Prevention of Bone Loss by Clodronate in Early Postmenopausal Women with Vertebral Osteopenia: A Dose-Finding Study

This double-masked, placebo-controlled study was undertaken to determine the efficacy and safety of oral clodronate in the prevention of bone loss in early postmenopausal women with vertebral osteopenia. Altogether 610 women with a mean age of 53 years were recruited for the study. They were 1–5 years postmenopausal and their lumbar spine bone mineral density (BMD) was at least 1 standard deviation below the mean of premenopausal women (T-score ≤−1). The subjects were randomized into five study groups to receive either placebo, clodronate 65 mg, 400 mg or 800 mg daily, or intermittent clodronate in 3 month cycles with 400 mg daily for 15 days followed with no treatment for 75 days for 3 years. One hundred and eighty-seven of 509 women who completed the primary study continued in the extension study of 2 years in which previous placebo users were switched to clodronate 800 mg daily, while previous users of 400 mg or 800 mg of clodronate used either placebo or 800 mg of clodronate daily. In the primary study clodronate was administered in the evening, and in the extension 1 h before breakfast on an empty stomach. In the primary study mean changes in lumbar spine BMD were −3.4% in the placebo group and +0.4% in 800 mg clodronate group [difference between groups at 3 years 3.8% (95% CI 2.7% to 4.9%, p<0.0001)], and in the trochanter area BMD −1.1% in the placebo group, and + 0.4% in the 800 mg clodronate group [difference between groups at 3 years 1.5% (95% CI 0.05% to 2.9%)]. During the extension study mean changes in lumbar spine BMD were +1.5% in the clodronate group and −0.2 % in the placebo group [difference between groups 1.7% (CI 0.4% to 3.0%, p = 0.010)] and in trochanter BMD were +2.5% in the clodronate group and no change in the placebo group [difference between groups 2.1% (CI 0.3% to 3.9%, p = 0.007)]. No statistically significant differences between the placebo and 800 mg clodronate groups were found in the femoral neck BMD. In the primary study the urinary excretion of type I collagen aminoterminal telopeptide (NTX) decreased by 44% (p<0.0001 compared with placebo) and that of deoxypyridinoline by 18% (p<0.0001) in the clodronate 800 mg group. In the extension study urinary NTX decreased by 51% (p<0.0001) in those who were switched to 800 mg of clodronate and increased by 67% (p<0.0001) in those who stopped using that dose. There was no difference in the frequency of gastrointestinal complaints between clodronate- and placebo-treated patients in the primary study, but they were more common among women who received clodronate in the extension phase. Clodronate in daily doses of 400–800 mg caused a slight elevation of aminotransferase levels, usually within the reference range. In bone biopsies no defect in mineralization was found. In conclusion, clodronate in a daily dose of 800 mg prevents early postmenopausal bone loss at the sites of the skeleton in which cancellous bone predominates. It effectively reduces bone resorption and bone turnover rate. Antifracture efficacy of clodronate remains to be established by prospective, placebo-controlled trials. Received: 4 March 2002 / Accepted: 9 July 2002     

Tc-99m HMPAO labeled leukocytes superior to bone scan in the detection of osteomyelitis in children.

Seven children (aged 7 to 16 years) with confirmed osteomyelitis underwent imaging with Tc-99m HMPAO labeled leukocytes and with Tc-99m diphosphonates. The patients were scanned at 1/2 hour and at 3 hours. The scans were evaluated visually, and the lesion-to-normal bone ratios were quantitated. All the lesions on leukocyte scans and six out of seven lesions in bone scans were readily detectable 1/2 hour after injection of the radiopharmaceutical, but 3 hours is the better imaging time. In quantitative analysis, the lesion-to-normal bone ratio increased with leukocytes significantly higher than with the bone scans (P less than 0.05). When the scintigraphic findings were compared with surgical and radiologic results, the leukocyte images detected and localized lesions better than the bone scans. According to these preliminary results, Tc-99m HMPAO labeled leukocytes seem to offer a rapid and accurate method for detecting bone infections.     

Incidence and survival in patients with pharyngeal cancer in northern Finland

A population-based survey was conducted in northern Finland in order to study the incidence rate and survival in patients with pharyngeal cancer diagnosed between 1986 to 1996. A total of 95 new patients with hypopharyngeal, oropharyngeal or nasopharyngeal cancers were identified. The overall age-adjusted incidence rates (per 100,000 years) were 1.28 in men and 0.60 in women, giving an overall incidence rate of 0.89. Most of the tumours were diagnosed at stage IV, and the median disease-specific survival times were 27.6 months for the patients with oropharyngeal cancer, 13.5 months for nasopharyngeal cancer and 17.7 for hypopharyngeal cancer. The most important factors that were associated with a poor prognosis were stage IV in oropharyngeal [Hazard ratio (HR) 3.68, 95% confidence interval (CI) 0.97-13.92] and hypopharyngeal cancer (HR 3.99, CI 1.51-10.67) and age over 65 years in nasopharyngeal cancer (HR 9.28, CI 1.79-47.99).     

Effect of Calcitonin on the Alcohol Drinking of Rats

Previous work has shown that calcitonin inhibits eating by rats and that it affects several neurotransmitter systems suspected to play a role in alcohol consumption. The present study was an initial test of whether calcitonin does affect voluntary alcohol consumption by male Wistar rats with prolonged alcohol experience. Calcitonin (20 IU/kg) or saline was injected subcutaneously on 10 consecutive days when the rats (n = 20) had continual access to 10% (v/v) ethanol solution, and to food and water. Using a cross-over design, the effects of 40 IU/kg calcitonin vs. saline were then examined in a second 10-day treatment period. Similar patterns of effects were obtained with both calcitonin doses, but the patterns differed with alcohol, food, and water intake. Alcohol drinking showed biphasic changes with both doses, producing highly significant Treatment x Day interactions (p < 1E-10 and p = 6E-7): it was significantly reduced on the first day of calcitonin treatment and significantly increased on the last few days. Food intake was reduced on all calcitonin days although most markedly on the first. Water drinking was not altered on the first calcitonin day, but was greatly increased on the second, then gradually returned toward the baseline. In a second experiment, the animals were switched to 1 hr of alcohol access per day, and calcitonin (20 IU/kg) was administered periodically to one group 4 hr before the alcohol access. Alcohol drinking was significantly reduced in all cases when the calcitonin injection was preceded by at least 1 day without calcitonin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lens opacity in patients with hypercholesterolemia and ischaemic heart disease

Lens opacity studies were performed using an electronic Lens Opacity Meter (Interzeag Opacity Lensmeter 701) in a population (n = 321) with ischaemic heart disease. These patients are participating in a trial targetting at the reduction of mortality and incidence of myocardial infarction using a cholesterol-lowering drug, simvastatin. A separate study to evaluate the reliability of the method showed good reproducibility. Repeated measurements after a short time-interval (2–10 days) gave statistically lower opacity values either due to a change in lens transparency or perhaps a change in pigment and cell dispersion in the acqueous caused by repeated mydriasis. Lens opacity values showed a highly significant positive correlation to age. Serum cholesterol, systolic blood pressure and smoking habits showed no significant correlations to the levels of lens opacity when adjustments for age were made.Abbreviations HMG-CoA hydroxy-methylglutarylcoenzyme A - 4S Scandinavian Simvastatin Survival Study - LOM lens opacity meter     

Chlamydia pneumoniae infection in human monocytes

Chlamydia pneumoniae infection has been associated with cardiovascular diseases in seroepidemiological studies and by demonstration of the pathogen in atherosclerotic lesions. It has the capacity to infect several cell types, including monocyte-derived macrophages, which play an essential role in the development of atherosclerosis. However, the persistence of C. pneumoniae in mononuclear cells is poorly understood. To study the morphology and biological characteristics of the infection, human peripheral blood monocytes were infected with C. pneumoniae. Freshly isolated monocytes resisted the development of infectious progeny, and confocal and transmission electron microscopy showed that the morphology of the inclusions and chlamydial particles was abnormal. Addition of tryptophan or antibodies against gamma interferon did not diminish the inhibition of C. pneumoniae, suggesting that other factors are involved in the chlamydiostatic activity of the monocytes. Chlamydial mRNA was expressed at least 3 days after infection, however, and a capability for infected monocytes to induce a positive lymphocyte proliferative response was detected for up to 7 days, indicating that C. pneumoniae remains metabolically active in the monocytes in vitro. These results are in accordance with the hypothesis that C. pneumoniae may participate in the maintenance of local immunological response and inflammation via infected monocytes and thus enhance atherosclerosis.     

Characterization of GPRA, a novel G protein-coupled receptor related to asthma

We recently identified a novel positional asthma susceptibility gene, GPRA, which belongs to the G protein-coupled receptor family. In the present studies, we show that isoform specific activation of GPRA-A with its agonist, Neuropeptide S (NPS) resulted in significant inhibition of cell growth. GPRA has several variants due to extensive alternative splicing. We observed that only the full-length variants, GPRA-A and GPRA-B, with 7 transmembrane topology are transported into the plasma membrane, while the truncated proteins retain intracellular compartments. To clarify disease mechanism, we studied co-expression of the variants without finding any indication that truncated variants would inhibit the receptor transport into the plasma membrane. By using in situ hybridization and immunohistochemistry, we detected ubiquitous expression of GPRA-B, and frequent expression of GPRA-A in the epithelia of several organs including bronchi and gastrointestinal tract. Furthermore, we observed aberrant mRNA and protein expression levels of GPRA in the asthmatic bronchi. Finally, we demonstrate that GPRA and NPS are co-expressed in bronchial epithelium. In summary, this study provides evidence that GPRA might have functional relevance in modulating asthma by increased expression levels in the relevant tissues under diseased state and by potential inhibitory effect of GPRA-A activation on cell growth.