Csaba Horváth

Decreased bone density, elevated serum osteoprotegerin, and β-cross-laps in Wilson disease

Osteopathia has been reported in Wilson disease (WD), but bone density has not been measured; therefore, we performed bone mineral density (BMD), bone mineral content (BMC), and quantitative bone ultrasound (QUS) assessments, as well as measured the serum levels of osteocalcin (OCN), β‐cross‐laps (β‐CTxs), and the recently discovered osteoprotegerin (OPG) and its ligand RANKL to investigate the underlying mechanism of osseous disorders. Serum OCN, β‐CTx, OPG, and RANKL levels were measured by ELISA in 21 WD patients and in 20 age‐ and gender‐matched healthy subjects. BMD, BMC, and QUS parameters were also determined. Osteoporosis was present in 9/21 (43%) WD patients. Abnormal QUS parameters were found in 7 (33%) of the patients. Although serum OCN levels were similar in patients and controls (29.93 ± 24.65 mg/ml vs. 29.84 ± 6.89 mg/ml), β‐CTx and OPG levels were significantly increased in WD compared with the healthy controls (625.4 ± 312.3 pg/ml vs. 423.6 ± 144.3 pg/ml and p = 0.022 and 7.2 ± 3.4 pM vs. 3.5 ± 1.0 pM and p < 0.001, respectively). No difference was observed in the RANKL level. There was a positive correlation between OCN and β‐CTx (r = 0.55; p = 0.01). We proved high occurrence of osteoporosis in WD. Negative bone remodeling balance is a consequence of increased bone resorption, which is indicated by elevated β‐CTx. The novel finding of elevated serum OPG may reflect a compensatory reaction to enhanced osteoclast activity, despite the normal OCN level.

Epidemiology of osteoporosis related fractures in Hungary from the nationwide health insurance database, 1999-2003

SummaryThe Hungarian national health insurance database was screened for fractures of patients aged 50–100, 1999–2003. On average, there were 343 hip, 1,579 forearm, 342 proximal humerus, 48 inpatient vertebral and 2,459 other fractures/100,000 inhabitants/year.IntroductionThe incidence of fractures differs among populations. Our aim was to study the incidence of fractures in Hungary, focusing on classical osteoporotic sites and to compare the results with those of other European countries.MethodsThe Hungarian National Health Insurance Fund database, covering 100% of the population, was screened for fractures of patients aged 50–100, 1999–2003. The search of vertebral fractures was restricted to those admitted to hospital. A gender and age-matched comparison was performed with available data from Europe.ResultsThere were mean 343 hip, 1,579 forearm, 342 proximal humerus, 48 inpatient vertebral and 2,459 other fractures/100,000 inhabitants/year; the female/male ratio was between 1.2–2.4. Multiple fractures occurred in 23.1% of the cases. Hip fracture incidence in Hungary lies between the rates of northern and southern countries of Europe.ConclusionsOur study offers nationwide epidemiological data on fractures in Hungary. The incidence of fractures increased by age, regardless of the type of fracture. Incidence of hip fractures in Hungary fits in the previously established geographic trends in Europe. Our results fulfil a need for fracture data from Central Europe.

Slight Decrease in Bone Mineralization in Cow Milk-Sensitive Children

BackgroundPatients with cow milk allergy (CMA) are potentially at risk for osteopenia because their milk-free diet usually contains a low calcium content. In our study, different parameters of bone mineralization in children with CMA were investigated. Patients and MethodsTwenty-seven CMA patients (mean age, 4.3 years; range, 3–8 years) were enrolled in the study. During a mean milk-free diet period of 11.8 months, children were fed extensively hydrolyzed or soy-based formulas. After a milk challenge test, 7 patients showed allergic symptoms, and the other 20 children had transient CMA. From the sera of all patients, the levels of sodium, potassium, chloride, calcium, phosphate, and magnesium ions, as well as alkaline phosphatase (AP), parathyroid hormone (PTH), osteocalcin, and beta-crosslaps, were determined. These values were compared with those of 20 healthy age-matched controls. Bone mineral density was measured as well. ResultsThe AP and PTH concentrations were higher in CMA patients than in the control group (AP: 610.2 U/L vs. 499.7 U/L, P < 0.01; PTH: 1.56 pmol/L vs. 0.83 pmol/L, P < 0.03), but all values were in the normal range. The osteocalcin concentration was similar in both groups, and the beta-crosslaps concentration was lower in CMA patients than in controls (0.92 vs. 1.47 ng/mL, P < 0.001). The mean Z score of bone mineral density in patients with CMA was −0.6. In 10 cases, the Z score was less than the −1 SD value. On the basis of the Z score, CMA patients were divided into two groups. The PTH concentration was significantly elevated in the group with lower Z score (2.24 pmol/L vs. 1.16 pmol/L;P < 0.03). ConclusionThe results suggest that, in children with CMA who are on a cow milk–free diet, slight disturbances of bone mineralization can be observed by osteodensitometry.

Three-year calcitonin combination therapy for postmenopausal osteoporosis with crush fractures of the spine

SummaryForty-five postmenopausal osteoporotic women with at least one osteoporotic vertebral crush fracture were randomized into three treatment groups. Each patient was on calcitonin, 50 U, on alternate days for 2 weeks monthly (350 U/month), and 500 mg/day oral calcium supplementation. In group II, this therapy was supplemented with phosphate (750 mg/day), and in group III, norandrostenolone decanoate (50 mg/month) was added to the calcitonin + calcium therapy. Bone mineral content, by single photon absorptiometry, of the radius midshaft and distal site (3 cm), as well as the lumbar and metacarpal radiomorphometrical indices were estimated semiannually. The therapeutic trial lasted 36 months except in the phosphate supplementation group, where, due to unfavorable results, treatment was discontinued after 24 months. Calcitonin practically prevented further bone loss for 24 months even in this relatively small and intermittent dosage. Phosphate supplementation was without benefit; however, according to the majority of the examined parameters, combination of calcitonin with the anabolic steroid norandrostenolone decanoate extended efficacy up to 36 months. This latter combination seems to be a promising, relatively inexpensive therapeutic regimen in the treatment of established postmenopausal osteoporosis.

X-linked hypophosphatemia: effects of treatment with recombinant human growth hormone

Abstract.The impact of recombinant human growth hormone (rhGH) treatment on growth, bone mineral metabolism, and bone mineral density (BMD) was evaluated in six children (3 girls, 3 boys) with familial hypophosphatemic rickets (XLH). Five were prepubertal (aged 6–8.8 years), one 15.3-year-old boy had combined XLH and GH deficiency, but had not been treated with rhGH previously. rhGH was administered daily for 1 year, at a dose of 1 IU/kg per week, combined with 1,25-dihydroxyvitamin D3 and oral phosphate therapy. Z scores for growth velocity and height improved significantly (–2.9 vs. 2.5, P <0.01, and –2.2 vs. –1.5, P <0.01, respectively). However, the ratio of Z score for height to that of subischial leg length decreased significantly (0.65 vs. 0.43, P <0.01), indicating disproportionate growth in favor of the trunk. The height-corrected BMD Z increased slightly (–0.99 vs. –0.94, P <0.05). A slight increase in serum phosphate occurred (0.78 vs. 0.88 mmol/l, P <0.02). Tubular reabsorption of phosphate/glomerular filtration rate increased from 0.45 mmol/l to 0.55 mmol at 6 months (P <0.02), but returned to the initial level at 12 months. These results indicate that children with XLH can benefit from the positive effect of rhGH on growth, however treatment could aggravate the already existing tendency to disproportionate growth. GH production should be evaluated in poorly growing patients with XLH, because it can mask GH deficiency. rhGH can be safely combined with conventional treatment in XLH. Further studies are needed to determine the effect of treatment on final height and maximal BMD.

Sodium transport and bone mineral density in hypercalciuria with thiazide treatment.

Abstract.Erythrocyte sodium-potassium (Na+/K+) -ATPase and sodium-lithium (Na+/Li+) countertransport activities were measured in 18 children (aged 9.6 years, range 6–16 years) with idiopathic hypercalciuria (IHU) to evaluate cellular Na handling. The effect of chronic thiazide administration on these parameters and on bone mineral density was also evaluated. Patients with IHU had significantly lower erythrocyte Na+/K+-ATPase activity than 23 age-matched healthy controls (mean±SEM 2,156±110 μmol P/l erythrocyte per hour vs. 3,165±175, P<0.01). Thiazide treatment significantly lowered urinary calcium excretion; this was followed by a slight suppression of intact parathyroid hormone (iPTH). The urinary calcium/creatinine ratio before and during treatment was 0.90±0.07 mmol/mmol versus 0.51±0.06 respectively, P<0.01. The corresponding iPTH levels were 5.9±0.6 pmol/l and 5.1±0.7, P<0.05. The Na+/K+-ATPase activity increased significantly (2,769±169 μmol P/l erythrocyte per hour vs. 2,156±110 in the control period, P<0.01) and the Na+/Li+ countertransport decreased (268±28 μmol Li/l erythrocyte per hour vs. 328+26 in the control period, P<0.03). The bone mineral density Z score rose from –1.3±0.26 to –0.8±0.22 (P<0.03). We conclude that IHU is accompanied by abnormalities of erythrocyte Na+/K+-ATPase and Na+/Li+ countertransport which are corrected by chronic hydrochlorothiazide administration. These changes could model alterations in renal tubular transport mechanisms still to be elucidated. Chronic thiazide treatment also has a positive effect on bone mineral density.

The reproducibility of nuclear morphometric measurements in invasive breast carcinoma

The intraobserver and interobserver reproducibility of computerized nuclear morphometry was determined in repeated measurements of 212 samples of invasive breast cancer. The influence of biological variation and the selection of the measurement area was also tested. Morphometrically determined mean nuclear profile area (Pearson’s r 0.89, grading efficiency (GE) 0.95) and standard deviation (SD) of nuclear profile area (Pearson’s r 0.84, GE 0.89) showed high reproducibility. In this respect, nuclear morphometry equals with other established methods of quantitative pathology and exceeds the results of subjective grading of nuclear atypia in invasive breast cancer. A training period of eight days was sufficient to produce clear improvement in consistency of nuclear morphometry results. By estimating the sources of variation it could be shown that the variation associated with the measurement procedure itself is small. Instead, sample associated variation is responsible for the majority of variation in the measurements (82.9% in mean nuclear profile area and 65.9% in SD of nuclear profile area). This study points out that when standardized methods are applied computerized morphometry is a reproducible and reliable method of assessing nuclear atypia in invasive breast cancer. For further improvement special emphasize should be put on sampling rules of selecting the microscope fields and measurement areas.

CYP3A7*1C Polymorphism, Serum Dehydroepiandrosterone Sulfate Level, and Bone Mineral Density in Postmenopausal Women

The CYP3A7 enzyme metabolizes some steroid hormones, including dehydroepiandrosterone sulfate (DHEAS). The age-related decline of serum DHEAS levels is believed to contribute to osteoporosis. Previously, the CYP3A7*1C polymorphism has been shown to cause a persistent high CYP3A7 enzyme activity, resulting in lower levels of DHEAS in men. We hypothesized that the CYP3A7*1C polymorphism might contribute to bone loss through decreased levels of serum DHEAS in postmenopausal women. Postmenopausal women (n = 319) were divided into two subgroups: 217 with osteoporosis and 102 healthy controls. Genotyping, serum DHEAS measurement, and osteodensitometry of the lumbar spine and femoral neck were carried out in all subjects. Homozygous CYP3A7*1C carriers had significantly lower BMD at the lumbar spine compared to wild types (T score −3.27 ± 1.02 in CYP3A7*1C homozygous mutants vs. −1.35 ± 1.53 in wild types, P = 0.041). This association remained significant after adjustment for menopausal age, serum DHEAS level, alcohol consumption, steroid intake, smoking habits, and previous fractures. No association was found between genotypes and serum DHEAS levels in the total study population or in the subgroups. Serum DHEAS levels correlated positively with bone mineral density at the lumbar spine (r = 0.59, P = 0.042) after correction for age. Our data suggest that the CYP3A7 polymorphism might have an influence on bone mass at the lumbar spine independently of serum DHEAS concentrations.

Serum leptin, soluble leptin receptor, free leptin index and bone mineral density in patients with primary biliary cirrhosis

Background/aim The pathophysiology of osteoporosis in chronic liver diseases is unknown. Recent data suggest that serum leptin is associated with bone mineral density (BMD). In animal studies leptin was found to be a potent inhibitor of bone formation. We investigated the relationship between serum leptin levels, soluble leptin receptor (sOB-R), free leptin index (FLI) and BMD in patients with primary biliary cirrhosis (PBC). Patients and methods Ninety-four female patients with PBC were included in this study; 122 healthy women served as controls. Serum leptin levels were measured by radioimmunoassay, sOB-R by enzyme-linked immunosorbent assay. BMD was measured by dual energy X-ray absorptiometry in the lumbar spine and femoral neck. Results Serum leptin was significantly lower in patients with PBC compared with healthy controls. No difference was found between the body mass index (BMI) of patients and controls. There was a strong positive correlation between leptin and BMI. In PBC no association was found between leptin, sOB-R and liver function tests, histological stages or the presence of osteoporosis. Osteoporosis was present in 38 patients. A positive correlation was found between serum leptin and femoral neck z-score even after adjustment for BMI, whereas serum sOB-R correlated inversely with the serum leptin level. There was no difference in FLI between the subgroups of PBC patients according to the stages of the disease. Conclusions We found a lower serum leptin level and a higher sOB-R in patients with PBC, which could not be explained by the difference in BMI. As leptin was associated with BMD, it may be hypothesized that leptin is involved in the complex regulation of bone metabolism in PBC.

Endothelin concentrations are elevated in plasma of patients with primary and secondary hyperparathyroidism

Endothelin Concentrations are Elevated in Plasma of Patients with Primary and Secondary Hyperparathyroidism P. Lakatos, A. Tátrai, 1 J. Földes, C. Horváth, J. Makó, P. H. Stern 1st Department of Medicine, Semmelweis University Medical School, Kora ́nyi 2/a, Budapest, H-1083, Hungary Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 E. Chicago Ave., Chicago, IL 60611, USA