Effect of testosterone treatment on the trabecular bone score in older men with low serum testosterone.

The trabecular bone score (TBS) is an indirect measure of vertebral bone microarchitecture. Our objective was to examine the effect of testosterone treatment on TBS. One hundred and ninety-seven hypogonadal men were randomized to testosterone or placebo. After 12 months, there was no difference in the changes in TBS by randomized group. INTRODUCTION: In the Bone Trial of the Testosterone Trials, testosterone treatment increased trabecular volumetric bone mineral density (vBMD) and increased estimated bone strength as determined by finite element analysis. The trabecular bone score (TBS) is an indirect measure of vertebral bone microarchitecture. TBS predicts fracture independent of lumbar spine areal (a) BMD. The objective of this study was to examine the effect of testosterone treatment on TBS compared to its effects on vBMD and aBMD. METHODS: Two hundred and eleven men were enrolled in the Bone Trial of the Testosterone Trials. Of these, 197 men had 2 repeat TBS and vBMD measurements; 105 men were allocated to receive testosterone, and 92 men to placebo for 1 year. TBS, aBMD, and vBMD were assessed at baseline and month 12. RESULTS: There was no difference in the percent change in TBS by randomized group: 1.6% (95% confidence intervals (CI) 0.2-3.9) in the testosterone group and 1.4% (95% CI -0.2, 3.1) in the placebo group. In contrast, vBMD increased by 6% (95% CI 4.5-7.5) in the testosterone group compared to 0.4% (95% CI -1.65-0.88) in the placebo groups. CONCLUSIONS: TBS is not clinically useful in monitoring the 1-year effect of testosterone treatment on bone structure in older hypogonadal men.

Long-term effects of lifestyle and metformin interventions in DPP on bone density.

In the Diabetes Prevention Program Outcome Study (DPPOS), a cohort at high risk of diabetes, randomization to intensive lifestyle intervention or metformin, both associated with weight loss, did not have long-term negative effects on BMD compared with the placebo group. Potential positive effects of metformin on bone warrant further investigation. INTRODUCTION: Randomization to lifestyle intervention (ILS) or metformin in the Diabetes Prevention Program (DPP) resulted in weight loss and reduced progression to diabetes. Weight loss is associated with reduced bone mineral density (BMD), but the long-term effects of these interventions on BMD are unknown. In the DPP Outcome Study (DPPOS), we determined if randomization to ILS or metformin, compared with placebo, was associated with differences in BMD approximately 16 years later. METHODS: Of 3234 DPP participants, 2779 continued in DPPOS and were offered ILS in group format. Those randomized to metformin were offered unmasked metformin. At DPPOS year 12, 1367 participants had dual-energy X-ray absorptiometry scans. BMD in metformin and ILS groups was compared to placebo using sex-specific linear regression models, adjusted for age, race/ethnicity, and weight and weight-bearing activity at DPP baseline. RESULTS: At DPPOS year 12, mean age was 66.5 (±9.5) years. Femoral neck BMD was similar in the ILS and placebo groups in men (difference = -0.021 g/cm2, 95%CI (-0.063, 0.021)) and in women (+0.014 g/cm2, 95%CI (-0.014, 0.042)). Femoral neck BMD was higher in the metformin compared to placebo group although not statistically different in men (+0.017 g/cm2, 95% CI (-0.023, 0.058)) and in women (+0.019 g/cm2, 95% CI (-0.009, 0.047)). Prevalence of osteoporosis was low and similar across treatment groups in men (0.9%; p=0.745) and women (2.4%; p=0.466). CONCLUSION: In a cohort at high risk of diabetes, lifestyle intervention or metformin did not appear to have long-term negative effects on BMD. Potential positive effects of metformin on bone warrant further research.

The rate of bone loss slows after 1-2 years of initial antiretroviral therapy: final results of the Strategic Timing of Antiretroviral Therapy (START) bone mineral density substudy.

OBJECTIVES: Initial antiretroviral therapy (ART) causes loss of bone mineral density (BMD) over the first 1-2 years. Whether this loss continues with longer therapy is unclear. We determined changes in bone and spine BMD over 5 years in adults receiving immediate or deferred initial ART. METHODS: In the Strategic Timing of Antiretroviral Therapy (START) BMD substudy, ART-naïve adults with CD4 counts > 500 cells/µL were randomized to immediate or deferred ART. Deferred group participants not yet on ART were offered ART after May 2015. Mean per cent changes in total hip and lumbar spine BMD (measured annually by dual-energy X-ray absorptiometry) were compared between groups using longitudinal mixed models. Fracture rates were also compared between groups for all START participants. RESULTS: Substudy participants (immediate group, n = 201; deferred group, n = 210; median age 32 years; 80% non-white; 24% female) were followed for a mean 4.5 years until December 2016. In the immediate group, > 96% used ART throughout. In the deferred group, 16%, 58% and 94% used ART at years 1, 3 and 5, respectively. BMD decreased more in the immediate group initially; groups had converged by year 3 at the spine and year 4 at the hip by intent-to-treat (ITT). BMD changes after year 1 were similar in the immediate group and in those off ART in the deferred group [mean difference: spine, 0.03% per year; 95% confidence interval (CI) -0.4, 0.4; P = 0.88; hip, -0.2% per year; 95% CI -0.7, 0.3; P = 0.37]. Fracture incidence did not differ significantly between groups (immediate group, 0.86/100 person-years versus deferred group, 0.85/100 person-years; hazard ratio 1.01; 95% CI 0.76, 1.35; P = 0.98). CONCLUSIONS: Significant ART-induced bone loss slowed after the first year of ART and became similar to that in untreated HIV infection.

Insights into the bisphosphonate holiday: a preliminary FTIRI study.

Bone composition evaluated by FTIRI analysis of iliac crest biopsies from post-menopausal women treated with alendronate for 10 years, continuously or alendronate for 5 years, followed by a 5-year alendronate-holiday, only differed with the discontinued biopsies having increased cortical crystallinity and heterogeneity of acid phosphate substitution and decreased trabecular crystallinity heterogeneity. INTRODUCTION: Bisphosphonates (BP) are the most commonly used and effective drugs to prevent fragility fractures; however, concerns exist that prolonged use may lead to adverse events. Recent recommendations suggest consideration of a BP "holiday" in individuals taking long-term BP therapy not at high risk of fracture. Data supporting or refuting this recommendation based on bone quality are limited. We hypothesized that a "holiday" of 5 years would cause no major bone compositional changes. METHODS: We analyzed the 31 available biopsies from the FLEX-Long-term Extension of FIT (Fracture Intervention Trial) using Fourier transform infrared imaging (FTIRI). Biopsies from two groups of post-menopausal women, a "Continuously treated group" (N = 16) receiving alendronate for ~ 10 years and a "Discontinued group" (N = 15), alendronate treated for 5 years taking no antiresorptive medication during the following 5 years. Iliac crest bone biopsies were provided at 10 years. RESULTS: Key FTIRI parameters, mineral-to-matrix ratio, carbonate-to-phosphate ratio, acid phosphate substitution, and collagen cross-link ratio as well as heterogeneity of these parameters were similar for Continuously treated and Discontinued groups in age-adjusted models. The Discontinued group had 2% greater cortical crystallinity (p = 0.01), 31% greater cortical acid phosphate heterogeneity (p = 0.02), and 24% lower trabecular crystallinity heterogeneity (p = 0.02). CONCLUSIONS: Discontinuation of alendronate for 5 years did not affect key FTIRI parameters, supporting the hypothesis that discontinuation would have little impact on bone composition. Modest differences were observed in three parameters that are not likely to affect bone mechanical properties. These preliminary data suggest that a 5-year BP holiday is not harmful to bone composition.

Predictors of change of trabecular bone score (TBS) in older men: results from the Osteoporotic Fractures in Men (MrOS) Study.

Among older men, characteristics that predict longitudinal changes in trabecular bone score (TBS) are different from characteristics that predict changes in bone mineral density (BMD). Most notably, weight loss is strongly associated with concomitant loss in BMD but with concomitant increases in TBS, when measured on Hologic densitometers. INTRODUCTION: Our objective was to compare and contrast predictors of changes in TBS, total hip BMD, and lumbar spine BMD. METHODS: Our study population was 3969 Osteoporotic Fractures in Men (MrOS) cohort participants (mean age 72.8 years) with repeat measures of TBS, lumbar spine and total hip BMD, body mass index (BMI) less than 37 kg/m2, and no use of bisphosphonate or glucocorticoid medications. TBS was scored (Med-Imaps Software version 2.1) and BMD measured on Hologic densitometers. RESULTS: One thousand four hundred forty-four men had a TBS decrease > 0.04 units (estimated least significant change for TBS), 795 men had a TBS increase > 0.04 units, and 1730 men had TBS change ≤ 0.04 units over mean follow-up of 4.6 years. Older age was not associated with TBS change, but was associated with greater decline in lumbar spine and total hip BMD. Compared to stable weight, > 10% weight loss was strongly associated with an increase in TBS [effect size = 1.24 (95% CI 1.12, 1.36)] and strongly associated with a decrease in total hip BMD [- 1.16 (95% CI - 1.19, - 1.03)]. Other predictors discordant for longitudinal changes of TBS and BMD included baseline BMI, walk speed, and ACE inhibitor use. CONCLUSIONS: Predictors of changes in TBS are different from predictors of changes in lumbar spine and total hip BMD. At least when assessed on Hologic densitometers, weight loss is associated with subsequent declines in spine and total hip BMD but subsequent increase in TBS. Faster walk speed may protect against loss of hip BMD, but is not associated with longitudinal changes of TBS.

Diagnosis and management of bone fragility in diabetes: an emerging challenge.

Fragility fractures are increasingly recognized as a complication of both type 1 and type 2 diabetes, with fracture risk that increases with disease duration and poor glycemic control. Yet the identification and management of fracture risk in these patients remains challenging. This review explores the clinical characteristics of bone fragility in adults with diabetes and highlights recent studies that have evaluated bone mineral density (BMD), bone microstructure and material properties, biochemical markers, and fracture prediction algorithms (i.e., FRAX) in these patients. It further reviews the impact of diabetes drugs on bone as well as the efficacy of osteoporosis treatments in this population. We finally propose an algorithm for the identification and management of diabetic patients at increased fracture risk.

Changes in bone mineral density over time by body mass index in the health ABC study.

UNLABELLED: Obesity appears protective against osteoporosis in cross-sectional studies. However, results from this longitudinal study found that obesity was associated with bone loss over time. Findings underscore the importance of looking at the longitudinal relationship, particularly given the increasing prevalence and duration of obesity among older adults. INTRODUCTION: Cross-sectional studies have found a positive association between body mass index (BMI) and bone mineral density (BMD), but little is known about the longitudinal relationship in US older adults. METHODS: We examined average annual rate of change in BMD by baseline BMI in the Health, Aging, and Body Composition Study. Repeated measurement of BMD was performed with dual-energy X-ray absorptiometry (DXA) at baseline and years 3, 5, 6, 8, and 10. Multivariate generalized estimating equations were used to predict mean BMD (femoral neck, total hip, and whole body) by baseline BMI (excluding underweight), adjusting for covariates. RESULTS: In the sample (n = 2570), 43 % were overweight and 24 % were obese with a mean baseline femoral neck BMD of 0.743 g/cm(2), hip BMD of 0.888 g/cm(2), and whole-body BMD of 1.09 g/cm(2). Change in total hip or whole-body BMD over time did not vary by BMI groups. However, obese older adults lost 0.003 g/cm(2) of femoral neck BMD per year more compared with normal weight older adults (p < 0.001). Femoral neck BMD change over time did not differ between the overweight and normal weight BMI groups (p = 0.74). In year 10, adjusted femoral neck BMD ranged from 0.696 g/cm(2) among obese, 0.709 g/cm(2) among normal weight, and 0.719 g/cm(2) among overweight older adults. CONCLUSIONS: Findings underscore the importance of looking at the longitudinal relationship between body composition and bone mineral density among older adults, indicating that high body mass may not be protective for bone loss over time.

Cortical bone laminar analysis reveals increased midcortical and periosteal porosity in type 2 diabetic postmenopausal women with history of fragility fractures compared to fracture-free diabetics.

UNLABELLED: We investigated the characteristics and spatial distribution of cortical bone pores in postmenopausal women with type 2 diabetes (T2D). High porosity in the midcortical and periosteal layers in T2D subjects with fragility fractures suggests that these cortical zones might be particularly susceptible to T2D-induced toxicity and may reflect cortical microangiopathy. INTRODUCTION: Elevated cortical porosity is regarded as one of the main contributors to the high skeletal fragility in T2D. However, to date, it remains unclear if diabetic cortical porosity results from vascular cortical changes or from an expansion in bone marrow space. Here, we used a novel cortical laminar analysis technique to investigate the characteristics and spatial radial distribution of cortical pores in a T2D group with prior history of fragility fractures (DMFx, assigned high-risk group) and a fracture-free T2D group (DM, assigned low-risk group) and to compare their results to non-diabetic controls with (Fx) and without fragility fractures (Co). METHODS: Eighty postmenopausal women (n = 20/group) underwent high-resolution peripheral quantitative computed tomography (HR-pQCT) of the distal tibia and radius. Cortical bone was divided into three layers of equal width including an endosteal, midcortical, and periosteal layer. Within each layer, total pore area (TPA), total pore number (TPN), and average pore area (APA) were calculated. Statistical analysis employed Mann-Whitney tests and ANOVA with post hoc tests. RESULTS: Compared to the DM group, DMFx subjects exhibited +90 to +365 % elevated global porosity (p = 0.001). Cortical laminar analysis revealed that this increased porosity was for both skeletal sites confined to the midcortical layer, followed by the periosteal layer (midcortical +1327 % TPA, p ≤ 0.001, periosteal +634 % TPA, p = 0.002), and was associated in both layers and skeletal sites with high TPN (+430 % TPN, p < 0.001) and high APA (+71.5 % APA, p < 0.001). CONCLUSION: High porosity in the midcortical and periosteal layers in the high-risk T2D group suggests that these cortical zones might be particularly susceptible to T2D-induced toxicity and may reflect cortical microangiopathy.

Oral anti-diabetic drugs and fracture risk, cut to the bone: safe or dangerous? A narrative review.

Fracture risk is higher in older adults with type 2 diabetes and may be influenced by treatments for diabetes. Oral anti-diabetic drugs have different effects on bone metabolism. The purpose of this review is to describe the effects of these drugs on bone metabolism and fracture risk. Osteoporosis is a progressive skeletal disorder that is characterized by compromised bone strength and increased risk of fracture. This condition has become an important global health problem, affecting approximately 200 million people worldwide. Another chronic and highly prevalent condition is diabetes mellitus, which affects more than 380 million people; both type 1 and type 2 diabetes are risk factors for fracture. Type 2 diabetes, in particular, is associated with impaired bone strength, although it is characterized by normal or elevated bone mineral density. Several therapeutic strategies are available to achieve the best outcomes in the management of diabetes mellitus but these have different effects on bone metabolism. The purpose of this narrative review is to describe the effects of oral hypoglycemic agents (metformin, sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-dependent glucose transporter 2 inhibitors) on bone metabolism and on the risk of developing fragility fractures in patients with type 2 diabetes. Both diabetes and osteoporosis represent a significant burden in terms of healthcare costs and quality of life. It is very important to choose therapies for diabetes that ensure good metabolic control whilst preserving skeletal health.

Volumetric femoral BMD, bone geometry, and serum sclerostin levels differ between type 2 diabetic postmenopausal women with and without fragility fractures.

UNLABELLED: While type 2 diabetes (T2D) is associated with higher skeletal fragility, specific risk stratification remains incompletely understood. We found volumetric bone mineral density, geometry, and serum sclerostin differences between low-fracture risk and high-fracture risk T2D women. These features might help identify T2D individuals at high fracture risk in the future. INTRODUCTION: Diabetic bone disease, an increasingly recognized complication of type 2 diabetes mellitus (T2D), is associated with high skeletal fragility. Exactly which T2D individuals are at higher risk for fracture, however, remains incompletely understood. Here, we analyzed volumetric bone mineral density (vBMD), geometry, and serum sclerostin levels in two specific T2D subsets with different fracture risk profiles. We examined a T2D group with prior history of fragility fractures (DMFx, assigned high-risk group) and a fracture-free T2D group (DM, assigned low-risk group) and compared their results to nondiabetic controls with (Fx) and without fragility fractures (Co). METHODS: Eighty postmenopausal women (n = 20 per group) underwent quantitative computed tomography (QCT) to compute vBMD and bone geometry of the proximal femur. Additionally, serum sclerostin, vitamin D, parathyroid hormone (PTH), HbA1c, and glomerular filtration rate (GFR) levels were measured. Statistical analyses employed linear regression models. RESULTS: DMFx subjects exhibited up to 33 % lower femoral neck vBMD than DM subjects across all femoral sites (-19 % ≤ ΔvBMD ≤ -33 %, 0.008 ≤ p ≤0.021). Additionally, DMFx subjects showed significantly thinner cortices (-6 %, p = 0.046) and a trend toward larger bone volume (+10 %, p = 0.055) relative to DM women and higher serum sclerostin levels when compared to DM (+31.4 %, p = 0.013), Fx (+25.2 %, p = 0.033), and control (+22.4 %, p = 0.028) subjects. CONCLUSION: Our data suggest that volumetric bone parameters by QCT and serum sclerostin levels can identify T2D individuals at high risk of fracture and might therefore show promise as clinical tools for fracture risk assessment in T2D. However, future research is needed to establish diabetes-specific QCT- and sclerostin-reference databases.

Serum 25-hydroxyvitamin D concentration does not independently predict incident diabetes in older women.

AIMS: To investigate whether 25-hydroxyvitamin D concentration was associated with incident diabetes in a large cohort of older women. METHODS: Data were analysed from women included in the Study of Osteoporotic Fractures, a cohort of community-dwelling women aged ≥65 years at enrolment. Serum 25-hydroxyvitamin D concentration was assessed at the year 6 visit, as were BMI and other factors associated with vitamin D and/or diabetes. Diabetes status was determined at each subsequent visit by self-report and medication use. Only those without prevalent diabetes at the year 6 visit were included in the present analysis (N = 5463, mean age 76.5 years). RESULTS: During a mean ±sd follow-up of 8.6 ± 4.4 years, incident diabetes was reported in 320 participants. The mean BMI was higher in those with a 25-hydroxyvitamin D concentration <20 ng/ml (<50 nmol/l) than in those with concentrations 20-30 or ≥30 ng/ml [50-74 or ≥75 nmol/l (P < 0.0001)]. A higher 25-hydroxyvitamin D concentration was associated with a 13% lower risk of incident diabetes after adjustment for age and clinic site [hazard ratio 0.87, 95% CI 0.76-0.99, per sd increase in 25-hydroxyvitamin D]; however, the addition of BMI to the model attenuated the estimated effect (hazard ratio 0.97, 95% CI 0.86-1.11). Adjustment for additional potential confounders yielded similar results. CONCLUSIONS: Serum 25-hydroxyvitamin D does not independently predict incident diabetes in older women. Although those with higher 25-hydroxyvitamin D concentrations are less likely to develop diabetes, this is mainly explained by their lower BMI.

Altered body composition in type 2 diabetes mellitus.

OBJECTIVE: To identify differences in amount and distribution of fat and lean soft tissue in a cross-sectional study of subjects with and without type 2 diabetes and to determine whether any differences are affected by race/ethnicity or sex. DESIGN AND METHODS: Overweight and obese (body mass index, BMI > or = 25 kg m(-2)) Black, White and Hispanic men (490) and women (825) with type 2 diabetes ((mean+/-s.d.) age 58.5+/-6.6; BMI 35.3+/-5.3) who had a baseline dual energy X-ray absorptiometry whole-body scan at the time of enrollment in the Look AHEAD clinical trial, and 242 healthy controls, 91 males and 151 females (age 55.3+/-8.6 years, BMI 30.7+/-4.2 kg m(-2)) who were participating in unrelated research and were scanned on the same densitometers. RESULTS: Adjusted for gender, age, race, clinical site and body size, total fat mass was smaller in persons with type 2 diabetes than in controls (-1.4+/-0.3 (s.e.); 34.5 vs 35.8 kg, P<0.001) while trunk fat was larger (1.3+/-0.2 (s.e.); 19.9 vs 18.6 kg, P<0.001) and leg fat was smaller (-1.5+/-0.2 (s.e.); 10.7 vs 12.3 kg, P<0.001). The arms of subjects with type 2 diabetes did not have significantly less fat compared to controls. Adjusted trunk lean mass was larger in type 2 diabetes by 0.6 kg (28.4 vs 27.8 kg, P<0.001) while leg lean was smaller by 0.5 kg (18.1 vs 18.6 kg, P<0.001). CONCLUSIONS: Type 2 diabetes is associated with less total fat, leg fat and leg lean mass and more truncal fat and lean mass than controls. The physiological processes producing these deviations in tissue distribution and their metabolic significance warrant further investigation.

Independent effects of peripheral nerve dysfunction on lower-extremity physical function in old age: the Women's Health and Aging Study.

OBJECTIVE: To determine the role of peripheral nerve dysfunction (PND) in the disablement pathway. RESEARCH DESIGN AND METHODS: Vibration perception threshold (VPT) was measured in 894 women aged > or = 65 years, and those with normal peripheral nerve function and with mild, moderate, and severe PND were identified. Lower-extremity impairments included quadriceps strength (kilograms) and three progressively difficult balance tasks (able/unable). Functional limitations included rising from a chair (able/unable) and usual pace and fast-paced walking speeds (meters/second). Level of PND was related to impairments and functional limitations in linear and logistic regression models that controlled for potentially confounding factors, including reported diabetes. RESULTS: Level of PND was associated with impaired balance (adjusted odds ratios: 2.21, 1.95, and 3.02 for mild, moderate, and severe PND, respectively, relative to normal, P < 0.05). PND was also associated with decrements in both usual and fast-paced walking speeds (-0.08, -0.08, and -0.15 m/s for usual pace and -0.13, -0.12, and -0.24 m/s for fast-paced walking speed for women with mild, moderate, and severe PND, respectively; P < 0.01 for all). Reported diabetes was not associated with these outcomes in the presence of PND. Some, but not all, of the association between PND and functional limitations was explained by the relationship between PND and impairments. CONCLUSIONS: PND is significantly associated with both lower-extremity impairments and functional limitations in older women, and PND appears to have independent effects on functional limitations. The independent effect of diabetes on these outcomes may be limited when PND is considered. Further research is needed to determine if PND is causally related to disability in old age.

Changes in vertebral bone marrow fat and bone mass after gastric bypass surgery: A pilot study.

Bone marrow fat may serve a metabolic role distinct from other fat depots, and it may be altered by metabolic conditions including diabetes. Caloric restriction paradoxically increases marrow fat in mice, and women with anorexia nervosa have high marrow fat. The longitudinal effect of weight loss on marrow fat in humans is unknown. We hypothesized that marrow fat increases after Roux-en-Y gastric bypass (RYGB) surgery, as total body fat decreases. In a pilot study of 11 morbidly obese women (6 diabetic, 5 nondiabetic), we measured vertebral marrow fat content (percentage fat fraction) before and 6 months after RYGB using magnetic resonance spectroscopy. Total body fat mass declined in all participants (mean ± SD decline 19.1 ± 6.1 kg or 36.5% ± 10.9%, p<0.001). Areal bone mineral density (BMD) decreased by 5.2% ± 3.5% and 4.1% ± 2.6% at the femoral neck and total hip, respectively, and volumetric BMD decreased at the spine by 7.4% ± 2.8% (p<0.001 for all). Effects of RYGB on marrow fat differed by diabetes status (adjusted p=0.04). There was little mean change in marrow fat in nondiabetic women (mean +0.9%, 95% CI -10.0 to +11.7%, p=0.84). In contrast, marrow fat decreased in diabetic women (-7.5%, 95% CI -15.2 to +0.1%, p=0.05). Changes in total body fat mass and marrow fat were inversely correlated among nondiabetic (r=-0.96, p=0.01) but not diabetic (r=0.52, p=0.29) participants. In conclusion, among those without diabetes, marrow fat is maintained on average after RYGB, despite dramatic declines in overall fat mass. Among those with diabetes, RYGB may reduce marrow fat. Thus, future studies of marrow fat should take diabetes status into account. Marrow fat may have unique metabolic behavior compared with other fat depots.

Older women with diabetes have an increased risk of fracture: a prospective study.

To determine whether type 2 diabetes is associated with fracture in older women, we analyzed data from 9654 women, age 65 yr or older, in the Study of Osteoporotic Fractures. Diabetes with age at onset 40 yr or older was reported by 657 women, of whom 106 used insulin. A total of 2624 women experienced at least one nonvertebral fracture during an average follow-up of 9.4 yr, and 388 had at least one vertebral fracture during an average interval of 3.7 yr. Although diabetes was associated with higher bone mineral density, it was also associated with a higher risk of specific fractures. Compared with nondiabetics, women with diabetes who were not using insulin had an increased risk of hip [relative risk (RR), 1.82; 95% confidence interval (CI), 1.24-2.69] and proximal humerus (RR, 1.94; 95% CI, 1.24-3.02) fractures in multivariate models controlling for age, body mass index, bone density, and other factors associated with fractures and diabetes. Insulin-treated diabetics had more than double the risk of foot (multivariate adjusted RR, 2.66; 95% CI, 1.18-6.02) fractures compared with nondiabetics. This study indicates that diabetes is a risk factor for hip, proximal humerus, and foot fractures among older women, suggesting that fracture prevention efforts should be a consideration in the treatment of diabetes.

Falls in older Mexican-American women.

OBJECTIVE: To determine the frequency of falls and identify risk factors for falls among older Mexican-American women. DESIGN: A prospective cohort study with an average follow-up of 2.7 years. SETTING: A clinical center at the Palo Alto Veterans Affairs Medical Center, California. PARTICIPANTS: 152 community-dwelling Mexican-American Caucasian women aged 59 years or older. OUTCOME MEASURES: Falls and injurious falls, as determined by monthly telephone interviews. RESULTS: The rate of falls was 508 per 1000 person-years (95% confidence interval (CI), 440-577). Injurious falls requiring medical attention occurred at a rate of 79 per 1000 person-years (95% CI, 52-107). Factors that were associated independently with an increased risk of falling were older age, a history of arthritis or rheumatism, a history of high thyroid, having fainted at least once in the year before baseline, current use of psychotropic medications, and walking fewer than 5 blocks a day. Those persons with an average time for the chair stand test had a lower risk of falling than those with the slowest times or the fastest times. CONCLUSIONS: The frequency of falls and injurious falls in this cohort of 152 relatively acculturated, healthy, older Mexican-American women was similar or slightly higher than previously reported rates for non-Hispanic Caucasian(s). Many of the factors associated with falls in this study were similar to those reported for non-Hispanic Caucasian women, suggesting that fall prevention measures tested mainly among non-Hispanic Caucasian women would also be appropriate for Mexican-American women.

Advanced glycation end product level, diabetes, and accelerated cognitive aging.

OBJECTIVE: Several studies report that diabetes increases risk of cognitive impairment; some have hypothesized that advanced glycation end products (AGEs) underlie this association. AGEs are cross-linked products that result from reactions between glucose and proteins. Little is known about the association between peripheral AGE concentration and cognitive aging. METHODS: We prospectively studied 920 elders without dementia, 495 with diabetes and 425 with normal glucose (mean age 74.0 years). Using mixed models, we examined baseline AGE concentration, measured with urine pentosidine and analyzed as tertile, and performance on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and repeatedly over 9 years. Incident cognitive impairment (a decline of >1.0 SD on each test) was analyzed with logistic regression. RESULTS: Older adults with high pentosidine level had worse baseline DSST score (p=0.05) but not different 3MS score (p=0.32). On both tests, there was a more pronounced 9-year decline in those with high and mid pentosidine level compared to those in the lowest tertile (3MS 7.0, 5.4, and 2.5 point decline, p overall <0.001; DSST 5.9, 7.4, and 4.5 point decline, p=0.03). Incident cognitive impairment was higher in those with high or mid pentosidine level than those in the lowest tertile (3MS: 24% vs 17%, odds ratio=1.55; 95% confidence interval 1.07-2.26; DSST: 31% vs 22%, odds ratio=1.62; 95% confidence interval 1.13-2.33). There was no interaction between pentosidine level, diabetes status, and cognitive decline. Multivariate adjustment for age, sex, race, education, hypertension, cardiovascular disease, estimated glomerular filtration rate, and diabetes diminished results somewhat but overall patterns remained similar. CONCLUSION: High peripheral AGE level is associated with greater cognitive decline in older adults with and without diabetes.

The association of bone mineral density measures with incident cardiovascular disease in older adults.

UNLABELLED: The associations of volumetric and areal bone mineral density (BMD) measures with incident cardiovascular disease (CVD) were studied in a biracial cohort of 2,310 older adults. BMD measures were inversely related to CVD in women and white men, independent of age and shared risk factors for osteoporosis and CVD. INTRODUCTION: We investigated the associations of volumetric (vBMD) and areal (aBMD) bone mineral density measures with incident cardiovascular disease (CVD) in older adults enrolled in the Health, Aging, and Body Composition study. METHODS: The incidence of CVD was ascertained in 2,310 well-functioning white and black participants (42% black; 55% women), aged 68-80 years. aBMD measures of the hip were assessed using DXA. Spine trabecular, integral, and cortical vBMD measures were obtained using QCT. RESULTS: During an average follow-up of 5.4 years, 23% of men and 14% of women had incident CVD. Spine vBMD measures were inversely associated with incident CVD in white men [HR(integral)=1.39, 95% CI 1.03-1.87; HR(cortical)=1.38, 95% CI 1.03-1.84], but not in black men. In women, aBMD measures of the total hip (HR = 1.36, 95% CI 1.03-1.78), femoral neck (HR = 1.44, 95% CI 1.10-1.90), and trochanter (HR = 1.34, 95% CI 1.04-1.72) exhibited significant associations with CVD in blacks, but not in whites. All associations were independent of age and shared risk factors between osteoporosis and CVD, and were not explained by inflammatory cytokines or oxidized LDL. CONCLUSION: Our results provide support for an inverse association between BMD and incident CVD. Further research should elucidate possible pathophysiological mechanisms linking osteoporosis and CVD.

Diabetes Mellitus: Does it Affect Bone?

Both diabetes and fractures affect a large proportion of older adults. Recent cohort studies indicate that diabetes itself is associated with increased risk of fracture of the hip, proximal humerus, and foot. Observational studies and animal models suggest that decreased bone strength in diabetes may contribute to fracture risk but this remains a controversial issue. Type 1 diabetes is associated with modest reductions in bone mineral density (BMD) but type 2 diabetes is often characterized by elevated BMD. This paradox of higher BMD but increased fracture risk in type 2 diabetes may be explained by a combination of more frequent falls and poorer bone quality. Diabetes can impact bone through multiple pathways, some with contradictory effects, including obesity, changes in insulin levels, higher concentrations of advanced glycation end products in collagen, hypercalciuria associated with glycosuria, reduced renal function, lower insulin-like growth factor-I, microangiopathy, and inflammation. A better understanding of how diabetes metabolism and treatments affect bone would improve fracture prevention efforts in older diabetic adults.

Characteristics of falls and risk of hip fracture in elderly men.

The steep rise in hip fracture incidence rates with age is not fully explained by an increase in the frequency of falls or by reduction in bone mineral density, suggesting that circumstances of falls may also affect the risk of hip fracture. Previous studies conducted mainly among women have identified the importance of the orientation of a fall in the etiology of hip fracture. In this case-control study among men of 45 years and older, we evaluated how the circumstances of falls affect the risk of hip fracture. We compared 214 cases with hip fracture due to a fall with 86 controls who had fallen within the past year but did not sustain a hip fracture. As expected, in multivariable age-adjusted analyses men who reported hitting the hip/thigh in a fall had a markedly elevated risk of hip fracture (OR = 97.8; 95% CI = 31.7-302). Hitting the knee in a fall was associated with reduced risk (OR = 0.24; 95% CI = 0.09-0.67). Other factors that were associated with reduced risk of hip fracture among men who fell were more hours of physical activity in the past year (OR = 0.84; 95% CI = 0.73-0.97, for each additional 4 h per week), a greater body mass index (OR = 0.60; 95% CI = 0.40-0.90, for each additional 4 kg/m2), and a history of a fracture when age 45 years or older (OR = 0.26; 95% CI = 0.10-0.69). Reported lower limb dysfunction was associated with increased risk of hip fracture (OR = 6.41; 95% CI = 2.09-19.6) among fallers. The increased risk associated with hitting the hip/thigh in a fall and the reduced risk associated with high body mass index suggest that preventive efforts for older men at high risk might include protective hip pads to reduce the force on the hip in a fall. Exercise and strength training programs may also reduce the risk of hip fracture among men who fall.