Prevention of osteoporosis: one step forward, two steps back

For many years, hormone replacement therapy (HRT) was the mainstay for osteoporosis prevention in postmenopausal women until a large randomized clinical trial raised serious safety concerns. This resulted in a big drop in HRT use and its demotion by regulatory authorities to second-line treatment. Many clinicians now feel that HRT is not safe to use, and recommend various alternatives for the treatment of osteoporosis. But how effective are these alternative therapies, are they any safer than HRT, and how do their costs compare? This review questions the validity of the safety concerns about HRT, and highlights the safety concerns about alternative therapies. It concludes that HRT is as safe as the other treatment options, and its efficacy and low cost demand that it be restored as a first-line treatment for the prevention of postmenopausal osteoporosis. Other therapies are available for use in osteoporosis, and the bisphosphonates are particularly effective for the treatment of the established disease. However, they must be used selectively and with caution, and are best restricted to those patients who are elderly or have severe disease. New treatments are emerging, but again caution must be taken until any long-term adverse effects have been identified.     

National Osteoporosis Society's Position statement on hormone replacement therapy in the prevention and treatment of osteoporosis

Hormone replacement therapy (HRT) has been shown to increase bone density, reduce the risk of fracture and can successfully relieve menopausal symptoms. From a time when HRT was the major therapeutic option for the management of osteoporosis, women and their clinicians now have a range of treatments available. Following the publication of the Women's Health Initiative (WHI) and the Million Women Study highlighting potential side-effects, such as breast cancer, heart disease and stroke, many doctors and women are now reluctant to use HRT. The National Osteoporosis Society felt that the role of HRT in the management of osteoporosis needed to be clarified. Using the Charity's expert clinical and scientific advisers, and through public consultation with members and key stakeholders, a Position Statement has been published. We conclude that HRT has a role to play in the management of osteoporosis in postmenopausal women below the age of 60 years. The key recommendations of the Position Statement are presented in this paper.     

Thyroid dysfunction in perimenopausal and postmenopausal women

Thyroid dysfunction is common, especially among women over the age of 50. In caring for peri- and post-menopausal women, it is important to recognize the changing clinical manifestations of thyroid disease with age. Postmenopausal women are at increased risk of both osteoporosis and cardiovascular disease, and untreated thyroid disease may exacerbate these risks. Screening for thyroid dysfunction in asymptomatic individuals is controversial, but aggressive case-finding should be pursued, especially in older women. Women with overt thyroid dysfunction should be treated. Therapy for women with subclinical thyroid dysfunction is more controversial, although women with levels of thyroid stimulating hormone (TSH) > or =10 mU/L should be treated, and treatment may be considered in symptomatic women with subclinical hypothyroidism and TSH values <10 mU/L, and in women with subclinical hyperthyroidism who have TSH values consistently <0.1 mU/L. In women who are treated with thyroxine, careful dose titration and monitoring are required in order to prevent the adverse consequences of iatrogenic subclinical hyperthyroidism or hypothyroidism. Finally, caution is required in diagnosing and treating thyroid dysfunction in women who are taking oral estrogens or selective estrogen receptor modulators.     

Harnessing hormonal signaling for cardioprotection

Cardiovascular disease is the leading cause of death in women in the Western world and is predominant among the elderly. A large body of evidence suggests that hormonal signaling plays a critical role in the regulation of cardioprotective mechanisms, as premenopausal women are at significantly lower risk of heart disease compared with men, but the risk greatly increases with the onset of menopause. This association indicates that estrogen may protect the heart from cardiovascular disease. Whereas a number of analyses of the effects of hormone replacement therapy (HRT) on postmenopausal women supported the idea that estrogen is a cardioprotective factor, the findings of the more recent Women's Health Initiative (WHI) study suggested that HRT may actually increase the risk of cardiovascular events. These conflicting reports have left both patients and clinicians reluctant to continue using current HRT regimes. The WHI findings do not, however, negate the epidemiological link between menopause and increased cardiovascular risk. Hence, the identification of the specific actions of estrogen that promote cardioprotective pathways without enhancing deleterious vascular mechanisms may provide novel estrogen-based alternatives to current HRT strategies. In this Review, we outline the known actions of estrogen on the cardiovascular system, focusing on cardioprotective mechanisms that may be targeted for the development of new therapeutic approaches.     

Homocysteine, menopause and cardiovascular disease

A high plasma concentration of total homocysteine (tHcy) and a deficiency of vitamins related to its metabolism, such as vitamin B12 and folate, have been associated with cardiovascular disease. Postmenopausal women have higher concentrations than age-matched premenopausal women, and plasma concentrations of homocysteine in postmenopausal women taking hormone replacement therapy are significantly lower than they are in those who do not take estrogen supplements. Because of the possible mixed effects of HRT on cardiovascular events, surrogate end-points must be evaluated with caution. While measuring homocysteine levels is relatively simple, evidence from well designed trials is awaited before population screening can be advocated. Also, the benefits of reducing homocysteine levels with folic acid and vitamin B6 and B12 supplements are highly debated.     

Dehydroepiandrosterone (DHEA) and the menopause: an update

Since we last reviewed this topic in 2001, considerably more information about dehydroepiandrosterone (DHEA) has accrued, but this has not necessarily left us any wiser about the use of this steroid in postmenopausal women. There is no further evidence that DHEA supplementation is likely to be useful in the prevention of cardiovascular disease or cognitive impairment, or in the promotion of wellbeing. Evidence has, however, accumulated for beneficial effects of DHEA on osteoporosis, both in postmenopausal women and in patients receiving long-term glucocorticoid therapy. What is also emerging is a link between low DHEA levels and cardiovascular risk, and between high DHEA levels and breast cancer risk. In fact, the benefits and adverse effects of DHEA administration in postmenopausal women increasingly resemble those of conventional hormone replacement therapy. Overall, we conclude that DHEA is not currently to be recommended for therapeutic use in the majority of postmenopausal women. However, DHEA supplementation may be of benefit in two specific groups of women: those with the lowest circulating levels of DHEA; and those for whom osteoporosis is a particular problem.     

Enhanced rate of resting energy expenditure in women using hormone-replacement therapy: preliminary results

Hormone-replacement therapy (HRT) attenuates the menopause-associated alterations in body composition. It is not known, however, whether this effect is a result of a concomitant increase in energy expenditure. The authors examined whether women submitted to a long-term HRT treatment presented greater energy expenditure than women who had never used HRT. We compared 13 postmenopausal women using HRT (>1 yr) with 13 age- (+/-2 yr) and body-mass-index-matched (BMI; +/-1.5 kg/m2) postmenopausal women not using HRT. Resting energy expenditure (REE; indirect calorimetry), body composition, and daily (DEE) and physical activity (PAEE) energy expenditure (accelerometry) were obtained. Although BMI, fat mass, fat-free mass, DEE, and PAEE were similar between groups, the HRT group displayed a significantly greater REE than the no-HRT group (Delta +222 kcal/day). In conclusion, the authors observed that a long-term treatment with HRT is associated with a greater REE in postmenopausal women. These results need to be confirmed.     

Relationships between person and health factors and job characteristics in women with systemic lupus erythematosus

This study compared personal and health factors and job characteristics in persons with Systemic Lupus Erythematosus (SLE) and a healthy control group and examined factors related to job characteristics. Fifteen women with SLE and 15 healthy controls completed a questionnaire regarding current employment, employer restrictions, job environment, type of work, and health factors interfering with work. Personal factors such as demographic information, disease severity, cognition, and degree of brain injury were also assessed. t-tests showed that persons with SLE worked significantly less than healthy controls but there were no significant differences between the groups for types of job or employee restrictions. In the group with SLE, health factors of mobility, dependence, musculoskeletal problems, neurological problems, and fatigue correlated with perceived social (r=0.53 to 0.67) and physical (r=0.56 to 0.87) work environments. None of the measures of cognition, brain injury or disease severity correlated with job characteristics. In the healthy controls, dependence at work correlated with physical environment and fatigue correlated with the social environment of the workplace. The results indicate that even persons with SLE who have mild disease are significantly different from healthy controls and might be at risk for discontinuing working.     

Commentary: Male Osteoporosis—Policy Gaps in Prevention and Treatment

Osteoporosis is a disabling disease affecting 10 million Americans, leading to increased risk of fractures and poor functional ability. Although typically thought of as a women's disease, millions of men are diagnosed with osteoporosis or low bone mass, and the risk for osteoporotic fractures is increasing. To address undetected and untreated osteoporosis among men, public health education should be targeted to males. Insurance programs, including Medicare, should add the heel qualitative ultrasound (QUS) for age-eligible men with follow-up every 2 years. Policy changes should address funding of targeted education and prevention programs for aging males, including coverage of screening tests.     

Medical Treatment of Women with Lupus. The case for sharing knowledge and decision-making

Few women patients in this study were found to be active partners in the medical management of systemic lupus erythematosus (SLE). Despite the growing emphasis on doctors and patients sharing knowledge and decision-making power, most of the women were struggling to have their symptoms and needs taken seriously, and appeared relatively powerless in relation to the medical profession. Acknowledging patient expertise requires that doctors share some of their power, and we suggest this may be especially problematic when medical resources and power are primarily located in the hands of white men, and when the patients are typically women and often from the black community. Implications for action that are considered include maximising the influence of women with SLE on research, training and practice.     

Compounded or confused? Bioidentical hormones and menopausal health

The aim of this article is to focus on compounded bioidentical hormone (BH) formulations for menopausal symptoms and to discuss the impact of these on women's choice of treatment. The practice of compounding BHs for individualized treatment of women with menopausal symptoms has developed in the USA. In spite of claims of superiority, there is no evidence to suggest that these formulations are any more efficacious or safe than conventional hormone replacement therapy (HRT). In fact, there are some concerns about dosing inconsistencies and usefulness of saliva testing that is carried out as part of this type of treatment. While there should be no serious safety issues for women, there is a mismatch between the reality of compounded BH formulations and women's perception of them.     

Improving quality of life after breast cancer: prevention of other diseases

Many women with breast cancer will be diagnosed at an early stage through screening programmes. Furthermore, most women affected by breast cancer will not die from it but from other diseases, owing to recent improvements in treatment. This article assesses whether breast cancer survivors suffer more frequently from other diseases. Specifically, it examines whether they have a higher incidence of other cancers, cardiovascular events and osteoporotic fractures. Women with breast cancer and three or more co-morbid conditions have a 20-fold higher rate of mortality from causes other than breast cancer and a 4-fold higher rate of all-cause mortality when compared with patients who have none. Breast cancer survivors are at increased risk of other cancers, such as stomach, colorectal and lung. Radiotherapy, trastuzumab and aromatase inhibitors increase the risk of cardiovascular disease. However, tamoxifen does not, although it is associated with an increased risk of venous thromboembolism. Aromatase inhibitors, but not tamoxifen, increase the risk of osteoporotoic fracture and bisphosphonate therapy should be considered.     

Grape flavonoids and menopausal health

Grape flavonoids are members of a larger group of plant compounds called polyphenols. Epidemiological evidence relating to the traditional Mediterranean diet, which is high in polyphenols, derived from vegetables and red wine, suggests that dietary polyphenols are of benefit to health and reduce the incidence of cardiovascular disease. Overall, the evidence is promising for the benefit of grape flavonoids in the form of red wine, red grape juice and related preparations for cardiovascular risk factors. There are data to suggest a reduction in platelet activation, inflammation and low-density lipoprotein oxidation, and improvement of endothelial function with grape flavonoids. The evidence for grape flavonoids and renal function, cognition and cancer is less clear. However, it is important to note that much of this research has been carried out in animal and cell models; relatively little work has been done in humans and specifically on the health of menopausal women. There are no general safety concerns with ingestion of grape products. Obviously, consumption of red wine should be within recommended limits and it should be noted that grape juice has high sugar content. Grape flavonoids are also available as a supplement. In conclusion, it is likely that grape flavonoids do benefit the menopausal women. Further research is needed on the mode and dosage of application to maximize these benefits.     

Insulin resistance and management of the menopause: a clinical hypothesis in practice

Insulin resistance (IR) is associated with a number of metabolic abnormalities including glucose intolerance, dyslipidemia and central obesity (the metabolic syndrome), which predispose to cardiovascular disease, diabetes mellitus and some cancers. The incidence of many of these conditions increases after the menopause, a time when IR also increases. Medical intervention to help alleviate menopausal symptoms, frequently vasomotor in origin, usually involves hormone replacement therapy (HRT), but some women may only experience partial symptom relief. We have hypothesized that this may be due to concurrent IR. Our approach is therefore to manage menopausal symptoms in conjunction with the treatment of any concurrent IR, achieved through a combination of hormone replacement, dietary intervention and, if necessary, an insulin sensitizer. We suggest that this approach may not only improve symptom relief but may also reduce the risk of developing more serious health complaints in the future.     

Gender differences in cardiovascular disease prevention

Risk factors are generally shared between men and women with the major differences being hormonal. Nine modifiable risk factors account for over 90% of the risk of a coronary event in men and women--smoking, hypertension, hyperlipidaemia, diabetes, abdominal obesity, lack of exercise, alcohol excess, reduced intake of fruit and vegetables, and psychosocial issues. Approximately half the decline in deaths from coronary heart disease (CHD), between 1980 and 2000, can be attributed to a reduction in the major risk factors and the other half to the use of evidence-based management. As educational efforts to increase awareness of cardiovascular disease (not cancer) to be the leading cause of death and disability in women are also associated with preventative action, it is important that health-care professionals educate themselves about CHD in women and communicate with women themselves, so that women can come forward for advice and evaluation.     

Osteoporosis in the aging population: the male perspective

The importance of senile osteoporosis in men as a public health problem has long been underestimated. Elderly men are at substantial risk for fracture, and morbidity after osteoporotic fractures appears to be more serious and mortality more common in men than in women. Risk factors for osteoporotic fractures in men appear to be qualitatively similar to those in women, but there are quantitative differences. Low bone mineral density (BMD) is an important risk factor for fracture in men; however, further clarification of the relationship between BMD, bone geometry and fracture risk is needed before formulating definitive proposals on operational densitometric criteria for diagnosis of osteoporosis in men and the identification of men at high risk for fracture. Understanding of the mechanisms underlying senile bone loss and the pathogenesis of senile osteoporosis in men remains fragmentary with, in particular, the need for further clarification regarding the precise impact of hormonal status in elderly men on skeletal homeostasis. Recommendations on prevention and treatment of senile osteoporosis in men should focus on the minimization of known risk factors for bone loss and falls. Testosterone treatment may be useful in those men with initially low serum testosterone. As to other pharmacological treatment modalities, prospective trials specifically in elderly men, and preferably with fracture incidence as the primary clinical endpoint, are required.     

Bazedoxifene: a new selective estrogen receptor modulator for postmenopausal osteoporosis

An ongoing need for safe and effective pharmacological therapies exists for postmenopausal osteoporosis, which imposes a significant burden on both women and the health-care system. Bazedoxifene is a novel selective estrogen receptor modulator with a unique tissue-selectivity profile. In phase 3 clinical trials of nearly 10,000 postmenopausal women, bazedoxifene was shown to significantly reduce the risk of new vertebral fracture versus placebo, with favourable effects on bone mineral density, bone turnover markers and the lipid profile. Moreover, in a subgroup of women at increased risk of fracture, bazedoxifene significantly decreased non-vertebral fracture risk versus both placebo and raloxifene. Bazedoxifene has been shown to be safe and well tolerated, with no evidence of endometrial or breast stimulation. These data suggest that bazedoxifene may offer significant clinical benefit for postmenopausal women with or at risk of developing osteoporosis, which may subsequently lessen the medical and economic burden of this disease.     

Physical activity and hormone-replacement therapy: interactive effects on cognition?

The purpose of this study was to examine the interactive effects of hormone-replacement therapy (HRT) and physical activity (PA) on the cognitive performance of older women. Postmenopausal women (n = 101) were recruited to complete a PA questionnaire, provide demographic information, and perform the digit-symbol substitution task (DSST) and the trail-making tests (TMT). Regression analyses were conducted for participants with complete data for each cognitive test (DSST n = 62; TMT n = 69). For both tasks, results indicated that PA and education were positively related and age was negatively related to cognitive performance. The interaction of HRT with PA did not add to the predicted variance of either measure of cognitive performance. This was true even after limiting the HRT users to women using unopposed estrogen. It is concluded that the beneficial relationship between PA and these two measures of cognitive performance in postmenopausal women exists irrespective of HRT use.     

Primary prevention of coronary heart disease in women

The British Menopause Society Council is committed to provide up-to-date authoritative reviews to aid health professionals to inform and advise women about key issues in postreproductive health. Coronary heart disease (CHD) is a leading cause of death in women. Observational studies have consistently shown estrogen to help prevent CHD in postmenopausal women. The large randomized controlled Women's Health Initiative (WHI) trial did not confirm these observational findings. However, further analyses of the WHI study as well as the observational Nurses' Health Study have now found that the timing of onset of hormone replacement therapy (HRT) use is important and that estrogen may have a protective role in CHD in women aged 50-59 years. This consensus statement will examine the evidence regarding HRT and non-estrogen therapies (lipid lowering agents, aspirin, antihypertensives, antidiabetic medications, selective estrogen receptor modulators [SERMs]) as well as diet, lifestyle and smoking cessation in the primary prevention of CHD in women.