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.     

吡格列酮对2型糖尿病患者骨转换生化指标的影响

目的 观察吡格列酮对2型糖尿病患者骨转换生化指标的影响.方法 比较70例2型糖尿病患者加用吡格列酮治疗12周前后血清I型原胶原N末端前肽(PINP)、总碱性磷酸酶(T-ALP)、骨钙素(OC)、I型胶原交联C末端肽(CTX)等骨转化指标的变化.结果 吡格列酮治疗12周后,2型糖尿病患者血清PINP和T-ALP水平较治疗前明显降低(P<0.01),并且这种下降作用主要来源于女性亚组的贡献.OC和CTX在治疗前后无明显变化.结论 吡格列酮可抑制骨形成,而对骨吸收则可能无明显影响,提示吡格列酮对2型糖尿病患者骨转换的影响主要是抑制骨形成.     

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.     

胰岛素、胰岛素原对胰岛素抵抗状态下HepG2细胞PAI-1分泌的影响

目的研究胰岛素、胰岛素原对胰岛素抵抗状态下ＨｅｐＧ２细胞ＰＡＩ１分泌的影响。方法选择在合成ＰＡＩ１方面与肝细胞相似的ＨｅｐＧ２细胞，以高浓度胰岛素诱导胰岛素抵抗后，分别用生理浓度的胰岛素、胰岛素原刺激２４小时，以观察胰岛素抵抗状态下ＰＡＩ１活性的变化。结果基础状态下胰岛素抵抗ＨｅｐＧ２细胞与非胰岛素抵抗ＨｅｐＧ２细胞相比，ＰＡＩ１活性差异不明显；胰岛素、胰岛素原刺激后，胰岛素抵抗ＨｅｐＧ２细胞ＰＡＩ１活性明显高于非胰岛素抵抗ＨｅｐＧ２细胞。当培液中同时加入１０－４Ｍ二甲双胍后，胰岛素、胰岛素原介导的ＰＡＩ１过量分泌得到明显抑制。结论在胰岛素抵抗状态下，胰岛素、胰岛素原刺激后ＨｅｐＧ２细胞ＰＡＩ１活性明显增加，而二甲双胍可明显抑制此现象。     

Physical activity and biochemical markers of bone turnover in elderly patients

To assess the role of physical therapy in improving the remodelling processes of bone turnover, biochemical markers of bone formation and resorption (osteocalcin, parathormone, bone-specific alcaline phosphatase, somatotropic hormone, C-terminal propeptide type I procollagen, somatomedin, insulin-like growth factor bound protein, C-terminal telopeptide type I collagen) have been investigated in elderly patients before and after a cycle of physical therapy. Patients of both sexes, immobilized on hospital admission day because of fractures or neurologic diseases, underwent physiotherapy for one month. Following physical treatment we found significant increases of osteocalcin, bone-specific alcaline phosphatase and somatomedin in the female group, while no significant difference was detected in males. Our data support that the mechanical stimulus significantly improves the recovery of osteoblastic activity in women, while in men the increases in bone remodelling markers are not significant. Differences in life-style between male and female patients are proposed as determinants in the bone remodelling response to physical therapy.     

New biochemical markers of bone turnover in serum

Measurement of serum NTx and serum CTx has been recently reported to be a sensitive for osteoporosis and metabolic bone disease. It indicates that the measurement of serum NTx and serum CTx, biochemical markers of bone resorption, predict long-term changes in vertebral BMD in elderly women receiving biophosphonate therapy and provide a useful tool to assess skeletal health.     

绝经后女性2型糖尿病患者骨转换生化指标的研究

目的探讨绝经后2型糖尿病(type2diabetes mellitus,T2DM)、T2DM合并骨质疏松(osteo-porosis,OP)及OP患者的糖代谢、骨代谢、骨密度(bone mineral density,BMD)变化及其相关性。方法 776位绝经后汉族女性被分为4组:T2DM组(218例),OP组(223例),T2DM+OP组(186例),健康对照组(149名)。分别测定受试者的骨代谢、糖代谢指标及血钙、血磷等相关指标,用双能X线仪测定不同部位BMD,并进行统计分析及相关性研究。结果 T2DM组腰椎BMD明显高于对照组,T2DM+OP组和OP组腰椎及股骨颈BMD低于对照组。T2DM组血清25羟基维生素D3、骨碱性磷酸酶(bone alkaline phosphate,BALP)、抗酒石酸酸性磷酸酶(tartrate-resistant acid phosphatase,TrACP)明显低于正常对照组(均P<0.01)。T2DM+OP组与对照组比较,血清骨钙素(osteocalcin,OT)、BALP、TrACP明显升高(P<0.01),而血清25羟基维生素D3则显著降低(P<0.01)。相关性分析显示,T2DM患者BMD与患者HbA1C、FPG、血清TrACP呈显著负相关,与血清OT、BALP、25羟基维生素D3、BMI呈显著正相关。结论 T2DM患者骨代谢呈低转换状态,因长期血糖控制不佳,T2DM组OP的危险性增加。血清BALP、OT、TrACP和25OHD可考虑作为T2DM合并OP的早期诊断生化指标。     

The effects of pitavastatin on glucose metabolism in patients with type 2 diabetes with hypercholesterolemia

BackgroundAlthough there have been several reports that statins cause insulin resistance that leads to the occurrence of type 2 diabetes in Caucasians, there has been no Japanese prospective studies investigating the effects of statins on the glucose metabolism system.Materials and methodsOur subjects were 86 Japanese patients with type 2 diabetes with hypercholesterolemia. Pitavastatin 2 mg/day was administered for 12 months and the lipid-related values, glucose metabolism values, and the presence/absence of side effects were investigated.ResultsNone of these factors was found to differ between before and after administration of pitavastatin in overall analysis of all subjects. In subgroup analysis, fasting blood glucose showed a decrease in the BMI ≥ 25 group and there was a significant difference between the BMI < 25 and BMI ≥ 25 groups (P-values: 0.021 and 0.0036). Although HbA1c showed an increase both in the group switched to pitavastatin and the BMI < 25 group (P-values: 0.035 and 0.033) and HOMA-β showed a decrease in the BMI < 25 group (P-values: 0.044), there were no significant differences in changes between each divided group and their counterparts.ConclusionIn the Japanese obese group with BMI ≥ 25, pitavastatin elicited a significant decrease in fasting blood glucose. It is not clear whether or not this is due to improved insulin resistance as a direct effect of pitavastatin, but in contrast to findings in Caucasians pitavastatin does not worsen insulin resistance in Japanese patients with type 2 diabetes complicated by hypercholesterolemia.     

Clinical application of biochemical markers of bone turnover

With the ageing population in most countries, disorders of bone and mineral metabolism are becoming increasingly relevant to every day clinical practice. Consequently, the interest in, and the need for effective measures to be used in the screening, diagnosis and follow-up of such pathologies have markedly grown. Together with clinical and imaging techniques, biochemical tests play an important role in the assessment and differential diagnosis of metabolic bone disease. In recent years, the isolation and characterisation of cellular and extracellular components of the skeletal matrix have resulted in the development of molecular markers that are considered to reflect either bone formation or bone resorption. These biochemical indices are non-invasive, comparatively inexpensive and, when applied and interpreted correctly, helpful tools in the diagnostic and therapeutic assessment of metabolic bone disease. This review provides an overview of the current evidence regarding the clinical use of biochemical markers of bone remodelling in bone disease, with an emphasis on osteoporosis.     

Fracture risk and biochemical markers of bone turnover

BMD is prescribed by the balance of bone resorption and osteogenesis. In osteoporosis, this balance collapses according to a certain cause, bone loss starts as a result because bone resorption exceeds osteogenesis. Since a bone turnover marker shows the bone metabolism at the time of measurement quantitatively, it is thought that the change in BMD is reflected. Therefore, it is in predicting bone reduction of the future and fast bone loser identifying is expected by measuring bone turnover markers. Reduction of bone density is large in high turnover of bone metabolism, and it is shown clearly by recent research that the risk of fracture goes up. There is the necessity for evaluation of the bone turnover markers which made fracture the end point also in Japan.     

Renal osteodystrophy and biochemical markers of bone turnover

Renal osteodystrophy which associates with high rates of morbidity in patients with chronic renal failure is not an uniform metabolic bone disease. Although bone histomorphometry is the most reliable diagnostic method, several biochemical markers have been proposed for evaluation of bone turnover in hemodialysis patients. This review assesses the value and the limitations of several serum markers of bone metabolism in patients with chronic renal failure.     

Short-term effects of surgery in post-menopausal patients with primary hyperparathyroidism and normal bone turnover.

The most common clinical presentation of primary hyperparathyroidism (PHPT) is nowadays characterized by a slight skeletal involvement. We studied 5 consecutive female patients with PHPT presenting with bone turnover marker levels within the reference range of our Center and whose bone mineral density values were above the usual fracture risk threshold. In each patient we measured, both in basal conditions and daily, for the first 5 days after surgery, the following indexes: serum total (T-ALP) and bone-specific (B-ALP) alkaline phosphatase activity, osteocalcin (BGP, by two different assays), together with the 24-hour urinary excretions of total pyridinoline (Pyr/Cr) and deoxypyridinoline (DPyr/Cr), free deoxypyridinoline (FD-Pyr/Cr), cross-linked N-telopeptide of type I collagen (NTx/Cr), and type I C-telopeptide (CTx/Cr). The markers of both bone formation and resorption significantly decreased after surgery (p<0.001 by multiple ANOVA). Individual post-surgical markers changes were all significant but T-ALP and FD-Pyr, the most pronounced percent reductions being shown by NTx and CTx. The time-course of such variations substantially differed among the various indexes. These results show that bone formation and resorption markers are up-regulated also in PHPT patients with mild skeletal involvement; acute removal of parathyroid hormone excess differently affected the markers of bone turnover in terms of both entity and time-course.     

Biological variability of biochemical markers of bone turnover in healthy women

To investigate day-to-day biological change of biochemical makers of bone turnover, we measured eight markers for 5 days in 10 healthy women. They aged 26-41 years (mean age; 31.1 years old), and had regular menstrual cycles. Fasting second void urine and blood was collected from them on five successive days. As serum marker, Estradiol (E2), intact PTH (i-PTH), Bone-specific alkaline phosphatase (BAP), and serum C-telopeptide (S-CTX) were measured. As urinary markers, urinary CTX (U-CTX), N-telopeptide (NTX), pyridinoline (Pyr) and deoxypyridinoline (Dpyr) were measured. Day-to-day physiological variations were different between bone markers. Variability of serum markers was less than that of urinary markers. Moreover, in the comparison of the same molecular marker, CTX, the variability of S-CTX was less than U-CTX. One should consider physiological variation of the marker to evaluate whether the change of the biochemical marker of bone turnover is significant or not.     

Comparison of effects of pitavastatin and atorvastatin on glucose metabolism in type 2 diabetic patients with hypercholesterolemia

Aims/Introduction

The distinct effects of different statins on glycemic control have not been fully evaluated. In this open‐label, prospective, cross‐over clinical trial, we compared the effects of pitavastatin and atorvastatin on glycemic control in type 2 diabetic patients with hypercholesterolemia.

Materials and Methods

A total of 28 Japanese type 2 diabetics with hypercholesterolemia treated with rosuvastatin (2.5 mg/day) for at least 8 weeks were recruited to this quasi‐randomized cross‐over study. At study entry, the patients assigned to sequence 1 received pitavastatin (2 mg/day) for 12 weeks in period 1 and atorvastatin (10 mg/day) for another 12 weeks in period 2, whereas patients assigned to sequence 2 received atorvastatin (10 mg/day) for 12 weeks in period 1 and pitavastatin (2 mg/day) for another 12 weeks in period 2. Blood samples were collected at three visits (baseline, after 12 and 24 weeks).

Results

Lipid control was similar in both statins. The difference in glycated hemoglobin between pitavastatin and atorvastatin treatments was −0.18 (95% confidence interval −0.34 to −0.02; P = 0.03). Compared with atorvastatin, pitavastatin treatment significantly lowered the levels of glycoalbumin, fasting glucose and homeostasis model assessment of insulin resistance.

Conclusions

Our results showed that treatment with pitavastatin had a more favorable outcome on glycemic control in patients with type 2 diabetes compared with atorvastatin. This trial was registered with UMIN (no. 000003554).     

Short-term administration of glucagon-like peptide-2. Effects on bone mineral density and markers of bone turnover in short-bowel patients with no colon

BACKGROUND: Glucagon-like peptide 2 (GLP-2) is a newly discovered intestinotrophic hormone. We have recently reported that a 5-week GLP-2 treatment improved the intestinal absorptive capacity of short-bowel patients with no colon. Additionally, GLP-2 treatment was associated with changes in body composition that included a significant increase in total body bone mass. This article describes the effect of GLP-2 on spinal and hip bone mineral density (BMD) and biochemical markers of bone turnover in these patients. METHODS: In an open-labelled pilot study, eight short-bowel patients (3M, 5F; mean age 49 years) with small-bowel resection and no colon received 400 microg s.c. of GLP-2 twice daily for 5 weeks. Four received home parenteral nutrition (mean length of residual jejunum 83 cm) and 4 did not (mean length of ileum resected 106 cm). The outcome measures were the mean percent change from baseline in spinal and hip BMD measured by dual-energy X-ray absorptiometry, changes in four biochemical markers of bone-turnover, PTH, 25-hydroxy vitamin-D, and the intestinal absorption of calcium. RESULTS: Mean +/- s(x) (SEM) percent changes in spinal and hip BMD were 1.1+/-0.4% (P < 0.05) and 1.9+/-0.8% (P = 0.06), respectively. The intestinal calcium absorption increased by 2.7% (P = 0.87). Serum ionized calcium increased in 5/8 patients with a concomitant decrease in serum PTH values. Three of the four markers of bone turnover decreased. CONCLUSION: A 5-week GLP-2 administration significantly increased spinal BMD in short-bowel patients with no colon. The mechanism by which GLP-2 affects bone metabolism remains unclear, but may be related to an increased mineralization of bone resulting from an improved intestinal calcium absorption.     

Utility of biochemical markers of bone turnover in the assessment of osteoporosis

Osteoporosis is characterized by both an imbalance between resorption and formation within the remodeling unit, and by an abnormalities of activation frequency, bone turnover. Bone mineral density (BMD) measurement is critical in the clinical evaluation of the patient at risk for osteoporosis, but it represents a static parameter that provides no insight into the rate of bone turnover in a given patient. The recent availability of biochemical markers for bone turnover are a major methodological advance. These measurements are noninvasive, and very useful in assessing turnover abnormalities of various osteoporotic states and in monitoring effects of treatment.     

The effects of hormonal contraceptives on bone turnover markers and bone health

Sex hormones are important regulators of bone metabolism. As hormonal contraceptives contain either oestrogens or progestins, or a combination thereof, it is conceivable that these widely used agents have an effect on bone metabolism and bone health. The main users of hormonal contraceptives, adolescent girls and young women, are still building bone and accruing bone mass and may therefore be particularly susceptible to the effects of hormonal contraceptives on bone. Despite these concerns, the effects of hormonal contraceptives on bone health are still poorly understood. As biochemical markers of bone turnover have been proven useful tools in the assessment and monitoring of bone metabolism, we reviewed the effects of combined and gestagen‐only hormonal contraceptives on bone turnover markers and related effects on bone mineral density and fracture risk in premenopausal women, as documented in the literature until January 2009.