Douglas P. Kiel

Abstract The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes) 1 . In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10-9), independent of chronological age, even after adjusting for additional risk factors (p<5.4x10-4), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10-43). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.

Background— DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. Methods and Results— To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine–phosphate–guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P &lt;1×10 −7 (18 760 CpGs at false discovery rate &lt;0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P &lt;1×10 −7 (2623 CpGs at false discovery rate &lt;0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. Conclusions— Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

Few studies have evaluated risk factors for bone loss in elderly women and men. Thus, we examined risk factors for 4-year longitudinal change in bone mineral density (BMD) at the hip, radius, and spine in elders. Eight hundred elderly women and men from the population-based Framingham Osteoporosis Study had BMD assessed in 1988-1989 and again in 1992-1993. BMD was measured at femoral neck, trochanter, Ward's area, radial shaft, ultradistal radius, and lumbar spine using Lunar densitometers. We examined the relation of the following factors at baseline to percent BMD loss: age, weight, change in weight, height, smoking, caffeine, alcohol use, physical activity, serum 25-OH vitamin D, calcium intake, and current estrogen replacement in women. Multivariate regression analyses were conducted with simultaneous adjustment for all variables. Mean age at baseline was 74 years +/-4.5 years (range, 67-90 years). Average 4-year BMD loss for women (range, 3.4-4.8%) was greater than the loss for men (range, 0.2-3.6%) at all sites; however, BMD fell with age in both elderly women and elderly men. For women, lower baseline weight, weight loss in interim, and greater alcohol use were associated with BMD loss. Women who gained weight during the interim gained BMD or had little change in BMD. For women, current estrogen users had less bone loss than nonusers; at the femoral neck, nonusers lost up to 2.7% more BMD. For men, lower baseline weight and weight loss also were associated with BMD loss. Men who smoked cigarettes at baseline lost more BMD at the trochanter site. Surprisingly, bone loss was not affected by caffeine, physical activity, serum 25-OH vitamin D, or calcium intake. Risk factors consistently associated with bone loss in elders include female sex, thinness, and weight loss, while weight gain appears to protect against bone loss for both men and women. This population-based study suggests that current estrogen use may help to maintain bone in women, whereas current smoking was associated with bone loss in men. Even in the elderly years, potentially modifiable risk factors, such as weight, estrogen use, and cigarette smoking are important components of bone health.

Osteoporosis and related fractures will be growing public health problems as the population ages. It is therefore of great importance to identify modifiable risk factors.We investigated associations between dietary components contributing to an alkaline environment (dietary potassium, magnesium, and fruit and vegetables) and bone mineral density (BMD) in elderly subjects.Dietary intake measures were associated with both cross-sectional (baseline) and 4-y longitudinal change in BMD among surviving members of the original cohort of the Framingham Heart Study. Dietary and supplement intakes were assessed by food-frequency questionnaire, and BMD was measured at 3 hip sites and 1 forearm site.Greater potassium intake was significantly associated with greater BMD at all 4 sites for men and at 3 sites for women (P < 0.05). Magnesium intake was associated with greater BMD at one hip site for both men and women and in the forearm for men. Fruit and vegetable intake was associated with BMD at 3 sites for men and 2 for women. Greater intakes of potassium and magnesium were also each associated with less decline in BMD at 2 hip sites, and greater fruit and vegetable intake was associated with less decline at 1 hip site, in men. There were no significant associations between baseline diet and subsequent bone loss in women.These results support the hypothesis that alkaline-producing dietary components, specifically, potassium, magnesium, and fruit and vegetables, contribute to maintenance of BMD.

KIEL, DOUGLAS P.; FELSON, DAVID T.; ANDERSON, JENNIFER J.; WILSON, PETER W. F.; MOSKOWITZ, MARK A. Author Information

Estrogen therapy prevents bone loss in postmenopausal women who take it early in the postmenopausal period. The risk of fracture is highest much later in life, however. We studied whether bone mass in elderly women was affected by earlier estrogen use and how long women needed to take estrogen for it to have a beneficial effect on bone density later in life.In 1988 and 1989, we measured bone mineral density at the femur, spine, shaft of the radius, and ultradistal radius in 670 white women in the Framingham Study cohort (mean age, 76 years; range, 68 to 96). These women had been followed prospectively through menopause and had been asked repeatedly about estrogen therapy. After excluding women who began taking estrogen after a fracture, we investigated whether postmenopausal estrogen therapy affected bone density; in these analyses we adjusted for age, weight, height, cigarette smoking, physical activity, and age at menopause.A total of 212 women (31.6 percent) had received estrogen therapy (mean estimated duration of treatment, 5 years). Only women who had taken estrogen for 7 to 9 years or for 10 or more years had significantly higher bone mineral density than women who had not taken estrogen (7 to 9 years of treatment, P < 0.05 at sites in the femur and the spine; > or = 10 years, P < 0.05 at all sites except the spine). In the women less than 75 years of age who had taken estrogen for seven or more years, the bone density was, averaging all sites, 11.2 percent greater than in women who had never received estrogen. Among women 75 years of age and older in whom the duration of therapy was comparable, bone density was only 3.2 percent higher than in women who had never taken estrogen.For long-term preservation of bone mineral density, women should take estrogen for at least seven years after menopause. Even this duration of therapy may have little residual effect on bone density among women 75 years of age and older, who have the highest risk of fracture.

The impact of abdominal arterial calcific deposits on the prediction of cardiovascular disease (CVD) over a long follow-up interval deserves greater scrutiny.Lateral lumbar radiographs were studied as a predictor of incident coronary heart disease (CHD), CVD, and CVD mortality in 1049 men and 1466 women (mean age, 61 years) who were followed from 1967 to 1989. Anterior and posterior wall calcific deposits in the aorta at the level of the first through fourth lumbar vertebrae were graded according to increasing severity using a previously validated rating scale for abdominal aortic calcium (AAC) that ranges from 0 to 24 points. There were 454 cases of CHD, 709 cases of CVD, and 365 CVD deaths. Proportional hazards logistic regression was used to test for associations between AAC and later events after adjustment for age, cigarette use, diabetes mellitus, systolic blood pressure, left ventricular hypertrophy, body mass index, cholesterol, and HDL cholesterol. In comparisons with the lowest AAC tertile, the multivariate age-adjusted relative risks (RR) for CVD were increased in tertile 2 (men: RR, 1.33; 95% confidence interval [CI], 1.02 to 1.74; women: RR, 1.25; 95% CI, 0.95 to 1.65) and tertile 3 (men: RR, 1.68; 95% CI, 1.25 to 2.27; women: RR, 1.78; 95% CI, 1.33 to 2.38). Similar results were obtained with CHD and CVD mortality.AAC deposits, detected by lateral lumbar radiograms, are a marker of subclinical atherosclerotic disease and an independent predictor of subsequent vascular morbidity and mortality.

Few studies have evaluated protein intake and bone loss in elders. Excess protein may be associated with negative calcium balance, whereas low protein intake has been associated with fracture. We examined the relation between baseline dietary protein and subsequent 4-year change in bone mineral density (BMD) for 391 women and 224 men from the population-based Framingham Osteoporosis Study. BMD (g/cm2) was assessed in 1988-1989 and in 1992-1993 at the femur, spine, and radius. Usual dietary protein intake was determined using a semiquantitative food frequency questionnaire (FFQ) and expressed as percent of energy from protein intake. BMD loss over 4 years was regressed on percent protein intake, simultaneously adjusting for other baseline factors: age, weight, height, weight change, total energy intake, smoking, alcohol intake, caffeine, physical activity, calcium intake, and, for women, current estrogen use. Effects of animal protein on bone loss also were examined. Mean age at baseline (+/-SD) of 615 participants was 75 years (+/-4.4; range, 68-91 years). Mean protein intake was 68 g/day (+/-24.0; range, 14-175 g/day), and mean percent of energy from protein was 16% (+/-3.4; range, 7-30%). Proportional protein intakes were similar for men and women. Lower protein intake was significantly related to bone loss at femoral and spine sites (p < or = 0.04) with effects similar to 10 lb of weight. Persons in the lowest quartile of protein intake showed the greatest bone loss. Similar to the overall protein effect, lower percent animal protein also was significantly related to bone loss at femoral and spine BMD sites (all p < 0.01) but not the radial shaft (p = 0.23). Even after controlling for known confounders including weight loss, women and men with relatively lower protein intake had increased bone loss, suggesting that protein intake is important in maintaining bone or minimizing bone loss in elderly persons. Further, higher intake of animal protein does not appear to affect the skeleton adversely in this elderly population.

Vitamin K has been associated with bone mineral density (BMD) and risk of hip fracture. The apolipoprotein (apo) E4 allele (APOE*E4) has been associated with bone fracture through a putative effect on vitamin K transport in blood. The objective was to determine the associations between vitamin K intake, apo E genotype, BMD, and hip fracture in a population-based cohort of elderly men and women. Dietary vitamin K intake was assessed with a food-frequency questionnaire in 335 men and 553 women (average age: 75.2 y) participating in the Framingham Heart Study in 1988–1989. Incidence of hip fractures was recorded from 1988 to 1995. BMD at the hip, spine, and arm was assessed on 2 separate occasions (1988–1989 and 1992–1993). Comparisons between apo E genotype and BMD were made relative to E4 allele status (at least 1 ϵ4 allele compared with no ϵ4 allele). Individuals in the highest quartile of vitamin K intake (median: 254 μg/d) had a significantly lower fully adjusted relative risk (0.35; 95% CI: 0.13, 0.94) of hip fracture than did those in the lowest quartile of intake (median: 56 μg/d). There were no associations between vitamin K intake and BMD in either men or women. No association was found between the E4 allele and BMD, and there were no significant interactions between the E4 allele and phylloquinone intake and BMD or hip fracture. Low vitamin K intakes were associated with an increased incidence of hip fractures in this cohort of elderly men and women. Neither low vitamin K intake nor E4 allele status was associated with low BMD.

To develop an evidence-based definition of sarcopenia that can facilitate identification of older adults at risk for clinically relevant outcomes (eg, self-reported mobility limitation, falls, fractures, and mortality), the Sarcopenia Definition and Outcomes Consortium (SDOC) crafted a set of position statements informed by a literature review and SDOC's analyses of eight epidemiologic studies, six randomized clinical trials, four cohort studies of special populations, and two nationally representative population-based studies.Thirteen position statements related to the putative components of a sarcopenia definition, informed by the SDOC analyses and literature synthesis, were reviewed by an independent international expert panel (panel) iteratively and voted on by the panel during the Sarcopenia Position Statement Conference. Four position statements related to grip strength, three to lean mass derived from dual-energy x-ray absorptiometry (DXA), and four to gait speed; two were summary statements.The SDOC analyses identified grip strength, either absolute or scaled to measures of body size, as an important discriminator of slowness. Both low grip strength and low usual gait speed independently predicted falls, self-reported mobility limitation, hip fractures, and mortality in community-dwelling older adults. Lean mass measured by DXA was not associated with incident adverse health-related outcomes in community-dwelling older adults with or without adjustment for body size.The panel agreed that both weakness defined by low grip strength and slowness defined by low usual gait speed should be included in the definition of sarcopenia. These position statements offer a rational basis for an evidence-based definition of sarcopenia. The analyses that informed these position statements are summarized in this article and discussed in accompanying articles in this issue of the journal. J Am Geriatr Soc 68:1410-1418, 2020.

To relate cancer since entry into the Framingham Heart Study with the risk of incident Alzheimer's disease and to estimate the risk of incident cancer among participants with and without Alzheimer's disease.Community based prospective cohort study; nested age and sex matched case-control study.Framingham Heart Study, USA.1278 participants with and without a history of cancer who were aged 65 or more and free of dementia at baseline (1986-90).Hazard ratios and 95% confidence intervals for the risks of Alzheimer's disease and cancer.Over a mean follow-up of 10 years, 221 cases of probable Alzheimer's disease were diagnosed. Cancer survivors had a lower risk of probable Alzheimer's disease (hazard ratio 0.67, 95% confidence interval 0.47 to 0.97), adjusted for age, sex, and smoking. The risk was lower among survivors of smoking related cancers (0.26, 0.08 to 0.82) than among survivors of non-smoking related cancers (0.82, 0.57 to 1.19). In contrast with their decreased risk of Alzheimer's disease, survivors of smoking related cancer had a substantially increased risk of stroke (2.18, 1.29 to 3.68). In the nested case-control analysis, participants with probable Alzheimer's disease had a lower risk of subsequent cancer (0.39, 0.26 to 0.58) than reference participants, as did participants with any Alzheimer's disease (0.38) and any dementia (0.44).Cancer survivors had a lower risk of Alzheimer's disease than those without cancer, and patients with Alzheimer's disease had a lower risk of incident cancer. The risk of Alzheimer's disease was lowest in survivors of smoking related cancers, and was not primarily explained by survival bias. This pattern for cancer is similar to that seen in Parkinson's disease and suggests an inverse association between cancer and neurodegeneration.

Background.Several consensus groups have previously published operational criteria for sarcopenia, incorporating lean mass with strength and/or physical performance. The purpose of this manuscript is to describe the prevalence, agreement, and discrepancies between the Foundation for the National Institutes of Health (FNIH) criteria with other operational definitions for sarcopenia.

Osteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies.To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes.Large-scale meta-analysis of genome-wide association data.5 international, multicenter, population-based studies.Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands.Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures.150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST.Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded.In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.

Background Although areal bone mineral density (aBMD) assessed by dual-energy x-ray absorptiometry (DXA) is the clinical standard for determining fracture risk, most older adults who sustain a fracture have T scores greater than −2·5 and thus do not meet the clinical criteria for osteoporosis. Importantly, bone fragility is due to low BMD and deterioration in bone structure. We assessed whether indices of high-resolution peripheral quantitative CT (HR-pQCT) were associated with fracture risk independently of femoral neck aBMD and the Fracture Risk Assessment Tool (FRAX) score. Methods We assessed participants in eight cohorts from the USA (Framingham, Mayo Clinic), France (QUALYOR, STRAMBO, OFELY), Switzerland (GERICO), Canada (CaMos), and Sweden (MrOS). We used Cox proportional hazard ratios (HRs) to estimate the association between HR-pQCT bone indices (per 1 SD of deficit) and incident fracture, adjusting for age, sex, height, weight, and cohort, and then additionally for femoral neck DXA aBMD or FRAX. Findings 7254 individuals (66% women and 34% men) were assessed. Mean baseline age was 69 years (SD 9, range 40–96). Over a mean follow-up of 4·63 years (SD 2·41) years, 765 (11%) participants had incident fractures, of whom 633 (86%) had femoral neck T scores greater than −2·5. After adjustment for age, sex, cohort, height, and weight, peripheral skeleton failure load had the greatest association with risk of fracture: tibia HR 2·40 (95% CI 1·98–2·91) and radius 2·13 (1·77–2·56) per 1 SD decrease. HRs for other bone indices ranged from 1·12 (95% CI 1·03–1·23) per 1 SD increase in tibia cortical porosity to 1·58 (1·45–1·72) per 1 SD decrease in radius trabecular volumetric bone density. After further adjustment for femoral neck aBMD or FRAX score, the associations were reduced but remained significant for most bone parameters. A model including cortical volumetric bone density, trabecular number, and trabecular thickness at the distal radius and a model including these indices plus cortical area at the tibia were the best predictors of fracture. Interpretation HR-pQCT indices and failure load improved prediction of fracture beyond femoral neck aBMD or FRAX scores alone. Our findings from a large international cohort of men and women support previous reports that deficits in trabecular and cortical bone density and structure independently contribute to fracture risk. These measurements and morphological assessment of the peripheral skeleton might improve identification of people at the highest risk of fracture. Funding National Institutes of Health National Institute of Arthritis Musculoskeletal and Skin Diseases.

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Abstract Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78 , associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

To identify the genetic determinants of fracture risk and assess the role of 15 clinical risk factors on osteoporotic fracture risk.Meta-analysis of genome wide association studies (GWAS) and a two-sample mendelian randomisation approach.25 cohorts from Europe, United States, east Asia, and Australia with genome wide genotyping and fracture data.A discovery set of 37 857 fracture cases and 227 116 controls; with replication in up to 147 200 fracture cases and 150 085 controls. Fracture cases were defined as individuals (>18 years old) who had fractures at any skeletal site confirmed by medical, radiological, or questionnaire reports. Instrumental variable analyses were performed to estimate effects of 15 selected clinical risk factors for fracture in a two-sample mendelian randomisation framework, using the largest previously published GWAS meta-analysis of each risk factor.Of 15 fracture associated loci identified, all were also associated with bone mineral density and mapped to genes clustering in pathways known to be critical to bone biology (eg, SOST, WNT16, and ESR1) or novel pathways (FAM210A, GRB10, and ETS2). Mendelian randomisation analyses showed a clear effect of bone mineral density on fracture risk. One standard deviation decrease in genetically determined bone mineral density of the femoral neck was associated with a 55% increase in fracture risk (odds ratio 1.55 (95% confidence interval 1.48 to 1.63; P=1.5×10-68). Hand grip strength was inversely associated with fracture risk, but this result was not significant after multiple testing correction. The remaining clinical risk factors (including vitamin D levels) showed no evidence for an effect on fracture.This large scale GWAS meta-analysis for fracture identified 15 genetic determinants of fracture, all of which also influenced bone mineral density. Among the clinical risk factors for fracture assessed, only bone mineral density showed a major causal effect on fracture. Genetic predisposition to lower levels of vitamin D and estimated calcium intake from dairy sources were not associated with fracture risk.

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10-8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

Older adults with type 2 diabetes (T2D) tend to have normal or greater areal bone mineral density (aBMD), as measured by DXA, than those who do not have diabetes (non-T2D). Yet risk of fracture is higher in T2D, including 40% to 50% increased hip fracture risk. We used HR-pQCT to investigate structural mechanisms underlying skeletal fragility in T2D. We compared cortical and trabecular bone microarchitecture, density, bone area, and strength in T2D and non-T2D. In secondary analyses we evaluated whether associations between T2D and bone measures differed according to prior fracture, sex, and obesity. Participants included 1069 members of the Framingham Study, who attended examinations in 2005 to 2008 and underwent HR-pQCT scanning in 2012 to 2015. Mean age was 64 ± 8 years (range, 40 to 87 years), and 12% (n = 129) had T2D. After adjustment for age, sex, weight, and height, T2D had lower cortical volumetric BMD (vBMD) (p < 0.01), higher cortical porosity (p = 0.02), and smaller cross-sectional area (p = 0.04) at the tibia, but not radius. Trabecular indices were similar or more favorable in T2D than non-T2D. Associations between T2D and bone measures did not differ according to sex or obesity status (all interaction p > 0.05); however, associations did differ in those with a prior fracture and those with no history of fracture. Specifically, cortical vBMD at the tibia and cortical thickness at the radius were lower in T2D than non-T2D, but only among those individuals with a prior fracture. Cortical porosity at the radius was higher in T2D than non-T2D, but only among those who did not have a prior fracture. Findings from this large, community-based study of older adults suggest that modest deterioration in cortical bone and reductions in bone area may characterize diabetic bone disease in older adults. Evaluation of these deficits as predictors of fracture in T2D is needed to develop prevention strategies in this rapidly increasing population of older adults. © 2017 American Society for Bone and Mineral Research.

ABSTRACT Osteoporosis‐related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fracture among people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, and subcutaneous pharmacotherapies are efficacious and can reduce risk of future fracture. Patients need education, however, about the benefits and risks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first‐line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive but may be beneficial for selected patients at high risk. Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the early post‐fracture period, prompt treatment is recommended. Adequate dietary or supplemental vitamin D and calcium intake should be assured. Individuals being treated for osteoporosis should be reevaluated for fracture risk routinely, including via patient education about osteoporosis and fractures and monitoring for adverse treatment effects. Patients should be strongly encouraged to avoid tobacco, consume alcohol in moderation at most, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease). © 2019 American Society for Bone and Mineral Research.

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10-11). Causal modeling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

Summary paragraph The Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, &gt;400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the &gt;400 million variants detected, 97% have frequency &lt;1% and 46% are singletons. These rare variants provide insights into mutational processes and recent human evolutionary history. The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and extends the reach of nearly all genome-wide association studies to include variants down to ~0.01% in frequency.

OBJECTIVES Analyses performed by the Sarcopenia Definitions and Outcomes Consortium (SDOC) identified cut‐points in several metrics of grip strength for consideration in a definition of sarcopenia. We describe the associations between the SDOC‐identified metrics of low grip strength (absolute or standardized to body size/composition); low dual‐energy x‐ray absorptiometry (DXA) lean mass as previously defined in the literature (appendicular lean mass [ALM]/ht 2 ); and slowness (walking speed &lt;.8 m/s) with subsequent adverse outcomes (falls, hip fractures, mobility limitation, and mortality). DESIGN Individual‐level, sex‐stratified pooled analysis. We calculated odds ratios (ORs) or hazard ratios (HRs) for incident falls, mobility limitation, hip fractures, and mortality. Follow‐up time ranged from 1 year for falls to 8.8 ± 2.3 years for mortality. SETTING Eight prospective observational cohort studies. PARTICIPANTS A total of 13,421 community‐dwelling men and 4,828 community‐dwelling women. MEASUREMENTS Grip strength by hand dynamometry, gait speed, and lean mass by DXA. RESULTS Low grip strength (absolute or standardized to body size/composition) was associated with incident outcomes, usually independently of slowness, in both men and women. ORs and HRs generally ranged from 1.2 to 3.0 for those below vs above the cut‐point. DXA lean mass was not consistently associated with these outcomes. When considered together, those who had both muscle weakness by absolute grip strength (&lt;35.5 kg in men and &lt;20 kg in women) and slowness were consistently more likely to have a fall, hip fracture, mobility limitation, or die than those without either slowness or muscle weakness. CONCLUSION Older men and women with both muscle weakness and slowness have a higher likelihood of adverse health outcomes. These results support the inclusion of grip strength and walking speed as components in a summary definition of sarcopenia. J Am Geriatr Soc 68:1429‐1437, 2020.

Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis.The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between -2·5 and -4·0 if no previous radiographic vertebral fracture, or between -1·5 and -4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than -4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66).Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43-40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45-60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40-0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39-0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68-0·87; all p<0·0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4·9% (341/6909) versus 9·6% (675/7011), HR 0·48, 95% CI 0·42-0·55; hip fractures 1·1% (86/8043) versus 2·0% (162/8028), 0·52, 0·40-0·67; non-vertebral fractures 6·4% (512/8043) versus 8·4% (675/8028), 0·74, 0·66-0·83; all p<0·0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3·4%) of 8043 patients in the odanacatib group versus 245 (3·1%) of 8028 in the placebo group (HR 1·12, 95% CI 0·95-1·34; p=0·18). New-onset atrial fibrillation or flutter occurred in 112 (1·4%) of 8043 patients in the odanacatib group versus 96 (1·2%) of 8028 in the placebo group (HR 1·18, 0·90-1·55; p=0·24). Odanacatib was associated with an increased risk of stroke (1·7% [136/8043] vs 1·3% [104/8028], HR 1·32, 1·02-1·70; p=0·034), but not myocardial infarction (0·7% [60/8043] vs 0·9% [74/8028], HR 0·82, 0·58-1·15; p=0·26). The HR for all-cause mortality was 1·13 (5·0% [401/8043] vs 4·4% [356/8028], 0·98-1·30; p=0·10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5·0%] of 8043 vs 343 [4·3%] of 8028, HR 1·17, 1·02-1·36; p=0·029, as did stroke (2·3% [187/8043] vs 1·7% [137/8028], HR 1·37, 1·10-1·71; p=0·0051).Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis.Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.

Osteoporosis is caused by an imbalance of osteoclasts and osteoblasts, occurring in close proximity to hematopoietic cells in the bone marrow. Recurrent somatic mutations that lead to an expanded population of mutant blood cells is termed clonal hematopoiesis of indeterminate potential (CHIP). Analyzing exome sequencing data from the UK Biobank, we found CHIP to be associated with increased incident osteoporosis diagnoses and decreased bone mineral density. In murine models, hematopoietic-specific mutations in Dnmt3a, the most commonly mutated gene in CHIP, decreased bone mass via increased osteoclastogenesis. Dnmt3a-/- demethylation opened chromatin and altered activity of inflammatory transcription factors. Bone loss was driven by proinflammatory cytokines, including Irf3-NF-κB-mediated IL-20 expression from Dnmt3a mutant macrophages. Increased osteoclastogenesis due to the Dnmt3a mutations was ameliorated by alendronate or IL-20 neutralization. These results demonstrate a novel source of osteoporosis-inducing inflammation.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.

Falls affect a large proportion of the elderly and can result in a variety of injuries, including hip fractures. Several studies have suggested that visual impairment contributes to falls, but studies have not used standardized definitions of visual impairment and have not examined injurious falls or fractures. We looked at the risk of hip fracture associated with visual impairment in those members of the Framingham Study Cohort who took part in the Framingham Eye Study in 1973–75. Of 2,633 subjects followed for 10 years after the eye exam, 110 sustained hip fractures. The fracture rates in those with moderately impaired (20/30 to 20/80) vision (8.5%) and poor (20/100 or worse) vision (11.3%) were higher than in those with good (20/25 or better) vision (3.0%). After adjustment for age, sex, weight, alcohol consumption, and (in women) estrogen use, the relative risk of fracture in those with moderate impairment was 1.54 (95% CI = 0.95–2.49), while for those with poor vision, the relative risk was 2.17 (95% CI = 1.24–3.80). Of note, those with moderately impaired vision in one eye and good vision in the other had a higher risk of fracture (relative risk = 1.94) than those with a similar degree of binocular impairment (relative risk = 2.11). Poor vision in one or both eyes was linked to an elevated fracture risk. This suggests that good stereoscopic vision may be necessary to prevent falls. The risk of fracture with poor and moderately impaired vision combined was increased in women (relative risk = 1.96, 95% CI = 1.23–3.11) but not in men (relative risk = 0.79, 95% CI = 0.23–2.72). 17.5% (17/97) of women with poor vision in at least one eye sustained a hip fracture during the 10 years of the study. Cataracts were the most common cause of fracture‐related visual impairment, but neither cataracts nor other common eye diseases had an independent effect on fracture risk after adjustment for visual acuity. In sum, visual impairment is an important risk factor for hip fracture, especially among elderly women.

Background: Several nutrients are known to affect bone mineral density (BMD). However, these nutrients occur together in foods and dietary patterns, and the overall effects of dietary choices are not well understood. Objective: We evaluated associations between dietary patterns and BMD in older adults. Design: Of the original Framingham Heart Study subjects, 907 aged 69–93 y completed food-frequency questionnaires as part of an osteoporosis study. We defined dietary patterns by cluster analysis. BMD was measured at the proximal right femur (femoral neck, trochanter, Ward's area) with a dual-photon absorptiometer and at the 33% radial shaft with a single-photon absorptiometer. We regressed BMD measures onto the cluster variable, adjusting for potential confounders. Results: Six dietary patterns were identified, with relatively greater proportions of intake from meat, dairy, and bread; meat and sweet baked products; sweet baked products; alcohol; candy; and fruit, vegetables, and cereal. After adjustment for multiple comparisons, men in the last group had significantly (P = 0.05) greater BMD than did 2–4 other groups at the hip sites and the candy group at the radius. Men in the candy group had significantly (P < 0.05) lower BMD than did those in the fruit, vegetables, and cereal group for 3 of the 4 sites. Women in the candy group had significantly (P < 0.01) lower BMD than did all but one other group at the radius. Conclusions: Dietary pattern is associated with BMD. High fruit and vegetable intake appears to be protective in men. High candy consumption was associated with low BMD in both men and women.

Increasing evidence suggests that silicon is important in bone formation. The main source of silicon for humans is the diet, but the bioavailability of silicon from solid foods is not well understood.We estimated the dietary intake of silicon by adults, separately for men and women and for different age groups. Foods that were major contributors to silicon intake were identified. We then estimated the gastrointestinal uptake of silicon from major food sources and studied how uptake correlated with the silicon contents of the foods.Silicon intakes were determined in cohorts from the original Framingham Study and the Framingham Offspring Study by using a 126-item food-frequency questionnaire. Gastrointestinal uptake of silicon from foods was estimated in 3-8 healthy subjects by using urinary silicon excretion as a surrogate measure of silicon uptake.Mean silicon intakes in men (30 and 33 mg/d in the original Framingham and Framingham Offspring cohorts, respectively) were significantly higher than those in women (24 and 25 mg/d in the 2 cohorts, respectively; P = 0.0001). Silicon intake decreased with age (P < 0.001, adjusted for sex). The major food sources were beer and bananas in men and bananas and string beans in women. Silicon was readily available from foods; a mean of 41% of the ingested silicon was excreted in urine. The silicon content of the foods consumed was significantly correlated with urinary silicon excretion (P = 0.019).Solid foods are a major source of available silicon. The association between dietary silicon intake and bone health should now be investigated.

Alcohol consumption has multiple effects on bone, and alcoholic men have a high risk of osteoporotic fracture. The objective of this study was to assess the association between alcohol consumption and bone mineral density in elders. The authors evaluated 1,154 members of the Framingham Heart Study Cohort at biennial examination 20 (1988-1989). Subjects ranged in age from 68 to 96 years. Bone density was assessed at the radius (ultradistal and shaft) and at the proximal femur and spine. Alcohol consumption, assessed every 2 years from examination 12 (1967-1969) through examination 20, was averaged. The association of alcohol intake with bone density was examined after adjustment for age, weight, height, smoking, and, in women, age at menopause and years of estrogen use. Women who drank at least 7 oz (206.99 ml)/week of alcohol had higher bone densities at most sites (4.2-13.0% range with 7.7% average differences across all sites) than women in the lightest category of intake (< 1 oz (29.57 ml)/week). Men who were heavy drinkers (> or = 14 oz (414 ml)/week) also had higher bone densities than light drinkers, but the difference was less than in women (3.9% average across all sites). Lesser amounts of intake did not affect bone density. The authors conclude that alcohol intake of at least 7 oz (206.99 ml)/week is associated with high bone density in postmenopausal women, an effect possibly related to the augmentation of endogenous estrogen levels by alcohol.

Low muscle mass has been assumed to be associated with disability, but no studies confirming this association have been published. High body weight and high body mass index, both rough indicators of body fatness, have been shown to increase the risk for disability; however, the specific role of body fatness has not been studied.The relations of skeletal muscle mass and percent body fat with self-reported physical disability were studied in 753 men and women aged 72 to 95 years. Cross-sectional data from biennial examination 22 (1992-1993) of the Framingham Heart Study were used. Body composition was assessed by dual-energy x-ray absorptiometry. Disability was scored as any versus none on a 9-item questionnaire.Total body and lower extremity muscle mass were not associated with disability in either men or women. However, a strong positive association between percent body fat and disability was observed. The odds ratio for disability in those in the highest tertile of body fatness was 2.69 (95% confidence interval 1.45-5.00) for women and 3.08 (1.22-7.81) for men compared to those in the lowest tertile. The increased risk could not be explained by age, education, physical activity, smoking, alcohol use, estrogen use (women only), muscle mass, and health status. Analyses restricting disability to mobility items gave similar results.In contrast to current assumptions, low skeletal muscle mass was not associated with self-reported physical disability. Persons with a high percent body fat had high levels of disability. Because it cannot be ruled out that persons with low skeletal muscle mass dropped out earlier in the study, prospective studies are needed to further assess the relationship between body composition and physical disability.

Bioelectrical impedance analysis (BIA) can potentially be used to estimate body composition in large populations studied at multiple sites. However, it is not clear whether age-specific BIA equations are necessary for accurate application of BIA to research on elderly subjects.We compared a published equation designed to predict fat-free mass (FFM) that had been derived in a young healthy population (mean age 27 y; mean BMI 23.9 kg/m2), with equations that we developed for the elderly by using data from 455 participants in the Framingham Heart Study (78 Y; 27.3 kg/m2), using dual-energy x-ray absorptiometry (DXA) as a reference technique. The BIA equations were then compared in an independent sample of 283 participants in the New Mexico Aging Process Study (76 y, 25.5 kg/m2), who also underwent BIA and DXA.When the young-population equation was applied to Framingham, it caused an overestimation of FFM in heavier subjects that was eliminated by use of the age-specific equation. However, when the two equations were tested in the New Mexico population, the published equation gave estimates of FFM that were closer to DXA than the Framingham equations did.The accuracy of a BIA equation depends on the body composition of the population of the population and the validation method rather than on age per se. Application of BIA to elderly populations requires uniform validation procedures in the actual study population, rather than reliance on age-specific equations.

Soft drink consumption may have adverse effects on bone mineral density (BMD), but studies have shown mixed results. In addition to displacing healthier beverages, colas contain caffeine and phosphoric acid (H3PO4), which may adversely affect bone.We hypothesized that consumption of cola is associated with lower BMD.BMD was measured at the spine and 3 hip sites in 1413 women and 1125 men in the Framingham Osteoporosis Study by using dual-energy X-ray absorptiometry. Dietary intake was assessed by food-frequency questionnaire. We regressed each BMD measure on the frequency of soft drink consumption for men and women after adjustment for body mass index, height, age, energy intake, physical activity score, smoking, alcohol use, total calcium intake, total vitamin D intake, caffeine from noncola sources, season of measurement, and, for women, menopausal status and estrogen use.Cola intake was associated with significantly lower (P < 0.001-0.05) BMD at each hip site, but not the spine, in women but not in men. The mean BMD of those with daily cola intake was 3.7% lower at the femoral neck and 5.4% lower at Ward's area than of those who consumed <1 serving cola/mo. Similar results were seen for diet cola and, although weaker, for decaffeinated cola. No significant relations between noncola carbonated beverage consumption and BMD were observed. Total phosphorus intake was not significantly higher in daily cola consumers than in nonconsumers; however, the calcium-to-phosphorus ratios were lower.Intake of cola, but not of other carbonated soft drinks, is associated with low BMD in women. Additional research is needed to confirm these findings.

Background: The role of total calcium intake in the prevention of hip fracture risk has not been well established. Objective: The objective of the study was to assess the relation of calcium intake to the risk of hip fracture on the basis of meta-analyses of cohort studies and clinical trials. Results: In women (7 prospective cohort studies, 170 991 women, 2954 hip fractures), there was no association between total calcium intake and hip fracture risk [pooled risk ratio (RR) per 300 mg total Ca/d = 1.01; 95% CI: 0.97, 1.05]. In men (5 prospective cohort studies, 68 606 men, 214 hip fractures), the pooled RR per 300 mg total Ca/d was 0.92 (95% CI: 0.82, 1.03). On the basis of 5 clinical trials (n = 5666 women, primarily postmenopausal, plus 1074 men) with 814 nonvertebral fractures, the pooled RR for nonvertebral fractures between calcium supplementation (800–1600 mg/d) and placebo was 0.92 (95% CI: 0.81, 1.05). On the basis of 4 clinical trials with separate results for hip fracture (6504 subjects with 139 hip fractures), the pooled RR between calcium and placebo was 1.64 (95% CI:1.02, 2.64). Sensitivity analyses including 2 additional small trials with <100 participants or per-protocol results did not substantially alter results. Conclusions: Pooled results from prospective cohort studies suggest that calcium intake is not significantly associated with hip fracture risk in women or men. Pooled results from randomized controlled trials show no reduction in hip fracture risk with calcium supplementation, and an increased risk is possible. For any nonvertebral fractures, there was a neutral effect in the randomized trials.

Low dietary vitamin K intake has been associated with an increased risk of hip fracture in men and women. Few data exist on the association between dietary vitamin K intake and bone mineral density (BMD).We studied cross-sectional associations between self-reported dietary vitamin K intake and BMD of the hip and spine in men and women aged 29-86 y.BMD was measured at the hip and spine in 1112 men and 1479 women (macro x +/- SD age: 59 +/- 9 y) who participated in the Framingham Heart Study (1996-2000). Dietary and supplemental intakes of vitamin K were assessed with the use of a food-frequency questionnaire. Additional covariates included age, body mass index, smoking status, alcohol use, physical activity score, and menopause status and current estrogen use among the women.Women in the lowest quartile of vitamin K intake (macro x: 70.2 microg/d) had significantly (P < or = 0.005) lower mean (+/- SEM) BMD at the femoral neck (0.854 +/- 0.006 g/cm(2)) and spine (1.140 +/- 0.010 g/cm(2)) than did those in the highest quartile of vitamin K intake (macro x: 309 microg/d): 0.888 +/- 0.006 and 1.190 +/- 0.010 g/cm(2), respectively. These associations remained after potential confounders were controlled for and after stratification by age or supplement use. No significant association was found between dietary vitamin K intake and BMD in men.Low dietary vitamin K intake was associated with low BMD in women, consistent with previous reports that low dietary vitamin K intake is associated with an increased risk of hip fracture. In contrast, there was no association between dietary vitamin K intake and BMD in men.

Alcoholics often sustain hip and other fractures. However, a detailed examination of the association between alcohol consumption and hip fractures has not been undertaken. Specifically, the effects of moderate alcohol intake, of alcohol consumption in the elderly, and of changes in consumption have not been studied. Using a retrospective cohort design, the authors evaluated this association in the population-based Framingham Heart Study cohort, a group studied over 35 years and queried repeatedly about their alcohol consumption. In 117,224 person-years of observation, 217 hip fractures occurred. Heavy current alcohol consumption (defined as seven or more ounces (207 ml or more) per week) was associated with a modestly increased risk of hip fracture for women (relative risk (RR) = 1.54) and for men (RR = 1.26) after adjustment for age. In a logistic regression analysis controlling for age, sex, weight, and smoking, current alcohol consumption was associated with a significant (p = 0.01) increase in risk of fracture. The relative risks at different ages were not uniform. For those aged less than 65 years, moderate (2–6 ounces (59.14–177.4 ml) per week) and heavy (seven or more ounces (207 ml or more) per week) were associated with a substantial and significant increased risk, but there was only a marginal and nonsignificant increase in risk in those aged 65 years or more. Examination of the effect of changing alcohol consumption over time indicated that among present heavy alcohol users, past light alcohol consumption reduced the risk (p = 0.03) of fracture, whereas in those with present light consumption, past heavy intake had little effect on fracture risk (p = nonsignificant). In conclusion, alcohol consumption, especially if long-term and heavy, increases the risk of hip fracture.

ObjectiveTo examine potential risk factors for hallux valgus in community-dwelling elders.MethodData from 600 MOBILIZE Boston Study participants (386 women and 214 men) were analyzed. Hallux valgus was defined as >15° angular deviation of the hallux with respect to the first metatarsal bone toward the lesser toes. Associations of hallux valgus with age, body mass index (BMI), race, education, pes planus, foot pain, and in women, history of high heel shoe use, were assessed using sex-specific Poisson regression with robust variance estimation for risk ratios (RR) and 95% confidence intervals (CI).ResultsHallux valgus was present in 58% of women and 25% of men. Higher BMI was inversely associated with presence of hallux valgus in women (P trend=0.001), with the strongest inverse association observed in those with BMI of 30.0 or more compared to those with normal BMI (RR=0.7, 95% CI: 0.5, 0.9). Women, who usually wore high-heeled shoes during ages 20–64 years compared to those who did not, had increased likelihood of hallux valgus (RR=1.2, 95% CI: 1.0, 1.5). Among men, those with BMI between 25.0 and 29.9 had increased likelihood of hallux valgus compared to those with normal BMI (RR=1.9, 95% CI: 1.0, 3.5). Men with pes planus were more likely to have hallux valgus (RR=2.1, 95% CI: 1.3, 3.3) compared to men without pes planus.ConclusionIn women, hallux valgus was associated with lower BMI and high heel use during ages 20–64, while in men, associations were observed with higher BMI and pes planus. Our results suggest that the etiologic mechanisms for hallux valgus may differ between men and women.

Caffeine increases urinary calcium output and has been implicated as a risk factor for osteoporosis. The authors examined the effect of caffeine on hip fracture risk in 3,170 individuals attending the 12th (1971-1973) Framingham Study examination. Coffee and tea consumption, age, Framingham examination number, weight, smoking, alcohol consumption, and estrogen use were used to evaluate hip fracture risk according to caffeine intake. Hip fractures occurred in 135 subjects during 12 years of follow-up. Fracture risk over each 2-year period increased with increasing caffeine intake (one cup of coffee = one unit of caffeine, one cup of tea = 1/2 unit of caffeine). For intake of 1.5-2.0 units per day, the adjusted relative risk (RR) of fracture was not significantly elevated compared with intake of one or less units per day. Consumption of greater than or equal to 2.5 units per day significantly increased the risk of fracture. Overall, intake of greater than two cups of coffee per day (four cups of tea) increased the risk of fracture. In summary, hip fracture risk was modestly increased with heavy caffeine use, but not for intake equivalent to one cup of coffee per day. Since caffeine use may be associated with other behaviors that are, themselves, risk factors for fracture, the association may be indirect. Further studies should be performed to confirm these findings.

To develop a fall risk model that can be used to identify prospectively nursing home residents at risk for falling. The secondary objective was to determine whether the nursing home environment independently influenced the development of falls.A prospective study involving 1 year of follow-up.Two hundred seventy-two nursing homes in the state of Washington.A total of 18,855 residents who had a baseline assessment in 1991 and a follow-up assessment within the subsequent year.Baseline Minimum Data Set items that could be potential risk factors for falling were considered as independent variables. The dependent variable was whether the resident fell as reported at the follow-up assessment. We estimated the extrinsic risk attributable to particular nursing home environments by calculating the annual fall rate in each nursing home and grouping them into tertiles of fall risk according to these rates.Factors associated independently with falling were fall history, wandering behavior, use of a cane or walker, deterioration of activities of daily living performance, age greater than 87 years, unsteady gait, transfer independence, wheelchair independence, and male gender. Nursing home residents with a fall history were more than three times as likely to fall during the follow-up period than residents without a fall history. Residents in homes with the highest tertile of fall rates were more than twice as likely to fall compared with residents of homes in the lowest tertile, independent of resident-specific risk factors.Fall history was identified as the strongest risk factor associated with subsequent falls and accounted for the vast majority of the predictive strength of the model. We recommend that fall history be used as an initial screener for determining eligibility for fall intervention efforts. Studies are needed to determine the facility characteristics that contribute to fall risk, independent of resident-specific risk factors.

Computed laminography with synchrotron radiation is developed and carried out for three-dimensional imaging of flat, laterally extended objects with high spatial resolution. Particular experimental conditions of a stationary synchrotron source have been taken into account by a scanning geometry different from that employed with movable conventional laboratory x-ray sources. Depending on the mechanical precision of the sample manipulation system, high spatial resolution down to the scale of 1μm can be attained nondestructively, even for objects of large lateral size. Furthermore, high beam intensity and the parallel-beam geometry enables easy use of monochromatic radiation for optimizing contrast and reducing imaging artifacts. Simulations and experiments on a test object demonstrate the feasibility of the method. Application to the inspection of solder joints in a flip-chip bonded device shows the potential for quality assurance of microsystem devices.

To better understand risk factors for falls among community‐dwelling elderly, we analyzed data from a sample of elderly Medicare beneficiaries interviewed in 1987 and a year later. Demographic, social, medical, and functional information were obtained by telephone interviews with 736 subjects (68% women) whose average age was 76.5 (range, 65–99). At baseline, 63 subjects reported a fall and 67 reported two or more stumbles without a fall in the past month. At the second interview follow‐up information on falls in the past year was obtained on 586 subjects. One hundred twenty‐seven (22%) subjects reported one or more falls. Baseline risk factors that were independent predictors of a fall at the second interview included two or more stumbles (adjusted odds ratio [AOR] 2.3, 95% confidence interval [CI], 1.2–4.5), one or more falls (AOR 5.9, 95% CI 2.9–12.2), having spent 4 or more days in bed in the past month (AOR 7.7, 95% CI 1.9–31.0), and self‐reported declining health status (AOR 2.0, 95% CI 1.1–3.5). Falls and stumbles are prevalent among community‐dwelling elderly. After controlling for covariates, we found subjects who reported two or more stumbles in the past month are at increased risk for a fall in the following year.

Past studies of the efficacy of hip protectors to prevent hip fracture in nursing home residents have had conflicting results, possibly due to potential biases from clustered randomization designs and modest adherence to intervention.To determine whether an energy-absorbing and energy-dispersing hip protector would reduce the risk of hip fracture when worn by nursing home residents.Multicenter, randomized controlled clinical trial in which 37 nursing homes were randomly assigned to having residents wear a 1-sided hip protector on the left or right hip. Participants were 1042 nursing home residents (mean [SD] aged 85 [7] years; 79% women) who consented and adhered to the hip protector use during a 2-week run-in period and were enrolled. Participating facilities were in greater Boston, Massachusetts, St Louis, Missouri, and Baltimore, Maryland from October 2002 to October 2004. Mean duration of participation for nursing home residents was 7.8 months. None were withdrawn because of adverse effects.Undergarments with a 1-sided hip protector made of a 0.32-cm outer layer of polyethylene (2.7 kg/m3) backed by a hard high-density polyethylene shield (0.95 cm) that was backed by 0.9 kg/m3 of 1.27-kg ethylene vinyl acetate foam. Each facility was visited 3 times per week to assess adherence and provide staff support.Adjudicated hip fracture occurrences on padded vs unpadded hips.After a 20-month follow-up (676 person-years of observation), the study was terminated due to a lack of efficacy. The incidence rate of hip fracture on protected vs unprotected hips did not differ (3.1%; 95% confidence interval [CI], 1.8%-4.4% vs 2.5%; 95% CI, 1.3%-3.7%; P = .70). For the 334 nursing home residents with greater than 80% adherence to hip protector use, the incidence rate of hip fracture on protected vs unprotected hips did not differ (5.3%; 95% CI, 2.6%-8.8% vs 3.5%; 95% CI, 1.3%-5.7%; P = .42). Overall adherence was 73.8%.In this clinical trial of an energy-absorbing/shunting hip protector conducted in US nursing homes, we were unable to detect a protective effect on the risk of hip fracture, despite good adherence to protocol. These results add to the increasing body of evidence that hip protectors, as currently designed, are not effective for preventing hip fracture among nursing home residents.clinicaltrials.gov Identifier: NCT00058864.

Background:Age-related decline in muscle strength is an important public health issue for older adults. Dietary protein has been associated with maintenance of muscle mass, yet its relation to muscle strength remains unclear.

Considerable data and media attention have highlighted a potential "crisis" in the treatment of osteoporosis. Specifically, despite the availability of several effective drugs to prevent fractures, many patients who need pharmacological therapy are either not being prescribed these medications or if prescribed a medication, are simply not taking it. Although there are many reasons for this "gap" in the treatment of osteoporosis, a major factor is physician and patient concerns over the risk of side effects, especially atypical femur fractures (AFFs) related to bisphosphonate (and perhaps other antiresorptive) drug therapy. In this perspective, we review the current state of undertreatment of patients at increased fracture risk and suggest possible short-, intermediate-, and long-term approaches to address patient concerns, specifically those related to AFF risk. We suggest improved patient and physician education on prodromal symptoms, extended femur scans using dual-energy X-ray absorptiometry (DXA) to monitor patients on antiresorptive treatment, better identification of high-risk patients perhaps using geometrical parameters from DXA and other risk factors, and more research on pharmacogenomics to identify risk markers. Although not the only impediment to appropriate treatment of osteoporosis, concern over AFFs remains a major issue and one that needs to be resolved for effective dissemination of existing treatments to reduce fracture risk. © 2017 American Society for Bone and Mineral Research.

ABSTRACT The American Society for Bone and Mineral Research and the United States National Osteoporosis Foundation (NOF) formed a working group to develop principles of goal-directed treatment and identify gaps that need to be filled to implement this approach. With goal-directed treatment, a treatment goal would first be established and choice of treatment determined by the probability of achieving that goal. Goals of treatment would be freedom from fracture, a T-score &amp;gt; –2.5, which is above the NOF threshold for initiating treatment, or achievement of an estimated risk level below the threshold for initiating treatment. Progress toward reaching the patient's goal would be periodically and systematically assessed by estimating the patient's compliance with treatment, reviewing fracture history, repeating vertebral imaging when indicated, and repeating measurement of bone mineral density (BMD). Using these data, a decision would be made to stop, continue, or change therapy. Some of these approaches can now be applied to clinical practice. However, the application of goal-directed treatment cannot be fully achieved until medications are available that provide greater increases in BMD and greater reduction in fracture risk than those that are currently approved; only then can patients with very high fracture risk and very low BMD achieve such goals. Furthermore, assessing future fracture risk in patients on treatment requires a new assessment tool that accurately captures the change in fracture risk associated with treatment and should also be sensitive to the importance of recent fractures as predictors of imminent fracture risk. Lastly, evidence is needed to confirm that selecting and switching treatments to achieve goals reduces fracture risk more effectively than current standard care. © 2016 American Society for Bone and Mineral Research. Abstract The fundamental principle of treat-to-goal for osteoporosis is that treatment should be selected according to having a high likelihood of achieving an acceptable level of fracture risk. This is different than but complementary to the current paradigm of monitoring for response to therapy, usually with bone density testing by DXA or bone turnover markers. A patient may respond to therapy yet continue to have an unacceptably high fracture risk. Response to treatment is essential but not necessarily sufficient in achieving an acceptable level of fracture risk.

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in <i>CYP2R1</i> the low-frequency (minor allele frequency=2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (−0.43 SD of standardized natural log-transformed 25OHD per A allele; p value=1.5 × 10⁻⁸⁸). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near <i>CYP2R1</i>. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78–2.78, p=1.26 × 10⁻¹²). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI=1.19–1.64, p=2.63 × 10⁻⁵) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency <i>CYP2R1</i> coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.

Objectives To compare the relative predictive power of handgrip and leg extension strength in predicting slow walking. Design Report of correlative analysis from two epidemiological cohort studies. Setting Foundation of the National Institutes of Health Sarcopenia Project. Participants Men and women aged 67 to 93 (N = 6,766). Measurements Leg strength, handgrip strength, and gait speed were measured. Strength cutpoints associated with slow gait speed were developed using classification and regression tree analyses and compared using ordinary least squares regression models. Results The cutpoints of lower extremity strength associated with slow gait speed were 154.6 N‐m in men and 89.9 N‐m in women for isometric leg extension strength and 94.5 N‐m in men and 62.3 N‐m in women for isokinetic leg extension strength. Weakness defined according to handgrip strength (odds ratios ( OR ) = 1.99 to 4.33, c‐statistics = 0.53 to 0.67) or leg strength ( OR s = 2.52 to 5.77; c‐statistics = 0.61 to 0.66) was strongly related to odds of slow gait speed. Lower extremity strength contributed 1% to 16% of the variance and handgrip strength contributed 3% to 17% of the variance in the prediction of gait speed depending on sex and mode of strength assessment. Conclusion Muscle weakness of the leg extensors and forearm flexors is related to slow gait speed. Leg extension strength is only a slightly better predictor of slow gait speed. Thus, handgrip and leg extension strength appear to be suitable for screening for muscle weakness in older adults.

Fat accumulation in muscle may contribute to age-related declines in muscle function and is indicated by reduced attenuation of x-rays by muscle tissue in computed tomography scans. Reduced trunk muscle attenuation is associated with poor physical function, low back pain, and increased hyperkyphosis in older adults. However, variations in trunk muscle attenuation with age, sex and between specific muscles have not been investigated. A cross-sectional examination of trunk muscle attenuation in computed tomography scans was performed in 60 younger (35–50 years) and 60 older (75–87 years) adults randomly selected from participants in the Framingham Heart Study Offspring and Third Generation Multidetector Computed Tomography Study. Computed tomography attenuation of 11 trunk muscles was measured at vertebral levels T8 and L3, and the effects of age, sex, and specific muscle on computed tomography attenuation of trunk muscles were determined. Muscle attenuation varied by specific muscle (p < .001), was lower in older adults (p < .001), and was generally lower in women than in men (p < .001), although not in all muscles. Age-related differences in muscle attenuation varied with specific muscle (p < .001), with the largest age differences occurring in the paraspinal and abdominal muscles. Trunk muscle attenuation is lower in older adults than in younger adults in both women and men, but such age-related differences vary widely between muscle groups. The reasons that some muscles exhibit larger age-related differences in fat content than others should be further explored to better understand age-related changes in functional capacity and postural stability.

Lack of consensus on how to diagnose sarcopenia has limited the ability to diagnose this condition and hindered drug development. The Sarcopenia Definitions and Outcomes Consortium (SDOC) was formed to develop evidence-based diagnostic cut points for lean mass and/or muscle strength that identify people at increased risk of mobility disability. We describe here the proceedings of a meeting of SDOC and other experts to discuss strategic considerations in the development of evidence-based sarcopenia definition.Presentations and panel discussions reviewed the usefulness of sarcopenia as a biomarker, the analytical approach used by SDOC to establish cut points, and preliminary findings, and provided strategic direction to develop an evidence-based definition of sarcopenia.The SDOC assembled data from eight epidemiological cohorts consisting of 18,831 participants, clinical populations from 10 randomized trials and observational studies, and 2 nationally representative cohorts. In preliminary assessments, grip strength or grip strength divided by body mass index was identified as discriminators of risk for mobility disability (walking speed <0.8 m/s), whereas dual-energy X-ray absorptiometry-derived lean mass measures were not good discriminators of mobility disability. Candidate definitions based on grip strength variables were associated with increased risk of mortality, falls, mobility disability, and instrumental activities of daily living disability. The prevalence of low grip strength increased with age. The attendees recommended the establishment of an International Expert Panel to review a series of position statements on sarcopenia definition that are informed by the findings of the SDOC analyses and synthesis of literature.International consensus on an evidence-based definition of sarcopenia is needed. Grip strength-absolute or adjusted for body mass index-is an important discriminator of mobility disability and other endpoints. Additional research is needed to develop a predictive risk model that takes into account sarcopenia components as well as age, sex, race, and comorbidities.

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34-52%) for TBLH-BMD, and 39% (95% CI: 30-48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29-56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.Bone mineral density and lean skeletal mass are heritable traits. Here, Medina-Gomez and colleagues perform bivariate GWAS analyses of total body lean mass and bone mass density in children, and show genetic loci with pleiotropic effects on both traits.

Background: Above-average dietary protein, as a single nutrient, improves musculoskeletal health. Evaluating the link between dietary protein and musculoskeletal health from a whole-diet perspective is important, as dietary guidelines focus on dietary patterns. Objective: We examined the prospective association of novel dietary protein food clusters (derived from established dietary pattern techniques) with appendicular lean mass (ALM), quadriceps strength (QS), and bone mineral density (BMD) in 2986 men and women, aged 19–72 y, from the Framingham Third Generation Study. Design: Total protein intake was estimated by food-frequency questionnaire in 2002–2005. A cluster analysis was used to classify participants into mutually exclusive groups, which were determined by using the percentage of contribution of food intake to overall protein intake. General linear modeling was used to 1) estimate the association between protein intake (grams per day) and BMD, ALM, appendicular lean mass normalized for height (ALM/ht2), and QS (2008–2011) and to 2) calculate adjusted least-squares mean outcomes across quartiles of protein (grams per day) and protein food clusters. Results: The mean ± SD age of subjects was 40 ± 9 y; 82% of participants met the Recommended Daily Allowance (0.8 g · kg body weight–1 · d–1). The following 6 dietary protein food clusters were identified: fast food and full-fat dairy, fish, red meat, chicken, low-fat milk, and legumes. BMD was not different across quartiles of protein intake (P-trend range = 0.32–0.82); but significant positive trends were observed for ALM, ALM/ht2 (P < 0.001), and QS (P = 0.0028). Individuals in the lowest quartile of total protein intake (quartile 1) had significantly lower ALM, ALM/ht2, and QS than did those in the higher quartiles of intake (quartiles 2–4; (P ranges = 0.0001–0.003, 0.0007–0.003, and 0.009–0.05, respectively). However, there were no associations between protein clusters and any musculoskeletal outcome in adjusted models. Conclusions: In a protein-replete cohort of adults, dietary protein is associated with ALM and QS but not with BMD. In this study, dietary protein food patterns do not provide further insight into beneficial protein effects on muscle outcomes.

The risk of cardiovascular events (CVEs) with alendronate use in real-world hip fracture patients is unknown. This study aimed to investigate the risk of CVE with and without use of alendronate in patients with hip fracture. We conducted a retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with hip fracture from 2005 through 2013 were followed until November 6, 2016. Alendronate and other antiosteoporosis medications use during the study period were examined. We matched treated and nontreated patients based on time-dependent propensity score. The risks of cardiovascular mortality, myocardial infarction, and stroke between treatment groups were evaluated using conditional Cox regression stratified by match pairs. To examine the associations over time, outcomes were assessed at 1 year, 3 years, 5 years, and 10 years. Among 34,991 patients with newly diagnosed hip fracture, 4602 (13.2%) received antiosteoporosis treatment during follow-up. Physical functioning or survival prospect was not significantly different between treated and nontreated patients. A total of 4594 treated patients were matched with 13,568 nontreated patients. Results of Cox regression analysis revealed that alendronate was associated with a significantly lower risk of 1-year cardiovascular mortality (HR 0.33; 95% CI, 0.17 to 0.65) and incident myocardial infarction (HR 0.55; 95% CI, 0.34 to 0.89), whereas marginally significant reduction in risk of stroke was observed at 5 years and 10 years (HR at 5 years: 0.82; 95% CI, 0.67 to 1.00; p = 0.049; HR at 10 years: 0.83; 95% CI, 0.69 to 1.01; p = 0.065). The strength of the association declined over time but remained significant. Similar results were observed when all nitrogen-containing bisphosphonates (N-BPs) were analyzed together. These findings were robust in multiple sensitivity analyses. Additional studies in other population samples and randomized clinical trials may be warranted to further understand the relationship between use of various antiosteoporosis medication and risk of CVE in patients with hip fracture. © 2018 American Society for Bone and Mineral Research.

The aim of this paper is to define terms commonly related to sarcopenia to enable standardization of these terms in research and clinical settings. The Global Leadership Initiative in Sarcopenia (GLIS) aims to bring together leading investigators in sarcopenia research to develop a single definition that can be utilized worldwide; work on a global definition of sarcopenia is ongoing. The first step of GLIS is to develop the common terminology, or a glossary, that will facilitate agreement on a global definition of sarcopenia as well as interpretation of clinical and research findings.Several terms that are commonly used in sarcopenia research are defined, including self-reported measures of function and ability; objective physical performance tests; and measures related to muscle function and size.As new methods and technologies are developed, these definitions may be expanded or refined over time. Our goal is to promote this common language to describe sarcopenia and its components in clinical and research settings in order to increase clinical awareness and research interest in this important condition. We hope that the use of common terminology in sarcopenia research will increase understanding of the concept and improve communication around this important age-related condition.

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures.The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors.A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible.Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed.These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).

The past 30 years have witnessed tremendous progress in our ability to diagnose and treat osteoporosis. Once considered an inevitable consequence of ageing, osteoporosis can now be accurately diagnosed using dual-energy x-ray absorptiometry (DXA). Fundamental advances in the understanding of the pathogenesis of osteoporosis have driven the development of highly effective treatments, including four bisphosphonates (alendronate, risedronate, ibandronate, and zole-dronate), a human monoclonal anti-body to the receptor activator of nuclear factor κB ligand (denosumab), parathyroid hormone/parathyroid hormone-related peptide analogues (teriparatide and abaloparatide), and a humanised monoclonal antibody to sclerostin (romosozumab).

Sarcopenia, the age-related loss of muscle mass and strength/function, is an important clinical condition. However, no international consensus on the definition exists.The Global Leadership Initiative in Sarcopenia (GLIS) aimed to address this by establishing the global conceptual definition of sarcopenia.The GLIS steering committee was formed in 2019-21 with representatives from all relevant scientific societies worldwide. During this time, the steering committee developed a set of statements on the topic and invited members from these societies to participate in a two-phase International Delphi Study. Between 2022 and 2023, participants ranked their agreement with a set of statements using an online survey tool (SurveyMonkey). Statements were categorised based on predefined thresholds: strong agreement (>80%), moderate agreement (70-80%) and low agreement (<70%). Statements with strong agreement were accepted, statements with low agreement were rejected and those with moderate agreement were reintroduced until consensus was reached.107 participants (mean age: 54 ± 12 years [1 missing age], 64% men) from 29 countries across 7 continents/regions completed the Delphi survey. Twenty statements were found to have a strong agreement. These included; 6 statements on 'general aspects of sarcopenia' (strongest agreement: the prevalence of sarcopenia increases with age (98.3%)), 3 statements on 'components of sarcopenia' (muscle mass (89.4%), muscle strength (93.1%) and muscle-specific strength (80.8%) should all be a part of the conceptual definition of sarcopenia)) and 11 statements on 'outcomes of sarcopenia' (strongest agreement: sarcopenia increases the risk of impaired physical performance (97.9%)). A key finding of the Delphi survey was that muscle mass, muscle strength and muscle-specific strength were all accepted as 'components of sarcopenia', whereas impaired physical performance was accepted as an 'outcome' rather than a 'component' of sarcopenia.The GLIS has created the first global conceptual definition of sarcopenia, which will now serve to develop an operational definition for clinical and research settings.

Background. Resistance-training intervention studies have demonstrated meaningful health benefits in older adults; however, most have used exercises performed at specific intensities on expensive equipment, which limit their widespread applicability. We tested whether two self-paced, less expensive exercise protocols could be effective and safe for modifying neuromotor performance and functional capacity in community-dwelling adults 65-95 years of age. Methods. One hundred and thirty-one subjects were randomized to a novel resistance training, walking, or control group. Subjects determined their level of resistance or walking intensity (self-paced) on a session-by-session basis. Muscle strength, balance, reaction time, stair climbing speed, and a timed pen pickup task were measured before and after the intervention period. Exercisers met three times per week for 10 months. Results. Significant improvements in tandem stance and single-legged stance with eyes open times and stair climbing speed were seen in both exercise groups. In addition, resistance trainers improved their muscle strength and ability to pick up an object from the floor and reduced the number of missteps taken during tandem walking, and walkers reduced tandem walking time. Controls showed no significant improvement in any variable. Conclusions. The two self-paced exercise protocols were effective at improving neuromotor performance and functional capacity in the study sample and show promise as a safe, effective, cost-efficient, acceptable exercise model for primary and secondary prevention in the general population of community-dwelling older adults.

Few epidemiological studies that rely on the food frequency questionnaire (FFQ) for dietary assessment have measured biomarkers of vitamin K intake to independently confirm associations between self-reported dietary vitamin K intake and disease risk. Associations were examined between two sensitive biomarkers of vitamin K status, plasma phylloquinone and serum percent undercarboxylated osteocalcin (%ucOC), and self-reported usual phylloquinone intake as estimated from a FFQ. The influence of other dietary and nondietary factors on plasma phylloquinone concentrations was also examined. Dietary phylloquinone intake was estimated using a FFQ in 369 men and 468 women of the Framingham Offspring Study. The prevalence of high %ucOC concentrations (>/= 20%), suggestive of a low vitamin K status, was 44% in men and 54% in women, respectively. After multivariate adjustment, the odds of a high %ucOC was 2.5 greater for women (odds ratio: 2.5; 95% confidence interval [CI]: 1.2-5.1) and almost three times greater for men (odds ratio: 2.8; 95% CI: 1.3-5.9) in the lowest dietary phylloquinone intake quintile category compared to the highest quintile category. Fasting triglyceride concentrations, smoking status and season were associated with plasma phylloquinone concentrations, independent of dietary phylloquinone intake. Phylloquinone and green vegetable intake was linearly associated with plasma phylloquinone, after adjustment for potential confounding factors. There were limitations in the use of the FFQ to predict plasma phylloquinone, evident in an observed plateau effect and required nondietary adjustment factors. Despite these caveats, these findings support the use of a FFQ for a relative assessment of vitamin K status in population-based studies.

Few studies of the GH axis and bone have focused specifically on elderly people. The objective of this study was to determine the association between insulin-like growth factor I (IGF-I) and bone mineral density (BMD) in 425 women and 257 men aged 72–94 who participated in the Framingham Osteoporosis Study component of the Framingham Heart Study in 1992–1993. Serum IGF-I level was determined by RIA. BMD at three femoral sites and the lumbar spine was determined by dual x-ray absorptiometry, and at the radius by single-photon absorptiometry. IGF-I level was positively associated with BMD at all five sites (Ward’s area, femoral neck, trochanter, radius, and lumbar spine) in women after adjustment for weight loss and other factors (P ≤ 0.01) and protein intake in a subset of participants (0.006 &amp;lt; P &amp;lt; 0.07). A threshold effect of higher BMD was evident at each of the 3 femoral sites and the spine (P &amp;lt; 0.03) but not at the radius for women in the highest quintile of IGF-I (≥179 g/liter) vs. those in the lowest four quintiles. IGF-I was not significantly associated with BMD in men. These results indicate that higher IGF-I levels are associated with greater BMD in very old women, and suggest that future clinical trials employing GH may have a role in the development of treatments for older women with osteoporosis.

The purpose of this study was to assess the incidence of fall-related fractures, and the circumstances surrounding these events, during a 5-year period among all residents of a long-term care facility.The study group was composed of residents with radiologically confirmed fractures that were the direct result of a fall occurring between the years 1988 and 1992. This group was 82% female and had a mean age of 89 +/- 6 years.The study was designed as a 5-year retrospective cohort study in a long-term care institution where annual incidence rates of fracture were assessed.There were 296 fall-related fractures during the 5-year period. Annual incidence rates remained fairly constant (72, 86, 84, 70, and 94 per 1000 person-years, respectively) despite a 54% decline in the use of physical restraints during the 5-year period. Hip fractures comprised almost 50% of all fractures. Based on incident reports of these fractures, 42% occurred during the day, 55% took place in the bedroom or adjoining bathroom. 67% occurred while the resident was ambulating, and a wet floor was in evidence in 16% of the incidents.Fracture incidence in this long-term care facility has remained stable despite reduced restraint use. The incident reporting system may contribute valuable information to the identification of factors that should receive further attention in studies of risk factors for fracture in the long-term care setting.

The choice of a phenotype is critical for the study of a complex genetically regulated process, such as aging. To date, most of the twin and family studies have focused on broad survival measures, primarily age at death or exceptional longevity. However, on the basis of recent studies of twins and families, biological age has also been shown to have a strong genetic component, with heritability estimates ranging from 27% to 57%. The aim of this review is twofold: first, to summarize growing consensus on reliable methods of biological age assessment, and second, to demonstrate validity of this phenotype for research in the genetics of aging in humans.

Objective: To determine if the association between smoking and osteoporotic fractures is related to the quantity of cigarettes smoked and to determine if smoking modifies the protection by estrogens. Design: Cohort study. Setting: A population-based cohort study, the Framingham Study. Participants: A total of 2873 women in the Framingham Study followed through examination 19 (1985-1987). Measurements: All fractures of the proximal femur sustained by women in the Framingham Study from 1948 to 1987 were ascertained. At almost all examinations, available information on cigarette smoking was used to classify women as "ever smokers" compared with "never smokers," and, among "ever smokers," "current" compared with "former smokers." A similar classification for estrogen use was created. Information on potentially confounding variables was taken from each examination, including age, adiposity (weight/ height2), alcohol consumption (ounces per week), and caffeine intake (coffee and tea). Results: Overall, 207 hip fractures occurred among 34 700 woman-examinations of observation. In the entire cohort, current smoking did not appear to increase hip fracture risk (adjusted odds ratio [AOR], 1.22; 95% Cl, 0.76 to 1.95; P > 0.2). Also overall, current estrogen use appeared to be protective (AOR, 0.38; Cl, 0.12 to 1.21, P= 0.10). Among current smokers, however, estrogen use did not protect against fracture (AOR for current use, 1.26; Cl, 0.29 to 5.45), whereas estrogen was protective in nonsmokers (AOR for current or past use, 0.37; Cl, 0.19 to 0.75; P= 0.005). Conclusions: Overall, smoking does not appear to increase the risk for hip fracture in women. Although estrogen replacement protects nonsmokers from fracture, smoking may negate the protective skeletal effects of estrogen replacement therapy.

A genome-wide scan was performed in a randomly ascertained set of 330 extended families from the population-based Framingham Study to identify chromosomal regions possibly linked to bone mineral density (BMD). A set of 401 microsatellite markers was typed at a 10-centimorgan (cM) average density throughout the genome. BMD was measured at the femoral neck, trochanter, Ward's area, and lumbar spine in 1557 participants of both Framingham cohorts. BMDs were adjusted for age, body mass index (BMI), height, alcohol, caffeine, calcium and vitamin D intakes, smoking, physical activity, and estrogen use in women within each sex and cohort. Strong heritabilities (values between 0.543 and 0.633) were found for the adjusted BMD at all sites. Two-point and multipoint quantitative linkage analyses were performed for each BMD site using the maximum likelihood variance components method. By two-point screening, loci of suggestive linkage were identified on chromosomes 6 and 21, with the maximum log10 of the odds ratio (LOD) scores of 2.34 for the trochanter at D21S1446 and 2.93 for the femoral neck at D6S2427. Lumbar spine BMD had maxima at D6S2427 (LOD = 1.88) and at D12S395 (LOD = 2.08). Multipoint linkage analysis revealed suggestive linkage of trochanteric BMD at a broad (approximately 20 cM) interval on chromosome 21q, with the peak linkage close to D21S1446 (LOD = 3.14). LOD scores were 2.13 at 8q24 with Ward's BMD and 1.92 at 14q21.3 with lumbar spine BMD. This largest genome screen to date for genes underlying normal variation in BMD, adjusted for a large number of covariates, will help to identify new positional candidate genes, otherwise unrecognized.

PURPOSE To determine if estrogen replacement therapy (ERT) is associated with improved tooth retention and lower risk of edentulism (no natural teeth remaining) in a cohort of elderly women. PATIENTS AND METHODS Subjects were 488 women, aged 72 to 95, who participated in the 23rd examination cycle (1994 to 1995) of the Framingham Heart Study, a population-based study begun in 1948. The number of teeth remaining and their location were recorded by a trained observer. History and duration of ERT were obtained from records kept since cycle 10 (1960 to 1963). Third molars were excluded from all analyses. RESULTS Women who ever used ERT were younger than nonusers by 1 year (80 ± 4 years, n = 184, versus 81 ± 4 years, n = 304, P = 0.019). Estrogen users had more teeth remaining than nonusers (12.5 ± 0.8 versus 10.7 ± 0.8 versus 10.7 ± 0.6 teeth, P = 0.046, mean ± SE) after controlling for age, smoking status, and education. Duration of estrogen use was an independent predictor of the number of teeth remaining (P = 0.015) such that each 4.2-year interval of use was associated with an increased mean retention of 1 tooth. Long-term estrogen users (more than 8 years, n = 48) had an average of 3.6 more teeth than women who never used estrogen (14.3 ± 1.5 versus 10.7 ± 0.6 teeth, P <0.02). The association with duration of use was present among different types of teeth (incisors, canines, and premolars) but less strong for molars. The odds of being edentulous were reduced by 6% for each 1-year increase in duration of estrogen use (odds ratio = 0.94, P = 0.038, 95% confidence interval = 0.90 to 0.99). CONCLUSIONS These data suggest that ERT protects against tooth loss and reduces the risk of edentulism. The associations of estrogen use and tooth retention are evident for all but the molars.

Background: The role of total calcium intake in the prevention of hip fracture risk has not been well established. Objective: The objective of the study was to assess the relation of calcium intake to the risk of hip fracture on the basis of meta-analyses of cohort studies and clinical trials. Results: In women (7 prospective cohort studies, 170 991 women, 2954 hip fractures), there was no association between total calcium intake and hip fracture risk [pooled risk ratio (RR) per 300 mg total Ca/d = 1.01; 95% CI: 0.97, 1.05]. In men (5 prospective cohort studies, 68 606 men, 214 hip fractures), the pooled RR per 300 mg total Ca/d was 0.92 (95% CI: 0.82, 1.03). On the basis of 5 clinical trials (n = 5666 women, primarily postmenopausal, plus 1074 men) with 814 nonvertebral fractures, the pooled RR for nonvertebral fractures between calcium supplementation (800–1600 mg/d) and placebo was 0.92 (95% CI: 0.81, 1.05). On the basis of 4 clinical trials with separate results for hip fracture (6504 subjects with 139 hip fractures), the pooled RR between calcium and placebo was 1.64 (95% CI:1.02, 2.64). Sensitivity analyses including 2 additional small trials with <100 participants or per-protocol results did not substantially alter results. Conclusions: Pooled results from prospective cohort studies suggest that calcium intake is not significantly associated with hip fracture risk in women or men. Pooled results from randomized controlled trials show no reduction in hip fracture risk with calcium supplementation, and an increased risk is possible. For any nonvertebral fractures, there was a neutral effect in the randomized trials.

Vitamin C is essential for collagen formation and normal bone development. We evaluated associations of total, supplemental, and dietary vitamin C intake with bone mineral density (BMD) at the hip [femoral neck, trochanter], spine, and radial shaft and 4-y BMD change in elderly participants from the Framingham Osteoporosis Study. Energy-adjusted vitamin C intakes were estimated from the Willett FFQ in 1988-89. Mean BMD and 4-y BMD change was estimated, for men and women, by tertile/category of vitamin C intake, adjusting for covariates. We tested for interaction with smoking, calcium, and vitamin E intake. Among 334 men and 540 women, the mean age was 75 y and mean vitamin D intake was 8.25 mug/d (women) and 8.05 mug/d (men). We observed negative associations between total and supplemental vitamin C intake and trochanter-BMD among current male smokers (P-trend = 0.01). Among male nonsmokers, total vitamin C intake was positively associated with femoral neck BMD (P-trend = 0.04). Higher total vitamin C intake was associated with less femoral neck and trochanter-BMD loss in men with low calcium (all P-trend </= 0.03) or vitamin E intakes (all P-trend = 0.03). Higher dietary vitamin C intake tended to be associated with lower femoral neck-BMD loss (P-trend = 0.09). These associations were attenuated but retained borderline significance (P-trend < 0.1) after adjusting for potassium intake (a marker of fruit and vegetable intake), suggesting that vitamin C effects may not be separated from other protective factors in fruit and vegetables. Null associations were observed among women. These results suggest a possible protective role of vitamin C for bone health in older men.

ABSTRACT Obesity has been traditionally considered to protect the skeleton against osteoporosis and fracture. Recently, body fat, specifically visceral adipose tissue (VAT), has been associated with lower bone mineral density (BMD) and increased risk for some types of fractures. We studied VAT and bone microarchitecture in 710 participants (58% women, age 61.3 ± 7.7 years) from the Framingham Offspring cohort to determine whether cortical and trabecular BMD and microarchitecture differ according to the amount of VAT. VAT was measured from CT imaging of the abdomen. Cortical and trabecular BMD and microarchitecture were measured at the distal tibia and radius using high-resolution peripheral quantitative computed tomography (HR-pQCT). We focused on 10 bone parameters: cortical BMD (Ct.BMD), cortical tissue mineral density (Ct.TMD), cortical porosity (Ct.Po), cortical thickness (Ct.Th), cortical bone area fraction (Ct.A/Tt.A), trabecular density (Tb.BMD), trabecular number (Tb.N), trabecular thickness (Tb.Th), total area (Tt.Ar), and failure load (FL) from micro–finite element analysis. We assessed the association between sex-specific quartiles of VAT and BMD, microarchitecture, and strength in all participants and stratified by sex. All analyses were adjusted for age, sex, and in women, menopausal status, then repeated adjusting for body mass index (BMI) or weight. At the radius and tibia, Ct.Th, Ct.A/Tt.A, Tb.BMD, Tb.N, and FL were positively associated with VAT (all p-trend &amp;lt;0.05), but no other associations were statistically significant except for higher levels of cortical porosity with higher VAT in the radius. Most of these associations were only observed in women, and were no longer significant when adjusting for BMI or weight. Higher amounts of VAT are associated with greater BMD and better microstructure of the peripheral skeleton despite some suggestions of significant deleterious changes in cortical measures in the non–weight bearing radius. Associations were no longer significant after adjustment for BMI or weight, suggesting that the effects of VAT may not have a substantial effect on the skeleton independent of BMI or weight. © 2016 American Society for Bone and Mineral Research.

Cognitive functions are important correlates of health outcomes across the life-course. Individual differences in cognitive functions are partly heritable. Epigenetic modifications, such as DNA methylation, are susceptible to both genetic and environmental factors and may provide insights into individual differences in cognitive functions. Epigenome-wide meta-analyses for blood-based DNA methylation levels at ~420,000 CpG sites were performed for seven measures of cognitive functioning using data from 11 cohorts. CpGs that passed a Bonferroni correction, adjusting for the number of CpGs and cognitive tests, were assessed for: longitudinal change; being under genetic control (methylation QTLs); and associations with brain health (structural MRI), brain methylation and Alzheimer's disease pathology. Across the seven measures of cognitive functioning (meta-analysis n range: 2557-6809), there were epigenome-wide significant (P < 1.7 × 10-8) associations for global cognitive function (cg21450381, P = 1.6 × 10-8), and phonemic verbal fluency (cg12507869, P = 2.5 × 10-9). The CpGs are located in an intergenic region on chromosome 12 and the INPP5A gene on chromosome 10, respectively. Both probes have moderate correlations (~0.4) with brain methylation in Brodmann area 20 (ventral temporal cortex). Neither probe showed evidence of longitudinal change in late-life or associations with white matter brain MRI measures in one cohort with these data. A methylation QTL analysis suggested that rs113565688 was a cis methylation QTL for cg12507869 (P = 5 × 10-5 and 4 × 10-13 in two lookup cohorts). We demonstrate a link between blood-based DNA methylation and measures of phonemic verbal fluency and global cognitive ability. Further research is warranted to understand the mechanisms linking genomic regulatory changes with cognitive function to health and disease.

Prior studies show vertebral strength from computed tomography-based finite element analysis may be associated with vertebral fracture risk. We found vertebral strength had a strong association with new vertebral fractures, suggesting that vertebral strength measures identify those at risk for vertebral fracture and may be a useful clinical tool. We aimed to determine the association between vertebral strength by quantitative computed tomography (CT)-based finite element analysis (FEA) and incident vertebral fracture (VF). In addition, we examined sensitivity and specificity of previously proposed diagnostic thresholds for fragile bone strength and low BMD in predicting VF. In a case-control study, 26 incident VF cases (13 men, 13 women) and 62 age- and sex-matched controls aged 50 to 85 years were selected from the Framingham multi-detector computed tomography cohort. Vertebral compressive strength, integral vBMD, trabecular vBMD, CT-based BMC, and CT-based aBMD were measured from CT scans of the lumbar spine. Lower vertebral strength at baseline was associated with an increased risk of new or worsening VF after adjusting for age, BMI, and prevalent VF status (odds ratio (OR) = 5.2 per 1 SD decrease, 95% CI 1.3–19.8). Area under receiver operating characteristic (ROC) curve comparisons revealed that vertebral strength better predicted incident VF than CT-based aBMD (AUC = 0.804 vs. 0.715, p = 0.05) but was not better than integral vBMD (AUC = 0.815) or CT-based BMC (AUC = 0.794). Additionally, proposed fragile bone strength thresholds trended toward better sensitivity for identifying VF than that of aBMD-classified osteoporosis (0.46 vs. 0.23, p = 0.09). This study shows an association between vertebral strength measures and incident vertebral fracture in men and women. Though limited by a small sample size, our findings also suggest that bone strength estimates by CT-based FEA provide equivalent or better ability to predict incident vertebral fracture compared to CT-based aBMD. Our study confirms that CT-based estimates of vertebral strength from FEA are useful for identifying patients who are at high risk for vertebral fracture.

Design, Setting, and ParticipantsGenome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.

Decline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta-analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P-value< 5 × 10(-8) ) and 39 suggestive (P-value< 5 × 10(-5) ) associations were observed from meta-analysis of the discovery cohorts. After meta-analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P-value = 5.20 × 10(-10) ). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer-binding protein-β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

Abdominal aortic calcification (AAC) can be accurately recognized on lateral spine images intended for vertebral fracture assessment, that are obtained with dual-energy X-ray absorptiometry (DXA). Greater amounts of AAC are common in the older population for whom DXA is routinely done, and have been consistently associated with incident atherosclerotic cardiovascular disease (ASCVD) events. AAC has also been associated with incident fractures in some prospective studies, but not in others. However, further research is needed to quantify the extent to which measurement of AAC improves prediction of ASCVD events and its impact on physician and patient ASCVD risk management. Additionally, research to develop better, more precise, automated, quantitative methods of AAC assessment on lateral spine densitometric images will hopefully lead to better prediction of clinical outcomes. In conclusion, although the prime indication for densitometric lateral spine imaging remains vertebral fracture assessment, AAC that is found incidentally on lateral spine images should be reported, so that patients and their health care providers are aware of its presence.

<h3>Importance</h3> The decision whether to surgically repair a hip fracture in nursing home (NH) residents with advanced dementia can be challenging. <h3>Objective</h3> To compare outcomes, including survival, among NH residents with advanced dementia and hip fracture according to whether they underwent surgical hip fracture repair. <h3>Design, Setting, and Participants</h3> We conducted a retrospective cohort study of 3083 NH residents with advanced dementia and hip fracture, but not enrolled in hospice care, using nationwide Medicare claims data linked with Minimum Data Set (MDS) assessments from January 1, 2008, through December 31, 2013. <h3>Methods</h3> Residents with advanced dementia were identified using the MDS. Medicare claims were used to identify hip fracture and to determine whether the fracture was managed surgically. Survival between surgical and nonsurgical residents was compared using multivariable Cox proportional hazards with inverse probability of treatment weighting (IPTW). All analyses took place between November 2015 and January 2018. Among 6-month survivors, documented pain, antipsychotic drug use, physical restraint use, pressure ulcers, and ambulatory status were compared between surgical and nonsurgical groups. <h3>Results</h3> Among 3083 residents with advanced dementia and hip fracture (mean age, 84.2 years; 79.2% female [n = 2441], 28.5% ambulatory [n = 879]), 2615 (84.8%) underwent surgical repair. By 6-month follow-up, 31.5% (n = 824) and 53.8% (n = 252) of surgically and nonsurgically managed residents died, respectively. After IPTW modeling, surgically managed residents were less likely to die than residents without surgery (adjusted hazard ratio [aHR], 0.88; 95% CI, 0.79-0.98). Among 2007 residents who survived 6 months, residents with surgical vs nonsurgical management had less docmented pain (29.0% [n = 465] vs 30.9% [n = 59]) and fewer pressure ulcers (11.2% [n = 200] vs 19.0% [n = 41]). In IPTW models, surgically managed residents reported less pain (aHR, 0.78; 95% CI, 0.61-0.99) and pressure ulcers (aHR, 0.64; 95% CI, 0.47-0.86). There was no difference between antipsychotic drug use and physical restraint use between the groups. Few survivors remained ambulatory (10.7% [n = 55] of surgically managed vs 4.8% [n = 1] without surgery). <h3>Conclusions and Relevance</h3> Surgical repair of a hip fracture was associated with lower mortality among NH residents with advanced dementia and should be considered together with the residents’ goals of care in management decisions. Pain and other adverse outcomes were common regardless of surgical management, suggesting the need for broad improvements in the quality of care provided to NH residents with advanced dementia and hip fracture.

Vitamin D plays an essential role in human health as it influences immune function, cell proliferation, differentiation and apoptosis. Vitamin D deficiency has been associated with numerous health outcomes, including bone disease, cancer, autoimmune disease, cardiovascular conditions and more. However, the causal role of vitamin D beyond its importance for bone health remains unclear and is under much debate. Twin and familial studies from past decades have demonstrated a nontrivial heritability of circulating vitamin D concentrations. Several large-scale genome-wide association studies (GWAS) have discovered associations of GC, NADSYN1/DHCR7, CYP2R1, CYP24A1, SEC23A, AMDHD1 with serum levels of vitamin D. A recent whole genome sequencing (WGS) study, combined with deep imputation of genome-wide genotyping, has identified a low-frequency synonymous coding variant at CYP2R1. Information on these genetic variants can be used as tools for downstream analysis such as Mendelian randomization. Here, we review the genetic determinants of circulating vitamin D levels by focusing on new findings from GWAS and WGS, as well as results from Mendelian randomization analyses conducted so far for vitamin D with various traits and diseases. The amount of variation in vitamin D explained by genetics is still small, and the putative causal relationship between vitamin D and other diseases remains to be demonstrated.

Folate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans.The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes.A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes.The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs.We identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies.

Age-adjusted hip fracture incidence is decreasing in the US. The decrease has been attributed to osteoporosis treatment, but the cause is unknown.To examine the decrease in hip fracture incidence over the past 40 years in the US.A population-based cohort study using participants in the Framingham Heart Study was conducted. A total of 4918 men and 5634 women were followed up prospectively for the first hip fracture between January 1, 1970, and December 31, 2010. Data were analyzed from May 1, 2019, to May 30, 2020.Incidence of hip fracture and contemporaneous prevalence of risk factors for hip fractures analyzed with age-period-cohort models.The study contained more than 105 000 person-years in 10 552 individuals with a gradual shift toward the offspring participants in the 1980s and 1990s. Women represented more than 55% of the study sample over the years. Adjusted for age, the incidence of hip fracture decreased by 4.4% (95% CI, 6.8%-1.9%) per year from 1970 to 2010. Both period associations (P < .001) and birth cohort associations (P < .001) were statistically significant. For example, in persons aged 85 to 89 years, the incidence of hip fracture was 759 per 100 000 person-years in the offspring group compared with 2018 per 100 000 person-years in the original cohort. The decrease in hip fracture incidence was coincident with a decrease in smoking and heavy drinking. Smoking decreased from 38% in the 1970s to 15% in the late 2000s, while heavy drinking decreased from 7.0% to 4.5%. The prevalence of other risk factors for hip fracture, such as underweight (body mass index <18.5), obesity (body mass index >30), and early menopause (age <45 years) were stable over the study period. When persons who never smoked were evaluated, a change in the incidence of -3.2% (95% CI, -6.0% to -0.4%) per year was observed. The difference between the decrease of the entire population and nonsmokers of 1.5% per year was similar to the hazard ratio conferred by smoking (hazard ratio, 1.5; 95% CI, 1.14-1.96).In this study, individuals born more recently appeared to have a low risk for hip fracture. Reductions in smoking and heavy drinking were the risk factor changes coincident with the observed decrease in hip fracture. Attributing the decrease in hip fracture incidence up to 2010 solely to better treatment is not supported by these data, emphasizing the need to treat patients with osteoporosis while continuing to encourage public health interventions for smoking cessation and heavy drinking.

ABSTRACT Although a relationship between vascular disease and osteoporosis has been recognized, its clinical importance for fracture risk evaluation remains uncertain. Abdominal aortic calcification (AAC), a recognized measure of vascular disease detected on single-energy images performed for vertebral fracture assessment, may also identify increased osteoporosis risk. In a prospective 10-year study of 1024 older predominantly white women (mean age 75.0 ± 2.6 years) from the Perth Longitudinal Study of Aging cohort, we evaluated the association between AAC, skeletal structure, and fractures. AAC and spine fracture were assessed at the time of hip densitometry and heel quantitative ultrasound. AAC was scored 0 to 24 (AAC24) and categorized into low AAC (score 0 and 1, n = 459), moderate AAC (score 2 to 5, n = 373), and severe AAC (score text-decoration:underline6, n = 192). Prevalent vertebral fractures were calculated using the Genant semiquantitative method. AAC24 scores were inversely related to hip BMD ( rs = –0.077, p = 0.013), heel broadband ultrasound attenuation ( rs = –0.074, p = 0.020), and the Stiffness Index ( rs = –0.073, p = 0.022). In cross-sectional analyses, women with moderate to severe AAC were more likely to have prevalent fracture and lumbar spine imaging-detected lumbar spine fractures, but not thoracic spine fractures (Mantel-Haenszel test of trend p &amp;lt; 0.05). For 10-year incident clinical fractures and fracture-related hospitalizations, women with moderate to severe AAC (AAC24 score &amp;gt;1) had increased fracture risk (HR 1.48; 95% CI, 1.15 to 1.91; p = 0.002; HR 1.46; 95% CI, 1.07 to 1.99; p = 0.019, respectively) compared with women with low AAC. This relationship remained significant after adjusting for age and hip BMD for clinical fractures (HR 1.40; 95% CI, 1.08 to 1.81; p = 0.010), but was attenuated for fracture-related hospitalizations (HR 1.33; 95% CI, 0.98 to 1.83; p = 0.073). In conclusion, older women with more marked AAC are at higher risk of fracture, not completely captured by bone structural predictors. These findings further support the concept that vascular calcification and bone pathology may share similar mechanisms of causation that remain to be fully elucidated © 2019 American Society for Bone and Mineral Research

BACKGROUND The Sarcopenia Definitions and Outcomes Consortium (SDOC) sought to identify cut points for muscle strength and body composition measures derived from dual‐energy x‐ray absorptiometry (DXA) that discriminate older adults with slow walking speed. This article presents the core analyses used to guide the SDOC position statements. DESIGN Cross‐sectional data analyses of pooled data. SETTING University‐based research assessment centers. PARTICIPANTS Community‐dwelling men (n = 13,652) and women: (n = 5,115) with information on lean mass by DXA, grip strength (GR), and walking speed. MEASUREMENTS Thirty‐five candidate sarcopenia variables were entered into sex‐stratified classification and regression tree (CART) models to agnostically choose variables and cut points that discriminate slow walkers (&lt;0.80 m/s). Models with alternative walking speed outcomes were also evaluated (&lt;0.60 and &lt;1.0 m/s and walking speed treated continuously). RESULTS CART models identified GR/body mass index (GRBMI) and GR/total body fat (GRTBF) as the primary discriminating variables for slowness in men and women, respectively. Men with GRBMI of 1.05 kg/kg/m 2 or less were approximately four times more likely to be slow walkers than those with GRBMI of greater than 1.05 kg/kg/m 2 . Women with GRTBF of less than 0.65 kg/kg were twice as likely to be slow walkers than women with GRTBF of 0.65 kg/kg or greater. Models with alternative walking speed outcomes selected only functions of GR as primary discriminators of slowness in both men and women. DXA‐derived lean mass measures did not consistently discriminate slow walkers. CONCLUSION GR with and without adjustments for body size and composition consistently discriminated older adults with slowness. CART models did not select DXA‐based lean mass as a primary discriminator of slowness. These results were presented to an SDOC Consensus Panel, who used them and other information to develop the SDOC Position Statements. J Am Geriatr Soc 68:1419‐1428, 2020.

Abstract The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS‐CoV‐2 infection. SARS‐CoV‐2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence‐associated secretory phenotype (SASP). The SASP can be amplified by infection‐related pathogen‐associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS‐CoV‐2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS‐CoV‐2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health‐funded, multicenter, placebo‐controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS‐CoV‐2 rtPCR‐positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long‐term care settings in the SARS‐CoV‐2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.

Skeletal and glycemic traits have shared etiology, but the underlying genetic factors remain largely unknown. To identify genetic loci that may have pleiotropic effects, we studied Genome-wide association studies (GWASs) for bone mineral density and glycemic traits and identified a bivariate risk locus at 3q21. Using sequence and epigenetic modeling, we prioritized an adenylate cyclase 5 (ADCY5) intronic causal variant, rs56371916. This SNP changes the binding affinity of SREBP1 and leads to differential ADCY5 gene expression, altering the chromatin landscape from poised to repressed. These alterations result in bone- and type 2 diabetes-relevant cell-autonomous changes in lipid metabolism in osteoblasts and adipocytes. We validated our findings by directly manipulating the regulator SREBP1, the target gene ADCY5, and the variant rs56371916, which together imply a novel link between fatty acid oxidation and osteoblast differentiation. Our work, by systematic functional dissection of pleiotropic GWAS loci, represents a framework to uncover biological mechanisms affecting pleiotropic traits.

This study examined the effect of birth cohort on incidence rates of hip fracture among women and men in the Framingham Study.Age-specific incidence rates of first hip fracture were presented according to tertile of year of birth for 5209 participants of the Framingham Study, a population-based cohort followed since 1948. Sex-specific incidence rate ratios were calculated by Cox regression to assess the relation between birth cohort and hip fracture incidence.An increasing trend in hip fracture incidence rates was observed with year of birth for women (trend, P =.05) and men (trend, P =.03). Relative to those born from 1887 to 1900 (incidence rate ratio [IRR] = 1.0), age-specific incidence rates were greatest in the most recent birth cohort, born from 1911 to 1921 (IRR = 1.4 for women, IRR = 2.0 for men), and intermediate in those born from 1901 to 1910 (IRR = 1.2 for women, IRR = 1.5 for men).Results suggest risk of hip fracture is increasing for successive birth cohorts. Projections that fail to account for the increase in rates associated with birth cohort underestimate the future public health impact of hip fracture in the United States.

Vitamin B12 is important to DNA synthesis and may affect bone formation. We examined the association between this vitamin and BMD in 2576 adults. Men with plasma B12 < 148 pM had significantly lower BMD at the hip, and women at the spine, relative to those with higher B12, and trends were similar for both at all sites. Low vitamin B12 may be a risk factor for low BMD.Vitamin B12 is important to DNA synthesis and may affect bone formation. It has been linked to osteoblastic activity in clinical studies and cell culture.We examined the relationship between plasma vitamin B12 status and BMD in 2576 adult participants in the Framingham Offspring Osteoporosis Study (1996-2001). BMD was measured by DXA at the hip and spine. Plasma vitamin B12 was measured by radioassay. Mean BMD measures were estimated for four categories of vitamin B12 concentration, based on commonly used cut-offs, using analysis of covariance, adjusted for age, BMI, physical activity score for the elderly (PASE), alcohol use, smoking status, total calcium and vitamin D intake, season of bone measurement, and for women, menopause status and current estrogen use. Further adjustment for protein intake and total homocysteine concentration was also performed.Both men and women with vitamin B12 concentrations <148 pM had lower average BMD than those with vitamin B12 above this cut-off. These differences were significant (p < 0.05) for men at most hip sites and for women at the spine. Significance remained after further adjustment for protein intake and plasma homocysteine.Vitamin B12 deficiency may be an important modifiable risk factor for osteoporosis.

Association between dietary protein and fracture risk is unclear. We examined association between energy-adjusted protein intake and hip fracture risk in elders. The risk of hip fracture was reduced in upper quartiles of protein intake when compared with lowest quartile. Studies of the association between dietary protein intake and hip fracture risk are conflicting. Therefore, we examined protein intake and hip fracture risk in a population-based group of elderly men and women. Five hundred seventy-six women and 370 men from the Framingham Osteoporosis Study with no previous history of hip fracture completed Food Frequency Questionnaires. Energy-adjusted protein intake was evaluated as a continuous variable and as quartiles. Incidence rates and hazard ratios were calculated, adjusting for age, BMI, sex, and energy intake. Among 946 participants (mean age 75 years), mean protein intake was found to be 68 gm/d. Increased protein intake was associated with a decreased risk of hip fracture compared to those in the lowest quartile of protein intake (Q2 HR = 0.70, Q3 HR = 0.56, and Q4 HR = 0.63; all p values ≥ 0.044), p for trend was 0.07. When a threshold effect was considered (Q2–4 vs Q1), intakes in the higher quartiles combined were associated with a significantly lower risk for hip fracture (HR = 0.63; p = 0.04). Our results are consistent with reduced risk of hip fracture with higher dietary protein intake. Larger prospective studies are needed to confirm and extend this finding in elderly men and women.

We found the risk of hip fracture was transiently elevated around twofold shortly after initiation of a loop or thiazide diuretic drug in a case-crossover and case–control study. No statistical association was found following the initiation of a comparator medication: ACE inhibitors. Awareness of these short-term risks may reduce hip fractures. Little is known about the acute effects of initiating a diuretic drug on risk of fracture. We evaluated the relationship between initiating a diuretic drug and the occurrence of hip fracture. The study sample included 2,118,793 persons aged ≥50 years enrolled in The Health Improvement Network (THIN) between 1986 and 2010. The effect of a new start of a diuretic drug or comparator medication (ACE inhibitor) on risk of hip fracture was assessed using a case-crossover and case–control study during the 1–7, 8–14, 15–21, and 22–28 days following drug initiation. Included were 28,703 individuals with an incident hip fracture over a mean of 7.9 years follow-up. In the case-crossover study, the risk of experiencing a hip fracture was increased during the first 7 days following loop diuretic drug initiation (OR = 1.8; 95 % CI, 1.2, 2.7). The elevated risk did not continue during the 8–14, 15–21, or 22–28 days following drug initiation. For thiazide diuretics, the risk of hip fracture was elevated 8–14 days after drug initiation (OR = 2.2; 95 % CI, 1.2, 3.9). No such association was observed in the 1–7, 15–21, or 22–28 days following thiazide drug initiation. ACE inhibitor initiation was not associated with a statistically significant increased risk of hip fracture. Similar results were observed using a case–control study. The risk of hip fracture was transiently elevated around twofold shortly after the new start of a loop or thiazide diuretic drug. Awareness of these short-term risks may reduce hip fractures and other injurious falls in vulnerable adults.

Deficits in balance and muscle function are important risk factors for falls in older adults. Aging is associated with significant declines in muscle size and density, but associations of trunk muscle size and density with balance and falls in older adults have not been previously examined.Trunk muscle size (cross-sectional area) and attenuation (a measure of tissue density) were measured in computed tomography scans (at the L2 lumbar level) in a cohort of older adults (mean ± SD age of 81.9±6.4) residing in independent living communities. Outcome measures were postural sway measured during quiet standing and Short Physical Performance Battery (SPPB) at baseline, and falls reported by participants for up to 3 years after baseline measurements.Higher muscle density was associated with reduced postural sway, particularly sway velocities, in both men and women, and better Short Physical Performance Battery score in women, but was not associated with falls. Larger muscle size was associated with increased postural sway in men and women and with increased likelihood of falling in men.The results suggest that balance depends more on muscle quality than on the size of the muscle. The unexpected finding that larger muscle size was associated with increased postural sway and increased fall risk requires further investigation, but highlights the importance of factors besides muscle size in muscle function in older adults.

ABSTRACT Genetic and environmental determinants of skeletal phenotypes such as bone mineral density (BMD) may converge through the epigenome, providing a tool to better understand osteoporosis pathophysiology. Because the epigenetics of BMD have been largely unexplored in humans, we performed an epigenome-wide association study (EWAS) of BMD. We undertook a large-scale BMD EWAS using the Infinium HumanMethylation450 array to measure site-specific DNA methylation in up to 5515 European-descent individuals (NDiscovery = 4614, NValidation = 901). We associated methylation at multiple cytosine-phosphate-guanine (CpG) sites with dual-energy X-ray absorptiometry (DXA)-derived femoral neck and lumbar spine BMD. We performed sex-combined and stratified analyses, controlling for age, weight, smoking status, estimated white blood cell proportions, and random effects for relatedness and batch effects. A 5% false-discovery rate was used to identify CpGs associated with BMD. We identified one CpG site, cg23196985, significantly associated with femoral neck BMD in 3232 females (p = 7.9 × 10−11) and 4614 females and males (p = 3.0 × 10−8). cg23196985 was not associated with femoral neck BMD in an additional sample of 474 females (p = 0.64) and 901 males and females (p = 0.60). Lack of strong consistent association signal indicates that among the tested probes, no large-effect epigenetic changes in whole blood associated with BMD, suggesting future epigenomic studies of musculoskeletal traits measure DNA methylation in a different tissue with extended genome coverage. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Psychotropic drugs increase the risk of falls, but they are still frequently prescribed to treat behavioral symptoms associated with dementia in the nursing home. We examined whether there is an acute increased risk of falls in the days following a change to an antipsychotic or benzodiazepine drug prescription.We collected information on 594 long-stay nursing home residents from two facilities who fell at least once between September 1, 2010 and May 31, 2013. Psychotropic drug changes were ascertained from the facilities' computerized medication administration log. We used the case-crossover design to compare the frequency of antipsychotic and benzodiazepine drug changes during the days before a fall with the frequency of drug changes at more remote times.Mean age was 87.5 years, and 75.1% were female. The risk of falls was higher in the 24 hours following benzodiazepine initiation compared with other times (odds ratio [OR] 3.79, 95% confidence interval [CI] 1.10, 13.00). There was no clear difference in risk following antipsychotic initiation (OR 2.42, CI 0.58, 10.06), but this could be due to the small sample size. Stopping a benzodiazepine was associated with a significantly reduced fall risk (OR 0.26, 95% CI 0.08-0.91).Benzodiazepines pose an immediate threat to fall risk, whereas it is less clear if antipsychotics also pose an immediate risk. Nursing home staff should be particularly vigilant in the days following the new prescription for a benzodiazepine in an effort to prevent injury.

ABSTRACT Lateral spine images are captured using bone densitometers for vertebral fracture assessment (VFA) in older women. Abdominal aortic calcification (AAC) is commonly seen on these images; however, the long-term prognosis in women with AAC remains uncertain. In a prospective study of 1052 community-dwelling ambulant white women over 70 years old abdominal aortic calcification 24 scale (AAC24) scores were calculated from digital lateral spine images captured during bone density testing in 1998 or 1999. Cardiovascular risk factors were assessed in 1998, whereas 14.5-year atherosclerotic vascular disease (ASVD)-related hospitalizations and deaths (events) were available through linked health records. Using established cut points for AAC 471 women (45%) had low AAC (AAC24 score 0 or 1), 387 (37%) moderate AAC (AAC24 score 2–5), and 197 (19%) had high AAC (AAC24 score ≥6). Over 14.5 years, 420 women experienced an ASVD event. Increasing severity of AAC was associated with increased absolute risk of ASVD events (37%, 39%, and 49%, respectively, p = 0.008 for trend), ASVD deaths (15%, 21%, and 27%, respectively, p &amp;lt; 0.001 for trend), and all-cause mortality (30%, 38%, and 44%, respectively, p &amp;lt; 0.001 for trend). After adjusting for Framingham risk scores, women with high AAC had increased relative hazard for ASVD events, HR 1.37 (95% CI, 1.07 to 1.77; p = 0.013) compared to women with low AAC. Similarly, women with moderate AAC and high AAC had increased relative hazards for ASVD deaths HR 1.41 (95% CI, 1.03 to 1.94; p = 0.034) and HR 1.80 (95% CI, 1.26 to 2.57; p = 0.001), or any deaths HR 1.30 (95% CI, 1.03 to 1.64; p = 0.026) and HR 1.53 (95% CI, 1.17 to 2.00; p = 0.002), compared to women with low AAC. In conclusion, more advanced AAC on images captured for VFA is associated with long-term ASVD hospitalizations and deaths before and after adjusting for Framingham risk scores. AAC assessment could be considered in addition to VFA to identify individuals who may benefit for more aggressive cardiovascular primary prevention strategies. © 2018 American Society for Bone and Mineral Research

ABSTRACT We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p &amp;lt; 5 × 10−9, adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2 &amp;gt; 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

ABSTRACT Dietary fiber may increase calcium absorption, but its role in bone mineralization is unclear. Furthermore, the health effect of dietary fiber may be different between sexes. We examined the association between dietary fiber (total fiber and fiber from cereal, fruits, vegetables, nuts, and legumes) and bone loss at the femoral neck, trochanter, and lumbar spine (L2 to L4) in older men and women. In the Framingham Offspring Study, at baseline (1996–2001), diet was assessed using the Willett food-frequency questionnaire, and bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Follow-up BMD was measured in 2001–2005 and 2005–2008 among 792 men (mean age 58.1 years; BMI 28.6 kg/m2) and 1065 women (mean age 57.3 years; BMI 27.2 kg/m2). We used sex-specific generalized estimating equations in multivariable regressions to estimate the difference (β) of annualized BMD change in percent (%ΔBMD) at each skeletal site per 5 g/d increase in dietary fiber. We further estimated the adjusted mean for bone loss (annualized %ΔBMD) among participants in each higher quartile (Q2, Q3, or Q4) compared with those in the lowest quartile (Q1) of fiber intake. Higher dietary total fiber (β = 0.06, p = 0.003) and fruit fiber (β = 0.10, p = 0.008) was protective against bone loss at the femoral neck in men but not in women. When examined in quartiles, men in Q2–Q4 of total fiber had significantly less bone loss at the femoral neck versus those in Q1 (all p &amp;lt; 0.04). For women, we did not observe associations with hip bone loss, although fiber from vegetables appeared to be protective against spine bone loss in women but not men. There were no associations with cereal fiber or nut and legume fiber and bone loss in men or women. Our findings suggest that higher dietary fiber may modestly reduce bone loss in men at the hip. © 2017 American Society for Bone and Mineral Research.

Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF] = 3%) was associated with higher vBMD (β = 0.22, p = 1.9 × 10-8 ) and decreased risk of radiographic vertebral fracture (odds ratio [OR] = 0.75; false discovery rate [FDR] p = 0.01). In 1p36.12, rs12742784 (MAF = 21%) was associated with higher vBMD (β = 0.09, p = 1.2 × 10-10 ) and decreased risk of clinical vertebral fracture (OR = 0.82; FDR p = 7.4 × 10-4 ). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (β = 0.28, FDR p = 0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (β = 0.12, FDR p = 1.7 × 10-3 , functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence. © 2016 American Society for Bone and Mineral Research.

Background: Previous studies showed beneficial effects of specific dairy foods on bone health in middle-aged adults.Objective: We examined the association of milk, yogurt, cheese, cream, fluid dairy (milk + yogurt), and milk + yogurt + cheese intakes with bone mineral density (BMD) and 4-y percentage of change in BMD [▵%BMD; femoral neck, trochanter, and lumbar spine (LS)]. We further assessed whether these associations were modified by vitamin D supplement use in this cohort of older adults.Methods: Food-frequency questionnaire responses, baseline BMD (hip and spine, n = 862 in 1988-1989), and follow-up BMD (n = 628 in 1992-1993) were measured in the Framingham study, a prospective cohort study of older Caucasian men and women aged 67-93 y. Outcomes included baseline BMD and ▵%BMD. Dairy-food intakes (servings per week) were converted to energy-adjusted residuals, and linear regression was used, adjusting for covariates. These associations were further examined by vitamin D supplement use.Results: The mean age of the participants was 75 y. In the full sample, dairy-food items were not associated with BMD (P = 0.11-0.99) or with ▵%BMD (P = 0.29-0.96). Among vitamin D supplement users, but not among nonusers, higher milk, fluid dairy, and milk + yogurt + cheese intakes were associated with higher LS BMD (P = 0.011-0.009). Among vitamin D supplement users, but not among nonusers, higher milk + yogurt + cheese intakes were protective against trochanter BMD loss (P = 0.009).Conclusions: In this population of older adults, higher intakes of milk, fluid dairy, and milk + yogurt + cheese were associated with higher LS BMD, and a higher intake of milk + yogurt + cheese was protective against trochanter BMD loss among vitamin D supplement users but not among nonusers. These findings underscore that the benefits of dairy intake on the skeleton may be dependent on vitamin D intake.

Strategies used to predict fracture in community-dwellers may not be useful in the nursing home (NH). Our objective was to develop and validate a model (Fracture Risk Assessment in Long-term Care [FRAiL]) to predict the 2-year risk of hip fracture in NH residents using readily available clinical characteristics.The derivation cohort consisted of 419,668 residents between May 1, 2007 and April 30, 2008 in fee-for service Medicare. Hip fractures were identified using Part A diagnostic codes. Resident characteristics were obtained using the Minimum Data Set and Part D claims. Multivariable competing risk regression was used to model 2-year risk of hip fracture. We validated the model in a remaining 1/3 sample (n = 209,834) and in a separate cohort in 2011 (n = 858,636).Mean age was 84 years (range 65-113 years) and 74.5% were female. During 1.8 years mean follow-up, 14,553 residents (3.5%) experienced a hip fracture. Fifteen characteristics in the final model were associated with an increased risk of hip fracture including dementia severity, ability to transfer and walk independently, prior falls, wandering, and diabetes. In the derivation sample, the concordance index was 0.69 in men and 0.71 in women. Calibration was excellent. Results were similar in the internal and external validation samples.The FRAiL model was developed specifically to identify NH residents at greatest risk for hip fracture, and it identifies a different pattern of risk factors compared with community models. This practical model could be used to screen NH residents for fracture risk and to target intervention strategies.

To summarize the evidence from recent studies on the shared genetics between bone and muscle in humans. Genome-wide association studies (GWAS) have successfully identified a multitude of loci influencing the variability of different bone or muscle parameters, with multiple loci overlapping between the traits. In addition, joint analyses of multiple correlated musculoskeletal traits (i.e., multivariate GWAS) have underscored several genes with possible pleiotropic effects on both bone and muscle including MEF2C and SREBF1. Notably, several of the proposed pleiotropic genes have been validated using human cells or animal models. It is clear that the study of pleiotropy may provide novel insights into disease pathophysiology potentially leading to the identification of new treatment strategies that simultaneously prevent or treat both osteoporosis and sarcopenia. However, the role of muscle factors (myokines) that stimulate bone metabolism, as well as osteokines that affect muscles, is in its earliest stage of understanding.

ABSTRACT The objective of this work was to study the risk of pneumonia and pneumonia mortality among patients receiving nitrogen‐containing bisphosphonates (N‐BPs), non‐N‐BP anti‐osteoporosis medications, and no anti‐osteoporosis medications after hip fracture. We studied a historical cohort using a population‐wide database. Patients with first hip fracture during 2005–2015 were identified and matched by time‐dependent propensity score. The cohort was followed until December 31, 2016, to capture any pneumonia and pneumonia mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox‐proportional hazards regression. Absolute risk difference (ARD) and number needed to treat (NNT) were calculated. We identified 54,047 patients with hip fracture. Of these, 4041 patients who received N‐BPs and 11,802 without anti‐osteoporosis medication were propensity score–matched. N‐BPs were associated with a significantly lower risk of pneumonia compared with no treatment (6.9 versus 9.0 per 100 person‐years; HR 0.76; 95% CI, 0.70 to 0.83), resulting in an ARD of 0.02 and NNT of 46. A similar association was observed with pneumonia mortality (HR 0.65; 95% CI, 0.56 to 0.75). When N‐BPs were compared with non‐N‐BP anti‐osteoporosis medications, the association remained significant. N‐BPs were associated with lower risks of pneumonia and pneumonia mortality. Randomized controlled trials are now required to determine whether N‐BPs, non–vaccine‐based medications, can reduce pneumonia incidence in high risk groups. © 2020 American Society for Bone and Mineral Research.

The extent to which the prevalence of muscle weakness in the US population varies by different putative grip strength constructs developed by the Sarcopenia Definitions and Outcomes Consortium (SDOC) has not been described.Cross-sectional analysis.Two nationally representative cohorts-2010 and 2012 waves of the Health and Retirement Survey and round 1 (2011) of the National Health and Aging Trends Survey.Adults aged 65 years and older (n = 12,984) were included in these analyses.We analyzed three constructs of muscle weakness developed by the SDOC, and found to be associated with mobility disability for men and women, respectively: absolute grip strength (<35.5 kg and 20 kg); grip strength standardized to body mass index (<1.05 kg/kg/m² and 0.79 kg/kg/m²); and grip strength standardized to weight (<0.45 kg/kg and 0.337 kg/kg). We estimated the prevalence of muscle weakness defined by each of these constructs in the overall older US population, and by age, sex, race, and ethnicity. We also estimated the sensitivity and specificity of each of the grip strength constructs to discriminate slowness (gait speed <0.8 m/s) in these samples.The prevalence of muscle weakness ranged from 23% to 61% for men and from 30% to 66% for women, depending on the construct used. There was substantial variation in the prevalence of muscle weakness by race and ethnicity. The sensitivity and specificity of these measures for discriminating slowness varied widely, ranging from 0.30 to 0.92 (sensitivity) and from 0.17 to 0.88 (specificity).The prevalence of muscle weakness, defined by the putative SDOC grip strength constructs, depends on the construct of weakness used. J Am Geriatr Soc 68:1438-1444, 2020.

Lower antioxidant serum concentrations have been linked to declines in lean mass and physical function in older adults. Yet population data on the effect of dietary antioxidants on loss of muscle strength and physical function are lacking.We sought to determine the association of antioxidant intake [vitamin C, vitamin E, and total and individual carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein + zeaxanthin)] with annualized change in grip strength and gait speed in adults from the Framingham Offspring study.This prospective cohort study included participants with a valid FFQ at the index examination and up to 2 prior examinations and at ≥2 measures of primary outcomes: grip strength (n = 2452) and/or gait speed (n = 2422) measured over 3 subsequent examinations. Annualized change in grip strength (kg/y) and change in gait speed (m/s/y) over the follow-up period were used. Linear regression was used to calculate β coefficients and P values, adjusting for covariates.Mean ± SD age of participants was 61 ± 9 y (range: 33-88 y). Median intakes (IQR, mg/d) of vitamin C, vitamin E, and total carotenoid across available examinations were 209.2 (133.1-394.2), 27.1 (7.4-199.0), and 15.3 (10.4-21.3), respectively. The mean follow-up time was ∼12 ± 2 y (range: 4.5-15.4 y). In the sex-combined sample, higher intakes of total carotenoids, lycopene, and lutein + zeaxanthin were associated with increased annualized change in grip strength [β (SE) per 10-mg higher intake/d, range: 0.0316 (0.0146) to 0.1223 (0.0603) kg/y)]. All antioxidants except for vitamin C were associated with faster gait speed [β (SE) per 10-mg higher intake/d, range: 0.00008 (0.00004) to 0.0187 (0.0081) m/s/y].Higher antioxidant intake was associated with increase in grip strength and faster gait speed in this cohort of adults. This finding highlights the need for a randomized controlled trial of dietary antioxidants and their effect on muscle strength and physical function.