This prospective study was designed to assess the effect of primary hyperparathyroidism on heart muscle, valves, and myocardial function. Echocardiography was used to evaluate changes in mechanical ...performance, the thickness of the left ventricular wall, myocardial calcific deposits, and valvular calcifications in patients with primary hyperparathyroidism.
Echocardiography was performed in 54 patients with hyperparathyroidism prior to surgery and 12 +/- 2 months after successful parathyroidectomy. A matched control group was followed for comparison.
In a blinded fashion, aortic and mitral valve calcifications were detected in 63% and 49% of patients with primary hyperparathyroidism (controls: 12% and 15%, respectively). Calcific deposits in the myocardium were found in 69% of patients with hyperparathyroidism and 17% of the control subjects. After parathyroidectomy and 12 months of normocalcemia, a significant regression of left ventricular hypertrophy (p < 0.001) was observed.
The present data show a high incidence of left ventricular hypertrophy, calcific deposits in the myocardium, and/or aortic and mitral valve calcification in patients with primary hyperparathyroidism. A 1-year follow-up after parathyroidectomy (and restoration of normocalcemia) discloses regression of hypertrophy, while calcifications persist without evidence of progression.
Diabetic kidney disease occurs in ∼ 25-40% of patients with type 2 diabetes. Given the high risk of progressive renal function loss and end-stage renal disease, early identification of patients with ...a renal risk is important. Novel biomarkers may aid in improving renal risk stratification. In this review, we first focus on the classical panel of albuminuria and estimated glomerular filtration rate as the primary clinical predictors of renal disease and then move our attention to novel biomarkers, primarily concentrating on assay-based multiple/panel biomarkers, proteomics biomarkers and metabolomics biomarkers. We focus on multiple biomarker panels since the molecular processes of renal disease progression in type 2 diabetes are heterogeneous, rendering it unlikely that a single biomarker significantly adds to clinical risk prediction. A limited number of prospective studies of multiple biomarkers address the predictive performance of novel biomarker panels in addition to the classical panel in type 2 diabetes. However, the prospective studies conducted so far have small sample sizes, are insufficiently powered and lack external validation. Adequately sized validation studies of multiple biomarker panels are thus required. There is also a paucity of studies that assess the effect of treatments on novel biomarker panels and determine whether initial treatment-induced changes in novel biomarkers predict changes in long-term renal outcomes. Such studies can not only improve our healthcare but also our understanding of the mechanisms of actions of existing and novel drugs and may yield biomarkers that can be used to monitor drug response. We conclude that this will be an area to focus research on in the future.
Bisphosphonates are the standard treatment for hypercalcemia of malignancy. We hypothesized that bisphosphonate treatment
and the subsequent fall in serum calcium might induce changes in the ...RANK/RANKL/OPG system, which plays a pivotal role in
the regulation of bone resorption. Soluble RANKL and OPG levels were measured in the serum of 15 hypercalcemic patients at
baseline and on 5 consecutive days following treatment with the aminobisphosphonate ibandronate. At day 0, the median soluble
OPG level was elevated (p=0.0021) in the hypercalcemic group as compared to normal controls, while the median serum RANKL
level was not significantly different. Ibandronate treatment and the resulting decrease (p<0.0001) in serum calcium levels
did not affect the serum concentrations of OPG, serum RANKL, or the serum RANKL/OPG ratio. In comparison with day 0, these
factors did not change significantly at any time-point analyzed.
Ghrelin plasma concentrations increase during fasting and fall rapidly after nutrient ingestion. We hypothesized that insulin or glucose could regulate ghrelin secretion by a feedback mechanism. In ...this randomized, double-blind, placebo-controlled crossover study, three different study days were carried out in nine healthy volunteers (age 26 +/- 6 years). On each day, stepwise increasing systemic glucose concentrations of 5.0, 8.3, and 11.1 mmol/l were attained by intravenous infusion of glucose, representing fasting and postprandial conditions. Ghrelin plasma concentration was studied during concomitant exogenous hyperinsulinemia, inhibition of endogenous insulin production by somatostatin infusion, and placebo time control, respectively. Elevated glucose concentrations increased circulating insulin to 612 +/- 85 pmol/l (P < 0.01), but they did not affect ghrelin concentrations. Prolonged hyperinsulinemia by exogenous infusion resulted in circulating insulin of 1,602 +/- 261 pmol/l (P < 0.01) and suppressed plasma ghrelin to 49.6% of baseline (P < 0.01). During administration of somatostatin, insulin concentration remained constant, but an even greater decrease in ghrelin to 39.5% of baseline was noted (P < 0.01). Hyperglycemia does not decrease ghrelin, and a reduction in ghrelin is only seen at supraphysiological insulin concentrations. In contrast, systemic ghrelin concentrations are decreased by somatostatin. The meal-related suppression of ghrelin appears not directly regulated by glucose or insulin.
Plasma Ghrelin Concentrations Are Not Regulated by Glucose or Insulin
A Double-Blind, Placebo-Controlled Crossover Clamp Study
Georg Schaller 1 ,
Adele Schmidt 2 ,
Johannes Pleiner 1 ,
Wolfgang ...Woloszczuk 3 ,
Michael Wolzt 1 and
Anton Luger 2 3
1 Department of Clinical Pharmacology, Vienna University, Vienna, Austria
2 Department of Endocrinology and Metabolism, Vienna University, Vienna, Austria
3 Ludwig Boltzmann Institute for Experimental Endocrinology, Vienna University, Vienna, Austria
Abstract
Ghrelin plasma concentrations increase during fasting and fall rapidly after nutrient ingestion. We hypothesized that insulin
or glucose could regulate ghrelin secretion by a feedback mechanism. In this randomized, double-blind, placebo-controlled
crossover study, three different study days were carried out in nine healthy volunteers (age 26 ± 6 years). On each day, stepwise
increasing systemic glucose concentrations of 5.0, 8.3, and 11.1 mmol/l were attained by intravenous infusion of glucose,
representing fasting and postprandial conditions. Ghrelin plasma concentration was studied during concomitant exogenous hyperinsulinemia,
inhibition of endogenous insulin production by somatostatin infusion, and placebo time control, respectively. Elevated glucose
concentrations increased circulating insulin to 612 ± 85 pmol/l ( P < 0.01), but they did not affect ghrelin concentrations. Prolonged hyperinsulinemia by exogenous infusion resulted in circulating
insulin of 1,602 ± 261 pmol/l ( P < 0.01) and suppressed plasma ghrelin to 49.6% of baseline ( P < 0.01). During administration of somatostatin, insulin concentration remained constant, but an even greater decrease in
ghrelin to 39.5% of baseline was noted ( P < 0.01). Hyperglycemia does not decrease ghrelin, and a reduction in ghrelin is only seen at supraphysiological insulin concentrations.
In contrast, systemic ghrelin concentrations are decreased by somatostatin. The meal-related suppression of ghrelin appears
not directly regulated by glucose or insulin.
Footnotes
Address correspondence and reprint requests to Dr. Michael Wolzt, Department of Clinical Pharmacology, Allgemeines Krankenhaus
Wien, Währinger Gürtel 18-20, A-1090 Wien, Austria. E-mail: michael.wolzt{at}univie.ac.at .
Received for publication 7 June 2002 and accepted in revised form 3 October 2002.
AUC G , area under the ghrelin concentration versus time curve; GH, growth hormone.
DIABETES
To compare hemodynamics and plasma big endothelin levels in patients awaiting heart transplantation who are receiving continuous IV therapy, and to establish their respective potency for predicting ...future cardiac events.
A randomized, prospective trial of ambulatory continuous treatment with IV prostaglandin E1 (PGE1) vs dobutamine. A subanalysis was conducted of all patients who completed 4 weeks of follow-up in regard to treatment effects on hemodynamics and big endothelin plasma levels.
Thirty-two listed heart transplant candidates who were refractory to oral treatment, 21 patients who were receiving PGE1, and 11 patients receiving dobutamine.
Hemodynamics and plasma big endothelin levels were measured at baseline and after 4 weeks. The cardiac index increased significantly (PGE1 group, 1.7 ± 0.4 vs 2.5 ± 0.6 L/min/m2; dobutamine group, 1.8 ± 0.3 vs 2.3 ± 0.6 L/min/m2; p < 0.05), whereas the systemic vascular resistance index (SVRI) decreased significantly only in the PGE1 group (3,352 ± 954 vs 2,178 ± 519 dyne · s · cm−5/m2; p < 0.05). The plasma big endothelin level decreased significantly (PGE1 group, 7.6 ± 3.1 vs 4.7 ± 2.6 fmol/mL; dobutamine group, 6.5 ± 3.7 vs 5.0 ± 2.6 fmol/mL; p < 0.01 for the time effect). Plasma big endothelin (β = 0.393;χ 2 = 10.8; p = 0.001) and SVRI (β = 0.003;χ 2 = 6.9; p < 0.01), both measured after 4 weeks of continuous treatment, were the only independent predictors of future outcome.
Continuous treatment over 4 weeks with either PGE1 or dobutamine in patients awaiting heart transplantation yields an improved hemodynamic state accompanied by a reduction of increased big endothelin levels. Plasma big endothelin measured after 4 weeks of continuous therapy provides prognostic information about future outcome.
Cathepsin K is a cysteine protease that plays an essential role in osteoclast function and in the degradation of protein components of the bone matrix by cleaving proteins such as collagen type I, ...collagen type II and osteonectin. Cathepsin K therefore plays a role in bone remodelling and resorption in diseases such as osteoporosis, osteolytic bone metastasis and rheumatoid arthritis. We examined cathepsin K in the serum of 100 patients with active longstanding rheumatoid arthritis. We found increased levels of cathepsin K compared with a healthy control group and found a significant correlation with radiological destruction, measured by the Larsen score. Inhibition of cathepsin K may therefore be a new target for preventing bone erosion and joint destruction in rheumatoid arthritis. However, further studies have to be performed to prove that cathepsin K is a valuable parameter for bone metabolism in patients with early rheumatoid arthritis.
Summary
Aim
Reasonable application of laboratory parameters in prevention, diagnosis, treatment and therapy monitoring of osteoporosis.
Target groups
Physicians from different specialist disciplines ...(general medicine, geriatrics, gynaecology, urology, internal medicine—especially endocrinology and metabolism, nephrology, laboratory medicine, rheumatology, nuclear medicine, orthopaedics, paediatrics, rehabilitation and physical medicine, radiology, social medicine, transplantation medicine, accident surgery), moreover social insurances, hospitals and self-help groups.
Background
Evaluation of aetiology of bone disorders, widening of the therapeutic spectrum for diseases of bone and knowledge on biochemical markers of bone turnover. Improvements in judging the success of therapy and in monitoring the compliance of patients. Research perspectives.
Bases
Scientific literature and guidelines, consensus meetings.
Résumé
Basic and specialized laboratory investigations are important in differentiation between primary and secondary osteoporosis for an adequate therapy. Biochemical markers of bone turnover are an additional aid in evaluation of individual fracture risk. These markers identify responders to bone therapy faster than surveillance of bone mineral density, which helps to improve patient’s compliance too. Characteristics, preanalytic precautions and applications are presented for selected markers of bone resorption and formation and for parameters regulating bone metabolism.
Abstract 1010
Osteoporosis represents an important cause of morbidity in adult patients with thalassemia. Osteoclast activity is elevated in thalassemia-induced osteoporosis, and thus bisphosphonates ...have been used for its management. Moreover, osteoblasts are also deregulated in thalassemia patients but there is very limited data for the underlying mechanisms of this deregulation. Osteocyte seems to be a key cell for the control of bone remodeling. Sclerostin is a secreted inhibitor of the wingless-type and integrase 1 (Wnt) canonical pathway which is produced by osteocytes and has inhibitory effects on bone formation by preventing the activation of lining cells as well as by inhibiting the function of active osteoblasts. The aim of this study was to evaluate, for the first time, the circulating levels of sclerostin in patients with thalassemia and osteoporosis who received therapy with zoledronic acid (ZOL) and explore possible correlations with clinical and laboratory data in an attempt to clarify if there is any role of sclerostin in the pathogenesis of bone loss in thalassemia. Sixty-six patients (22M/44F, median age 42 years) with thalassemia-induced osteoporosis who participated in a phase 2, randomized, placebo-controlled trial, which was previously published, were studied. In summary, patients were blindly randomized to receive ZOL at a dose of 4 mg, iv, in 15 min infusion, every 6 months (group A, n=23) or every 3 months (group B, n=21), or to receive placebo every 3 months (group C, n=22) for a 12-month period (Voskaridou et al, Hametologica 2006;91:1193-202). Bone mineral density (BMD) of the lumbar spine (L1-L4), femoral neck (FN) and distal radius (R) was determined using Dual-energy X-ray Absorptiometry before and 12 months post-ZOL treatment. Circulating sclerostin was measured in the serum of all patients at baseline and after 12 months of therapy, using an ELISA methodology developed by BDF for Biomedica Medizinprodukte (Vienna, Austria), along with a series of serum bone indices: i) bone resorption markers C-terminal telopeptide of collagen type-1 (CTX) and tartrate resistant-acid phosphatase (TRACP-5b); ii) bone formation markers bone-alkaline phosphatase (bALP), osteocalcin and C-terminal propeptide of collagen type-I (CICP); iii) osteoclast regulators RANKL, osteoprotegerin (OPG) and osteopontin and iv) dickkopf-1 (Dkk-1), which is another inhibitor of Wnt signaling, as previously described (Voskaridou et al, Haematologica 2009;94:725-8). The above bone markers were also evaluated in 30, age- and gender-matched, healthy controls (11M/19F, median age 44 years), while sclerostin was also measured in 62 women with post-menopausal osteoporosis (median age 63 years). At baseline, patients with thalassemia and osteoporosis had elevated circulating levels of sclerostin (median: 605 pg/mL, range: 22–1227 pg/mL) compared to healthy controls (250 pg/mL, 0–720 pg/mL, p<0.001) and reduced levels of sclerostin compared with postmenopausal women with osteoporosis (840 pg/mL, 181–1704 pg/mL, p<0.001). Patients with thalassemia had also increased values of CTX (p<0.001), Dkk-1 (p<0.001), bALP (p<0.001), CICP (p=0.003), TRACP-5b (p<0.01), and sRANKL/OPG ratio (p=0.001). Sclerostin levels correlated with BMD in all studied sites L1-L4 (r=0.454, p<0.001), R (r=0.324, p=0.01) and FN (r=0.268, p=0.035). Similar results were obtained for post-menopausal women with osteoporosis for L1-L4 BMD (r=0.501, p<0.001). The other Wnt inhibitor, Dkk-1 also correlated with BMD of L1-L4 (r=-0.290, p=0.022) and R (r=-0.415, p=0.001). Patients who received ZOL did not alter their sclerostin levels after 12 months of therapy, but reduced their circulating Dkk-1 (from 39.6±16.6 to 28.9±16.3 pmol/L, p=0.004). In contrast, placebo group patients showed an increase of sclerostin levels (p=0.01) and a borderline increase of Dkk-1 (p=0.08). In conclusion, the results of this study show that circulating sclerostin is elevated in thalassemia patients with osteoporosis and correlated with their BMD. Furthermore, the high Dkk-1 serum levels and their association with BMD observed in these patients support the notion of a disrupted Wnt signaling in patients with thalassemia and osteoporosis which leads, in turn, to osteoblast deregulation. These findings give the rationale for the use of novel drugs targeting sclerostin and Dkk-1 in patients with thalassemia-induced osteoporosis.
No relevant conflicts of interest to declare.
Nonsustained effect of short-term bisphosphonate therapy on bone turnover three years after renal transplantation.
We recently showed that two doses of 4mg of zoledronic acid (ZOL) ameliorated the ...bone loss and improved bone histology within the first six months after kidney transplantation. The aim of the present study was to evaluate whether this early short-term intervention exhibited a sustained bone-sparing effect.
A homogenous group of 20 de novo renal transplant recipients were equally randomized to two infusions of 4mg of ZOL or placebo at two weeks and three months after engraftment. Patients were followed up for three years by sequential determination of bone densitometry and specific biochemical markers.
From month six to three years after transplantation, both treatment groups exhibited an improvement of bone mineralization. Femoral neck bone mineral density z-scores increased statistically significantly from -1.3 (2.6) to -0.2 (3.6) in the placebo group and from -1.6 (2.9) to -1.2 (1.9) in the ZOL group (median, range). Biochemical parameters of osteoblast activity such as osteocalcin and bone-specific alkaline phosphatase did not increase significantly in both groups. Osteoprotegerin, a marker of osteoclast inhibition, was significantly elevated over the first six months in the ZOL group, but decreased to similar levels, as in the placebo group, over the next two and a half years. Other markers of osteoclast activity such as c-telopeptide of type 1 collagen, calcitonin, and intact parathyroid hormone were not different between six months and three years in either group.
The early bone-sparing effect of short-term ZOL therapy confers no sustained benefit versus placebo at three year post-transplantation.
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