In postmenopausal women with osteoporosis, denosumab significantly improved trabecular bone score (TBS), an index of trabecular microarchitecture

Background/Purpose: The trabecular bone score (TBS), a novel graylevel texture index determined from lumbar spine DXA scans, correlates with 3D parameters of trabecular bone microarchitecture known to predict fracture. TBS may enhance the identification of patients at increased risk for vertebral fracture independently of bone mineral density (BMD) (Boutroy JBMR 2010; Hans JBMR 2011). Denosumab treatment for 36 months decreased bone turnover, increased BMD, and reduced new vertebral fractures in postmenopausal women with osteoporosis (Cummings NEJM 2009). We explored the effect of denosumab on TBS over 36 months and evaluated the association between TBS and lumbar spine BMD in women who had DXA scans obtained from eligible scanners for TBS evaluation in FREEDOM. Methods: FREEDOM was a 3-year, randomized, double-blind trial that enrolled postmenopausal women with a lumbar spine or total hip DXA T-score __2.5, but not __4.0 at both sites. Women received placebo or 60 mg denosumab every 6 months. A subset of women in FREEDOM participated in a DXA substudy where lumbar spine DXA scans were obtained at baseline and months 1, 6, 12, 24, and 36. We retrospectively applied, in a blinded-to-treatment manner, a novel software program (TBS iNsightR v1.9, Med-Imaps, Pessac, France) to the standard lumbar spine DXA scans obtained in these women to determine their TBS indices at baseline and months 12, 24, and 36. From previous studies, a TBS _1.35 is considered as normal microarchitecture, a TBS between 1.35 and _1.20 as partially deteriorated, and 1.20 reflects degraded microarchitecture. Results: There were 285 women (128 placebo, 157 denosumab) with a TBS value at baseline and _1 post-baseline visit. Their mean age was 73, their mean lumbar spine BMD T-score was _2.79, and their mean lumbar spine TBS was 1.20. In addition to the robust gains in DXA lumbar spine BMD observed with denosumab (9.8% at month 36), there were consistent, progressive, and significant increases in TBS compared with placebo and baseline (Table & Figure). BMD explained a very small fraction of the variance in TBS at baseline (r2_0.07). In addition, the variance in the TBS change was largely unrelated to BMD change, whether expressed in absolute or percentage changes, regardless of treatment, throughout the study (all r2_0.06); indicating that TBS provides distinct information, independently of BMD. Conclusion: In postmenopausal women with osteoporosis, denosumab significantly improved TBS, an index of lumbar spine trabecular microarchitecture, independently of BMD.

Which screening strategy using BMD measurements would be most cost effective for hip fracture prevention in elderly women? A decision analysis based on a Markov model.

INTRODUCTION: Hip fractures are responsible for excessive mortality, decreasing the 5-year survival rate by about 20%. From an economic perspective, they represent a major source of expense, with direct costs in hospitalization, rehabilitation, and institutionalization. The incidence rate sharply increases after the age of 70, but it can be reduced in women aged 70-80 years by therapeutic interventions. Recent analyses suggest that the most efficient strategy is to implement such interventions in women at the age of 70 years. As several guidelines recommend bone mineral density (BMD) screening of postmenopausal women with clinical risk factors, our objective was to assess the cost-effectiveness of two screening strategies applied to elderly women aged 70 years and older. METHODS: A cost-effectiveness analysis was performed using decision-tree analysis and a Markov model. Two alternative strategies, one measuring BMD of all women, and one measuring BMD only of those having at least one risk factor, were compared with the reference strategy "no screening". Cost-effectiveness ratios were measured as cost per year gained without hip fracture. Most probabilities were based on data observed in EPIDOS, SEMOF and OFELY cohorts. RESULTS: In this model, which is mostly based on observed data, the strategy "screen all" was more cost effective than "screen women at risk." For one woman screened at the age of 70 and followed for 10 years, the incremental (additional) cost-effectiveness ratio of these two strategies compared with the reference was 4,235 euros and 8,290 euros, respectively. CONCLUSION: The results of this model, under the assumptions described in the paper, suggest that in women aged 70-80 years, screening all women with dual-energy X-ray absorptiometry (DXA) would be more effective than no screening or screening only women with at least one risk factor. Cost-effectiveness studies based on decision-analysis trees maybe useful tools for helping decision makers, and further models based on different assumptions should be performed to improve the level of evidence on cost-effectiveness ratios of the usual screening strategies for osteoporosis.

Cancer du sein chez la jeune femme: traitements adjuvants et désir de grossesse [Breast cancer in young women: adjuvant therapy and fertility]

Prognosis of breast cancer women has been dramatically improved by the adjuvant therapies. As the vast majority of patients are cured, the importance of long-term quality of life is growing. The question of the maternity is an essential concern for the young women who have to receive chemotherapy or several years of endocrine therapy. This problem is often underestimated and may lead to emotional distress, depression or anxiety. A regional multidisciplinary working group was set up in order to offer optimal information about fertility and cancer as to propose specific therapeutic reproduction options, when applicable. Specificity of the young patients' breast cancer, the treatment approaches and their impact on fertility are discussed in this paper.

Angiotensin II favors progression to heart failure in diabetic hearts: role of myocardial fatty acid oxidation downregulation

Purpose: Diabetic myocardium is particularly vulnerable to develop heart failure in response to chronic stress conditions including hypertension or myocardial infarction. We have recently observed that angiotensin II (Ang II)-mediated downregulation of the fatty acid oxidation pathway favors occurrence of heart failure by myocardial accumulation of lipids (lipotoxicity). Because diabetic heart is exposed to high levels of circulating fatty acid, we determined whether insulin resistance favors development of heart failure in mice with Ang II-mediated myocardial remodeling.Methods: To study the combined effect of diabetes and Ang II-induced heart remodeling, we generated leptin-deficient/insulin resistant (Lepob/ob) mice with cardiac targeted overexpression of angiotensinogen (TGAOGN). Left ventricular (LV) failure was indicated by pulmonary congestion (lung weight/tibial length>+2SD of wild-type mice). Myocardial metabolism and function were assessed during in vitro isolated working heart perfusion.Results: Forty-eight percent of TGAOGN mice without insulin resistance exhibited pulmonary congestion at the age of 6 months associated with increased myocardial BNP expression (+375% compared with WT) and reduced LV power (developed pressure x cardiac output; -15%). The proportion of mice presenting heart failure was markedly increased to 71% in TGAOGN mice with insulin resistance (TGAOGN/Lepob/ob). TGAOGN/Lepob/ob mice with heart failure exhibited further increase of BNP compared with failing non-diabetic TGAOGN mice (+146%) and further reduction of cardiac power (-59%). Mice with insulin resistance alone (Lepob/ob) did not exhibit signs of heart failure or LV dysfunction. Myocardial fatty acid oxidation measured during in vitro perfusion was markedly increased in non-failing hearts from Lepob/ob mice (+380% compared with WT) and glucose oxidation decreased (-72%). In contrast, fatty acid and glucose oxidation did not differ from Lepob/ob mice in hearts from TGAOGN/Lepob/ob mice without heart failure. However, both fatty acid and glucose oxidation were markedly decreased (-47% and -48%, respectively, compared with WT/Lepob/+) in failing hearts from TGAOGN/Lepob/ob mice. Reduction of fatty acid oxidation was associated with marked reduction of protein expression of a number of regulatory enzymes implied in fatty acid oxidation.Conclusions: Insulin resistance favors the progression to heart failure during chronic exposure of the myocardium to Ang II. Our results are compatible with a role of Ang II-mediated downregulation of fatty acid oxidation, potentially promoting lipotoxicity.

Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00).

BACKGROUND: The aim of this study was to evaluate the efficacy and tolerability of fulvestrant, an estrogen receptor antagonist, in postmenopausal women with hormone-responsive tumors progressing after aromatase inhibitor (AI) treatment. PATIENTS AND METHODS: This is a phase II, open, multicenter, noncomparative study. Two patient groups were prospectively considered: group A (n=70) with AI-responsive disease and group B (n=20) with AI-resistant disease. Fulvestrant 250 mg was administered as intramuscular injection every 28 (+/-3) days. RESULTS: All patients were pretreated with AI and 84% also with tamoxifen or toremifene; 67% had bone metastases and 45% liver metastases. Fulvestrant administration was well tolerated and yielded a clinical benefit (CB; defined as objective response or stable disease [SD] for >or=24 weeks) in 28% (90% confidence interval [CI] 19% to 39%) of patients in group A and 37% (90% CI 19% to 58%) of patients in group B. Median time to progression (TTP) was 3.6 (95% CI 3.0 to 4.8) months in group A and 3.4 (95% CI 2.5 to 6.7) months in group B. CONCLUSIONS: Overall, 30% of patients who had progressed following prior AI treatment gained CB with fulvestrant, thereby delaying indication to start chemotherapy. Prior response to an AI did not appear to be predictive for benefit with fulvestrant.

Renal responses to three types of renin-angiotensin system blockers in patients with diabetes mellitus on a high-salt diet: a need for higher doses in diabetic patients?

Objective Activation of the renal renin-angiotensin system in patients with diabetes mellitus appears to contribute to the risk of nephropathy. Recently, it has been recognized than an elevation of prorenin in plasma also provides a strong indication of risk of nephropathy. This study was designed to examine renin-angiotensin system control mechanisms in the patient with diabetes mellitus.Methods We enrolled 43 individuals with type 2 diabetes mellitus. All individuals were on a high-salt diet to minimize the contribution of the systemic renin-angiotensin system. After an acute exposure to captopril (25 mg), they were randomized to treatment with either irbesartan (300 mg) or aliskiren (300 mg) for 2 weeks.Results All agents acutely lowered blood pressure and plasma aldosterone, and increased renal plasma flow and glomerular filtration rate. Yet, only captopril and aliskiren acutely increased plasma renin and decreased plasma angiotensin II, whereas irbesartan acutely affected neither renin nor angiotensin II. Plasma renin and angiotensin II subsequently did increase upon chronic irbesartan treatment. When given on day 14, irbesartan and aliskiren again induced the above hemodynamic, renal and adrenal effects, yet without significantly changing plasma renin. Irbesartan at that time did not affect plasma angiotensin II, whereas aliskiren lowered it to almost zero.Conclusion The relative resistance of the renal renin response to acute (irbesartan) and chronic (irbesartan and aliskiren) renin-angiotensin system blockade supports the concept of an activated renal renin-angiotensin system in diabetes, particularly at the level of the juxtaglomerular cell, and implies that diabetic patients might require higher doses of renin-angiotensin system blockers to fully suppress the renal renin-angiotensin system. J Hypertens 29: 2454-2461 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Coronary artery disease screening in diabetic patients: how good is guideline adherence?

INTRODUCTION: Diabetic patients are at high risk for coronary artery disease (CAD), which is the leading cause of death in this population. The Swiss Society of Endocrinology-Diabetology (SSED) recommends CAD screening for diabetic patients with > or = 2 additional cardiovascular risk factors (CVRF), by stress echocardiography (SE) or myocardial perfusion imaging (MPI). The aim of this study was to assess the application of these guidelines and the treatment of CVRF in the diabetes outpatient clinics of the five Swiss University Hospitals. METHODS: The study was initiated in Lausanne and the study questionnaires were circulated to the endocrinologists of the five Swiss University Hospitals. Practitioners were asked to include consecutive patients attending the diabetes outpatient clinics over one month. Prevalence of CAD, screening methods for CAD, prevalence of CVRF, biological analyses over the last 6 months and medical therapy were recorded. RESULTS: A total of 302 subjects were included. The mean age was 53 +/- 14 years, 68% had type 2 diabetes, 27% type 1 and 5% other types. Among T2DM with > or = 2 CVRF, 45% were screened for CAD according to SSED guidelines. In T2DM 25% had blood pressure < or = 130/80 mm Hg, 15% a lipid profile within target, 23% HbA1c < or = 7.0%. Overall, 2% achieved all 3 targets. CONCLUSIONS: Only 45% of T2DM with > or = 2 CVRF were screened for CAD according to SSED guidelines and 2% of T2DM had proper control over all CVRF. Efforts are still necessary to improve CAD prevention and screening of diabetic patients in Swiss University Hospitals.

Breast cancer in younger women in Switzerland 1996-2009 : a longitudinal population-based study

BACKGROUND: Breast cancer (BC) is the most commonly diagnosed cancer and a leading cause of death in younger women. METHODS: We analysed incidence, mortality and relative survival (RS) in women with BC aged 20-49 years at diagnosis, between 1996 and 2009 in Switzerland. Trends are reported as estimated annual percentage changes (EAPC). RESULTS: Our findings confirm a slight increase in the incidence of BC in younger Swiss women during the period 1996-2009. The increase was largest in women aged 20-39 years (EAPC 1.8%). Mortality decreased in both age groups with similar EAPCs. Survival was lowest among women 20-39 years (10-year RS 73.4%). We observed no notable differences in stage of disease at diagnosis that might explain these differences. CONCLUSIONS: The increased incidence and lower survival in younger women diagnosed with BC in Switzerland indicates possible differences in risk factors, tumour biology and treatment characteristics that require additional examination.

Treatment of genital mycoplasma in colonized pregnant women in late pregnancy is associated with a lower rate of premature labour and neonatal complications.

Mycoplasma hominis and Ureaplasma spp. may colonize the human genital tract and have been associated with adverse pregnancy outcomes such as preterm labour and preterm premature rupture of membranes. However, as these bacteria can reside in the normal vaginal flora, there are controversies regarding their true role during pregnancy and so the need to treat these organisms. We therefore conducted a retrospective analysis to evaluate the treatment of genital mycoplasma in 5377 pregnant patients showing symptoms of potential obstetric complications at 25-37 weeks of gestation. Women presenting with symptoms were routinely screened by culture for the presence of these bacteria and treated with clindamycin when positive. Compared with uninfected untreated patients, women treated for genital mycoplasma demonstrated lower rates of premature labour. Indeed preterm birth rates were, respectively, 40.9% and 37.7% in women colonized with Ureaplasma spp. and M. hominis, compared with 44.1% in uncolonized women (Ureaplasma spp., p 0.024; M. hominis, p 0.001). Moreover, a reduction of neonatal complications rates was observed, with 10.9% of newborns developing respiratory diseases in case of Ureaplasma spp. colonization and 5.9% in the presence of M. hominis, compared with 12.8% in the absence of those bacteria (Ureaplasma spp., p 0.050; M. hominis, p <0.001). Microbiological screening of Ureaplasma spp. and/or M. hominis and pre-emptive antibiotic therapy of symptomatic pregnant women in late pregnancy might represent a beneficial strategy to reduce premature labour and neonatal complications.

Women's decision making and experience of subsequent pregnancy following stillbirth.

INTRODUCTION: This study sought to increase understanding of women's thoughts and feelings about decision making and the experience of subsequent pregnancy following stillbirth (intrauterine death after 24 weeks' gestation). METHODS: Eleven women were interviewed, 8 of whom were pregnant at the time of the interview. Modified grounded theory was used to guide the research methodology and to analyze the data. RESULTS: A model was developed to illustrate women's experiences of decision making in relation to subsequent pregnancy and of subsequent pregnancy itself. DISCUSSION: The results of the current study have significant implications for women who have experienced stillbirth and the health professionals who work with them. Based on the model, women may find it helpful to discuss their beliefs in relation to healing and health professionals to provide support with this in mind. Women and their partners may also benefit from explanations and support about the potentially conflicting emotions they may experience during this time.

Social freezing in Switzerland and worldwide--a blessing for women today?

This is a critical review of the medical, ethical, judicial and financial aspects of the so called "social freezing", the cryopreservation of a woman's oocytes for non-medical purposes. The possibility of storing the eggs of fertile women in order to prevent age-related fertility decline is being widely promoted by fertility centres and the lay press throughout the world. Research data has shown that social freezing should ideally be performed on women around 25 years of age in order to increase their chances of a future pregnancy. In reality, it is mostly performed after the age of 35. Unfortunately, social freezing is in general not a solution for the underlying societal problems to fit in with professionally active women and having children. It only delays the existing problems. Furthermore, it creates a lot of potential new problems. A great deal more should be undertaken to offer real solutions to the underlying societal problems which are in part: pre-school education, care in the event of childhood illness, and the many weeks of school holidays, acceptance of professionally active women having children, and more job offers with a workload <100%.). Furthermore, society should be informed about the decreasing chances of pregnancy with increasing maternal (and paternal) age as well as the increasing risks of miscarriage and obstetric/neonatal complications. Detailed information for woman considering social freezing is crucial. Every doctor, proposing social freezing to his patients, should be up to date with all these details. Follow-up studies on the outcome of these children are needed.