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1.  Association of total protein intake with bone mineral density (BMD) and bone loss in men and women from the Framingham Offspring Study 
Public health nutrition  2013;17(11):2570-2576.
To examine the association of % of total energy from protein (protein%) with bone mineral density (BMD, g/cm2) and bone loss at the femoral neck (FN), trochanter (TR); L2–L4 spine (LS). To examine calcium as an effect modifier.
The Framingham Offspring Study.
1,280 men and 1,639 women completed an FFQ in 1992–95 or 1995–98 and baseline DXA-BMD measurement in 1996–2000. 495 men and 680 women had follow-up BMD measured in 2002–2005.
Cohort study using multivariable regression to examine the association of protein% with each BMD, adjusting for covariates. Statistical interaction between protein% and calcium (total, dietary; supplemental) intake was examined.
The mean age at baseline was 61y(±9). In the cross-sectional analyses, protein% was positively associated with all BMD sites (P:0.02–0.04) in women but not in men. Significant interactions were observed with total calcium intake (<800 vs. ≥800 mg/d) in women at all bone sites (P:0.002–0.02). Upon stratification, protein% was positively associated with all BMD sites (P:0.04–0.10) in women with low calcium intakes but not with high calcium intakes. In the longitudinal analyses, in men, higher protein% was associated with more TR-bone loss (P=0.01) while no associations were seen in women, regardless of calcium intake.
This suggests that greater protein intake benefits women especially those with lower calcium intakes. However, protein effects are not significant for short term changes in bone density. Contrastingly, in men, higher protein intakes lead to greater TR-bone loss. Longer follow-up is required to examine the impact of protein on bone loss.
PMCID: PMC4103961  PMID: 24168918
Protein; bone mineral density; bone loss; diet; calcium
2.  Milk and yogurt consumption are linked with higher bone mineral density but not with hip fracture: the Framingham Offspring Study 
Archives of osteoporosis  2013;8(0):119.
To examine associations of milk, yogurt, cheese, cream, most dairy (total dairy without cream) and fluid dairy (milk+yogurt) with bone density (BMD) at femoral neck (FN), trochanter (TR) and spine, and with incident hip fracture over 12-y follow-up in the Framingham Offspring Study.
3,212 participants completed a food frequency questionnaire (1991–1995 or 1995–1998) and were followed for hip fracture until 2007. 2,506 participants had DXA BMD (1996–2001). Linear regression was used to estimate adjusted mean BMD while Cox-proportional hazards regression was used to estimate adjusted hazard ratios (HR) for hip fracture risk. Final models simultaneously included dairy foods adjusting for each other.
Mean baseline age was 55 (±1.6)y, range: 26–85). Most dairy intake was positively associated with hip and spine BMD. Intake of fluid dairy and milk were related with hip but not spine BMD. Yogurt intake was associated with TR-BMD alone. Cheese and cream intakes were not associated with BMD. In final models, yogurt intake remained positively associated with TR-BMD, while cream tended to be negatively associated with FN-BMD. Yogurt intake showed a weak protective trend for hip fracture [HR(95%CI): ≤4 serv/wk: 0.46 (0.21–1.03) vs. >4 serv/wk: 0.43 (0.06–3.27)]. No other dairy groups showed a significant association (HRs range: 0.53–1.47) with limited power (n, fractures=43).
Milk and yogurt intakes were associated with hip but not spine BMD, while cream may adversely influence BMD. Thus, not all dairy products are equally beneficial for the skeleton. Suggestive fracture results for milk and yogurt intakes need further confirmation.
PMCID: PMC3641848  PMID: 23371478
dairy; milk; yogurt; bone mineral density; hip fracture; dietary intake; bone health
4.  Heritability of Prevalent Vertebral Fracture and Volumetric Bone Mineral Density and Geometry at the Lumbar Spine in Three Generations of the Framingham Study 
Genetic factors likely contribute to the risk for vertebral fractures; however, there are few studies on the genetic contributions to vertebral fracture (VFrx), vertebral volumetric bone mineral density (vBMD) and geometry. Also the heritability (h2) for VFrx and its genetic correlation with phenotypes contributing to VFrx risk have not been established. This study aims to estimate the h2 of vertebral fracture, vBMD and cross-sectional-area (CSA) derived from quantitative computed tomography (QCT) scans, and to estimate the extent to which they share common genetic association in adults of European ancestry from three generations of Framingham Heart Study (FHS) families. Members of the FHS families were assessed for VFrx by lateral radiographs or QCT lateral scout views at 13 vertebral levels (T4-L4) using Genant’s semi-quantitative (SQ) scale (grades 0–3). Vertebral fracture was defined as having at least 25% reduction in height of any vertebra. We also analyzed QCT scans at the L3 level for integral (In.BMD) and trabecular (Tb.BMD) vBMD and cross-sectional area (CSA). Heritability estimates were calculated, and bivariate genetic correlation analysis was performed, adjusting for various covariates. For VFrx, we analyzed 4,099 individuals (148 VFrx cases) including 2,082 women and 2,017 men from 3 generations. Estimates of crude and multivariable-adjusted h2 were 0.43 to 0.69 (P< 1.1×10−2). 3,333 individuals including 1,737 men and 1,596 women from 2 generations had VFrx status and QCT-derived vBMD and CSA information. Estimates of crude and multivariable-adjusted h2 for vBMD and CSA ranged from 0.27 to 0.51. In a bivariate analysis, there was a moderate genetic correlation between VFrx and multivariable-adjusted In.BMD (−0.22) and Tb.BMD (−0.29). Our study suggests vertebral fracture, vertebral vBMD and CSA in adults of European ancestry are heritable, underscoring the importance of further work to identify the specific variants underlying genetic susceptibility to vertebral fracture, bone density and geometry.
PMCID: PMC3375687  PMID: 22222934
vertebral fracture; bone mineral density; heritability; QCT
5.  Genetic diversity is a predictor of mortality in humans 
BMC Genetics  2014;15(1):159.
It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.
We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person’s risk of death by 1.57%.
This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-014-0159-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4301661  PMID: 25543667
Heterozygosity; Human; Survival; GWAS
6.  Safety and severity of accelerations delivered from whole body vibration exercise devices to standing adults 
Whole Body Vibration (WBV) devices are used as a means to augment training, and their potential to treat a range of musculoskeletal diseases and injuries is now being considered. The goal of this work is to determine the degree to which acceleration delivered by WBV devices at the plantar surfaces of a standing human is transmitted through the axial and appendicular skeleton, and how this mechanical challenge corresponds to the safety Threshold Limit Values (TLV) established by the International Standards Organization ISO-2631.
Non-blinded laboratory assessment of a range of WBV devices as it pertains to acceleration transmission to healthy volunteers.
Using skin and bite-bar mounted accelerometers, transmissibility to the tibia and cranium was determined in six healthy adults standing on a programmable WBV device as a function of frequency and intensity. Measures of transmissibility were then made from three distinct types of WBV platforms, which delivered a 50-fold range of peak-to-peak acceleration intensities (0.3 to 15.1g p-p; where 1g is earth’s gravitational field).
For a given frequency, transmissibility was independent of intensity when below 1g. Transmissibility declined non-linearly with increasing frequency. Depending on the WBV device, vibration ranged from levels considered safe by ISO-2631 for up to eight hours each day (0.3gp-p @ 30Hz), to levels that were seven times higher than what is considered a safe threshold for even one minute of exposure each day (15.1g p-p @ 30Hz). Transmissibility to the cranium was markedly attenuated by the degree of flexion in the knees.
Vibration can have adverse effects on a number of physiologic systems. This work indicates that readily accessible WBV devices markedly exceed ISO guidelines for safety, and extreme caution must be practiced when considering their use.
PMCID: PMC3688642  PMID: 23453990
Back Pain; Muscle Strength; Rehabilitation; Physical Therapy; Injury; Sports Medicine
7.  Is Kyphosis Related to Mobility, Balance and Disability? 
To determine the association of increased kyphosis with declines in mobility, balance and disability among community-living older adults.
18-month follow-up visit data from 2006–2009 for 620 participants from the population-based MOBILIZE Boston Study of older adults was used. Cross-sectional multivariable regression analyses were performed to assess the relationship between kyphosis (measured using the kyphosis index (KI)) and measures of mobility performance (Short Physical Performance Battery (SPPB)), balance (Berg Balance Score (BBS)) and disability (self-reported difficulty walking a quarter-mile or climbing a flight of stairs). We then evaluated men and women separately. Adjustment variables included demographic factors (age, gender, race, education), body-mass index, self-rated health, comorbidities (heart disease, diabetes, stroke, depressive symptoms), back pain, knee pain and falls self-efficacy.
After full adjustment, greater KI was associated with lower SPPB scores (adj. β = −0.08, p = 0.01), but not BBS (adj. β = −0.09, p = 0.23) or self-reported disability (adj. β = 1.00, 95% CI, 0.93 –1.06). In gender-specific analyses, KI was only associated with SPPB in women.
Greater kyphosis is associated with poorer mobility performance, but not balance or self-reported disability. This association with SPPB was only observed among women. Mechanisms by which increased kyphosis influence physical performance should be explored prospectively.
PMCID: PMC3805732  PMID: 23636086
Kyphosis; Mobility; Balance; Disability
8.  Insights from the conduct of a device trial in older persons: Low Magnitude Mechanical Stimulation for Musculoskeletal Health 
Osteoporosis is a common complication of aging. Alternatives to pharmacologic treatment are needed for older adults. Non-pharmacologic treatment with low magnitude, high frequency mechanical stimulation has been shown to prevent bone loss in animal and human studies.
The VIBES (Vibration to Improve Bone Density in Elderly Subjects) study is a randomized, double-blind, sham-controlled trial of the efficacy of low magnitude, high frequency mechanical stimulation in 200 men and women aged 60 years and older with bone mineral density T-scores by dual-x-ray absorptiometry between –1 and –2.5 at entry. Participants are healthy, cognitively intact residents of independent living communities in the Boston area who receive free calcium and Vitamin D supplements. They are randomly assigned to active or sham treatment and stand on their assigned platform once daily for 10 minutes. All platforms have adherence data collection software downloadable to a laptop computer. Adverse events are closely monitored. 174 participants were randomized and will be followed for two years. Almost all active subjects have attained one year of follow-up. Bone mineral density is measured by both dual x-ray absorptiometry and quantitative computed tomography at baseline and annually. The main analysis will compare mean changes from baseline in volumetric bone density by quantitative computed tomography in active and sham groups. Adherence and treatment effect magnitude will also be evaluated. Secondary analyses will compare changes in three biochemical markers of bone turnover as well as longitudinal comparisons of muscle and balance endpoints.
The VIBES trial has completed its first year of data collection and encountered multiple challenges leading to valuable lessons learned about the areas of recruitment from independent living communities, deployment of multi-user mechanical devices using radio frequency identification cards and electronic adherence monitoring, organization of transportation for imaging at a central site, and the expansion of study aims to include additional musculoskeletal outcomes.
These lessons will guide future investigations in studies of individuals of advanced age.
PMCID: PMC3136380  PMID: 20571129
osteoporosis; BMD; balance; muscle mass; fractures; vibration; falls; bone; DXA; QCT
9.  Cross-Calibration and Comparison of Variability in Two Bone Densitometers in a Research Setting: The Framingham Experience 
New technology introduced over time results in changes in densitometers during longitudinal studies of bone mineral density (BMD). This requires that a cross-calibration process be completed to translate measurements from the old densitometer to the new one. Previously described cross-calibration methods for research settings have collected single measures on each densitometer and used linear regression to estimate cross-calibration corrections. Thus, these methods may produce corrections that have limited precision and underestimate the variability in converted BMD values. Furthermore, most prior studies have included small samples recruited from specialized populations. Increasing the sample size, obtaining multiple measures on each machine, and utilizing linear mixed models to account for between- and within-subject variability may improve cross-calibration estimates. The purpose of this study was to conduct an in vivo cross-calibration of a Lunar DPX-L with a Lunar Prodigy densitometer using a sample of 249 healthy volunteers who were scanned twice on each densitometer, without repositioning, at both the femur and spine. Scans were analyzed using both automated and manual placement of regions of interest. Wilcoxon rank-sum tests and Bland-Altman plots were used to examine possible differences between repeat scans within and across densitometers. We used linear mixed models to determine the cross-calibration equations for the femoral neck, trochanter, total hip and lumbar spine (L2-L4) regions. Results using automated and manual placement of the regions of interest did not differ significantly The DPX–L exhibited larger median absolute differences in repeat scans for femoral neck [0.016 vs. 0.012, p=0.1] and trochanter [0.011 vs. 0.009, p=0.06] BMD values compared to the Prodigy. The Bland-Altman plots revealed no statistically significant linear relation between the difference in paired measures between machines and mean BMD. In our large sample of healthy volunteers we did detect systematic differences between the DPX-L and Prodigy densitometers. Our proposed cross-calibration method, which includes acquiring multiple measures and using linear mixed models, provides researchers with a more realistic estimate of the variance of cross-calibrated BMD measures, potentially reducing the chance of making a type I error in longitudinal studies of changes in BMD.
PMCID: PMC2908922  PMID: 20347371
cross-calibration; densitometer; bone mineral density; DXA; mixed models; Framingham Osteoporosis Study
10.  Vertebral Size, Bone Density, and Strength in Men and Women Matched for Age and Areal Spine BMD 
To explore the possible mechanisms underlying sex-specific differences in skeletal fragility that may be obscured by two-dimensional areal bone mineral density (aBMD) measures, we compared quantitative computed tomography (QCT)-based vertebral bone measures among pairs of men and women from the Framingham Heart Study Multidetector Computed Tomography Study who were matched for age and spine aBMD. Measurements included vertebral body cross-sectional area (CSA, cm2), trabecular volumetric BMD (Tb.vBMD, g/cm3), integral volumetric BMD (Int.vBMD, g/cm3), estimated vertebral compressive loading and strength (Newtons) at L3, the factor-of-risk (load-to-strength ratio), and vertebral fracture prevalence. We identified 981 male-female pairs (1:1 matching) matched on age (± 1 year) and QCT-derived aBMD of L3 (± 1%), with an average age of 51 years (range 34 to 81 years). Matched for aBMD and age, men had 20% larger vertebral CSA, lower Int.vBMD (−8%) and Tb.vBMD (−9%), 10% greater vertebral compressive strength, 24% greater vertebral compressive loading, and 12% greater factor-of-risk than women (p < 0.0001 for all), as well as higher prevalence of vertebral fracture. After adjusting for height and weight, the differences in CSA and volumetric bone mineral density (vBMD) between men and women were attenuated but remained significant, whereas compressive strength was no longer different. In conclusion, vertebral size, morphology, and density differ significantly between men and women matched for age and spine aBMD, suggesting that men and women attain the same aBMD by different mechanisms. These results provide novel information regarding sex-specific differences in mechanisms that underlie vertebral fragility.
PMCID: PMC4149904  PMID: 23955966
11.  Adherence to Hip Protectors and Implications for U.S. Long-Term Care Settings 
Determine nursing home characteristics related to adherence to use of a hip protector (HP) to prevent fracture; also describe adherence and related resident characteristics.
A multi-center, randomized controlled trial of a HP in which adherence to wearing the HP was monitored by research staff three times a week for up to 21 months; data were collected by interviews and chart review.
Thirty-five nursing homes in Boston, St. Louis, and Baltimore.
A total of 797 eligible residents, 633 (79%) of whom passed the run-in period, 397 (63%) of whom remained in the study until the end of follow-up.
Residents wore a single HP on their right or left side.
In addition to regular monitoring of adherence, data were collected regarding facility characteristics, staffing, policies and procedures, perception of HPs and related experience, and research staff ratings of environmental and overall quality; and also resident demographic characteristics, and function, health, and psychosocial status.
Facility characteristics related to more adherence were not being chain-affiliated; less Medicaid case-mix; fewer residents wearing HPs; more paraprofessional staff training; more rotating workers; and having administrators who were less involved in meetings.
Efforts to increase adherence to the use of HPs should focus on facilities with more Medicaid case-mix to reduce disparities in care, and those that have less of a culture of training. Staff may need support to increase adherence, and when adherence cannot be maintained, HP use should be targeted to those who remain adherent.
PMCID: PMC2846526  PMID: 20142065
hip fracture; nursing homes; compliance
12.  Meta-Analysis of Genome-Wide Scans Provides Evidence for Sex- and Site-Specific Regulation of Bone Mass 
Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner.
BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied.
Materials and Methods
Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing.
For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct.
This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance.
PMCID: PMC4016811  PMID: 17228994
osteoporosis; BMD; linkage; meta-analysis; genome search; genome scan
13.  An Evidence-Based Comparison of Operational Criteria for the Presence of Sarcopenia 
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.
The FNIH Sarcopenia Project used data from nine studies including: Age, Gene and Environment Susceptibility-Reykjavik Study; Boston Puerto Rican Health Study; a series of six clinical trials from the University of Connecticut; Framingham Heart Study; Health, Aging, and Body Composition Study; Invecchiare in Chianti; Osteoporotic Fractures in Men Study; Rancho Bernardo Study; and Study of Osteoporotic Fractures. Participants included in these analyses were aged 65 and older and had measures of body mass index, appendicular lean mass, grip strength, and gait speed.
The prevalence of sarcopenia and agreement proportions was higher in women than men. The lowest prevalence was observed with the FNIH criteria (1.3% men and 2.3% women) compared with the International Working Group and the European Working Group for Sarcopenia in Older Persons (5.1% and 5.3% in men and 11.8% and 13.3% in women, respectively). The positive percent agreements between the FNIH criteria and other criteria were low, ranging from 7% to 32% in men and 5% to 19% in women. However, the negative percent agreement were high (all >95%).
The FNIH criteria result in a more conservative operational definition of sarcopenia, and the prevalence was lower compared with other proposed criteria. Agreement for diagnosing sarcopenia was low, but agreement for ruling out sarcopenia was very high. Consensus on the operational criteria for the diagnosis of sarcopenia is much needed to characterize populations for study and to identify adults for treatment.
PMCID: PMC3991139  PMID: 24737561
Muscle; Sarcopenia; Lean mass.
14.  Criteria for Clinically Relevant Weakness and Low Lean Mass and Their Longitudinal Association With Incident Mobility Impairment and Mortality: The Foundation for the National Institutes of Health (FNIH) Sarcopenia Project 
This analysis sought to determine the associations of the Foundation for the National Institutes of Health Sarcopenia Project criteria for weakness and low lean mass with likelihood for mobility impairment (gait speed ≤ 0.8 m/s) and mortality. Providing validity for these criteria is essential for research and clinical evaluation.
Among 4,411 men and 1,869 women pooled from 6 cohort studies, 3-year likelihood for incident mobility impairment and mortality over 10 years were determined for individuals with weakness, low lean mass, and for those having both. Weakness was defined as low grip strength (<26kg men and <16kg women) and low grip strength-to-body mass index (BMI; kg/m2) ratio (<1.00 men and <0.56 women). Low lean mass (dual-energy x-ray absorptiometry) was categorized as low appendicular lean mass (ALM; <19.75kg men and <15.02kg women) and low ALM-to-BMI ratio (<0.789 men and <0.512 women).
Low grip strength (men: odds ratio [OR] = 2.31, 95% confidence interval [CI] = 1.34–3.99; women: OR = 1.99, 95% CI 1.23–3.21), low grip strength-to-BMI ratio (men: OR = 3.28, 95% CI 1.92–5.59; women: OR = 2.54, 95% CI 1.10–5.83) and low ALM-to-BMI ratio (men: OR = 1.58, 95% CI 1.12–2.25; women: OR = 1.81, 95% CI 1.14–2.87), but not low ALM, were associated with increased likelihood for incident mobility impairment. Weakness increased likelihood of mobility impairment regardless of low lean mass. Mortality risk patterns were inconsistent.
These findings support our cut-points for low grip strength and low ALM-to-BMI ratio as candidate criteria for clinically relevant weakness and low lean mass. Further validation in other populations and for alternate relevant outcomes is needed.
PMCID: PMC3991140  PMID: 24737560
Muscle; Sarcopenia; Mobility; Impairment.
15.  Cutpoints for Low Appendicular Lean Mass That Identify Older Adults With Clinically Significant Weakness 
Low lean mass is potentially clinically important in older persons, but criteria have not been empirically validated. As part of the FNIH (Foundation for the National Institutes of Health) Sarcopenia Project, this analysis sought to identify cutpoints in lean mass by dual-energy x-ray absorptiometry that discriminate the presence or absence of weakness (defined in a previous report in the series as grip strength <26kg in men and <16kg in women).
In pooled cross-sectional data stratified by sex (7,582 men and 3,688 women), classification and regression tree (CART) analysis was used to derive cutpoints for appendicular lean body mass (ALM) that best discriminated the presence or absence of weakness. Mixed-effects logistic regression was used to quantify the strength of the association between lean mass category and weakness.
In primary analyses, CART models identified cutpoints for low lean mass (ALM <19.75kg in men and <15.02kg in women). Sensitivity analyses using ALM divided by body mass index (BMI: ALMBMI) identified a secondary definition (ALMBMI <0.789 in men and ALMBMI <0.512 in women). As expected, after accounting for study and age, low lean mass (compared with higher lean mass) was associated with weakness by both the primary (men, odds ratio [OR]: 6.9 [95% CI: 5.4, 8.9]; women, OR: 3.6 [95% CI: 2.9, 4.3]) and secondary definitions (men, OR: 4.3 [95% CI: 3.4, 5.5]; women, OR: 2.2 [95% CI: 1.8, 2.8]).
ALM cutpoints derived from a large, diverse sample of older adults identified lean mass thresholds below which older adults had a higher likelihood of weakness.
PMCID: PMC3991141  PMID: 24737559
Muscle; Sarcopenia; Cutpoints.
16.  The FNIH Sarcopenia Project: Rationale, Study Description, Conference Recommendations, and Final Estimates 
Low muscle mass and weakness are common and potentially disabling in older adults, but in order to become recognized as a clinical condition, criteria for diagnosis should be based on clinically relevant thresholds and independently validated. The Foundation for the National Institutes of Health Biomarkers Consortium Sarcopenia Project used an evidence-based approach to develop these criteria. Initial findings were presented at a conference in May 2012, which generated recommendations that guided additional analyses to determine final recommended criteria. Details of the Project and its findings are presented in four accompanying manuscripts.
The Foundation for the National Institutes of Health Sarcopenia Project used data from nine sources of community-dwelling older persons: Age, Gene/Environment Susceptibility-Reykjavik Study, Boston Puerto Rican Health Study, a series of six clinical trials, Framingham Heart Study, Health, Aging, and Body Composition, Invecchiare in Chianti, Osteoporotic Fractures in Men Study, Rancho Bernardo Study, and Study of Osteoporotic Fractures. Feedback from conference attendees was obtained via surveys and breakout groups.
The pooled sample included 26,625 participants (57% women, mean age in men 75.2 [±6.1 SD] and in women 78.6 [±5.9] years). Conference attendees emphasized the importance of evaluating the influence of body mass on cutpoints. Based on the analyses presented in this series, the final recommended cutpoints for weakness are grip strength <26kg for men and <16kg for women, and for low lean mass, appendicular lean mass adjusted for body mass index <0.789 for men and <0.512 for women.
These evidence-based cutpoints, based on a large and diverse population, may help identify participants for clinical trials and should be evaluated among populations with high rates of functional limitations.
PMCID: PMC3991146  PMID: 24737557
Aging; Sarcopenia; Muscle; Outcomes; Weakness.
17.  Grip Strength Cutpoints for the Identification of Clinically Relevant Weakness 
Weakness is common and contributes to disability, but no consensus exists regarding a strength cutpoint to identify persons at high risk. This analysis, conducted as part of the Foundation for the National Institutes of Health Sarcopenia Project, sought to identify cutpoints that distinguish weakness associated with mobility impairment, defined as gait speed less than 0.8 m/s.
In pooled cross-sectional data (9,897 men and 10,950 women), Classification and Regression Tree analysis was used to derive cutpoints for grip strength associated with mobility impairment.
In men, a grip strength of 26–32 kg was classified as “intermediate” and less than 26 kg as “weak”; 11% of men were intermediate and 5% were weak. Compared with men with normal strength, odds ratios for mobility impairment were 3.63 (95% CI: 3.01–4.38) and 7.62 (95% CI 6.13–9.49), respectively. In women, a grip strength of 16–20 kg was classified as “intermediate” and less than 16 kg as “weak”; 25% of women were intermediate and 18% were weak. Compared with women with normal strength, odds ratios for mobility impairment were 2.44 (95% CI 2.20–2.71) and 4.42 (95% CI 3.94–4.97), respectively. Weakness based on these cutpoints was associated with mobility impairment across subgroups based on age, body mass index, height, and disease status. Notably, in women, grip strength divided by body mass index provided better fit relative to grip strength alone, but fit was not sufficiently improved to merit different measures by gender and use of a more complex measure.
Cutpoints for weakness derived from this large, diverse sample of older adults may be useful to identify populations who may benefit from interventions to improve muscle strength and function.
PMCID: PMC3991145  PMID: 24737558
Muscle; Sarcopenia; Grip strength; Physical function; Gait speed.
18.  Genetic Variation at the Low Density Lipoprotein Receptor-Related Protein 5 (LRP5) Locus Modulates Wnt Signaling and the Relationship of Physical Activity with Bone Mineral Density in Men 
Bone  2006;40(3):587-596.
Polymorphisms in the LRP5 gene have been associated with bone mineral density (BMD) in men and/or women. However, the functional basis for this association remains obscure. We hypothesized that LRP5 alleles could modulate Wnt signaling and the relationship between physical activity and BMD.
This genetic association study was performed in the population-based Framingham Study Offspring Cohort, and included a subset of 1797 unrelated individuals who provided blood samples for DNA and who had BMD measurements of the hip and spine. Ten single-nucleotide polymorphisms (SNPs) spanning the LRP5 gene were genotyped and used for association and interaction analyses with BMD by regression methods. LRP5 haplotypes were transiently co-expressed with Wnt3a, MesD and Dkk1 in HEK293 cells and their activity evaluated by the TCF-Lef reporter assay.
Six out of ten SNPs in LRP5 were associated with one or more of the femur or spine BMDs in men or women after adjustment for covariates, and these associations differed between genders. In men ≤age 60 years, 3 SNPs were significantly associated with BMD: rs2306862 on Exon 10 with femoral neck BMD (p=0.01) and Ward’s BMD (p=0.01); rs4988321/p. V667M with Ward’s BMD (p=0.02); and intronic rs901825 with trochanter BMD (p=0.03). In women, 3 SNPs in intron 2 were significantly associated with BMD: rs4988330 for trochanter (p=0.01) and spine BMD (p=0.003); rs312778 with femoral neck BMD (p=0.05); and rs4988331 with spine BMD (p=0.04). For each additional rare allele, BMD changed by 3–5% in males and 2–4% in females. Moreover, there was a significant interaction between physical activity and rs2306862 in exon 10 (p for interaction=0.02) and rs3736228/p. A1330V in exon 18 (p for interaction=0.05) on spine BMD in men. In both cases, the TT genotype was associated with lower BMD in men with higher physical activity scores, conversely with higher BMD in men with lower physical activity scores. In vitro, TCF-Lef activity in presence of Wnt3a was significantly reduced in cells expressing LRP5 haplotypes carrying the T allele of exon 10 and 18 compared to the wild-type allele, whereas co-expression of Dkk1 completely inhibited Wnt3a response through all LRP5 haplotypes.
In summary, genetic variation in exons 10 and 18 of the LRP5 gene modulates Wnt signaling and the relationship between physical activity and BMD in men. These observations suggest that Wnt-LRP5 may play a role in the adaptation of bone to mechanical load in humans, and may explain some gender-related differences in bone mass.
PMCID: PMC1845172  PMID: 17137849
19.  Variations of CT-Based Trunk Muscle Attenuation by Age, Sex, and Specific Muscle 
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.
PMCID: PMC3605905  PMID: 22904095
Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous SNPs of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n= 4,061 women, ages 20 to 45) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. Following imputation, age- and weight-adjusted BMD values were tested for association with each SNP. Association of a SNP in the WNT16 gene (rs3801387; p=1.7 × 10−9) and multiple SNPs in the ESR1/C6orf97 (rs4870044; p=1.3 × 10−8) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven Replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n=5,597 for femoral neck; 4,744 for lumbar spine). When the data from the Discovery and Replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p=1.3 × 10−11; ESR1/C6orf97 joint p= 1.4 × 10−10). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p< 1 × 10−5). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period.
PMCID: PMC3691010  PMID: 23074152
Bone mineral density; GWAS; premenopausal; meta-analysis; genetics
21.  Sarcopenia Definitions Considering Body Size and Fat Mass Are Associated With Mobility Limitations: The Framingham Study 
Sarcopenia defined by lean mass has been inconsistently associated with disability in elders. Studies suggest that definitions should consider body size and additional influences of high fat mass (FM; sarcopenic-obesity). We examined sarcopenia accounting for body size, and sarcopenic-obesity, in relation to mobility limitations among 767 elderly men and women (mean age 79 years) from the Framingham Study.
Whole-body dual-energy x-ray absorptiometry measured appendicular lean mass (ALM) and total FM in 1992–1995. Sarcopenia was defined in two ways: ALM/height squared (ALM/ht2) and ALM adjusted for height and FM (residuals). Sarcopenic-obesity categories (referent, obese, sarcopenic, and sarcopenic-obese) were defined by cross-classifying ALM/ht2 and obesity (% body fat: more than 30 for men and more than 40 for women). Mobility limitation was defined as self-reported inability to walk one-half mile, climb stairs, or perform heavy housework. Sex-specific logistic regression calculated odds ratios (OR) and 95% confidence intervals (CI) for mobility limitation, adjusting for covariates.
Sixteen percent of men and 30% of women had mobility limitation. Among men, both ALM/ht2 (OR = 6.3, 95% CI = 2.5–16.1) and residuals (OR = 4.6, 95% CI = 2.0–10.5) sarcopenia were associated with increased limitation. For sarcopenic-obesity, odds of limitation was higher in sarcopenic (OR = 6.1, 95% CI = 2.2–16.9) and sarcopenic-obese categories (OR = 3.5, 95% CI = 1.0–12.7) but suggested no synergistic effect. In women, only residuals sarcopenia was associated with higher odds of limitation (OR = 1.8, 95% CI = 1.2–2.9).
Low lean mass is associated with mobility limitations after accounting for body size and fat, and lean and FM have independent effects on mobility in elders. These findings support previous reports that sarcopenia definitions should consider body size and fat.
PMCID: PMC3598358  PMID: 22503991
Sarcopenia; Lean mass; Disability
22.  Repeat Bone Mineral Density Screening and Prediction of Hip and Major Osteoporotic Fracture 
Screening for osteoporosis with bone mineral density (BMD) is recommended for older adults. It is unclear whether repeating a BMD screening test improves fracture risk assessment.
To determine whether changes in BMD after 4 years provide additional information on fracture risk beyond baseline BMD and to quantify the change in fracture risk classification after a second BMD measure.
Population-based cohort study involving 310 men and 492 women from the Framingham Osteoporosis Study with 2 measures of femoral neck BMD taken from 1987 through 1999.
Risk of hip or major osteoporotic fracture through 2009 or 12 years following the second BMD measure.
Mean age was 74.8 years. The mean (SD) BMD change was −0.6% per year (1.8%). Throughout a median follow-up of 9.6 years, 76 participants experienced an incident hip fracture and 113 participants experienced a major osteoporotic fracture. Annual percent BMD change per SD decrease was associated with risk of hip fracture (hazard ratio [HR], 1.43 [95% CI, 1.16 to 1.78]) and major osteoporotic fracture (HR, 1.21 [95% CI, 1.01 to 1.45]) after adjusting for baseline BMD. At 10 years’ follow-up, 1 SD decrease in annual percent BMD change compared with the mean BMD change was associated with 3.9 excess hip fractures per 100 persons. In receiver operating characteristic (ROC) curve analyses, the addition of BMD change to a model with baseline BMD did not meaningfully improve performance. The area under the curve (AUC) was 0.71 (95% CI, 0.65 to 0.78) for the baseline BMD model compared with 0.68 (95% CI, 0.62 to 0.75) for the BMD percent change model. Moreover, the addition of BMD change to a model with baseline BMD did not meaningfully improve performance (AUC, 0.72 [95% CI, 0.66 to 0.79]). Using the net reclassification index, a second BMD measure increased the proportion of participants reclassified as high risk of hip fracture by 3.9% (95% CI, −2.2% to 9.9%), whereas it decreased the proportion classified as low risk by −2.2% (95% CI, −4.5% to 0.1%).
In untreated men and women of mean age 75 years, a second BMD measure after 4 years did not meaningfully improve the prediction of hip or major osteoporotic fracture. Repeating a BMD measure within 4 years to improve fracture risk stratification may not be necessary in adults this age untreated for osteoporosis.
PMCID: PMC3903386  PMID: 24065012
23.  Correlations of Clinical and Laboratory Measures of Balance in Older Men and Women: The MOBILIZE Boston Study 
Arthritis care & research  2012;64(12):1895-1902.
Impaired balance is associated with falls in older adults. However, there is no accepted gold standard on how balance should be measured. Few studies have examined measures of postural sway and clinical balance concurrently in large samples of community-dwelling older adults. We examined the associations among four types of measures of laboratory- and clinic-based balance in a large population-based cohort of older adults.
We evaluated balance measures in the MOBILIZE Boston Study (276 men, 489 women, 64–97 years). Measures included: (1) laboratory-based anteroposterior (AP) path length and average sway speed, mediolateral (ML) average sway and root-mean-square, and area of ellipse postural sway; (2) Short Physical Performance Battery (SPPB); (3) Berg Balance Scale; and (4) one-leg stand. Spearman Rank Correlation Coefficients (r) were assessed among the balance measures.
Area of ellipse sway was highly correlated with the ML sway measures (r >0.9, p < 0.0001), and sway speed was highly correlated with AP sway (r=0.97, p < 0.0001). The Berg Balance Scale was highly correlated with SPPB (r=0.7, p<0.001), and one-leg stand (r=0.8, p<0.001). Correlations between the laboratory- and clinic-based balance measures were low but statistically significant (0.2 < r < 0.3, p<0.0001).
Clinic-based balance measures, and laboratory-based measures comparing area of ellipse with ML sways or sway speed with AP sway, are highly correlated. Clinic- with laboratory-based measures are less correlated. As both laboratory- and clinic-based measures inform balance in older adults but are not highly correlated with each other, future work should investigate the differences.
PMCID: PMC3467339  PMID: 22745045
24.  Procollagen type III N-terminal peptide (P3NP) and lean mass: a cross-sectional study 
Procollagen type III N-terminal peptide (P3NP) is released during collagen synthesis in muscle. Increased circulating P3NP is a marker not only of muscle growth, but also of muscle repair and fibrosis. Thus, P3NP may be a potential biomarker for sarcopenia.
To determine the association between plasma P3NP and lean mass and strength
Design, Setting, and Participants
A cross-sectional study of men and women from the Framingham Offspring Study. Participants included a convenience sample of 687 members with a measure of plasma P3NP and lean mass, and 806 members with P3NP and quadriceps strength assessment.
Linear regression was used to estimate the association between total and appendicular lean mass and plasma P3NP, and quadriceps strength and P3NP
Mean age was 58 years. Median plasma P3NP was similar in men (3.4 mg/L), premenopausal women (3.1 mg/L), and postmenopausal women (3.0 mg/L). In adjusted models, higher P3NP was associated with a modest decrease in total and appendicular lean mass in postmenopausal women [β= −0.13 unit P3NP/kg total lean mass; p=0.003]. A similar trend was found among premenopausal women, although results were not statistically significant [β=−0.10 unit P3NP/kg total lean mass; p=0.41]. No association between P3NP and lean mass was observed in men. P3NP was not associated with strength in men or women.
Our results suggest that plasma P3NP might be a useful biomarker of muscle mass in postmenopausal women if longitudinal studies demonstrate that it has adequate sensitivity and specificity to predict muscle loss.
PMCID: PMC3828748  PMID: 24244927
procollagen type III N-telopeptide; P3NP; lean mass
25.  Assessment of Gene-by-Sex Interaction Effect on Bone Mineral Density 
Liu, Ching-Ti | Estrada, Karol | Yerges-Armstrong, Laura M. | Amin, Najaf | Evangelou, Evangelos | Li, Guo | Minster, Ryan L. | Carless, Melanie A. | Kammerer, Candace M. | Oei, Ling | Zhou, Yanhua | Alonso, Nerea | Dailiana, Zoe | Eriksson, Joel | García-Giralt, Natalia | Giroux, Sylvie | Husted, Lise Bjerre | Khusainova, Rita I. | Koromila, Theodora | Kung, Annie WaiChee | Lewis, Joshua R. | Masi, Laura | Mencej-Bedrac, Simona | Nogues, Xavier | Patel, Millan S. | Prezelj, Janez | Richards, J Brent | Sham, Pak Chung | Spector, Timothy | Vandenput, Liesbeth | Xiao, Su-Mei | Zheng, Hou-Feng | Zhu, Kun | Balcells, Susana | Brandi, Maria Luisa | Frost, Morten | Goltzman, David | González-Macías, Jesús | Karlsson, Magnus | Khusnutdinova, Elza K. | Kollia, Panagoula | Langdahl, Bente Lomholt | Ljunggren, Östen | Lorentzon, Mattias | Marc, Janja | Mellström, Dan | Ohlsson, Claes | Olmos, José M. | Ralston, Stuart H. | Riancho, José A. | Rousseau, François | Urreizti, Roser | Van Hul, Wim | Zarrabeitia, María T. | Castano-Betancourt, Martha | Demissie, Serkalem | Grundberg, Elin | Herrera, Lizbeth | Kwan, Tony | Medina-Gómez, Carolina | Pastinen, Tomi | Sigurdsson, Gunnar | Thorleifsson, Gudmar | vanMeurs, Joyce B.J. | Blangero, John | Hofman, Albert | Liu, Yongmei | Mitchell, Braxton D. | O’Connell, Jeffrey R. | Oostra, Ben A. | Rotter, Jerome I | Stefansson, Kari | Streeten, Elizabeth A. | Styrkarsdottir, Unnur | Thorsteinsdottir, Unnur | Tylavsky, Frances A. | Uitterlinden, Andre | Cauley, Jane A. | Harris, Tamara B. | Ioannidis, John P.A. | Psaty, Bruce M. | Robbins, John A | Zillikens, M. Carola | vanDuijn, Cornelia M. | Prince, Richard L. | Karasik, David | Rivadeneira, Fernando | Kiel, Douglas P. | Cupples, L. Adrienne | Hsu, Yi-Hsiang
Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed eQTL analysis and bioinformatics network analysis.
We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS-) and femoral neck (FN-) BMD, in 25,353 individuals from eight cohorts. In a second stage, we followed up the 12 top SNPs (P<1×10−5) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs.
We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 & p-value = 3.0×10−5; female effect = −0.007 & p-value=3.3×10−2) and eleven suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (P<5×10−8) gene-by-sex interaction in the joint analysis of discovery and replication cohorts.
Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found influencing BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP.
PMCID: PMC3447125  PMID: 22692763
gene-by-sex; interaction; BMD; association; aging

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