Association of DPP-4 activity with BMD, body composition, and incident hip fracture: the Cardiovascular Health Study.

There was no association of plasma DPP-4 activity levels with bone mineral density (BMD), body composition, or incident hip fractures in a cohort of elderly community-dwelling adults. INTRODUCTION: Dipeptidyl peptidase IV (DPP-4) inactivates several key hormones including those that stimulate postprandial insulin secretion, and DPP-4 inhibitors (gliptins) are approved to treat diabetes. While DPP-4 is known to modulate osteogenesis, the relationship between DPP-4 activity and skeletal health is uncertain. The purpose of the present study was to examine possible associations between DPP-4 activity in elderly subjects enrolled in the Cardiovascular Health Study (CHS) and BMD, body composition measurements, and incident hip fractures. METHODS: All 1536 male and female CHS participants who had evaluable DXA scans and plasma for DPP-4 activity were included in the analyses. The association between (1) BMD of the total hip, femoral neck, lumbar spine, and total body; (2) body composition measurements (% lean, % fat, and total body mass); and (3) incident hip fractures and plasma levels of DPP-4 activity were determined. RESULTS: Mean plasma levels of DPP-4 activity were significantly higher in blacks (227 ± 78) compared with whites (216 ± 89) (p = 0.04). However, there was no significant association of DPP-4 activity with age or gender (p ≥ 0.14 for both). In multivariable adjusted models, there was no association of plasma DPP-4 activity with BMD overall (p ≥ 0.55 for all) or in gender stratified analyses (p ≥ 0.23). There was also no association of DPP-4 levels and incident hip fractures overall (p ≥ 0.24) or in gender stratified analyses (p ≥ 0.39). CONCLUSION: Plasma DPP-4 activity, within the endogenous physiological range, was significantly associated with race, but not with BMD, body composition, or incident hip fractures in elderly community-dwelling subjects.

Clinical utility of routine laboratory testing to identify possible secondary causes in older men with osteoporosis: the Osteoporotic Fractures in Men (MrOS) Study.

UNLABELLED: We investigated the value of routine laboratory testing for identifying underlying causes in older men diagnosed with osteoporosis. Most osteoporotic and nonosteoporotic men had ≥1 laboratory abnormality. Few individual laboratory abnormalities were more common in osteoporotic men. The benefit of routine laboratory testing in older osteoporotic men may be low. INTRODUCTION: To evaluate the utility of recommended laboratory testing to identify secondary causes in older men with osteoporosis, we examined prevalence of laboratory abnormalities in older men with and without osteoporosis. METHODS: One thousand five hundred seventy-two men aged ≥65 years in the Osteoporotic Fractures in Men study completed bone mineral density (BMD) testing and a battery of laboratory measures, including serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), 25-OH vitamin D, total testosterone, spot urine calcium/creatinine ratio, spot urine albumin/creatinine ratio, creatinine-derived estimated glomerular filtration rate, 24-h urine calcium, and 24-h urine free cortisol. Using cross-sectional analyses, we calculated prevalence ratios (PRs) and 95 % confidence intervals (CI) for the association of any and specific laboratory abnormalities with osteoporosis and the number of men with osteoporosis needed to test to identify one additional laboratory abnormality compared to testing men without osteoporosis. RESULTS: Approximately 60 % of men had ≥1 laboratory abnormality in both men with and without osteoporosis. Among individual tests, only vitamin D insufficiency (PR, 1.13; 95 % CI, 1.05-1.22) and high alkaline phosphatase (PR, 3.05; 95 % CI, 1.52-6.11) were more likely in men with osteoporosis. Hypercortisolism and hyperthyroidism were uncommon and not significantly more frequent in men with osteoporosis. No osteoporotic men had hypercalciuria. CONCLUSIONS: Though most of these older men had ≥1 laboratory abnormality, few routinely recommended individual tests were more common in men with osteoporosis than in those without osteoporosis. Possibly excepting vitamin D and alkaline phosphatase, benefit of routine laboratory testing to identify possible secondary causes in older osteoporotic men appears low. Results may not be generalizable to younger men or to older men in whom history and exam findings raise clinical suspicion for a secondary cause of osteoporosis.

What analytic method should clinicians use to derive spine T-scores and predict incident fractures in men? Results from the MrOS study.

UNLABELLED: In this study, the area under the curve was highest when using the lowest vertebral body T-score to diagnose osteoporosis. In men for whom hip imaging is not possible, the lowest vertebral body T-score improves the ability to diagnose osteoporosis in men who are likely to have an incident fragility fracture. INTRODUCTION: Spine T-scores have limited ability to predict fragility fracture. We hypothesized that using lowest vertebral body T-score to diagnose osteoporosis would better predict fracture. METHODS: Among men enrolled in the Osteoporotic Fractures in Men Study, we identified cases with incident clinical fracture (n = 484) and controls without fracture (n = 1,516). We analyzed the lumbar spine bone mineral density (BMD) in cases and controls (n = 2,000) to record the L1-L4 (referent), the lowest vertebral body, and International Society for Clinical Densitometry (ISCD)-determined T-scores using a male normative database and the L1-L4 T-score using a female normative database. We compared the ability of method to diagnose osteoporosis and, therefore, to predict incident clinical fragility fracture, using area under the receiver operator curves (AUCs) and the net reclassification index (NCI) as measures of diagnostic accuracy. ISCD-determined T-scores were determined in only 60 % of participants (n = 1,205). RESULTS: Among 1,205 men, the AUC to predict incident clinical fracture was 0.546 for L1-L4 male, 0.542 for the L1-L4 female, 0.585 for lowest vertebral body, and 0.559 for ISCD-determined T-score. The lowest vertebral body AUC was the only method significantly different from the referent method (p = 0.002). Likewise, a diagnosis of osteoporosis based on the lowest vertebral body T-score demonstrated a significantly better net reclassification index (NRI) than the referent method (net NRI +0.077, p = 0.005). By contrast, the net NRI for other methods of analysis did not differ from the referent method. CONCLUSION: Our study suggests that in men, the lowest vertebral body T-score is an acceptable method by which to estimate fracture risk.

Bone mineral density and fractures in older men with chronic obstructive pulmonary disease or asthma.

SUMMARY: In 5,541 community dwelling men, chronic obstructive pulmonary disease, or asthma was associated with lower bone mineral density (BMD) at the spine and total hip and an increased risk of vertebral and nonvertebral fractures independent of age, body mass index, and smoking. Men prescribed with corticosteroids had the lowest BMD. INTRODUCTION: It is unclear whether chronic obstructive pulmonary disease (COPD) is independently associated with BMD and fractures. METHODS: In 5,541 men from the Osteoporotic Fractures in Men Study, history of COPD or asthma, current treatment with corticosteroids, BMD, bone loss after 4.5 years and fractures were ascertained. RESULTS: Seven hundred fourteen (13%) men reported COPD or asthma, of which 103 were prescribed an oral steroid and 177 an inhaled steroid. Independent of confounders, men prescribed corticosteroids for COPD or asthma had the lowest BMD and a 2-fold increased risk of vertebral osteoporosis compared to men with no history of COPD or asthma (OR 2.13, 95% CI (confidence interval) 1.15-3.93 oral steroids; OR 2.05, 95% CI 1.27-3.31 inhaled steroids). During follow-up, BMD increased at the spine, but there was no difference in bone loss at the hip. However, men with COPD or asthma had a 2.6- and 1.4-fold increased risk of vertebral and nonvertebral fractures, respectively. CONCLUSION: Chronic obstructive pulmonary disease or asthma was associated with lower BMD at the spine and hip and increased risk of vertebral and nonvertebral fractures independent of age, clinic site, BMI, and smoking. A history of COPD or asthma may be a useful clinical risk factor to identify patients with osteoporosis.

Renal function and rate of hip bone loss in older men: the Osteoporotic Fractures in Men Study.

UNLABELLED: Older men with reduced renal function are at increased risk of hip bone loss. Given the robustness of this association across different measures and a growing body of literature, our findings indicate that clinicians should take into account renal function when evaluating older men for osteoporosis risk and bone loss. Future randomized controlled trials should test whether interventions in this high risk population are effective in preventing bone loss and decreasing fracture incidence. INTRODUCTION: Studies examining whether kidney impairment, not requiring dialysis, is associated with osteoporosis have reported conflicting results. METHODS: We tested the hypothesis that reduced renal function in older men as manifested by higher concentrations of cystatin C or lower levels of estimated glomerular filtration rate (eGFR) is associated with higher rates of bone loss. We measured serum cystatin C, serum creatinine and total hip bone mineral density (BMD) at baseline in a cohort of 404 older men enrolled in the Osteoporotic Fractures in Men (MrOS) Study and followed them prospectively for an average of 4.4 years for changes in BMD. Associations between renal function and change in hip BMD were examined using linear regression. RESULTS: In multivariable analysis, the mean rate of decline in total hip BMD showed an increase in magnitude with higher cystatin C concentration (mean annualized percent change -0.29, -0.34, -0.37 and -0.65% for quartiles 1 to 4; p for trend=0.004). Similarly, adjusted rates of hip bone loss were higher among men with lower eGFR as defined by the modification of diet in renal disease formula (mean annualized percent change -0.58, -0.39, -0.37, and -0.31 for quartiles 1 to 4; p for trend=0.02), but not among men with lower eGFR as defined by the Cockcroft-Gault formula (mean annualized percent change -0.47, -0.44, -0.31 and -0.43 for quartiles 1 to 4; p for trend=0.48). CONCLUSIONS: Older men with reduced renal function are at increased risk of hip bone loss. Our findings suggest that health care providers should consider renal function when evaluating older men for risk factors for bone loss and osteoporosis.

Association between aortic calcification and total and cardiovascular mortality in older women.

OBJECTIVES: To determine whether older women with abdominal aortic calcification had a greater cardiovascular and all-cause mortality, as such data are limited in older adults. DESIGN: Prospective cohort study with a mean follow-up of 13 years. SETTING: Community-based sample with four US clinical centres. SUBJECTS: A total of 2056 women aged > or =65 years with abdominal aortic calcification assessed on baseline radiographs. MAIN OUTCOME MEASURE: Mortality rate (all, cardiovascular, cancer or other cause) adjudicated from death certificates and hospital records. RESULTS: The prevalence of abdominal aortic calcification increased with age, ranging from 60% at age 65-69 years to 96% at 85 years and older. Participants with aortic calcification were more likely to die during follow-up of any cause (47% vs. 27%) or a cardiovascular-specific cause (18% vs. 11%, both P < 0.001) than those without aortic calcification. In age-adjusted analyses, aortic calcification was associated with a greater rate of all-cause and cause-specific mortality (cardiovascular, cancer, and other, all P < or = 0.01). In analyses adjusted for age and cardiovascular risk factors, aortic calcification was associated with an increased rate of all-cause mortality (HR: 1.37, 95% CI: 1.15-1.64), and noncardiovascular noncancer mortality (HR: 1.57, 95% CI: 1.17-2.11). The associations between aortic calcification and cancer mortality (HR: 1.44, 95% CI: 1.00-2.08) or cardiovascular mortality (HR: 1.18, 95% CI: 0.88-1.57) showed a similar pattern without reaching statistical significance, but was slightly stronger for mortality from coronary heart disease (HR: 1.53, 95% CI: 0.91-2.56). CONCLUSIONS: Abdominal aortic calcification in older women is associated with increased mortality. Future research should examine potential mechanisms for this association.

Endogenous sex steroids, weight change and rates of hip bone loss in older men: the MrOS study.

INTRODUCTION: Lower levels of endogenous sex steroids or declines in these hormones may contribute to the increased rates of bone loss observed in older adults experiencing weight loss. We hypothesized that among older men with weight loss, higher rates of bone loss at the hip would be observed in men with lower baseline bioavailable sex steroids or those with greater declines in these hormones. METHODS: To test this hypothesis, body weight, hip bone mineral density (BMD) using dual energy x-ray absorptiometry and endogenous sex steroids in paired serum samples by sensitive immunoassays were measured at a baseline and at a second examination that was held an average of 1.8 years later in 1267 older men enrolled in the Osteoporotic Fractures in Men (MrOS) study. RESULTS: Men experiencing weight loss had higher rates of hip bone loss than those with stable weight or weight gain within each quartile of baseline sex steroid level [p values for test of trend across weight change categories <0.010 within each quartile of bioavailable estradiol and testosterone and <0.060 within each quartile of sex hormone-binding globulin (SHBG)]. Results were similar when a change in sex steroids was substituted for baseline sex steroids in the analyses. Among men with weight loss, the rate of decline in total hip BMD showed a stepwise increase in magnitude with decreasing baseline bioavailable estradiol (p value for trend <0.040), with increasing baseline SHBG (p value for trend<0.030) and with greater decreases in bioavailable testosterone from baseline (p value for trend <0.001). CONCLUSIONS: These findings support the hypothesis that the impact of weight loss in older men on rates of hip bone loss may be increased by the presence of a sex steroid insufficiency.

The influence of ionic strength upon relaxation from rigor induced by flash photolysis of caged-ATP in skinned murine skeletal muscle fibres.

The influence of ionic strength upon relaxation kinetics from rigor in skinned murine extensor digitorum longus (EDL) skeletal muscle fibres was examined using photolysis of caged-ATP at low Ca2+. The ionic strength was adjusted with either KMeSO3 or ethylene glycolbis-(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid, dipotassium salt (K2EGTA) in the range of tau /2 = 65-215mM, or I.E. 49-194mM, where I.E. denotes ionic equivalent. Following rigor development at a tau /2 of 165-215mM (I.E. 144-194mM), the liberation of approximately 0.5mM ATP resulted in an initial 6-to 10-ms detachment phase with a decline in force of approximately 10-20% followed by a 10-to 30-ms reattachment with up to a 60% increase compared to the corresponding rigor level and a final detachment leading to complete relaxation. Interestingly, when similar ATP concentrations were liberated at lower ionic strengths between a tau /2 of 65mM and 110mM (I.E. 60-100mM), the initial detachment phase was shortened and force decreased by only approximately 5-10%, while the following reattachment phase was lengthened and led to an increased steady-state force of approximately 20-80% without final relaxation. ATP-induced detachment and subsequent reattachment were mainly determined by the currently present ionic strength and were relatively independent of the preceding rigor state which had been developed at higher or lower ionic strengths. The effects of phosphate and apyrase on the force transient suggest that reattachment of ADP- binding crossbridges may contribute to the increase in tension at high and even more at low ionic strengths. The study shows that the kinetics of initial fast relaxation and subsequent redevelopment of force following flash photolysis of similar ATP concentrations are markedly modified by the ionic strength in the narrow range of between 65mM and 215mM.