An open, randomized study was performed to assess the effects of supportive pamidronate treatment on morbidity from bone metastases in breast cancer patients.
Eighty-one pamidronate patients and 80 ...control patients were monitored for a median of 18 and 21 months, respectively, for events of skeletal morbidity and the radiologic course of metastatic bone disease. The oral pamidronate dose was 600 mg/d (high dose HD) during the earliest study years, then changed to 300 mg/d (low dose LD) because of gastrointestinal toxicity. Twenty-nine of 81 pamidronate (HD/LD) patients first received 600 mg/d and were then changed to 300 mg/d; 52 of 81 pamidronate LD patients received 300 mg/d throughout the study. Tumor treatment was unrestricted.
An overall intent-to-treat analysis was performed. In the pamidronate group, the occurrence of hypercalcemia, severe bone pain, and symptomatic impending fractures decreased by 65%, 30%, and 50%, respectively; event-rates of systemic treatment and radiotherapy decreased by 35% (P < or = .02). The event-free period (EFP), radiologic course of disease, and survival did not improve. Subgroup analyses suggested a dose-dependent treatment effect. Compared with their controls, in pamidronate HD/LD patients, events occurred 60% to 90% less frequently (P < or = .03) and the EFP was prolonged (P = .002). In pamidronate LD patients, event-rates decreased by 15% to 45% (P < or = .04). Gastrointestinal toxicity of pamidronate caused a 23% drop-out rate, but other cancer-associated factors seemed to contribute to this toxicity.
Pamidronate treatment of breast cancer patients efficaciously reduced skeletal morbidity. The effect appeared to be dose-dependent. Further research on dose and mode of treatment is mandatory.
Osteogenic cells mediate PTH-stimulated osteoclastic bone resorption by a yet unidentified mechanism. We show that primairy rat osteoblast-like cells and the clonal osteogenic sarcoma cell line ...UMR-106 produce interleukin-6 (IL-6) and that bPTH(1-84) and synthetic hPLP(1-34) stimulate this production dose-dependently. With both peptides a close relation between IL-6 and cyclic-AMP production was found, though for PTH concentrations higher than 2.10(-8) M a clear dissociation was observed. Significant IL-6 activity was also detected in media of cultures of 17-day-old fetal mouse radii and metacarpals which was clearly stimulated by PTH. The source of IL-6 in these bone explants seems to be the osteogenic (cartilage) cells. Treatment of bone explants with IL-6 induced osteoclastic resorption which, however, depended on the bone resorption system used. This bone resorbing action of IL-6 is exerted probably through an effect on the formation of osteoclasts (osteoclastogenesis) rather than on the activation of already existing mature osteoclasts. We suggest that IL-6 produced by osteogenic cells may be a mediator in PTH-stimulated osteoclastic bone resorption.
The efficacy of bisphosphonates in the treatment of conditions characterized by increased osteoclastic bone resorption has been established. Recent evidence indicates that these compounds are also ...effective in the treatment of patients with osteoporosis. Two main protocols have been tried. One is based on the intermittent administration of the bisphosphonate, which is expected to decrease bone resorption, and give a drug-free period during which bone formation may proceed at a normal rate, leading to a positive calcium balance. The other argues that the resetting of the equilibrium in a cyclical process is, as a rule, incomplete and continuous low-grade suppression of resorption will result in a continuing positive bone balance. Intermittent administration of the first generation bisphosphonate, etidronate, for up to three years increases trabecular bone density, stabilizes it after two years, and appears to reduce the rate of new vertebral fractures in women with postmenopausal osteoporosis. Longer follow-up studies are needed before this beneficial effect is unequivocally established. Continuous administration of the second-generation bisphosphonate, pamidronate, increases spinal bone density in patients with osteoporosis linearly for up to four years, and is associated with a low rate of new vertebral fractures. These results need to be confirmed in controlled studies involving more patients. There are indications that pamidronate given continuously can prevent glucocorticoid-induced bone loss. There is no information about the effects of bisphosphonates on non-vertebral fractures. There are limited data about the use of bisphosphonates in the prevention of postmenopausal bone loss. Extensive studies on efficacy and safety are needed before this treatment is offered as an alternative to hormone replacement therapy.
Crystal agglomeration is a major element in calcium oxalate urinary stone formation. The effects of urines from 36 healthy subjects and 86 calcium oxalate renal stone formers on calcium oxalate ...monohydrate crystallization kinetics were studied using a seeded crystal growth method in which the solubility, the growth and the agglomeration of the crystals are measured as three separate and system-independent parameters. The urines of healthy subjects were found to increase the solubility and to strongly inhibit the growth and the agglomeration of calcium oxalate monohydrate crystals. The urines of stone formers had a similar effect on the solubility, but a significantly lower ability to inhibit the crystal growth and the crystal agglomeration. Of these two kinetic processes the inhibition of crystal agglomeration was more clearly affected, with 55% of the stone formers having abnormally low values, while the changes in crystal growth inhibition occurred within the normal range. The defect in crystal agglomeration inhibition was related to stone frequency, and urines from patients with very high stone frequency rates had also the most severely impaired ability to inhibit the agglomeration of the calcium oxalate monohydrate crystals. The inhibitory effect of urines on crystal agglomeration was found to be related to its citrate content (r = 0.68, P < 0.001). All patients with hypocitraturia, except two, had also abnormally low values for crystal agglomeration inhibition. In a group of 15 hypocitraturic stone formers, alkali treatment for a mean period of 18 months resulted in a parallel increase in urinary citrate excretion and in the ability of urines to inhibit crystal agglomeration (r = 0.77, P < 0.001). These results show that defective inhibition of the kinetic process of crystal agglomeration constitutes a major physicochemical mechanism of calcium oxalate renal stone formation, which appears to be modulated by urinary citrate concentrations.
Osteoclast-devoid bone explants were cultured together with embryonic liver as a source of osteoclast precursors, but separated from each other by a filter. Cells migrated through the filter toward ...the calcified matrix and acquired the characteristics of mature, tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts upon contact with the bone explant. Migration and attachment could be visualized separately. Progressive reduction of filter pore size resulted in progressive reduction of resorption because the use of smaller pores made it increasingly difficult for cells to pass. Indeed, the use of 0.22-micron filters, through which no cells can pass, but which still allow full passage of medium, completely blocked the resorption. When migrating cells from fetal liver were arrested for 10 days by using a combination of filters with different pore sizes, the arrested cells showed a tendency to fuse just opposite the mineralized matrix. Furthermore, a great number of the arrested cells expressed the macrophage-specific cell-surface antigen F4/80 and showed acid phosphatase activity, but none of these cells were tartrate resistant. The acquisition of tartrate-resistant acid phosphatase activity upon contact with the bone explant and subsequent resorption of this explant could be prevented by exposure of the system to the bisphosphonate dimethyl-APD (Me2-APD), whereas migration of cells through the filter was not affected. We suggest that the bisphosphonate interferes with a matrix factor that is essential for the attachment and subsequent transformation of the osteoclast precursor into the mature phenotype.
Modulation of calcium oxalate monohydrate crystallization kinetics in vitro. The effects of several low and high molecular weight (mol wt) compounds on the kinetics of calcium oxalate crystallization ...were examined using a seeded crystal growth method in which the solubility, the growth and the agglomeration of calcium oxalate crystals were measured as three separate and system-independent parameters. Git-rate, magnesium, phosphate, pyrophosphate, chondroitinsulphate, pen-tosanpolysulphate and heparin were tested in a wide range of concentrations. The solubility of calcium oxalate crystals Was increased only by citrate and magnesium. The crystal growth was inhibited by all compounds tested, but those with the high mol wt had the greatest effect at low concentrations. In contrast, inhibition of crystal agglomeration was achieved only by the low mol wt compounds; citrate was found to be the most potent inhibitor at concentrations likely to be present in normal urine. The high mol wt substances, despite their potent crystal growth inhibitory activity, had no effect on agglomeration. The results show that growth and agglomeration of calcium oxalate crystals are separate processes which are differently modulated by various compounds. They further provide a possible explanation for the pathogenetic role of citrate in hypocitraturic renal stone disease.
The development of new bisphosphonates for clinical use requires congruence between the results of basic and clinical investigations. We have previously shown that this can be achieved with the use ...of an in vitro coculture mouse metacarpal resorption system sensitive to the activation of osteoclast precursors together with a clinical protocol in which the rate of decrease in urinary hydroxyproline excess with bisphosphonate treatment is assessed in patients with Paget's disease. In these studies bisphosphonates of known potencies were used. In the present study we have evaluated these approaches prospectively in the assessment of the antiresorptive potency of the new bisphosphonate (3-dimethylamino-1-hydroxypropylidene)-1,1-bisphosphonate (dimethyl-APD). A total of 42 patients with Paget's disease of bone received dimethyl-APD in doses predicted from the in vitro system. A total of 24 patients received the bisphosphonate intravenously (2, 4, and 8 mg/day) in groups of 8 patients each and 18 orally (100, 200, and 400 mg/day) in groups of 6 patients each for 10 days. Dimethyl-APD therapy was highly effective in inhibiting bone resorption. Urinary hydroxyproline excretion reached 30.9 +/- 5.6, 17.1 +/- 3.1, and 2.1 +/- 5.3% of initial excess after 10 days treatment with intravenous dimethyl-APD, 2, 4, and 8 mg/day, and 37.4 +/- 18, 10.4 +/- 8.5, and 13 +/- 4.1% with oral therapy, 100, 200, and 400 mg/day, respectively. Comparison of the antiresorptive potency of dimethyl-APD with that of APD showed that the former is roughly five times more potent, as predicted in the in vitro study.
Introduction
Continuous progress in atrial fibrillation (AF) ablation techniques has led to an increasing number of procedures with improved outcome. However, about 30–50% of patients still ...experience recurrences within 1 year after their ablation. Comprehensive translational research approaches integrated in clinical care pathways may improve our understanding of the complex pathophysiology of AF and improve patient selection for AF ablation.
Objectives
Within the “IntenSive mOlecular and eLectropathological chAracterization of patienTs undergoIng atrial fibrillatiOn ablatioN” (ISOLATION) study, we aim to identify predictors of successful AF ablation in the following domains: (1) clinical factors, (2) AF patterns, (3) anatomical characteristics, (4) electrophysiological characteristics, (5) circulating biomarkers, and (6) genetic background. Herein, the design of the ISOLATION study and the integration of all study procedures into a standardized pathway for patients undergoing AF ablation are described.
Methods
ISOLATION (NCT04342312) is a two-center prospective cohort study including 650 patients undergoing AF ablation. Clinical characteristics and routine clinical test results will be collected, as well as results from the following additional diagnostics: determination of body composition, pre-procedural rhythm monitoring, extended surface electrocardiogram, biomarker testing, genetic analysis, and questionnaires. A multimodality model including a combination of established predictors and novel techniques will be developed to predict ablation success.
Discussion
In this study, several domains will be examined to identify predictors of successful AF ablation. The results may be used to improve patient selection for invasive AF management and to tailor treatment decisions to individual patients.
131 patients with osteolytic metastases from breast cancer were randomised to receive long-term oral treatment with aminohydroxy-propylidene-bisphosphonate (APD), 300 mg daily (n = 70), or to act as ...controls (n = 61) in a multicentre trial. Specific antitumour therapy was at the discretion of the clinician and variable. An interim analysis was made after a median follow-up of 13 months in the APD group and 14 months in the controls. There was a significant reduction in pathological fractures and severe bone pain in the APD group, and hypercalcaemia was prevented. Consequently the necessity for radiotherapy for skeletal complications was more than halved; the number of systemic therapy changes was also reduced. Gastrointestinal side-effects of APD led to a drop-out of 8% of patients. Oral supportive APD therapy is simple and convenient, and significantly reduced skeletal morbidity in advanced breast cancer.
After baseline studies, 21 patients with osteoporosis were treated with human parathyroid hormone fragment (PTH 1-34) given as once-daily subcutaneous injections for 6-24 months. The dose used did ...not cause hypercalcaemia even in the first few hours after injection. Calcium and phosphate balances improved in some patients, but there was no significant improvement in the group values. There were, however, substantial increases in iliac trabecular bone volume: the mean increase, confirmed by repeat blind measurements, was 70% above mean baseline volume. The new bone was histologically normal. Those patients who had the largest increases in 47Ca-kinetic and histomorphometric indices of new bone formation showed the greatest increases in trabecular bone volume, suggesting that treatment with human parathyroid hormone fragment caused a dissociation between formation and resorption rates that was confined to trabecular bone. Since vertebrae are four-fifths composed of trabecular bone, this hormone fragment may prove useful in treating patients with the crush fracture syndrome.
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