Do estrogen or selective estrogen receptor modulators improve quality of life for women with postmenopausal osteoporosis?

Osteoporotic fractures result in significant deficits in health-related quality of life (HRQOL). The accumulation of deficits resulting from osteoporosis and fractures is now recognized as a major cause of reduced HRQOL in women after the menopause and in later life. Some of these same postmenopausal women may also have deficits in HRQOL related to vasomotor symptoms during the menopausal transition. Although estrogen therapy has not been shown to improve overall HRQOL in late postmenopausal women in randomized, controlled trials, it may improve menopausal symptoms. In contrast, selective estrogen receptor modulators (SERMs) such as raloxifene may increase vasomotor symptoms. Although estrogen is not indicated for the primary prevention of osteoporosis, estrogen therapy may be considered for the postmenopausal woman at risk of osteoporotic fracture who is symptomatic and who is not at high risk of breast cancer or cardiovascular events. Raloxifene decreases risk of invasive breast cancer and may be considered in women at high risk of breast cancer. Decision making about osteoporosis treatment should also consider the impact of the treatment on HRQOL.     

Bone and hormones. Estrogens and antiestrogens: action on osteoporosis

ESTROGEN INSUFFICIENCY: Estrogens play a cardinal role in bone tissue in women. Estrogen insufficiency leads to accelerated bone loss within 5 to 8 years after menopause. HORMONE SUBSTITUTION THERAPY: Substitution therapy prevents postmenopausic bone loss (lumbar vertebrae, hip, radius) and reduces the risk of osteoporotic fracture. Cohort studies have demonstrated that women given hormone substitution therapy for at least 7 years have a significantly higher bone density than untreated women. Although still controversial, it would appear that the risk of breast cancer increases with prolonged use of hormone substitution therapy. SERM: Observations in patients given tamoxifen, an antiestrogen used in the treatment of breast cancer, have led to the concept of selective estrogen receptor modulators (SERM), a new class of compounds with estrogen agonistic or antagonistic activity, depending on the tissue. Among these molecules, raloxifen has reached advanced clinical testing phases. Phase III trials have demonstrated that raloxifen can prevent bone loss and reduce the risk of vertebral fractures while reducing total cholesterol and LDL-cholesterol in menopaused women without stimulating the endometrium. SERMs are a promising alternative to hormone substitution therapy for the treatment of menopaused women.     

Hormone replacement and selective estrogen receptor modulators (SERMS) in the prevention and treatment of postmenopausal osteoporosis

For many years, hormone replacement therapy (HRT) has been regarded as one of the most reliable means of prophylaxis and treatment for postmenopausal osteoporosis. As HRT ameliorates menopausal symptoms, it is widely prescribed among early postmenopausal women. A variety of different modes of replacement that suit each individual requirement are available in terms of schedule (cyclic or combined application of gestagens) and route of application (oral or transdermal). HRT effectively prevents spinal bone loss and delays bone loss at the hip up to a very old age. With continued use after menopause, HRT might theoretically halve the incidence of vertebral and hip fractures. However, long-term use or use of HRT in old age is rarely practiced, and the actual benefit of a transient use for future fracture prevention remains unclear. Raloxifene is the first member of the novel class of selective estrogen receptor modulators (SERMs) that has been approved for the prophylaxis and treatment of postmenopausal osteoporosis. It combines the positive effects of estrogen on the skeleton with estrogen-antagonistic effects on sex tissues. Thus, raloxifene maintains bone mass and decreases the incidence of vertebral fractures in osteoporotic women, but avoids many of the side effects that are responsible for the poor long-term compliance to HRT such as resumption or continuation of regular menses, breast tenderness, or breast cancer. It even markedly reduces the risk of breast cancer. Both estrogen and raloxifene are characterized by a large number of extraskeletal effects that have to be taken into account when counseling postmenopausal women on the use of these agents for the prevention or treatment of osteoporosis.     

Osteoporosis prevalence and levels of treatment in primary care: the Australian BoneCare Study.

The level of recognition and treatment of osteoporosis is not well characterized in primary care. In data from a large sample of postmenopausal women attending 927 primary care physicians, 29% of women reported one or more fractures after menopause. The great majority (72%) were not on any osteoporosis-specific therapy. INTRODUCTION: Osteoporosis is often first recognized at the time of a low-trauma fracture. However, by this stage, the risk of subsequent fractures has already risen substantially. Moreover, in many countries, only a small proportion of women, who have already sustained fractures, receive a treatment shown to reduce this increased risk of further fractures. MATERIALS AND METHODS: This project was initiated to examine the prevalence of osteoporotic fractures, risk factors for osteoporosis, and use of antifracture therapy among postmenopausal Australian women. More than 88,000 women from 927 primary care physicians returned over 69,358 surveys. Of these, 57,088 reported the presence of a postmenopausal fracture or risk factors. RESULTS: Among these randomly selected postmenopausal women, 29% reported having had one or more low-trauma fractures after menopause (44% substantiated in current records). One-third of these women reported multiple fractures. The prevalence of all types of fractures, except rib and ankle, increased with age and low body weight. Those who reported fractures were also more likely to report early menopause, corticosteroid use, and a family history of osteoporosis. Moreover, those with vertebral fractures were more likely to record height loss, kyphosis, and back pain. Physical inactivity, low calcium intake, and smoking had no consistent relationship with any fracture outcome. Of the women who reported a fracture after menopause, only 28% were on any specific therapy for osteoporosis, and 7% were on calcium alone. Of those who had been told they had osteoporosis by a doctor, 40% were receiving specific osteoporosis therapy. CONCLUSIONS: In this large study of postmenopausal Australian women attending primary care physicians, 29% reported at least one low-trauma fracture after menopause. Less than one-third of these women were on specific treatment for osteoporosis, and only 40% were ever told they had osteoporosis. Therefore, osteoporotic fractures are common in postmenopausal Australian women, and few, despite their substantially increased risk of further fractures, are on any specific anti-osteoporotic therapy. These data support the need for more effective education for the community and medical practitioners of the clinical significance of osteoporotic fractures and alternatives for treatment.     

Raloxifene (Evista) in the treatment of postmenopausal osteoporosis--the profile of the patient

Osteoporosis, breast cancer and cardiovascular diseases are major health problems among postmenopausal women. Several pharmacologic options for treatment of osteoporosis are available, including hormone replacement therapy (HRT), bisphosphonates, calcitonin and selective estrogen receptor modulators. However, longterm HRT is associated with unwanted side effects such as vaginal bleeding and breast cancer and bisphosphonates, besides bone, have no other benefits. Therefore, raloxifene, the first of the second-generation of SERMs represents a significant improvement in the treatment of postmenopausal women. It could have either estrogen agonist (bone) or antagonist (breast) activity according to the type of estrogen-responsive tissue. Raloxifene prevents bone loss, reduces the number of vertebral fractures in women with and without prevalent vertebral fractures, induces reduction of estrogen-receptor positive invasive breast cancer and has potential beneficial effect on cardiovascular diseases in women with high risk. CORE study, that was recently published, confirmed previously observed reduction of invasive breast cancer in women treated with raloxifene (MORE study), while the data on skeletal effects after 8-years treatment with raloxifene will be published in the near future. Further studies (RUTH, STAR) will provide additional information on efficacy and safety of raloxifene.     

Clinical results of selective estrogen receptor modulators (SERM)

The SERMs (selective estrogen receptor modulators) are a new class of molecules that bind to the estrogen receptor, resulting in an estradiol agonist or antagonist response according to the target tissue. Raloxifene, a new SERM, has been shown to prevent postmenopausal bone loss, to reduce the risk of vertebral fractures in osteoporotic women, to decrease serum cholesterol and its LDL fraction, and to reduce significantly the risk of breat cancer. Raloxifene is available in France for the prevention of post-menopausal osteoporosis.     

Résultats cliniques des modulateurs sélectifs du récepteur des estrogènes (SERM)

The SERMs (selective estrogen receptor modulators) are a new class of molecules that bind to the estrogen receptor, resulting in an estradiol agonist or antagonist response according to the target tissue. Raloxifene, a new SERM, has been shown to prevent postmenopausal bone loss, to reduce the risk of vertebral fractures in osteoporotic women, to decrease serum cholesterol and its LDL fraction, and to reduce significantly the risk of breat cancer. Raloxifene is available in France for the prevention of post-menopausal osteoporosis.     

Specific estrogen receptor modulators (SERMs)

PRINCIPLE CHARACTERISTICS: Specific estrogen receptor modulators (SERMs) are non-steroid molecules that maintain some of the agonist properties of estrogens on bone tissue and cardiovascular system, but not their stimulating effects on the gynecological sphere. OLD AND NEW MOLECULES: SERMs were formerly known as "antiestrogens" in reference to their primary inhibition of breast tumor growth. Hence, tamoxifen has been used for many years as adjuvant treatment of breast cancer. However, its long-term use is limited by the risk of endometrial hyperplasia, which has led to the development of new molecules devoid of this side effect. Among these molecules, raloxifen, more specifically reserved for the prevention of osteoporosis in menopausal women, has been the subject of major pre-clinical and clinical developments. THE EFFECTS OF RALOXIFEN: In the prevention of postmenopausal bone loss and vertebral fractures, the effects of raloxifen have been established in several randomized, double-blind studies against placebo, which were the basis of its current marketing authorization. Moreover, raloxifen has a favorable effect on lipid profile and, contrary to oral estrogens, does not increase the C-Reactive protein. Endometrial tolerance is good and it is associated with a significant reduction in the incidence of breast cancer in elderly osteoporotic women. ITS PLACE IN THERAPY: Raloxifen's properties raise the question of its place, together with hormone replacement therapy (HRT), in the management of menopausal women. Its absence of efficacy in the control of the climacteric syndrome does not a priori make it a treatment of choice at the beginning of postmenopausal phase. However, its effects in the prevention of vertebral fracture, its good gynecological tolerance and the fact that it is easy to administer, are arguments for its administration in the prevention of osteoporosis in 60 year-old women or in relay to HRT. Its safety on gynecological level privileges its use in all women exhibiting benign breast or uterine pathologies at the origin of poor tolerance to HRT.     

Targeting of hormone replacement therapy immediately after menopause

The aim of this study was to model the effect of short (3-year) treatments with hormone replacement therapy (HRT) at the time of menopause on the risk of osteoporotic fracture, and to assess the impact of strategies to target high-risk individuals. From the relationship between bone mineral density (BMD) and fracture risk, treatment that increased bone mineral density at the hip by 6% over untreated women would save 35 vertebral, 62 hip, 13 proximal humeral, and 16 forearm fractures per 1000 women. The number needed to treat (NNT) to prevent one of these fractures was 8. The NNT fell modestly by targeting HRT to women with low bone mass or osteoporosis (NNT 6 and 5, respectively). The gains in fractures saved from targeting women with low bone mass or osteoporosis were offset by the requirement for assessment by BMD. Changes in the assumptions about the efficacy of HRT had a modest impact on fractures saved compared with the effect of changing assumptions concerning the offset of effect when treatment was stopped. We conclude that comparatively short courses of HRT might be effectively offered to all suitable women at menopause provided that the effects on bone persist when treatment is stopped.     

Osteoporotic compression fractures of the spine; current options and considerations for treatment.

BACKGROUND CONTEXT: Vertebral compression fractures affect at least one-fourth of all postmenopausal women. The most significant risk factor is osteoporosis, most commonly seen among Caucasian women a decade or so after menopause. Osteoporosis typically results from inadequate accumulation of bone mass during childhood and early adulthood followed by rapid resorption after menopause. Primary treatment of osteoporosis includes consideration of underlying metabolic abnormalities and provision of supplemental calcium/vitamin D in conjunction with bisphosphonates or calcitonin, or both. Routine hormone replacement therapy has fallen out of favor because of concerns regarding adverse effects identified in long-term follow-up studies. Acute osteoporotic vertebral compression fracture management includes bracing, analgesics, and functional restoration. Patients with chronic pain beyond 2 months may be appropriate candidates for vertebral body augmentation, ie, vertebroplasty or balloon tamp reduction. Open surgical management with decompression and stabilization should be reserved for the rare patient with neural compression and progressive deformity with neurologic deficits. PURPOSE: To review current principles in the evaluation and treatment of osteoporotic compression fractures of the spine. STUDY DESIGN/SETTING: A literature review on management of the osteoporotic spine. METHODS: MEDLINE search of all English-language literature published between 1981 and 2005 on surgical and nonsurgical treatment of the osteoporotic spine. The references selected for listing at the conclusion of this review are those containing specific information cited within the text. RESULTS: Over 200 separate scientific and clinical studies addressing the epidemiology, pathophysiology, diagnosis, and treatment of osteoporotic vertebral compression fractures were reviewed. CONCLUSIONS: Osteoporotic vertebral compression fractures are a common presenting complaint to spinal care specialists. Thorough differential diagnosis should be considered before attributing fractures to osteoporosis. Appropriate evaluation and medical treatment of underlying osteoporosis should be recommended or instituted. Nonsurgical management of the spinal fracture should focus on pain control and maximizing functional outcome. The role of surgical treatment remains controversial and should be reserved for patients who fail initial nonsurgical management options.     

Skeletal Manifestations of Treatment of Breast Cancer on Premenopausal Women

With increasing use of screening mammography and more effective adjuvant systemic therapies, the majority of women diagnosed with early stage breast cancer will be long-term survivors and experience personal cures. Among the common side effects of adjuvant therapies is treatment-related bone loss, primarily as a result of estrogen deprivation. Whereas this occurs in both postmenopausal and premenopausal women, this brief review will focus on pre- or perimenopausal women when initially diagnosed with breast cancer. An important distinction is between those women who retain ovarian function despite cancer or preventative treatments and the more common situation of premenopausal women who as result of cancer treatments undergo ovarian failure or early menopause. Some women with treatment-related ovarian failure will have sufficient treatment-related bone loss to be at increased risks of subsequent nontraumatic fractures and/or osteoporosis and will be candidates for antiresorptive treatments. The noncancer treatment risk factors, screening and treatments for the management of osteopenia and osteoporosis are generally the same in postmenopausal women with and without breast cancer. However, premenopausal women with relatively rapid onset of treatment-related ovarian failure and bone loss pose several challenges. Awareness of treatment-related bone loss and risks of subsequent osteoporosis is a high priority in an ever-increasing population of breast cancer survivors.     

Nasal salmon calcitonin in osteoporosis

Conclusion Nasal sCT is a safe drug with few and mild side effects and compared with HRT is often more attractive to elderly, osteoporotic women. Under controlled conditions, nasal sCT reduces the rate of new fractures by two-thirds compared with calcium treatment alone [10] and increases spinal bone mass dose dependently.Conclusively, nasal sCT is indicated for treating women who have passed the menopause some years ago. The treatment should be administered discontinuously. The nasal formulation has been approved for treatment of osteoporosis in a variety of European and South American countries, and has also been filed with appropriate governmental authorities for consideration of approval in many countries throughout the world, including the US. Should calcitonin treatment be generalized in women who are 10–15 years postmenopausal, the costs will undoubtedly be reduced. Compared with the effect of HRT on early postmenopausal bone loss, the effect of nasal sCT is only marginal. Thus, HRT prevents both the cortical and trabecular bone loss throughout the entire treatment period [38]. Furthermore, HRT is inexpensive and its adverse event profile has been fully clarified except in respect to the possible change in the risk of breast cancer [39]. Nasal sCT can be effective in women soon after the menopause—by decreasing the rate of vertebral bone loss and lowering the bone turnover—as an alternative to hormone replacement therapy either when estrogens are contraindicated or for women who are not candidates for estrogen therapy.     

绝经后骨质疏松症的治疗进展

骨质疏松症是一个与老龄化进程息息相关的全球性健康问题，骨质疏松症患者不仅经常被漏诊，而且常常不能得到及时治疗。正因为如此，骨质疏松症直接导致了高发病率、高死亡率以及生活质量的下降。雌激素缺乏是绝经后骨量丢失的一个主要影响因素，50岁女性其一生中发生骨折风险的概率大约是50 %，对骨质疏松症进行针对性的治疗可以预防这些骨折的发生。除此之外，非药物性的治疗还包括健康饮食、防止跌倒以及适当的体育锻炼；药物治疗主要包括钙剂、维生素D以及抗骨吸收药物（选择性雌激素受体调节剂、激素替代治疗、双膦酸盐类药物、狄迪诺塞麦）、骨形成药物（特立帕肽）和混合型制剂（雷尼酸锶）在内的骨活性药物。双膦酸盐类药物（阿仑膦酸钠、利塞膦酸钠、伊班膦酸钠和唑来膦酸钠）是目前骨质疏松症治疗中最常应用的抗骨吸收药物，但由于其依从性、耐受性较差，加之不良反应的影响，会限制其从抗骨吸收治疗中的获益。目前已在研发针对骨细胞信号传导研究基础上的一些新药，并且正在进行疗效评估的临床试验。     

Fractures Before Menopause: A Red Flag for Physicians

There is substantial interest in the early identification of women at risk for osteoporotic fractures, so that preventive measures may be instituted early. We examined whether women with a history of fractures before menopause were at an increased risk of fractures after menopause. We obtained information about any lifetime fractures of the hip, arm, spine, wrist, leg, ankle, foot and finger from 9086 ambulatory white women ages 65 years and older participating in the Study of Osteoporotic Fractures. We also measured bone mineral density and recorded history of falls, maternal fracture history, drug use, diet, functional status, and other characteristics commonly associated with osteoporotic fractures. We used proportional hazards models to estimate the effects of fractures that occurred before menopause on the risk of fractures after menopause, in particular those that occurred during the 12 years of study follow-up. The risk of fractures of all types during the study period was greater among women with a premenopausal fracture of any type compared with women without a premenopausal fracture (hazard ratio (HR), 1.33; 95% confidence interval (CI), 1.14–1.56; p<0.001). Adjustment for possible confounders, including bone mineral density, had only a modest effect (HR, 1.25; 95% CI, 1.03–1.50; p<0.02). An increased risk of fracture among women with a premenopausal fracture was also seen after stratification by estrogen use, propensity to fall and maternal fracture history. Premenopausal fractures are therefore a risk factor for subsequent fractures independent of other risk factors for osteoporotic fractures, such as bone mineral density. A fracture history, including fractures before menopause, should be obtained when making decisions about preventive treatments. Received: 17 April 2000 / Accepted: 14 June 2000     

Evidence that type I osteoporosis results from enhanced responsiveness of bone to estrogen deficiency

Type I osteoporosis occurs within 20 years after menopause and is associated with excessive cancellous bone loss and fractures of the vertebrae and distal radius. We have suggested that it may be caused by estrogen deficiency plus some additional factor predisposing to excessive bone loss. One such factor might be a greater degree of sex steroid deficiency, a possibility that could not be previously excluded because assays of sufficient sensitivity have only recently become available. Thus, we studied 36 women with vertebral fractures due to typical high turnover type I postmenopausal osteoporosis and 36 normal postmenopausal women using new ultrasensitive assays with detection limits of 1 pg/ml for estradiol, 5 pg/ml for estrone and 5 ng/dl for testosterone to test if type I osteoporosis results from enhanced responsiveness of bone to estrogen deficiency. Mean levels of serum sex steroids were identical in both groups, but bone turnover was increased by up to 55% in the women with type I osteoporosis. Moreover, compared with controls, the osteoporotic women had a 51% higher (P<0.01) serum osteoprotegerin level, which was likely a compensatory response to the increased bone turnover. In the osteoporotic women, 1-year treatment with transdermal estrogen in 14 women reduced total deoxypyridinoline, an index of bone resorption, by 58% as compared with placebo treatment in 17 women (P<0.001). Thus, as compared to controls, postmenopausal osteoporotic women had comparable sex steroid levels but higher bone turnover levels that were responsive to estrogen therapy. This is consistent with the hypothesis that the greater bone loss in type I osteoporosis is the result of impaired responsiveness of bone to low postmenopausal levels of sex steroids.     

Osteoporosis in males and females: Is there really a difference?

The prevalence of osteoporosis increases with advancing age. Fractures are more common in women than in men and, apart from the menopause, the reasons for this difference remain poorly understood. The growth period is crucial to skeletal development and results in larger bones in males than in females. The sudden drop in estrogen levels that characterizes the menopause contrasts with the gradual decline in sex hormones seen in aging men, and the proportion of individuals with hypogonadism is considerably lower among older men than among older women. Although estrogens play a crucial role in bone homeostasis in both men and women, via direct and indirect mechanisms, differences exist between the sexes in hormonal physiopathology and its consequences on bone tissue. Many genetic and environmental factors influence the fracture risk. Although women are more prone to fractures, the mortality rate associated with fractures is higher in men. Most of the osteoporosis medications were developed for the treatment of postmenopausal osteoporosis and some are licensed for use only in women. Overall, the diagnosis of osteoporosis is somewhat less neglected than previously, but the treatment of high-risk individuals (those with a history of fracture) remains inadequate, most notably among males.     

Selective estrogen receptor modulators in chronic renal failure

BACKGROUND: In addition to renal osteodystrophy, postmenopausal women on dialysis could be at risk of osteoporosis. Hormone replacement therapy (HRT) could have beneficial effects as well as potentially serious risks, especially in uremic women, due to the pharmacokinetics of estradiol in renal failure. Therapeutic alternatives, such as the selective estrogen receptor modulators (SERMs), have shown the benefits of estrogen on bone and serum lipid levels, without its adverse effects on the breast and endometrium, in nonuremic women. METHODS: Recent data on the effect of the SERM raloxifene in bone and lipid metabolism in osteoporotic postmenopausal women on dialysis is reviewed. Since the estrogen receptor (ER) gene has been suggested as a candidate marker for osteoporosis, we investigated whether ER polymorphism could have predicted the BMD response to raloxifene. RESULTS: Hemodialyzed women on raloxifene demonstrated increased trabecular bone mineral density (BMD) and decreased bone resorption markers. Similarly, LDL-cholesterol values dropped significantly. ER gene polymorphism analysis of baseline BMD parameters did not differ between PP/xx or Pp/Xx groups. Nevertheless, patients on raloxifene with PP/xx genotypes, but not those with Pp/Xx, showed a higher trabecular BMD after one year on treatment, suggesting that homozygous women for P or x alleles of the ER have a better BMD response to raloxifene. CONCLUSION: Raloxifene and, most likely, other SERMs, could represent a good alternative to HRT in postmenopausal uremic women.     

Osteoporotic Vertebral Fractures

Abstract Due to a demographic increase in patients with osteoporosis the epidemiology of vertebral fractures changes. Osteoporosis is characterized by low bone density, microarchitectural deterioration of bone tissue and impaired bone strength, which leads to an increased bone fragility and susceptibility to fracture. Asymptomatic vertebral deformity was found to be associated with subsequent risk of symptomatic fractures, particularly vertebral fracture, and increased risk of mortality after a fracture. After the first osteoporotic fracture at any site the risk for further fractures increases dramatically. Osteoporosis represents, besides the origin of such vertebral fractures and impaired bone healing, a problem in osteofixation and implant stability in fracture treatment in orthopedic surgery. Two new treatment strategies of percutaneous vertebro- and kyphoplasty have gained worldwide attention in the treatment of osteoporotic vertebral fracture and short-term observational studies and case-control studies indicate that the results are favorable, regarding both pain relief and functional status. Actually, it cannot be decided whether the internal application of bone cement to the vertebral body is effective in the long run. Special attention has to be given to the underlying osteoporosis in order to reduce the incidence of further fractures in the patients at risk. Diagnosis and treatment of osteoporosis have to be part of the treatment concept of osteoporotic vertebral fractures. Thus, it is important that orthopedic surgeons identify, assess and treat patients with fragility fractures for osteoporosis according to the currently available treatment protocols.     

绝经后妇女骨质疏松性骨折易发因素的流行病学研究

目的 探讨绝经后妇女骨质疏松性骨折的分布特征和易发因素。方法 以社区50-69岁绝经1年以上妇女为研究对象,问卷调查危险因素,双能X线骨密度仪测量骨密度(Bone MineralDensity,BMD),胸腰椎侧位X摄片分析椎体骨折,结合病史问询调查骨折发生。结果 绝经后妇女骨质疏松性骨折的发生率随年龄和绝经年限的延长而上升,尤其是绝经后的15-20年,骨质疏松性骨折的发生率明显升高。至少有一处以上骨折的绝经后妇女较无骨折妇女的年龄大、绝经年龄早、绝经年限长、生育次数多、哺乳月份长(P<0.01)。结论 绝经早、生育胎数多、哺乳时间长等因素是绝经后妇女骨质疏松性骨折的重要危险因素,可作为骨折高危人群的筛选指标以及制定相应干预措施的依据。