (frail compared with prefrail/not frail) (HR 0.92 (95% CI 0.48-1.76) and HR (0.86 (95% CI 0.46-1.61) respectively. CONCLUSION: Phenylalanine and tyrosine are not significant contributors to hip fractures or frailty in older men and women.

The association of microvascular disease and endothelial dysfunction with vertebral trabecular bone mineral density : The MESA study.

Retinopathy and albuminuria are associated with hip fracture risk. We investigated whether these disorders and endothelial dysfunction (which underlies microvascular diseases) were associated with low trabecular bone density. No significant associations were found, suggesting that microvascular diseases are not related to fracture risk through low trabecular bone density. PURPOSE: Microvascular diseases of the eye, kidney, and brain are associated with endothelial dysfunction and increased hip fracture risk. To explore the basis for higher hip fracture risk, we comprehensively examined whether markers of microvascular disease and/or endothelial dysfunction are related to trabecular bone mineral density (BMD), a proximate risk factor for osteoporotic fractures. METHODS: Among 6814 participants in the Multi-Ethnic Study of Atherosclerosis study (MESA), we derived thoracic vertebral trabecular BMD from computed tomography of the chest and measured urine albumin to creatinine ratios (UACR), retinal arteriolar and venular widths, flow mediated dilation (FMD) of the brachial artery after 5 min of ischemia; and levels of five soluble endothelial adhesion markers (ICAM-1, VCAM-1, L-selectin, P-selectin, and E-selectin). Linear regression models were used to examine the association of trabecular BMD with markers of microvascular disease and with markers of endothelial dysfunction. RESULTS: We observed no significant associations of UACR, retinal arteriolar or venular widths, or FMD with BMD. We also observed no statistically significant association of spine trabecular BMD with levels of endothelial adhesion markers. Men and women had largely similar results. CONCLUSION: We conclude that there is little evidence to connect thoracic spine trabecular BMD to microvascular disorders or to endothelial dysfunction among multi-ethnic middle-aged and older adults. Other factors beyond trabecular BMD (e.g., bone quality or predisposition to falling) may be responsible for the associations of microvascular disease with osteoporotic fractures.

A plasma protein-based risk score to predict hip fractures.

As there are effective treatments to reduce hip fractures, identification of patients at high risk of hip fracture is important to inform efficient intervention strategies. To obtain a new tool for hip fracture prediction, we developed a protein-based risk score in the Cardiovascular Health Study using an aptamer-based proteomic platform. The proteomic risk score predicted incident hip fractures and improved hip fracture discrimination in two Trøndelag Health Study validation cohorts using the same aptamer-based platform. When transferred to an antibody-based proteomic platform in a UK Biobank validation cohort, the proteomic risk score was strongly associated with hip fractures (hazard ratio per s.d. increase, 1.64; 95% confidence interval 1.53-1.77). The proteomic risk score, but not available polygenic risk scores for fractures or bone mineral density, improved the C-index beyond the fracture risk assessment tool (FRAX), which integrates information from clinical risk factors (C-index, FRAX 0.735 versus FRAX + proteomic risk score 0.776). The developed proteomic risk score constitutes a new tool for stratifying patients according to hip fracture risk; however, its improvement in hip fracture discrimination is modest and its clinical utility beyond FRAX with information on femoral neck bone mineral density remains to be determined.

Large-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures.

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.

Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. To increase the understanding of the underlying mechanisms, we performed a meta-analysis of the associations between 4860 circulating proteins and risk of fractures using two large cohorts, including 6430 participants with 643 incident hip fractures. We identified 23 proteins/aptamers associated with incident hip fractures. Two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR were most strongly associated with hip fracture risk. High levels of several inflammation-related proteins were also associated with increased hip fracture risk. 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. Future mechanistic studies should investigate the underlying biology of these novel protein biomarkers which may be potential drug targets.

Cardiovascular Outcomes in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study).

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes. The effects of glucose-lowering medications on cardiovascular outcomes in individuals with type 2 diabetes and low cardiovascular risk are unclear. We investigated cardiovascular outcomes by treatment group in participants randomly assigned to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin, in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study). METHODS: A total of 5047 participants with a mean±SD age of 57.2±10.0 years, type 2 diabetes duration of 4.0±2.7 years, and low baseline prevalence of cardiovascular disease (myocardial infarction, 5.1%; cerebrovascular accident, 2.0%) were followed for a median of 5 years. Prespecified outcomes included between-group time-to-first event analyses of MACE-3 (composite of major adverse cardiovascular events: cardiovascular death, myocardial infarction, and stroke), MACE-4 (MACE-3+unstable angina requiring hospitalization or revascularization), MACE-5 (MACE-4+coronary revascularization), MACE-6 (MACE-5+hospitalization for heart failure), and the individual components. MACE outcomes and hospitalization for heart failure in the liraglutide-treated group were compared with the other groups combined using Cox proportional hazards models. MACE-6 was also analyzed as recurrent events using a proportional rate model to compare all treatment groups. RESULTS: We observed no statistically significant differences in the cumulative incidence of first MACE-3, MACE-4, MACE-5, or MACE-6, or their individual components, by randomized treatment group. However, when compared with the other treatment groups combined, the liraglutide-treated group had a significantly lower risk of MACE-5 (adjusted hazard ratio, 0.70 [95% CI, 0.54-0.91]; P=0.021), MACE-6 (adjusted hazard ratio, 0.70 [95% CI, 0.55-0.90]; P=0.021), and hospitalization for heart failure (adjusted hazard ratio, 0.49 [95% CI, 0.28-0.86]; P=0.022). Compared with the liraglutide group, significantly higher rates of recurrent MACE-6 events occurred in the groups treated with glimepiride (rate ratio, 1.61 [95% CI, 1.13-2.29]) or sitagliptin (rate ratio 1.75; [95% CI, 1.24-2.48]). CONCLUSIONS: This comparative effectiveness study of a contemporary cohort of adults with type 2 diabetes, largely without established cardiovascular disease, suggests that liraglutide treatment may reduce the risk of cardiovascular events in patients at relatively low risk compared with other commonly used glucose-lowering medications. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794143.

Impact of Insulin Sensitivity and ß-Cell Function Over Time on Glycemic Outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE): Differential Treatment Effects of Dual Therapy.

OBJECTIVE: To compare the effects of insulin sensitivity and ß-cell function over time on HbA1c and durability of glycemic control in response to dual therapy. RESEARCH DESIGN AND METHODS: GRADE participants were randomized to glimepiride (n = 1,254), liraglutide (n = 1,262), or sitagliptin (n = 1,268) added to baseline metformin and followed for mean ± SD 5.0 ± 1.3 years, with HbA1c assessed quarterly and oral glucose tolerance tests at baseline, 1, 3, and 5 years. We related time-varying insulin sensitivity (HOMA 2 of insulin sensitivity [HOMA2-%S]) and early (0-30 min) and total (0-120 min) C-peptide (CP) responses to changes in HbA1c and glycemic failure (primary outcome HbA1c ≥7% [53 mmol/mol] and secondary outcome HbA1c >7.5% [58 mmol/mol]) and examined differential treatment responses. RESULTS: Higher HOMA2-%S was associated with greater initial HbA1c lowering (3 months) but not subsequent HbA1c rise. Greater CP responses were associated with a greater initial treatment response and slower subsequent HbA1c rise. Higher HOMA2-%S and CP responses were each associated with lower risk of primary and secondary outcomes. These associations differed by treatment. In the sitagliptin group, HOMA2-%S and CP responses had greater impact on initial HbA1c reduction (test of heterogeneity, P = 0.009 HOMA2-%S, P = 0.018 early CP, P = 0.001 total CP) and risk of primary outcome (P = 0.005 HOMA2-%S, P = 0.11 early CP, P = 0.025 total CP) but lesser impact on HbA1c rise (P = 0.175 HOMA2-%S, P = 0.006 early CP, P < 0.001 total CP) in comparisons with the glimepiride and liraglutide groups. There were no differential treatment effects on secondary outcome. CONCLUSIONS: Insulin sensitivity and ß-cell function affected treatment outcomes irrespective of drug assignment, with greater impact in the sitagliptin group on initial (short-term) HbA1c response in comparison with the glimepiride and liraglutide groups.

Albuminuria: An Underappreciated Risk Factor for Cardiovascular Disease.

Albuminuria, an established biomarker of the progression of chronic kidney disease, is also recognized as a biomarker for the risk of cardiovascular disease. Elevated urinary albumin excretion indicates kidney damage and systemic vascular disease, including myocardial capillary disease and arterial stiffness. Albuminuria is associated with an increased risk of coronary artery disease, stroke, heart failure, arrhythmias, and microvascular disease. There are now several therapeutic agents that can lead to albuminuria lowering and a reduction in cardiovascular risk. However, screening for albuminuria is still low. Considering the importance of multidisciplinary management of patients with cardiovascular disease, it is crucial that health care professionals managing such patients are aware of the benefits of albuminuria surveillance and management.

Dexamethasone Suppression Testing in a Contemporary Cohort with Adrenal Incidentalomas in Two U.S. Integrated Healthcare Systems.

Autonomous cortisol secretion (ACS) from an adrenal adenoma can increase the risk for comorbidities and mortality. The dexamethasone suppression test (DST) is the standard method to diagnose ACS. A multi-site, retrospective cohort of adults with diagnosed adrenal tumors was used to understand patient characteristics associated with DST completion and ACS. Time to DST completion was defined using the lab value and result date; follow-up time was from the adrenal adenoma diagnosis to the time of completion or censoring. ACS was defined by a DST > 1.8 µg/dL (50 nmol/L). The Cox proportional hazards regression model assessed associations between DST completion and patient characteristics. In patients completing a DST, a logistic regression model evaluated relationships between elevated ACS and covariates. We included 24,259 adults, with a mean age of 63.1 years, 48.1% obese, and 28.7% with a Charlson comorbidity index ≥ 4. Approximately 7% (n = 1768) completed a DST with a completion rate of 2.36 (95% CI 2.35, 2.37) per 100 person-years. Fully adjusted models reported that male sex and an increased Charlson comorbidity index were associated with a lower likelihood of DST completion. Current or former smoking status and an increased Charlson comorbidity index had higher odds of a DST > 1.8 µg/dL. In conclusion, clinical policies are needed to improve DST completion and the management of adrenal adenomas.

Albuminuria Screening in People With Type 2 Diabetes in a Managed Care Organization.

Introduction: Albuminuria-an increased amount of urine albumin, in milligrams, adjusted for grams of urine creatinine-is an early marker of diabetic kidney disease. Several new classes of medications are now available that effectively lower albuminuria levels with the potential to delay or prevent the progression of diabetic kidney disease. However, screening for albuminuria in the U.S. is low in population-based studies (<10% to ∼50% at most). In this study, we examine whether screening for albuminuria was improved in an integrated model of healthcare delivery following the recommendations of the National Committee for Quality Assurance mandate (an umbrella group for the managed healthcare industry) to screen for albuminuria. Methods: We examined screening for albuminuria over a 2-year period among people with Type 2 diabetes in a U.S. HMO with an electronic medical record, onto which automated laboratory ordering for albuminuria could be added when a patient appeared at the laboratory (for any reason) if albuminuria testing had not been obtained within the previous 365 days. Participants under this plan received diabetes education at no cost and panel managers to guide their diabetes care. Logistic regression using data from 2020 and 2021, separately, evaluated the relationship between patient characteristics and the likelihood of albuminuria screening. Results: There were 20,688 and 22,487 participants with Type 2 diabetes mellitus in 2020 and 2021, respectively, who were analyzed. Approximately 80% were screened for albuminuria in both years. African American participants and those aged >64 years were more likely to have completed albuminuria screening. Screened individuals had lower HbA1c, blood pressure, and low-density lipoprotein cholesterol levels than those who were not screened. Conclusions: In an integrated healthcare model, it is possible to achieve consistently high rates of albuminuria screening in people with Type 2 diabetes, especially in groups at high risk for kidney disease.

The Association of Tryptophan and Its Metabolites With Incident Hip Fractures, Mortality, and Prevalent Frailty in Older Adults: The Cardiovascular Health Study.

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 (p ≥ 0.64), mortality (p ≥ 0.20), or cross-sectional frailty status (p ≥ 0.13) after multiple testing adjustment. Randomized clinical trials examining whether increasing trp intake is beneficial for osteoporosis are needed. © 2023 The Authors. JBMR Plus 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.

Association of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study.

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 CD4+CD28- 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.

BMI, insulin sensitivity, and cognition in early type 2 diabetes: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study.

OBJECTIVE: This study explored the association of BMI and insulin sensitivity with cognitive performance in type 2 diabetes. METHODS: A cross-sectional analysis of data from the baseline assessment of the Glycemia Reduction Approaches in Diabetes: a Comparative Effectiveness Study (GRADE) was conducted. BMI was used as a surrogate of adiposity and the Matsuda index as the measure of insulin sensitivity. Cognitive tests included the Spanish English Verbal Learning Test, the Digit Symbol Substitution Test, and the letter and animal fluency tests. RESULTS: Cognitive assessments were completed by 5018 (99.4%) of 5047 participants aged 56.7 ± 10.0 years, of whom 36.4% were female. Higher BMI and lower insulin sensitivity were related to better performance on memory and verbal fluency tests. In models including BMI and insulin sensitivity simultaneously, only higher BMI was related to better cognitive performance. CONCLUSIONS: In this study, higher BMI and lower insulin sensitivity in type 2 diabetes were cross-sectionally associated with better cognitive performance. However, only higher BMI was related to cognitive performance when both BMI and insulin sensitivity were considered simultaneously. The causality and mechanisms for this association need to be determined in future studies.

Plasma Levels of Branched Chain Amino Acids, Incident Hip Fractures, and Bone Mineral Density of the Hip and Spine.

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 (SD 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. 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 Cardiovascular Health Study. SETTING: Community. PARTICIPANTS: A total of 1850 men (38% of cohort) and women; mean age 73 years. 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 SD 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 = .03) and femoral neck (P = .02), but not the lumbar spine (P = .07). CONCLUSIONS: Plasma levels of the BCAA leucine may be associated with higher BMD in older men and women. However, given the lack of significant association with hip fracture risk, further information is needed to determine whether BCAAs would be novel targets for osteoporosis therapies.

Mortality Following Hip Fracture in Older Adults With and Without Coronary Heart Disease.

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.

The associations of markers of endothelial dysfunction with hip fracture risk.

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.

Age-Related Factors Associated With The Risk of Hip Fracture.

OBJECTIVE: Advancing age is a powerful risk factor for hip fractures. The biological mechanisms through which aging impacts the risk of hip fractures have not been well studied. METHODS: Biological factors associated with "advancing age" that help to explain how aging is associated with the risk of hip fractures are reviewed. The findings are based on analyses of the Cardiovascular Health Study, an ongoing observational study of adults aged ≥65 years with 25 years of follow-up. RESULTS: The following 5 age-related factors were found to be significantly associated with the risk of hip fractures: (1) microvascular disease of the kidneys (albuminuria and/or elevated urine-albumin-to-creatinine ratio) and brain (abnormal white matter disease on brain magnetic resonance imaging); (2) increased serum levels of carboxymethyl-lysine, an advanced glycation end product that reflects glycation and oxidative stress; (3) reduced parasympathetic tone, as derived from 24-hour Holter monitoring; (4) carotid artery atherosclerosis in the absence of clinical cardiovascular disease; and (5) increased transfatty acid levels in the blood. Each of these factors was associated with a 10% to 25% increased risk of fractures. These associations were independent of traditional risk factors for hip fractures. CONCLUSION: Several factors associated with older age help to explain how "aging" may be associated with the risk of hip fractures. These same factors may also explain the high risk of mortality following hip fractures.

Association of covert brain infarcts and white matter hyperintensities with risk of hip fracture in older adults: the Cardiovascular Health Study.

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.