Summary This report describes the epidemiology, burden, and treatment of osteoporosis in the 27 countries of the European Union (EU27). Introduction Osteoporosis is characterized by reduced bone mass and disruption of bone architecture, resulting in increased risk of fragility fractures which represent the main clinical consequence of the disease. Fragility fractures are associated with substantial pain and suffering, disability and even death for affected patients and substantial costs to society. The aim of this report was to characterize the burden of osteoporosis in the EU27 in 2010 and beyond. Methods The literature on fracture incidence and costs of fractures in the EU27 was reviewed and incorporated into a model estimating the clinical and economic burden of osteoporotic fractures in 2010.Results Twenty-two million women and 5.5 million men were estimated to have osteoporosis; and 3.5 million new fragility fractures were sustained, comprising 610,000 hip fractures, 520,000 vertebral fractures, 560,000 forearm fractures and 1,800,000 other fractures (i.e. fractures of the pelvis, rib, humerus, tibia, fibula, clavicle, scapula, sternum and other femoral fractures). The economic burden of incident and prior fragility fractures was estimated at € 37 billion. Incident fractures represented 66 % of this cost, long-term fracture care 29 % and pharmacological prevention 5 %. Previous and incident fractures also accounted for 1,180,000 quality-adjusted life years lost during 2010. The costs are expected to increase by 25 % in 2025. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are untreated and the number of patients on treatment is declining.

Summary This report describes epidemiology, burden, and treatment of osteoporosis in each of the 27 countries of the European Union (EU27). Introduction In 2010, 22 million women and 5.5 million men were estimated to have osteoporosis in the EU; and 3.5 million new fragility fractures were sustained, comprising 620,000 hip fractures, 520,000 vertebral fractures, 560,000 forearm fractures and 1,800,000 other fractures. The economic burden of incident and prior fragility fractures was estimated at € 37 billion. Previous and incident fractures also accounted for 1,180,000 quality-adjusted life years lost during 2010. The costs are expected to increase by 25 % in 2025. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are untreated and the number of patients on treatment is declining. The aim of this report was to characterize the burden of osteoporosis in each of the EU27 countries in 2010 and beyond. Methods The data on fracture incidence and costs of fractures in the EU27 were taken from a concurrent publication in this journal (Osteoporosis in the European Union: (2013( ) 8:137 DOI 10.1007 Medical Management, Epidemiology and Economic Burden) and country specific information extracted. Results The clinical and economic burden of osteoporotic fractures in 2010 is given for each of the 27 countries of the EU. The costs are expected to increase on average by 25 % in 2025. The majority of individuals who have sustained an osteoporosis-related fracture or who are at high risk of fracture are untreated and the number of patients on treatment is declining. Conclusions In spite of the high cost of osteoporosis, a substantial treatment gap and projected increase of the economic burden driven by aging populations, the use of pharmacological prevention of osteoporosis has decreased in recent years, suggesting that a change in healthcare policy concerning the disease is warranted.

Abnormal vascularization of solid tumours results in the development of microenvironments deprived of oxygen and nutrients that harbour slowly growing and metabolically stressed cells. Such cells display enhanced resistance to standard chemotherapeutic agents and repopulate tumours after therapy. Here we identify the small molecule VLX600 as a drug that is preferentially active against quiescent cells in colon cancer 3-D microtissues. The anticancer activity is associated with reduced mitochondrial respiration, leading to bioenergetic catastrophe and tumour cell death. VLX600 shows enhanced cytotoxic activity under conditions of nutrient starvation. Importantly, VLX600 displays tumour growth inhibition in vivo. Our findings suggest that tumour cells in metabolically compromised microenvironments have a limited ability to respond to decreased mitochondrial function, and suggest a strategy for targeting the quiescent populations of tumour cells for improved cancer treatment.

Published by Elsevier B.V. All rights reserved. IntroductionIn normal cells, adenosine triphosphate (ATP) production is to at least 90% provided by mitochondrial oxidative phosphorylation, while tumour cells are to approximately 50% dependent on cytoplasmic, aerobic glycolysis (Shaw, 2006;Matoba et al., 2006), a tumour-specific feature usually termed the Warburg effect. The switch from oxidative phosphorylation to glycolysis is connected to tumourspecific alterations in the expression and/or modification of proteins involved in the electron transport chain in mitochondria, leading to decreased efficiency of the oxidative phosphorylation process (Plas and Thompson, 2002;Harper et al., 2002;Shaw, 2006;Kim and Dang, 2006;Matoba et al., 2006). This would ultimately lead to lower ATP yields, but aerobic glycolysis compensates the tumour cell for the loss of mitochondrial ATP by providing ATP independently of oxidative phosphorylation. The bioenergetic switch to glycolysis likely confers various growth advantages on the tumour cell: not only does it support growth also under hypoxia, but it helps meet the increased requirements for energy as well as building blocks for macromolecule syntheses. The increased glycolytic activity thus provides the tumour cell with higher levels of NADH and acetyl-CoA to fuel the citric acid cycle and to support fatty acid synthesis. Because oxidative phosphorylation is seldom or never completely down-regulated, tumour cells may also up-regulate the use of energy-rich fatty acids as fuel; this pathway * Corresponding author.

BackgroundCisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained.MethodsIn HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration–time curve (AUC). Statistical tests were two-sided.ResultsIn HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 μM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 μg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 μM × minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics.ConclusionCisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.

In spite of the high cost of osteoporosis, a substantial treatment gap and projected increase of the economic burden driven by an aging population, the use of pharmacological prevention of osteoporosis is significantly less than optimal, suggesting that a change in health care policy concerning the disease is warranted.

Inhibition of energy production as a strategy for potentiation of anticancer chemotherapy was investigated using 1 glycolysis inhibitor and 1 fatty acid b-oxidation inhibitor-2-deoxyglucose and etomoxir, respectively, both known to be clinically well tolerated. Eighteen anticancer drugs were screened for potentiation by these inhibitors. 2-deoxyglucose potentiated acute apoptosis (24 hr) induced mainly by some, but not all, genotoxic drugs, whereas etomoxir had effect only on cisplatin. By contrast, etomoxir did potentiate the overall, 48 hr effects of some genotoxic drugs, and was in addition more efficient than deoxyglucose in potentiating the overall effects of several non-genotoxic drugs. Both types of potentiation were largely lost in the absence of p53. Because cisplatin was potentiated by both energy inhibitors in both types of assay, it was investigated at additional concentrations and over longer time. Both energy inhibitors strongly potentiated non-apoptotic concentrations of cisplatin in p53-wildtype as well as in p53-deficient, cisplatin-resistant HCT116 colon carcinoma cells. Reduced ATP levels correlated with, but were not sole determinants, the antiproliferative effects. We conclude that the longterm effects of cisplatin potentiation are important and either p53-independent or improved by a lack of p53. We also conclude that although the potentiated drugs as yet have no obvious mechanistic factor in common, the strategy holds promise with genotoxic as well non-genotoxic anticancer drugs. ' 2008 Wiley-Liss, Inc.Key words: chemopotentiation; antiproliferation; apoptosis; glycolysis; b-oxidation Interest in tumour cell energy metabolism as a therapeutic target is on the increase. It is well known that tumour cells are highly dependent on glycolysis for ATP production also under aerobic conditions (the Warburg effect) and that this is connected to decreased oxidative phosphorylation in mitochondria. Glycolysis provides pyruvate for the mitochondrial Krebs' cycle which in turn provides reducing equivalents for the electron transport chain required for oxidative phosphorylation. In addition, glucose and hexokinase-the first enzyme in glycolysis-are required for subsequent NADPH and NADPH-dependent biosyntheses, e.g., purine synthesis. The glucose dependence of tumour cells is reflected in increased cellular uptake of glucose and increased expression of glycolysis-related genes such as glucose transporters, hexokinase and glyceraldehyde-3-phosphate dehydrogenase.1-5 The increased levels of glucose transporters and glucose uptake is indeed clinically exploited for imaging of tumours using positron emission tomography (PET) based on tumour uptake of 18 F-deoxyglucose (18-FDG).Tumour biology and tumour cell phenotypic traits are greatly influenced by the changes in energy metabolism. It has thus been shown that tumour progression and drug resistance correlate with a set of metabolic shifts. 6 In the first phase, tumour cells are still sensitive to therapy, show high mitochondrial inner membrane potential (...

Hip, vertebral, and distal forearm fractures incur substantial loss in QoL and for patients with hip or vertebral fracture, QoL is markedly impaired for at least 18 months.