Role of bisphosphonates in the management of postmenopausal osteoporosis: an update on recent safety anxieties

Following their introduction in the 1990s, bisphosphonates have become the mainstay of treatment in the management of postmenopausal osteoporosis, and their use continues to rise. Commonly noted adverse effects in clinical practice include gastrointestinal side-effects, acute phase reactions (predominately seen with intravenous preparations) cutaneous reactions and more rarely, ocular side-effects. However, recent reports of potentially serious adverse effects of bisphosphonate therapy, including atypical subtrochanteric and femoral shaft fractures, atrial fibrillation, oesophageal carcinoma and osteonecrosis of the jaw, have prompted concerns regarding the long-term safety of this class of drugs. This review summarizes the benefits and potential adverse effects of bisphosphonates used in the treatment of postmenopausal osteoporosis. Although evidence of a definitive casual relationship between bisphosphonate therapy and serious adverse effects is lacking, concern remains particularly in relation to atypical subtrochanteric and femoral shaft fractures. This has important consequences in terms of determining optimum duration of therapy and how best to target therapy at those most at risk. Recently, attention has focused on individual fracture risk assessment in order to optimize the risk-benefit ratio of treatment for individual patients. A review of the role of hormone replacement therapy in younger women with significant risk of osteoporotic fractures may be timely in these circumstances.     

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.     

Systemic lupus erythematosus and hormone replacement therapy

The indications for hormone replacement therapy (HRT) in postmenopausal women is the treatment of climacteric symptoms and the prevention of osteoporosis. Women with systemic lupus erythematosus (SLE) are more likely to have a premature menopause, osteoporosis and cardiovascular disease. HRT can induce SLE flares and cardiovascular or venous thromboembolic events. Therefore it should not be used in women with active disease or those with antiphospholipid (aPL) antibodies. In general, it should be used only for patients without active disease, a history of thrombosis or aPL antibodies. Non-oral administration of estrogen is recommended because of its lesser effect on coagulation. With regard to the progestogen, progesterone or pregnane derivatives are preferred. Otherwise, non-estrogen-based strategies should be used.     

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.     

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.     

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.     

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.     

The use of selective estrogen receptor modulators on bone health in men

Selective estrogen receptor modulators (SERMs) represent a class of drugs that act as agonist or antagonist for estrogen receptor in a tissue-specific manner. The SERMs drugs are initially used for the prevention and treatment of osteoporosis in postmenopausal women. Bone health in prostate cancer patients has become a significant concern, whereby patients undergo androgen deprivation therapy is often associated with deleterious effects on bone. Previous preclinical and epidemiological findings showed that estrogens play a dominant role in improving bone health as compared to testosterone in men. Therefore, this evidence-based review aims to assess the available evidence derived from animal and human studies on the effects of SERMs on the male skeletal system. The effects of SERMs on bone mineral density (BMD)/content (BMC), bone histomorphometry, bone turnover, bone strength and fracture risk have been summarized in this review.     

Functional foods for cardiovascular disease in women

Cardiovascular disease (CVD) is the leading cause of death in women. Functional food consumption can play an important role in the prevention and treatment of CVD. The purpose of this review is to establish recommendations for the intake of functional food ingredients in a healthy diet, such as soy proteins and isoflavone, omega-3 fatty acids (FAs) from fish oils (FOs) including eicosapentaenoic acid (EPA) and docoshexaenoic acid (DHA) and plant sterols-(PS) enriched foods - for prevention and treatment of CVD in postmenopausal women. First, controversial results exist on CVD risk factors after intake of soy protein and isoflavone that indicates that further clinical studies need to be done to better understand their role in maintaining and improving cholesterol levels. However, since soy contains polyunsaturated fats, replacing some higher fat meat protein sources with soy products may contribute to cardiovascular health. Secondly, FOs, including EPA and DHA, have shown promising effects for lowering triglyceride levels. In addition, emerging research appears to show that omega-3 FAs may have additional health effects with improved arterial health and a reduction in oxidative stress in postmenopausal women. Thirdly, foods and beverages supplemented with PS may reduce cholesterol; therefore, are a worthy addition to interventions aimed at lowering heart disease risk in women. Overall, incorporating functional foods into a healthy diet may be beneficial in helping to reduce lipids levels and thus the risk of CVD.     

Metabolic syndrome and the menopause

The metabolic syndrome consists of a combination of risk factors that include abdominal obesity, atherogenic dyslipidaemia, hypertension and insulin resistance. It increases the risk of cardiovascular disease and type 2 diabetes. The increased risk of cardiovascular disease is higher in women than in men. The first manifestation of metabolic syndrome may occur in pregnancy presenting as gestational diabetes or preeclampsia. Both conditions are associated with increased insulin resistance. Also metabolic syndrome is more common in polycystic ovarian syndrome. It has been suggested that there is a metabolic syndrome resulting from the menopause due to estrogen deficiency, as many of the risk factors are more prevalent in postmenopausal women. Also estrogen replacement improves insulin sensitivity and reduces the risk of diabetes. The key elements in managing the metabolic syndrome are weight reduction, increasing physical activity and diet modification. If blood pressure, lipid and glycaemic control are not achieved through these interventions then pharmacological therapy will be required.     

Calcium and vitamin D--for whom and when

The basis of 'nutritional' interventions for the prevention of postmenopausal osteoporosis and osteoporotic fracture is a large topic with much genetic and biochemical evidence, as well as the results of randomized controlled trials, to guide the investigator and clinician. The efficacy of treatment with calcium and vitamin D was once controversial, but with the advent of controlled clinical trials using bone mineral density as an endpoint it has become clear that calcium with or without vitamin D therapy can lead to reductions in the rate of bone loss in postmenopausal women of all ages. Furthermore, with certain caveats, calcium with vitamin D therapy in the older postmenopausal woman can lead to useful reductions in fracture rates and falls, especially in populations with reduced exposure to sunlight, which is potentially the majority of postmenopausal women in both developed and developing countries. However, estrogen, selective estrogen receptor modulators (SERMs) and bisphosphonates (especially when given in combination with calcium and vitamin D) are more efficacious in preventing fracture, particularly in postmenopausal patients with impaired bone structure.     

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.     

Mental health around and after the menopause

The menopause is a time in a woman's life when it is recognized that biological and social changes can impact upon mental wellbeing. Several studies have investigated the relationship between menopause and psychological symptoms, especially depression, with mixed results. In part, this is due to a considerable overlap between depressive symptoms and those due to declining estrogen levels, causing challenges in assessment. However it appears that vulnerable women are at a higher risk of succumbing to depression during menopausal transition. Antidepressants remain the mainstay of treating depressive symptoms, with little conclusive evidence for hormone replacement therapy. Memory problems during menopause are a common complaint, but there is no demonstrated link to subsequent dementia. This paper also reviews considerations of diagnosis and treatment of postmenopausal depression.     

Tissue-selective agents: selective estrogen receptor modulators and the tissue-selective estrogen complex

Menopause has been associated with vasomotor symptoms, vulvar-vaginal atrophy and osteoporosis. One of the goals in exploring the potential of selective estrogen receptor modulators (SERMs) was to determine if they could prevent fractures, reduce menopausal symptoms and treat vaginal atrophy, while being neutral or protective on the uterus, breast and cardiovascular system. However, no SERM to date has achieved this goal. More recently, the idea of pairing a SERM with estrogen(s), known as a tissue-selective estrogen complex (TSEC), has been studied in postmenopausal women. A TSEC combines the complementary tissue-selective activities of a SERM and estrogen(s), in an attempt to gain the benefits of each with better overall tolerability. The Selective estrogen Menopause And Response to Therapy (SMART) trials were multicentre, randomized, double-blind, placebo- and active-controlled phase 3 studies evaluating the safety and efficacy of the SERM, bazedoxifene (BZA) paired with conjugated estrogens (CEs) in healthy postmenopausal women. In the first SMART trial, BZA/CE protected the endometrium from estrogenic stimulation, relieved hot flushes and maintained bone mass, with rates of amenorrhea, breast pain and overall adverse events similar to those with placebo in more than 3400 women over two years. BZA 20 mg was the lowest effective dose of BZA in BZA/CE to protect the endometrium and maintain bone mass when paired with CE 0.625 mg and CE 0.45 mg. In SMART-2, these BZA/CE doses significantly reduced the frequency and severity of hot flushes over 12 weeks. Collectively, these data support the TSEC containing BZA/CE as a new paradigm for treating menopausal symptoms and preventing osteoporosis while protecting the endometrium from unopposed estrogenic stimulation.     

Aging, physical activity, and hormones in women--a review

Women experience significant changes in endocrine function during aging. Decreasing levels of anabolic hormones may be associated with musculoskeletal atrophy and decrease in function that is observed in older women and, as a result, there has been an increase in the use of pharmacological hormone therapies. It is difficult to distinguish, however, between physiological changes that are truly age related and those that are associated with lifestyle factors such as physical activity participation. Some research has shown that circulating levels of anabolic hormones such as DHEA(S) and IGF-I in older women are related to physical activity, muscle function, and aerobic power. Exercise-intervention studies have generally shown that increasing age blunts the acute hormonal response to exercise, although this might be explained by a lower exercise intensity in older women. There have been relatively few studies that examine hormonal adaptations to exercise training. Physical activity might have an effect on hormone action as a result of changes in protein carriers and receptors, and future research needs to clarify the effect of age and exercise on these other components of the endocrine system. The value and safety of hormone supplements must be examined, especially when used in combination with an exercise program.     

Web-based survey 'Contraception and attitudes to sexual behaviour' completed by women accessing a UK menopause website

Background and methodology Sociodemographic trends mean increasing numbers of new relationships in later life. These trends may not only have health consequences for women and health services but also impact on the targeting of sexual health messages. This study aimed to examine attitudes and knowledge surrounding contraception, sexual health and unwanted pregnancy among those accessing the website www.menopausematters.co.uk. A voluntary online survey was completed. RESULTS: Survey was completed by 550 respondents. Three hundred and sixty-six women, 94% of whom self-classified as pre- or perimenopausal, had been sexually active with a male partner in the previous four weeks. Commonest contraceptive methods used by perimenopausal and postmenopausal women were condoms, combined oral contraceptive pill (COCP) and male sterilization. Up to 42% of women surveyed were unhappy with their contraception. A total of 27% premenopausal, 32% perimenopausal women and 40% postmenopausal used no contraception. One-third of women were unhappy about this and 19 unplanned pregnancies had occurred. The majority of women were informed regarding COCP use over 35 years, hormone replacement therapy, emergency contraception and ceasing contraception. The majority of women were unaware that more terminations of pregnancy are performed in women over 40 than any other age group per total pregnancies.Almost a third of women were unaware that chlamydia incidence is increasing in older women. Most would use condoms in new relationship. Discussion and conclusions Women accessing www.menopausematters.co.uk are well informed about contraception and sexual health. The majority of those accessing the site are sexually active, but many use no contraception, or are unhappy with their chosen method, leaving them vulnerable to unwanted pregnancy or sexually transmitted infection.     

Androgen replacement therapy in aging men with secondary hypogonadism

Many animal and human studies show that supraphysiological doses of dehydroepiandrosterone (DHEA) can influence body composition and carbohydrate and lipid metabolism. Most studies have concentrated on women and have not been randomized, thus creating controversial results. With this in mind, we designed a cross-over double-blind placebo-controlled study of 12 men aged 59.0 ± 4.8 years, who received either 50 mg/24 h DHEA or placebo for 3 months to assess the influence of DHEA on the content and distribution of fat tissue and serum insulin, glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol levels, as well as testosterone, estradiol, DHEA-sulfate (S), prostate-specific antigen (PSA) concentrations and indexes of insulin sensitivity and resistance. Patients were recruited from university employees attending for periodic health checks, with normal hepatic and renal function with endogenous DHEA-S level < 1500 ng/dl. Our results did not reveal any significant changes in study parameters, apart from a statistically significant increase in DHEA-S levels after therapy with active substance.     

The future of the new selective estrogen receptor modulators

Selective estrogen receptor modulators (SERMs) are compounds that display mixed estrogen agonist/antagonist activity. Currently, four SERMs are licensed for clinical use: tamoxifen, toremifene, clomifene and raloxifene. The STAR and RUTH trials have provided useful data about the potential role of SERMs in the primary prevention of breast cancer and cardiovascular disease in postmenopausal women. New-generation SERMs, such as bazedoxifene, arzoxifene, lasofoxifene and ospemifene, are currently being evaluated. The aim is to find a SERM that conserves the skeleton and prevents breast cancer without increasing the risk of endometrial cancer and venous thromboembolism, and without inducing hot flushes. Technological advances in the study of estrogen receptor activation will provide key information for drug development.     

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.     

Quality of life in obese postmenopausal women

The aim of this review was to identify the ways in which obesity affects the health-related quality of life (HRQoL) of postmenopausal women. This was considered important because a growing body of literature has identified obesity as a significant predictor for a poor psychological wellbeing and negative HRQoL, particularly in women, and because during the transition through the menopause women tend to accumulate more body weight. After searching eight electronic databases, only nine papers appeared meaningful. Although a meta-analysis was not possible, we found that a body mass index (BMI) > 30 kg/m2 was associated with a poor HRQoL in postmenopausal women; particularly in the areas associated with physical functioning, energy and vitality, and health perceptions. Thus, clinical management of obese postmenopausal women should focus on weight reduction and exercise in an attempt to improve wellbeing in these areas. However, the paucity of research, the different instruments chosen to measure HRQoL and the methodological limitations of the studies identified, prevented firm conclusions being made about whether the relationship between BMI and HRQoL is linear in postmenopausal women. Further research is needed to explore this relationship; particularly in comparison with underweight postmenopausal women and obese premenopausal women, where a few papers have identified these women as having a worse HRQoL than their obese postmenopausal counterparts. Other measures of central adiposity, including waist circumference and waist-hip ratio are recommended as useful supplemental measures to BMI in future studies.