Low dose and short-term therapy of tibolone reduces the cardiovascular disease risk in postmenopausal women

<正>Objective:To investigate the effects of low dose tibolone short-term therapy on clinic, endocrine and markers of cardiovascular disease in healthy postmenopausal women. Methods: A prospective study involved a total of 42 eligible postmenopausal women. 22 cases as group A and 20 cases as group B. Complete baseline work-up including Kupperman score, body mass index (BMI), gonadotropin (FSH, LH) , estrogen (E2), testosterone (T) , sex hormone binding globulin (SHBG), plasminogen activator inhibitor type 1 (PAI-1), tissue plas-minogen activator (tPA), high-sensitivity C-response protein (hs-CRP), nitrogen oxide (NO) and fasting lipid, glucose(FPG) , insulin(FINS) were performed in all subjects. Postmenopausal women in group A were treated with 1. 25 mg tibolone daily. Women in group B were treated with 0. 625 mg tibolone daily. Women both in group A and group B were given calcium 600 mg with vitamin D 125IU per day. At the end of the 12-weeks therapy, subjects were re-evaluated and above parameters were measured. Results: No significant differences between group A and group B were found at baseline. Twenty-eight cases (fourteen cases in each group) completed the study. Kupperman score decreased from (22. 1±8. 0) and (25. 4±7. 5) to (7. 7±4. 5) and (5. 2±4. 5) and plasminogen activator inhibitor type 1 decreased from (95. 8±32. 4)μg/L and (102. 9±42. 6)μg/L to (72. 2±39. 6)μg/L and (79. 9±30. 1)μg/L significantly in group A and group B respectively after treatment. In group A, Blood pressure decreased significantly from (120±10)/(83±6) mmHg to (110±14)/(77±9) mmHg (P<0. 05), testosterone increased significantly from (0. 6±0. 4) nmol/L to (1. 3±1. 1) nmol/L (P<0. 05), free testosterone increased from (0. 001±0. 002) nmol/L to (0. 003±0.003) nmol/L significantly (P<0. 01), SHBG decreased from (7. 6±4. 9) nmol/L to (4. 3±2. 9) nmol/L significantly (P<0. 05) , total cholesterol decreased from (5. 4±0. 8) mmol/L to (5. 0±0. 8) mmol/L significantly (P<0. 01) , ApoA decreased from (1. 8±0. 3) mg/dl to (1. 7±0. 3) mg/dl significantly (P<0. 05) , fasting glucose decreased from (5. 6±0. 8) mmol/L to (3. 9±1. 1) mmol/L significantly (P<0. 01) and no significant differences in BMI, FSH, LH, E2, tPA, hs-CRP, NO, TG, HDL-C, LDL-C, apoB were found after treatment. In group B, there were no significant differences in other parameters found after treatment except Kupperman score and PAI-1. Conclusions: 1. 25 mg/d tibolone short-term therapy was associated with improved fibrinolyt-ic factors and decreased Kupperman score, blood pressure, total cholesterol and fasting blood glucose level. 0. 625 mg/d tibolone therapy resulted in decrease Kupperman score and improvement of fibrinolytic factors. These changes relieve climacteric symptoms and may have some benefits on preventing the development of cardiovascular disease. An increased testosterone and free testosterone levels in 1. 25 mg dose of tibolone therapy may increase energy level, general well-being and sexual desire in postmenopausal women. Low dose tibolone replacement therapy is a convenient effective HRT for postmenopausal women     

Dose–response study of denosumab on bone mineral density and bone turnover markers in Japanese postmenopausal women with osteoporosis

Summary  

The efficacy and safety of denosumab were evaluated in Japanese postmenopausal women with osteoporosis. Total hip and distal 1/3 radius bone mineral densities (BMDs) were increased, and lumbar spine BMD was increased in magnitude with increasing dose. Bone turnover markers significantly decreased compared with placebo. Denosumab was well tolerated in Japanese subjects.     

Is it necessary to screen for celiac disease in postmenopausal osteoporotic women?

Decreased bone mass is a frequent finding in celiac patients, and subclinical celiac disease (CD) appears to be unusually overrepresented among patients with idiopathic osteoporosis. Since silent CD may be more common than previously believed, it has been suggested that all osteoporotic patients should be checked for occult CD. The aim of this study was to explore the prevalence of CD in a well-defined population of postmenopausal osteoporotic women. We evaluated 127 consecutive postmenopausal patients (mean age: 68 years; range: 50-82 years) with verified osteoporosis. The observed prevalence of CD in this group was compared to that observed in a group of 747 women recruited for a population-based study. The screening algorithm used to diagnose CD was based on a 3-level screening using type IgA and IgG antigliadin antibodies (AGA) in all the patients (1st level) followed by antiendomysial antibodies (EmA) and total IgA (2nd level) of samples testing positive, and intestinal biopsy of positive cases (3rd level). At the end of the serological screening, only 1 of 127 osteoporotic women was eligible for jejunal biopsy showing a characteristic celiac flat mucosa (prevalence 7.9 x 1,000; 95% CI 0.2-43.1). In addition, CD was diagnosed in 6 of 747 women of the population-based study (prevalence: 8.0 x 1,000; 95% CI 3.3-18.3). There was no significant difference between the two groups. Therefore, our study showed that the prevalence of CD in postmenopausal osteoporotic women was lower than that reported in previous studies and similar to that of the general population. In conclusion, although the relatively small size of the group tested does not allow us to be conclusive, the results suggest that a case finding policy in postmenopausal osteoporosis would have a high cost/benefit ratio except for patients not responding to conventional therapies, or presenting borderline laboratory results.     

Vitamin A intake and the risk of hip fracture in postmenopausal women: the Iowa Women’s Health Study

Excessive intake of vitamin A is postulated to have a detrimental effect on bone by inducing osteoporosis. This may lead to an increased risk of fracture, particularly in persons who are already at risk of osteoporosis. However, few studies have specifically examined the association of vitamin A intake through diet and supplement use, with fractures in a cohort of older, community-dwelling women. We prospectively followed a cohort of 34,703 postmenopausal women from the Iowa Womens Health Study to determine if high levels of vitamin A and retinol intake through food and supplement use were associated with an increased risk of hip or all fractures. A semiquantitative food frequency questionnaire was used to obtain the participants baseline vitamin A and retinol intake. Participants were followed for a mean duration of 9.5 years for incident self-reported hip and nonhip fractures. After multivariate adjustment, it was revealed that users of supplements containing vitamin A had a 1.18-fold increased risk of incident hip fracture (n=525) compared with nonusers (95% CI, 0.99 to 1.41), but there was no evidence of an increased risk of all fractures (n=6,502) among supplement users. There was also no evidence of a dose-response relationship in hip fracture risk with increasing amounts of vitamin A or retinol from supplements. Furthermore, our results showed no association between vitamin A or retinol intake from food and supplements, or food only, and the risk of hip or all fractures. In conclusion, we found little evidence of an increased risk of hip or all fractures with higher intakes of vitamin A or retinol among a cohort of older, postmenopausal women.     

Association of sleep duration with chronic kidney disease and proteinuria in adults: a systematic review and dose–response meta-analysis

International Urology and Nephrology - Previous studies have found that sleep duration may be associated with chronic kidney disease (CKD) and proteinuria in adults. However, the correlation...     

A double-blind placebo-controlled trial on the effects of 25 mg estradiol implants on the urge syndrome in postmenopausal women

The aim of this prospective double-blind randomized placebo-controlled trial was to determine the effect of systemic estrogen on the 'urge syndrome' in postmenopausal women. The trial took place in a tertiary referral urogynecology unit. Postmenopausal women with the 'urge syndrome' were randomly allocated to receive a 25 mg 17beta-estradiol implant or placebo implant. Serum estradiol levels and endometrial thickness were measured on entry to the trial and at 1, 3 and 6 months. The following outcome measures were employed: videocystourethrography, frequency volume chart, visual analogue score of symptoms, and King's Health Care Quality of life Questionnaire. Forty women were included. Subjectively there was a significant improvement in urgency in both groups and urge incontinence in the estradiol group, but no significant differences between the groups. Objectively no significant differences were demonstrated between the groups. Nine women in the estradiol group had vaginal bleeding, and 5 had a hysterectomy during or after the study. Despite using numerous outcome measures to examine its effect, 25 mg estradiol implants did not produce a greater improvement in the 'urge syndrome' than placebo and had a high complication rate.     

Performance of osteoporosis risk assessment tools in postmenopausal women aged 45–64 years

Osteoporosis risk factor assessment is of uncertain utility in women under 65 years of age. Previous comparative studies of osteoporosis risk assessment tools were not stratified by age. We compared the discriminatory ability of three previously validated osteoporosis risk assessment tools in a referral population of postmenopausal women aged 45–64 years (n=2539) and aged 65–96 years (n=1496) seen at a university-based outpatient osteoporosis center in Belgium. Risk scores for the Osteoporosis Self-assessment Tool, Osteoporosis Risk Assessment Instrument, and Simple Calculated Osteoporosis Risk Estimation were calculated for each patient. The reference standard was osteoporosis at the femoral neck, defined as a T-score –2.5 based on bone mineral density measured by dual energy X-ray absorptiometry. Osteoporosis was present in 139 of 2539 (5.5%) women aged 45–64 years and 241 of 1496 (16.1%) women aged 65 years or older. The tools had similar overall discriminatory ability to identify women with osteoporosis [area under the ROC curve 0.750–0.768, P=0.23 for women aged 45–64 years; area under the ROC curve 0.745–0.762, P=0.06 for women aged 65 years or older (P>0.05 indicates no difference among tools)]. The likelihood ratios for the high-risk score categories ranged from 3.60 to 6.73 for the younger women and 3.45 to 6.99 for the older women when different score thresholds were set to maximize the performance of each tool in each age group. We conclude that the diagnostic accuracy of three osteoporosis risk assessment tools was similar in postmenopausal women aged 45–64 years and women aged 65 years or older. Use of structured risk assessment tools to identify women at high risk of osteoporosis in the early postmenopausal period warrants further study. Of the three tools evaluated, the OST is the simplest and has the best potential for use in clinical practice.     

Does Alendronate reduce the risk of fracture in men? A meta-analysis incorporating prior knowledge of anti-fracture efficacy in women

Background  

Alendronate has been found to reduce the risk of fractures in postmenopausal women as demonstrated in multiple randomized controlled trials enrolling thousands of women. Yet there is a paucity of such randomized controlled trials in osteoporotic men. Our objective was to systematically review the anti-fracture efficacy of alendronate in men with low bone mass or with a history of prevalent fracture(s) and incorporate prior knowledge of alendronate efficacy in women in the analysis.     

A meta-analysis of the effect of strontium ranelate on the risk of vertebral and non-vertebral fracture in postmenopausal osteoporosis and the interaction with FRAX?

Summary  

The aim of the present study was to determine the efficacy of strontium ranelate as a function of baseline fracture risk. Treatment with strontium ranelate was associated with a significant 31% decrease in all clinical osteoporotic fractures (vertebral fractures included). Hazard ratios for the effect of strontium ranelate on the fracture outcome did not change significantly with increasing fracture probability.     

Improved adherence with PTH(1–84) in an extension trial for 24 months results in enhanced BMD gains in the treatment of postmenopausal women with osteoporosis

Summary

The purpose of this study is to examine the effect of PTH(1–84) treatment over 24 months followed by 12 months discontinuation on BMD, bone turnover markers, fractures and the impact of adherence on efficacy.

Introduction

There is limited information about the effect of PTH(1-84) after 18 months and limited data about the impact of compliance on response to anabolic therapy.

Methods

Seven hundred and eighty-one subjects who received active PTH(1–84) in the Treatment of Osteoporosis with Parathyroid hormone trial for approximately 18 months were entered into a 6-month open-label extension. Thereafter, they were followed for 12 additional months after discontinuation of treatment. Endpoints examined included changes in BMD and biochemical markers.

Results

PTH(1–84) treatment over 24 months increased BMD at the lumbar spine by 6.8 % above baseline (p?<?0.05).The total corresponding BMD increases at the hip and femoral neck were 1.1 and 2.2 % above baseline. Larger increases in spine BMD were observed in participants with ≥80 % adherence to daily injections of PTH(1–84) (8.3 % in adherent vs 4.9 % in poorly adherent patients). Total hip BMD gains were 1.7 % in adherent vs 0.6 % in poorly adherent participants. Markers of bone turnover (BSAP and NTx) peaked 6 months after starting PTH(1–84) treatment and declined slowly but remained above baseline at 24 months. After discontinuation of PTH(1–84) treatment (at 24 months), bone turnover markers returned to near baseline levels by 30 months. The adherent group sustained significantly fewer fractures than the poorly adherent group.

Conclusions

PTH(1–84) treatment over 24 months results in continued increases in lumbar spine BMD. Adherence to treatment with PTH(1–84) for up to 24 months is also associated with greater efficacy.     

Prevalence of renal impairment among osteoporotic women in the USA,NHANES 2005–2008: Is treatment with bisphosphonates an option?

Summary

Bisphosphonates are the first-line treatment for osteoporotic (OP) women; however, therapy is not recommended in severe renal impairment (RI). This study examined RI prevalence among OP women. Nearly a quarter of women had moderate RI, and 3.59 % would not be recommended for bisphosphonates, demonstrating a need for better therapeutic alternatives.

Introduction

Bisphosphonates are the recommended first-line treatment for postmenopausal women with OP. However, bisphosphonates are cleared through the kidney, and therapy is not recommended in severe RI due to adverse treatment effects observed with intravenous formulations. The objective of this study was to examine the prevalence of RI among women with OP aged ≥50 years in the USA.

Methods

Women with OP aged ≥50 years were identified using the 2005–2008 National Health and Nutrition Examination Survey (NHANES) data. OP was defined as prior OP diagnosis, previous hip or spine fracture, or measured lumbar spine/femoral neck bone mineral density (BMD) T-score <?2.5. The 2005 Modification of Diet in Renal Disease (MDRD) formula was used to calculate the glomerular filtration rate (GFR). Moderate and severe RI was defined as GFR 30–59 and 15–29 mL/min, respectively. Bisphosphonate therapy was considered not recommended among women with OP if GFR was <35 mL/min.

Results

The prevalence of OP among women in USA aged ≥50 years was 27 % (12.7 million). Nearly a quarter of women with OP (23.54?±?2.02 %; 2.9 million) had moderate RI and 1.88?±?0.28 % (230,000) had severe RI. Correspondingly, bisphosphonate therapy would not be recommended for an estimated 439,000 women with OP (3.59?±?0.73 %).

Conclusions

Nearly a quarter of postmenopausal women with OP have moderate RI, and over 3 % would not be recommended for bisphosphonate treatment. These data reveal a need for better therapeutic alternatives that can be used in this patient population.     

Reduced colon cancer incidence and mortality in postmenopausal women treated with an oral bisphosphonate—Danish National Register Based Cohort Study

Summary

In this Danish national register-based cohort study, we examined the effects of alendronate on the development of colon cancers and survival. The incidence of colon cancer and mortality rate, once colon cancer had been diagnosed, were lower in patients treated with alendronate, posing the question whether alendronate acts as chemopreventive.

Introduction

When bisphosphonates are given by mouth, around 99% remains non-absorbed in the intestine. Based on their biochemical actions, we predicted that oral bisphosphonates might prevent colon cancers.

Methods

This is a Danish national register-based cohort study. We identified 30,606 women aged 50+, mean age 71.9?years, who had not previously taken treatments for osteoporosis, who began to take alendronate in 1996–2005, and assigned 124,424 individually age- and gender-matched control subjects. The main outcome measure was colorectal cancers incidence and post-diagnosis survival in patients taking oral alendronate for osteoporosis.

Results

Cox proportional hazards analysis of death due to colon cancer showed lower risk in alendronate users, crude hazard ratio (HR) 0.69 (95% CI 0.59–0.81) with an adjusted HR of 0.62 (95% CI 0.52–0.72). The reduction in risk comprised both a lower incidence of colon cancer-adjusted HR 0.69 (95% CI 0.60–0.79) and a lower mortality once colon cancer had been diagnosed, adjusted HR 0.82 (95% CI 0.70–0.97). Weekly alendronate was associated with a greater risk reduction than daily alendronate. The main findings were unaffected by excluding patients from the analysis who had pulmonary disease, a major co-morbid condition in users of alendronate and an important cause of death.

Conclusions

The risk of overall deaths from cancer and in particular death caused by colon cancer was significantly and substantially decreased (40%) in patients treated with alendronate, with survival curves deviating progressively after 2?years. Also, the incidence of colon cancer was lower in those patients.     

Above- or below-elbow casts for distal third forearm fractures in children? A meta-analysis of the literature

Introduction  

Fractures of the distal third forearm are common fractures in childhood. Most of these fractures can be treated non-operatively by means of closed reduction and immobilization. The purpose of this meta-analysis is to investigate whether above- or below-elbow cast should be considered the first-choice for conservative treatment.     

The dose–response effect of insulin sensitivity on albuminuria in children according to diabetes type

Background

Insulin resistance is associated with microalbuminuria among youth with diabetes mellitus. We sought to determine the dose–response effect of insulin sensitivity (IS) on the magnitude of albuminuria and whether there is a threshold below which urine albumin excretion increases.

Methods

These analyses included participants from the SEARCH for Diabetes in Youth Study with incident diabetes who completed a baseline study visit (n?=?2988). We estimated IS using a validated equation incorporating waist circumference, HbA1C, and fasting serum triglycerides. Multivariate regression analyses were performed to assess the effect of IS on urine albumin creatinine ratio (UACR), stratified by diabetes type. The IS threshold was then determined using segmented regressions within each diabetes type and incorporated into the multivariate model.

Results

There was an association between IS and UACR in type 2 diabetes only (beta?=??0.39; p?<?0.001). There was strong statistical evidence for a threshold effect of IS score on UACR in the group of youth with type 2 (beta?=?0.40; p?<?0.001) but not type 1 diabetes (p?=?0.3).

Conclusions

In cross-sectional analyses, there is a negative association between IS and UACR in youth with type 2 but not type 1 diabetes, and this association likely includes a threshold effect of IS on UACR.