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Abstract Background The standard care in patients with a painful osteoporotic vertebral compression fracture (VCF) is conservative therapy. Percutaneous vertebroplasty (PV), a minimally invasive technique, is gaining popularity as a new treatment option. Many prospective and retrospective studies have reported on the effectiveness and safety of PV, but no large randomized controlled trial (RCT) has been published. Objective To estimate cost-effectiveness of PV compared to conservative therapy in terms of: pain reduction, quality of life, complications, secondary fractures and mortality. Materials and methods The VERTOS II study is designed as a prospective, multicenter RCT. Patients with a painful VCF with bone edema on MR imaging, local back pain for 6 weeks or less, osteopenia and aged 50 years or older, after obtaining informed consent are included and randomized for PV or conservative therapy. In total 200 patients will be enrolled. Follow-up is at regular intervals during a 1-year period with standard questionnaires, addressing: clinical symptoms, pain medication, Visual Analogue Scale (VAS) score, quality of life and cost-effectiveness. Secondary fractures, necessary additional therapies and complications are recorded. Conclusion The VERTOS II study is the first methodologically sound RCT designed to assess the cost-effectiveness of PV compared to conservative therapy in patients with an acute osteoporotic VCF. Trial registration http://www.clinicaltrials.gov, NCT00232466

Background: Postmenopausal women are prone to develop functional disabilities as a result of reduction in muscle strength and muscle mass caused by diminished levels of female sex hormones. While hormone replacement therapy may counteract these changes, conventional hormone replacement therapy is associated with potential harmful effects, such as an increased risk of breast cancer, and its prescription is not recommended. For this reason newer alternative drugs, such as tibolone, a synthetic steroid with estrogenic, progestogenic and androgenic activity, and raloxifene, a selective estrogen receptor modulator, may be more appropriate. This trial investigates the effect of tibolone and raloxifene on muscle strength.Methods: We recruited 318 elderly women in our single-center randomized, double-blind, double-dummy, placebo-controlled trial. Participants were randomized to tibolone 1.25 mg (Org OD 14, Organon NV, the Netherlands) plus placebo, raloxifene 60 mg (Evista(R), Eli Lilly, United States) plus placebo or two placebo tablets daily for 24 months.The primary aim is to determine if there is a difference between tibolone and placebo or if there is a difference between raloxifene and placebo. Primary endpoints are muscle strength and bone mineral density. The secondary endpoints are postural balance, body composition, cognitive function, anxiety, mood and quality of life. The secondary aim is to determine if there is a difference between tibolone and raloxifene. The measure of effect is the change from the baseline visit to the visits after 3 months, 6 months, 12 months, and 24 months. A follow-up measurement is planned at 30 months to determine whether any effects are sustained after cessation of the study. By December 2007 the blind will be broken and the data analyzed.Trial Registration Number: NTR: 1232. [ABSTRACT FROM AUTHOR]

Background: In pseudoxanthoma elasticum (PXE), low pyrophosphate levels may cause ectopic mineralization, leading to skin changes, visual impairment, and peripheral arterial disease., Objectives: The authors hypothesized that etidronate, a pyrophosphate analog, might reduce ectopic mineralization in PXE., Methods: In the Treatment of Ectopic Mineralization in Pseudoxanthoma Elasticum trial, adults with PXE and leg arterial calcifications (n = 74) were randomly assigned to etidronate or placebo (cyclical 20 mg/kg for 2 weeks every 12 weeks). The primary outcome was ectopic mineralization, quantified with 18 fluoride positron emission tomography scans as femoral arterial wall target-to-background ratios (TBR femoral ). Secondary outcomes were computed tomography arterial calcification and ophthalmological changes. Safety outcomes were bone density, serum calcium, and phosphate., Results: During 12 months of follow-up, the TBR femoral increased 6% (interquartile range [IQR]: -12% to 25%) in the etidronate group and 7% (IQR: -9% to 32%) in the placebo group (p = 0.465). Arterial calcification decreased 4% (IQR: -11% to 7%) in the etidronate group and increased 8% (IQR: -1% to 20%) in the placebo group (p = 0.001). Etidronate treatment was associated with significantly fewer subretinal neovascularization events (1 vs. 9, p = 0.007). Bone density decreased 4% ± 12% in the etidronate group and 6% ± 9% in the placebo group (p = 0.374). Hypocalcemia (<2.20 mmol/l) occurred in 3 versus 1 patient (8.1% vs. 2.7%, p = 0.304). Eighteen patients (48.6%) treated with etidronate, compared with 0 patients treated with placebo (p < 0.001), experienced hyperphosphatemia (>1.5 mmol/l) and recovered spontaneously., Conclusions: In patients with PXE, etidronate reduced arterial calcification and subretinal neovascularization events but did not lower femoral 18 fluoride sodium positron emission tomography activity compared with placebo, without important safety issues. (Treatment of Ectopic Mineralization in Pseudoxanthoma elasticum; NTR5180)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Although the incidences of osteoporosis and atherosclerosis increase with age, there is growing evidence that the coincidental occurrence of both diseases may be independent of age. In general, studies in men are scarce and results are inconsistent., Objective: to investigate the relationship between atherosclerosis and bone mineral density, and the influence of insulin sensitivity and low grade inflammation on this relationship in 332 men without CVD., Methods: Aortic Pulse wave velocity (PWV), augmentation index (AIX) and measurements of carotid intima media thickness (CIMT) were assessed. BMD measurements were performed with dual-X-ray absorptiometry (DEXA), subcutaneous fat by ultrasonography. Serum concentrations of lipids, hsCRP, glucose and insulin were measured. Insulin sensitivity was calculated by use of the quantitative insulin sensitivity (QUICKI). We used multivariate linear regression models to examine the association of hsCRP, insulin sensitivity, PWV, Aix, CIMT with BMD., Results: A higher CIMT was significantly associated with higher BMD after multivariate adjustment (ß 99.7; p=0.02). Further adjustment for weight attenuated the estimates towards non-significant. No association was found between PWV or AIX and BMD. Lower insulin sensitivity was associated with higher BMD (ß -645.1; p<0.01). After adjustment for weight this association was no longer significant. A similar effect was seen for the association between hsCRP and BMD., Conclusion: In this population of healthy, non-obese, men without a history of cardiovascular disease the positively association between cardiovascular parameters and BMD was mainly explained by weight, suggesting that in this population weight plays a protective role in the development of osteoporosis., Competing Interests: Frederiek van den Bos – Reports no disclosures; Marielle Emmelot-Vonk – Reports no disclosures; Harald Verhaar – Reports no disclosure; Yvonne van der Schouw – Reports no disclosures

Subclinical or undiagnosed vertebral fractures on routine chest computed tomography (CT) may be useful for detecting patients at increased risk of future hip fractures who might benefit from preventive interventions. We investigated whether prevalent vertebral fractures on routine chest CT are associated with future hip fractures. From a source population of 5679 patients ≥40 years old undergoing chest CT in one of three Dutch hospitals between 2002 and 2005, patients hospitalized for hip fractures (n = 149) during a median follow-up of 4.4 years were identified. Following a case-cohort design, a random sample of 576 patients was drawn from the source population and added to the cases. In this group, the presence and severity of vertebral fractures was determined using semiquantitative vertebral fracture assessment and multivariate case-cohort appropriate Cox modeling. We found that cases were older (69 versus 63 years) and more often female (48% versus 38%) than the source population. Compared with those with no fracture, patients with any vertebral fracture had triple the risk of future hip fracture (age- and gender-adjusted hazard ratio [HR] = 3.1, 95% confidence interval [CI] 2.1-4.7). This HR rose to 3.8 (CI 2.6-5.6) if mild fractures were discounted. Future fracture risk increased significantly with increasing severity of vertebral fracture status: from mild (HR = 2.4, CI 1.5-3.7) and moderate (HR = 4.8, CI 2.5-9.2) to severe (HR = 6.7, CI 2.9-15.5). The same was true for having higher cumulative fracture grades: 1 to 3 (HR = 2.7, CI 1.8-4.1), 4 to 6 (HR = 4.8, CI 2.2-10.5), or ≥7 (HR = 11.2, CI 3.7-34.6). In conclusion, prevalent vertebral fractures on routine clinical chest CT are associated with future hip fracture risk., (© 2014 American Society for Bone and Mineral Research.)

Background: patients with Parkinson's disease (PD) have a high risk of sustaining osteoporotic fractures as a result of falls and reduced bone mass., Objective: to summarise the underlying pathophysiological mechanisms of bone loss in PD by reviewing the available literature., Methods: a Medline search was performed for articles published between January 1975 and January 2011, using the keywords 'bone mineral density', 'bone loss', 'bone metabolism', 'osteoporosis', 'osteopenia', 'Parkinson's disease' and 'Parkinsonism'., Results: PD patients have a lower bone mineral density (BMD) than age-matched controls. Bone loss in PD is multifactorial, resulting from immobility, decreased muscle strength, and low body weight. Vitamin D deficiency is also important, not only because it reduces BMD, but also because cell function in the substantia nigra depends on vitamin D. Lastly, hyperhomocysteinaemia, an independent risk factor for osteoporosis, is common in PD, due to levodopa use, as well as vitamin B12 and folic acid deficiency. A few studies have demonstrated that treatment with bisphosphonates, vitamin D and calcium can increase BMD and reduce fractures in PD patients., Conclusion: bone loss in PD is multifactorial. It is clinically important because of the concomitant risk of fractures. Screening for osteoporosis should be considered more often, and therapeutic interventions should be initiated.

Background: Hypercalcaemia resulting from primary hyperparathyroidism (PHPT) can cause a wide range of symptoms, including cognitive disorders, psychiatric symptoms and muscle weakness. Parathyroid surgery is the only definite cure for PHPT. When surgery is contraindicated or patients decide against it, several non-surgical treatment options are available., Objective: To illustrate the treatment options of symptomatic hypercalcaemia caused by PHPT in the elderly and discuss these options in consideration of the available evidence., Design: Consecutive case series., Setting: University hospital., Patients: Four older patients aged 79-87 years with symptomatic hypercalcaemia resulting from PHPT., Results: Three patients had a parathyroid adenoma shown on a sestamibi scan. Normocalcaemia and resolution of symptoms was achieved by different treatment scenarios encompassing forced saline hydration, forced diuresis, intravenous pamidronate and cinacalcet, a calcimimetic drug. In one patient, no parathyroid abnormalities were revealed with imaging. Treatment with cinacalcet resulted in normocalcaemia and a strong improvement of symptoms., Conclusion: In clinical practice, different treatment scenarios are chosen for the treatment of elderly patients with symptomatic hypercalcaemia caused by PHPT. The introduction of cinacalcet offers a new treatment paradigm. We propose to apply cinacalcet preceding elective surgery as an alternative option to standard therapy or as maintenance dose when surgery is not possible.

Recently, two articles are published about the effectiveness of a multifactorial fall prevention programme performed by two falls clinics in the Netherlands. Both studies have shown negative results. The question is if those two studies are representative for the real situation in most falls clinics in the Netherlands. Two important differences are the selection of the patients and the completion of the fall prevention program. It is important to select the patients with the highest fall risk (> or = 2 falls/year and/or > or = 4 fall risk factors) and to provide an active and direct management of the identified fall risk factors to improve the effectiveness of falls clinics.

Background: To study the prevalence of eighteen geriatric conditions in older patients at admission, their reporting rate in discharge summaries and the impact of these conditions on mortality and functional decline one year after admission., Method: A prospective multicenter cohort study conducted between 2006 and 2008 in two tertiary university teaching hospitals and one regional teaching hospital in the Netherlands. Patients of 65 years and older, acutely admitted and hospitalized for at least 48 hours, were invited to participate. Eighteen geriatric conditions were assessed at hospital admission, and outcomes (mortality, functional decline) were assessed one year after admission., Results: 639 patients were included, with a mean age of 78 years. IADL impairment (83%), polypharmacy (61%), mobility difficulty (59%), high levels of primary caregiver burden (53%), and malnutrition (52%) were most prevalent. Except for polypharmacy and cognitive impairment, the reporting rate of the geriatric conditions in discharge summaries was less than 50%. One year after admission, 35% had died and 33% suffered from functional decline. A high Charlson comorbidity index score, presence of malnutrition, high fall risk, presence of delirium and premorbid IADL impairment were associated with mortality and overall poor outcome (mortality or functional decline). Obesity lowered the risk for mortality., Conclusion: Geriatric conditions were highly prevalent and associated with poor health outcomes after admission. Early recognition of these conditions in acutely hospitalized older patients and improving the handover to the general practitioner could lead to better health outcomes and reduce the burden of hospital admission for older patients.

Background and Purpose: The reported incidence of PCE during PV varies, depending on the sensitivity of diagnostic tests used. To assess the true incidence of PCE, we performed native chest CT during follow-up in a large proportion of patients from the VERTOS II trial., Materials and Methods: VERTOS II is a prospective multicenter randomized controlled trial comparing PV with conservative therapy in 202 patients. After a mean follow-up of 22 months (median, 21 months; range, 6-42 months), 54 of 78 patients (69%) with 80 vertebrae treated with PV underwent native chest CT to detect possible PCE. The presence, location, number, and size of PCE were recorded. In addition, the presence of pulmonary parenchymal changes adjacent to PCE was noted. Possible risk factors for PCE, such as age, sex, number of treated vertebrae, cement volume per vertebra, and presence and location of perivertebral cement leakage, were evaluated., Results: PCE was detected in 14 of 54 patients (26% 95% CI, 16%-39%). All patients were asymptomatic. Cement emboli were small and randomly distributed in peripheral small vessels. There were no reactive pulmonary changes. Cement leakage in the azygos vein was the only risk factor for the occurrence of PCE (OR, 43; 95% CI, 5-396)., Conclusions: Small and clinically silent PCE occurred in a quarter of patients treated with PV. Cement leakage into the azygos vein was the only risk factor. With time, these small cement emboli remained inert, without inflammatory pulmonary response. Standard postprocedural CT or chest radiographs are not necessary.

Background and Purpose: PV is increasingly used as treatment for osteoporotic VCFs. However, controversy exists as to whether PV increases the risk for new VCFs during follow-up. The purpose of our research was to assess the incidence of new VCFs in patients with acute VCFs randomized to PV and conservative therapy., Materials and Methods: VERTOS II is a prospective multicenter randomized controlled trial comparing PV with conservative therapy in 202 patients. Incidence, distribution, and timing of new VCFs during follow-up were assessed from spine radiographs. In addition, further height loss during follow-up of treated VCFs was measured., Results: After a mean follow-up of 11.4 months (median, 12.0; range, 1-24 months), 18 new VCFs occurred in 15 of 91 patients after PV and 30 new VCFs in 21 of 85 patients after conservative therapy. This difference was not significant (P = .44). There was no higher fracture risk for adjacent-versus-distant vertebrae. Mean time to new VCF was 16.2 months after PV and 17.8 months after conservative treatment (logrank, P = .45). The baseline number of VCFs was the only risk factor for occurrence (OR, 1.43; 95% CI, 1.05-1.95) and number (P = .01) of new VCFs. After conservative therapy, further height loss of treated vertebrae occurred more frequently (35 of 85 versus 11 of 91 patients, P < .001) and was more severe (P < .001) than after PV., Conclusions: Incidence of new VCFs was not different after PV compared with conservative therapy after a mean of 11.4 months' follow-up. The only risk factor for new VCFs was the number of VCFs at baseline. PV contributed to preservation of stature by decreasing both the incidence and severity of further height loss in treated vertebrae.

Ampicillin-resistant Enterococcus faecium (ARE) and vancomycin-resistant E. faecium (VRE) are important nosocomial pathogens. We quantified effects of probiotics and antibiotics on intestinal acquisition of ARE colonization in patients hospitalized in two non-intensive care unit (non-ICU) wards with high ARE prevalence. In a prospective cohort study with crossover design, all patients with a length of stay of >48 h were offered a multispecies probiotic product twice daily until discharge (4.5 months, intervention period) or not (4.5 months, control period). Perianal ARE carriage was determined <48 h after admission, twice weekly, and <48 h before discharge. The first isolates were genotyped by multiple-locus variable-number tandem repeat analysis (MLVA). Risk factors for acquisition were determined by Cox proportional hazards modeling, with special emphasis on ecological postantibiotic effects and delays between actual acquisition and culture positivity. Of 530 patients included, 94 (18%) were ARE colonized on admission. Of the remaining 436 noncolonized patients, 92 acquired ARE colonization: 28 (25%) of 110 probiotic users and 64 (20%) of 326 control patients (chi(2) test, P = 0.325). In all, 661 ARE strains were isolated from 186 patients, of which 186 were genotyped. In both wards, two MLVA types (MTs; MT1 and MT159) were responsible for >80% of acquisitions. Both MTs were genetically different from the probiotic E. faecium strain. Antibiotics to which ARE is resistant (hazard ratio [HR], 7.73 [95% confidence interval (CI), 4.52 to 13.22]), an ecological postantibiotic effect (HR, 7.11 [95% CI, 3.10 to 16.30]), and age (HR, 1.01 [95% CI, 0.99 to 1.02]) were associated with ARE acquisition. The HR of probiotics was 1.43 (95% CI, 0.88 to 2.34). In a setting with high selective antibiotic pressure, probiotics failed to prevent acquisition of multiresistant enterococci.

Older, more vulnerable individuals are increasingly often described in the literature as being frail. Because frailty is often perceived as being undesirable and associated with high health risks, it is important to establish how we can predict, recognize, and treat frailty. Frailty is predisposed by advancing age in combination with physiological deterioration, especially a loss of muscle mass and bone density. Although the symptoms of frailty are diverse, the most common symptoms are a deterioration of activities of daily living (ADL), mobility, nutritional status, cognition, and endurance. The consequences of frailty are institutionalization, morbidity, and mortality. The main determinants of frailty are limitations in ADL, weight loss, diminished mobility or patterns of activity, lowered serum cholesterol level, and sensitivity to change. There is no gold standard for the measurement of frailty, and often studies use a combination of instruments. Although a couple of multidimensional instruments have been developed to measure frailty in its totality, the reliability and validity of these instruments have yet to be established. Successful interventions against frailty include increasing muscle strength through training and individualized recommendations made on the basis of an extensive geriatric assessment.

Serum testosterone levels decline significantly with aging and this has been associated with reduced sexual function. We have conducted a double-blind, randomized, placebo-controlled trial to investigate the effect of testosterone supplementation on sexual function in 237 elderly men with a testosterone level <13.7 nmol l(-1). Participants were randomly assigned to receive oral testosterone undecanoate or a placebo for 6 months. A total of 207 men completed the study. After treatment, there were no differences in scores on sexual function between the groups. Subanalysis showed that although a baseline testosterone level in the lowest tertile was associated with significantly lower scores for sexual fantasies, desire of sexual contact and frequency of sexual contact, supplementation of testosterone did not result in improvement on any of these items in this group. In conclusion, the findings do not support the view that testosterone undecanoate supplementation for 6 months to elderly men with low-normal testosterone concentrations favorably affects sexual function.

Background and Purpose: During percutaneous polymethylmethacrylate (PMMA) vertebroplasty (PV), PMMA cement may migrate into the venous system and subsequently be transported to the pulmonary arteries. Frequency, outcome, and imaging findings of PMMA pulmonary embolism are poorly understood. We retrospectively assessed the frequency and outcome of PMMA embolism during PV in a large patient cohort and evaluated the relationship of the volume of injected PMMA to the occurrence of pulmonary PMMA embolism., Materials and Methods: Between 2001 and 2007, 532 osteoporotic compression fractures in 299 consecutive patients were treated with PV. PMMA embolism was defined as venous PMMA migration toward the lungs visible on biplane fluoroscopy during PV. CT was performed immediately and 1 year after PMMA migration., Results: Venous PMMA migration occurred during 11 PVs in 11 patients (2.1%, 95% confidence interval, 1.1-3.7%). CT in 8 patients demonstrated small peripheral pulmonary PMMA emboli. All 11 patients remained asymptomatic during 1-year follow-up. Repeat CT scanning after 1 year in 6 patients demonstrated unchanged pulmonary PMMA deposits without late reactive changes. Mean injected cement volume in patients with and without PMMA embolism was not different (3.6 +/- 1.06 mL versus 3.3 +/- 1.16 mL, P = .43). Similar comparison for thoracic and thoracolumbar vertebrae yielded P values of .07 and .9., Conclusion: Pulmonary PMMA embolism during PV is an infrequent complication without permanent clinical sequelae. After 1 year, no pulmonary reaction was seen on CT. No definite relationship of PMMA emboli with injected cement volume could be established.

Many older people, especially women, and their doctors still see osteoporosis as part of the natural course of ageing instead of as a preventable or treatable disorder. Height loss, hyperkyphosis, back pain, and fractures are accepted as consequences of ageing. The notion that it is too late to start treatment in a late stage of the disease forms another barrier to treatment. Although most studies of fracture reduction with medical treatment were not designed for the "geriatric" population, the average age of participants in most clinical trials was about 70 years. In all major studies patients also received calcium and vitamin D supplements. Nowadays, clinicians can choose from several effective treatments for the prevention of osteoporotic fractures in high-risk postmenopausal women. Data on the anti-fracture potential of calcium/vitamin D, raloxifene, bisphosphonates, strontium ralenate, and parathyroid hormone are now available. Bisphosphonates and strontium ralenate are good choices for first- or second-line treatment, while for the time being parathyroid hormone should only be used for the second-line treatment of osteoporosis in the elderly.

Background: Physical activity is beneficial for healthy ageing. It may also help maintain good cognitive function in older age. Aerobic activity improves cardiovascular fitness, but it is not known whether this sort of fitness is necessary for improved cognitive function. Studies in which activity, fitness and cognition are reported in the same individuals could help to resolve this question., Objectives: To assess the effectiveness of physical activity, aimed at improving cardiorespiratory fitness, on cognitive function in older people without known cognitive impairment., Search Strategy: We searched MEDLINE, EMBASE, PEDro, SPORTDiscus, PsycINFO, CINAHL, Cochrane Controlled Trials Register (CENTRAL), Dissertation abstracts international and ongoing trials registers on 15 December 2005 with no language restrictions., Selection Criteria: All published randomised controlled trials comparing aerobic physical activity programmes with any other intervention or no intervention with participants older than 55 years of age were eligible for inclusion., Data Collection and Analysis: Eleven RCTs fulfilling the inclusion criteria are included in this review. Two reviewers independently extracted the data from these included studies., Main Results: Eight out of 11 studies reported that aerobic exercise interventions resulted in increased cardiorespiratory fitness of the intervention group (an improvement on the maximum oxygen uptake test which is considered to be the single best indicator of the cardiorespiratory system) of approximately 14% and this improvement coincided with improvements in cognitive capacity. The largest effects on cognitive function were found on motor function and auditory attention (effect sizes of 1.17 and 0.50 respectively). Moderate effects were observed for cognitive speed (speed at which information is processed; effect size 0.26) and visual attention (effect size 0.26)., Authors' Conclusions: There is evidence that aerobic physical activities which improve cardiorespiratory fitness are beneficial for cognitive function in healthy older adults, with effects observed for motor function, cognitive speed, auditory and visual attention. However, the majority of comparisons yielded no significant results. The data are insufficient to show that the improvements in cognitive function which can be attributed to physical exercise are due to improvements in cardiovascular fitness, although the temporal association suggests that this might be the case. Larger studies are still required to confirm whether the aerobic training component is necessary, or whether the same can be achieved with any type of physical exercise. At the same time, it would be informative to understand why some cognitive functions seem to improve with (aerobic) physical exercise while other functions seem to be insensitive to physical exercise. Clinicians and scientists in the field of neuropsychology should seek mutual agreement on a smaller battery of cognitive tests to use, in order to render research on cognition clinically relevant and transparent and heighten the reproducibility of results for future research.

Background: The standard care in patients with a painful osteoporotic vertebral compression fracture (VCF) is conservative therapy. Percutaneous vertebroplasty (PV), a minimally invasive technique, is gaining popularity as a new treatment option. Many prospective and retrospective studies have reported on the effectiveness and safety of PV, but no large randomized controlled trial (RCT) has been published., Objective: To estimate cost-effectiveness of PV compared to conservative therapy in terms of: pain reduction, quality of life, complications, secondary fractures and mortality., Materials and Methods: The VERTOS II study is designed as a prospective, multicenter RCT. Patients with a painful VCF with bone edema on MR imaging, local back pain for 6 weeks or less, osteopenia and aged 50 years or older, after obtaining informed consent are included and randomized for PV or conservative therapy. In total 200 patients will be enrolled. Follow-up is at regular intervals during a 1-year period with standard questionnaires, addressing: clinical symptoms, pain medication, Visual Analogue Scale (VAS) score, quality of life and cost-effectiveness. Secondary fractures, necessary additional therapies and complications are recorded., Conclusion: The VERTOS II study is the first methodologically sound RCT designed to assess the cost-effectiveness of PV compared to conservative therapy in patients with an acute osteoporotic VCF., Trial Registration: http://www.clinicaltrials.gov, NCT00232466.

Purpose: To prospectively assess the short-term clinical outcome of patients with subacute or chronic painful osteoporotic vertebral compression fractures (VCF) treated with percutaneous vertebroplasty (PV) compared with optimal pain medication (OPM)., Methods: Randomization of patients in 2 groups: treatment by PV or OPM. After 2 weeks, patients from the OPM arm could change therapy to PV. Patients were evaluated 1 day and 2 weeks after treatment. Visual analog score (VAS) for pain and analgesic use were assessed before, and 1 day and 2 weeks after start of treatment. Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO) and Roland-Morris Disability (RMD) questionnaire scores were assessed before and 2 weeks after start of treatment. Follow-up scores in patients requesting PV treatment after 2 weeks OPM treatment were compared with scores during their OPM period., Results: Eighteen patients treated with PV compared with 16 patients treated with OPM had significantly better VAS and used less analgesics 1 day after treatment. Two weeks after treatment, the mean VAS was less but not significantly different in patients treated with OPM, whereas these patients used significantly less analgesics and had better QUALEFFO and RMD scores. Scores in the PV arm were influenced by occurrence of new VCF in 2 patients. After 2 weeks OPM, 14 patients requested PV treatment. All scores, 1 day and 2 weeks after PV, were significantly better compared with scores during conservative treatment., Conclusion: Pain relief and improvement of mobility, function, and stature after PV is immediate and significantly better in the short term compared with OPM treatment.

In ageing men testosterone levels decline, while cognitive function, muscle and bone mass, sexual hair growth, libido and sexual activity decline and the risk of cardiovascular diseases increase. We set up a double-blind, randomized placebo-controlled trial to investigate the effects of testosterone supplementation on functional mobility, quality of life, body composition, cognitive function, vascular function and risk factors, and bone mineral density in older hypogonadal men. We recruited 237 men with serum testosterone levels below 13.7 nmol/L and ages 60-80 years. They were randomized to either four capsules of 40 mg testosterone undecanoate (TU) or placebo daily for 26 weeks. Primary endpoints are functional mobility and quality of life. Secondary endpoints are body composition, cognitive function, aortic stiffness and cardiovascular risk factors and bone mineral density. Effects on prostate, liver and hematological parameters will be studied with respect to safety. Measure of effect will be the difference in change from baseline visit to final visit between TU and placebo. We will study whether the effect of TU differs across subgroups of baseline waist girth (< 100 cm vs. > or = 100 cm; testosterone level (< 12 versus > or = 12 nmol/L), age (< median versus > or = median), and level of outcome under study (< median versus > or = median). At baseline, mean age, BMI and testosterone levels were 67 years, 27 kg/m2 and 10.72 nmol/L, respectively.

An extensive study was carried out in the Netherlands on the occurrence of a number of estrogenic compounds in surface water, sediment, biota, wastewater, rainwater and on the associated effects in fish. Compounds investigated included natural and synthetic hormones, phthalates, alkylphenol(ethoxylate)s and bisphenol-A. The results showed that almost all selected (xeno-)estrogens were present at low concentrations in the aquatic environment. Locally, they were found at higher levels. Hormones and nonylphenol(ethoxylate)s were present in concentrations that are reportedly high enough to cause estrogenic effects in fish. Field surveys did not disclose significant estrogenic effects in male flounder (Platichthys flesus) in the open sea and in Dutch estuaries. Minor to moderate estrogenic effects were observed in bream (Abramis brama) in major inland surface waters such as lowland rivers and a harbor area. The prevalence of feminizing effects in male fish is largest in small regional surface waters that are strongly influenced by sources of potential hormone-disrupting compounds. High concentrations of plasma vitellogenin and an increased prevalence of ovotestes occurred in wild male bream in a small river receiving a considerable load of effluent from a large sewage treatment plant. After employing in vitro and in vivo bioassays, both in situ and in the laboratory, we conclude that in this case hormones (especially 17 alpha-ethynylestradiol) and possibly also nonylphenol(ethoxylate)s are primarily responsible for these effects.

An inadequate serum vitamin D status is commonly seen in elderly people as the result of various risk factors interacting in this population. Apart from the well-known effects on bone metabolism, this condition is also associated with muscle weakness, predominantly of the proximal muscle groups. Muscle weakness below a certain threshold affects functional ability and mobility, which puts an elderly person at increased risk of falling and fractures. Therefore, we wanted to determine the rationale behind vitamin D supplementation in elderly people to preserve and possibly improve muscle strength and subsequently functional ability. From experimental studies it was found that vitamin D metabolites directly influence muscle cell maturation and functioning through a vitamin D receptor. Vitamin D supplementation in vitamin D-deficient, elderly people improved muscle strength, walking distance, and functional ability and resulted in a reduction in falls and non-vertebral fractures. In healthy elderly people, muscle strength declined with age and was not prevented by vitamin D supplementation. In contrast,severe comorbidity might affect muscle strength in such a way that restoration of a good vitamin D status has a limited effect on functional ability. Additional research is needed to further clarify to what extent vitamin D supplementation can preserve muscle strength and prevent falls and fractures in elderly people.

Changes in body composition occur around the menopausal transition. The major characteristics are a decline in fat-free mass and an increase in body fat as a percentage of body weight. These alterations might be affected by age only or by menopause-related changes in hormone concentration. In this study the effects of tibolone, a tissue-specific compound with favorable effects on bone, vagina, and climacteric symptoms, were determined on body composition using bioelectrical impedance analysis. The focus was especially on fat mass, fat-free mass, and total body water in a group of 85 healthy women (mean +/- SD age, 54.2 +/- 4.7 yr), between 1-15 yr postmenopausal. Participants were randomly assigned to either tibolone (2.5 mg; n = 42) or identically appearing placebo tablets (n = 43) daily for 12 months. All analyses were based on the intent to treat group and last visit. Compared with placebo, tibolone significantly increased fat-free mass by 0.85 kg (P = 0.003) and total body water by 0.78 liter (P = 0.001). No significant difference was observed on the fat mass parameter (P = 0.16). From these results it can be concluded that tibolone may counteract the postmenopausal changes in body composition.

Objective: we measured muscle strength and functional mobility in healthy men and women over the adult age range to investigate the changes with age and sex, and to establish the effects of the anthropometric indices height and weight., Design: cross-sectional study., Subjects and Methods: we recruited 74 healthy women (mean age 49.0, range 20-90) and 81 healthy men (mean age 51.6, range 20-90). We measured maximum isometric knee extension strength, handgrip strength and explosive leg extensor power. We assessed functional mobility quantitatively with the timed 'get up and go' test and the modified Cooper test., Results: older subjects had lower values for muscle strength and muscle power than young subjects. Times for the timed 'get up and go' test were longer and distances in the modified Cooper test shorter. At about the age of 55, women showed an acceleration in the decline of isometric knee extension strength and handgrip strength (between 20 and 55 years, knee strength decreased by 10.3% and handgrip strength decreased by 8.2%, between 55 and 80 years the decreases were 40.2% and 28% respectively). Men showed a more gradual declines over the adult age range, with decreases in knee and handgrip strength of 24% and 19.6% between 20 and 55 years, and 23% and 17.4% between 55 and 80 years. The age-related decline is partly associated with differences in height and body weight. Women had higher correlations between muscle strength and functional mobility tests than men., Conclusions: muscle strength and functional mobility decline with age in healthy people; in women we observed an accelerated decrement in muscle strength above the age of 55. Lower values in healthy old subjects are partly associated with differences in height and body weight.

In order to validate a classification system for the prediction of the toxic effect concentrations of organic environmental pollutants to fish, all available fish acute toxicity data were retrieved from the ECETOC database, a database of quality-evaluated aquatic toxicity measurements created and maintained by the European Centre for the Ecotoxicology and Toxicology of Chemicals. The individual chemicals for which these data were available were classified according to the rulebase under consideration and predictions of effect concentrations or ranges of possible effect concentrations were generated. These predictions were compared to the actual toxicity data retrieved from the database. The results of this comparison show that generally, the classification system provides adequate predictions of either the aquatic toxicity (class 1) or the possible range of toxicity (other classes) of organic compounds. A slight underestimation of effect concentrations occurs for some highly water soluble, reactive chemicals with low log K(ow) values. On the other end of the scale, some compounds that are classified as belonging to a relatively toxic class appear to belong to the so-called baseline toxicity compounds. For some of these, additional classification rules are proposed. Furthermore, some groups of compounds cannot be classified, although they should be amenable to predictions. For these compounds additional research as to class membership and associated prediction rules is proposed.

The GH/insulin-like growth factor-I (GH/IGF-I) axis is known to be involved in aging of physiological functions. Recent studies indicate that the GH/IGF-I axis may be associated with cognitive functioning. The aim of the present study was to determine whether the age-related decline in circulating levels of IGF-I, as an index of anabolic status, is associated with cognitive functions that are known to decline with aging, but not with cognitive functions not sensitive to aging. Twenty five healthy older men with well-preserved functional ability participated in the study. We also administered neuropsychological tests of general knowledge, vocabulary, basic visual perception, reading ability, visuoconstructive ability, perceptual-motor speed, mental tracking, and verbal long-term memory. Performance on the last four tests decline with aging, whereas the first four of these tests have been shown not to be sensitive to cognitive aging. Mean age of the subjects was 69.1 +/- 3.4 (SD) yr (range 65-76 yr), their mean body mass index was 27.0 +/- 2.4 kg/m2, and their mean IGF-I level was 122 ng/mL (range: 50-220). We found IGF-I levels to be significantly associated with the performances (controlled for education) on the Digit Symbol Substitution test (r = 0.52, P = 0.009) and the Concept Shifting Task (r = -0.55, P = 0.005), which measure perceptual-motor and mental processing speed. Subjects with higher IGF-I levels performed better on these tests, performance on which is known to decline with aging. In conclusion, the results of this study support the hypothesis that circulating IGF-I may play a role in the age-related reduction of certain cognitive functions, specifically speed of information processing.

Systematic toxicity testing, using conventional toxicology methodologies, of single chemicals and chemical mixtures is highly impractical because of the immense numbers of chemicals and chemical mixtures involved and the limited scientific resources. Therefore, the development of unconventional, efficient, and predictive toxicology methods is imperative. Using carcinogenicity as an end point, we present approaches for developing predictive tools for toxicologic evaluation of chemicals and chemical mixtures relevant to environmental contamination. Central to the approaches presented is the integration of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) and quantitative structure--activity relationship (QSAR) modeling with focused mechanistically based experimental toxicology. In this development, molecular and cellular biomarkers critical to the carcinogenesis process are evaluated quantitatively between different chemicals and/or chemical mixtures. Examples presented include the integration of PBPK/PD and QSAR modeling with a time-course medium-term liver foci assay, molecular biology and cell proliferation studies. Fourier transform infrared spectroscopic analyses of DNA changes, and cancer modeling to assess and attempt to predict the carcinogenicity of the series of 12 chlorobenzene isomers. Also presented is an ongoing effort to develop and apply a similar approach to chemical mixtures using in vitro cell culture (Syrian hamster embryo cell transformation assay and human keratinocytes) methodologies and in vivo studies. The promise and pitfalls of these developments are elaborated. When successfully applied, these approaches may greatly reduce animal usage, personnel, resources, and time required to evaluate the carcinogenicity of chemicals and chemical mixtures.

Mixture toxicity is a topic that has become a matter of concern during the last two decades. One of the major problems with assessing the toxicity of mixtures and the associated human and environmental risk is the large number of possible mixtures, as well as the fact that the actual mixture effect for a given set of constituents might strongly depend on the actual composition of the mixture, i.e., the ratios of the constituent, as well as their nature. This paper presents a possible approach to describe and thereby better understand the pharmacokinetics and dynamics of complex mixtures by combining quantitative structure-activity relationships to predict needed parameters, lumping to reduce the complexity of the problem, and physiologically based pharmacokinetic/pharmacodynamic modeling to integrate all this information into a complete toxicological description of the mixture. It is our hope that by presenting this conceptual approach we might be able to stimulate some criticisms and discussions in the toxicology community regarding this complex and yet very important area of research.

The proportions of T cell subsets and Leu 7+ cells and the spontaneous cell-mediated cytotoxicity (SCMC) of isolated mononuclear cells have been determined across the mesenteric vascular bed and along the intestinal mucosal-mesenteric lymph node (MLN) axis in patients undergoing abdominal surgery. Whereas the proportion of T4+ and T8+ cells were similar in simultaneously taken PVB and mesenteric venous blood (MVB), the proportion of Leu 7+ cells was higher in MVB in 16 of 17 studies (15.4 +/- 6.8%, 10.8 +/- 5.1%). Additional studies showed that the proportions of lymphocyte subsets in peripheral arterial blood are the same as those in PVB. Thus, an enrichment of Leu 7+ cells occurs across the mesenteric vascular bed. Isolated intestinal and MLN mononuclear cells contained similarly high proportions of T4+ and T8+ cells as in PVB but Leu 7+ cells made up a minority subpopulation in intestinal (1.3 +/- 0.8%) and MLN mononuclear cells (1.0 +/- 0.9%). The SCMC of intestinal and MLN mononuclear cells was low and paralleled the proportion of Leu 7+ cells. Despite the higher proportions of Leu 7+ cells in MVB, the SCMC was less than that of PVB in eight patients with inflamed intestine and not significantly different from PVB in seven patients with normal intestines. These paradoxical findings were at least in part due to inhibitory factors in mesenteric plasma. In conclusion, NK cells appear to be largely confined within the vascular system and the enrichment of Leu 7+ cells across the mesenteric vascular bed suggests that this compartmentalization may be due to differences in the traffic of lymphocyte subpopulations through the intestinal mucosa and MLN.

A method is described for the synthesis and characterization of N-(2-hydroxy-3-butenyl)-N'-phenylthiourea, and its cyclization product, 1-phenyl-5-vinyl-2-imidazolidinethione (PVIZT). Fourteen coded oil samples associated with toxic oil syndrome cases in Spain were examined by gas chromatography-electron impact mass spectrometry for the presence of PVIZT. Although these samples were obtained from households where cases of toxic oil syndrome had been recorded, they differed extremely with regard to their anilide and sulphur contents. In one sample PVIZT was detected at an estimated concentration of 1 mg/kg.