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Objective Nonalcoholic fatty liver disease (NAFLD) is associated with low bone mineral density (BMD); however, it is not known whether early-stage NAFLD may be associated with BMD after accounting for BMI or visceral adipose tissue (VAT). Methods This was a cross-sectional study of 3,462 Framingham Heart Study participants who underwent computed tomographic measurement of liver fat, VAT volume, volumetric spine BMD, vertebral cross-sectional area (CSA), and vertebral compressive strength. This study excluded heavy alcohol consumers. Multivariable linear regression models were used to assess the association between NAFLD and volumetric BMD, CSA, and vertebral compressive strength after accounting for covariates, including BMI or VAT. Results A total of 2,253 participants (mean age, 51.2 [SD 10.7] years; 51.1% women) were included. In multivariable-adjusted models, positive associations between NAFLD and integral BMD, trabecular BMD, and vertebral compressive strength were observed. However, results were attenuated and no longer significant after additionally adjusting for BMI or VAT. NAFLD was observed to be weakly associated with a lower vertebral CSA in adjusted models. Conclusions In a community-based cohort, the associations between NAFLD and BMD and vertebral strength were confounded by BMI and VAT. However, NAFLD was associated with a reduced vertebral CSA in adjusted models.

The spatial heterogeneity in trabecular bone density within the vertebral centrum is associated with vertebral strength and could explain why volumetric bone mineral density (vBMD) exhibits low sensitivity in identifying fracture risk. This study evaluated whether the heterogeneity and spatial distribution of trabecular vBMD are associated with prevalent vertebral fracture. We examined the volumetric quantitative computed tomography (QCT) scans of the L3 vertebra in 148 participants in the Framingham Heart Study Multidetector CT study. Of these individuals, 37 were identified as cases of prevalent fracture, and 111 were controls, matched on sex and age with three controls per case. vBMD was calculated within 5-mm contiguous cubic regions of the centrum. Two measures of heterogeneity were calculated: (i) interquartile range (IQR); and (ii) quartile coefficient of variation (QCV). Ratios in the spatial distributions of the trabecular vBMD were also calculated: anterior/posterior, central/outer, superior/mid-transverse, and inferior/mid-transverse. Heterogeneity and spatial distributions were compared between cases and controls using Wilcoxon rank sum tests and t tests and tested for association with prevalent fractures with conditional logistic regressions independent of integral vBMD. Prevalent fracture cases had lower mean ± SD integral vBMD (134 ± 38 versus165 ± 42 mg/cm3 , p < .001), higher QCV (0.22 ± 0.13 versus 0.17 ± 0.09, p = .003), and lower anterior/posterior rBMD (0.65 ± 0.13 versus 0.78 ± 0.16, p < .001) than controls. QCV was positively associated with increased odds of prevalent fracture (OR 1.61; 95% CI, 1.04 to 2.49; p = .034), but this association was not independent of integral vBMD (p = .598). Increased anterior/posterior trabecular vBMD ratio was associated with decreased odds of prevalent fracture independent of integral vBMD (OR 0.38; 95% CI, 0.20 to 0.71; p = .003). In conclusion, increased trabecular vBMD in the anterior versus posterior centrum, but not trabecular vBMD heterogeneity, was associated with decreased risk of prevalent fracture independent of integral vBMD. Regional measurements of trabecular vBMD could aid in determining the risk and underlying mechanisms of vertebral fracture. © 2019 American Society for Bone and Mineral Research.

Weight loss in older adults is associated with increased bone loss and fracture. Little is known about the potential impact of weight loss on cortical and trabecular bone density, microarchitecture, and strength. In this study, participants were members of the Framingham Offspring Cohort (769 women, 595 men; mean age 70 ± 8 years), who underwent high-resolution peripheral quantitative computed tomography (HR-pQCT) scanning at the tibia and radius in 2012 to 2016. Weight measurements taken every 4 to 6 years were used to assess recent weight change over 6 years and long-term change over 40 years. General linear models, adjusting for age, sex, height, smoking, and diabetes, were used to evaluate the association between HR-pQCT indices and relative long-term and recent weight change. We found that long-term and recent weight loss were associated with lower cortical density and thickness, higher cortical porosity, and lower trabecular density and number. Associations were stronger for the tibia than radius. Failure load was lower in those individuals with long-term but not short-term weight loss. Deterioration in both cortical and trabecular indices, especially at the weight-bearing skeleton, characterizes bone fragility associated with long-term and recent weight loss in older adults. © 2018 American Society for Bone and Mineral Research.

Relative age-related deficit in trunk muscle density was greater in women than men whereas the relative decrease in muscle mass with age was similar in both sexes. The greater muscle fat content and greater age-related fat accumulation among women may contribute to women suffering more functional disabilities than men. A better understanding of the effect of aging on trunk musculature will have implications for physical function, disability, pain, and risk of injury in older adults. Thus, we determined the age- and sex-related differences in muscle density and size of both thoracic and lumbar trunk muscles. In this cross-sectional study, muscle density and size were measured from quantitative computed tomography (QCT) scans for 10 trunk muscle groups at different vertebral levels in 250 community-based men and women aged 40 to 90 years from the Framingham Offspring and Third Generation cohorts. Trunk muscles in men were 20–67% larger and had 5–68% higher density than in women. The relative age-related deficits in muscle size were similar in both sexes, and decreased on average by ~ 8% per decade in both sexes. In contrast, women had greater age-related decreases in muscle density than men (− 17% in women, and − 11% in men, p

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

There is increasing evidence that bone and vascular calcification share common pathogenesis. Little is known about potential links between bone and valvular calcification. The purpose of this study was to determine the association between spine bone mineral density (BMD) and vascular and valvular calcification. Participants included 1317 participants (689 women, 628 men) in the Framingham Offspring Study (mean age 60 years). Integral, trabecular, and cortical volumetric bone density (vBMD) and arterial and valvular calcification were measured from computed tomography (CT) scans and categorized by sex-specific quartiles (Q4 = high vBMD). Calcification of the coronary arteries (CAC), abdominal aorta (AAC), aortic valve (AVC), and mitral valve (MVC) were quantified using the Agatston Score (AS). Prevalence of any calcium (AS >0) was 69% for CAC, 81% for AAC, 39% for AVC, and 20% for MVC. In women, CAC increased with decreasing quartile of trabecular vBMD: adjusted mean CAC = 2.1 (Q4), 2.2 (Q3), 2.5 (Q2), 2.6 (Q1); trend p = 0.04. However, there was no inverse trend between CAC and trabecular vBMD in men: CAC = 4.3 (Q4), 4.3 (Q3), 4.2 (Q2), 4.3 (Q1); trend p = 0.92. AAC increased with decreasing quartile of trabecular vBMD in both women (AAC = 4.5 [Q4], 4.8 [Q3], 5.4 [Q2], 5.1 [Q1]; trend p = 0.01) and men (AAC = 5.5 [Q4], 5.8 [Q3], 5.9 [Q2], 6.2 [Q1]; trend p = 0.01). We observed no association between trabecular vBMD and AVC or MVC in women or men. Finally, cortical vBMD was unrelated to vascular calcification and valvular calcification in women and men. Women and men with low spine vBMD have greater severity of vascular calcification, particularly at the abdominal aorta. The inverse relation between AAC and spine vBMD in women and men may be attributable to shared etiology and may be an important link on which to focus treatment efforts that can target individuals at high risk of both fracture and cardiovascular events.

Objective To evaluate the association between thoracic kyphosis and physical function. Design Prospective cohort. Setting Framingham, Massachusetts. Participants Framingham Heart Study Offspring and Third Generation cohort members who had computed tomography (CT) performed between 2002 and 2005 and physical function assessed a mean 3.4 years later (N = 1,100; mean age 61 ± 8, range 50–85). Measurements Thoracic kyphosis (Cobb angle, T4-T12) was measured in degrees using supine CT scout images. Participants were categorized according to Cobb angle to compare those in the highest quartile (Q4, most-severe kyphosis) with those in the lowest quartiles (Q1-Q3). Quick walking speed (m/s), chair-stand time (seconds), grip strength (kg), and self-reported impairments were assessed using standardized procedures. Analyses were adjusted for age, height, weight, smoking, follow-up time, vertebral fractures, and prevalent spinal degeneration. Results Thoracic kyphosis was not associated with physical function in women or men, and these results were consistent in those younger than 65 and those aged 65 and older. For example, walking speed was similar in adults younger than 65 with and without severe kyphosis (women, Q4: 1.38 m/s, Q1-Q3: 1.40 m/s, P = .69; men, Q4: 1.65 m/s, Q1-Q3: 1.60 m/s; P = .39). Conclusion In healthy relatively high-functioning women and men, kyphosis severity was not associated with subsequent physical function. Individuals at risk of functional decline cannot be targeted based on supine CT thoracic curvature measures alone.

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

Atherosclerosis and osteoporosis are chronic diseases that progress with age, and studies suggest aortic calcification, an indicator of atherosclerosis, is inversely associated with BMD. The OPG/RANK/RANKL system has been proposed as a shared regulatory system for bone and vasculature. Denosumab (DMAb), a monoclonal antibody against RANKL, improved BMD and reduced fracture risk in the FREEDOM trial. We evaluated whether or not treatment with DMAb influenced progression of aortic calcification (AC) and incidence of cardiovascular (CV) adverse events. We included 2,363 postmenopausal women with osteoporosis (1,142 placebo, 1,221 DMAb), selected from 7,808 participants in the FREEDOM trial (3,906 placebo, 3,902 DMAb), at high risk of CV events according to modified Raloxifene Use for the Heart (RUTH) criteria. CV adverse events were reported by participants. AC scores were assessed using a semi-quantitative method from lateral spine x-rays. Change in AC score from baseline to 12 (N = 1,377), 24 (N = 1,231) and 36 months (N = 1,045) was calculated as AC score at follow-up minus AC score at baseline. AC progression was defined as change in AC score > 0. Baseline characteristics, CV risk factors, and AC scores were similar between treatment groups. Mean age of participants was 74 years (range, 60–90), 88% were white, and 77% had AC score > 0 at baseline. Frequency of AC progression over 3 years did not differ between women in placebo (22%) and DMAb (22%) groups (p = 0.98). AC progression did not differ between treatment groups when analyzed by baseline estimated glomerular filtration rate or by baseline AC scores. Frequency of CV adverse events did not differ between placebo (40%) and DMAb (38%) groups (p = 0.26). In conclusion, DMAb treatment had no effect on progression of AC or incidence of CV adverse events compared to placebo.

Vascular calcifications and bone health seem to be etiologically linked via common risk factors such as aging and subclinical chronic inflammation. Epidemiologic studies have shown significant associations between low bone mineral density (BMD), fragility fractures and calcifications of the coronary arteries and the abdominal aorta. In the last decade, high-resolution peripheral quantitative computed tomography (HR-pQCT) has emerged as in-vivo research tool for the assessment of peripheral bone geometry, density, and microarchitecture. Although vascular calcifications are frequently observed as incidental findings in HR-pQCT scans, they have not yet been incorporated into quantitative HR-pQCT analyses. We developed a semi-automated algorithm to quantify lower leg arterial calcifications (LLACs), captured by HR-pQCT. The objective of our study was to determine validity and reliability of the LLAC measure. HR-pQCT scans were downscaled to a voxel size of 250μm. After subtraction of bone volumes from the scans, LLACs were detected and contoured by a semi-automated, dual-threshold seed-point segmentation. LLAC mass (in mg hydroxyapatite; HA) was calculated as the product of voxel-based calcification volume (mm(3)) and mean calcification density (mgHA/cm(3))/1000. To determine validity, we compared LLACs to coronary artery calcifications (CACs), as quantified by multi-detector computed tomography (MDCT) and Agatston scoring in forty-six patients on chronic hemodialysis. Moreover, we investigated associations of LLACs with age, time on dialysis, type-2 diabetes mellitus, history of stroke, and myocardial infarction. In a second step, we determined intra- and inter-reader reliability of the LLAC measure. In the validity study, LLACs were present (>0mgHA) in 76% of patients, 78% of patients had CACs (>0mgHA). Median LLAC was 6.65 (0.08-24.40)mgHA and median CAC as expressed by Agatston score was 266.3 (15.88-1877.28). We found a significant positive correlation between LLAC and CAC (rho=0.6; p

Background Adequate calcium intake is known to protect the skeleton. However, studies that have reported adverse effects of calcium supplementation on vascular events have raised widespread concern. Objective We assessed the association between calcium intake (from diet and supplements) and coronary artery calcification, which is a measure of atherosclerosis that predicts risk of ischemic heart disease independent of other risk factors. Design This was an observational, prospective cohort study. Participants included 690 women and 588 men in the Framingham Offspring Study (mean age: 60 y; range: 36-83 y) who attended clinic visits and completed food-frequency questionnaires in 1998-2001 and underwent computed tomography scans 4 y later in 2002-2005. Results The mean age-adjusted coronary artery-calcification Agatston score decreased with increasing total calcium intake, and the trend was not significant after adjustment for age, BMI, smoking, alcohol consumption, vitamin D-supplement use, energy intake, and, for women, menopause status and estrogen use. Multivariable-adjusted mean Agatston scores were 2.36, 2.52, 2.16, and 2.39 (P-trend = 0.74) with an increasing quartile of total calcium intake in women and 4.32, 4.39, 4.19, and 4.37 (P-trend = 0.94) in men, respectively. Results were similar for dietary calcium and calcium supplement use. Conclusions Our study does not support the hypothesis that high calcium intake increases coronary artery calcification, which is an important measure of atherosclerosis burden. The evidence is not sufficient to modify current recommendations for calcium intake to protect skeletal health with respect to vascular calcification risk.

We used volumetric quantitative computed tomography (QCT) scans to evaluate volumetric bone density (vBMD), geometry, and strength in the thoracic (T8 to T10) and lumbar (L3 to L5) spine and determined how these parameters varied with age, sex, and spinal region. Participants included 690 participants of the Framingham Study, 40 to 87 years old (mean, 61 years). In both women and men, trabecular vBMD declined with age similarly for lumbar and thoracic regions, whereas cortical vBMD and integral vBMD, vertebral strength, and compressive force declined more at the lumbar spine than thoracic spine (interaction, p < 0.01). Notably, in men, cortical vBMD increased (β = 0.0004, p = 0.01), and vertebral strength did not change (β = 1.9305, p = 0.66) at the thoracic spine with age. In both women and men, vertebral cross-sectional area increased less and the factor-of-risk increased more with age at the lumbar than at the thoracic region (interaction, p < 0.01). For example, in women, the factor-of-risk for forward flexion increased (worsened) with age 6.8-fold more in the lumbar spine (β = 0.0157), compared with the thoracic spine (β = 0.0023). vBMD and vertebral strength declined more and the factor-of-risk increased more with age in women than men (interaction, p < 0.01). For instance, integral vBMD for the lumbar spine declined 36% from 40 to 75 years of age in women compared with 18% in men. There was little or no age-related change in the forces applied to the thoracic vertebrae in either women or men. Age-related changes were greater in the lumbar spine than in the thoracic region and greater in women than men. Whereas women lost bone density and strength at both the thoracic and lumbar spine, in men, vertebral strength declined only at the lumbar spine. Our study confirms the importance of evaluating determinants of vertebral strength in both the thoracic and lumbar spine and in both women and men to understand mechanisms underlying the structural failure of vertebral bodies with aging.

Intra-and inter-reader reliability of semi-automated quantitative vertebral morphometry measurements was determined using lateral computed tomography (CT) scout views. The method requires less time than conventional morphometry. Reliability was excellent for vertebral height measurements, good for height ratios, and comparable to semi-quantitative grading by radiologists for identification of vertebral fractures.Underdiagnosis and undertreatment of vertebral fracture (VFx) is a well-known problem worldwide. Thus, new methods are needed to facilitate identification of VFx. This study aimed to determine intra- and inter-reader reliability of semi-automated quantitative vertebral morphometry based on shape-based statistical modeling (SpineAnalyzer, Optasia Medical, Cheadle, UK).Two non-radiologists independently assessed vertebral morphometry from CT lateral scout views at two time points in 96 subjects (50 men, 46 women, 70.3 ± 8.9 years) selected from the Framingham Heart Study Offspring and Third Generation Multi-Detector CT Study. VFxs were classified based solely on morphometry measurements using Genant's criteria. Intraclass correlation coefficients (ICCs), root mean squared coefficient of variation (RMS CV) and kappa (k) statistics were used to assess reliability.We analyzed 1,246 vertebrae in 96 subjects. The analysis time averaged 5.4 ± 1.7 min per subject (range, 3.2-9.1 min). Intra-and inter-reader ICCs for vertebral heights were excellent (0.95) for all vertebral levels combined. Intra-and inter-reader RMS CV for height measurements ranged from 2.5% to 3.9% and 3.3% to 4.4%, respectively. Reliability of vertebral height ratios was good to fair. Based on morphometry measurements alone, readers A and B identified 51-52 and 46-59 subjects with at least one prevalent VFx, respectively, and there was a good intra-and inter-reader agreement (k = 0.59-0.69) for VFx identification.Semi-automated quantitative vertebral morphometry measurements from CT lateral scout views are convenient and reproducible, and may facilitate assessment of VFx.

Tracking falls among elders is challenging. In this reliability study, which took place between October 2007 and February 2008, the authors compared participants’ daily recordings of falls on calendars with a telephone survey of recall of falls over the previous 3 months within the population-based MOBILIZE Boston Study cohort, a cohort of 765 elders. From the cohort, 218 participants were randomly selected. Falls were tracked prospectively on daily calendars (mailed back monthly). Telephone recalls of falls over the previous 3 months were conducted in January and February 2008. Agreement, sensitivity, and specificity were calculated to compare the occurrence of falls as determined by 3-month recall with falls recorded by daily calendar (gold standard) during the same 3-month period. Results showed good agreement between recall and calendars: 27 persons reported a fall by both methods. However, while the 3-month recall correctly classified persons who did not fall (164 persons by both methods), it missed 25% of participants who fell (of 36 participants with a calendar-reported fall, 9 did not report a fall by telephone recall). Kappa was 0.74 (95% confidence interval: 0.68, 0.80), sensitivity was 75%, and specificity was 96%. Retrospective 3-month recall of falls resulted in underreporting of falls by as much as 25% compared with daily calendars. Calendars should be considered the preferred method of ascertaining falls in longitudinal studies.

Clinical studies often face the difficult problem of how to account for participants who die without experiencing the study outcome of interest. In a geriatric population with considerable comorbidities, the competing risk of death is especially high. Traditional approaches to describe risk of disease include Kaplan-Meier survival analysis and Cox proportional hazards regression, but these methods can overestimate risk of disease by failing to account for the competing risk of death. This report discusses traditional survival analysis and competing risk analysis as used to estimate risk of disease in geriatric studies. Furthermore, it illustrates a competing risk approach to estimate risk of second hip fracture in the Framingham Osteoporosis Study and compares the results with traditional survival analysis. In this example, survival analysis overestimated the 5-year risk of second hip fracture by 37% and the 10-year risk by 75% compared with competing risk estimates. In studies of older individuals in which a substantial number of participants die during a long follow-up, the cumulative incidence competing risk estimate and competing risk regression should be used to determine incidence and effect estimates. Use of a competing risk approach is critical to accurately determining disease risk for elderly individuals and therefore best inform clinical decision-making.

Better assessment of the association between cardiovascular disease and osteoporosis in older men may help identify shared etiologies for bone and heart health in this population. We assessed the association of BMD and bone turnover markers (BTMs) with risk of cardiovascular events (myocardial infarction or stroke) in 744 menor=50 yr of age. During the 7.5-yr prospective follow-up, 43 strokes and 40 myocardial infarctions occurred in 79 men. After adjustment for confounders (age, weight, height, smoking, education, physical activity, self-reported history of diabetes, hypertension, and prevalent ischemic heart disease), men in the lowest quartile of BMD at the spine, whole body, and forearm had a 2-fold increased risk of cardiovascular events. Men in the highest quartile of bone resorption markers (deoxypyridinoline [DPD], C-telopeptide of type I collagen) had a 2-fold increased risk of cardiovascular events (e.g., multivariable-adjusted hazard ratio [including additional adjustment for BMD] was 2.11 [95% CI: 1.26-3.56], for the highest quartile of free DPD relative to the lowest three quartiles). The results were similar for men without prevalent ischemic heart disease and for myocardial infarction and stroke analyzed separately. Our data suggest that men with low BMD or high bone resorption may be at increased risk of myocardial infarction and stroke in addition to fracture. Thus, men with osteoporosis may benefit from screening for cardiovascular disease. Further study to elucidate the biological mechanism shared by bone and vascular disease may help efforts to identify men at risk or develop treatment.

OBJECTIVES: To determine the incidence and predictors of subsequent fracture in nursing home residents with a hip fracture, accounting for the competing risk of death. DESIGN: Dynamic cohort study. SETTING: Hebrew Rehabilitation Center, a 725-bed, long-term care facility in Boston, Massachusetts. PARTICIPANTS: Long-term care residents with a surgically repaired hip fracture (1999–2006) followed through June 30, 2007, for the occurrence of subsequent fracture at any skeletal site. MEASUREMENTS: Information on age, sex, anatomic location, type of repair, body mass index (BMI), comorbidities, functional status, cognitive status, and medication use were evaluated as potential risk factors for subsequent fracture. RESULTS: The study included 184 residents with a baseline hip fracture. Thirty-nine residents (7 men, 32 women) experienced a subsequent fracture over a median follow-up of 1.1 years. After the baseline hip fracture, 6% of residents experienced a subsequent fracture within 6 months, 12% within 1 year, and 21% within 5 years. In addition, 23% of residents died within 6 months, 31% within 1 year, and 60% within 5 years. High functional status was associated with a five times greater risk of subsequent fracture (high vs low functional status, hazard ratio=5.10, P

This study evaluates baseline characteristics of 704 women and men in the Framingham Study with respect to long-term risk of incident vertebral fracture. Incidence was 24% in women and 10% in men. Few factors in middle-aged persons, except prevalent (moderate) fracture and alcohol consumption (in men), predicted long-term incidence of vertebral fracture. Introduction: We studied potential risk factors in women and men in middle adult years to help identify individuals at increased long-term risk of vertebral fracture in advanced age. Materials and Methods: Participants included Framingham cohort members who underwent radiographic examinations at baseline in 1967–1969 (mean age, 53 years) and follow-up in 1992–1993. Semiquantitative methods were used to determine incident fracture, defined as any vertebral body graded normal at baseline and at least mildly deformed (20–25% reduction or more in any vertebral height) at follow-up. Information on potential risk factors was obtained from examinations conducted at or before baseline radiography. Results: Prevalence of vertebral fracture was similar (14%) in women and men, although incidence was greater in women (24%) than men (10%). Alcohol consumption increased fracture risk in men. Multivariable-adjusted ORs increased from 1.78 in men who consumed 1–3 oz of alcohol per week in middle-age years to 4.61 in those with intakes of ≥4 oz/week (trend, P = 0.0099). Age, height, weight, grip strength, physical activity, metacarpal cortical area, and estrogen use (in women) had little or no influence on cumulative incidence of vertebral fracture. Results were similar when fracture was restricted to (at least) moderate severity; however, participants with moderate to severe fracture prevalent at baseline had five times the incidence of moderate to severe fracture during follow-up compared with those without moderately to severe prevalent fractures. Conclusions: Few factors in middle-aged persons, except prevalent fracture and alcohol consumption (in men), predict long-term incidence of vertebral fracture. The explanation underlying this finding is not readily apparent, however, risk factors for vertebral fracture may be more relevant to older individuals, with respect to short-term fracture risk, than to middle-aged adults in relation to long-term risk with aging.

Osteoporosis and related fractures represent a major, and growing, public health concern for the United States and worldwide. The pathogenesis of osteoporosis is complex, requiring attention to the different life phases involved in growth, maintenance, and loss of bone, in addition to non-skeletal factors associated with falls and fractures. While the current clinical definition is based upon bone density measurements, other determinants of skeletal strength, particularly bone quality, are important to identify for future areas of research and prevention efforts. This epidemiologic review describes the definition, pathogenesis, and risk factors, as well as the frequency and impact of osteoporosis, with particular emphasis upon hip fracture.

The increased prevalence of osteoporosis among people with homocystinuria suggests that a high serum homocysteine concentration may weaken bone by interfering with collagen cross-linking, thereby increasing the risk of osteoporotic fracture. We examined the association between the total homocysteine concentration and the risk of hip fracture in men and women enrolled in the Framingham Study.We studied 825 men and 1174 women, ranging in age from 59 to 91 years, from whom blood samples had been obtained between 1979 and 1982 to measure plasma total homocysteine. The participants in our study were followed from the time that the sample was obtained through June 1998 for incident hip fracture. Sex-specific, age-adjusted incidence rates of hip fracture were calculated for quartiles of total homocysteine concentrations. Cox proportional-hazards regression was used to calculate hazard ratios for quartiles of homocysteine values.The mean (+/-SD) plasma total homocysteine concentration was 13.4+/-9.1 micromol per liter in men and 12.1+/-5.3 micromol per liter in women. The median duration of follow-up was 12.3 years for men and 15.0 years for women. There were 41 hip fractures among men and 146 among women. The age-adjusted incidence rates per 1000 person-years for hip fracture, from the lowest to the highest quartile for total homocysteine, were 1.96 (95 percent confidence interval, 0.52 to 3.41), 3.24 (0.97 to 5.52), 4.43 (1.80 to 7.07), and 8.14 (4.20 to 12.08) for men and 9.42 (5.72 to 13.12), 7.01 (4.29 to 9.72), 9.58 (6.42 to 12.74), and 16.57 (11.84 to 21.30) for women. Men and women in the highest quartile had a greater risk of hip fracture than those in the lowest quartile--the risk was almost four times as high for men and 1.9 times as high for women.These findings suggest that the homocysteine concentration, which is easily modifiable by means of dietary intervention, is an important risk factor for hip fracture in older persons.

Laboratory studies have suggested a role for cholesterol in the pathogenesis of both osteoporosis and atherosclerosis. The purpose of this prospective study was to assess whether cholesterol levels, repeatedly measured over three decades in young and middle-aged adult women and men, predicted bone mineral density (BMD) at advanced age. Study participants included 712 women and 450 men enrolled in the Framingham Osteoporosis Study, aged 32-61 years at baseline (1953-55) who underwent bone densitometry 34 years later (1988-1989). BMD was measured at the proximal femur (neck, trochanter, and Ward's triangle) and lumbar spine using dual-photon absorptiometry and at the one-third radial shaft and ultradistal radius using single-photon absorptiometry. Sex-specific multivariable linear regression was used to model each BMD site as a function of total cholesterol level, adjusted for age, cigarette smoking, alcohol consumption, body mass index, systolic blood pressure, diabetes, and estrogen use (women). No significant association between total cholesterol and BMD was found in women for any of the bone sites considered. For example, adjusted mean BMD at the lumbar spine was similar in women from the lowest to highest quartile of total cholesterol, respectively, 1.07, 1.08, 1.06, 1.07 g/cm2; P for trend=0.98. Similarly, the findings in men largely showed no association between cholesterol and BMD, although there was an isolated finding of a statistically significant trend in decreasing mean radial shaft BMD with increasing total cholesterol, 0.73, 0.72, 0.72, 0.70 g/cm2, lowest to highest quartile, P for trend=0.02. Cholesterol levels in women and men from young adulthood to middle age years do not appear to have long-term clinical implications for osteoporosis later in life.

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

Increased kyphosis is a common condition among older adults that may, directly or indirectly, be a risk factor for poor mobility and disability. Epidemiologic studies have demonstrated that age-related hyperkyphosis, which some authors define as having a kyphosis angle greater than 40 degrees,1,2 affects 20–40% of older adults.3 This condition has been associated with other medical problems, such as falls,4 osteoarthritis, osteoporosis, impaired pulmonary function, and mortality3. In addition, kyphosis may affect physical function and disability through both its effect on standing posture and the aforementioned associated medical problems. Previous studies regarding the effect of kyphosis on physical function have not been consistent. Some studies have found greater kyphosis to be associated with worse physical function, balance or mortality5–9. However, two studies reported no relationship between increased kyphosis and balance10,11. Of the few studies that have evaluated kyphosis and mobility, most are limited by small sample size and the exclusion of men6,8–10,12–16. Few have focused primarily on the geriatric population; one demonstrated that the association between kyphosis and physical function was stronger in women than men7 and the other showed that seniors with greater degrees of kyphosis were more likely to have poorer physical function5. The differing results observed among studies of increased kyphosis may be due to multiple reasons, including the method used to measure kyphosis or the specific outcomes used. Kado and colleagues concluded that there is a need to better understand these relationships within a population-based sample of older adults3. To address this concern we conducted an analysis of kyphosis using the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) Boston Study data, a population-based study of community-living older adults. We hypothesized that increased kyphosis would be associated with declines in balance performance, and both observed and self-reported mobility.

Clinical studies are often faced with the difficult problem of how to account for participants who die without experiencing the study outcome of interest. In a geriatric population with considerable co-morbidities, the competing risk of death is especially high. Traditional approaches to describe risk of disease include Kaplan-Meier survival analysis and Cox proportional hazards regression; however, these methods can overestimate risk of disease by failing to account for the competing risk of death. In this report, we discuss traditional survival analysis and competing risk analysis as used to estimate risk of disease in geriatric studies. Furthermore, we provide an illustration of a competing risk approach to estimate risk of second hip fracture in the Framingham Osteoporosis Study, and we compare the results with traditional survival analysis. In this example, survival analysis overestimated the five-year risk of second hip fracture by 37% and the ten-year risk by 75% compared with competing risk estimates. We conclude, that in studies of older individuals in which a substantial number of participants die during a long follow-up, the Cumulative Incidence Competing Risk (CICR) estimate and Competing Risk Regression (CRR) should be used to determine incidence and effect estimates. Use of a competing risk approach is critical to accurately determine disease risk for elderly individuals, and therefore best inform clinical decision-making.

Conducting research in elderly populations is important, but challenging. In this paper, the authors describe specific challenges that have arisen and solutions that have been used in carrying out The MOBILIZE Boston Study, a community-based, prospective cohort study in Massachusetts focusing on falls among 765 participants aged 70 years or older enrolled during 2005-2007. To recruit older individuals, face-to-face interactions are more effective than less personal approaches. Use of a board of community leaders facilitated community acceptance of the research. Establishing eligibility for potential participants required several interactions, so resources must be anticipated in advance. Assuring a safe and warm environment for elderly participants and offering a positive experience are a vital priority. Adequate funding, planning, and monitoring are required to provide transportation and a fully accessible environment in which to conduct study procedures as well as to select personnel highly skilled in interacting with elders. It is hoped that this paper will encourage and inform future epidemiologic research in this important segment of the population.

To determine the incidence and predictors of subsequent fracture in nursing home residents with a hip fracture, accounting for the competing risk of death.Dynamic cohort study.Hebrew Rehabilitation Center, a 725-bed, long-term care facility in Boston, Massachusetts.Long-term care residents with a surgically repaired hip fracture (1999-2006) followed through June 30, 2007, for the occurrence of subsequent fracture at any skeletal site.Information on age, sex, anatomic location, type of repair, body mass index (BMI), comorbidities, functional status, cognitive status, and medication use were evaluated as potential risk factors for subsequent fracture.The study included 184 residents with a baseline hip fracture. Thirty-nine residents (7 men, 32 women) experienced a subsequent fracture over a median follow-up of 1.1 years. After the baseline hip fracture, 6% of residents experienced a subsequent fracture within 6 months, 12% within 1 year, and 21% within 5 years. In addition, 23% of residents died within 6 months, 31% within 1 year, and 60% within 5 years. High functional status was associated with a five times greater risk of subsequent fracture (high vs low functional status, hazard ratio=5.10, P.005). Age, sex, BMI, comorbidities, cognitive status, and medication use were not associated with subsequent fracture.Hip fractures are a sentinel event in nursing home residents, with a high incidence of subsequent fracture and death occurring within 1 year. Identification of prefracture characteristics and postfracture complications associated with mortality should help guide secondary prevention efforts in nursing home residents.

The objective of this study was to determine the relation between bone mass and the incidence of coronary heart disease in women and men. Participants included 2,059 cohort members of the Framingham Study (1,236 women and 823 men aged 47-80 years) who underwent posteroanterior hand radiography and were free from cardiovascular disease at baseline (1967-1970) and who were then followed for 30 years through the end of 1997 for the incidence of coronary heart disease. The incidence of coronary heart disease decreased from 15.65/1,000 person-years among women in the lowest metacarpal cortical area quartile to 11.76/1,000 person-years among women in the highest quartile (p(trend) = 0.03), and the inverse relation persisted after adjustment for confounders (highest vs. lowest quartile of metacarpal cortical area: hazard ratio = 0.73, 95% confidence interval: 0.53, 1.00; p(trend) = 0.03). In contrast, no association was present in men (highest vs. lowest quartile of metacarpal cortical area: hazard ratio = 1.14, 95% confidence interval: 0.84, 1.56; p(trend) = 0.55).

Racial differences in cervical cancer mortality in Chicago were examined. Age-adjusted mortality in Blacks (10.0/100,000) was over twice the rate found in Whites (4.6/100,000). Age-specific rates also showed significant excess mortality among Blacks. After stratification by a group-level defined poverty indicator, the race differential in age-adjusted rates remained significant. The race differential in age-specific rates diminished in the group with more than 30% living below the national poverty level, in contrast to the group with 30% or fewer living below the national poverty level, in whom race differences were more marked. Methodological issues concerning hysterectomy prevalence, Hispanic ethnicity, and social class must be considered with respect to interpretation of these findings.

Background Older persons with hip fractures remain at increased risk of subsequent hip fractures. However, little is known about the frequency and characteristics of persons who sustain a second hip fracture. Methods Participants included 481 members of the Framingham Heart Study who sustained an initial hip fracture between April 1952 and December 31, 2003. Participants were followed up until a second hip fracture, death, dropout, or study completion. Age, sex, falls, stroke, dementia, residence, recent weight change, body mass index, and functional status were considered potential predictors of a second hip fracture. Results During a median of 4.2 years of follow-up, 71 subjects (14.8%) experienced a second hip fracture. Following a first hip fracture, 2.5% of subjects experienced a second hip fracture within 1 year, and 8.2% of subjects (9.7% of women) experienced a second hip fracture within 5 years. One-year mortality following an initial hip fracture was 15.9% compared with 1-year mortality following a second hip fracture of 24.1%. The risk of a second hip fracture increased with age (hazard ratio [HR] per 5-year increase in age, 1.5; 95% confidence interval [CI], 1.1-1.8) and with high functional status (HR compared with moderate functional status, 2.7; 95% CI, 1.1-6.9). There was a statistically nonsignificant association between low functional status and the risk of second hip fracture (HR compared with moderate functional status, 3.7; 95% CI, 0.9-14.8). Conclusions Among survivors of an initial hip fracture, the incidence of a second hip fracture is substantial. Older age and functional status may be important predictors of a second hip fracture. There seems to be adequate time between the first and second hip fractures for interventions that may reduce second hip fractures.

Background Falls are the sixth leading cause of death in elderly people in the U.S. Despite progress in understanding risk factors for falls, many suspected risk factors have not been adequately studied. Putative risk factors for falls such as pain, reductions in cerebral blood flow, somatosensory deficits, and foot disorders are poorly understood, in part because they pose measurement challenges, particularly for large observational studies. Methods The MOBILIZE Boston Study (MBS), an NIA-funded Program Project, is a prospective cohort study of a unique set of risk factors for falls in seniors in the Boston area. Using a door-to-door population-based recruitment, we have enrolled 765 persons aged 70 and older. The baseline assessment was conducted in 2 segments: a 3-hour home interview followed within 4 weeks by a 3-hour clinic examination. Measures included pain, cerebral hemodynamics, and foot disorders as well as established fall risk factors. For the falls follow-up, participants return fall calendar postcards to the research center at the end of each month. Reports of falls are followed-up with a telephone interview to assess circumstances and consequences of each fall. A second assessment is performed 18 months following baseline. Results Of the 2382 who met all eligibility criteria at the door, 1616 (67.8%) agreed to participate and were referred to the research center for further screening. The primary reason for ineligibility was inability to communicate in English. Results from the first 600 participants showed that participants are largely representative of seniors in the Boston area in terms of age, sex, race and Hispanic ethnicity. The average age of study participants was 77.9 years (s.d. 5.5) and nearly two-thirds were women. The study cohort was 78% white and 17% black. Many participants (39%) reported having fallen at least once in the year before baseline. Conclusion Our results demonstrate the feasibility of conducting comprehensive assessments, including rigorous physiologic measurements, in a diverse population of older adults to study non-traditional risk factors for falls and disability. The MBS will provide an important new data resource for examining novel risk factors for falls and mobility problems in the older population.