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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

The microanatomy of trabecular bone in young normal and osteoporotic elderly males

Normally there is a gradual continual loss of cortical and trabecular bone in both men and women as they age. Osteopenia and osteoporosis are conditions in which the loss results in brittle bones that fracture easily. Males with low testosterone and hypogonadism are predisposed to osteoporosis and prevention tends to be overshadowed by the greater problem in postmenopausal women. The ability of the skeleton to resist external forces depends partly upon the amount of bone present and partly upon other factors including cancellous bone microarchitecture. This is examined in iliac crest bone biopsies from idiopathic osteoporotic men, mean age 60 ± 12 SD years [n = 16]. These were compared with a healthy control group (autopsy samples), mean age 30 ± 8.9 years [n = 28] with the aim of examining the pattern of cancellous atrophy in male idiopathic osteoporosis. Undecalcified specimens were embedded in methylmethacrylate and prepared for histomorphometry. Sections were analysed using an automated trabecular analysis system (TAS), whereby a binary image was created. Area measurements including the trabecular surface and distance measurements including the trabecular width were made. The binary image was thinned to its medial framework and the node and terminus number as indices of trabecular interconnection were recorded, together with the strut length. Results (median (range)) showed a lower percentage bone volume in the elderly osteoporotic male, 10.2% (5.4–23.1) compared to young normals 25.2% (14.6–43.9), p < 0.001. The trabeculae tended to be thinner, 95.7 µm (66.7–170.7) c.f. 120.8 µm (75.8–208.6) and considerably fewer in number, 11.1 (2.1–31.4) c.f. 48.3 (25.4–66.9), p < 0.001 per field and in particular the number of nodes, 2.1 (0.15–14) c.f. 40.6 (10.3–74.1) per field and the node: terminus ratio fell to 0.13 (0.01–1.19) c.f. controls 0.98 (0.24–6.69), p < 0.001. It was concluded that the pattern of cancellous atrophy in male idiopathic osteoporosis differs from normal aging and resembles that in postmenopausal women. Results using the automated TAS confirm previous observations made manually.     

Osteoporosis knowledge and attitudes: a cross-sectional study among college-age students

OBJECTIVE: The authors' purpose in this study was to investigate the influence of knowledge of osteoporosis, attitudes regarding osteoporosis, and knowledge of dietary calcium on dairy product intake in both male and female college-age students. PARTICIPANTS: The authors conducted this cross-sectional study on 911 men and women enrolled in 2 demographically similar universities. METHODS: A modified osteoporosis knowledge questionnaire assessed participant's general osteoporosis knowledge and perceived disease risk. RESULTS: The authors found that knowledge of osteoporosis and calcium did not significantly influence dairy product intake. Attitude regarding osteoporosis was a significant predictor of dairy product intake in men but was not significant for the women. CONCLUSIONS: The authors recommend development and implementation of educational programs designed to increase awareness of calcium-rich food sources as well as other risk factors of this crippling disease.     

Clinical effects of growth hormone on bone: a review

Growth hormone (GH) stimulates bone turnover. Deficiency of GH due to hypopituitarism is related to low bone mineral density and increased fracture risk. GH substitution increases and thus normalizes bone mineral density in these patients, which is one of a number of arguments for GH substitution in hypopituitarism. In contrast, a possible therapeutic use of GH in idiopathic osteoporosis and glucocorticoid-induced osteoporosis is speculative and not established. Reduction of osteoporosis risk is an argument brought up for a use of GH in healthy elderly persons (anti-aging medicine). However, since only very limited data are available yet, this cannot be based on scientific evidence, and there are important concerns about the safety of use of GH in healthy elderly persons.     

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.     

Pheromonal influences on sociosexual behavior in postmenopausal women

To determine whether a putative human sex‐attractant pheromone increases specific sociosexual behaviors of postmenopausal women, we tested a chemically synthesized formula derived from research with underarm secretions from heterosexually active, fertile women that was recently tested on young women. Participants (n = 44, mean age = 57 years) were postmenopausal women who volunteered for a double‐blind placebo‐controlled study designed “to test an odorless pheromone, added to your preferred fragrance, to learn if it might increase the romance in your life.” During the experimental 6‐week period, a significantly greater proportion of participants using the pheromone formula (40.9%) than placebo (13.6%) recorded an increase over their own weekly average baseline frequency of petting, kissing, and affection (p = .02). More pheromone (68.2%) than placebo (40.9%) users experienced an increase in at least one of the four intimate sociosexual behaviors (p = .04). Sexual motivation frequency, as expressed in masturbation, was not increased in pheromone users. These results suggest that the pheromone formulation worn with perfume for a period of 6 weeks has sex‐attractant effects for postmenopausal women.     

Pheromonal influences on sociosexual behavior in postmenopausal women

To determine whether a putative human sex-attractant pheromone increases specific sociosexual behaviors of postmenopausal women, we tested a chemically synthesized formula derived from research with underarm secretions from heterosexually active, fertile women that was recently tested on young women. Participants (n = 44, mean age = 57 years) were postmenopausal women who volunteered for a double-blind placebo-controlled study designed, to test an odorless pheromone, added to your preferred fragrance, to learn if it might increase the romance in your life. During the experimental 6-week period, a significantly greater proportion of participants using the pheromone formula (40.9%) than placebo (13.6%) recorded an increase over their own weekly average baseline frequency of petting, kissing, and affection (p = .02). More pheromone (68.2%) than placebo (40.9%) users experienced an increase in at least one of the four intimate sociosexual behaviors (p = .04). Sexual motivation frequency, as expressed in masturbation, was not increased in pheromone users. These results suggest that the pheromone formulation worn with perfume for a period of 6 weeks has sex-attractant effects for postmenopausal women.     

The predictive role of bone turnover markers for BMD in middle-aged men

Measurement of bone turnover markers has been proposed as a potentially valuable clinical laboratory aid in osteoporosis risk assessment. These markers may allow quantitative evaluation of rates of bone loss, and thereby identify persons at risk for osteoporosis at an earlier stage. As far as we know, this is the longest longitudinal study on bone turnover markers conducted in adult men. The objectives of this study were to determine whether markers of bone formation (type I procollagen amino-terminal propeptide, PINP, and carboxy-terminal propeptide, PICP), and of bone resorption (type I collagen carboxy-terminal telopeptide, ICTP), are predictive of changes in lumbar spine and femoral neck BMD over a 5-year period, and to determine the ability of the bone resorption marker urine amino-terminal telopeptide (NTx) to explain the variance in BMD change over the past 5 years in a group of men 35–69 years old. In this group, NTx was the only marker to correlate significantly with BMD changes at the femoral neck (r = ?0.21), but not at the spine. The use of the biochemical markers studied to predict change in bone density in adult men in middle-aged years is of very limited value.     

Sexually transmitted infections in the older woman

Dependent upon sexual behaviour peri- and postmenopausal women are increasingly at risk of sexually transmitted infections, although the overall rates remain low when compared with younger people. Symptoms are often non-specific or absent and may be misinterpreted as being due to the menopause. In addition, both the women and their clinicians may not be aware of their infection risk, thus leading to a delayed or missed diagnosis. Risk assessment and referral for screening of infections should be carried out wherever appropriate.     

The Health Belief Model and the Contraceptive Behavior of College Women: Implications for Health Education

Abstract

“The Incidence of Primary Cardiac Arrest During Vigorous Exercise,” David S. Siscovick, et al. To examine the risk of primary cardiac arrest during vigorous exercise, we interviewed the wives of 133 men without known prior heart disease who had had primary cardiac arrest. Cases were classified according to their activity at the time of cardiac arrest and the amount of their habitual vigorous activity. From interviews with wives of a random sample of healthy men, we estimated the amount of time members of the community spent in vigorous activity.

Among men with low levels of habitual activity, the relative risk of cardiac arrest during exercise compared with that of other times was 56 (95% confidence limits, 23 to 131). The risk during exercise among men at the highest level of habitual activity was also elevated, but only by a factor of 5 (95% confidence limits, 2 to 14). However, among the habitually vigorous men, the overall risk of cardiac arrest—i.e., during and not during vigorous activity—was only 40% that of the sedentary men (95% confidence limits, 0.23 to 0.67).

Although the risk of primary cardiac arrest is transiently increased during vigorous exercise, habitual vigorous exercise is associated with an overall decreased risk of primary cardiac arrest. (New England Journal of Medicine 1984;311:874-7.)

“Osteoporosis in Women with Anorexia Nervosa,” Nancy A. Rigotti, et al. Because estrogen deficiency predisposes to osteoporosis, we assessed the skeletal mass of women with anorexia nervosa, using direct photon absorptiometry to measure radial bone density in 18 anorectic women and 28 normal controls. The patients with anorexia had significantly reduced mean bone density as compared with the controls (0.64 ±0.06 vs. 0.72 ±0.04 g per square centimeter, P < 0.001). Vertebral compression fractures developed in two patients, and bone biopsy in one of them demonstrated osteoporosis. Bone density in the patients was not related to the estradiol level (r = 0.02). Levels of parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were normal despite low calcium intakes.

The patients with anorexia who reported a high physical activity level had a greater bone density than the patients who were less active (P < 0.001); this difference could not be accounted for by differences in age, relative weight, duration of illness, or serum estradiol levels. The bone density of physically active patients did not differ from that of active or sedentary controls.

We conclude that women with anorexia nervosa have a reduced bone mass due to osteoporosis, but that a high level of physical activity may protect their skeletons. (New England Journal of Medicine 1984;311:1601-6.)     

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.