Nitric oxide: new evidence for novel therapeutic indications

Background: Nitric oxide (NO) deficiency is implicated in many pathophysiological processes in mammals. NO is a ubiquitous molecule involved in multiple cellular functions. Uncontrolled or inappropriate production of NO may lead to several disease states including septic shock, rheumatoid and inflammatory arthropathies, and expansion of cerebral damage after stroke. However, to date, there are no therapeutic agents available that can overcome these conditions. Similarly, underproduction of NO by NO synthase or enhanced breakdown of NO also leads to diseases such as hypertension, ischemic conditions, pre-eclampsia, premature delivery, among others. NO donor therapies are indicated in these conditions. Results: Nitroglycerin and nitrates (NO donors) have been used as therapeutic agents for the past century, particularly to treat vascular disease, and the only significant adverse effects are headaches. NO donors are highly cost-effective and have beneficial effects in multiple body systems. When the body cannot generate NO via NO synthase or due to rapid turnover leading to inadequate amounts of NO available for biological homeostasis, administration of exogenous NO, or prolongation of the actions of endogenous NO, are practical ways to supplement NO. Conclusion: Recipients of such therapy include patients with angina pectoris, coronary artery disease, hypertension, osteoporosis, gastrointestinal motility disorders, pregnancy-related disorders including premature delivery, pre-eclampsia, vulvodynia, and erectile dysfunction in men. Postmenopausal NO deficiency is rectified with hormone replacement therapy, which enhances local production of NO. Declining local NO production secondary to estrogen deficiency in postmenopausal women and perhaps in older men could be one of the reasons for age-related increased incidences of cardiovascular events and sexual dysfunction. Thus, in addition to supplementation of NO compounds in acute situations like alleviating angina and erectile dysfunction, chronic NO therapy is cost-effective in decreasing cardiovascular events, and improving the urogenital system and skeletal health.     

Isoflavones extracted from<Emphasis Type="Italic">sophorae fructus</Emphasis> upregulate IGF-I and TGF-β and inhibit osteoclastogenesis in rat born marrow cells

Isoflavones have been a central subject in research on the natural phytoestrogens found in Leguminosae. Their effects on bone formation and remodeling are important in that they can act like estrogen by binding on estrogen receptors on the target cell surface. We, therefore, believed that isoflavones may help in the treatment of patients with estrogen deficiency disease such as estrogen replacement therapy (ERT) for osteoporosis. As commonly known, osteoporosis is one of the hormonal deficiency diseases, especially in menopausal women. When estrogen is no longer produced in the body a remarkable bone remodeling process occurs, and the associated events are regulated by growth factors in the osteoblast lineage. In the present study, we investigated whether isoflavones (Isocal) extracted from Sophorae fructus affect the growth factors IGF-I and TGF-beta that have been known to be related with bone formation. In the study, we found that the active control (PIII) effectively enhanced the level of nitric oxide (NO) and growth factors, and thereby inhibited osteoclastogenesis. The most efficient concentration was 10(-8)% within five days, whereas the comparative control (soybean isoflavone) was not as effective even at a lower concentration. In conclusion, the products which contain enriched glucosidic isoflavone and nutrient supplements such as shark cartilage and calcium can be used for osteoporosis therapy by enhancing the production of IGF-I and TGF-beta. Furthermore, the NO produced through endothelial constitutive NO synthase (ecNOS) may play a role in inhibiting bone reabsorption.     

Developing drugs to treat osteoporosis: lessons learned?

Background: Selective estrogen-receptor modulators (SERMs) are drugs that act as estrogen receptor agonists or antagonists depending on the target tissue. Theoretically this class of agents would be an ideal substitute for hormone replacement therapy (HRT), if their effects on the skeleton matched those of estrogen while their actions on other tissues were either neutral or beneficial. Objective: To evaluate a Phase III trial of a new SERM, arzoxefine, for prevention of osteoporosis in younger postmenopausal women. Methods/results: Arzoxifene induced modest but significant increases in bone mineral density versus a control group during 2 years of therapy, with minor adverse events. However, fracture efficacy and other patient-specific outcomes were not evaluated. Conclusion: Despite a positive study of surrogate end points (bone density and biochemical markers of bone turnover), arzoxifene was withdrawn from further FDA evaluation, principally because of long-term side effects and lack of non-vertebral fracture efficacy in the companion Phase III fracture study. Each SERM has a unique profile on bone and other tissues. Regulatory approval of this class of agents may remain problematic for the immediate future.     

Risk factors for osteoporosis

SUMMARY

Background: Although postmenopausal African–American women are at lower risk for osteoporosis-related fractures compared with white women, fractures in African–American women are associated with significantly higher morbidity and mortality. Therefore, early diagnosis and treatment of osteoporosis in this population is just as important as it is for other ethnic groups and worthy of the attention of physicians and healthcare organizations.

Objective: The purpose of this study was to evaluate risk factors for osteoporosis in postmenopausal African–American women.

Design: This was a retrospective, case-control study in 201 postmenopausal African–American women at a community-based osteoporosis center. Spine and hip bone mineral density measurements were obtained by dual-energy x-ray absorptiometry. Patient and family medical history, past and present pharmaceutical use, and dietary and exercise habits were collected using a patient self-administered questionnaire.

Results: Using the manufacturer's African–American referent database, 56 women had osteoporosis, 99 had osteopenia, and 46 had normal bone mineral density. Risk factors more common in the osteoporotic group compared with the normal group included sedentary lifestyle (P < 0.03), family history of osteoporosis (P < 0.03), low body mass index (P < 0.05), and history of bilateral oophorectomy (P < 0.03). Polyarthritis was more prevalent in the normal versus the osteoporotic group (P < 0.001). In addition, premenopausal use of oral contraceptives (P < 0.005) and postmenopausal use of estrogen therapy (P < 0.05) were more common in the normal compared with the osteoporotic group.

Conclusions: Many risk factors for osteoporosis in African–American women are similar to those in white women and can aid in the selection of patients in need of bone density testing.     

Effects of ginkgo biloba on <Emphasis Type="Italic">in vitro</Emphasis> osteoblast cells and ovariectomized rat osteoclast cells

Ginkgo biloba extract (GBE) has a selective estrogen receptor modulator (SERM)-like biphasic effect on estrogen, and could be a potential alternative to hormone replacement therapy (HRT). Here, we investigated whether GBE can ameliorate estrogen-depleted osteoporosis in in vitro osteoblast cells and in estrogen-deprived ovariectomized (OVX) rats, a classical animal model for postmenopausal osteoporosis. GBE (50–150 μg/mL) significantly increased ALP (Alkaline phosphatase) activity of osteoblast cells, indicating that GBE promotes osteoblast mineralization. OVX rats exposed to GBE (100 and 200 mg/kg/day, oral treatment), raloxifene (3 mg/kg/day, oral treatment) or estradiol (E₂, 10 μg/kg/day, subcutaneous injection) decreased osteoclast resorptive activity compared with OVX rats. GBE and raloxifene did not increase uterine weight compared with OVX rats, while E₂ and Sham control did, suggesting that GBE has no uterotrophic activity, which is a disadvantage of estrogen therapy. In OVX rats, GBE did not restore severe bone density loss induced by OVX, indicating that GBE may be insufficient as therapeutic material for severe osteoporosis. However, despite its no effects on bone density loss in OVX rats, GBE did stimulate osteoblast differentiation and antiosteoclastic activity in vitro. Therefore, GBE may have preventive potential on osteoporosis as do other phytoestrogens.     

Drug Evaluation Oncologic,Endocrine & Metabolic: Alendronate (Fosamax®): clinical utility in metabolic bone disease

Alendronate is a member of the class of drugs known as bisphosphonates, potent inhibitors of bone resorption which act via inhibition of osteoclast function. Unlike first generation bisphosphonates, alendronate does not appear to have deleterious effects on bone mineralisation at doses which inhibit bone resorption. Bisphosphonates have been studied in the management of a broad range of skeletal disorders characterised by increased bone turnover, including hypercalcaemia of malignancy, metastatic bone disease, primary and secondary hyperparathyroidism, and Paget's disease of bone. More recently, bisphosphonates have also been studied in the prevention and treatment of established bone loss in patients with osteoporosis. In this respect, alendronate has recently been shown to increase bone mass in the spine, femoral neck and total body of postmenopausal women with osteoporosis, and to reduce the incidence of vertebral, hip and wrist fractures, the progression of vertebral deformities and height loss in these subjects. The drug appears to be safe and well tolerated apart from a low incidence of chemical oesophagitis. Alendronate therefore offers a promising alternative to hormone replacement therapy for treatment of osteoporosis in postmenopausal women and may also play a role in the management of other types of osteoporosis.     

Formononetin prevents ovariectomy-induced bone loss in rats

The major risk factor of postmenopausal osteoporosis is estrogen deficiency. Hormone replacement therapy is efficacious against osteoporosis, but it induces several significant adverse effects. In this study, therefore, we compared therapeutic potencies of three phytoestrogens: genistein, daidzein, and formononetin. Our result showed that in Saos-2 cells, formononetin and genistein (5 × 10⁻⁷ M) treatment increased alkaline phosphatase activity by 33.0 ± 5.8% and 21.1 ± 4.0%. Genistein inhibited osteoclast formation in a dose-dependent manner. In OVX rats, formononetin-treated groups given 1 and 10 mg/kg/day displayed increased trabecular bone areas (TBAs) within the tibia. Genistein- and daidzein-treated groups also displayed increased tibial TBAs. TBAs of the lumbar vertebrae were higher in all treated groups than in the control group. In conclusion, formononetin as well as other isoflavones, such as daidzein and genistein, inhibited bone loss caused by estrogen-deficiency.     

The role and efficacy of denosumab in the treatment of osteoporosis: an update

Introduction: Bone strength determinants such as bone mineral density and bone quality parameters are determined by life-long remodeling of skeletal tissue. Denosumab is a fully human mAb receptor activator of NF-κB ligand, which selectively inhibits osteoclastogenesis, the end product of a cascade interaction among numerous systemic and local factors and osteoblasts. It has been approved for clinical use by the FDA in the US and by the European Medicines Agency in Europe since June 2010 (trade name Prolia^?, Amgen, Thousand Oaks, CA, USA).

Areas covered: This review establishes the concerns and provides insights in issues concerning the cost-effectiveness and safety profile of this new pharmaceutical agent. There is an effort to clarify the special characteristics and the anti-catabolic role of denosumab in the bone tissue homeostasis and more specifically its potential clinical applications and clinical results in the field of postmenopausal osteoporosis.

Expert opinion: Administrated as a subcutaneous injection every 6 months, denosumab has been shown to decrease bone turnover and increase bone mineral density in postmenopausal women with low bone mass or osteoporosis and reduce vertebral, hip and nonvertebral fracture risk in postmenopausal women with osteoporosis. The rapid, sustained and reversible effect in suppressing osteoclastic bone resorption, the return of responsiveness on rechallenge, its good tolerability and ease of administration are features that distinguish it from other antiresorptive therapies.     

Treatment of osteoporosis and reduction in risk of invasive breast cancer in postmenopausal women with raloxifene

INTRODUCTION: Raloxifene, a non-steroidal selective estrogen receptor modulator (SERM), offers a new dimension for the treatment and prevention of osteoporosis and risk reduction of invasive breast cancer in postmenopausal populations at high risk. Both osteoporosis and breast cancer are important public health issues for postmenopausal women. It is well known that estrogen and estrogen receptors play an important role in the pathogenesis of both diseases. Initially, hormone replacement therapy (HRT) was used for the purpose of preventing and treating postmenopausal osteoporosis. However, HRT significantly contributed to an increase in breast cancer risk. The SERM, raloxifene, is used for the prevention and for the treatment of postmenopausal osteoporosis and reducing the risk of invasive breast cancer in postmenopausal women. AREAS COVERED: This article reviews the emerging evidence of the efficacy of raloxifene in postmenopausal women, summarizes the results and places in perspective their therapeutic uses for women having either a high risk of osteoporosis or breast cancer. Emerging clinical evidence suggests bisphosphonates, currently used as drugs for the treatment of osteoporosis, may also reduce breast cancer risk. The status of other SERMs and bisphosphonates are included for completeness. A Medline search of raloxifene, osteoporosis, breast cancer and SERMs was used to derive a database of 355 references. EXPERT OPINION: Readers will understand the value of raloxifene to prevent osteoporosis and breast cancer in postmenopausal women. Although most women do not require pharmacotherapy for menopausal symptoms, many are severely affected by osteoporosis or breast cancer at and beyond menopause and, for such women, pharmacologic intervention is important if they are to retain an acceptable quality of life. It is reasonable to use raloxifene or bisphosphonate as an appropriate drug that targets symptom-free postmenopausal women for treatment and prevention of osteoporosis but raloxifene is proven to reduce the incidence of invasive breast cancer.     

Transdermal estradiol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of menopausal complaints

The estradiol transdermal therapeutic system is a cutaneous delivery device which delivers estradiol into the systemic circulation via the stratum corneum at a constant rate for up to 4 days. Physiological levels of estradiol (the major estrogen secreted by the ovaries in premenopausal women) can therefore be maintained in postmenopausal women with low daily doses because first-pass hepatic metabolism is avoided. In short term clinical studies, the beneficial effects of transdermal estradiol on plasma gonadotrophins, maturation of the vaginal epithelium, metabolic parameters of bone resorption and menopausal symptoms (hot flushes, sleep disturbance, genitourinary discomfort and mood alteration) appear to be comparable to those of oral and subcutaneous estrogens, while the undesirable effects of oral estrogens on hepatic metabolism are avoided. As with oral or injectable estrogen replacement therapy, concomitant sequential progestagen is recommended for patients with an intact uterus during transdermal estradiol administration, in order to reduce endometrial stimulation. Transdermal estradiol has been well tolerated in clinical trials, with local irritation at the site of application being the most common adverse effect. The incidence of systemic estrogenic effects appears to be comparable to that observed with oral therapy. Thus, transdermal estradiol offers near-physiological estrogen replacement in postmenopausal women in a convenient low-dose form which may avoid some of the complications of higher dose oral therapy. Long term epidemiological studies are warranted to determine whether transdermal estradiol therapy provides protection against osteoporosis and fractures and cardiovascular disease equivalent to that offered by oral and injectable estrogens. However, despite the importance of such data, it seems reasonable to conclude at this stage of its development that transdermal estradiol represents an important advance in hormone replacement therapy.     

Risk factors for osteoporosis in postmenopausal African-American women

BACKGROUND: Although postmenopausal African-American women are at lower risk for osteoporosis-related fractures compared with white women, fractures in African-American women are associated with significantly higher morbidity and mortality. Therefore, early diagnosis and treatment of osteoporosis in this population is just as important as it is for other ethnic groups and worthy of the attention of physicians and healthcare organizations. OBJECTIVE: The purpose of this study was to evaluate risk factors for osteoporosis in postmenopausal African-American women. DESIGN: This was a retrospective, case-control study in 201 postmenopausal African-American women at a community-based osteoporosis center. Spine and hip bone mineral density measurements were obtained by dual-energy x-ray absorptiometry. Patient and family medical history, past and present pharmaceutical use, and dietary and exercise habits were collected using a patient self-administered questionnaire. RESULTS: Using the manufacturer's African-American referent database, 56 women had osteoporosis, 99 had osteopenia, and 46 had normal bone mineral density. Risk factors more common in the osteoporotic group compared with the normal group included sedentary lifestyle (P < 0.03), family history of osteoporosis (P < 0.03), low body mass index (P < 0.05), and history of bilateral oophorectomy (P < 0.03). Polyarthritis was more prevalent in the normal versus the osteoporotic group (P < 0.001). In addition, premenopausal use of oral contraceptives (P < 0.005) and postmenopausal use of estrogen therapy (P < 0.05) were more common in the normal compared with the osteoporotic group. CONCLUSIONS: Many risk factors for osteoporosis in African-American women are similar to those in white women and can aid in the selection of patients in need of bone density testing.     

Relationship between bone mass,invasive breast cancer incidence and raloxifene therapy in postmenopausal women with low bone mass or osteoporosis

ABSTRACT

Objective: To evaluate the relationship between bone mass and risk of breast cancer and to determine the effect of raloxifene therapy on breast cancer incidence in women categorized by bone mass into low bone mass and osteo­porosis subgroups.

Design: In this post hoc analysis, data were analyzed from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, enrolling postmenopausal women with low bone mass (N = 7705), and the Continuing Outcomes Relevant to Evista (CORE) trial, a follow-up to MORE enrolling 4011 MORE participants. Total follow-up was for up to 8 years. Women with a total hip bone mineral density (BMD) T-score <?–1 to >?–2.5 or T-score ≤?–2.5 (referent, NHANES III database) were classified as having low bone mass or osteoporosis, respectively. Women with a pre-existing vertebral fracture were considered as having osteoporosis irrespective of BMD T-score. Analyses were performed for invasive breast cancers and invasive estrogen-receptor (ER) positive breast cancers.

Results: Women with low bone mass (N = 3829) had a twofold higher incidence of invasive ER-positive breast cancer than those with osteoporosis (N = 3836) (HR 2.13, 95% CI 1.12–4.03). The incidence of all invasive breast cancers did not differ significantly between the bone mass groups. The incidences of invasive and invasive ER-positive breast cancers were 65–78% lower in women assigned raloxifene versus placebo in both the low bone mass and osteoporosis groups (?p < 0.05).

Conclusions: In this post hoc analysis of postmeno­pausal women participating in MORE and CORE, bone mass was a predictor of invasive ER-positive breast cancer. Raloxifene treatment reduced the risk of invasive and invasive ER-positive breast cancers in women with low bone mass and those with osteoporosis. Since participants were older postmenopausal women with low bone mass, whether these findings can be generalized to other postmenopausal women is unclear.     

雌激素治疗绝经后骨质疏松的Meta-分析

目的 系统评价雌激素类药物治疗绝经后骨质疏松的疗效及安全性。方法 检索PubMed、EMbase、CochraneLibrary、中国生物医学文献数据库（CBM）、中国学术期刊全文数据库（CNKI）、维普中文期刊全文数据库（VIP）和万方数据库中关于雌激素治疗绝经后骨质疏松的临床随机对照研究（RCT），依据纳排标准纳入文献，运用软件ReviewManager 5.0和Stata 14.0进行疗效和安全性的系统评价。结果 共纳入15篇RCTs，包括13 280例患者。结果表明雌激素类药物对改变绝经后骨质疏松患者的腰椎骨密度［MD=1.08，95% CI（0.75，1.40），P<0.001］、椎体骨折发生率［OR=0.61，95% CI（0.52，0.71），P<0.001］、血清骨钙素［MD=-16.03，95% CI（-18.68，-13.67），P<0.001］等指标具有特异性。网状Meta-结果表明雌激素中巴多昔芬对于提高腰椎BMD的效果最好。雌激素治疗极少发生严重不良反应，普通不良反应发生率（潮热、肌肉痉挛等）较低。结论 雌激素类药物对绝经后骨质疏松的治疗具有积极意义，显著减低了椎体骨折发生率并改善了患者的骨密度；雌激素类药物治疗的不良反应发生率较低，安全性高。     

Transdermal estradiol. A review of its pharmacological profile, and therapeutic potential in the prevention of postmenopausal osteoporosis.

The estradiol transdermal therapeutic system is a percutaneous delivery device which, when affixed to the skin, delivers estradiol (the major estrogen in premenopausal women) into the systemic circulation at a constant rate for up to 4 days. Because this method of delivery avoids first-pass hepatic metabolism, premenopausal levels of estradiol can be maintained in postmenopausal women using very low dosages. Bone density decreases at an accelerated rate after the menopause, which can lead to development of osteoporosis and increased fracture risk. In common with other estrogen therapies, transdermal estradiol provides protection against osteoporosis following spontaneous or surgical menopause, as evidenced by both biochemical markers of bone resorption and, in a small number of studies, measurement of bone mineral density. Protection against further vertebral fractures was also demonstrated in women with established osteoporosis in one study. Transdermal estradiol also has beneficial effects on vaginal cytology and menopausal symptoms similar to those of oral estrogens. The tolerability of transdermal estradiol appears to be very good, the most common adverse effect being local irritation at the application site. As with other estrogens, transdermal estradiol can be given continuously or in 4-week (3 weeks on/1 week off) cycles, and concomitant progestogen therapy is recommended in women with intact uteri, in order to minimise the risk of endometrial hyperplasia. Available evidence thus suggests that transdermal estradiol may represent an attractive alternative to other forms of estrogen therapy for the prevention, and possibly treatment, of postmenopausal osteoporosis.     

Raloxifene hydrochloride.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and therapeutic role of raloxifene hydrochloride are reviewed. Raloxifene is a selective estrogen-receptor modulator (SERM) that has been approved for use in the prevention and treatment of osteoporosis in postmenopausal women. A SERM interacts with estrogen receptors, functioning as an agonist in some tissues and an antagonist in other tissues. Because of their unique pharmacologic properties, these agents can achieve the desired effects of estrogen without the possible stimulatory effects on the breasts or uterus. Raloxifene is rapidly absorbed from the gastrointestinal tract and undergoes extensive first-pass glucuronidation. Approximately 60% of a dose is absorbed; however, absolute bioavailability is only 2%. The volume of distribution is 2348 L/kg for a single oral dose of 30-150 mg, and the elimination half-life averages 32.5 hours. In clinical trials in postmenopausal women, raloxifene had an estrogen-like effect on bone turnover and increased bone mineral density. It reduced the risk of fractures in women with osteoporosis. Raloxifene also seemed to reduce the risk of breast cancer and positively influenced blood lipid markers of cardiovascular disease. Raloxifene is generally well tolerated; the most common adverse effects are hot flashes and leg cramps. A serious adverse effect is venous thromboembolism. The recommended dosage is 60 mg/day orally without regard to meals. Ultimately, it will be information on cardiovascular or breast cancer benefits that will determine the future role of raloxifene. Raloxifene is an alternative to traditional hormone replacement therapy for the prevention and treatment of osteoporosis in selected postmenopausal women. More study is needed to verify possible benefits related to heart disease and breast cancer.     

Lasofoxifene,a new selective estrogen receptor modulator for the treatment of osteoporosis and vaginal atrophy

Selective estrogen receptor modulators (SERMs) represent a class with a growing number of compounds that act as either estrogen receptor (ER) agonists or antagonists in a tissue-specific manner. The purpose of this article is to review the effects of lasofoxifene, a new-generation SERM that has completed the Phase III development program for the prevention and treatment of osteoporosis and vaginal atrophy in postmenopausal women. This compound selectively binds to both ERs with high affinity. Lasofoxifene also has a remarkably improved oral bioavailability with respect to other SERMs such as raloxifene and tamoxifen, owing to increased resistance to intestinal wall glucuronidation. In both preclinical and short-term clinical studies, this compound showed a favorable safety profile and demonstrated a proven efficacy in preventing bone loss and lowering cholesterol levels. More recently, Phase III clinical trials have confirmed the efficacy and safety of this new SERM in the prevention of bone loss and vertebral and nonvertebral fractures. Moreover, in postmenopausal women with osteoporosis, lasofoxifene treatment also reduced ER positive breast cancer risk and the occurrence of vaginal atrophy. With its increased potency and efficacy on the prevention of nonvertebral fractures and its positive effects on the vagina, this new SERM may represent an alternative therapy for osteoporosis in postmenopausal women.     

A risk-benefit assessment of estrogen therapy in postmenopausal women

Estrogen therapy is extremely effective in relieving menopausal symptoms such as hot flushes, night sweats, urogenital atrophy and certain psychological symptoms. The short term side effects from this therapy are usually mild and self-limiting. They are more common in women who commence hormone replacement therapy some years after the menopause than in those who start treatment at about the time of the ovarian failure. Pre-existing gynaecological conditions such as fibroids and endometriosis can be worsened by estrogen therapy. The majority of published studies suggest a beneficial effect of postmenopausal estrogen therapy on cardiovascular and cerebrovascular disease. These effects may be mediated by favourable changes in lipids, but other mechanisms may also be involved. It is uncertain whether the adverse changes in lipids caused by progestogen therapy will reduce any of the benefits of estrogen therapy on the cardiovascular system. Osteoporosis is the major bone disease of the Western world; long term estrogen therapy will prevent its development in most postmenopausal women. The risk of endometrial carcinoma is increased with unopposed estrogen therapy; this increased risk appears to be abolished if a progestogen is added at an adequate dose and duration for each cycle. The risk of ovarian or cervical cancer is not increased with estrogen therapy. There may be an increased risk of breast carcinoma with long term postmenopausal estrogen use, but the studies show inconsistent results.     

雌激素加钙剂与钙剂对比治疗绝经后妇女骨质疏松症的骨密度测定分析

目的 对使用雌激素加钙剂与钙剂治疗绝经后骨质疏松症妇女的骨密度进行测定分析。方法 将绝经后患骨质疏松症的妇女分成两组,一组75例,每天口服结合型雌激素（贝美力）0.3mg加含钙元素1g的钙剂,连脬6个月;另一组37例,每天口服含钙元素1g的钙剂,连服6个月,用以色列MYRIAD-SOUNDSCAN-2000型骨量超声测定仪检测胫骨中段骨密度。结果 口服雌激素加钙剂组骨密度总有效率100%,口服钙剂组骨密度总有效率70.3%。结论 使用雌激素加钙剂与钙剂均可以达到增加绝经后妇女的骨密度,预防和治疗绝经后骨质疏松症的目的,使用雌激素加钙剂较单补钙剂疗效更好。     

Full length parathyroid hormone,PTH(1-84), for the treatment of severe osteoporosis in postmenopausal women

ABSTRACT

Objective: To review and analyse the evidence supporting the use of full length parathyroid hormone, PTH(1-84), in the treatment of osteoporosis based on a search of several literature sources; articles selected for review were published between 1990 and 2008.

Background: PTH(1-84) is approved for the treatment of osteoporosis in postmenopausal women at high risk of fracture in Europe. It was well tolerated in clinical trials and demonstrated bone building properties and fracture prevention particularly for the lumbar spine in the treatment of postmenopausal women.

Results: The TOP clinical trial showed that PTH(1-84) treatment for 18 months resulted in a 61% reduction (p = 0.001) in new vertebral fracture incidence when compared with placebo and reduced the risk of a first vertebral fracture by 68% (p = 0.006) in women without a prevalent fracture at baseline. PTH(1-84) increased bone mineral density (BMD) at vertebral and non-vertebral sites the lumbar spine BMD increasing regardless of T-score, age, prior osteoporosis therapy or number of years post-menopause. The PaTH study showed that treatment with PTH(1-84) for 12 months increased BMD at the trabecular spine and hip. Lumbar spine BMD gains were largest with sequential administration of PTH(1-84) followed by alendronate but were smaller with concurrent administration involving anabolic and antiresorptive agents. Lumbar spine BMD increases were also seen in trials involving PTH with raloxifene and PTH in combination with hormone replacement therapy.

Conclusions: PTH(1-84) has demonstrated effective bone building qualities and extends the therapeutic options available to osteoporotic women. The use of PTH(1-84) followed by sequential administration of an antiresorptive has proved effective at increasing trabecular BMD and points towards new treatment regimens offering improvements in BMD and fracture prevention.     

Hormone Replacement Therapy and Breast Cancer: Revisiting the Issues

ObjectiveTo assess current ideas about the benefits and risks of estrogen and hormone replacement therapy (ERT/HRT) in post·menopausal women.Data SourcesMEDLINE searches, supplemented by various texts, of the literature on HRT, ERT, and selective estrogen receptor modulators (SERMs): tamoxifen, toremifene, and raloxifene.Data SynthesisHRT is primarily used for improving quality of life in women suffering from vasomotor symptoms associated with menopause. HRT is beneficial in postmenopausal women for preventing cardiovascular disease, osteoporosis, and Alzheimer's disease. Review of meta-analyses of clinical trials showed that ERT/HRT ever·users (patients who have ever used ERT/HRT) did not have an increased risk of breast cancer, but current users did have an increased risk, with some studies reporting increasing risk with duration of ERT. No relationship was found between dose or the addition of progestin to ERT and increased breast cancer risk. Overall breast cancer mortality rates associated with HRT were decreased in current users. In general, HRT does not increase the risk of breast cancer in women with a family history of the disease, compared with those without a family history. New HRT strategies that could potentially prevent breast cancer are now being developed. The SERMs tamoxifen and toremifene appear to have positive clinical effects on bone and serum lipids; they are currently being investigated for use as breast cancer chemopreventive agents. Raloxifene, a new SERM used for the prevention of osteoporosis, is an alternative for women who cannot tolerate HRT. Unfortunately, these SERMS have anti-estrogenic effects and thus cause vasomotor adverse effects such as hot flashes and vaginal dryness. In addition, SERMs do not protect against heart disease or prevent osteoporosis as well as does HRT.ConclusionPresently, SERMs will not become first-line HRT, as the positive effects of ERT/HRT may out·weigh any potentially increased risk of breast cancer. The development of new agents with pharmacodynamic profiles similar to that of ERT/HRT but lacking its adverse effects would be greatly beneficial for postmenopausal women.