Efficacy of teriparatide compared with risedronate on FRAX®-defined major osteoporotic fractures: results of the VERO clinical trial.

FRAX® calculates the 10-year probability of major osteoporotic fractures (MOF), which are considered to have a greater clinical impact than other fractures. Our results suggest that, in postmenopausal women with severe osteoporosis, those treated with teriparatide had a 60% lower risk of FRAX®-defined MOF compared with those treated with risedronate. INTRODUCTION: The VERO trial was an active-controlled fracture endpoint clinical trial that enrolled postmenopausal women with severe osteoporosis. After 24 months, a 52% reduction in the hazard ratio (HR) of clinical fractures was reported in patients randomized to teriparatide compared with risedronate. We examined fracture results restricted to FRAX®-defined major osteoporotic fractures (MOF), which include clinical vertebral, hip, humerus, and forearm fractures. METHODS: In total, 1360 postmenopausal women (mean age 72.1 years) were randomized to receive subcutaneous daily teriparatide (20 µg) or oral weekly risedronate (35 mg). Patient cumulative incidence of ≥ 1 FRAX®-defined MOF and of all clinical fractures were estimated by Kaplan-Meier analyses, and the comparison between treatments was based on the stratified log-rank test. Additionally, an extended Cox model was used to estimate HRs at different time points. Incidence fracture rates were estimated at each 6-month interval. RESULTS: After 24 months, 16 (2.6%) patients in the teriparatide group had ≥ 1 low trauma FRAX®-defined MOF compared with 40 patients (6.4%) in the risedronate group (HR 0.40; 95% CI 0.23-0.68; p = 0.001). Clinical vertebral and radius fractures were the most frequent FRAX®-defined MOF sites. The largest difference in incidence rates of both FRAX®-defined MOF and all clinical fractures between treatments occurred during the 6- to 12-month period. There was a statistically significant reduction in fractures between groups as early as 7 months for both categories of clinical fractures analyzed. CONCLUSION: In postmenopausal women with severe osteoporosis, treatment with teriparatide was more efficacious than risedronate, with a 60% lower risk of FRAX®-defined MOF during the 24-month treatment period. Fracture risk was statistically significantly reduced at 7 months of treatment. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov Identifier: NCT01709110 EudraCT Number: 2012-000123-41.

Early changes in biochemical markers of bone formation during teriparatide therapy correlate with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis.

UNLABELLED: Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. INTRODUCTION: To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. METHODS: A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 µg/day, n = 45) and risedronate (35 mg/week, n = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. RESULTS: PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. CONCLUSIONS: Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.

Rapid Onset and Sustained Efficacy (ROSE) study: results of a randomised, multicentre trial comparing the effect of zoledronic acid or alendronate on bone metabolism in postmenopausal women with low bone mass.

SUMMARY: The ROSE study compared a once-yearly intravenous dose of zoledronic acid with a once-weekly oral dose of alendronate in postmenopausal women. Once-yearly zoledronic acid showed a greater and faster reduction in the levels of two markers of bone turnover and may be an effective option for the treatment of osteoporosis. INTRODUCTION: The open-label Rapid Onset and Sustained Efficacy (ROSE) study was designed to compare a once-yearly intravenous (iv) dose of zoledronic acid with a once-weekly oral dose of alendronate with respect to markers of bone turnover in approximately 600 postmenopausal women in Germany. METHODS: Levels of N-telopeptide of collagen type I (NTx) and procollagen 1 C terminal extension peptide (P1NP) were assessed during the study. The primary objective was to assess if zoledronic acid was superior to alendronate in reducing serum NTx levels after 12 months' treatment. RESULTS: A significantly greater reduction in NTx levels from baseline to month 12 (as determined by the area under the curve) was observed in patients treated with zoledronic acid (n = 408) versus those receiving alendronate (n = 196; 0.282 ng/mL vs. 0.270 ng/mL; P = 0.012). The reduction in levels of P1NP after 1 year was also significantly greater in patients treated with zoledronic acid compared with those receiving alendronate (28.21 vs. 25.53 ng/mL; P = 0.0024). The overall incidence of adverse events was similar between groups; both treatments were generally well tolerated. Although post-dose symptoms, including the incidence of influenza-like symptoms, were higher with zoledronic acid than alendronate initially, the incidence was similar between groups from days 4-360. Gastrointestinal symptoms were more frequent with alendronate than zoledronic acid throughout the study. CONCLUSION: In this study, once-yearly iv zoledronic acid provided a greater and faster reduction in the levels of NTx and P1NP versus once-weekly oral alendronate.

[Computer-assisted perioperative blood glucose control in metabolically stable diabetic patients and diabetic patients with coronary disease--a contribution to computer-assisted optimal therapy of diabetes]. / Die computergestützte perioperative Blutglucoseführung bei stoffwechsellabilen und koronarykranken Diabetikern--Ein Beitrag zur rechnergestützten Optimierung der Diabetestherapie.

Issuing from the metabolic changes under perioperative conditions the problems and the significance of a subtile perioperative management of the metabolism in diabetics with labile metabolism and coronary disease are described. The device-technical components and the function of a computer-assisted regulation and advisory system (Glucon) for the support of the perioperative management of blood glucose and for the parenteral glucose supply in diabetics during large operative interventions. When the system was applied for several days under submaximal metabolization of glucose nearly normoglycaemia conditions could be achieved. The system is proposed as alternative to the conventional perioperative blood glucose management for diabetics with labile metabolism and coronary diseases in large operations.

Interaction between glucose utilization and left ventricular heart function in type I-diabetics.

The aim of the present study was to check whether equal, therapeutically relevant, positively inotropic doses of different adrenergic agents elicit equal inotropic and metabolic effects in 6 type I-diabetics as in 6 matched nondiabetic subjects. The effects of increasing doses of norepinephrine (NE)- and orciprenaline (0.12, 0.20, 0.33 microgram/kg min) on heart function (systolic time interval, heart rate, blood pressure) and on serum fatty acid (NEFA), glucose, lactate, pyruvate and insulin concentrations were recorded. In the therapeutic dose range, NE, and orciprenaline elicited in diabetics without clinical signs of any cardiovascular disease a diminished myocardial inotropic response (20-40%), less marked vascular effects (vasoconstriction, vasodilatation), but greater metabolic changes in right atrial blood (NEFA, pyruvate, lactate) compared to matched controls (p less than 0.05). The smaller increase of cardiac performance in diabetics to exogenous catecholamines cannot be explained by sympathetic cardiac denervation, since chronotropic beta 1-beta 2-stimulation with orciprenaline provoked nearly equal dose-dependent changes in diabetics and controls. It is suggested that the smaller positive inotropic effect during NE and orciprenaline infusion in type I-diabetics is a result first of all of alterations in myocardial energy turnover in diabetes due to reduced myocardial glucose utilization. It seems necessary to secure continuous myocardial glucose utilization and subnormal NEFA concentrations in the serum during the therapeutic application of inotropic adrenergic agents in severe cardiac failure and cardiogenic shock in diabetics.

Effects of computer controlled submaximal glucose utilization on myocardial energy potential and on survival time during acute strophantin intoxication in dogs.

We checked the effect of a 4 hourly computer controlled submaximal glucose utilization (CCSGU) of 12.01 +/- 1.19 mg/kg min under normoglycaemic conditions and of a simultaneous diminishing of myocardial NEFA supply on trigger mechanism of ventricular fibrillation during acute strophantin intoxication (4 micrograms/kg min) in 17 mongrel dogs. Dogs treated with CCSGU (protective group, n = 8) showed a nearly 30% (p less than 0.01) major survival time (47.6 +/- 3.6 min) before ventricular fibrillation occurred in comparison to a control group (33.1 +/- 3.7 min, n = 9). CCSGU induced a 90% higher left ventricular hydraulic work (5.18 +/- 0.57 Nm/g heart weight) during strophantin infusion compared to controls (2.75 +/- 0.47). No significant myocardial NEFA extraction was evident in the protective group. During CCSGU myocardial oxygen extraction was on a lower level in rest (15.8 +/- 1.0%, p less than 0.01) as well as during strophantin infusion (11.3 +/- 2.6%, p less than 0.01) compared to controls. In dogs treated with CCSGU nearly equal myocardial levels of HEP and lactate were found compared to controls in spite of a major survival time and higher left ventricular hydraulic work. A higher myocardial glycogen content was observed in the protective group (45.1 +/- 6.7 mumol/g w.w.) in comparison to controls (28.1 +/- 2.9, p less than 0.05). Our results prove that CCSGU using the device system GLUCON induces a shift in substrate utilization from NEFA to glucose, decreases myocardial oxygen extraction, increases myocardial glycogen content, enlarges heart work and protects against strophantin induced ventricular fibrillation.

[Effect of the beta-receptor blockers propranolol and talinolol on glucose-orciprenaline induced insulin secretion, glucose tolerance and the behavior of nonesterified free fatty acids in metabolically normal probands]. / Der Einfluss der beta-Rezeptorenblocker Propranolol und Talinolol auf die glukose-orziprenalinduzierte Insulinsekretion, die Glukosetoleranz und das Verhalten der unveresterten freien Fettsäuren bei stoffwechselgesunden Probanden.

With the help of a special clinico-pharmacological test arrangement on 5 test persons with healthy metabolism was proved that the oral treatment with the selective beta 1-blocker Cordanum (Talinolol, 0.3 g/die) and with the non-selective beta 1-beta 2-blocker Obsidan (Propranolol, 0.12 g/die) leads to a complete suppression of the insulin secretion which can be additionally mobilised via beta 2-adrenoreceptors in test persons with healthy metabolism. In contrast to Talinolol under the treatment ith the unspecific beta-blocker Propranolol a clear blocking of the beta 2-mediated glycogenolysis which can be evoked with the help of Orciprenalin and of the lipolysis evocable via beta 1-receptors was observed. Due to the more insignificant metabolic side-effects, with regard to an intact energy supply and the maintainance of the physical functional capacity, the selective beta 1-blocker Talinolol is preferred in the long-term therapy of cardiovascular diseases.

[Effect of noradrenergic stimulation on the peripheral venous concentrations of thyroxine and triiodothyronine in young test subjects with normal metabolism]. / Der Einfluss der noradrenergen Stimulation auf die peripheren venösen Thyroxin- und Trijodthyroninkonzentrationen stoffwechselgesunder jugendlicher Probanden.

The influence of intravenous noradrenalin infusions in increasing dosages lasting 60 minutes on the peripheral venous total T3- and total T4-concentrations of blood, blood pressure and heart rate was established on 5 test persons during a period of 110 minutes. Immediately after the addition of 0.12 micrograms NA/kg Kgw./min an increasing tendency of the T4-concentration in the venous blood occurred, respectively. Under influence of higher NA-doses (0.20 and 0.33 micrograms/kg Kgw./min) the noradrenergically induced T4-increase (p < 0.05) with average increases of the T4-level by 28.7 and 22.3%, respectively, in comparison to the initial values was statistically secured. The total T3-concentration did not show any statistically secure changes under NA-infusion. The fundamental possibilities of an influence of the intravenously applied NA on the production of the hormone of the thyroid gland, the secretion of the thyroid hormone and the peripheral conversion are discussed. Using findings of animal experiments the supposition of the immediate influence of the NA on the follicle cells of the thyroid gland and the secretory process gains importance. The clinical importance of the adrenergic modulation of the thyroxin secretion for the clinician is discussed.

[Criticism of the K value-utility and evidence of the glucose assimilation coefficient]. / Kritik am K-Wert.--Anwendbarkeit und Aussage des Glukoseassimilationskoeffizienten.

Theoretical statements concerning the calculation of the K-value and explanations of the practical approach in the estimation of the K-value are the initial position. It is proved that it is not possible after a standardized glucose supply to establish by means of the K-value a true gradation of the glucose assimilation, which is independent on the population and lies on an absolute proportion scale, of any test persons on various conditions. Up to now this fact is not taken into consideration when the K-value is used and judged for the characterization of the glucose assimilation and leads to weighty errors in the kinetic evaluation of the measuring data. Since both the height of the fasting blood glucose and the speed of the glucose elimination are included as diagnostic separation criteria in the K-value, it is, on the other hand, well suited for the delimitation of latent, asymptomatic and manifest diabetics from persons with healthy metabolism.

[Behavior of the body weight in 2261 maturity-onset diabetics under conditions of ambulatory care]. / Das Verhalten des Körpergewichtes bei 2261 Maturity-onset-Diabetikern unter den Bedingungen der ambulanten Betreuung.

Of 2,261 maturity-onset-diabetics (970 males, 1,691 females) body weight, size and Broca-index were established at the beginning of the treatment, one year after the beginning of the treatment and at the date of analysis (x=5.7 years after the manifestation of diabetes). 72% of the females and 49% of the males had a Broca-index of more than 10 at the beginning of the treatment. The average loss of weight of the diabetics of adult type with overweight with a Broca-index of more than 5 was in the first year 7.6 kg in males and 5.2 kg in females. In the first year after beginning of the disease in the diet group and in the buformin group was achieved an average reduction of weight in males of about 7 kg and in females of about 6 kg. After the first year of treatment in the groups mentioned the body weight remained or rose to one kg. The patients treated with sulfonylureas--compared with the diet-biguanide group--showed in the first year of treatment, indeed, a loss of weight which was about 50% smaller, however, also in the following years (x=4.7) a further continuous reduction of weight could be recognized. The initial results and the late results in the treatment of elderly diabetics with overweight show that, compared with former years, partial success is to be achieved with reduction cures performed in outpatient departments. The importance of the reduction of weight in elderly diabetics for the improvement of the carbohydrate tolerance and the fat metabolism is emphasized.

[Type distribution of hyperlipoproteinemias in 645 diabetics]. / Die Typenverteilung der Hyperlipoproteinämien bei 645 Diabetikern.

On 645 diabetics of the treatment-groups diet (n = 180), sulfonylurea therapy (n = 250), biguanide therapy (n = 50), and insulin therapy (n = 165) the concentrations of cholesterol and triglyceride were determined and the lipoprotein electrophoresis was carried out. 29% of the diabetics showed hyperliproteinaemias, males and females in the same frequency. In about 54% the type IV was observed most frequently, then followed the types IIb with 25% and the type IIa with about 13%. The dependence of triglycerides on the metabolic situation and the body weight was proved in diabetics. The cholesterol values were independent on form of therapy, body weight and metabolic situation. In the group with sulfonylurea in about 49%, in the group with insulin in about 37% and in the group with diet and buformin only in about 32% a hyperlipoproteinaemia was proved. The opinion is represented that the high percentage of hyperlipoproteinaemia in diabetics and the connected with this additionally increased risk for vascular complications should lead to the introduction of diagnostics and therapy of hyperlipoproteinaemia into the programme of the diabetes dispensaries of the GDR. For the treatment of diabetes the principle should be taken into consideration that a diabetes is optimally regulated only then, when apart from the blood sugar values also the blood fats are within the normal.

[Vital microscopic investigation of terminal blood vessels in patients with diabetes mellitus]. / Vitalmikroskopische Untersuchungen an der Endstrombahn bei Patienten mit Diabetes mellitus

It is reported on findings of vital-microscopic investigations at the terminal vascular system of the conjunctiva bulbi and the mucous membrane of the lips carried out on 50 juvenile diabetics and 50 test persons of the same age. By quantitative establishment of the morphological and functional changes of the vessels and the aggregation of the erythrocytes in the different regions of the terminal vascular system we succeeded in delimitating all 50 diabetes as individuum or as collective (x equals 10.7 +/- 1.5) from the test persons (x equals 3.4 +/- 0.9) by means of a point system (p less than 0.001). In 4 figures typical vascular findings are demonstrated. No pathognomonic significance was ascribed to the individual vascular findings. The morphological and functional changes of the vascular wall are regarded as an expression of fundamental reactive possibilities of the vessels of the terminal vascular system after influence of different factors of risk. As criteria of the findings were used: venular sacculations, meander-like forms, convolutions, haemorrhages, aneurysms, reticular structures, varieties of calibres, changed arteriolarvenular relations of the inner diameter of the vessels, constant proof of aggregates of erythrocytes with temporary standstill of the flow in the different parts of the terminal vascular system. The author is of the opinion that with simultanuous establishment of the morphological and functional changes of wall of the vessel and content of the vessel degenerative changes in diabetes mellitus are provable earlier than at the eye-ground by means of ophthalmocoscopy when only morphological findings are established. The reciprocities between the vascular changes and the rheological properties of the blood are described.

[Misplaced implantation of a pacemaker electrode in a coronary vein]. / Die fehlortige Implantation von Herzschrittmachersonden in einer Koronarvene

The wrong implantation of pacemaker electrodes into a coronary vein is in most cases accidentally diagnosed when thoracic X-ray pictures are made in two planes. It is to be excluded not with certainly in the sagittal ray-path of the thoracic X-ray picture and in the ECG of the extremities. The diagnostic criteria for the recognition of a false position are the end of the electrode which is in the frontal ray-path directed dorsally to the spine and a right bundle branch block in the ECG existing since implantation. Pacemaker-synchronous contractions of the diaphragm as well as an increased already at the time of implantation stimulus threshold may be references. Description of an own observation with an up to now long-term stimulation through a coronary vein without complications lasting 15 months, in which a correction of the position is not regarded as necessary due to the regular function of the pacemaker.

[Complications of cardiac pacemakers]. / Komplikationen bei der permanenten Herzschrittmachertherapie

Since the number of patients with pacemakers increases and the further decentralisation of the care of these patients is planned the survey has the purpose to inform as many physicians as possible about the complications of the pacemaker therapy. In the several paragraphs the problems of the regular and anticipated exhaustion of the battery, defects of the electronic constituents of the pacemaker, fracture of the cable, dislocation of the electrodes, disturbances of the transmission between endocardium and myocardium, disturbances of rhythm under pacemaker-therapy, disturbing influences by intra- and extracorporal causes, surgical complications and implantations in the false place are reported on. Knowledge and early recognition of the complications in the pacemaker-therapy will furthermore favourably influence the long-term prognosis of this group of patients.

[Fundamental problems on the care of patients with permanent artificial pacemaker therapy]. / Grundsätzliche Probleme der Betreuung von Patienten mit permanenter Herzschrittmachertherapie

In the GDR the number of patients with pacemakers increases with about 900 new implantations each year. The further decentralisation of the care of patients with pacemakers proposed by the team pacemaker therapy demands the inclusion of more physicians into the care of these patients. The pacemaker systems used at present in the GDR are described as well as the practical approach in the control of the function of the pacemakers is discussed. In the figures typical electrocardiographic pictures of various models of pacemakers are demonstrated.