Vascular function and skeletal fragility: A study of tonometry, brachial hemodynamics, and bone microarchitecture.

Osteoporosis and cardiovascular disease frequently occur together in older adults; however, a causal relationship between these two common conditions has not been established. By the time clinical cardiovascular disease develops, it is often too late to test whether vascular dysfunction developed before or after the onset of osteoporosis. Therefore, we assessed the association of vascular function, measured by tonometry and brachial hemodynamic testing, with bone density, microarchitecture, and strength, measured by high-resolution peripheral quantitative computed tomography (HR-pQCT), in 1391 individuals in the Framingham Heart Study. We hypothesized that decreased vascular function (pulse wave velocity, primary pressure wave, brachial pulse pressure, baseline flow amplitude and brachial flow velocity) contributes to deficits in bone density, microarchitecture and strength, particularly in cortical bone, which is less protected from excessive blood flow pulsatility than the trabecular compartment. We found that individuals with increased carotid-femoral pulse wave velocity had lower cortical volumetric bone mineral density (tibia: -0.21 [-0.26,-0.15] standardized beta [95% confidence interval], radius: -0.20 [-0.26,-0.15]), lower cortical thickness (tibia: -0.09 [-0.15,-0.04], radius: -0.07 [-0.12,-0.01]) and increased cortical porosity (tibia: 0.20 [0.15,0.25], radius: 0.21 [0.15,0.27]). However, these associations did not persist after adjustment for age, sex, height, and weight. These results suggest that vascular dysfunction with aging may not be an etiologic mechanism that contributes to the co-occurrence of osteoporosis and cardiovascular disease in older adults. Further study employing longitudinal measures of HR-pQCT parameters is needed to fully elucidate the link between vascular function and bone health.

Osteoporosis and heart disease are both medical conditions that commonly develop in older age. It is not known whether abnormal functioning of blood vessels contributes to the development of bone fragility with aging. In this study, we investigated the relationship between impaired blood vessel function and bone density and micro-structure in a group of 1391 people enrolled in the Framingham Heart Study. Blood vessel function was measured using specialized tools to assess blood flow and pressure. Bone density and micro-structure were measured using advanced imaging called high-resolution peripheral quantitative computed tomography (HR-pQCT). We found that people with impaired blood vessel function tended to have lower bone density and worse deterioration in bone micro-structure. However, once we statistically controlled for age and sex and other confounders, we did not find any association between blood vessel function and bone measures. Overall, our results showed that older adults with impaired blood vessel function do not exhibit greater deterioration in the skeleton.

Association of bone fracture with 30-year body mass index (BMI) trajectories: findings from the Framingham Heart Study : Bone fracture and 30-year BMI trajectories.

A knowledge gap exists in associating later life's osteoporotic fracture and middle adulthood's BMI trajectories. We observed an association showing those transitioning from overweight to normal weight face a higher fracture risk in late adulthood, emphasizing the potential benefits of maintaining a stable BMI to reduce late-life fractures. PURPOSE: Numerous studies on the relationship between obesity and fractures have relied on body mass index (BMI) at a single time point, yielding inconclusive results. This study investigated the association of BMI trajectories over middle adulthood with fracture risk in late adulthood. METHODS: This prospective cohort study analyzed 1772 qualified participants from the Framingham Original Cohort Study, with 292 (16.5%) incident fractures during an average of 17.1-year follow-up. We constructed BMI trajectories of age 35-64 years based on latent class mixed modeling and explored their association with the risk of fracture after 65 years using the Cox regression. RESULTS: The result showed that compared to the BMI trajectory Group 4 (normal to slightly overweight; see "Methods" for detailed description), Group 1 (overweight declined to normal weight) had a higher all-fracture risk after age 65 (hazard ratio [HR], 2.22, 95% CI, 1.13-4.39). The secondary analysis focusing on lower extremity fractures (pelvis, hip, leg, and foot) showed a similar association pattern. CONCLUSIONS: This study suggested that people whose BMI slightly increased from normal weight to low-level overweight during 30 years of middle adulthood confer a significantly lower risk of fracture in later life than those whose BMI declined from overweight to normal weight. This result implies the potentially beneficial effects of avoiding weight loss to normal weight during middle adulthood for overweight persons, with reduced fracture risk in late life.

Fracture risk based on high-resolution peripheral quantitative computed tomography measures does not vary with age in older adults-the bone microarchitecture international consortium prospective cohort study.

Fracture risk increases with lower areal bone mineral density (aBMD); however, aBMD-related estimate of risk may decrease with age. This may depend on technical limitations of 2-dimensional (2D) dual energy X-ray absorptiometry (DXA) which are reduced with 3D high-resolution peripheral quantitative computed tomography (HR-pQCT). Our aim was to examine whether the predictive utility of HR-pQCT measures with fracture varies with age. We analyzed associations of HR-pQCT measures at the distal radius and distal tibia with two outcomes: incident fractures and major osteoporotic fractures. We censored follow-up time at first fracture, death, last contact or 8 years after baseline. We estimated hazard ratios (HR) and 95%CI for the association between bone traits and fracture incidence across age quintiles. Among 6835 men and women (ages 40-96) with at least one valid baseline HR-pQCT scan who were followed prospectively for a median of 48.3 months, 681 sustained fractures. After adjustment for confounders, bone parameters at both the radius and tibia were associated with higher fracture risk. The estimated HRs for fracture did not vary significantly across age quintiles for any HR-pQCT parameter measured at either the radius or tibia. In this large cohort, the homogeneity of the associations between the HR-pQCT measures and fracture risk across age groups persisted for all fractures and for major osteoporotic fractures. The patterns were similar regardless of the HR-pQCT measure, the type of fracture, or the statistical models. The stability of the associations between HR-pQCT measures and fracture over a broad age range shows that bone deficits or low volumetric density remain major determinants of fracture risk regardless of age group. The lower risk for fractures across measures of aBMD in older adults in other studies may be related to factors which interfere with DXA but not with HR-pQCT measures.

Muscle Reference Values From Thoracic and Abdominal CT for Sarcopenia Assessment: The Framingham Heart Study.

BACKGROUND: Loss of muscle mass is a known feature of sarcopenia and predicts poor clinical outcomes. Although muscle metrics can be derived from routine computed tomography (CT) images, sex-specific reference values at multiple vertebral levels over a wide age range are lacking. OBJECTIVE: The aim of this study was to provide reference values for skeletal muscle mass and attenuation on thoracic and abdominal CT scans in the community-based Framingham Heart Study cohort to aid in the identification of sarcopenia. MATERIALS AND METHODS: This secondary analysis of a prospective trial describes muscle metrics by age and sex for participants from the Framingham Heart Study without prior history of cancer who underwent at least 1 CT scan between 2002 and 2011. Using 2 previously validated machine learning algorithms followed by human quality assurance, skeletal muscle was analyzed on a single axial CT image per level at the 5th, 8th, 10th thoracic, and 3rd lumbar vertebral body (T5, T8, T10, L3). Cross-sectional muscle area (cm 2 ), mean skeletal muscle radioattenuation (SMRA, in Hounsfield units), skeletal muscle index (SMI, in cm 2 /m 2 ), and skeletal muscle gauge (SMRA·SMI) were calculated. Measurements were summarized by age group (<45, 45-54, 55-64, 65-74, ≥75 years), sex, and vertebral level. Models enabling the calculation of age-, sex-, and vertebral-level-specific reference values were created and embedded into an open access online Web application. RESULTS: The cohort consisted of 3804 participants (1917 [50.4%] males; mean age, 55.6 ± 11.8 years; range, 33-92 years) and 7162 CT scans. Muscle metrics qualitatively decreased with increasing age and female sex. CONCLUSIONS: This study established age- and sex-specific reference values for CT-based muscle metrics at thoracic and lumbar vertebral levels. These values may be used in future research investigating the role of muscle mass and attenuation in health and disease, and to identify sarcopenia.

Performance of FRAX in older adults with frailty: the Framingham Heart Study.

We compared the performance of FRAX according to frailty status in 3554 individuals from the Framingham Study. During 10-year follow-up, 6.9% and 3.0% of participants with and without frailty experienced MOF. Discrimination profiles were lower in participants with frailty compared to those without, but they improved when FRAX included BMD. INTRODUCTION: Frailty increases fracture risk. FRAX was developed to predict fractures but never validated in individuals with frailty. We aimed to compare the predictive performance of FRAX (v4.3) in individuals with and without frailty. METHODS: We conducted a cohort study using the Framingham Heart Study. Frailty was defined by the Fried phenotype. Major osteoporotic fractures (MOF) were ascertained from medical records during 10-year follow-up. To evaluate discrimination and calibration of FRAX, we calculated the area-under-the-receiver-operating characteristics curves (AUC) using logistic regression models and observed-to-predicted fracture probabilities. Analyses were stratified by frailty status. RESULTS: Frailty was present in 550/3554 (15.5%) of participants. Participants with frailty were older (81.1 vs. 67.6 years), female (68.6% vs. 55.1%), and had greater mean FRAX scores (MOF: 15.9% vs. 10.1%) than participants without frailty. During follow-up, 38 participants with frailty (6.9%) and 91 without (3.0%) had MOFs. The AUC for FRAX (without BMD) was lower in participants with frailty (0.584; 95% CI 0.504-0.663) compared to those without (0.695; 95% CI 0.649-0.741); p value = 0.02. Among participants with frailty, the AUC improved when FRAX included BMD (AUC 0.658, p value < 0.01). FRAX overestimated MOF risk, with larger overestimations in individuals without frailty. Performance of FRAX for hip fracture was similar. CONCLUSION: FRAX may have been less able to identify frail individuals at risk for fracture, as compared with individuals without frailty, unless information on BMD is available. This suggests that BMD captures features important for fracture prediction in frail persons. Future fracture prediction models should be developed among persons with frailty.

A Fracture Risk Assessment Tool for High Resolution Peripheral Quantitative Computed Tomography.

Most fracture risk assessment tools use clinical risk factors combined with bone mineral density (BMD) to improve assessment of osteoporosis; however, stratifying fracture risk remains challenging. This study developed a fracture risk assessment tool that uses information about volumetric bone density and three-dimensional structure, obtained using high-resolution peripheral quantitative compute tomography (HR-pQCT), to provide an alternative approach for patient-specific assessment of fracture risk. Using an international prospective cohort of older adults (n = 6802) we developed a tool to predict osteoporotic fracture risk, called µFRAC. The model was constructed using random survival forests, and input predictors included HR-pQCT parameters summarizing BMD and microarchitecture alongside clinical risk factors (sex, age, height, weight, and prior adulthood fracture) and femoral neck areal BMD (FN aBMD). The performance of µFRAC was compared to the Fracture Risk Assessment Tool (FRAX) and a reference model built using FN aBMD and clinical covariates. µFRAC was predictive of osteoporotic fracture (c-index = 0.673, p < 0.001), modestly outperforming FRAX and FN aBMD models (c-index = 0.617 and 0.636, respectively). Removal of FN aBMD and all clinical risk factors, except age, from µFRAC did not significantly impact its performance when estimating 5-year and 10-year fracture risk. The performance of µFRAC improved when only major osteoporotic fractures were considered (c-index = 0.733, p < 0.001). We developed a personalized fracture risk assessment tool based on HR-pQCT that may provide an alternative approach to current clinical methods by leveraging direct measures of bone density and structure. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Bone Microarchitecture Phenotypes Identified in Older Adults Are Associated With Different Levels of Osteoporotic Fracture Risk.

Prevalence of osteoporosis is more than 50% in older adults, yet current clinical methods for diagnosis that rely on areal bone mineral density (aBMD) fail to detect most individuals who have a fragility fracture. Bone fragility can manifest in different forms, and a "one-size-fits-all" approach to diagnosis and management of osteoporosis may not be suitable. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides additive information by capturing information about volumetric density and microarchitecture, but interpretation is challenging because of the complex interactions between the numerous properties measured. In this study, we propose that there are common combinations of bone properties, referred to as phenotypes, that are predisposed to different levels of fracture risk. Using HR-pQCT data from a multinational cohort (n = 5873, 71% female) between 40 and 96 years of age, we employed fuzzy c-means clustering, an unsupervised machine-learning method, to identify phenotypes of bone microarchitecture. Three clusters were identified, and using partial correlation analysis of HR-pQCT parameters, we characterized the clusters as low density, low volume, and healthy bone phenotypes. Most males were associated with the healthy bone phenotype, whereas females were more often associated with the low volume or low density bone phenotypes. Each phenotype had a significantly different cumulative hazard of major osteoporotic fracture (MOF) and of any incident osteoporotic fracture (p < 0.05). After adjustment for covariates (cohort, sex, and age), the low density followed by the low volume phenotype had the highest association with MOF (hazard ratio = 2.96 and 2.35, respectively), and significant associations were maintained when additionally adjusted for femoral neck aBMD (hazard ratio = 1.69 and 1.90, respectively). Further, within each phenotype, different imaging biomarkers of fracture were identified. These findings suggest that osteoporotic fracture risk is associated with bone phenotypes that capture key features of bone deterioration that are not distinguishable by aBMD. © 2021 American Society for Bone and Mineral Research (ASBMR).

Higher Hand Grip Strength Is Associated With Greater Radius Bone Size and Strength in Older Men and Women: The Framingham Osteoporosis Study.

Mechanical loading by muscles elicits anabolic responses from bone, thus age-related declines in muscle strength may contribute to bone fragility in older adults. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to determine the association between grip strength and distal radius bone density, size, morphology, and microarchitecture, as well as bone strength estimated by micro-finite element analysis (µFEA), among older men and women. Participants included 508 men and 651 women participating in the Framingham Offspring Study with grip strength measured in 2011-2014 and HR-pQCT scanning in 2012-2015. Separately for men and women, analysis of covariance was used to compare HR-pQCT measures among grip strength quartiles and to test for linear trends, adjusting for age, height, weight, smoking, and physical activity. Mean age was 70 years (range, 50-95 years), and men had higher mean grip strength than the women (37 kg vs. 21 kg). Bone strength estimated by µFEA-calculated failure load was higher with greater grip strength in both men (p < 0.01) and women (p = 0.04). Higher grip strength was associated with larger cross-sectional area in both men and women (p < 0.01), with differences in area of 6% and 11% between the lowest to highest grip strength quartiles in men and women, respectively. Cortical thickness was positively associated with grip strength among men only (p = 0.03). Grip strength was not associated with volumetric BMD (vBMD) in men. Conversely, there was a trend for lower total vBMD with higher grip strength among women (p = 0.02), though pairwise comparisons did not reveal any statistically significant differences in total vBMD among grip strength quartiles. Bone microarchitecture (cortical porosity, trabecular thickness, trabecular number) was not associated with grip strength in either men or women. Our findings suggest that the positive association between hand grip strength and distal radius bone strength may be driven primarily by bone size. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Risk Factors for Incident Fracture in Older Adults With Type 2 Diabetes: The Framingham Heart Study.

OBJECTIVE: To identify risk factors for fracture in type 2 diabetes. RESEARCH DESIGN AND METHODS: This prospective study included members of the Framingham Original and Offspring Cohorts. Type 2 diabetes was defined as fasting plasma glucose >125 mg/dL or use of type 2 diabetes therapy. We used repeated-measures Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% CIs for associations between potential predictors and incidence of fragility fracture. RESULTS: Participants included 793 individuals with type 2 diabetes. Mean ± SD age was 70 ± 10 years; 45% were women. A total of 106 incident fractures occurred over 1,437 observation follow-up intervals. Fracture incidence increased with age (adjusted HRs 1.00, 1.44 [95% CI 0.65, 3.16], and 2.40 [1.14, 5.04] for <60, 60-70, and >70 years, respectively; P trend = 0.02), female sex (2.23 [1.26, 3.95]), HbA1c (1.00, 2.10 [1.17, 3.75], and 1.29 [0.69, 2.41] for 4.45-6.46% [25-47 mmol/mol], 6.50-7.49% [48-58 mmol/mol], and 7.50-13.86% [58-128 mmol/mol]; P trend =0.03), falls in past year (1.00, 1.87 [0.82, 4.28], and 3.29 [1.34, 8.09] for no falls, one fall, and two or more falls; P trend =0.03), fracture history (2.05 [1.34, 3.12]), and lower grip strength (0.82 [0.69, 0.99] per 5-kg increase). Femoral neck bone mineral density, BMI, smoking, physical function, chronic diseases, medications, and physical function were not associated with fracture incidence. CONCLUSIONS: Prior falls, fractures, low grip strength, and elevated HbA1c are risk factors for fractures in older adults with type 2 diabetes. Evaluation of these factors may improve opportunities for early intervention and reduce fractures in this high-risk group.

Association Between Liver Fat and Bone Density is Confounded by General and Visceral Adiposity in a Community-Based Cohort.

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.

Bone Turnover Markers Do Not Predict Fracture Risk in Type 2 Diabetes.

Type 2 diabetes (T2D) is characterized by increased fracture risk despite higher BMD and reduced bone turnover. BMD underestimates fracture risk in T2D, but the predictive role of bone turnover markers (BTMs) on fracture risk in T2D has not been explored. Thus, we sought to determine whether BTMs predict incident fractures in subjects with T2D. For this case-cohort study, we used data from the Health, Aging, and Body Composition (Health ABC) Study of well-functioning older adults, aged 70 to 79 years at baseline (April 1997-June 1998). The case-cohort sample consisted of (i) the cases, composed of all 223 participants who experienced incident fractures of the hip, clinical spine, or distal forearm within the first 9 years of study follow-up; and (ii) the subcohort of 508 randomly sampled participants from three strata at baseline (T2D, prediabetes, and normoglycemia) from the entire Health ABC cohort. A total of 690 subjects (223 cases, of whom 41 were in the subcohort) were included in analyses. BTMs (C-terminal telopeptide of type I collagen [CTX], osteocalcin [OC], and procollagen type 1 N-terminal propeptide [P1NP]) were measured in archived baseline serum. Cox regression with robust variance estimation was used to estimate the adjusted hazard ratio (HR) for fracture per 20% increase in BTMs. In nondiabetes (prediabetes plus normoglycemia), fracture risk was increased with higher CTX (HR 1.10; 95% confidence interval [CI], 1.01 to 1.20 for each 20% increase in CTX). Risk was not increased in T2D (HR 0.92; 95% CI, 0.81 to 1.04; p for interaction .045). Similarly, both OC and P1NP were associated with higher risk of fracture in nondiabetes, but not in T2D, with p for interaction of .078 and .109, respectively. In conclusion, BTMs did not predict incident fracture risk in T2D but were modestly associated with fracture risk in nondiabetes. © 2020 American Society for Bone and Mineral Research.

Heterogeneity and Spatial Distribution of Intravertebral Trabecular Bone Mineral Density in the Lumbar Spine Is Associated With Prevalent Vertebral Fracture.

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.

Effect of Insulin Resistance on BMD and Fracture Risk in Older Adults.

CONTEXT: Adults with type 2 diabetes (T2D) have higher fracture risk compared with nondiabetics, despite having higher bone mineral density (BMD). Insulin resistance (IR) has been associated with increased BMD. It is not known if IR increases fracture risk. OBJECTIVE: We investigated the relationship among IR HOMA-IR, BMD, and incident nonspine fractures in nondiabetic individuals. DESIGN: Participants included 2398 community-dwelling, nondiabetic older adults (age 74 ± 3 years, 53% women, 38% black) in the Health, Aging and Body Composition Prospective Cohort Study [median follow-up: 12 (interquartile range: 6) years]. RESULTS: The cut-off values for the HOMA-IR quartiles were 1.05, 1.54, and 2.33. Total hip BMD was 0.104 g/cm2 higher in the fourth vs the first HOMA-IR quartile (P < 0.001). This difference was attenuated after adjustment for BMI (adjusted mean difference 0.007 g/cm2; P = 0.371). In unadjusted models, fracture risk was lower in those with higher HOMA-IR [hazard ratio (HR) 0.86 (95% CI 0.73 to 1.01) and 0.65 (95% CI 0.47 to 0.89) for the third and fourth quartile, respectively, vs the first quartile]. However, after adjustment for BMD and BMI, fracture risk was significantly higher in the third quartile (HR 1.19, 95% CI 1.00 to 1.41) and tended to be increased in the fourth quartile (HR 1.12, 95% CI 0.87 to 1.46) vs the first quartile. CONCLUSIONS: Greater IR is associated with higher BMD in nondiabetic older adults. In contrast to the relationship between T2D and fracture risk, we did not find consistent evidence that greater IR is associated with increased fracture risk after adjustment for BMI and BMD.

A Longitudinal Study of Trunk Muscle Properties and Severity of Thoracic Kyphosis in Women and Men: The Framingham Study.

BACKGROUND: Cross-sectional studies suggest that trunk muscle morphology in the lumbar spine is an important determinant of kyphosis severity in older adults. The contribution of age-related changes in muscle morphology in the thoracic and lumbar spine to progression of kyphosis is not known. Our objective was to determine cross-sectional and longitudinal associations of thoracic and lumbar muscle size and density with kyphosis. METHODS: Participants were 1,087 women and men (mean age: 61 years) of the Framingham Heart Study who underwent baseline and follow-up quantitative computed tomography (QCT) scanning 6 years apart. We used QCT scans to measure trunk muscle cross-sectional area (CSA, cm2) and density (HU) at the thoracic and lumbar spine and Cobb angle (degrees) from T4 to T12. Linear regression models estimated the association between muscle morphology and kyphosis. RESULTS: At baseline, smaller muscle CSA and lower density of thoracic (but not lumbar) spine muscles were associated with a larger (worse) Cobb angle in women and men. For example, each standard deviation decrease in baseline thoracic paraspinal muscle CSA was associated with a larger baseline Cobb angle in women (3.7 degrees, 95% CI: 2.9, 4.5) and men (2.5 degrees, 95% CI: 1.6, 3.3). Longitudinal analyses showed that loss of muscle CSA and density at the thoracic and lumbar spine was not associated with progression of kyphosis. CONCLUSIONS: Our findings suggest that kyphosis severity is related to smaller and lower density trunk muscles at the thoracic spine. Future studies are needed to determine how strengthening mid-back musculature alters muscle properties and contributes to preventing kyphosis progression.

Cortical and trabecular bone microarchitecture as an independent predictor of incident fracture risk in older women and men in the Bone Microarchitecture International Consortium (BoMIC): a prospective study.

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

Correspondence between bone mineral density and intervertebral disc degeneration across age and sex.

The distribution of bone tissue within the vertebra can modulate vertebral strength independently of average density and may change with age and disc degeneration. Our results show that the age-associated decrease in bone density is spatially non-uniform and associated with disc health, suggesting a mechanistic interplay between disc and vertebra. PURPOSE: While the decline of bone mineral density (BMD) in the aging spine is well established, the extent to which age influences BMD distribution within the vertebra is less clear. Measures of regional BMD (rBMD) may improve predictions of vertebral strength and suggest how vertebrae might adapt with intervertebral disc degeneration. Thus, we aimed to assess how rBMD values were associated with age, sex, and disc height loss (DHL). METHODS: We measured rBMD in the L3 vertebra of 377 participants from the Framingham Heart Study (41-83 years, 181 M/196 F). Integral (Int.BMD) and trabecular BMD (Tb.BMD) were measured from QCT images. rBMD ratios (anterior/posterior, superior/mid-transverse, inferior/mid-transverse, and central/outer) were calculated from the centrum. A radiologist assigned a DHL severity score to adjacent intervertebral discs (L2-L3 and L3-L4). RESULTS: Int.BMD and Tb.BMD were both associated with age, though the decrease across age was greater in women (Int.BMD, - 2.6 mg/cm3 per year; Tb.BMD, - 2.6 mg/cm3 per year) than men (Int.BMD, - 0.5 mg/cm3 per year; Tb.BMD, - 1.2 mg/cm3 per year). The central/outer (- 0.027/decade) and superior/mid-transverse (- 0.018/decade) rBMD ratios were negatively associated with age, with similar trends in men and women. Higher Int.BMD or Tb.BMD was associated with increased odds of DHL after adjusting for age and sex. Low central/outer ratio and high anterior/poster and superior/mid-transverse ratios were also associated with increased odds of DHL. CONCLUSIONS: Our results indicate that the distribution of bone within the L3 vertebra is different across age, but not between sexes, and is associated with disc degeneration.

Long-Term and Recent Weight Change Are Associated With Reduced Peripheral Bone Density, Deficits in Bone Microarchitecture, and Decreased Bone Strength: The Framingham Osteoporosis Study.

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.

A longitudinal study of disc height narrowing and facet joint osteoarthritis at the thoracic and lumbar spine, evaluated by computed tomography: the Framingham Study.

BACKGROUND CONTEXT: Prevalence and progression of disc height narrowing (DHN) and facet joint osteoarthritis (FJOA) in the thoracic and lumbar regions in non-clinical populations are not well established. PURPOSE: The present study aimed to use computed tomography (CT) images to determine the prevalence and progression of DHN and FJOA according to age, sex, and spinal region. STUDY DESIGN: This is a 6-year longitudinal study. SAMPLE: A total of 1,195 members of the Framingham Study (mean baseline age 61±9 years) were included in the study. OUTCOME MEASURES: We compared the prevalence and progression (new or worsening) of moderate-to-severe DHN and FJOA by age, sex, and spinal region. METHODS: A musculoskeletal radiologist evaluated DHN and FJOA from T4/T5 to L4/L5 on baseline and follow-up CT images using a semi-quantitative scale: 0=normal, 1=mild, 2=moderate, and 3=severe. RESULTS: One-third or more of women and men ages 40-59 years at baseline had imaged-based evidence of prevalent DHN, more than half had prevalent FJOA, and DHN and FJOA prevalence increased approximately two- to fourfold in those age 60-69 and 70-89 years at baseline, respectively (p<.01). Progression of DHN and FJOA occurred more frequently at the lumbar than at the thoracic spine and more in women than in men (DHN: odds ratio [OR]=1.42, 95% confidence interval [CI]=1.07, 1.88; FJOA: OR=1.70, CI=1.33, 2.17). CONCLUSIONS: Prevalence and progression of moderate-to-severe DHN and FJOA are common in non-clinical populations of older adults. The high frequency of spinal degeneration observed on CTs in this community-based study may contribute to challenges in interpreting the clinical significance of imaging evidence of DHN and FJOA. Future studies investigating the association of CT-based spinal degenerative features with pain and functional impairments in population-based samples are needed to help determine the clinical significance of imaged-based findings of DHN and FJOA.

Diabetes and Deficits in Cortical Bone Density, Microarchitecture, and Bone Size: Framingham HR-pQCT Study.

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

Thoracic Kyphosis and Physical Function: The Framingham Study.

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.