Urinary cystatin C as a potential risk marker for cardiovascular disease and chronic kidney disease in patients with obesity and metabolic syndrome.

BACKGROUND AND OBJECTIVES: Obesity and metabolic syndrome (MS) increase the risk of cardiovascular disease (CVD), chronic kidney disease (CKD), and all-cause mortality. Serum cystatin C (S-CysC), a marker of GFR, has been shown to be associated with CVD and CKD. This study was designed to elucidate the association of urinary CysC (U-CysC), a marker of renal tubular dysfunction, with CVD and CKD risk factors in patients with obesity and MS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The U-CysC-creatinine ratio (UCCR) was examined in 343 Japanese obese outpatients enrolled in the multi-centered Japan Obesity and Metabolic Syndrome Study. RESULTS: UCCR was positively correlated with urine albumin-creatinine ratio (UACR) and S-CysC and negatively correlated with estimated GFR (eGFR). Among obese patients, UCCR was significantly higher in MS patients than in non-MS patients. UCCR had significant correlations with the number of components of MS and arterial stiffness, all of which are CVD predictors, similarly to UACR (P<0.05). Interestingly, diet- and exercise-induced weight reduction for 3 months significantly decreased only UCCR among all of the renal markers examined (P<0.01), in parallel with the decrease in BMI, HbA1c, and arterial stiffness, suggesting the beneficial effect of weight reduction on renal tubular dysfunction. CONCLUSIONS: This study demonstrates that UCCR is significantly associated with renal dysfunction, the severity of MS, arterial stiffness, and weight change in obese patients. The data of this study suggest that U-CysC could serve as a CVD and CKD risk factor in patients with obesity and MS.

Highly purified eicosapentaenoic acid reduces cardio-ankle vascular index in association with decreased serum amyloid A-LDL in metabolic syndrome.

A recent clinical trial revealed that highly purified eicosapentaenoic acid (EPA), an n-3 polyunsaturated fatty acid, reduces the incidence of cardiovascular diseases. However, the detailed mechanism underlying the anti-atherogenic effect of EPA is still poorly understood. In this study, we examined the effect of EPA on cardio-ankle vascular index (CAVI), a new index of arterial stiffness that is less influenced by blood pressure (BP), as well as on serum amyloid A-low-density lipoprotein (SAA-LDL), an oxidized LDL (oxLDL), in the metabolic syndrome. Ninety-two obese Japanese subjects with metabolic syndromes were randomly divided into two groups (n=46): the EPA-treated group (1.8 g administered daily for 3 months) and the control group. Measurements were taken to assess the changes in glucose-lipid metabolism, SAA-LDL, C-reactive protein (CRP), leptin, adiponectin and pulse wave velocity (PWV), and CAVI. EPA treatment significantly reduced the levels of immunoreactive insulin, triglycerides, SAA-LDL, CRP, PWV and CAVI and increased the levels of adiponectin relative to the control group for 3 months (P<0.05). Stepwise multivariate linear regression analysis revealed that the only significant determinant for a decrease in CAVI by EPA is a reduction in SAA-LDL (P<0.05). Moreover, the EPA-induced reduction of SAA-LDL was only significantly correlated with a decrease in total cholesterol and an increase in adiponectin (P<0.05). This study is the first demonstration that EPA improves arterial stiffness and is less influenced by BP, possibly through the suppression of SAA-LDL, thereby leading to a reduction in the frequency of cardiovascular disease development in metabolic syndrome.

Effects of risedronate or alfacalcidol on bone mineral density, bone turnover, back pain, and fractures in Japanese men with primary osteoporosis: results of a two-year strict observational study.

Although osteoporosis in men is already a major public health problem, there is still a dearth of data about the effects of risedronate in male osteoporosis, especially in Japanese with primary osteoporosis. Therefore, the objective of our study was to investigate the effects of risedronate on bone mineral density (BMD), bone turnover, back pain, and fractures in these patients prospectively for two years (at baseline, three months, six months, twelve months, and twenty-four months) both longitudinally and compared with those of alfacalcidol. The subjects enrolled for this study were 66 Japanese male patients with untreated primary osteoporosis (mean age 63.52 +/- 8.7 years), who were divided into two groups (44 with risedronate and 22 with alfacalcidol). We measured BMD by dual energy X-ray absorptiometry at three sites-the lumbar spine, femoral neck, and distal radius. Risedronate treatment significantly increased BMD at the lumbar spine and at the femoral neck, reduced bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx), and reduced back pain, both longitudinally and compared with alfacalcidol treatment. We observed a lower rate of incident fracture in risedronate users. However, multiple logistic regression analysis revealed that this trend was not statistically significant, possibly because of the small number of patients enrolled. These potentially beneficial effects of risedronate on bone in male patients with primary osteoporosis suggest the possibility that osteoporosis should be treated with risedronate regardless of gender in order to effectively prevent subsequent osteoporotic fractures.

Efficacy of risedronate in Japanese male patients with primary osteoporosis.

OBJECTIVE: Although osteoporosis in men previously was relatively neglected, bisphosphonates have been strongly suggested as potent therapeutic agents. However, there are few studies on the effects of risedronate in male osteoporosis, especially in Japanese with primary osteoporosis. The aim of our study was to prospectively evaluate the effects of risedronate on bone mineral density (BMD) and bone turnover in Japanese male patients. METHODS: According to the therapeutic regimen, the subjects were divided into two groups (group A, 22 with risedronate; group B, 10 without risedronate). During a one-year study duration, we measured bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx) every 3 months, and BMD at 7 sites by dual-energy X-ray absorptiometry every 6 months. PATIENTS: The subjects were 32 Japanese male patients with untreated primary osteoporosis. RESULTS: In group A, but not in group B, BMD was significantly increased at the lumbar spine both at 6 months and 12 months, and at the femoral neck at 12 months, compared with baseline. Likewise, in group A, but not in group B, both BAP and NTx were significantly decreased at all time points measured (3 months, 6 months, and 12 months), compared with baseline. CONCLUSION: These results confirmed the beneficial effects of risedronate upon increasing BMD and reducing bone turnover markers in Japanese male patients with primary osteoporosis, comparable to those previously reported in postmenopausal patients with osteoporosis.

Three-month changes in bone turnover markers and bone mineral density response to raloxifene in Japanese postmenopausal women with osteoporosis.

It has been well established that raloxifene (RLX) improves bone turnover, increases bone mineral density (BMD), and reduces the risk of fractures. However, it remains obscure how to monitor the therapeutic effects of RLX, while numerous clinical trials for other antiresorptive agents have suggested that greater short-term reductions of bone turnover markers (BTMs) can predict greater increases in BMD and greater reduction in risk of future fractures. The purpose of this study was to investigate associations between short-term reductions of BTMs and subsequent changes of BMD after 1-year treatment with RLX. Seventy-three Japanese postmenopausal women with untreated osteoporosis were selected for this study. Reductions in BTMs [bone-specific alkaline phosphatase (BAP) or serum N-terminal telopeptide of type I collagen (NTx)] after 3 months did not correlate with increases of BMD at any major sites (lumbar spine, femoral neck, total neck, and distal 1/3 radius) either after 6 months or after 12 months. Our results suggest that short-term reductions or 3-month reductions of BTMs with RLX treatment cannot be used to predict increases of BMD. However, this does not directly mean that short-term reductions or 3-month reductions of BTMs with RLX treatment cannot be used to predict risk reduction of future fractures or the ultimate effects of RLX on bone. Further studies with fracture endpoints in longer observation and larger number of patients are warranted to establish how to monitor the therapeutic effects of RLX or early identification of responders or nonresponders to RLX treatment.

Association between baseline values of bone turnover markers and bone mineral density and their response to raloxifene treatment in Japanese postmenopausal women with osteoporosis.

It has been well established that raloxifene improves bone turnover, increases bone mineral density (BMD), and reduces the risk of fractures. However, it remains obscure which patients are more likely to respond to treatment with raloxifene in patients with postmenopausal osteoporosis. The purpose of this study was to investigate associations between baseline values of BMD and bone turnover markers (BTMs) and changes of those values after 1-year treatment with raloxifene. Sixty-eight Japanese postmenopausal women with untreated osteoporosis were selected for this study, among whom 58 patients (mean age 70.40 +/- 9.2 years) completed this study. Lower baseline values of BMD at the lumbar spine, the femoral neck, and the distal radius were significantly correlated with greater increases of BMD at those corresponding sites after 1-year treatment with raloxifene. On the other hand, higher baseline values of bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx) were significantly correlated with greater reductions of BAP and NTx, respectively, after 1-year treatment with raloxifene. Although longer and larger studies with fracture endpoints are needed, our findings suggest that baseline values of BMD and BTMs can be used to predict subsequent skeletal response to raloxifene therapy in Japanese postmenopausal women with osteoporosis.

Increased bone turnover in patients with hypercholesterolemia.

Osteoporosis has been linked with arteriosclerotic vascular diseases, suggesting that hypercholesterolemia or dyslipidemia may be a common pathogenetic factor underlying these diseases. However, little is known about the relationship between osteoporosis and hypercholesterolemia. The purpose of this study was, therefore, to investigate the effects of hypercholesterolemia upon bone metabolism, by measuring bone turnover markers in hypercholesterolemic patients. This study included 281 Japanese patients with hypercholesterolemia, and 267 control subjects. Serum bone-specific alkaline phosphatase (BAP) of the patients was significantly higher than that of the controls in women. Serum N-terminal telopeptide of type I collagen (NTx) of the patients was significantly higher than that of the controls in both men and women. In addition, both BAP and NTx in men showed a significantly negative correlation with high density lipoprotein cholesterol (HDL-C). On the other hand, in women, both BAP and NTx showed a significantly positive correlation with total cholesterol and low density lipoprotein cholesterol (LDL-C). These results indicate increased bone turnover in hypercholesterolemic or dyslipidemic patients regardless of gender, and suggest the importance of treating hypercholesterolemia or dyslipidemia in order to prevent not only arteriosclerotic complications but also osteoporotic bone loss and subsequent fractures.

Efficacy of combined treatment with raloxifene and alfacalcidol on bone density and biochemical markers of bone turnover in postmenopausal osteoporosis.

Because both raloxifene (RLX) and alfacalcidol (ALF) have been established as therapeutic agents for osteoporosis, it is tempting to speculate that the combination therapy of RLX and ALF might provide benefits over that of either one alone. However, the efficacy of the combination therapy has not been reported yet. The purpose of this study was thus to assess the efficacy of the combination therapy on bone mineral density (BMD) and bone turnover in patients with postmenopausal osteoporosis. Sixty postmenopausal patients (mean age 71.62 +/- 9.9 years) with untreated osteoporosis were selected for this study, and were randomly divided into two groups by therapeutic regimen. Group A consisted of 28 patients treated with RLX plus ALF, while Group B consisted of 32 patients with RLX alone. Among them, 20 in group A and 22 in group B completed this study. Contrary to our expectations, at either 6 months or 12 months after the initiation of treatment, RLX plus ALF did not increase BMD at any of the skeletal sites measured, including lumbar spine, femur, and radius, nor did it reduce bone-specific alkaline phosphatase or N-terminal telopeptide of type I collagen more than RLX alone. Our results do not support the hypothesis that the combination therapy of RLX and ALF exerts more beneficial effects on bone compared than with RLX alone. However, it still remains unclear from this study whether the combination therapy of RLX and ALF is more efficacious in preventing fractures compared with RLX alone. Further studies are needed to clarify these issues.

Short-term effects of pitavastatin on biochemical markers of bone turnover in patients with hypercholesterolemia.

OBJECT: No consensus has been reached whether clinical use of statins has beneficial effects on bone health, partly due to lower statin concentrations because of first-pass metabolism by the liver. We thus evaluated the effects of pitavastatin, which does not undergo first-pass metabolism, on bone metabolism. METHODS: According to the therapeutic regimen, the subjects were divided into two groups (group A, 66 with pitavastatin; group B, 35 without pitavastatin). Bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx) as bone turnover markers (BTMs) were compared between the two groups and between at baseline and after 3 months of treatment in each group. Correlations between baseline characteristics and deltaBTMs, and between delta lipid profile and deltaBTMs were investigated using both Pearson's correlation analysis and multivariate analysis. PATIENTS: The subjects were 101 patients with untreated hypercholesterolemia. RESULTS: After 3 months of treatment, BAP in group A did not change significantly compared with either the baseline value or that in group B. However, NTx in group A significantly decreased compared with both the baseline value and that in group B. In addition, deltaNTx was negatively correlated with NTx at baseline, and the significance of this correlation persisted after multiple regression analysis. CONCLUSION: Our findings suggest that pitavastatin may have potentially beneficial effects on bone metabolism primarily by reducing bone resorption rather than by stimulating bone formation. Further studies with more patients and longer duration are warranted to evaluate its effects, if any, on prevention of osteoporosis and subsequent fractures.

Clinical significance of 1-year treatment with raloxifene on bone and lipid metabolism in Japanese postmenopausal women with osteoporosis.

It has been well established that raloxifene (RLX) has beneficial effects on bone primarily in Caucasian women. However, to date, there is a dearth of data for Japanese postmenopausal women. In this study, we prospectively evaluated the effects of RLX on bone and lipid metabolism in fifty Japanese postmenopausal patients with untreated osteoporosis. We measured bone mineral density (BMD) by dual-energy X-ray absorptiometry at 7 sites including the lumbar spine, femoral neck, and distal radius. BMD was significantly increased at the lumbar spine both at 6 months and at 12 months compared with at baseline (p<0.01 for both), although the possibility could not be completely excluded that this increase may be partly explained by an apparent increase induced by degenerative changes in lumbar vertebrae since we had no control subjects to compare and be more certain of the findings in this study. Both bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx) significantly decreased both at 6 months (p<0.01 for both) and at 12 months (p<0.01 for both) compared with at baseline, but not below the lower limit of the reference value. Total cholesterol and low-density lipoprotein cholesterol were significantly improved while triglycerides and high-density lipoprotein cholesterol were unaltered. Although longer and larger studies with fracture endpoints are needed to draw definite conclusions, our findings suggest the favorable effects of RLX on bone and lipid metabolism in Japanese postmenopausal women with osteoporosis as in Caucasian women.

Short-term effects of atorvastatin on bone turnover in male patients with hypercholesterolemia.

No consensus has been reached on whether the 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, known as statins, have beneficial effects on bone health. The purpose of our study was to evaluate the effects of atorvastatin on bone metabolism by means of measuring bone turnover markers in male patients with hypercholesterolemia both at diagnosis and prospectively after 3 months of treatment. Twenty-two Japanese male patients (mean age 62.36 +/- 10.1 years) with untreated hypercholesterolaemeia were selected for this study. After 3-months treatment of atorvastatin, total cholesterol and low density lipoprotein cholesterol significantly decreased as expected (p<0.001 for both parameters). Bone-specific alkaline phosphatase (BAP) did not change significantly (p = 0.444). However, serum N-terminal telopeptide of type I collagen (NTx) significantly decreased by -19.86 +/- 26.4% (p = 0.020). In addition, delta NTx during the course of this study was negatively correlated with NTx at baseline (r = -0.645, p = 0.0008). Although there was a tendency of positive correlations of delta NTx with delta total cholesterol, delta triglycerides, and delta low density lipoprotein cholesterol, and of negative correlations of delta NTx and delta BAP with delta high density lipoprotein cholesterol, none of them reached statistical significance. Our findings suggest that atorvastatin may have potentially beneficial effects on bone metabolism in patients with hypercholesterolemia mostly by reducing bone resorption rather than by stimulating bone formation. Further studies with more patients and longer duration are warranted to evaluate its effects, if any, on prevention of osteoporosis and subsequent fractures.

[Negative correlation between BMD and HbA1C in patients with type 2 diabetes].

This study included 145 patients with type 2 diabetes, and 95 non-diabetic control. We measured bone mineral density (BMD) at the sites with different cortical/cancellous bone ratio (lumbar spine, femoral neck, and distal radius). BMD and Z score at the distal radius were significantly lower in type 2 diabetic patients than those in control subjects. In type 2 diabetic patients, negative correlation between BMD and the mean HbA(1C) during the last 2 years was found significantly at the distal radius in both sexes. These results indicate the selective cortical bone loss in type 2 diabetes, and suggest the importance of evaluating BMD at the radius as well and keeping good metabolic control to prevent bone loss in type 2 diabetic patients.

Safety and efficacy of low-dose pioglitazone (7.5 mg/day) vs. standard-dose pioglitazone (15 mg/day) in Japanese women with type 2 diabetes mellitus.

It is well known that pioglitazone, a potent thiazolidinedione, improves metabolic control. However, weight gain or peripheral edema may be of major clinical concern when using this agent. The purpose of our study was to prospectively evaluate the effects of low-dose pioglitazone (7.5 mg/day) on metabolic control, weight gain and the incidence of edema compared with a standard dose of pioglitazone (15.0 mg/day) in patients with type 2 diabetes mellitus (T2DM). Ninety-five Japanese female patients (mean age 58.4 +/- 10.4 years) with newly diagnosed T2DM were selected for this study. They were randomly divided into the following 2 groups according to therapy regimens, and examined every month for 6 months after diagnosis. Group A consisted of 54 patients treated with low-dose pioglitazone orally; Group B, the control-group, consisted of 41 patients treated with standard-dose pioglitazone orally. The incidence of peripheral edema was significantly much lower in group A (2/54) than in group B (11/41) (p = 0.0014). In addition, % change of body weight during the 6-month treatment in group A was significantly less than that in group B (p < 0.0001). On the other hand, the % change of biochemical parameters including HbA1c did not differ significantly between group A and group B, although glucose and lipid control significantly improved from baseline in both groups. Our results demonstrate the safety and efficacy of low-dose pioglitazone, suggesting that it could be another good choice of treatment for Japanese women with T2DM.

Clinical significance of risedronate for osteoporosis in the initial treatment of male patients with Graves' disease.

It has been well established that hyperthyroidism leads to diminished bone mineral density (BMD), and that a previous history of hyperthyroidism remains a risk factor for fractures. However, little is known about how to manage the reduction in BMD caused by hyperthyroidism. The purpose of this study was to evaluate the efficacy of risedronate for the treatment of osteoporosis/osteopenia in patients with Graves' disease (GD). Of 34 Japanese male patients with newly diagnosed GD, 27 with osteoporosis/osteopenia were included in this study. They were randomly divided into two groups by therapeutic regimen. Group A consisted of 14 patients treated with an antithyroid drug and risedronate. Group B consisted of 13 patients treated with the same antithyroid drug only. We used dual-energy X-ray absorptiometry to measure BMD at the lumber spine, femoral neck, and distal radius at baseline, and at 6 and 12 months after the trial. Bone-specific alkaline phosphatase and urinary N-terminal telopeptide of type I collagen normalized by creatinine were significantly more reduced in group A than in group B after both 6 and 12 months. The percentage increases in BMD at the lumbar spine and distal radius were significantly greater in group A than in group B. These beneficial effects of risedronate for patients with osteoporosis/osteopenia caused by GD may lead to a reduced risk of future fractures. We thus conclude that risedronate should be considered for the treatment of decreased bone mass associated with GD.

Anaplastic thyroid carcinoma associated with Graves' disease.

This report concerns a 79-year-old woman with coexisting anaplastic thyroid carcinoma (ATC) and Graves' disease (GD). The patient was referred to our clinic because of palpitation and a palpable mass on the left side of her neck. Thyroid function tests showed hyperthyroidism with elevated thyroid-stimulating antibodies. Ultrasonography of the thyroid demonstrated an adenomatous nodule-like marcated nodule (27.6 x 26.5 x 36.4 mm) with cystic degeneration inside the left lobe. (123)I thyroid scintigraphic imaging showed a cold area corresponding to the nodule with continuous uptake in the remaining thyroid tissue despite suppressed TSH levels. These findings led to a diagnosis of GD. On the other hand, the thyroid nodule could not be definitely diagnosed even after fine needle aspiration biopsy (FNAB) which produced findings suggestive of both papillary thyroid carcinoma and ATC. Open biopsy of the nodule showed an ATC. Regional lymph node metastases as well as multiple lung metastases, which could not be found at the initial visit, had been already developed by that time. Our case is pathophysiologically interesting because it suggests that GD or thyroid-stimulating antibodies (TSAb) may stimulate malignant transformation of differentiated carcinoma. It is also clinically important because it indicates that all thyroid nodules, particularly palpable cold nodules, associated with GD require careful management to detect malignancy because they are at higher risk of harboring malignancy.

Papillary thyroid carcinoma without metastases manifesting as an autonomously functioning thyroid nodule.

A 59-year-old woman with papillary thyroid carcinoma inside of an autonomously functioning thyroid nodule is described in this report. The patient was referred to our clinic because of rapid weight loss and swelling on the left side of the neck. Ultrasonography of the thyroid demonstrated a nonhomogeneous nodule in the lower part of an enlarged left lobe. Both 99mTc and 123I thyroid scintigraphic imaging showed a hot area corresponding to the nodule with lower uptake in the remaining thyroid tissue. Histopathological examination of the nodule revealed papillary adenocarcinoma, and the immunohistochemistry proved weak but positive staining for triiodothyronine and thyroxine. Based on these findings, the nodule was diagnosed as a functioning papillary adenocarcinoma. Although thyroid carcinoma manifesting as a hot nodule on the radionuclide isotope scan is an extremely rare occurrence, the current case is clinically important because it suggests that the diagnosis of a hot nodule cannot always rule out thyroid carcinoma in the nodule, and that even a hot nodule requires careful management so that the malignancy is not overlooked.