Update on bazedoxifene: A novel selective estrogen receptor modulator

In the elderly population, osteoporosis is a significant clinical problem leading to disability and even death. Many patients remain untreated, despite effective therapies, because of patients’ unwillingness to take current therapies or inability to tolerate the therapies. For this reason, ongoing research continues to search for more effective and tolerable osteoporosis agents. Bazedoxifene is a selective estrogen receptor modulator (SERM) currently in development for osteoporosis prevention and treatment. A new drug application (NDA) for postmenopausal osteoporosis prevention was recently submitted to the FDA. Preclinical and clinical studies with bazedoxifene demonstrate more tissue selectivity than other SERMs. In particular, bazedoxifene has minimal if any agonist activity in the uterus and is able to antagonize effects of estrogen on the uterus. Animal studies and early clinical studies suggest effects in the bone similar to other SERMs with prevention of postmenopausal bone loss. Until more data on efficacy and safety are published, however, its role in osteoporosis is unknown.     

Mechanisms of action of antiresorptive therapies of postmenopausal osteoporosis

In the treatment of osteoporosis, the aim of the antiresorptive therapy is to restore bone density by decreasing bone remodeling. The process of bone remodeling plays a role in plasma calcium homeostasis and serves to modify bone architecture in order to meet changing mechanical needs, to maintain osteocyte viability, and to repair microdamage in bone matrix. Estrogen deficiency results in a number of detrimental effects on bone, including suppression of osteocyte survival as well as impairment of osteoblast response to mechanical stimuli and repair of ageing bone. In this review, effects of available antiresorptive therapies on endocrine regulations of bone metabolism in postmenopausal osteoporosis are compared. The aim of antiresorptive treatment is to ensure adequate bone remodeling, reparation of microdamage of bone, and increased bone strength. Ideally, this effect should be maintained long-term. Several agents are approved for the treatment of osteoporosis. Calcitonin transiently inhibits osteoclast activity without decreasing osteoblast collagen synthesis. Aminobisphosphonates decrease bone remodeling by decreasing osteoclast activity and by inducing osteoclast apoptosis. This allows more time for secondary mineralization to proceed to completion in the existing bone tissue mass, so increasing the mechanical resistance of bone to loading. Estrogens and raloxifene (a selective estrogen receptor modulator that acts as an estrogen agonist in bone) suppress bone remodeling to the premenopausal range, maintaining the function of osteoblasts and osteocytes. In the placebo-controlled osteoporosis treatment trials, all the above treatments reduced the risk of fractures. Raloxifene therapy was also associated with a favorable or neutral effect in the cardiovascular system, and a reduced incidence of breast cancer. Selection of appropriate drug for treatment of postmenopausal osteoporosis should take into account the long-term effect of the antiresorptive agent on bone. Moreover, the effects on other tissues ++should also be considered, and this encompasses both safety concerns, as well as the potentially beneficial effects on other tissues. Further investigation is needed to evaluate the different modes of action of these agents, and their long-term effects on bone and other tissues.     

Salmon calcitonin nasal spray : An effective alternative to estrogen therapy in select postmenopausal women

The efficacy and safety of estrogen replacement therapy (ERT) and salmon calcitonin in the treatment of postmenopausal osteoporosis are reviewed with special consideration given to patients for whom ERT, the primary antiresorptive therapy for osteoporosis, is not indicated, tolerable, or is refused. The various formulations of estrogen and salmon calcitonin, for which the nasal spray formulation was recently approved for use in the United States, are reviewed in depth with reference to dose ranges, side effects, and convenience. Data regarding increases in bone mineral density (BMD) produced by each agent are presented. Specifically, the range of increases in BMD induced by ERT and salmon calcitonin are comparable. Given the substantial public health consequences of postmenopausal osteoporosis and osteoporotic fractures, the primary care physician is increasingly faced with the need to educated and recruit postmenopausal patients to appropriate therapy with the optimal agent for that particular patient. In the many patients who are unable or unwilling to accept, initiate, and comply with prescribed ERT, alternative therapeutic options are necessary Based on the established safety profile of salmon calcitonin, ease of administration, an uncomplicated dosing regimen, no reported drug interactions, and the lack of uterine bleeding associated with ERT or gastrointestinal adverse effects of other agents used to treat osteoporosis, salmon calcitonin nasal spray is an appropriate alternative approach for the treatment of postmenopausal bone loss.     

Defining the role of raloxifene as a therapeutic agent for postmenopausal osteoporosis: focus on its pharmacological properties

In this semiar, I propose to describe the pharmacological properties of raloxifene that provide a basis for its role in the treatment of postmenopausal osteoporosis. These pharmacological properties can be described as providing therapeutic benefits in the following three areas: 1) reduction in bone turnover, 2) increases in bone mineral density, and 3) risk reduction in fractures. While reloxifene shares these effects with conventional bisphosphonates that are in common use for postmenopausal osteoporosis, it exerts its antiresorptive effects through a different mechanism of action from those of the bisphosphonates. Furthermore, raloxifene exerts its stimulatory or inhibitory effects on estrogen in a tissue-specific fashion as a selective estrogen-receptor-modulator (SERM), thereby providing a wide range of clinical benefits that result from its ability to exert estrogen-like beneficial effects in tissues other than bone while at the same time inhibiting estrogen-like deleterious effects in other tissues. I therefore propose to define the role of raloxifene as a viable therapeutic option in the treatment of postmenopausal osteoporosis in light of these unique pharmacological features. Current data suggests that raloxifene can be positioned somewhere in between hormone replacement therapy (HRT) and bisphosphonates, and is highly likely to be suitable for use in patients between the ages of 55 and 70, while other agents may be indicated in special populations, such as premenopausal patients, postmenopausal patients with hot flushes, or elderly patients who may be placed at accelerated risk of developing femoral neck fractures. Thus, as a novel therapeutic option with unique clinical benefits, a far greater role may be expected for raloxifene in the treatment of postmenopausal osteoporosis than for other conventional therapeutic agents.     

SERMs and SERMs with estrogen for postmenopausal osteoporosis

Bone loss with aging places postmenopausal women at a higher risk for osteoporosis and its consequences such as fractures, pain, disability, and increased morbidity and mortality. Approximately 200 million patients worldwide are affected. The Third National Health and Nutrition Examination Survey (NHANES III) estimated that up to 18% of US women aged 50 and older have osteoporosis and up to 50% have osteopenia. Greater than 2 million osteoporotic related fractures occurred in the United States with direct healthcare costs exceeding $17 billion. Hormone Replacement Therapy (HRT) was a popular option for postmenopausal women before the Women’s Health Initiative (WHI). Several agents are available in the U.S., including bisphosphonates, hormone therapy, calcitonin, parathyroid hormone and the selective estrogen receptor modulator (SERM) raloxifene. There are concerns about long term safety and compliance. Therefore, other agents are under investigation. SERMs are a diverse group of agents that bind to the estrogen receptor and each SERM appears to have a unique set of clinical responses, which are not always consistent with the typical responses seen with other SERMs. This article will discuss the SERMs approved in the United States, tamoxifene and raloxifene, and investigational SERMs. The ideal SERM would include the beneficial effects of estrogen in bone, heart and the central nervous system, with neutral or antagonistic effects in tissues where estrogen effects are undesirable(breast and endometrium). A new target in treating postmenopausal osteoporosis is the tissue estrogen complex or the pairing of a SERM with a conjugated estrogen known as a tissue selective estrogen complex (TSEC). This novel approach is currently being evaluated with bazodoxifene which could yield the beneficial effects of estrogens and SERMS, while potentially being more tolerable and safer than either therapy alone.     

Comparative effects of antiresorptive agents on bone mineral density and bone turnover in postmenopausal women

Postmenopausal osteoporosis is a common clinical entity; its complications represent a significant burden to society. In recent years the choice of therapies available for the treatment of postmenopausal osteoporosis has increased dramatically. There are a number of antiresorptive agents currently available including hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), bisphosphonates, and dual action bone agents. It is difficult to truly compare these therapies given the lack of direct head-to head studies. The efficacy of antiresorptive therapies can be assessed in a number of ways including measurement of bone mineral density (BMD), assessment of bone turnover markers, and fracture reduction. Other important factors include ease of administration and consequent patient compliance. This article reviews the currently available antiresorptive agents and their effects on the above outcome measures.     

Effects and safety of SERM in animal study

SERM (estrogen receptor modulator) has the different effects of both estrogen agonist and antagonist depending on the organs. Raloxifene has been developed as a medicine for the treatment of postmenopausal osteoporosis, which reduces bone loss by suppressing bone resorption after ovariectomy (estrogen agonist for bone), while not increasing the proliferation of uterine endometrium or estrogen sensitive mammary cancer (estrogen antagonist for uterus or mamma).     

Role of estrogens in the management of postmenopausal bone loss

It is well known that estrogen deficiency is the major determinant of bone loss in postmenopausal women. Estrogen is important to the bone remodeling process through direct and indirect actions on bone cells. The largest clinical experience exists with estrogen therapy, demonstrating its successful prevention of osteoporosis as well as its positive influence on oral bone health, vasomotor and urogenital symptoms, and cardiovascular risk factors, which may not occur with other nonestrogen-based treatments. Compliance with HRT, however, is typically poor because of the potential side effects and possible increased risk of breast or endometrial cancer. Nevertheless, there is now evidence that lower doses of estrogens in elderly women may prevent bone loss while minimizing the side effects seen with higher doses of estrogen. Additionally, when adequate calcium, vitamin D, and exercise are used in combination with estrogen-based treatments, more positive increases occur in bone density. The benefits and risks of HRT must be assessed on a case-by-case basis, and the decision to use HRT is a matter for each patient in consultation with her physician. Estrogen-based therapy remains the treatment of choice for the prevention of osteoporosis in most postmenopausal women, and there may be a role for estrogen to play in the prevention of corticosteroid osteoporosis. Combination therapies using estrogen should probably be reserved for patients who continue to fracture on single therapy or should be used in patients who present initially with severe osteoporosis.     

Treatment of osteoporosis with bisphosphonates

Bisphosphonates are safe and effective agents for treatment and prevention of osteoporosis. Alendronate and risedronate are the best studied of all agents for osteoporosis in terms of efficacy and safety. They increase bone mass. In patients who have established osteoporosis, they reduce the risk of vertebral fractures. They are the only agents shown in prospective trials to reduce the risk of hip fractures and other nonvertebral fractures. They are approved by the US FDA for prevention of bone loss in recently menopausal women, for treatment of postmenopausal osteoporosis, and for management of glucocorticoid-induced bone loss. Other bisphosphonates (e.g., etidronate for oral use, pamidronate for intravenous infusion) are also available and can be used off-label for patients who cannot tolerate approved agents. Bisphosphonates combined with estrogen produce greater gains in bone mass compared with either agent used alone; whether there is a greater benefit of combination therapy on fracture risk is not clear. Combining a bisphosphonate with raloxifene or calcitonin is probably safe, although data on effectiveness are lacking.     

Efficacy and safety of Xianling Gubao capsule in treating postmenopausal osteoporosis: A protocol for systematic review and meta-analysis

Background:postmenopausal osteoporosis is a systemic metabolic skeletal disease associated with menopause-related estrogen withdrawal. postmenopausal osteoporosis is characterized by low bone mass, bone microstructure destruction, leading to increased bone brittleness and be prone to fracture, resulting in disability and death. At present, the commonly used drugs are estrogen, calcium, bone formation promoter and bone resorption inhibitor, and the side effects are obvious. In Traditional Chinese medicine, kidney-tonifying differentiating medicine is guided by the whole concept, Xianling Gubao capsule as the representative, the treatment of postmenopausal osteoporosis has certain therapeutic advantages, but lacks evidence-based medicine evidence. The purpose of this study is to systematically study the efficacy and safety of Xianling Gubao capsule in the treatment of postmenopausal osteoporosis.Methods:use computer to search English databases (PubMed, Embase, Web of Science, the Cochrane Library) and Chinese databases (China Knowledge Network, Wanfang, Weipu, Chinese Biomedical Database), in addition manually search Baidu academic, Google academic, from the establishment of database to October 2020, for randomized controlled clinical study of postmenopausal osteoporosis in the Xianling Gubao capsule treatment. Two researchers independently did the data extraction and literature quality evaluation, using RevMan5.3 software to do meta-analysis of the included literature.Results:this study assessed the efficacy and safety of xianling gubao capsule in the treatment of postmenopausal osteoporosis by total effective rate, bone density after treatment, blood calcium level after treatment, blood phosphorus level after treatment, pain score, quality of life and so on.Conclusion:this study will provide reliable evidence-based evidence for the clinical application of Xianling Gubao capsule in the treatment of postmenopausal osteoporosis.OSF Registration number:DOI 10.17605/OSF.IO/TP394     

Which is the better choice, estrogen or SERMs in postmenopausal women?

Hormone replacement therapy (HRT) increases the bone mineral density (BMD) and reduces the risk of vertebral and hip fractures in postmenopausal women. But, long term HRT slightly increases the risk of breast cancer. Raloxifene is a selective estrogen receptor modulator that has estrogen agonist effects in the skeleton and cardiovascular system and estrogen antagonist effects in the uterus and breast. Raloxifene effectively prevents bone loss and significantly, increases lumbar spine, hip, and total body bone mineral density, raloxifene reduces the risk of vertebral fracture. Raloxifene treatment leads to no increase in vaginal bleeding or mastaigia and to greater than 70% reduction in risk for invasive breast cancer. But raloxifene increases the hot flashes in postmenopausal women. In conclusion, HRT is optimal therapy for prevention and treatment of osteoporosis in postmenopausal women with menopausal symptoms, raloxifene is optimal therapy for prevention and treatment of osteoporosis in postmenopausal women without menopausal symptoms.     

Lasofoxifene, a next generation estrogen receptor modulator: preclinical studies

Estrogen replacement therapy, in spite of efficacy in the prevention of osteoporotic fractures, has significant side effects and risks that limit its widespread usage in postmenopausal women. Thus significant medical need exists to find modalities that prevent osteoporosis, but without the side effects of estrogen. Selective estrogen receptor modulators (SERMs) have the potential to provide the skeletal benefits of estrogen without the increased risk of uterine and breast cancer. Tamoxifen, a first generation SERM is approved for the prevention and treatment of breast cancer, and raloxifene, a second generation SERM has been approved for the prevention and treatment of osteoporosis. Lasofoxifene, a new potent, nonsteroidal SERM, binds with high affinity to human estrogen receptors and acts as a tissue selective estrogen antagonist or agonist. In preclinical models of postmenopausal osteoporosis, lasofoxifene inhibited bone turnover and prevented bone loss throughout the skeleton. In studies designed to investigate the combination of lasofoxifene with estrogen, lasofoxifene blocked the hypertrophic effects of estrogen in the uterus, but did not block the bone protective effects. In immature and aged female rats, lasofoxifene did not affect the uterine weight and uterine histology. In preclinical studies designed to evaluate the effects of lasofoxifene on the uterus, a slight increase in wet uterine weight was observed in immature and aged female rats, but this difference was not observed in dry uterine weight suggesting that the increased uterine weight was due to increased water content in the tissue. In preclinical studies designed to evaluate the effects of lasofoxifene in breast cancer, lasofoxifene inhibited breast tumor formation in mice injected with human MCF-7 breast cancer cells and in rats bearing mammary carcinomas. Thus, in preclinical models, lasofoxifene, a next generation SERM, prevents estrogen deficiency-induced bone loss, inhibits breast tumor formation, and reduces serum cholesterol, without causing uterine hypertrophy. These data suggest that lasofoxifene is a new potential therapy for the prevention of osteoporosis in postmenopausal women.     

Who will benefit from treatment with selective estrogen receptor modulators (SERMs)?

Clinical trials have demonstrated that the selective estrogen receptor modulator raloxifene can reduce the risk of vertebral fracture, but have not unequivocally demonstrated an effect on non-vertebral fracture. Consequently it is recommended that raloxifene be used mainly in postmenopausal women with milder osteoporosis as a preventive measure or for treatment in those with predominantly spinal osteoporosis. Since the effects of raloxifene on bone mineral density and bone turnover may reverse soon after cessation, it is recommended that raloxifene be used as long-term therapy for 5-10 years. Because of its quicker offset, use of raloxifene may have advantages over potent bisphosphonates if use of anabolic agents are contemplated in an individual patient.     

Hormone replacement therapy and fractures in older adults

Estrogen deficiency in women is associated with accelerated bone loss, and estrogen replacement therapy has been proven to be effective in preventing osteoporosis and fractures in postmenopausal women. The introduction of selective estrogen receptor modulators that have an estrogen-like effect on the skeleton but have a different pattern of effects on other tissues may have an important role in the management of osteoporosis in women in the near future. In men, androgen deficiency has been shown to be associated with osteoporosis. Although androgen replacement in hypogonadal men may decrease bone resorption and increase bone mass, long-term placebo-controlled trials are needed to better define the benefits and risks of such therapy before it can be recommended. Sex hormone deficiency is linked to the development of osteoporosis in both women and men. In women, hormonal replacement by estrogen or the newly developed selective estrogen receptor modulators may prevent the development of osteoporosis and its related fractures. In men, there is early evidence that testosterone replacement therapy may enhance bone mass in hypogonadal men.     

选择性雌激素受体调节剂雷洛昔芬阻止去卵巢大鼠骨丢失的机制

目的　了解选择性雌激素受体调节剂雷洛昔芬 (RLX)阻止去卵巢大鼠骨丢失的机制。对骨质疏松症模型大鼠进行雌激素及选择性雌激素受体调节剂类药物RLX治疗 ,观察其对去卵巢大鼠骨组织光镜、电镜及骨密度 (BMD)等各种指标的影响。　方法　用 3月龄雌性SD大鼠 32只 ,随机分为卵巢未切除组、卵巢切除组、雌激素治疗组、RLX治疗组 ,5个月后处死 ,检测股骨、腰椎及全身BMD、子宫重量、骨形态。　结果　卵巢切除组经RLX治疗 3个月后腰椎、股骨、全身BMD增加35 %、4 0 %、2 1% ,分别为 (0 2 5 6± 0 0 2 2 ) g/cm2 、(0 2 93± 0 0 15 ) g/cm2 和 (0 36 8± 0 0 2 5 ) g/cm2 ;RLX组大鼠骨小梁表面的破骨细胞数比卵巢切除组减少 ;与卵巢切除组相比 ,雌激素治疗组的子宫重量增加了 5 5 % ,而RLX组则对子宫无明显刺激作用。　结论　RLX及雌激素都具有防治骨质疏松的作用 ,RLX能阻止去卵巢所造成的骨丢失。     

骨质疏松症的联合治疗与序贯治疗

联合和序贯治疗骨质疏松症是为了追求更大疗效的一种选择,本文检索分析近45年来发表的此类临床研究结果。目前尚无证据表明两种抗骨吸收联合治疗有降低骨折发生率的叠加作用（如双膦酸盐加ERT或雷洛昔芬,雌激素加降钙素）,仅观察到联合治疗可以降低骨转换和增加骨密度的结果。联合甲状腺激素（PTH）同抗骨吸收药物,随着药物的不同对骨密度的效果各异。在停止使用促进骨形成剂PTH后序贯使用双膦酸盐、雷洛昔芬或锶盐,可以防止因停用PTH后的骨丢失,可能成为未来治疗严重的绝经后骨质疏松症的重要选择。     

Effects of raloxifene on bone mineral metabolism in postmenopausal Japanese women on hemodialysis

In addition to renal osteodystrophy, postmenopausal women on hemodialysis are at high risk for osteoporosis. Recent studies reported the effects of raloxifene, a selective estrogen receptor modulator for osteoporosis, in postmenopausal women. The present study evaluated the efficacy of raloxifene and its effects on bone mineral metabolism in postmenopausal Japanese patients on dialysis. In a prospective, multicentre study, 17 postmenopausal women on chronic hemodialysis with severe osteoporosis (bone mineral density [BMD]≤2 SD by bone densitometry) were treated with 60 mg/day raloxifene hydrochloride for 12 months. The study also included 10 age-matched control women. Vitamin D and calcium salts were not changed during the study. Intact parathyroid hormone (iPTH), serum calcium and phosphorus, and bone resorption marker (NTx) were measured, and BMD were determined by DEXA, at 0, 6, and 12 months after administration of raloxifene. The mean lumbar spine BMD at baseline was similar in the two groups. Raloxifene therapy (for 12 months) improved lumbar spine BMD (by 2.6%) in 53% of the patients, while 70% of the control group showed a reduction in BMD (by 4.0%). Raloxifene significantly decreased serum calcium and increased iPTH. Our results suggested that raloxifene improved trabecular BMD in postmenopausal Japanese women on hemodialysis. The effects of raloxifene on serum calcium and serum iPTH level suggest it improves bone resorption. Vitamin D and/or calcium salts should be added to raloxifene treatment to avoid secondary hyperparathyroidism.     

Osteoporosis: gender differences and similarities.

Although osteoporosis has traditionally been considered a disease of women, men also incur substantial bone loss with aging, and elderly men have age-specific hip fracture incidence rates and vertebral fracture prevalence rates that are at least half those in women. Early postmenopausal bone loss (which results in the syndrome of type I osteoporosis) is due to the direct skeletal consequences of estrogen deficiency, manifested by an increase in bone resorption without an adequate increase in bone formation. Recent evidence indicates that even late postmenopausal bone loss (type II or 'smile' osteoporosis) in women may be due to estrogen deficiency. In particular, the late consequences of estrogen deficiency in elderly women result in abnormalities in calcium homeostasis and increases in parathyroid hormone secretion, leading to increased bone resorption and bone loss. The etiology of bone loss in aging men has remained relatively unclear. Recent evidence from a male deficient in estrogen receptor-alpha and in two males with aromatase deficiency indicate that estrogen may play a significant role in bone metabolism in men. Moreover, several large epidemiologic studies have found that bone mineral density correlates better with serum estrogen than testosterone in aging men. Thus estrogen deficiency may lead to bone loss in men.     

Bisphosphonate treatment of osteoporosis

Bisphosphonates represent the agents of choice for most patients with osteoporosis. They are the best studied of all agents for the prevention of bone loss and reduction in fractures. They increase BMD, primarily at the lumbar spine, but also at the proximal femur. In patients who have established osteoporosis, bisphosphonates reduce the risk of vertebral fractures, and are the only agents in prospective trials to reduce the risk of hip fractures and other nonvertebral fractures. Bisphosphonates reduce the risk of fracture quickly. The risk of radiographic vertebral deformities is reduced after 1 year of treatment with risedronate [68]. The risk of clinical vertebral fractures is reduced after 1 year of treatment with alendronate [69] and just 6 months' treatment with risedronate [157]. The antifracture effect of risedronate has been shown to continue through 5 years of treatment [158]. Alendronate and risedronate are approved by the FDA for prevention of bone loss in recently menopausal women, for treatment of postmenopausal osteoporosis, and for prevention (risedronate) and treatment (alendronate and risedronate) of glucocorticoid-induced osteoporosis. Alendronate is also approved for treatment of osteoporosis in men. Other bisphosphonates (etidronate for oral use, pamidronate and zoledronate for intravenous infusion) are also available and can be used off label for patients who cannot tolerate approved agents. Although bisphosphonates combined with estrogen or raloxifene produce greater gains in bone mass compared with single-agent treatment, the use of two antiresorptive agents in combination cannot be recommended because the benefit on fracture risk has not been demonstrated and because of increased cost and side effects.     

Lasofoxifene (CP-336,156), a novel selective estrogen receptor modulator,in preclinical studies

Estrogen replacement therapy is reported to reduce the incidence of vertebral fractures in postmenopausal women, however, its compliance is limited because of side effects and safety concerns. Estrogen’s side effects on breast and uterine tissues leading to the potential increased risk of uterine and breast cancer limit widespread estrogen usage. Thus, there is a significant medical need for a therapy that protects against postmenopausal bone loss but is free of estrogen’s negative effects on reproductive tissues. Selective estrogen receptor modulators (SERMs) have been investigated as an alternative to hormone replacement therapy. One such compound, raloxifene, has been approved for the prevention and treatment of osteoporosis. Lasofoxifene (LAS), a new, nonsteroidal, and potent SERM, is an estrogen antagonist or agonist depending on the target tissue. LAS selectively binds with high affinity to human estrogen receptors. In ovariectomized (OVX) rat studies, LAS prevented the decrease in femoral bone mineral density, tibial and lumbar vertebral trabecular bone mass at an ED₁₀₀ of about 60 μg/kg/day. LAS inhibited the activation of trabecular and endocortical bone resorption and bone turnover in tibial metaphyses and diaphyses, and lumbar vertebral body in OVX rats. In addition, LAS decreased total serum cholesterol, inhibited body weight gain and increased soleus muscle weight in OVX rats. Similarly, LAS prevented bone loss induced by orchidectomy or aging in male rats by decreasing bone resorption and bone turnover while it had no effect in the prostate. Further, LAS decreased total serum cholesterol in intact aged male rats or in orchidectomized male rats. Synergestic skeletal effects were found with LAS in combination with bone anabolic agents such as prostaglandin E₂ (PGE₂), parathyroid hormone (PTH) or a growth hormone secretagoue (GHS) in OVX rats. In combination with estrogen, LAS inhibited the uterine stimulating effects of estrogen but did not block the bone protective effects of estrogen. In immature and aged female rats, LAS did not affect the uterine weight and uterine histology. In OVX adult female rats, LAS slightly but significantly increased uterine weight. These results demonstrated that LAS produced effects on the skeleton indistinguishable from estrogen in female and male rats. However, unlike estrogen, LAS had little effect on uterine weight and cellular proliferation of uterus in female rats. In preclinical anti-tumor studies, LAS inhibited human breast cancer growth in mice bearing MCF7 tumors, prevented NMU-induced mammary carcinomas and possessed chemotherapeutic effects in NMU-induced carcinomas in rats. Therefore, we conclude that LAS possesses the antiestrogenic effects in breast tissue and estrogenic effects in bone and serum cholesterol, but lacks estrogen’s side effects on uterine tissue. These data support the therapeutic potential of LAS for the prevention and treatment of postmenopausal bone loss and mammary carcinomas in humans.