Effects of ultra-low-dose estrogen therapy on muscle and physical function in older women

OBJECTIVES: To determine the effects of ultra-low-dose hormone therapy on muscle mass and physical function in community-dwelling women. DESIGN: Double-blind, placebo-controlled trial. SETTING: Clinical research center in Connecticut. PARTICIPANTS: Healthy, community-dwelling women aged 65 and older (n=167). INTERVENTION: Eligible women were randomly assigned to treatment with 0.25 mg 17-beta estradiol or placebo for 36 months. All women (estradiol or placebo) with an intact uterus received micronized progesterone 100 mg/d for 2 weeks every 6 months. All participants received 1,300 mg elemental calcium with 1,000 IU vitamin D per day. MEASUREMENTS: Appendicular skeletal muscle mass (ASM), lean body mass (LBM), and percentage body fat were measured using dual x-ray absorptiometry. Sarcopenia was defined as skeletal muscle mass (ASM/height2) 2 standard deviations or less than young, healthy reference population mean. Physical activity (Physical Activity Scale in the Elderly (PASE)) and performance were measured. Serum estrone, estradiol, and sex hormone-binding globulin were measured. RESULTS: The prevalence of sarcopenia at baseline was 13%. There were no baseline differences between groups except for PASE score and chair rise time, in which the estrogen group had better performance. No changes in ASM, LBM, percentage of body fat, or physical performance were found after 3 years of estrogen therapy. CONCLUSION: Sarcopenia was present in 13% of this group of community-dwelling, postmenopausal older women. Ultra-low-dose estrogen therapy neither improves nor harms ASM. Similarly, no changes in body fat or physical performance were detected.     

Osteoporosis. Pathogenesis, diagnosis, and treatment in older adults

Osteoporosis is a major cause of disability and excess mortality in older men and women. Hip fracture incidence accelerates approximately 10 years after menopause in women and after age 70 in men. Approximately 1 million Americans suffer fragility fractures each year at a cost of over 14 billion dollars. The disability, mortality, and cost of hip and vertebral fractures are substantial in the rapidly growing, aging population so that prevention of osteoporosis is a major public health concern. BMD is used to make the diagnosis of osteoporosis before incident fracture and predict fracture risk. Recommendations for treatment and prevention of osteoporosis based on BMD score have been published by the World Health Organization and the National Osteoporosis Foundation. In a process that continues throughout life, bone repairs itself by the coupled action of bone resorption followed by bone formation, sometimes referred to as bone turnover. Osteoblasts and osteoclasts are the primary cells involved in bone formation and resorption, respectively. The process of bone turnover is regulated by hormones, such as PIH and local factors such as IL-1 and prostaglandins. Following attainment of peak bone mass at age 25, bone loss begins, accelerates in women at menopause and slows again but continues into advanced years at a rate of 1% to 2% per year, similar to premenopausal bone loss rate. The leading theories of the mechanism of bone loss in older individuals is calcium deficiency leading to secondary hyperparathyroidism and sex hormone deficiency. Risk factors such as age, gender, ethnic background, smoking, exercise, and nutrition, and medical conditions associated with osteoporosis should be evaluated and modified when possible to prevent further bone loss. Osteoporosis treatment and prevention include weight-bearing exercise, calcium and vitamin D supplementation, estrogen replacement, bisphosphonates, selective estrogen receptor antagonists, and calcitonin. Although there is no currently approved treatment for osteoporosis in men, many of the treatments approved for osteoporosis in women hold promise to be beneficial in men.     

The effect of raloxifene on markers of bone turnover in older women living in long-term care facilities

OBJECTIVES: To examine the effect of raloxifene on bone turnover in elderly women. DESIGN: Clinical intervention. SETTING: Long-term care facilities. PARTICIPANTS: Nineteen women completed the study, mean age 85 (range 76-99). INTERVENTION: Raloxifene 60 mg was given daily for 12 weeks. MEASUREMENTS: Markers of bone turnover were plasma C-telopeptides of type I collagen (CTx), urine cross-linked N-telopeptides of type I collagen (NTx) and serum tartrate-resistant acid phosphatase (TRAP 5b), plasma osteocalcin, and serum bone alkaline phosphatase. Other markers were serum 25-OH vitamin D, parathyroid hormone, ionized calcium, and phosphate. Markers were measured at baseline, after calcium and vitamin D had been taken for 6 weeks, after raloxifene had been taken for 12 weeks, and 6 weeks after raloxifene had been stopped. Paired sample t test was used to examine changes in markers at each time point. RESULTS: Plasma CTx decreased on average by 31%, urinary NTx by 35%, plasma osteocalcin by 25%, serum bone alkaline phosphatase by 15% (P<.01), and serum TRAP 5b by 10% (P<.05) on treatment. CONCLUSION: Raloxifene reduces bone turnover in elderly women living in long-term care facilities. The effect of raloxifene on bone turnover is comparable with that seen in younger postmenopausal women.     

Estrogen replacement raises rat CRP without evidence of complement activation

Given current controversies regarding anti- and pro-inflammatory effects of estrogen, there is a need to explore relationships between gonadal hormones and inflammation using appropriate animal models. It has been proposed that rats are not appropriate for such research since, contrary to the effect of estrogen in humans, earlier animal studies had reported that estrogen downregulates serum C-reactive protein (rCRP) levels in the rat. With these considerations in mind, we re-examined the effects of estrogen withdrawal and replacement on CRP expression and complement activation in the rat. F-344 rats underwent bilateral ovariectomy or sham surgery at 9-10 months of age. Four months later, ovariectomized rats were treated with traditional high-dose 17beta-estradiol (Hi-E2) capsules, lower-dose (Lo-E2) 17beta-estradiol capsules, or placebo capsules for 7 days prior to sacrifice. Levels of plasma rat C-reactive protein (rCRP) were significantly lower in ovariectomized vs. sham-operated animals (415.5 +/- 10.6 vs. 626.6 +/- 23.0 mg/L, p < 0.001). Estrogen replacement significantly raised rCRP levels in ovariectomized animals (690.0 +/- 28.0 mg/L in Lo-E2 and 735.5 +/- 35.8 mg/L in Hi-E2, respectively, p < 0.001). Plasma rCRP levels correlated significantly with both hepatic rCRP (r = 0.79, p < 0.001) and serum estradiol (r = 0.70, p < 0.001) levels. However, no significant differences were observed in indices of complement activation (C4b/c) or CRP-complement complex generation (rCRP-C3 complex). In the mature female rat, ovariectomy reduces and estrogen replacement raises rCRP. Effects of estrogen on plasma rCRP induction are mediated, at least in part, through hepatic mechanisms and do not appear to require or be associated with complement activation.     

Strategies for enrolling diverse older women in an osteoporosis trial

OBJECTIVES: This study reviewed a consumer-oriented process for recruiting research volunteers age 65 or older for an osteoporosis clinical trial. METHODS: Odds ratios were used to estimate the relative importance of methods to enroll research volunteers from three racial or ethnic groups. RESULTS: Nine hundred and four women were screened; 168 African American, White, and Hispanic women enrolled. Mailings and media were effective when the target population was large and knowledgeable about the disease and treatment being investigated. Efficiency of mailings was increased when individuals in the mailing list were familiar with research and the research center. An interpersonal approach was more effective than a media-based approach when the target population was small, unaware of their personal risk of the disease, and unfamiliar with research and research center. DISCUSSION: Information on the characteristics of potential volunteers and their communities will enable readers to evaluate the applicability of recruitment methods used.     

The effect of 3-year treatment with 0.25 mg/day of micronized 17beta-estradiol on cognitive function in older postmenopausal women

OBJECTIVES: To evaluate the effect of ultra-low-dose (0.25 mg/d) micronized 17beta-estradiol on cognitive function in older postmenopausal women. DESIGN: Randomized, placebo-controlled trial conducted for 3 years. SETTING: Academic health center in greater Hartford, Connecticut. PARTICIPANTS: Fifty-seven healthy, community-dwelling, older postmenopausal women. INTERVENTION: Women received 0.25 mg/d of micronized 17beta-estradiol (estrogen therapy (ET), n=32) or placebo (n=25); all women who had not had a hysterectomy received 100 mg/d of oral micronized progesterone for 2-week periods every 6 months. MEASUREMENTS: Neuropsychological measures of memory, language, mood, and executive function were collected at baseline, 3 months, and 36 months. Measures of executive function included the Controlled Oral Word Association Test, the Trail Making Test, and the Wisconsin Card Sorting Test. The Boston Naming Test was used to measure language skills. The Symbol Digit Modalities Test was used as a measure of sustained attention. Measures of memory included the Complex Figure Test, Fuld Object Memory Test, and a selected subtest from the Wechsler Memory Scale. Scores from the Geriatric Depression Scale and the Beck Anxiety Inventory were used to assess symptoms of depression. RESULTS: No differences were found between ET and placebo on any of the neurocognitive measures or depression instruments, nor were there any differences when the groups were stratified according to age. CONCLUSION: This small study, which had adequate power to detect change in some but not all domains of cognition tested, revealed that low-dose estrogen neither benefits nor harms cognitive function in older women after 3 years of treatment, but confirmation is needed from larger trials.     

The Application of ‘Elite Interviewing’ Methodology in Transdisciplinary Research: a Record of Process and Lessons Learned during a 3-Year Pilot in Urban Planetary Health Research

This paper sets out the rationale and process for the interviewing methodology utilized during a 3-year research pilot, ‘Moving Health Upstream in Urban Development’ (UPSTREAM). The project had two primary aims: firstly, to attempt to value economically the health cost benefits associated with the quality of urban environments and secondly, to engage with those in control of urban development in the UK in order to determine what are the barriers to and opportunities for creating healthy urban environments, including those identified through the utilisation of economic valuation. Engagement at senior level with those who have most control over key facets of planning and development implementation—such as land disposal, investment, development delivery and planning permission—was central to the approach, which encompassed the adoption of ‘elite interviewing’, a method developed in the USA in the 1950s and used in the political sciences but relatively unutilized in the health and environmental sciences [¹]. Two rounds of semi-structured interviews were undertaken with 15 senior decision-makers from the UK’s main urban development delivery agencies, both public and private. The ‘elite interviewing’ approach successfully enabled the UPSTREAM project to capture and analyse the information received from the interviewees, all of whom held influential or leadership posts in organisations that are important actors in the process of planning, developing and constructing the built environment in the UK. Having academic and practitioner research leads on an equal footing created some minor tensions, but it also appeared to strengthen the rigor of the approach through a broad knowledge of context ‘in-house’. This form of co-production at times challenged academic traditions in qualitative analysis, but it also appeared to build trust with interviewees and provided greater clarity of the real-world context under investigation. Findings from this study are written up in a separate paper.