Takami Miki

Serum Osteoprotegerin Levels Are Associated With the Presence and Severity of Coronary Artery Disease

Background—Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family. OPG-deficient mice develop severe osteoporosis and medial arterial calcification of the aorta and renal arteries. OPG immunoreactivity was demonstrated in the normal blood vessels and in early atherosclerotic lesions. A recent clinical study suggests that there is a significant correlation between elevated serum OPG levels and cardiovascular mortality. We examined whether serum OPG levels are associated with the progression of coronary artery disease (CAD). Methods and Results—Serum OPG levels were examined in 201 patients who underwent coronary angiography because of stable chest pain. The number of diseased vessels was used to represent the severity of CAD. Serum OPG levels were measured by ELISA and were significantly greater in patients with significant stenosis of the coronary arteries than in those without stenosis. As the severity of CAD increased, there was a significant increase in serum OPG levels. Serum OPG levels were 0.94±0.34, 1.04±0.38, 1.19±0.38, and 1.44±0.54 ng/mL (medians 0.91, 0.99, 1.09, and 1.37) for the subjects with normal coronary arteries or luminal irregularities, 1-vessel disease, 2-vessel disease, and 3-vessel disease, respectively. Multivariate logistic regression analysis revealed that serum OPG levels were significantly associated with the presence of CAD [odds ratio, 5.2; 95% confidence interval, 1.7 to 16.0]. Conclusions—Our data show that serum OPG levels are associated with the presence and severity of CAD, suggesting that OPG may be involved in the progression of CAD.

Insulin Resistance as an Independent Predictor of Cardiovascular Mortality in Patients with End-Stage Renal Disease

Insulin resistance is closely associated with atherosclerosis and cardiovascular mortality in the general population. Patients with end-stage renal disease (ESRD) are known to have insulin resistance, advanced atherosclerosis, and a high cardiovascular mortality rate. We evaluated whether insulin resistance is a predictor of cardiovascular death in a cohort of ESRD. A prospective observational cohort study was performed in 183 nondiabetic patients with ESRD treated with maintenance hemodialysis. Insulin resistance was evaluated by the homeostasis model assessment method (HOMA-IR) using fasting glucose and insulin levels at baseline, and the cohort was followed for a mean period of 67 mo. Forty-nine deaths were recorded, including 22 cardiovascular deaths. Cumulative incidence of cardiovascular death by Kaplan-Meier estimation was significantly different between subjects in the top tertile of HOMA-IR (1.40 to 4.59) and those in the lower tertiles of HOMA-IR (0.28 to 1.39), and the hazard ratio (HR) was 2.60 (95% confidence interval [CI], 1.12 to 6.01; P = 0.026) in the univariate Cox proportional hazards model. In multivariate Cox models, the positive association between HOMA-IR and cardiovascular mortality remained significant (HR, 4.60; 95% CI, 1.83 to 11.55; P = 0.001) and independent of age, C-reactive protein, and presence of preexisting vascular complications. Further analyses showed that the effect of HOMA-IR on cardiovascular mortality was independent of body mass index, hypertension, and dyslipidemia. In contrast, HOMA-IR did not show such a significant association with noncardiovascular mortality. These results indicate that insulin resistance is an independent predictor of cardiovascular mortality in ESRD.

Parathyroid hormone regulates fibroblast growth factor-23 in a mouse model of primary hyperparathyroidism.

The importance of fibroblast growth factor 23 (FGF-23) in the pathogenesis of phosphate wasting disorders has been established, but controversy remains about how parathyroid hormone (PTH), which also stimulates urinary phosphate excretion, regulates the circulating level of FGF-23. We found that the serum FGF-23 concentration was higher in PTH-cyclin D1 transgenic mice, a model of primary hyperparathyroidism, than in wild-type mice. The serum FGF-23 concentration was significantly and directly correlated with serum PTH and calcium, and inversely correlated with phosphate levels in 90- to 118-week-old mice (all P < 0.005). Quantitative real-time reverse-transcriptase PCR revealed abundant expression of fgf23 in bone, especially in calvaria. The fgf23 expression in calvaria was significantly higher in the transgenic mice compared to the wild-type mice, and correlated well with serum FGF-23 levels. There was a direct correlation between the expression of fgf23 and the expression of osteocalcin and ALP, suggesting that activation of osteoblasts is important in the regulation of FGF-23. Serum FGF-23 levels decreased in the transgenic mice after parathyroidectomy. In conclusion, PTH plays a major role in the regulation of serum FGF-23 level in primary hyperparathyroidism, likely via activation of osteoblasts in bone.

Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese Society for Bone and Mineral Research (2004)

Glucocorticoids (GCs) are widely used to treat various inflammatory, immunologic, and allergic disorders that cause rheumatic, respiratory, bowel, hepatic, neurological, renal, and skin diseases. Osteoporosis is the most common and important adverse effect of GC therapy, and fractures occur in 30–50 % of adult patients receiving long-term GC therapy [1, 2]. Glucocorticoid-induced osteoporosis (GIO) is the most common type of secondary osteoporosis, and it occurs in patients of all ages, from children to the elderly. An early rapid decrease of bone mineral density (8–12 %) occurs within several months of starting GC therapy, although bone mineral density decreases more slowly thereafter, with the annual loss being approximately 2–4 % [3]. In addition, it is known that there is a significant increase in the risk of vertebral and hip fractures before marked bone loss occurs [4]. Therefore, it is important to prevent early bone loss and to decrease in fracture risk as early as possible after the start of GC therapy. Based on the concept of early prevention and treatment, the American College of Rheumatology (ACR) developed recommendations for the prevention and treatment of GIO

Platelet P-Selectin Expression Is Associated With Atherosclerotic Wall Thickness in Carotid Artery in Humans

Background—Recent genetic animal models reveal important roles of platelet P-selectin on progression of atherosclerosis. In the present study, we examine the relation between platelet P-selectin expression and atherosclerotic parameters in 517 subjects. Methods and Results—Unrelated subjects (n=517; 235 male and 282 female), including 187 with type 2 diabetes, 184 with hypertension, and 366 with hyperlipidemia, were enrolled in the study. P-selectin expression was determined by whole-blood flow cytometry. Arterial stiffness (stiffness index &bgr;) and arterial wall thickness (intima-media thickness [IMT]) were determined by carotid ultrasound. P-selectin expression was significantly and positively correlated with carotid IMT and stiffness index &bgr;. Multiple regression analyses showed that the association of the percentage of P-selectin–positive platelets with carotid IMT was independent of other clinical factors. Moreover, the percentage of P-selectin–positive platelets was higher in subjects with carotid plaque and was an independent factor associated with occurrence of carotid plaque analyzed by multiple logistic regression analysis. Finally, the percentage of P-selectin–positive platelets was positively associated with age, body mass index, systolic and diastolic blood pressure, and HbA1c and inversely associated with HDL cholesterol. Conclusions—Platelet P-selectin is independently associated with atherosclerotic arterial wall changes in human subjects.

Guidelines for the use of biochemical markers of bone turnover in osteoporosis (2004)

A definition of osteoporosis was agreed upon at the 1993 consensus conference held in Hong Kong. It states that osteoporosis is “characterized by low bone mass and the microarchitectural deterioration of bony tissue, with a consequent increase in bone fragility and susceptibility to fracture.” This definition had been internationally used without revision until recently, when the definition was significantly changed at a National Institutes of Health (NIH) consensus conference in 2000 [1]. According to the consensus statement, osteoporosis is defined as “a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture.” Bone strength is determined by integrating bone mineral density (BMD) and bone quality. BMD is expressed as grams of mineral per area or volume, and, currently, BMD is defined by the individual peak bone density and the resorption rate from the peak. Bone quality is determined by characteristics of the bone matrix, such as microarchitecture, bone turnover, microdamage accumulation, the degree of calcification, and collagen [2,3]. Currently, it is thought that bone quality may not be clinically assessed by measures other than the determination of bone metabolism with biochemical markers of bone turnover. The change in definition may be the result of more recent findings [4], one that demonstrates bone fractures routinely occur despite patients having modest BMD levels, and another that has shown no significant reduction in the risk of a fracture occurring in patients taking one of the two standard medications, one that significantly increases BMD and the other that moderately increases it.

High Striatal Amyloid β-Peptide Deposition Across Different Autosomal Alzheimer Disease Mutation Types

BACKGROUND Supported by compelling genetic data regarding early-onset familial Alzheimer disease (AD), the amyloid beta-peptide (Abeta)-centric theory holds that Abeta is involved in the pathogenesis of sporadic AD. Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes lead to increased Abeta levels before symptoms arise. OBJECTIVES To evaluate the pattern of Pittsburgh Compound B (PiB) retention in subjects with different autosomal dominant mutations associated with familial AD vs that in healthy age-matched control subjects and subjects with probable sporadic AD, to correlate Abeta burden as measured by PiB with available clinical and cognitive data, and to compare the regional brain patterns of PiB retention and fluorodeoxyglucose F 18 (FDG) uptake. DESIGN Correlation analysis of positron emission tomography (PET) imaging studies. SETTING Academic research. PARTICIPANTS Seven PSEN1 mutation carriers and 1 APP mutation carrier underwent PiB and FDG PET imaging. Amyloid beta-peptide burden and FDG uptake were established using standardized uptake values normalized to pons. MAIN OUTCOME MEASURE Primary outcomes were PET results, which were compared with those of a well-characterized cohort of 30 healthy control subjects and 30 subjects with probable sporadic AD. RESULTS All mutation carriers had high PiB retention in the striatum, with some also having cortical PiB retention in ventrofrontal and posterior cingulate/precuneus areas. The striatal pattern of PiB retention was similar in the PSEN1 and APP mutation carriers. Neither striatal nor cortical Abeta burden was related to cognitive status. CONCLUSIONS Consistent with previous studies, the pattern of Abeta deposition in familial AD differs from that in sporadic AD, with higher striatal and somewhat lower cortical PiB retention in familial AD. The pattern and degree of Abeta deposition were not associated with mutation type nor cognitive status.

Guidelines for the use of bone metabolic markers in the diagnosis and treatment of osteoporosis (2012 edition)

Recently the clinical application of bone metabolic markers has achieved significant progress and the measurements of these indices give us a better understanding of the pathogenesis of osteoporosis. Bone metabolic markers were adapted to select drug treatment for osteoporosis and to evaluate drug efficacy. Therefore, the proper application and assessment of bone metabolic markers in clinical practice is very important. To achieve these aims, the committee on the guidelines for the use of biochemical markers of bone turnover in osteoporosis authorized by the Japan Osteoporosis Society has summarized recent progress in bone markers and proposed the proper utilization of bone markers. Although the use of bone metabolic markers now has an important role in the daily management of osteoporosis, their use in Japan is still insufficient because of insurance coverage limitations. Since the Japan Osteoporosis Society first created the 2001 guidelines, new bone metabolic markers have been introduced into clinical practice. The availability of new osteoporosis treatments that promote bone formation has changed the clinical application of bone metabolic markers in current practice. Therefore, revisions to the current clinical practice are needed which led to the proposal to create these new 2012 guidelines.

Case–control study of risk of Parkinson's disease in relation to hypertension, hypercholesterolemia, and diabetes in Japan

This case-control study investigated the associations of a history of hypertension, hypercholesterolemia, and diabetes mellitus with the risk of Parkinsons disease (PD) in Japan. Included were 249 cases within 6 years of onset of PD. Controls were 368 inpatients and outpatients without a neurodegenerative disease. Data on the vascular risk factors and confounders were obtained from a self-administered questionnaire. The vascular risk factors were defined based on drug treatment. Adjustment was made for sex, age, region of residence, pack-years of smoking, years of education, leisure-time exercise, body mass index, dietary intake of energy, cholesterol, vitamin E, alcohol, and coffee and the dietary glycemic index. The proportions of hypertension, hypercholesterolemia, and diabetes mellitus prior to the onset of PD were 23.7%, 9.6%, and 4.0%, respectively, in cases. Hypertension, hypercholesterolemia, and diabetes mellitus were significantly associated with a decreased risk of PD: the adjusted ORs were 0.43 (95% CI: 0.29-0.64), 0.58 (95% CI: 0.33-0.97), and 0.38 (95% CI: 0.17-0.79), respectively. No significant differences were observed in the association of vascular risk factors with the risk of PD between men and women. We found evidence of significant inverse associations of hypertension, hypercholesterolemia, and diabetes mellitus with the risk of PD in Japan. Further well-designed investigations of the association of vascular risk factors with the risk of PD are needed, particularly large-scale prospective studies in Asia.

Risk factors for osteoporosis in men

Abstract. We evaluated the risk factors for osteoporosis in men. The subjects of this study consisted of 686 healthy middle-aged (40–59 years) men who had undergone bone mineral density (BMD) measurement and medical examination, including physical strength. BMD of L2-4 was measured at the anterior-posterior position, using dual X-ray absorptiometry. Physical investigations, such as height, weight, and physical strength, were carried out on the examination day. Details of tobacco and alcohol consumption, exercise, and food intake were described on a questionnaire completed by the subjects. Sixty-five (9.5%) of the 686 subjects had a BMD less than 2.5 SD below the peak bone mass (PBM), 182 (26.5%) had a BMD between 1 SD and 2.5 SD below the PBM; and 439 (64.0%) had a BMD no less than 1 SD below the PBM. Body mass index (BMI) and leg strength were significant positive determinants of BMD, and smoking was a significant negative determinant on multiple regression analysis, with a coefficient of determination of 9.5%. Calcium intake, exercise, and alcohol consumption were not significant determinants of BMD. These results suggest that poor lifestyle behaviors (i.e., smoking) accelerate the reduction of bone density.