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1.  Variations of CT-Based Trunk Muscle Attenuation by Age, Sex, and Specific Muscle 
Background.
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.
Methods.
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.
Results.
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.
Conclusions.
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.
doi:10.1093/gerona/gls168
PMCID: PMC3605905  PMID: 22904095
2.  Sarcopenia Definitions Considering Body Size and Fat Mass Are Associated With Mobility Limitations: The Framingham Study 
Background.
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.
Methods.
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.
Results.
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).
Conclusions.
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.
doi:10.1093/gerona/gls109
PMCID: PMC3598358  PMID: 22503991
Sarcopenia; Lean mass; Disability
3.  Repeat Bone Mineral Density Screening and Prediction of Hip and Major Osteoporotic Fracture 
IMPORTANCE
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.
OBJECTIVES
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.
DESIGN, SETTING, AND PARTICIPANTS
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.
MAIN OUTCOMES AND MEASURES
Risk of hip or major osteoporotic fracture through 2009 or 12 years following the second BMD measure.
RESULTS
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%).
CONCLUSIONS AND RELEVANCE
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.
doi:10.1001/jama.2013.277817
PMCID: PMC3903386  PMID: 24065012
4.  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.
Purpose
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1007/s11657-013-0119-2
PMCID: PMC3641848  PMID: 23371478
dairy; milk; yogurt; bone mineral density; hip fracture; dietary intake; bone health
5.  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.
Objective
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1002/acr.21783
PMCID: PMC3467339  PMID: 22745045
6.  Procollagen type III N-terminal peptide (P3NP) and lean mass: a cross-sectional study 
Background
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.
Objective
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.
Measurements
Linear regression was used to estimate the association between total and appendicular lean mass and plasma P3NP, and quadriceps strength and P3NP
Results
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.
Conclusion
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
7.  Dynamic Parameters of Balance Which Correlate to Elderly Persons with a History of Falls 
PLoS ONE  2013;8(8):e70566.
Poor balance in older persons contributes to a rise in fall risk and serious injury, yet no consensus has developed on which measures of postural sway can identify those at greatest risk of falling. Postural sway was measured in 161 elderly individuals (81.8y±7.4), 24 of which had at least one self-reported fall in the prior six months, and compared to sway measured in 37 young adults (34.9y±7.1). Center of pressure (COP) was measured during 4 minutes of quiet stance with eyes opened. In the elderly with fall history, all measures but one were worse than those taken from young adults (e.g., maximal COP velocity was 2.7× greater in fallers than young adults; p<0.05), while three measures of balance were significantly worse in fallers as compared to older persons with no recent fall history (COP Displacement, Short Term Diffusion Coefficient, and Critical Displacement). Variance of elderly subjects' COP measures from the young adult cohort were weighted to establish a balance score (“B-score”) algorithm designed to distinguish subjects with a fall history from those more sure on their feet. Relative to a young adult B-score of zero, elderly “non-fallers” had a B-score of 0.334, compared to 0.645 for those with a fall history (p<0.001). A weighted amalgam of postural sway elements may identify individuals at greatest risk of falling, allowing interventions to target those with greatest need of attention.
doi:10.1371/journal.pone.0070566
PMCID: PMC3734288  PMID: 23940592
8.  The Hip Impact Protection Project: Design and Methods 
Background
Nearly 340,000 hip fractures occur each year in the U.S. With current demographic trends, the number of hip fractures is expected to double at least in the next 40 years.
Purpose
The Hip Impact Protection Project (HIP PRO) was designed to investigate the efficacy and safety of hip protectors in an elderly nursing home population. This paper describes the innovative clustered matched-pair research design used in HIP PRO to overcome the inherent limitations of clustered randomization.
Methods
Three clinical centers recruited 37 nursing homes to participate in HIP PRO. They were randomized so that the participating residents in that home received hip protectors for either the right or left hip. Informed consent was obtained from either the resident or the resident's responsible party. The target sample size was 580 residents with replacement if they dropped out, had a hip fracture, or died. One of the advantages of the HIP PRO study design was that each resident was his/her own case and control, eliminating imbalances, and there was no confusion over which residents wore pads (or on which hip).
Limitations
Generalizability of the findings may be limited. Adherence was higher in this study than in other studies because of: (1) the use of a run-in period, (2) staff incentives, and (3) the frequency of adherence assessments. The use of a single pad is not analogous to pad use in the real world and may have caused unanticipated changes in behavior. Fall assessment was not feasible, limiting the ability to analyze fractures as a function of falls. Finally, hip protector designs continue to evolve so that the results generated using this pad may not be applicable to other pad designs. However, information about factors related to adherence will be useful for future studies.
Conclusions
The clustered matched-pair study design avoided the major problem with previous cluster-randomized investigations of this question – unbalanced risk factors between the experimental group and the control group. Because each resident served as his/her own control, the effects of unbalanced risk factors on treatment effect were virtually eliminated. In addition, the use of frequent adherence assessments allowed us to study the effect of various demographic and environmental factors on adherence, which was vital for the assessment of efficacy.
doi:10.1177/1740774508095120
PMCID: PMC3725461  PMID: 18697849
9.  Genetic variation in TRPS1 may regulate hip geometry as well as bone mineral density 
Bone  2012;50(5):1188-1195.
Trps1 has been proposed as a candidate gene for a mouse bone mineral density (BMD) QTL on Chromosome (Chr) 15, but it remained unclear if this gene was associated with BMD in humans. We used newly available data and advanced bioinformatics techniques to confirm that Trps1 is the most likely candidate gene for the mouse QTL. In short, by combining the raw genetic mapping data from two F2 generation crosses of inbred strains of mice, we narrowed the 95% confidence interval of this QTL down to the Chr 15 region spanning from 6 to 24 cM. This region contains 131 annotated genes. Using block haplotyping, all other genes except Trps1 were eliminated as candidates for this QTL. We then examined associations of 208 SNPs within 10kb of TRPS1 with BMD and hip geometry, using human genome-wide association study (GWAS) data from the GEFOS consortium. After correction for multiple testing, six TRPS1 SNPs were significantly associated with femoral neck BMD (P=0.0015–0.0019; adjusted P=0.038–0.048). We also found that three SNPs were highly associated with femoral neck width in women (rs10505257, P = 8.6x10−5, adjusted P=2.15x10−3; rs7002384, P = 5.5x10−4, adjusted P=01.38x10−2). In conclusion, we demonstrated that combining association studies in humans with murine models provides an efficient strategy to identify new candidate genes for bone phenotypes.
doi:10.1016/j.bone.2012.01.011
PMCID: PMC3322322  PMID: 22306695
Trichorhinophalangeal syndrome I; mouse models; human genetic association study; bone mineral density
10.  New loop diuretic prescriptions may be an acute risk factor for falls in the nursing home 
Purpose
Although chronic use of diuretics has been implicated as a risk factor for falls, it is unknown whether changes in diuretic drugs are associated with an acutely elevated risk of falls. We evaluated the relationship between change in a diuretic prescription (new prescription or increased dose) and the occurrence of documented falls among nursing home residents.
Methods
Participants of the cohort were 1,785 long term care residents of two, large nursing homes (2005–2010; Boston, MA). A self-matched, case-crossover analysis was used to examine whether there is an acutely increased risk of falling in the day following a diuretic drug change compared to days without a diuretic drug change. Odds ratios with 95% confidence intervals were calculated using conditional logistic regression models.
Results
During a mean follow-up of 8.4 months, 1,181 participants experienced an incident fall. Nine participants experienced a diuretic change on the day before the fall. The odds of falling one day following a change in a diuretic was elevated (OR: 2.08, 95% CI 0.89, 4.86). The association was stronger and reached nominal statistical significance when loop diuretics were examined separately (OR: 2.46, 95% CI 1.02, 5.92). We estimated that for every 271 loop diuretic drug changes, one excess fall occurred.
Conclusions
Nursing home residents are at an increased risk of falls in the day following a new prescription or increased dose of a loop diuretic drug. Extra precautions should be taken immediately following a loop diuretic drug change in an effort to prevent falls.
doi:10.1002/pds.3256
PMCID: PMC3330142  PMID: 22422651
diuretic; fall; nursing home
11.  A Polymorphism in a Gene Encoding Perilipin 4 Is Associated with Height but not with Bone Measures in Individuals from the Framingham Osteoporosis Study 
Calcified tissue international  2011;90(2):96-107.
There is increasing interest in identifying new pathways and candidate genes that confer susceptibility to osteoporosis. There is evidence that adipogenesis and osteogenesis may be related, including a common bone marrow progenitor cell for both adipocytes and osteoblasts. Perilipin 1 (PLIN1) and Perilipin 4 (PLIN4) are members of the PATS family of genes and are involved in lipolysis of intracellular lipid deposits. A previous study reported gender-specific associations between one polymorphism of PLIN1 and bone mineral density (BMD) in a Japanese population. We hypothesized that polymorphisms in PLIN1 and PLIN4 would be associated with bone measures in adult Caucasian participants of the Framingham Osteoporosis Study (FOS). We genotyped 1,206 male and 1,445 female participants of the FOS for four single-nucleotide polymorphism (SNPs) in PLIN1 and seven SNPs in PLIN4 and tested for associations with measures of BMD, bone ultrasound, hip geometry, and height. We found several gender-specific significant associations with the measured traits. The association of PLIN4 SNP rs8887, G>A with height in females trended toward significance after simulation testing (adjusted P = 0.07) and remained significant after simulation testing in the combined-sex model (adjusted P = 0.033). In a large study sample of men and women, we found a significant association between one SNP in PLIN4 and height but not with bone traits, suggesting that PATS family genes are not important in the regulation of bone. Identification of genes that influence human height may lead to a better understanding of the processes involved in growth and development.
doi:10.1007/s00223-011-9552-7
PMCID: PMC3628693  PMID: 22210160
Perilipin 1; Perilipin 4; Bone mineral density; Bone geometry; Framingham Osteoporosis Study
12.  Forum on Aging and Skeletal Health: Summary of the Proceedings of an ASBMR Workshop 
With the aging of the population, the scope of the problem of age-related bone loss and osteoporosis will continue to increase. As such, it is critical to obtain a better understanding of the factors determining the acquisition and loss of bone mass, from childhood to senescence. While there have been significant advances in recent years in our understanding of both the basic biology of aging and a clinical definition of age-related frailty, few of these concepts in aging research have been adequately evaluated for their relevance and application to skeletal aging or fracture prevention. The March 2011 “Forum on Aging and Skeletal Health”, sponsored by the NIH and ASBMR, sought to bring together leaders in aging and bone research to enhance communications among diverse fields of study so as to accelerate the pace of scientific advances needed to reduce the burden of osteoporotic fractures. This report summarizes the major concepts presented at this meeting and in each area, identifies key questions to help set the agenda for future research in skeletal aging.
doi:10.1002/jbmr.488
PMCID: PMC3625440  PMID: 21915901
Aging; growth and development; menopause
13.  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.
doi:10.1002/jbmr.1537
PMCID: PMC3375687  PMID: 22222934
vertebral fracture; bone mineral density; heritability; QCT
14.  Diuretic Initiation and the Acute Risk of Hip Fracture 
Purpose
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.
Methods
The study sample included 2, 118, 793 persons aged ≥ 50 years enrolled in The Health Improvement Network (THIN) between 1986–2010. 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.
Results
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.
Conclusions
The risk of hip fracture was transiently elevated around two-fold 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.
doi:10.1007/s00198-012-2053-3
PMCID: PMC3594771  PMID: 22790610
loop diuretic; thiazide diuretic; hip fracture; acute risk
15.  Re-evaluating the Implications of Recurrent Falls in Older Adults: Location Changes the Inference 
OBJECTIVE
To compare characteristics of indoor and outdoor recurrent fallers and explore some implications for clinical practice, in which a fall risk assessment for all recurrent fallers has been recommended.
DESIGN
Prospective cohort study.
SETTING
MOBILIZE Boston, a study of falls etiology among community-dwelling older individuals from randomly sampled households in the Boston MA area.
PARTICIPANTS
713 women and men, mainly of age 70 years and older, with at least one year of follow-up.
MEASUREMENTS
Data at baseline and an 18-month follow-up examination were collected by questionnaire and comprehensive clinic examination. During follow-up participants recorded falls on daily calendars. A telephone interview queried location and circumstances of each fall.
RESULTS
145 participants reported recurrent falls (≥ 2 falls) during the first year. Those who had fallen only outdoors had good health characteristics, whereas those who had fallen only indoors were generally in poor health. For instance, 25.5% of indoor-only recurrent fallers had gait speeds < 0.6 meters/second compared to 2.9% among outdoor-only recurrent fallers; the respective percentages were 44.7% and 8.8% for Berg balance score < 48. Recurrent indoor fallers generally had poor health characteristics regardless of their activity at the time of their falls, whereas recurrent outdoor fallers who fell during vigorous activity or walking were especially healthy. A report of any recurrent falls in the first year did not predict number of positive findings on either a comprehensive or abbreviated fall risk assessment at the 18-month follow-up examination.
CONCLUSION
Characteristics of community-dwelling older people with recurrent indoor and outdoor falls are very different. If confirmed, these results suggest that different types of fall risk assessment are needed for specific categories of recurrent fallers.
doi:10.1111/j.1532-5415.2011.03834.x
PMCID: PMC3302971  PMID: 22283236
recurrent falls; risk factors; aging research; fall risk assessment
16.  Plasma Phosphatidylcholine Concentrations of Polyunsaturated Fatty Acids Are Differentially Associated With Hip Bone Mineral Density and Hip Fracture in Older Adults: The Framingham Osteoporosis Study 
Polyunsaturated fatty acids (PUFAs) may influence bone health. The objective of this work was to examine associations between plasma phosphatidylcholine (PC) PUFA concentrations and hip measures: (1) femoral neck bone mineral density (FN-BMD) (n = 765); (2) 4-year change in FN-BMD (n = 556); and (3) hip fracture risk (n = 765) over 17-year follow-up among older adults in the Framingham Osteoporosis Study. BMD measures were regressed on quintile of plasma PC PUFAs (docosahexaenoic acid [DHA], linoleic acid [LA], and arachidonic acid [AA]), adjusted for covariates. Hazard ratios (HR) and 95% confidence interval (CI) for hip fracture were estimated by quintile of plasma PC PUFAs, adjusted for covariates. Higher concentrations of PC DHA were associated with loss of FN-BMD over 4 years in women (p-trend = 0.04), but was protective in men in the uppermost quintile compared to men grouped in the lower four quintiles, in post hoc analysis (p = 0.01). PC LA concentrations were inversely associated with baseline FN-BMD in women (p-trend = 0.02), and increased hip fracture risk in women and men (p-trend = 0.05), but body mass index (BMI) adjustment attenuated these associations (p-trend = 0.12 and p-trend = 0.14, respectively). A trend toward a protective association was observed between PC AA and baseline FN-BMD in men (p-trend = 0.06). Women and men with the highest PC AA concentrations had 51% lower hip fracture risk than those with the lowest (HR = 0.49, 95% CI = 0.24–1.00). Opposing effects of PC DHA on FN-BMD loss observed in women and men need further clarification. Bone loss associated with PC LA may be confounded by BMI. High PC AA concentrations may be associated with reduced hip fracture risk.
doi:10.1002/jbmr.1581
PMCID: PMC3565380  PMID: 22392875
DOCOSAHEXAENOIC ACID; LINOLEIC ACID; ARACHIDONIC ACID; BMD; FRACTURE
17.  The Factor-of-Risk Biomechanical Approach Predicts Hip Fracture In Men and Women: The Framingham Study 
Osteoporosis International  2011;23(2):513-520.
Purpose
Alternative methods of predicting hip fracture are needed since 50% of adults who fracture do not have osteoporosis by BMD measurements. One method, factor-of-risk (φ), computes the ratio of force on the hip in a fall, to femoral strength. We examined the relation between φ and hip fracture in 1,100 subjects from the Framingham Study with measured hip BMD, along with weight, height and age, collected in 1988-89.
Methods
We estimated both peak and attenuated force applied to the hip in a sideways fall from standing height, where attenuated force incorporated cushioning effects of trochanteric soft tissue. Femoral strength was estimated from femoral neck BMD, using cadaveric femoral strength data. Sex-specific, age-adjusted survival models were used to calculate hazard ratios (HR) and 95% confidence intervals for the relation between φpeak,φattenuated and their components, with hip fracture.
Results
In 425 men and 675 women (mean age 76 yrs), 136 hip fractures occurred over median follow-up of 11.3 yrs. φ was associated with increased age-adjusted risk for hip fracture. One standard deviation increase in φpeak and φattenuated was associated with HR of 1.88 and 1.78 in men and 1.23 and 1.41 in women, respectively. Examining components of φ, in women, we found fall force and soft tissue thickness were predictive of hip fracture independent of femoral strength, (was estimated from BMD).
Conclusions
Thus, both φpeak and φattenuated predict hip fracture in men and women. These findings suggest additional studies of φ predicting hip fracture using direct measurements of trochanteric soft tissue.
doi:10.1007/s00198-011-1569-2
PMCID: PMC3289518  PMID: 21344243
Hip fracture; Factor-of-Risk; bone strength; cohort study; fracture prediction; elderly
18.  Self-reported adherence with the use of a device in a clinical trial as validated by electronic monitors: the VIBES study 
Background
Adherences to treatments that require a behavioral action often rely on self-reported recall, yet it is vital to determine whether real time self reporting of adherence using a simple logbook accurately captures adherence. The purpose of this study was to determine whether real time self-reported adherence is an accurate measurement of device usage during a clinical trial by comparing it to electronic recording.
Methods
Using data collected from older adult men and women (N=135, mean age 82.3 yrs; range 66 to 98 yrs) participating in a clinical trial evaluating a vibrating platform for the treatment of osteoporosis, daily adherence to platform treatment was monitored using both self-reported written logs and electronically recorded radio-frequency identification card usage, enabling a direct comparison of the two methods over one year. Agreement between methods was also evaluated after stratification by age, gender, time in study, and cognition status.
Results
The two methods were in high agreement (overall intraclass correlation coefficient = 0.96). The agreement between the two methods did not differ between age groups, sex, time in study and cognitive function.
Conclusions
Using a log book to report adherence to a daily intervention requiring a behavioral action in older adults is an accurate and simple approach to use in clinical trials, as evidenced by the high degree of concordance with an electronic monitor.
Trial registration
Clinicaltrials.gov NCT00396994
doi:10.1186/1471-2288-12-171
PMCID: PMC3533958  PMID: 23150931
19.  Large common deletions associate with mortality at old age 
Human Molecular Genetics  2011;20(21):4290-4296.
Copy-number variants (CNVs) are a source of genetic variation that increasingly are associated with human disease. However, the role of CNVs in human lifespan is to date unknown. To identify CNVs that influence mortality at old age, we analyzed genome-wide CNV data in 5178 participants of Rotterdam Study (RS1) and positive findings were evaluated in 1714 participants of the second cohort of the Rotterdam Study (RS2) and in 4550 participants of Framingham Heart Study (FHS). First, we assessed the total burden of rare (frequency <1%) and common (frequency >1%) CNVs for association with mortality during follow-up. These analyses were repeated by stratifying CNVs by type and size. Secondly, we assessed individual common CNV regions (CNVR) for association with mortality. We observed that the burden of common but not of rare CNVs influences mortality. A higher burden of large (≥500 kb) common deletions associated with 4% higher mortality [hazard ratio (HR) per CNV 1.04, 95% confidence interval (CI) 1.02–1.07, P = 5.82 × 10−5] in the 11 442 participants of RS1, RS2 and FHS. In the analysis of 312 individual common CNVRs, we identified two regions (11p15.5; 14q21.3) that associated with higher mortality in these cohorts. The 11p15.5 region (combined HR 1.59, 95% CI 1.31–1.93, P = 2.87 × 10−6) encompasses 41 genes, of which some have previously been related to longevity, whereas the 14q21.3 region (combined HR 1.57, 95% CI 1.19–2.07, P = 1.53 × 10−3) does not encompass any genes. In conclusion, the burden of large common deletions, as well as common CNVs in 11p15.5 and 14q21.3 region, associate with higher mortality.
doi:10.1093/hmg/ddr340
PMCID: PMC3188993  PMID: 21835882
20.  Antidepressant Prescriptions: An Acute Window for Falls in the Nursing Home 
Background.
Although many studies have implicated antidepressants as a risk factor for falls, it is not clear if risk accrues with duration of use or if there are acute risks associated with initiation of the prescription. We conducted a case-crossover study of nursing home residents with a fall to determine the effect of an antidepressant change (defined as the new prescription of an antidepressant or increasing the dose of a previously used antidepressant) on fall risk.
Methods.
Among 1,181 nursing home fallers, we compared the frequency of antidepressant changes during the hazard period (1–7 days before the fall) with the frequency of antidepressant changes during the control period (8–14 days before the fall). Odds ratios were estimated using conditional logistic regression models. Results were estimated for non-selective serotonin reuptake inhibitors (SSRI) and SSRI prescriptions, separately.
Results.
Mean age was 88 years, and 71% were females. Seventy participants experienced an antidepressant change during the hazard and/or control periods. The maximum effect of falling occurred within 2 days of a non-SSRI change (odds ratio: 4.7, 95% confidence interval, 1.3–16.2). The effect on falling was no longer significant at 5 days (odds ratio: 1.9, 95% confidence interval, 0.9–4.0). No association was found between SSRI changes and falls.
Conclusions.
Nursing home residents are at high risk of falls during the days following a new prescription or increased dose of a non-SSRI antidepressant. Increased surveillance should occur, particularly during the first 48 hours, in an effort to decrease falls.
doi:10.1093/gerona/glr113
PMCID: PMC3202899  PMID: 21764842
Antidepressant; Fall; Nursing home
21.  Dementia Medications and Risk of Falls, Syncope, and Related Adverse Events Meta-Analysis of Randomized Controlled Trials 
Background
Conflicting evidence exists on whether cholinesterase inhibitors and memantine increase the risk of falls, syncope, and related events, defined as fracture and accidental injury.
Objectives
To evaluate the effect of cholinesterase inhibitors and memantine on the risk of falls, syncope, and related events
Design, Setting, Participants, and Intervention
Meta-analysis of 54 placebo-controlled randomized trials and extension studies of cholinesterase inhibitors and memantine that reported falls, syncope, and related events in cognitively impaired older adults. Trials were identified from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (no language restriction, through July 2009), and manual search.
Measurements
Falls, syncope, fracture, and accidental injury
Results
Compared to placebo, cholinesterase inhibitor use was associated with an increased risk of syncope (odds ratio [95% confidence interval]: 1.53 [1.02-2.30]), but not with other events (falls: 0.88 [0.74-1.04]; fracture: 1.39 [0.75-2.56]; accidental injury: 1.13 [0.87-1.45]). Memantine use was associated with fewer fractures (0.21 [0.05-0.85]), but not with other events (fall: 0.92 [0.72-1.18]; syncope: 1.04 [0.35-3.04]; accidental injury: 0.80 [0.56-1.12]). There was no differential effect by type and severity of cognitive impairment, residential status, nor length of follow-up. However, due to underreporting and small number of events, a potential benefit or risk cannot be excluded.
Conclusion
Cholinesterase inhibitors may increase the risk of syncope, with no effects on falls, fracture, and accidental injury in cognitively impaired older adults. Memantine may have a favorable effect on fracture, with no effects on other events. More research is needed to confirm the reduction in fractures observed for memantine.
doi:10.1111/j.1532-5415.2011.03450.x
PMCID: PMC3260523  PMID: 21649634
Cholinesterase Inhibitors; Memantine; Falls; Syncope; Dementia
22.  Mechanical Contributions of the Cortical and Trabecular Compartments Contribute to Differences in Age-Related Changes in Vertebral Body Strength in Men and Women Assessed by QCT-Based Finite Element Analysis 
The biomechanical mechanisms underlying sex-specific differences in age-related vertebral fracture rates are ill defined. To gain insight into this issue, we used finite element analysis of clinical computed tomography (CT) scans of the vertebral bodies of L3 and T10 of young and old men and women to assess age- and sex-related differences in the strength of the whole vertebra, the trabecular compartment, and the peripheral compartment (the outer 2 mm of vertebral bone, including the thin cortical shell). We sought to determine whether structural and geometric changes with age differ in men and women, making women more susceptible to vertebral fractures. As expected, we found that vertebral strength decreased with age 2-fold more in women than in men. The strength of the trabecular compartment declined significantly with age for both sexes, whereas the strength of the peripheral compartment decreased with age in women but was largely maintained in men. The proportion of mechanical strength attributable to the peripheral compartment increased with age in both sexes and at both vertebral levels. Taken together, these results indicate that men and women lose vertebral bone differently with age, particularly in the peripheral (cortical) compartment. This differential bone loss explains, in part, a greater decline in bone strength in women and may contribute to the higher incidence of vertebral fractures among women than men. © 2011 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.287
PMCID: PMC3179306  PMID: 21542000
VERTEBRAL FRACTURE; FINITE ELEMENT ANALYSIS; QUANTITATIVE COMPUTED TOMOGRAPHY; BONE LOSS; VERTEBRAL STRENGTH; BONE STRENGTH; BIOMECHANICS
23.  Associations of APOE Gene Polymorphisms with Bone Mineral Density and Fracture Risk: A Meta-Analysis 
Purpose
Apolipoprotein E (APOE) has been studied for its potential role in osteoporosis risk. It is hypothesized that genetic variation at APOE locus, known as E2, E3, and E4, may modulate bone mineral density (BMD) through its effects on lipoproteins and vitamin K transport. The purpose of this study was to determine the association of the APOE-E4 gene polymorphism with bone-related phenotypes.
Methods
We conducted a meta-analysis that combined newly-analyzed individual data from two community-based cohorts, the Framingham Offspring Study (N=1,495) and the Vitamin K Clinical Trial (N=377), with fifteen other eligible published reports. Bone phenotypes included BMD measurements of the hip (total hip and trochanteric and femoral neck sites) and lumbar spine (from the L2 to L4 vertebrae) and prevalence or incidence of vertebral, hip and other fractures.
Results
In sex-pooled analyses, APOE4 carriers had a 0.018 g/cm2 lower weighted mean trochanteric BMD than non carriers (p=0.0002) with no evidence for between-study heterogeneity. A significant association was also detected with lumbar spine BMD (p=0.006); however, inter-study heterogeneity was observed. Associations with lumbar spine and trochanteric BMD were observed predominantly in women and became less significant in meta-regression (p=0.055 and 0.01, respectively). There were no consistent associations of APOE4 genotype with BMD at other skeletal sites or with fracture risk.
Conclusions
Based on these findings, there is insufficient evidence to support a strong and consistent association of the APOE genotype with BMD and fracture incidence.
doi:10.1007/s00198-010-1311-5
PMCID: PMC3144470  PMID: 20533025
Apolipoprotein E; BMD; Fracture; meta-analysis; polymorphism
24.  Large-Scale Analysis of Association Between LRP5 and LRP6 Variants and Osteoporosis 
Jama  2008;299(11):1277-1290.
Context
Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population.
Objective
To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk.
Design and Setting
Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.
Main Outcome Measures
Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.
Results
The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n =25 052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P=3.3 × 10−8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P=2.6 × 10−9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P =3.8 × 10−5) and 8 mg/cm2 (P=5.0×10−6) for the Met667 and Val1330 alleles, respectively (n=25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08–1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01–1.24 for Val1330 [1988 fractures among 20 096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05–1.24 per allele [7876 fractures among 31 435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01–1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments.
Conclusions
Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P<10−7] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
doi:10.1001/jama.299.11.1277
PMCID: PMC3282142  PMID: 18349089
25.  Genetics of the Musculoskeletal System: A Pleiotropic Approach 
The risk of osteoporotic fracture can be viewed as a function of loading conditions and the ability of the bone to withstand the load. Skeletal loads are dominated by muscle action. Recently, it has become clear that bone and muscle share genetic determinants. Involution of the musculoskeletal system manifests as bone loss (osteoporosis) and muscle wasting (sarcopenia). Therefore, the consideration of pleiotropy is an important aspect in the study of the genetics of osteoporosis and sarcopenia. This Perspective will provide the evidence for a shared genetic influence on bone and muscle. We will start with an overview of accumulating evidence that physical exercise produces effects on the adult skeleton, seeking to unravel some of the contradictory findings published thus far. We will provide indications that there are pleiotropic relationships between bone structure/mass and muscle mass/function. Finally, we will offer some insights and practical recommendations as to the value of studying shared genetic factors and will explore possible directions for future research. We consider several related questions that together comprise the general paradigm of bone responses to mechanical loading and the relationship between muscle strength and bone parameters, including the genetic factors that modulate these responses. We believe that further progress in understanding the common genetic etiology of osteoporosis and sarcopenia will provide valuable insight into important biological underpinnings for both conditions and may translate into new approaches to reduce the burdens of both conditions through improved diagnosis, prevention, and early targeted treatment.
doi:10.1359/jbmr.080218
PMCID: PMC3280426  PMID: 18269309
genetics; pleiotropy; osteoporosis; sarcopenia; development; aging

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