Variability of Parathyroid Hormone and Other Markers of Bone Mineral Metabolism in Patients Receiving Hemodialysis

Background and objectives: Clinical management of mineral bone disorder in patients with kidney failure is guided by biochemical targets, in particular parathyroid hormone (PTH) concentration. The biologic variation of PTH and other bone mineral markers was measured in hemodialysis patients to better define their role in management.Design, setting, participants, & measurements: Intact PTH, biointact (whole-molecule) PTH, calcium, albumin-adjusted calcium, phosphate, and alkaline phosphatase (ALP) were measured in nonfasting samples obtained twice a week (both short-dialysis interval) over a 6-week period in 22 stable hemodialysis patients. Concurrently, samples were obtained from 12 healthy volunteers. Intraindividual coefficients of variance (CV_I) were calculated and used to derive the reference change value (RCV) required to be 95% certain that a change has occurred.Results: CV_I of all markers was significantly (P < 0.05) greater in patients than in healthy volunteers. For phosphate, ALP, and PTH this implies that an increased number of samples is required to estimate an individual''s homeostatic set point. CV_I of intact PTH was 25.6% in hemodialysis patients and 19.2% in healthy volunteers. A greater RCV should be used for patients (72%) compared with healthy volunteers (54%). Ideally 26 specimens should be measured to estimate a patient''s intact PTH homeostatic set point (within ±10%) with 95% probability. The CV_I of biointact PTH was at least as high as that for intact PTH.Conclusions: The uncertainty of PTH estimation in an individual significantly undermines its value as a tool in the management of chronic kidney disease-mineral bone disorder using current management approaches.Almost universally, patients with ESRD have disturbances in bone and mineral metabolism (1). This group of disorders, termed chronic kidney disease-mineral and bone disorder (CKD-MBD) encompasses pathogenically linked biochemical abnormalities, bone diseases, and vascular and soft tissue calcification (2) and contributes to morbidity (3,4) and mortality (2,5,6). Common laboratory manifestations include disturbances in calcium, phosphate, and parathyroid hormone (PTH) concentrations (7), and these markers are the subjects of routine monitoring with accompanying target ranges (8–10). In particular, management is guided by PTH concentration, which has effectively replaced alkaline phosphatase (ALP) as a marker of bone turnover. U.K. and U.S. guidelines recommend maintenance of PTH within a range of 150 to 300 ng/L (8,9), although this has proved difficult to achieve (11). Recent guidelines from Kidney Disease Improving Global Outcomes (KDIGO) suggest that a broader range of PTH concentrations (approximately 150 to 675 ng/L) may be tolerated with management changes being initiated in response to trends in PTH concentration (10).Hitherto, management guidelines for CKD-MBD have given little consideration to biologic variability. Laboratory analytes are subject to three main sources of variation: preanalytical, analytical, and biologic. If sources of preanalytical variation are minimized (e.g., by standardizing sampling procedures), then intraindividual biologic variation (CV_I) can be estimated by subtracting analytical variation (CV_A) from total variation (CV_T) (12). CV_I is the random fluctuation around an individual''s homeostatic set point. Numerical data on biologic variation can be used to evaluate the significance of changes in serial results and the number of samples required to produce a precise estimate of the homeostatic set point (12). CV_I can be used to determine how much an analyte''s concentration must vary by between two results before the change is considered significant: This is termed the critical difference or reference change value (RCV).There is an extensive literature concerning biologic variation of markers (see http://www.westgard.com/biodatabase1.htm, accessed December 1, 2009), but there are few data on PTH variability and this has only been reported in healthy subjects (13,14). The biologic variation of some analytes in disease differs from that of healthy subjects (15,16), and RCVs calculated from healthy individuals may be lower than appropriate for specific clinical situations, resulting in “false-positive” signals for patients being monitored. This could lead to inappropriate medical decisions (e.g., an unnecessary change in treatment dose).In the area of CKD-MBD, a further confounder may be the nature of the analyte being detected. Targets for PTH concentration are based on the use of so-called “intact” PTH assays, which were initially thought to detect full-length PTH (1-84) (17). However, it is now appreciated that they also detect large N-terminally truncated fragments, predominantly PTH (7-84), which does not have the same biologic efficacy (18,19). Recently assays have been developed with the ability to detect whole-molecule PTH (1-84) without crossreactivity with PTH (7-84) (20). For the purposes of this paper, we have described these assays as “intact” and “biointact,” respectively.A recent international guideline emphasized the need for increased understanding of intraindividual variation in the laboratory markers of CKD-MBD (10). The aims of the study presented here were to establish

1. The biologic variation of PTH and other markers of bone mineral metabolism in hemodialysis patients and whether this differs from that in health.
2. How many measurements are required to establish a true homeostatic set point in any individual?
3. How much does the concentration need to vary by to truly represent any underlying change (i.e., what is the RCV)?
4. The influence of PTH (7-84) on observed biologic variation.

     

类风湿关节炎患者骨密度与骨代谢指标的临床意义

目的探讨类风湿关节炎(rheumatoid arthritis,RA)患者骨代谢指标、骨密度(bone mineraldensity,BMD)、骨矿物质含量(bone mineral conten,BMC)的变化及临床意义。方法选择2011年3月至2012年7月安徽医科大学附属省立医院风湿免疫科RA患者(RA组)及健康者(对照组),采用双能X线骨密度仪检测各组受试者前臂BMD和BMC含量,检测2组骨钙素(bone gla protein,BGP)、I型胶原交联羧基末端肽(C-terminal telopeptides of type I collagen,CTX)、红细胞沉降率(erythrocyte sedimentation rate,ESR)、C反应蛋白(C reactive protein,CRP)、类风湿因子(rheumatoid factor,RF)和抗环瓜氨酸肽抗体(anti-cyclic citrullinated peptide antibody,抗-CCP)。摄双手X线正位片,进行X线分期,计算患者疾病活动指数(disease activity score 28,DAS28)。结果 RA组患者71例,对照组20例。RA组骨代谢指标CTX和BGP明显高于对照组,差异有统计学意义(均P0.05)。RA组前臂BMD、BMC,均低于对照组的BMD和BMC,差异有统计学意义(均P0.01)。直线相关分析示RA组CTX与BMD和BMC均呈负相关(r=-0.301,P=0.014;r=-0.296,P=0.015);与病程、RF呈正相关(r=0.382,P=0.001;r=0.263,P=0.029);多元线性回归分析显示前臂BMD与RF、年龄呈负相关(r=-7.544、r=-3.254,P均0.01);前臂BMC与DAS28呈负相关(t=-4.440,P0.01);相关分析显示BMD、BMC与X线分期均呈负相关(r=-0.289、r=-0.284,P均0.01),CTX与X线分期成正相关(r=0.333,P=0.005)。结论 RA患者骨代谢呈高转换型骨丢失,骨代谢指标及骨密度、骨矿盐含量可以预测RA患者出现骨破坏;RF可能为RA患者骨破坏的危险因素。     

Consistent Control of Mineral and Bone Disorder in Incident Hemodialysis Patients

Background and objectives: In 2003, the National Kidney Foundation introduced guidelines for the control of parathyroid hormone, calcium, and phosphorus in hemodialysis patients.Design, setting, participants, & measurements: A cohort study was conducted of 22,937 incident hemodialysis patients who were identified from a large national provider between July 1, 2000, and June 30, 2002, and followed through June 30, 2004. Consistent achievement was determined (1) as the simultaneous control of multiple markers over time and (2) as the time in target for each marker during the first year of dialysis. Mortality risk was assessed with Cox proportional hazards models.Results: In the simultaneous control analysis, patients who achieved target for none of the markers had a 51% greater risk for death than those who achieved target for all three markers (reference group). Patients who achieved any target for any single marker had a 35 to 39% higher risk for death, and patients who achieved target for any two of the three markers had a 15 to 21% higher risk for death compared with the reference group. In the time in target analysis, patients with parathyroid hormone in target for 4 quarters had a 25% lower risk for death compared with those who did so for ≤1 quarter (reference group). Patients with calcium in target for 4 quarters had a 14% lower risk, and patients with phosphorus in target for 4 quarters had a 38% lower risk.Conclusions: Consistent control of the markers of bone metabolism and disease within published targets is a strong predictor of survival in hemodialysis patients.Mineral and bone disorder (MBD) affects the majority of patients with chronic kidney disease and is characterized by imbalances in serum levels of parathyroid hormone (PTH), calcium (Ca), and phosphorus (P) (1,2). In recognition of the growing body of evidence linking abnormalities of bone and mineral metabolism with adverse clinical outcomes and consistent with their goal of improving the quality of care and outcomes of patients with kidney disease, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) published the Bone Metabolism and Disease treatment guidelines in October 2003 (1). These guidelines contain specific treatment targets for PTH (150 to 300 pg/ml), Ca (within the normal range, particularly the lower end from 8.4 to 9.5 mg/dl), P (3.5 to 5.5 mg/dl), and Ca-P product (Ca × P; <55 mg²/dl²) (3). Although elevations in each of these biochemical markers, as well as elevations in Ca × P have been associated with increased morbidity and mortality in dialysis patients, the authors of the guidelines acknowledge that additional evidence from epidemiologic studies, including randomized trials, is needed to inform future revisions to these guidelines (3–10).The percentage of patients who met the KDOQI targets around the time of their introduction in 2003 ranged from 21 to 26% for PTH, 29 to 49% for Ca, 39 to 55% for P, and 54 to 73% for Ca × P (10–13). Most concerning was that only 5 to 7.3% of dialysis patients simultaneously met all four targets (PTH, Ca, P, and Ca × P). According to one study that evaluated target achievement both before and after the KDOQI treatment guidelines were introduced, a majority of patients remained outside at least some of the target ranges even after implementation (6.6 and 10.9% met all for targets in 2003 and 2004, respectively) (12). Another study evaluated the effects of guideline-induced changes in non–calcium-containing phosphate binders, vitamin D use, and dialysate calcium levels and found that serum P and serum PTH levels increased in association with a modest reduction in serum Ca (14).One of the difficulties in achieving multiple KDOQI targets consistently is that most existing treatment approaches reflect a compromise between controlling PTH and controlling Ca and P (14). Some newer therapies (e.g., Renagel [Genzyme Corporation, Cambridge, MA], Sensipar [Amgen, Inc., Thousand Oaks, CA]), as well as combinations of therapeutic agents, may make it easier to achieve consistent control of multiple MBD parameters (15). Currently, there is no information to assist physicians in understanding the tradeoffs being made by achieving one target at the expense of another. Similarly, although one recent study suggests that short-term control of these markers is associated with lower mortality, no study has investigated the significance of long-term control of these parameters (16). The goal of our study was to determine whether more consistent control of PTH, Ca, and P (or Ca × P) within the KDOQI target ranges was associated with better survival compared with less consistent control, where consistency was defined as either the number of markers in target at one time or the duration of time in target for each marker.     

维持性血液透析患者骨代谢指标变化及相关分析

目的 调查维持性血液透析患者中钙、磷及血清全段甲状旁腺激素（iPTH）水平的差异。方法 以98例透析龄＞3月的血液透析患者作为调查对象，根据患者透析龄的长短将患者分为透析龄<12月组、12月<透析龄<36月组以及透析龄≥36月组；生物化学仪分析各组间血钙、血磷、血肌酐、尿素氮等，采用ELISA法检测患者透析前iPTH水平。结果 血液透析患者随透析龄延长iPTH 水平逐步升高 （P<0.05）；在短透析龄（透析龄＜36月）患者中糖尿病患者iPTH水平低于非糖尿病者，差异具有显著性 （P<0.05）；回归分析显示，iPTH与血磷和透析龄相关。结论 长期血液透析患者iPTH水平随透析龄延长而升高且与高血磷相关。     

Effects of a Single,High Oral Dose of 25‐Hydroxycholecalciferol on the Mineral Metabolism Markers in Hemodialysis Patients

Vitamin D deficiency is common in dialysis patients with chronic kidney disease. Low levels have been associated with increased cardiovascular risk and mortality. We evaluated the administration of a high, single oral dose of 25‐OH cholecalciferol (3 mg of Hidroferol, 180 000 IU) in patients on chronic hemodialysis. The 94 chronic hemodialysis patients with vitamin D deficiency 25 (OH)D <30 ng/mL included in the study were randomized into two groups. Follow‐up time was 16 weeks. Neither the usual treatment for controlling Ca/P levels nor the dialysis bath (calcium of 2.5 mEq/L) were modified. Of the 86 patients who finished the study, 42 were in the treated group and 44 in the control group. An increase in 25(OH)D levels was observed in the treated group that persisted after 16 weeks and was associated with a significant decrease in parathyroid hormone (PTH) levels during the 8 weeks post‐treatment. Baseline 1,25(OH)₂D levels of the treated group increased two weeks after treatment (5.9 vs. 21.9 pg/mL, P < 0.001) but gradually reduced to 8.4 at week 16. The administration of a single 3 mg dose of 25‐OH cholecalciferol seems safe in patients on hemodialysis and maintains sufficient levels of 25(OH)D with a decrease in PTH for 3 months.     

Markers of Bone Metabolism in Patients With Chronic Pancreatitis and Pancreatic Ductal Adenocarcinoma

There are no studies comparing some of the most important markers, such as vitamin D, parathormone, osteocalcin, bone alkaline phosphatase, and calcium, in patients with chronic benign and malignant pancreatic diseases. Our objective was to comparatively evaluate serum markers of bone metabolism in patients with chronic pancreatitis and in those with ductal pancreatic adenocarcinoma. Sixty-three consecutive subjects were studied: 30 patients with a firm diagnosis of chronic pancreatitis and 33 having histologically confirmed pancreatic adenocarcinoma. Serum 25-hydroxyvitamin D, bone alkaline phosphatase, osteocalcin, parathormone, and calcium were determined using commercially available kits. Taking into consideration the clinical variables of all 63 patients studied, 25-hydroxyvitamin D was inversely correlated with only the body mass index (P = 0.007), whereas it was not correlated with age (P = 0.583) or fecal elastase-1 concentrations (P = 0.556). Regarding the other substances studied, parathormone was positively correlated with only the age of the patients (P = 0.015). Of the 5 substances studied, only bone alkaline phosphates were significantly different (P < 0.001) between patients with chronic pancreatitis and those with pancreatic ductal adenocarcinoma. Within the 2 groups of patients, the 23 patients with chronic pancreatitis without diabetes mellitus had serum concentrations of 25-hydroxyvitamin D significantly lower (P = 0.045) than those with chronic pancreatitis having diabetes mellitus, whereas smokers with pancreatic ductal adenocarcinoma had serum concentrations of calcium significantly higher (P < 0.001) as compared to nonsmokers. Altered bone metabolism seems to be associated with chronic diseases of the pancreas; however, the mechanism should be better elucidated.     

Impact of Weekly Teriparatide on the Bone and Mineral Metabolism in Hemodialysis Patients With Relatively Low Serum Parathyroid Hormone: A Pilot Study

Adynamic bone disease in HD patients is characterized by skeletal resistance to parathyroid hormone (PTH) or suppression of PTH release, leading to a downregulated bone turnover and bone fracture. Hence, we examined the efficacy of weekly teriparatide for HD patients with low PTH indicating adynamic bone disease without a history of parathyroidectomy. Fifteen HD patients with low PTH were recruited in this prospective observational study. Of them, 10 received teriparatide for 12 months and five nontreated patients were enrolled as control. Primary outcomes were defined as the changes in bone mineral density and bone turnover markers. Bone mineral density at the lumbar spine increased by 3.7% and 2.5% at 6 and 12 months, respectively, and bone formation markers increased, while bone resorption markers did not change in the teriparatide group. At 12 months after teriparatide administration, endogenous PTH was secreted followed by the recovery of low bone turnover. 40% of patients in the teriparatide group dropped out due to adverse events and the most common adverse event was transient hypotension. This study suggests that weekly teriparatide for HD patients with low PTH in the absence of parathyroidectomy accelerates bone formation and bone turnover, leading to increased trabecular bone mass and secretion of endogenous PTH.     

Relationship between Bone Mineral Content and Frequency of Postmenopausal Fractures

To elucidate the relationship between bone mineral content (BMC) and the frequency of postmenopausal fractures, we performed an epidemiologic investigation in a representative sample of 70-year-old women. Anamnestic data concerning postmenopausal fractures due to minor trauma were recorded and lateral X-rays of the spine were taken for evaluation of spinal fractures. BMC was measured by ¹²⁵I photon absorptiometry. The 285 women studied were allocated into quintiles according to their BMC value. In 77 women, there were 131 definite osteoporotic fractures (i.e., spinal crush, and fracture of the hip, proximal humerus, and distal forearm), and in 48 women, there were 162 other non-violent fractures (i.e., spinal wedge and other long bone fractures). The frequencies of osteoporotic fractures varied inversely with the mean BMC values for each quintile (r=0.959, p<0.01). The difference in frequency of osteoporotic fractures between the first and fifth quintiles was highly significant (p > 0.001). In contrast, other non-violent fractures appeared to be unrelated to BMC. It is concluded that low BMC levels predispose to osteoporotic fractures.     

Bone and Mineral Metabolism in Adult Celiac Disease

Bone mineral density (125I photon absorptiometry) was lower in 20 untreated adult celiac patients than in sex- and age-matched controls (p less than 0.001), and plasma alkaline phosphatase, parathyroid hormone, urinary hydroxyproline/creatinine levels were higher than normal (p less than 0.05, less than 0.001, less than 0.05, respectively). Gluten-free diet was started, and the patients were divided randomly into two treatment groups, one which received oral 25-hydroxyvitamin D 50 micrograms/day and one which did not. After 12 months' treatment, bone turnover markers showed a decrease, which did not reach statistical significance, and bone mineral density did not show significant modifications compared with base line in either group. It was found that a gluten-free diet followed for 1 yr can prevent further bone loss, but no significant differences were detected between the two groups.     

Genetic African Ancestry and Markers of Mineral Metabolism in CKD

Background and objectives

Disorders of mineral metabolism are more common in African Americans with CKD than in European Americans with CKD. Previous studies have focused on the differences in mineral metabolism by self-reported race, making it difficult to delineate the importance of environmental compared with biologic factors.

Design, setting, participants, & measurements

In a cross-sectional analysis of 3013 participants of the Chronic Renal Insufficiency Cohort study with complete data, we compared markers of mineral metabolism (phosphorus, calcium, alkaline phosphatase, parathyroid hormone, fibroblast growth factor 23, and urine calcium and phosphorus excretion) in European Americans versus African Americans and separately, across quartiles of genetic African ancestry in African Americans (n=1490).

Results

Compared with European Americans, African Americans had higher blood concentrations of phosphorus, alkaline phosphatase, fibroblast growth factor 23, and parathyroid hormone, lower 24-hour urinary excretion of calcium and phosphorus, and lower urinary fractional excretion of calcium and phosphorus at baseline (P<0.001 for all). Among African Americans, a higher percentage of African ancestry was associated with lower 24-hour urinary excretion of phosphorus (P_trend<0.01) in unadjusted analyses. In linear regression models adjusted for socio-demographic characteristics, kidney function, serum phosphorus, and dietary phosphorus intake, higher percentage of African ancestry was significantly associated with lower 24-hour urinary phosphorus excretion (each 10% higher African ancestry was associated with 39.6 mg lower 24-hour urinary phosphorus, P<0.001) and fractional excretion of phosphorus (each 10% higher African ancestry was associated with an absolute 1.1% lower fractional excretion of phosphorus, P=0.01).

Conclusions

A higher percentage of African ancestry was independently associated with lower 24-hour urinary phosphorus excretion and lower fractional excretion of phosphorus among African Americans with CKD. These findings suggest that genetic variability might contribute to racial differences in urinary phosphorus excretion in CKD.     

Relationship Between Epicardial Adipose Tissue,Inflammation and Volume Markers in Hemodialysis and Transplant Patients

Cardiovascular (CV) diseases are still the most important cause of morbidity and mortality in both patients receiving hemodialysis (HD) treatment and individuals with renal transplantation (Rtx). Measurement of epicardial adipose tissue (EAT) thickness is an easily applied, cheap, and useful recent method predicting increased CV risk. We aimed to compare EAT changes in HD and Rtx patients and the association between EAT and inflammatory and CV volume markers in both groups. A total of 124 patients: 45 Rtx, 43 HD patients and 36 healthy controls were enrolled in the study. Laboratory parameters and inflammatory markers (interleukin‐6 [IL‐6] and high sensitive C‐reactive protein [Hs‐CRP]) were evaluated from venous blood samples after an overnight fast. EAT thickness was measured with transthoracic echocardiography. The levels of Hs‐CRP, IL‐6, systolic and diastolic blood pressures, left atrial (LA) diameter, left atrial index (LAI), left ventricular mass (LVM) and LVM index (LVMI) were significantly higher in the HD patients than in the other groups. EAT was positively correlated with age, body mass index (BMI), time on dialysis, serum creatinine, total cholesterol, Low density lipoprotein‐cholesterol, and LVM in Rtx group and positively correlated with age, BMI, duration of dialysis, Hs‐CRP, IL‐6, LAI and LVMI and inversely correlated with inferior vena cava collapse index (IVC‐CI) in HD group. EAT thickness of RTx patients (whose previous HD duration was similar to those in HD group) are similar to the healthy population and significantly thinner than patients on HD.     

Bone Metabolism and Bone Status in Osteoporotic Patients

ABSTRACT. We have studied bone turnover and bone status in 29 patients with hip fractures and compared them with normal subjects and patients with arthritis of the hip. Markers for bone formation, bone Gla protein, alkaline phosphatase and whole body retention of ^99mTc-diphosphonate, and fasting urinary hydroxyproline, a marker for bone resorption, were all significantly higher in the hip fracture group than in the control group. The serum concentrations of 1,25-dihydroxyvitamin D were similar in the three groups, whereas the serum 25-hydroxyvitamin D concentration in the control group was higher than in the patient groups. The bone mineral content (BMC) measured in the distal forearm and the spine was lower than normal in the hip fracture group. We conclude that patients with hip fractures have an increased bone turnover with no signs of bimodality and low BMC values at all locations.     

Tumor Markers in Patients Undergoing Hemodialysis and Kidney Transplantation

Objective: To evaluate the effect of dialysis and kidney transplantation on serum levels of several tumor markers such as PSA, AFP, CA125, CA19- 9, CA15-3, CEA and to compare with normal age matched controls. Methods: Between September of 2000 and July of 2001, the following tumor markers: PSA, AFP, CA125, CA19-9, CA15-3 and CEA were measured by ELISA Method in 29 hemodialyzed patients (group A), in 30 successfully transplanted patients (group B) and in 30 normal volunteers who did not present any clinical symptoms or signs of neoplasia. Results: The serum level of CEA was above the cutoff limit in 6.7% of hemodialyzed patients (group A) but was in the normal range in transplanted and control groups. The level of CEA were significantly higher in hemodialyzed patients in comparison to other groups (p<0.003). Serum levels of AFP and PSA were not significantly different between the three groups (p=0.595 and p=0.545, respectively). Although serum level of CA 19-9 was elevated in 3.3% of hemodialyzed and control group the differences between the three groups were not significant (p=0.507). Serum level of CA 125 was elevated in 13.3% of group A, 13.8% of group B and 6.7% of control group (p=0.347). Serum level of CA15-3 was elevated in 13.3%, 6.9% of group A, B and control group, respectively and the differences were not significant (p=0.156). Conclusion: Hemodialyzed and transplanted patients show a high false positive rate of CEA, CA125 and CA15-3 and may be unreliable for monitoring of malignancies in these patients while other markers evaluated (AFP, PSA and CA 19.9) appear to maintain their specificity in these situations.     

Effects of Intravenous Pamidronate on Renal Function,Bone Mineral Metabolism and Bone Mass in Patients With Severe Osteoporosis

IntroductionTo analyze the effects of intravenous pamidronate (APD) on bone remodelling, bone mineral density (BMD), fractures and bone mineral metabolism parameters, and the rate of adverse events, with special attention to renal function, in patients with osteoporosis with intolerance and/or any contraindication to oral bisphosphonates.MethodsWe analyzed prospectively 17 osteoporotic patients (age, 66.8 ± 9.4 years): 65% women, 82% with prevalent vertebral fractures. All patients received APD therapy (30 mg intravenously every 3 months) and were followed up for 1 year. We analyzed serum amino-terminal propeptide of type I procollagen and urinary N-terminal cross-linked telopeptide of type I collagen (as markers of bone turnover), serum calcium, phosphate, parathormone, 25OH-vitamin D, creatinine, and the creatinine clearance: at baseline, 1 week after starting APD treatment, and thereafter for every 3 months (before infusion) during 1 year. We also analyzed lumbar and femoral BMD at baseline and after 1 year, the incidence of new fractures, and the treatment-related adverse events.ResultsOne week after starting APD treatment, a significant decrease of N-terminal cross-linked telopeptide of type I collagen (32%) (P < 0.05) and an increase of parathormone values (72%) (P < 0.01) were observed, without significant differences found thereafter. No significant differences were observed in BMD evolution and in the other parameters analyzed throughout the study, nor in impairment of renal function. Sixty-four percent of patients suffered new skeletal fractures, 41% of patients showed flu-like syndrome after APD infusion, and 1 patient was withdrawn from treatment because of adverse events.ConclusionsPatients with severe osteoporosis receiving APD infusions had a high rate of fractures without significant changes in bone mass or in bone markers; nevertheless, such a therapeutic regimen showed a good renal safety profile, suggesting that APD at this dosage is safe but ineffective for treating severe osteoporosis.     

Low Bone Mineral Density and Impaired Bone Metabolism in Young Alcoholic Patients Without Liver Cirrhosis: A Cross-Sectional Study

Background: Osteoporosis is regularly mentioned as a consequence of alcoholism. Ethanol′s direct effect on bone‐modeling cells as well as alcoholism‐related “life‐style factors” such as malnutrition, lack of exercise, hormonal changes, and liver cirrhosis are discussed as potential causative factors. Methods: In a cross‐sectional study, we have examined 57 noncirrhotic alcoholic patients (37 male, 20 female) aged 27 to 50 years. Patients suffering from comorbid somatic diseases and with co‐medication known to have an influence on bone mineral density (e.g., glucocorticoids, heparin, anticonvulsant agents, oral contraceptives) were excluded. We determined bone mineral density (BMD) by dual x‐ray absorptiometry (DXA) in the lumbar spine (L1–L4) and the proximal right femur (femoral neck, total hip) as well as parameters of bone metabolism. Results: In males but not females, BMD was significantly reduced in the lumbar region, as well as in the proximal femur (femoral neck, total hip). Nine male patients (24.3% of men) and 1 female patient (5% of women) had low BMD (defined as Z‐score ≤ ?2.0). As expected, there was a positive correlation between body mass index (BMI) and BMD. Alcohol‐related factors (e.g., duration of abuse, consumed amount of alcohol per day) as well as smoking were not associated with a significant effect on BMD. All of the 20 women examined showed elevated estradiol levels, which may have served as a protective factor. In this study, 75.7% of the men and 90% of the women had vitamin D insufficiency or deficiency (plasma levels of 25‐hydroxy‐vitamin D < 30 ng/ml). Conclusions: Our study indicates that younger alcoholic patients without other diseases may suffer from an increased risk to develop low BMD and a disturbance of vitamin D metabolism. Nutritional factors or less exposure to sunlight may play an important role in bone loss in young alcoholic patients. BMD measurement and assessment of bone metabolism should be considered in all patients with chronic alcoholism.     

Relationship between Local and Total Bone Mineral Content after Gastric Surgery

We compared the total body bone mineral mass (TBBM), assessed by the dualphoton technique, with the local bone mineral mass (BMC), measured by single- photon absorptiometry, in 27 ulcus patients treated by either gastric resection or parietal cell vagotomy. Except for raised concentrations of serum alkaline phosphatase in the Billroth I resection group, the biochemical findings and the measurements of bone mass (local and total) were normal. A highly significant correlation between local and total body bone mineral mass was found in both patients (r = 0.84) and controls (r = 0.91). Since the relationship between these two measurements is identical in the patient population and in the age-matched control group, it is concluded that the local BMC may be useful to estimate total bone mass after gastric surgery.     

Role of the Klotho Gene in Bone and Mineral Metabolism

Klotho was originally identified when a random insertional mutation disrupting the mouse gene caused an abnormal phenotype with accelerated aging and shortened lifespan. Klotho appears to play an important role in the renal handling of calcium and phosphate, in part by interacting with the FGF23 signaling system. In general, klotho tends to decrease phosphate retention and 1,25-dihydroxyvitamin D3 synthesis. It directly stimulates calcium reabsorption in the kidney and tends to increases serum calcium, but may have opposite indirect effects related to the changes in vitamin D metabolism. Klotho may also influence the response of the parathyroids to hypocalcemia and may interact with other biological systems, including Wnt, OPG/RANKL, insulin/IGF-I, and sex steroids. The actual relevance of klotho in human physiology has been recently illustrated by the identification of some rare patients with loss-of-function and gain-of-function mutations of the Klotho gene. Several studies also suggest that certain polymorphisms of the gene may influence human aging and the development of age-related diseases, such as arteriosclerosis or osteoporosis, but further investigations are needed to elucidate their true importance.     

Bone Mineral Density in Hemophilia Patients

Patients with hemophilia suffer from low bone mineral density (BMD) due to several risk factors including arthropathy and resulting immobility. Recent studies have shown variable frequency of low BMD in this group of patients. This study attempts to assess the prevalence of low BMD (osteoporosis and osteopenia) and the associated risk factors in a group of Iranian hemophilia patients. Patients with moderate or severe hemophilia underwent BMD measurement by dual energy X-ray absorptiometry. The results were correlated with other variables including physical activity, calcium intake and demographic data. Forty two patients with the mean age of 31 years (range 18–72) completed the study. The prevalence of osteoporosis in the spine and the left femoral neck was 23.8 and 14.6 %, respectively, and osteopenia in the spine and femoral neck was seen in 45.2 and 31.7 % of the patients, respectively based on the WHO T-score criteria. We found only cigarette smoking to be significantly related to low BMD (P < 0.001). There were two cases of pathologic fracture at femoral neck and forearm (4.8 %). Low BMD is very common in patients with hemophilia. Appropriate assessment of BMD and control of predisposing factors such as prophylactic factor replacement (to prevent hemarthrosis) and cessation of cigarette smoking are warranted.     

Relationship Between High Circulating Adiponectin With Bone Mineral Density and Bone Metabolism in Elderly Males With Chronic Heart Failure

BackgroundThe aim of the study was to investigate the associations of adiponectin and leptin to bone mass and bone specific surrogates in elderly males with chronic heart failure (CHF).Methods and ResultsSeventy-three males (mean age 68 ± 7 years) with stable mild to moderate CHF and 20 healthy individuals age- and body mass index–matching underwent dual energy x-ray absorptiometry measurements (bone mineral density (BMD) at hip and lumbar spine, total bone mineral content, and body composition); echocardiography; 6-minute walk test; grip strength; and biochemical assessment including adiponectin, leptin, bone specific surrogates (osteocalcin, β-CrossLaps, osteoprotegerin [OPG], receptor activator of nuclear factor κB ligand [RANKL]), parathyroid hormone, 25-hydroxy vitamin D, testosterone, sex hormone-binding globulin, and NT-pro-BNP. Serum adiponectin, osteocalcin, β-CrossLaps, OPG, RANKL, and parathyroid hormone were significantly increased in CHF patients, whereas 25-hydroxy vitamin D was significantly lower compared to healthy controls. The significant positive association was found between adiponectin level with osteocalcin, β-CrossLaps, OPG, and RANKL among CHF patients. In multivariate regression analysis, adiponectin was a significant determinant of total hip BMD, although the variance was small (r² = 0.239), whereas leptin was determinant for total bone mineral content (r² = 0.469) in patients with CHF.ConclusionsSerum adiponectin is an independent predictor of BMD in elderly males with mild to moderate CHF, and showed a positive correlation to bone specific surrogates. Adiponectin, as cardioprotective hormone, seems to be able to exert a negative effect on bone mass in chronic heart failure. Further research is needed to confirm the potential for adipokines in the crosstalk between bone and energy metabolism in CHF patients.