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.

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.

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.

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.

Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing.

BACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology. METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations. CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

An evaluation of a sustained senior mentor program for medical students.

Background/Objective Medical student geriatrics education using community-based volunteer older persons, known as a Senior Mentor Program (SMP), began decades ago. Though these programs have been described and evaluated against curriculum objectives, the full breadth of students' learning from SMPs has not been reported. Methods We conducted a qualitative study using content analysis of reflections of Year 2 medical students submitted during a single visit home-based SMP. Written reflections of 102 randomly selected students from 2016-2018 were inductively coded and grouped into themes. Older persons from the SMP site assisted in coding and quotation selection. Results We discerned six themes from the evaluation of student reflections: student insight, interview and exam, social community, challenges with aging, strengths (responses to challenges), and physical infrastructure. Conclusion A single home visit with older adults enables pre-clinical medical students to learn about multiple positive aspects of aging.

Association of Back Pain with Mortality: a Systematic Review and Meta-analysis of Cohort Studies.

BACKGROUND: Back pain is the most common cause of disability worldwide. While disability generally is associated with greater mortality, the association between back pain and mortality is unclear. Our objective was to examine whether back pain is associated with increased mortality risk and whether this association varies by age, sex, and back pain severity. METHODS: A systematic search of published literature was conducted using PubMed, Web of Science, and Embase databases from inception through March 2019. We included English-language prospective cohort studies evaluating the association of back pain with all-cause mortality with follow-up periods >5 years. Three reviewers independently screened studies, abstracted data, and appraised risk of bias using the Quality in Prognosis Studies (QUIPS) tool. A random-effects meta-analysis estimated combined odds ratios (OR) and 95% confidence intervals (CI), using the most adjusted model from each study. Potential effect modification by a priori hypothesized factors (age, sex, and back pain severity) was evaluated with meta-regression and stratified estimates. RESULTS: We identified eleven studies with 81,337 participants. Follow-up periods ranged from 5 to 23 years. The presence of any back pain, compared to none, was not associated with an increase in mortality (OR, 1.06; 95% CI, 0.97 to 1.16). However, back pain was associated with mortality in studies of women (OR, 1.22; 95% CI, 1.02 to 1.46) and among adults with more severe back pain (OR, 1.26; 95% CI, 1.14 to 1.40). CONCLUSION: Back pain was associated with a modest increase in all-cause mortality among women and those with more severe back pain.

Lower urinary tract symptoms are associated with musculoskeletal pain among older men: Preliminary evidence for central sensitization as a mechanism?

AIMS: Features of central sensitization (CS) are present in almost all chronic pain conditions, including painful urinary conditions and back pain. Recently CS was proposed as a mechanism of nonpainful lower urinary tract symptoms (LUTS). Using musculoskeletal pain as an indicator of CS, we investigated whether the prevalence of musculoskeletal pain is greater among community-dwelling men with moderate or severe LUTS compared to those with mild LUTS. METHODS: We conducted a cross-sectional study of 5966 men ≥65 years who attended the Osteoporotic Fractures in Men Study baseline visit. LUTS were assessed with the American Urological Association Symptom Index (AUA-SI) and categorized as none/mild (0-7), moderate (8-19), or severe (≥20). Self-reported back, neck, hip, or knee pain within the 12 months before baseline was categorized as any pain and multilocation pain. We tested our hypothesis using odds ratios (OR) and 95% confidence intervals (CI) estimated from multivariable logistic regression models. RESULTS: The adjusted odds of any pain were higher among men with moderate (OR 1.49, 95% CI: 1.29-1.72) and severe LUTS (OR 1.76, 95% CI: 1.28-2.40) compared to those with no/mild LUTS. The adjusted odds of pain at ≥ 2 locations were 69% higher among men with moderate (OR 1.69, 95% CI: 1.45-196) and more than double among men with severe LUTS (OR 2.24, 95% CI: 1.62-3.10) compared to men with no/mild LUTS. CONCLUSIONS: Musculoskeletal pain, especially at multiple locations, is associated with greater LUTS severity among older men. CS may represent a novel shared mechanism of pain and LUTS.

Accuracy of Biomarker Testing for Neuropathologically Defined Alzheimer Disease in Older Adults With Dementia.

BACKGROUND: Biomarker accuracy for Alzheimer disease (AD) is uncertain. PURPOSE: To summarize evidence on biomarker accuracy for classifying AD in older adults with dementia. DATA SOURCES: Electronic bibliographic databases (searched from January 2012 to November 2019 for brain imaging and cerebrospinal fluid [CSF] tests and from inception to November 2019 for blood tests), ClinicalTrials.gov (to November 2019), and systematic review bibliographies. STUDY SELECTION: English-language studies evaluating the accuracy of brain imaging, CSF testing, or blood tests for distinguishing neuropathologically defined AD from non-AD among older adults with dementia. Studies with low or medium risk of bias were analyzed. DATA EXTRACTION: Two reviewers rated risk of bias. One extracted data; the other verified accuracy. DATA SYNTHESIS: Fifteen brain imaging studies and 9 CSF studies met analysis criteria. Median sensitivity and specificity, respectively, were 0.91 and 0.92 for amyloid positron emission tomography (PET), 0.89 and 0.74 for 18F-labeled fluorodeoxyglucose (18F-FDG) PET, 0.64 and 0.83 for single-photon emission computed tomography, and 0.91 and 0.89 for medial temporal lobe atrophy on magnetic resonance imaging (MRI). Individual CSF biomarkers and ratios had moderate sensitivity (range, 0.62 to 0.83) and specificity (range, 0.53 to 0.69); in the few direct comparisons, ß-amyloid 42 (Aß42)/phosphorylated tau (p-tau) ratio, total tau (t-tau)/Aß42 ratio, and p-tau appeared more accurate than Aß42 and t-tau alone. Single studies suggested that amyloid PET, 18F-FDG PET, and CSF test combinations may add accuracy to clinical evaluation. LIMITATIONS: Studies were small, biomarker cut points and neuropathologic AD were inconsistently defined, and methods with uncertain applicability to typical clinical settings were used. Few studies directly compared biomarkers, assessed test combinations, evaluated whether biomarkers improved classification accuracy when added to clinical evaluation, or reported harms. CONCLUSION: In methodologically heterogeneous studies of uncertain applicability to typical clinical settings, amyloid PET, 18F-FDG PET, and MRI were highly sensitive for neuropathologic AD. Amyloid PET, 18F-FDG PET, and CSF test combinations may add accuracy to clinical evaluation. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018117897).

Efficacy and Safety of Testosterone Treatment in Men: An Evidence Report for a Clinical Practice Guideline by the American College of Physicians.

Background: Testosterone treatment rates in adult men have increased in the United States over the past 2 decades. Purpose: To assess the benefits and harms of testosterone treatment for men without underlying organic causes of hypogonadism. Data Sources: English-language searches of multiple electronic databases (January 1980 to May 2019) and reference lists from systematic reviews. Study Selection: 38 randomized controlled trials (RCTs) of at least 6 months' duration that evaluated transdermal or intramuscular testosterone therapies versus placebo or no treatment and reported prespecified patient-centered outcomes, as well as 20 long-term observational studies, U.S. Food and Drug Administration review data, and product labels that reported harms information. Data Extraction: Data extraction by a single investigator was confirmed by a second, 2 investigators assessed risk of bias, and evidence certainty was determined by consensus. Data Synthesis: Studies enrolled mostly older men who varied in age, symptoms, and testosterone eligibility criteria. Testosterone therapy improved sexual functioning and quality of life in men with low testosterone levels, although effect sizes were small (low- to moderate-certainty evidence). Testosterone therapy had little to no effect on physical functioning, depressive symptoms, energy and vitality, or cognition. Harms evidence reported in trials was judged to be insufficient or of low certainty for most harm outcomes. No trials were powered to assess cardiovascular events or prostate cancer, and trials often excluded men at increased risk for these conditions. Observational studies were limited by confounding by indication and contraindication. Limitation: Few trials exceeded a 1-year duration, minimum important outcome differences were often not established or reported, RCTs were not powered to assess important harms, few data were available in men aged 18 to 50 years, definitions of low testosterone varied, and study entry criteria varied. Conclusion: In older men with low testosterone levels without well-established medical conditions known to cause hypogonadism, testosterone therapy may provide small improvements in sexual functioning and quality of life but little to no benefit for other common symptoms of aging. Long-term efficacy and safety are unknown. Primary Funding Source: American College of Physicians. (PROSPERO: CRD42018096585).

Brief Cognitive Tests for Distinguishing Clinical Alzheimer-Type Dementia From Mild Cognitive Impairment or Normal Cognition in Older Adults With Suspected Cognitive Impairment.

BACKGROUND: The accuracy and harms of brief cognitive tests for identifying clinical Alzheimer-type dementia (CATD) are uncertain. PURPOSE: To summarize evidence on accuracy and harms of brief cognitive tests for CATD in older adults with suspected cognitive impairment. DATA SOURCES: Electronic bibliographic databases (from inception to November 2019) and systematic review bibliographies. STUDY SELECTION: English-language, controlled observational studies in older adults that evaluated the accuracy of brief cognitive tests (standalone tests; memory, executive function, and language tests; and brief multidomain batteries) for distinguishing CATD from mild cognitive impairment (MCI) or normal cognition as defined by established diagnostic criteria. Studies with low or medium risk of bias (ROB) were analyzed. DATA EXTRACTION: Two reviewers rated ROB. One reviewer extracted data; the other verified extraction accuracy. DATA SYNTHESIS: Fifty-seven studies met analysis criteria. Many brief, single cognitive tests were highly sensitive and specific for distinguishing CATD from normal cognition. These included standalone tests (clock-drawing test, median sensitivity 0.79 and specificity 0.88 [8 studies]; Mini-Mental State Examination, 0.88 and 0.94 [7 studies]; Montreal Cognitive Assessment, 0.94 and 0.94 [2 studies]; and Brief Alzheimer Screen, 0.92 and 0.97 [1 study]), memory tests (list delayed recall, 0.89 and 0.94 [5 studies]), and language tests (category fluency, 0.92 and 0.89 [9 studies]). Accuracy was lower in distinguishing mild CATD from normal cognition and distinguishing CATD from MCI. No studies reported on testing harms. LIMITATIONS: Studies were small. Few test metrics were evaluated by multiple studies. Few studies directly compared different tests, scores, cut points, or test combinations. CONCLUSION: Many brief, single cognitive tests accurately distinguish CATD from normal cognition in older adults but are less accurate in distinguishing mild CATD from normal cognition or CATD from MCI. No studies reported on testing harms. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018117897).

Benefits and Harms of Prescription Drugs and Supplements for Treatment of Clinical Alzheimer-Type Dementia.

BACKGROUND: Effects of drug treatment of clinical Alzheimer-type dementia (CATD) are uncertain. PURPOSE: To summarize evidence on the effects of prescription drugs and supplements for CATD treatment. DATA SOURCES: Electronic bibliographic databases (inception to November 2019), ClinicalTrials.gov (to November 2019), and systematic review bibliographies. STUDY SELECTION: English-language trials of prescription drug and supplement treatment in older adults with CATD that report cognition, function, global measures, behavioral and psychological symptoms of dementia (BPSD), or harms. Minimum treatment was 24 weeks (≥2 weeks for selected BPSD). DATA EXTRACTION: Studies with low or medium risk of bias (ROB) were analyzed. Two reviewers rated ROB. One reviewer extracted data; another verified extraction accuracy. DATA SYNTHESIS: Fifty-five studies reporting non-BPSD outcomes (most ≤26 weeks) and 12 reporting BPSD (most ≤12 weeks) were analyzed. Across CATD severity, mostly low-strength evidence suggested that, compared with placebo, cholinesterase inhibitors produced small average improvements in cognition (median standardized mean difference [SMD], 0.30 [range, 0.24 to 0.52]), no difference to small improvement in function (median SMD, 0.19 [range, -0.10 to 0.22]), no difference in the likelihood of at least moderate improvement in global clinical impression (median absolute risk difference, 4% [range, 2% to 4%]), and increased withdrawals due to adverse events. In adults with moderate to severe CATD receiving cholinesterase inhibitors, low- to insufficient-strength evidence suggested that, compared with placebo, add-on memantine inconsistently improved cognition and improved global clinical impression but not function. Evidence was mostly insufficient about prescription drugs for BPSD and about supplements for all outcomes. LIMITATION: Most drugs had few trials without high ROB, especially for supplements, active drug comparisons, BPSD, and longer trials. CONCLUSION: Cholinesterase inhibitors and memantine slightly reduced short-term cognitive decline, and cholinesterase inhibitors slightly reduced reported functional decline, but differences versus placebo were of uncertain clinical importance. Evidence was mostly insufficient on drug treatment of BPSD and on supplements for all outcomes. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42018117897).

Associations between novel jump test measures, grip strength, and physical performance: the Osteoporotic Fractures in Men (MrOS) Study.

BACKGROUND/AIMS: Weight-bearing jump tests measure lower extremity muscle power, velocity, and force, and may be more strongly related to physical performance than grip strength. However, these relationships are not well described in older adults. METHODS: Participants were 1242 older men (mean age 84 ± 4 years) in the Osteoporotic Fractures in Men (MrOS) Study. Jump peak power (Watts/kg body weight), force (Newton/kg body weight) at peak power, and velocity (m/s) at peak power were measured by jump tests on a force plate. Grip strength (kg/kg body weight) was assessed by hand-held dynamometry. Physical performance included 400 m walk time (s), 6 m usual gait speed (m/s), and 5-repeated chair stands speed (#/s). RESULTS: In adjusted Pearson correlations, power/kg and velocity moderately correlated with all performance measures (range r = 0.41-0.51; all p < 0.001), while correlations for force/kg and grip strength/kg were weaker (range r = 0.20-0.33; all p < 0.001). Grip strength/kg moderately correlated with power/kg (r = 0.44; p < 0.001) but not velocity or force/kg. In adjusted linear regression with standardized ßs, 1 SD lower power/kg was associated with worse: 400 m walk time (ß = 0.47), gait speed (ß = 0.42), and chair stands speed (ß = 0.43) (all p < 0.05). Associations with velocity were similar (400 m walk time: ß = 0.42; gait speed: ß = 0.38; chair stands speed: ß = 0.37; all p < 0.05). Force/kg and grip strength/kg were more weakly associated with performance (range ß = 0.18-0.28; all p < 0.05). CONCLUSIONS/DISCUSSION: Jump power and velocity had stronger associations with physical performance than jump force or grip strength. This suggests lower extremity power and velocity may be more strongly related to physical performance than lower extremity force or upper extremity strength in older men.

Long-Term Drug Therapy and Drug Discontinuations and Holidays for Osteoporosis Fracture Prevention: A Systematic Review.

Background: Optimal long-term osteoporosis drug treatment (ODT) is uncertain. Purpose: To summarize the effects of long-term ODT and ODT discontinuation and holidays. Data Sources: Electronic bibliographic databases (January 1995 to October 2018) and systematic review bibliographies. Study Selection: 48 studies that enrolled men or postmenopausal women aged 50 years or older who were being investigated or treated for fracture prevention, compared long-term ODT (>3 years) versus control or ODT continuation versus discontinuation, reported incident fractures (for trials) or harms (for trials and observational studies), and had low or medium risk of bias (ROB). Data Extraction: Two reviewers independently rated ROB and strength of evidence (SOE). One extracted data; another verified accuracy. Data Synthesis: Thirty-five trials (9 unique studies) and 13 observational studies (11 unique studies) had low or medium ROB. In women with osteoporosis, 4 years of alendronate reduced clinical fractures (hazard ratio [HR], 0.64 [95% CI, 0.50 to 0.82]) and radiographic vertebral fractures (both moderate SOE), whereas 4 years of raloxifene reduced vertebral but not nonvertebral fractures. In women with osteopenia or osteoporosis, 6 years of zoledronic acid reduced clinical fractures (HR, 0.73 [CI, 0.60 to 0.90]), including nonvertebral fractures (high SOE) and clinical vertebral fractures (moderate SOE). Long-term bisphosphonates increased risk for 2 rare harms: atypical femoral fractures (low SOE) and osteonecrosis of the jaw (mostly low SOE). In women with unspecified osteoporosis status, 5 to 7 years of hormone therapy reduced clinical fractures (high SOE), including hip fractures (moderate SOE), but increased serious harms. After 3 to 5 years of treatment, bisphosphonate continuation versus discontinuation reduced radiographic vertebral fractures (zoledronic acid; low SOE) and clinical vertebral fractures (alendronate; moderate SOE) but not nonvertebral fractures (low SOE). Limitation: No trials studied men, clinical fracture data were sparse, methods for estimating harms were heterogeneous, and no trials compared sequential treatments or different durations of drug holidays. Conclusion: Long-term alendronate and zoledronic acid therapies reduce fracture risk in women with osteoporosis. Long-term bisphosphonate treatment may increase risk for rare adverse events, and continuing treatment beyond 3 to 5 years may reduce risk for vertebral fractures. Long-term hormone therapy reduces hip fracture risks but has serious harms. Primary Funding Source: National Institutes of Health and Agency for Healthcare Research and Quality. (PROSPERO: CRD42018087006).

The Association of Aromatic Amino Acids with Incident Hip Fracture, aBMD, and Body Composition from the Cardiovascular Health Study.

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

Efficacy of newer medications for lower urinary tract symptoms attributed to benign prostatic hyperplasia: a systematic review.

We conducted a systematic review to evaluate the efficacy and adverse effects of newer drugs used to treat lower urinary tract symptoms (LUTS). The drugs were either Food and Drug Administration (FDA) approved for benign prostatic hyperplasia (BPH) or not FDA approved for BPH but have been evaluated for treatment of BPH since 2008. We searched bibliographic databases through September 2017. We included randomized controlled trials (RCTs) lasting one month or longer published in English. Outcomes of interest were LUTS assessed by validated measures. Efficacy was interpreted using established thresholds indicating clinical significance that identified the minimal detectable difference. Twenty-three unique, generally short-term, RCTs evaluating over 9000 participants were identified. Alpha-blocker silodosin and phosphodiesterase type 5 inhibitor tadalafil were more effective than placebo in improving LUTS (moderate strength evidence) but these drugs had more adverse effects, including abnormal ejaculation (silodosin). Anticholinergics were only effective versus placebo when combined with an alpha-blocker. Evidence was generally low strength or insufficient for other drugs. Evidence was insufficient to assess long-term efficacy, prevention of symptom progression, need for surgical intervention, or long-term adverse effects. Longer trials are needed to assess the effect of these therapies on response rates using established minimal detectable difference thresholds, disease progression, and harms.

Does Cognitive Training Prevent Cognitive Decline?: A Systematic Review.

Background: Structured activities to stimulate brain function-that is, cognitive training exercises-are promoted to slow or prevent cognitive decline, including dementia, but their effectiveness is highly debated. Purpose: To summarize evidence on the effects of cognitive training on cognitive performance and incident dementia outcomes for adults with normal cognition or mild cognitive impairment (MCI). Data Sources: Ovid MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and PsycINFO through July 2017, supplemented by hand-searches. Study Selection: Trials (published in English) lasting at least 6 months that compared cognitive training with usual care, waitlist, information, or attention controls in adults without dementia. Data Extraction: Single-reviewer extraction of study characteristics confirmed by a second reviewer; dual-reviewer risk-of-bias assessment; consensus determination of strength of evidence. Only studies with low or medium risk of bias were analyzed. Data Synthesis: Of 11 trials with low or medium risk of bias, 6 enrolled healthy adults with normal cognition and 5 enrolled adults with MCI. Trainings for healthy older adults were mostly computer based; those for adults with MCI were mostly held in group sessions. The MCI trials used attention controls more often than trials with healthy populations. For healthy older adults, training improved cognitive performance in the domain trained but not in other domains (moderate-strength evidence). Results for populations with MCI suggested no effect of training on performance (low-strength and insufficient evidence). Evidence for prevention of cognitive decline or dementia was insufficient. Adverse events were not reported. Limitation: Heterogeneous interventions and outcome measures; outcomes that mostly assessed test performance rather than global function or dementia diagnosis; potential publication bias. Conclusion: In older adults with normal cognition, training improves cognitive performance in the domain trained. Evidence regarding prevention or delay of cognitive decline or dementia is insufficient. Primary Funding Source: Agency for Healthcare Research and Quality.

Pharmacologic Interventions to Prevent Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer-Type Dementia: A Systematic Review.

Background: Optimal treatment to prevent or delay cognitive decline, mild cognitive impairment (MCI), or dementia is uncertain. Purpose: To summarize current evidence on the efficacy and harms of pharmacologic interventions to prevent or delay cognitive decline, MCI, or dementia in adults with normal cognition or MCI. Data Sources: Several electronic databases from January 2009 to July 2017, bibliographies, and expert recommendations. Study Selection: English-language trials of at least 6 months' duration enrolling adults without dementia and comparing pharmacologic interventions with placebo, usual care, or active control on cognitive outcomes. Data Extraction: Two reviewers independently rated risk of bias and strength of evidence; 1 extracted data, and a second checked accuracy. Data Synthesis: Fifty-one unique trials were rated as having low to moderate risk of bias (including 3 that studied dementia medications, 16 antihypertensives, 4 diabetes medications, 2 nonsteroidal anti-inflammatory drugs [NSAIDs] or aspirin, 17 hormones, and 7 lipid-lowering agents). In persons with normal cognition, estrogen and estrogen-progestin increased risk for dementia or a combined outcome of MCI or dementia (1 trial, low strength of evidence); high-dose raloxifene decreased risk for MCI but not for dementia (1 trial, low strength of evidence); and antihypertensives (4 trials), NSAIDs (1 trial), and statins (1 trial) did not alter dementia risk (low to insufficient strength of evidence). In persons with MCI, cholinesterase inhibitors did not reduce dementia risk (1 trial, low strength of evidence). In persons with normal cognition and those with MCI, these pharmacologic treatments neither improved nor slowed decline in cognitive test performance (low to insufficient strength of evidence). Adverse events were inconsistently reported but were increased for estrogen (stroke), estrogen-progestin (stroke, coronary heart disease, invasive breast cancer, and pulmonary embolism), and raloxifene (venous thromboembolism). Limitation: High attrition, short follow-up, inconsistent cognitive outcomes, and possible selective reporting and publication. Conclusion: Evidence does not support use of the studied pharmacologic treatments for cognitive protection in persons with normal cognition or MCI. Primary Funding Source: Agency for Healthcare Research and Quality.

Over-the-Counter Supplement Interventions to Prevent Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer-Type Dementia: A Systematic Review.

Background: Optimal interventions to prevent or delay cognitive decline, mild cognitive impairment (MCI), or dementia are uncertain. Purpose: To summarize the evidence on efficacy and harms of over-the-counter (OTC) supplements to prevent or delay cognitive decline, MCI, or clinical Alzheimer-type dementia in adults with normal cognition or MCI but no dementia diagnosis. Data Sources: Multiple electronic databases from 2009 to July 2017 and bibliographies of systematic reviews. Study Selection: English-language trials of at least 6 months' duration that enrolled adults without dementia and compared cognitive outcomes with an OTC supplement versus placebo or active controls. Data Extraction: Extraction performed by a single reviewer and confirmed by a second reviewer; dual-reviewer assessment of risk of bias; consensus determination of strength of evidence. Data Synthesis: Thirty-eight trials with low to medium risk of bias compared ω-3 fatty acids, soy, ginkgo biloba, B vitamins, vitamin D plus calcium, vitamin C or ß-carotene, multi-ingredient supplements, or other OTC interventions with placebo or other supplements. Few studies examined effects on clinical Alzheimer-type dementia or MCI, and those that did suggested no benefit. Daily folic acid plus vitamin B12 was associated with improvements in performance on some objectively measured memory tests that were statistically significant but of questionable clinical significance. Moderate-strength evidence showed that vitamin E had no benefit on cognition. Evidence about effects of ω-3 fatty acids, soy, ginkgo biloba, folic acid alone or with other B vitamins, ß-carotene, vitamin C, vitamin D plus calcium, and multivitamins or multi-ingredient supplements was either insufficient or low-strength, suggesting that these supplements did not reduce risk for cognitive decline. Adverse events were rarely reported. Limitation: Studies had high attrition and short follow-up and used a highly variable set of cognitive outcome measures. Conclusion: Evidence is insufficient to recommend any OTC supplement for cognitive protection in adults with normal cognition or MCI. Primary Funding Source: Agency for Healthcare Research and Quality.

Physical Activity Interventions in Preventing Cognitive Decline and Alzheimer-Type Dementia: A Systematic Review.

Background: The prevalence of cognitive impairment and dementia is expected to increase dramatically as the population ages, creating burdens on families and health care systems. Purpose: To assess the effectiveness of physical activity interventions in slowing cognitive decline and delaying the onset of cognitive impairment and dementia in adults without diagnosed cognitive impairments. Data Sources: Several electronic databases from January 2009 to July 2017 and bibliographies of systematic reviews. Study Selection: Trials published in English that lasted 6 months or longer, enrolled adults without clinically diagnosed cognitive impairments, and compared cognitive and dementia outcomes between physical activity interventions and inactive controls. Data Extraction: Extraction by 1 reviewer and confirmed by a second; dual-reviewer assessment of risk of bias; consensus determination of strength of evidence. Data Synthesis: Of 32 eligible trials, 16 with low to moderate risk of bias compared a physical activity intervention with an inactive control. Most trials had 6-month follow-up; a few had 1- or 2-year follow-up. Evidence was insufficient to draw conclusions about the effectiveness of aerobic training, resistance training, or tai chi for improving cognition. Low-strength evidence showed that multicomponent physical activity interventions had no effect on cognitive function. Low-strength evidence showed that a multidomain intervention comprising physical activity, diet, and cognitive training improved several cognitive outcomes. Evidence regarding effects on dementia prevention was insufficient for all physical activity interventions. Limitation: Heterogeneous interventions and cognitive test measures, small and underpowered studies, and inability to assess the clinical significance of cognitive test outcomes. Conclusion: Evidence that short-term, single-component physical activity interventions promote cognitive function and prevent cognitive decline or dementia in older adults is largely insufficient. A multidomain intervention showed a delay in cognitive decline (low-strength evidence). Primary Funding Source: Agency for Healthcare Research and Quality.