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.

Genetic variants modify the associations of concentrations of methylmalonic acid, vitamin B-12, vitamin B-6, and folate with bone mineral density.

BACKGROUND: Elevated plasma homocysteine has been found to be associated with an increased risk of osteoporosis, especially hip and vertebral fractures. The plasma concentration of homocysteine is dependent on the activities of several B vitamin-dependent enzymes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and cystathionine ß-synthase (CBS). OBJECTIVES: We investigated whether genetic variants in some of the genes involved in 1 carbon metabolism modify the association of B vitamin-related measures with bone mineral density (BMD) and strength. METHODS: We measured several B vitamins and biomarkers in participants of the Framingham Offspring Study, and performed analyses of methylmalonic acid (MMA) continuously and <210 nmol/L; pyridoxal-5'-phosphate; vitamin B-12 continuously and ≥258 pmol/L; and folate. The outcomes of interest included areal and volumetric BMD, measured by DXA and quantitative computed tomography (QCT), respectively. We evaluated associations between the bone measures and interactions of single nucleotide polymorphism with a B vitamin or biomarker in Framingham participants (n = 4310 for DXA and n = 3127 for QCT). For analysis of DXA, we validated the association results in the B-PROOF cohort (n = 1072). Bonferroni-corrected locus-wide significant thresholds were defined to account for multiple testing. RESULTS: The interactions between rs2274976 and vitamin B-12 and rs34671784 and MMA <210 nmol/L were associated with lumbar spine BMD, and the interaction between rs6586281 and vitamin B-12 ≥258 pmol/L was associated with femoral neck BMD. For QCT-derived traits, 62 interactions between genetic variants and B vitamins and biomarkers were identified. CONCLUSIONS: Some genetic variants in the 1-carbon methylation pathway modify the association of B vitamin and biomarker concentrations with bone density and strength.  These interactions require further replication and functional validation for a mechanistic understanding of the role of the 1-carbon metabolism pathway on BMD and risks of fracture.

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.

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.

Lower Lean Mass Measured by Dual-Energy X-ray Absorptiometry (DXA) is Not Associated with Increased Risk of Hip Fracture in Women: The Framingham Osteoporosis Study.

Although muscle mass influences strength in older adults, it is unclear whether low lean mass measured by dual-energy X-ray absorptiometry (DXA) is an independent risk factor for hip fracture. Our objective was to determine the association between DXA lean mass and incident hip fracture risk among 1978 women aged 50 years and older participating in the Framingham Study Original and Offspring cohorts. Leg and total body lean mass (kg) were assessed from whole-body DXA scans collected in 1992-2001. Hip fracture follow-up extended from DXA assessment to the occurrence of fracture, death, drop-out, or end of follow-up in 2007. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) estimating the relative risk of hip fracture associated with a 1-kg increase in baseline lean mass. Mean age was 66 years (range 50-93). Over a median of 8 years of follow-up, 99 hip fractures occurred. In models adjusted for age, height, study cohort, and percent total body fat, neither leg (HR 1.11; 95% CI 0.94, 1.31) nor total body (HR 1.06; 95% CI 0.99, 1.13) lean mass were associated with hip fracture. After further adjustment for femoral neck bone mineral density, leg lean mass results were similar (HR 1.10; 95% CI 0.93, 1.30). In contrast, 1 kg greater total body lean mass was associated with 9% higher hip fracture risk (HR 1.09; 95% CI 1.02, 1.18). Our findings suggest that in women, lower lean mass measured by DXA is not associated with increased risk of hip fracture.

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.

Bone Strength Estimated by Micro-Finite Element Analysis (µFEA) Is Heritable and Shares Genetic Predisposition With Areal BMD: The Framingham Study.

Genetic factors contribute to the risk of bone fractures, partly because of effects on bone strength. High-resolution peripheral quantitative computed tomography (HR-pQCT) estimates bone strength using micro-finite element analysis (µFEA). The goal of this study was to investigate if the bone failure load estimated by HR-pQCT-based µFEA is heritable and to what extent it shares genetic regulation with areal bone mineral density (aBMD). Bone microarchitecture was measured by HR-pQCT at the ultradistal tibia and ultradistal radius in adults from the Framingham Heart Study (n = 1087, mean age 72 years; 57% women). Radial and tibial failure load in compression were estimated by µFEA. Femoral neck (FN) and ultradistal forearm (UD) aBMD were measured by dual-energy X-ray absorptiometry (DXA). Heritability (h2 ) of failure load and aBMD and genetic correlations between them was estimated adjusting for covariates (age and sex). Failure load values at the non-weight-bearing ultradistal radius and at the weight-bearing ultradistal tibia were highly correlated (r = 0.906; p < 0.001). Estimates of h2 adjusted for covariates were 0.522 for the radius and 0.497 for the tibia. Additional adjustment for height did not impact on the h2 results, but adjustment for aBMD at the UD and FN somewhat decreased h2 point estimates: 0.222 and 0.380 for radius and tibia, respectively. In bivariate analysis, there was a high phenotypic and genetic correlation between covariate-adjusted failure load at the radius and UD aBMD (ρP = 0.826, ρG = 0.954, respectively), whereas environmental correlations were lower (ρE = 0.696), all highly significant (p < 0.001). Similar correlations were observed between tibial failure load and femoral neck aBMD (ρP = 0.577, ρG = 0.703, both p < 0.001; ρE = 0.432, p < 0.05). These data from adult members of families from a population-based cohort suggest that bone strength of distal extremities estimated by micro-finite element analysis is heritable and shares some genetic composition with areal BMD, regardless of the skeletal site. © 2017 American Society for Bone and Mineral Research.

Visceral Adipose Tissue Is Associated With Bone Microarchitecture in the Framingham Osteoporosis Study.

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

Heritability and Genetic Correlations for Bone Microarchitecture: The Framingham Study Families.

High-resolution peripheral quantitative computed tomography (HR-pQCT) measures bone microarchitecture and volumetric bone mineral density (vBMD), important risk factors for osteoporotic fractures. We estimated the heritability (h2 ) of bone microstructure indices and vBMD, measured by HR-pQCT, and genetic correlations (ρG ) among them and between them and regional aBMD measured by dual-energy X-ray absorptiometry (DXA), in adult relatives from the Framingham Heart Study. Cortical (Ct) and trabecular (Tb) traits were measured at the distal radius and tibia in up to 1047 participants, and ultradistal radius (UD) aBMD was obtained by DXA. Heritability estimates, adjusted for age, sex, and estrogenic status (in women), ranged from 19.3% (trabecular number) to 82.8% (p < 0.01, Ct.vBMD) in the radius and from 51.9% (trabecular thickness) to 98.3% (cortical cross-sectional area fraction) in the tibia. Additional adjustments for height, weight, and radial aBMD had no major effect on h2 estimates. In bivariate analyses, moderate to high genetic correlations were found between radial total vBMD and microarchitecture traits (ρG from 0.227 to 0.913), except for cortical porosity. At the tibia, a similar pattern of genetic correlations was observed (ρG from 0.274 to 0.948), except for cortical porosity. Environmental correlations between the microarchitecture traits were also substantial. There were high genetic correlations between UD aBMD and multivariable-adjusted total and trabecular vBMD at the radius (ρG = 0.811 and 0.917, respectively). In summary, in related men and women from a population-based cohort, cortical and trabecular microarchitecture and vBMD at the radius and tibia were heritable and shared some h2 with regional aBMD measured by DXA. These findings of high heritability of HR-pQCT traits, with a slight attenuation when adjusting for aBMD, supports further work to identify the specific variants underlying volumetric bone density and fine structure of long bones. Knowledge that some of these traits are genetically correlated can serve to reduce the number of traits for genetic association studies. © 2016 American Society for Bone and Mineral Research.

Oxandrolone Augmentation of Resistance Training in Older Women: A Randomized Trial.

INTRODUCTION: Sarcopenia is disproportionately present in older women with disability, and optimum treatment is not clear. We conducted a double-blind, randomized, placebo-controlled trial to determine whether oxandrolone administration in elderly women improves body composition or physical function beyond that which occurs in response to progressive resistance training (PRT). METHODS: Twenty-nine sedentary women (age 74.9 ± 6.8 yr; 5.9 ± 2.8 medications per day) were randomized to receive high-intensity PRT (three times a week for 12 wk) combined with either oxandrolone (10 mg·d(-1)) or an identical placebo. Peak strength was assessed for leg press, chest press, triceps, knee extension, and knee flexion. Power was assessed for leg press and chest press. Physical function measures included static and dynamic balance, chair rise, stair climb, gait speed, and 6-min walk test. Body composition was assessed using dual energy x-ray absorptiometry. RESULTS: Oxandrolone treatment augmented increases in lean tissue for the whole body (2.6 kg; 95% confidence interval (CI), 1.0-4.2 kg; P = 0.003), arms (0.3 kg; 95% CI, 0.1-0.5 kg; P = 0.001), legs (0.8 kg; 95% CI, 0.1-1.4 kg; P = 0.018), and trunk (1.4 kg; 95% CI, 0.4-2.3 kg; P = 0.004). Oxandrolone also augmented loss of fat tissue of the whole body (-1 kg; 95% CI, -1.6 to -0.4; P = 0.002), arms (-0.2 kg; 95% CI, -0.5 to -0.02 kg; P = 0.032), legs (-0.4 kg; 95% CI, -0.6 to -0.1; P = 0.009), and tended to reduce trunk fat (-0.4 kg; 95% CI, -0.9 to 0.04; P = 0.07). Improvements in muscle strength and power, chair stand, and dynamic balance were all significant over time (P < 0.05) but not different between groups (P > 0.05). CONCLUSIONS: Oxandrolone improves body composition adaptations to PRT in older women over 12 wk without augmenting muscle function or functional performance beyond that of PRT alone.

Association of total protein intake with bone mineral density and bone loss in men and women from the Framingham Offspring Study.

OBJECTIVE: To examine (i) the association of percentage of total energy intake from protein (protein intake %) with bone mineral density (BMD, g/cm2) and bone loss at the femoral neck, trochanter and lumbar spine (L2-L4) and (ii) Ca as an effect modifier. SETTING: The Framingham Offspring Study. SUBJECTS: Men (n 1280) and women (n 1639) completed an FFQ in 1992-1995 or 1995-1998 and underwent baseline BMD measurement by dual-energy X-ray absorptiometry in 1996-2000. Men (n 495) and women (n 680) had follow-up BMD measured in 2002-2005. DESIGN: Cohort study using multivariable regression to examine the association of protein intake % with each BMD, adjusting for covariates. Statistical interaction between protein intake % and Ca (total, dietary, supplemental) intake was examined. RESULTS: The mean age at baseline was 61 (sd 9) years. In the cross-sectional analyses, protein intake % was positively associated with all BMD sites (P range: 0·02-0·04) in women but not in men. Significant interactions were observed with total Ca intake (<800 mg/d v. ≥800 mg/d) in women at all bone sites (P range: 0·002-0·02). Upon stratification, protein intake % was positively associated with all BMD sites (P range: 0·04-0·10) in women with low Ca intakes but not in those with high Ca intakes. In the longitudinal analyses, in men, higher protein intake % was associated with more bone loss at the trochanter (P = 0·01) while no associations were seen in women, regardless of Ca intake. CONCLUSIONS: This suggests that greater protein intake benefits women especially those with lower Ca intakes. However, protein effects are not significant for short-term changes in bone density. Contrastingly, in men, higher protein intakes lead to greater bone loss at the trochanter. Longer follow-up is required to examine the impact of protein on bone loss.

Vertebral size, bone density, and strength in men and women matched for age and areal spine BMD.

To explore the possible mechanisms underlying sex-specific differences in skeletal fragility that may be obscured by two-dimensional areal bone mineral density (aBMD) measures, we compared quantitative computed tomography (QCT)-based vertebral bone measures among pairs of men and women from the Framingham Heart Study Multidetector Computed Tomography Study who were matched for age and spine aBMD. Measurements included vertebral body cross-sectional area (CSA, cm(2) ), trabecular volumetric BMD (Tb.vBMD, g/cm(3) ), integral volumetric BMD (Int.vBMD, g/cm(3) ), estimated vertebral compressive loading and strength (Newtons) at L3 , the factor-of-risk (load-to-strength ratio), and vertebral fracture prevalence. We identified 981 male-female pairs (1:1 matching) matched on age (± 1 year) and QCT-derived aBMD of L3 (± 1%), with an average age of 51 years (range 34 to 81 years). Matched for aBMD and age, men had 20% larger vertebral CSA, lower Int.vBMD (-8%) and Tb.vBMD (-9%), 10% greater vertebral compressive strength, 24% greater vertebral compressive loading, and 12% greater factor-of-risk than women (p < 0.0001 for all), as well as higher prevalence of vertebral fracture. After adjusting for height and weight, the differences in CSA and volumetric bone mineral density (vBMD) between men and women were attenuated but remained significant, whereas compressive strength was no longer different. In conclusion, vertebral size, morphology, and density differ significantly between men and women matched for age and spine aBMD, suggesting that men and women attain the same aBMD by different mechanisms. These results provide novel information regarding sex-specific differences in mechanisms that underlie vertebral fragility.

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.

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 (h(2)) for VFrx and its genetic correlation with phenotypes contributing to VFrx risk have not been established. This study aims to estimate the h(2) 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 (T(4) to L(4)) using Genant's semiquantitative (SQ) scale (grades 0 to 3). Vertebral fracture was defined as having at least 25% reduction in height of any vertebra. We also analyzed QCT scans at the L(3) level for integral (In.BMD) and trabecular (Tb.BMD) vBMD and CSA. Heritability estimates were calculated, and bivariate genetic correlation analysis was performed, adjusting for various covariates. For VFrx, we analyzed 4099 individuals (148 VFrx cases) including 2082 women and 2017 men from three generations. Estimates of crude and multivariable-adjusted h(2) were 0.43 to 0.69 (p < 1.1 × 10(-2)). A total of 3333 individuals including 1737 men and 1596 women from two generations had VFrx status and QCT-derived vBMD and CSA information. Estimates of crude and multivariable-adjusted h(2) 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.

QCT measures of bone strength at the thoracic and lumbar spine: the Framingham Study.

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 (ß = 0.0004, p = 0.01), and vertebral strength did not change (ß = 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 (ß = 0.0157), compared with the thoracic spine (ß = 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.

Height loss predicts subsequent hip fracture in men and women of the Framingham Study.

Although height is a risk factor for osteoporotic fracture, current risk assessments do not consider height loss. Height loss may be a simple measurement that clinicians could use to predict fracture or need for further testing. The objective was to examine height loss and subsequent hip fracture, evaluating both long-term adult height loss and recent height loss. Prospective cohort of 3081 adults from the Framingham Heart Study. Height was measured biennially since 1948, and cohort followed for hip fracture through 2005. Adult height loss from middle-age years across 24 years and recent height loss in elderly years were considered. Cox proportional hazard regression was used to estimate association between height loss and risk of hip fracture. Of 1297 men and 1784 women, mean baseline age was 66 years (SD = 7.8). Average height loss for men was 1.06 inches (0.76), and for women was 1.12 inches (0.84). A total of 11% of men and 15% of women lost ≥2 inches of height. Mean follow-up was 17 years, during which 71 men and 278 women had incident hip fractures. For each 1-inch of height loss, hazard ratio (HR) = 1.4 in men [95% confidence interval (CI): 1.00, 1.99], and 1.04 in women (95% CI: 0.88, 1.23). Men and women who lost ≥2 inches of height had increased fracture risk (compared with 0 to <2 inches) of borderline significance: men HR = 1.8, 95% CI: 0.86, 3.61; women HR = 1.3, 95% CI: 0.90, 1.76. Recent height loss in elders significantly increased the risk of hip fracture, 54% in men and 21% in women (95% CI: 1.14, 2.09; 1.03, 1.42, respectively). Adult height loss predicted hip fracture risk in men in our study. Recent height loss in elderly men and women predicted risk of hip fracture.

Dietary acid load is not associated with lower bone mineral density except in older men.

High dietary acid load may be detrimental to bone mineral density (BMD), although sufficient calcium intake might neutralize this effect. In observational studies, the association between BMD and dietary acid load, estimated by net endogenous acid production (NEAP) and potential renal acid load (PRAL), has been inconsistent, and the potential modifying effect of calcium intake has not been assessed. We therefore examined the cross-sectional associations of estimated NEAP and PRAL with BMD in the Framingham Osteoporosis Study. We hypothesized that higher estimated NEAP and PRAL would be associated with lower BMD, but only among those with total calcium intake < 800 mg/d. BMD of the femoral neck and lumbar spine was measured, and estimated NEAP and PRAL were calculated via FFQ among 1069 Framingham Original (1988-1989, 1992-1993; 62% women, mean age 76 y) and 2919 Offspring (1996-2001; 56% women, mean age 60 y) cohort participants. Cohort- and sex-specific ANCOVA was used to calculate multivariable-adjusted mean BMD for estimated NEAP and PRAL quartiles. Assuming no uncontrolled confounding, estimated NEAP, but not PRAL, was inversely associated with femoral neck BMD (P-trend = 0.04) in Original cohort men, whereas neither was associated with lumbar spine BMD. Estimated NEAP and PRAL were not associated with BMD at any site among Original cohort women or Offspring cohort men and women. There were no significant interactions between either estimated NEAP or PRAL and total calcium intake. These results suggest that, with a possible exception of older men, dietary acid load does not have a measureable negative effect on bone health, regardless of total calcium intake.

Protective effect of high protein and calcium intake on the risk of hip fracture in the Framingham offspring cohort.

The effect of protein on bone is controversial, and calcium intake may modify protein's effect on bone. We evaluated associations of energy-adjusted tertiles of protein intake (ie, total, animal, plant, animal/plant ratio) with incident hip fracture and whether total calcium intake modified these associations in the Framingham Offspring Study. A total of 1752 men and 1972 women completed a baseline food frequency questionnaire (1991-1995 or 1995-1998) and were followed for hip fracture until 2005. Hazard ratios (HRs) were estimated using Cox proportional hazards regression adjusting for confounders. Baseline mean age was 55 years (SD 9.9 years, range 26 to 86 years). Forty-four hip fractures occurred over 12 years of follow-up. Owing to significant interaction between protein (total, animal, animal/plant ratio) and calcium intake (p interaction range = .03 to .04), stratified results are presented. Among those with calcium intakes less than 800 mg/day, the highest tertile (T3) of animal protein intake had 2.8 times the risk of hip fracture [HR = 2.84, 95% confidence interval (CI) 1.20-6.74, p = .02] versus the lowest tertile (T1, p trend = .02). In the 800 mg/day or more group, T3 of animal protein had an 85% reduced hip fracture risk (HR = 0.15, 95% CI 0.02-0.92, p = .04) versus T1 (p trend = .04). Total protein intake and the animal/plant ratio were not significantly associated with hip fracture (p range = .12 to .65). Our results from middle-aged men and women show that higher animal protein intake coupled with calcium intake of 800 mg/day or more may protect against hip fracture, whereas the effect appears reversed for those with lower calcium intake. Calcium intake modifies the association of protein intake and the risk of hip fracture in this cohort and may explain the lack of concordance seen in previous studies.

Foot pain: is current or past shoewear a factor?

OBJECTIVE: Foot pain is common, yet few studies have examined the condition in relationship to shoewear. In this cross-sectional study of men and women from the population-based Framingham Study, the association between foot pain and type of shoewear was examined. METHODS: Data were collected on 3,378 members of the Framingham Study who completed the foot examination in 2002-2008. Foot pain (both generalized and at specific locations) was measured by the response to the question "On most days, do you have pain, aching or stiffness in either foot?" Shoewear was recorded for the present time and 5 past age categories, by the subject's choice of the appropriate shoe from a list. The responses were categorized into 3 groups (good, average, or poor shoes). Sex-specific multivariate logistic regression models were used to examine the effect of shoewear (average shoes were the referent group) on generalized and location-specific foot pain, adjusting for age and weight. RESULTS: In women, compared with average shoes, those who wore good shoes in the past were 67% less likely to report hindfoot pain (P = 0.02), after adjusting for age and weight. In men, there was no association between foot pain, at any location, and shoewear, possibly due to the fact that <2% wore bad shoe types, making it difficult to see any relationship. CONCLUSION: Even after taking age and weight into account, past shoewear use in women remained associated with hindfoot pain. Future studies should address specific support and structural features of shoewear.

Survival of aged nursing home residents with hip fracture.

BACKGROUND: Little is known about mortality in nursing home residents with hip fracture. This study examined the effect of pre-fracture characteristics, hospital complications, and post-fracture complications on mortality in residents with hip fracture. METHODS: This is a retrospective cohort study of 195 long-term care residents (153 women, 42 men) with hip fracture (1999-2006) followed for mortality until June 30, 2007. Pre-fracture characteristics (age, sex, cognition, functional status, comorbidities, body mass index), hospital complications (acute myocardial infarction, congestive heart failure, delirium, infection) and 6-month complications (delirium, pneumonia, pressure ulcer, urinary tract infection [UTI]) were evaluated as potential predictors of mortality. RESULTS: During a median follow-up of 1.4 years, 150 participants (76.9%) died. Male residents were nearly twice as likely to die compared with female residents (hazard ratio [HR] = 1.9, 95% confidence interval [CI] 1.2-3.0). Other pre-fracture characteristics associated with increased mortality included older age (HR per 5 years = 1.3, 95% CI 1.1-1.6), low functional status (HR = 1.7, 95% CI 1.0-3.0), anemia (HR = 1.6, 95% CI 1.1-2.5), and coronary artery disease (HR = 2.0, 95% CI 1.3-2.9). Mortality was 70% greater among residents with a pressure ulcer or pneumonia within 6 months of hip fracture (pressure ulcer, HR = 1.7, 95% CI 1.2-2.6; pneumonia, HR = 1.7, 95% CI 1.1-2.7). Individual hospital complications and post-fracture delirium and UTI were not significant predictors of mortality. CONCLUSIONS: In addition to pre-fracture characteristics, potentially modifiable post-fracture complications including pressure ulcer and pneumonia were associated with increased mortality in nursing home residents with hip fracture. Prevention strategies to reduce pressure ulcers and pneumonia may help reduce mortality in this frail population.