Long-term trajectories of low back pain in older men: A prospective cohort study with 10-year analysis of the MrOS Study.

While low back pain (LBP) may persist or recur over time, few studies have evaluated the individual course of LBP over a long-term period, particularly among older adults. Based on data from the longitudinal Osteoporotic Fractures in Men (MrOS) study, we aimed to identify and describe different LBP trajectories in older men and characterize members in each trajectory group. A total of 5,976 community-dwelling men (mean age=74.2) enrolled at six US sites were analyzed. Participants self-reported LBP (yes/no) every 4 months during a maximum of 10 years. Latent class growth modelling was performed to identify unique LBP trajectory groups that explained variation in the LBP data. The association of baseline characteristics with trajectory group membership was assessed using univariable and multivariable multinominal logistic regression. A five-class solution was chosen; no/rare LBP (n=2442/40.9%), low frequency-stable LBP (n=1040/17.4%), low frequency-increasing LBP (n=719/12%), moderate frequency-decreasing LBP (n=745/12.5%) and high frequency-stable LBP (n=1030/17.2%). History of falls (OR=1.52), history of LBP (OR=6.37), higher physical impairment (OR=1.51-2.85) and worse psychological function (OR=1.41-1.62) at baseline were all associated with worse LBP trajectory groups in this sample of older men. These findings present an opportunity for targeted interventions and/or management to older men with worse or increasing LBP trajectories and associated modifiable risk factors, to reduce the impact of LBP and improve quality of life.

Hip Fracture Risk Assessment Tools for Adults Aged 80 Years and Older.

Importance: While adults aged 80 years and older account for 70% of hip fractures in the US, performance of fracture risk assessment tools in this population is uncertain. Objective: To compare performance of the Fracture Risk Assessment Tool (FRAX), Garvan Fracture Risk Calculator, and femoral neck bone mineral density (FNBMD) alone in 5-year hip fracture prediction. Design, Setting and Participants: Prognostic analysis of 3 prospective cohort studies including participants attending an index examination (1997 to 2016) at age 80 years or older. Data were analyzed from March 2023 to April 2024. Main Outcomes and Measures: Participants contacted every 4 or 6 months after index examination to ascertain incident hip fractures and vital status. Predicted 5-year hip fracture probabilities calculated using FRAX and Garvan models incorporating FNBMD and FNBMD alone. Model discrimination assessed by area under receiver operating characteristic curve (AUC). Model calibration assessed by comparing observed vs predicted hip fracture probabilities within predicted risk quintiles. Results: A total of 8890 participants were included, with a mean (SD) age at index examination of 82.6 (2.7) years; 4906 participants (55.2%) were women, 866 (9.7%) were Black, 7836 (88.1%) were White, and 188 (2.1%) were other races and ethnicities. During 5-year follow-up, 321 women (6.5%) and 123 men (3.1%) experienced a hip fracture; 818 women (16.7%) and 921 men (23.1%) died before hip fracture. Among women, AUC was 0.69 (95% CI, 0.67-0.72) for FRAX, 0.69 (95% CI, 0.66-0.72) for Garvan, and 0.72 (95% CI, 0.69-0.75) for FNBMD alone (FNBMD superior to FRAX, P = .01; and Garvan, P = .01). Among men, AUC was 0.71 (95% CI, 0.66-0.75) for FRAX, 0.76 (95% CI, 0.72-0.81) for Garvan, and 0.77 (95% CI, 0.72-0.81) for FNBMD alone (P < .001 Garvan and FNBMD alone superior to FRAX). Among both sexes, Garvan greatly overestimated hip fracture risk among individuals in upper quintiles of predicted risk, while FRAX modestly underestimated risk among those in intermediate quintiles of predicted risk. Conclusions and Relevance: In this prognostic study of adults aged 80 years and older, FRAX and Garvan tools incorporating FNBMD compared with FNBMD alone did not improve 5-year hip fracture discrimination. FRAX modestly underpredicted observed hip fracture probability in intermediate-risk individuals. Garvan markedly overpredicted observed hip fracture probability in high-risk individuals. Until better prediction tools are available, clinicians should prioritize consideration of hip BMD, life expectancy, and patient preferences in decision-making regarding drug treatment initiation for hip fracture prevention in late-life adults.

Associations of empirically derived dietary patterns and cognitive performance in older men: Results of the Osteoporotic Fractures in Men (MrOS) study.

OBJECTIVE: The aim of this study was to examine associations between empirically derived dietary pattern scores and cognition, as well as risk of cognitive decline, over an average of 4.6 (± 0.3) years in older men. MATERIALS AND METHODS: This analysis was conducted as part of the Osteoporotic Fractures in Men (MrOS) prospective cohort study. Diet was assessed at Visit 1 (3/2000-4/2002) by food frequency questionnaire, and dietary patterns (Western and Prudent) were derived by factor analysis. The analytic cohort comprised 4231 community-dwelling American men who were aged 65 years or more. Cognitive function was assessed with the Modified Mini-Mental State exam (3MS) and the Trails B test at Visit 1 and at Visit 2 (3/2005-5/2006). Associations between dietary pattern score and cognition and risk of cognitive decline were estimated using mixed effects regression models. Model 1 was adjusted for age, clinic site and total energy intake (TEI). Model 2 was further adjusted for calcium and vitamin D supplement use, body mass index (BMI), physical activity, smoking, diabetes and hypertension (Western diet group) and education, calcium and vitamin D supplement use, depression, BMI, physical activity, smoking and stroke (Prudent diet group). RESULTS: Adherence to the Western dietary pattern was associated with higher 3MS scores and shorter Trails B test time at Visit 1 in Model 2. Adherence to the Prudent dietary pattern was associated with higher 3MS scores in Model 1 but not Model 2. There were no independent associations between dietary pattern scores and risk of cognitive decline 4.6 (± 0.3) years later at Visit 2. CONCLUSION: The results do not support a robust protective effect of the Prudent dietary pattern on cognition in the MrOS cohort. Associations between the Western dietary pattern and better cognitive scores should be interpreted with caution. Further research is needed to understand the complex interactions between dietary patterns and cognition in older men.

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.

Association of back pain with all-cause and cause-specific mortality among older men: a cohort study.

OBJECTIVE: We evaluated whether more severe back pain phenotypes-persistent, frequent or disabling back pain-are associated with higher mortality among older men. METHODS: In this secondary analysis of a prospective cohort, the Osteoporotic Fractures in Men (MrOS) study, we evaluated mortality rates by back pain phenotype among 5215 older community-dwelling men (mean age, 73 years, SD = 5.6) from six U.S. sites. The primary back pain measure used baseline and year five back pain questionnaire data to characterize participants as having: no back pain; non-persistent back pain; infrequent persistent back pain; or frequent persistent back pain. Secondary measures of back pain from year five questionnaire included disabling back pain phenotypes. The main outcomes measured were all-cause and cause-specific mortality. RESULTS: After the year five exam, during up to 18 years of follow-up (mean follow-up=10.3 years), there were 3513 deaths (1218 cardiovascular, 764 cancer, 1531 other). A higher proportion of men with frequent persistent back pain versus no back pain died (78% versus 69%; sociodemographic-adjusted HR = 1.27, 95%CI=1.11-1.45). No association was evident after further adjusting for health-related factors such as self-reported general health and comorbid chronic health conditions (fully-adjusted HR = 1.00; 95%CI=0.86-1.15). Results were similar for cardiovascular mortality and other mortality, but we observed no association of back pain with cancer mortality. Secondary back pain measures including back-related disability were associated with increased mortality risk that remained statistically significant in fully-adjusted models. CONCLUSION: While frequent persistent back pain was not independently associated with mortality in older men, additional secondary disabling back pain phenotypes were independently associated with increased mortality. Future investigations should evaluate whether improvements in disabling back pain effect general health and well-being or mortality.

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.

Balancing fracture risk versus risk of mortality before fracture among women aged 80 years or older.

BACKGROUND: Most fractures occur in women aged ≥80 years but competing mortality unrelated to fracture may limit the benefit of osteoporosis drug therapy for some women in late life. Our primary aim was to develop separate prediction models for non-spine fracture (NSF) and mortality before fracture to identify subsets of women with varying fracture versus mortality risks. METHODS: Separate prediction models were developed for NSF and mortality before NSF for 4895 women aged ≥80 years enrolled in the Study of Osteoporotic Fractures (SOF) or the Health Aging and Body Composition (HABC) study. Proportional hazards models modified to account for competing mortality were used to identify candidate risk factors for each outcome. Predictors associated with NSF or mortality (p < 0.2) were included in separate competing risk models to estimate the cumulative incidence of NSF and mortality before NSF during 5 years of follow-up. This process was repeated to develop separate prediction models for hip fracture and mortality before hip fracture. RESULTS: Significant predictors of NSF (race, total hip BMD, grip strength, prior fracture, falls, and use of selective serotonin reuptake inhibitors, benzodiazepines, or oral/transdermal estrogen) differed from predictors of mortality before NSF (age, walking speed, multimorbidity, weight change, shrinking, smoking, self-rated health, dementia, and use of warfarin). Within nine subsets of women defined by tertiles of risk, 5-year outcomes varied from 28% NSF and 8% mortality in the high-risk NSF/low-risk mortality subset, to 9% NSF and 22% mortality in the low-risk NSF/high-risk mortality subset. Similar results were seen for predictors of hip fracture and mortality before hip fracture. CONCLUSION: Considerable variation in 5-year competing mortality risk is present among women in late life with similar 5-year NSF risk. Both fracture risk and life expectancy should inform shared clinical decision-making regarding initiation or continuation of osteoporosis drug therapy for women aged ≥80 years.

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.

Stressful life events and low back pain in older men: A cross-sectional and prospective analysis using data from the MrOS study.

BACKGROUND: Stressful life events, such as loss of a partner, loss of a pet or financial problems, are more common with increasing age and may impact the experience of pain. The aim of the current study is to determine the cross-sectional and prospective association between stressful life events and low back pain reporting in the Osteoporotic Fracture in Men Study, a cohort of older men aged ≥65 years. METHODS: At a study visit (March 2005-May 2006), 5149 men reported whether they had experienced a stressful life event or low back pain in the prior 12 months. Following that visit, data on low back pain patients were gathered through triannual questionnaires every 4 months for 1 year. Multivariable logistic regression analyses estimated the association of stressful life events with recent past low back pain or future low back pain. RESULTS: N = 2930, (57%) men reported at least one stressful life event. The presence of a stressful life event was associated with greater odds of any low back pain (OR = 1.42 [1.26-1.59]) and activity-limiting low back pain (OR = 1.74 [1.50-2.01]) in the same period and of any low back pain (OR = 1.56 [1.39-1.74]) and frequent low back pain (OR = 1.80 [1.55-2.08]) in the following year. CONCLUSION: In this cohort of men, the presence of stressful life events increased the likelihood of reporting past and future low back pain. SIGNIFICANCE: Stressful life events such as accident or illness to a partner are common in later life and may impact the experience of pain. We present cross-sectional and prospective data highlighting a consistent association between stressful life events and low back pain in older men. Further, there is evidence to suggest that this relationship is upregulated by an individual's living situation. This information may be used to strengthen a biopsychosocial perspective of an individual's pain experience.

2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: The objective is to update recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. METHODS: An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: For adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x-ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision-making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high-dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: The objective is to update recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. METHODS: An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: For adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x-ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision-making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high-dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

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.

The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis.

BACKGROUND: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease and mortality. METHODS: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT4, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT4, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality. INTERPRETATION: There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes. FUNDING: None.

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.

Advantages and Disadvantages of Random Forest Models for Prediction of Hip Fracture Risk Versus Mortality Risk in the Oldest Old.

Targeted fracture prevention strategies among late-life adults should balance fracture risk versus competing mortality risk. Models have previously been constructed using Fine-Gray subdistribution methods. We used a machine learning method adapted for competing risk survival time to evaluate candidate risk factors and create models for hip fractures and competing mortality among men and women aged 80 years and older using data from three prospective cohorts (Study of Osteoporotic Fractures [SOF], Osteoporotic Fracture in Men study [MrOS], Health Aging and Body Composition study [HABC]). Random forest competing risk models were used to estimate absolute 5-year risk of hip fracture and absolute 5-year risk of competing mortality (excluding post-hip fracture deaths). Models were constructed for both outcomes simultaneously; minimal depth was used to rank and select variables for smaller models. Outcome specific models were constructed; variable importance was used to rank and select variables for inclusion in smaller random forest models. Random forest models were compared to simple Fine-Gray models with six variables selected a priori. Top variables for competing risk random forests were frailty and related components in men while top variables were age, bone mineral density (BMD) (total hip, femoral neck), and frailty components in women. In both men and women, outcome specific rankings strongly favored BMD variables for hip fracture prediction while frailty and components were strongly associated with competing mortality. Model discrimination for random forest models varied from 0.65 for mortality in women to 0.81 for hip fracture in men and depended on model choice and variables included. Random models performed slightly better than simple Fine-Gray model for prediction of competing mortality, but similarly for prediction of hip fractures. Random forests can be used to estimate risk of hip fracture and competing mortality among the oldest old. Modest gains in performance for mortality without hip fracture compared to Fine-Gray models must be weighed against increased complexity. © 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.

Performance of Fracture Risk Assessment Tools by Race and Ethnicity: A Systematic Review for the ASBMR Task Force on Clinical Algorithms for Fracture Risk.

The American Society of Bone and Mineral Research (ASBMR) Professional Practice Committee charged an ASBMR Task Force on Clinical Algorithms for Fracture Risk to review the evidence on whether current approaches for differentiating fracture risk based on race and ethnicity are necessary and valid. To help address these charges, we performed a systematic literature review investigating performance of calculators for predicting incident fractures within and across race and ethnicity groups in middle-aged and older US adults. We included English-language, controlled or prospective cohort studies that enrolled US adults aged >40 years and reported tool performance predicting incident fractures within individual race and ethnicity groups for up to 10 years. From 4838 identified references, six reports met eligibility criteria, all in women. Just three, all from one study, included results in non-white individuals. In these three reports, non-white women experienced relatively few major osteoporotic fractures (MOFs), especially hip fractures, and risk thresholds for predicting fractures in non-white women were derived from risks in the overall, predominantly white study population. One report suggested the Fracture Risk Assessment Tool (FRAX) without bone mineral density (BMD) overestimated hip fracture similarly across race and ethnicity groups (black, Hispanic, American Indian, Asian, white) but overestimated MOF more in non-white than White women. However, these three reports were inconclusive regarding whether discrimination of FRAX or the Garvan calculator without BMD or of FRAX with BMD for MOF or hip fracture differed between white versus black women. This uncertainty was at least partly due to imprecise hip fracture estimates in black women. No reports examined whether ratios of observed to predicted hip fracture risks within each race or ethnicity group varied across levels of predicted hip fracture risk. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

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.