Postmenopausal osteoporosis management

Osteoporosis is perhaps the widest-ranging social, physical, and economic impact of estrogen deficiency. Postmenopausal bone loss is the major determinant of osteoporosis. Osteoporotic risk can be determined by measuring bone mineral density using dual X-ray absorptiometry. The radiation free quantitative bone ultrasound is emerging in the assessment of bone structure giving reliable estimates of fracture risk. Diet and exercise are important in determining a woman's risks for osteoporosis. Hormone replacement therapy clearly decreases bone turnover and prevents postmenopausal bone loss and reduces fractures. Tibolone as well as raloxifene prevent bone loss and solid data demonstrate a reduction of vertebral fractures after raloxifene administration.     

Bone metabolism and the perimenopause overview,risk factors,screening, and osteoporosis preventive measures

In summary, FDA-approved therapies for prevention and treatment of osteoporosis are all antiresorptive agents. There are no approved therapies at this time that stimulate bone formation, although one such agent (PTH) is awaiting approval. Screening perimenopausal women at risk should identify osteopenic women early in the menopause before the accelerated bone loss of estrogen deficiency causes further irreversible erosion in bone density. The National Osteoporosis Foundation advocates initiating therapy to reduce fracture risk in postmenopausal women with T scores below -2 in the absence or factors and with T scores below -1.5 if other risk factors are present. Estrogen, alendronate, residronate, and raloxifene have all been shown to reduce the incidence of radiographic vertebral fractures in women at risk. Only alendronate and residronate have been shown in large randomized trials to reduce the incidence of nonvertebral fractures including hip fractures in women with postmenopausal osteoporosis. These antiresorptive therapies provide benefits above and beyond those of calcium and vitamin D alone. There is insufficient published evidence from randomized controlled trials convincingly to support a role for soy products, androgens, calcitonin, or fluoride in prevention of postmenopausal osteoporosis or reduction of fracture rates in women at risk.     

Risk of fracture and treatment to prevent osteoporosis-related fracture in postmenopausal women. A review

OBJECTIVE: To review the antifracture efficacy of pharmacologic therapy approved by the U.S. Food and Drug Administration for the treatment of postmenopausal osteoporosis. STUDY DESIGN: For this literature review, published trials of antiresorptive therapy with the bisphosphonates risedronate and alendronate, the selective estrogen receptor modulator raloxifene and calcitonin were reviewed; hormone replacement therapy was not included as this modality is not indicated for treatment of osteoporosis. RESULTS: In controlled trials of postmenopausal women with osteoporosis, risedronate reduced the incidence of clinically evident vertebral fracture after 6 months of therapy and radiographically detected vertebral and nonvertebral fracture after 1 year. In similar trials, alendronate also reduced the risk of clinical vertebral fractures in 1 year. Risedronate and alendronate were both well tolerated, but some trials of alendronate were closed to women with recent upper gastrointestinal disease. In a large, controlled trial, raloxifene demonstrated a significant reduction in the risk of clinical vertebral fracture but not in the risk of nonvertebral fracture. Raloxifene is also associated with a 3-fold increased risk of thromboembolism. Calcitonin reduced the incidence of vertebral fracture, but there are no conclusive data on prevention of nonvertebral fracture. CONCLUSION: Antiresorptive therapy can reduce the risk of osteoporotic vertebral fracture. The bisphosphonates are also effective in reducing the risk of hip fracture in women with osteoporosis.     

绝经后妇女血清骨钙素水平及其它相关因素与骨质疏松关系的研究

应用放射免疫法和单光子骨密度测定法测定了１１３例绝经前后妇女的血清骨钙素水平（ＢＧＰ）、尺桡骨平均骨密度（ＢＭＤ），并测定了甲状旁腺激素（ＰＴＨ）、降钙素（ＣＴ）、雌二醇（Ｅ２）等多种骨代谢参数。结果：绝经后妇女血清ＢＧＰ升高，绝经５年内升高最为明显，ＢＭＤ逐渐下降，ＢＧＰ与ＢＭＤ呈正相关，骨转换水平升高。提示绝经后妇女因缺乏雌激素存在骨质丢失。这一过程可能是在多种因素参与下，骨形成和骨吸收之间不平衡所致。     

Raloxifene in postmenopausal women

Since the diffusion of the WHI's trial and MWS results, which reported a negative risk/benefit balance of hormone therapy, the management of postmenopausal women has deeply changed over the last 2-3 years. In particular, for the prevention of osteoporosis, the use of other efficient agents tends now to be more widely recommended rather than estrogens. The SERMs with raloxifene are new molecules that have estrogen agonist effects on bone and estrogen antagonist or neutral effects on endometrial and breast tissue. The efficacy of raloxifene to inhibit postmenopausal bone loss as well as to reduce the incidence of vertebral fractures has been demonstrated in women at high risk for osteoporosis through a large randomized placebo-controlled trial involving several thousands of postmenopausal women (MORE trial). Furthermore, the extraskeletal effects of raloxifene might represent an advantage for a global management approach of postmenopausal women, although to date, its exclusive indication is namely the prevention of osteoporosis. However, the estrogen antagonist effects of raloxifene on breast tissue as well as its good safety profile with regard to both the endometrium and the risk of heart diseases are likely to make raloxifene of particular interest for women around the age of 60 years old. Adverse events associated with raloxifene only included an increase in the absolute risk of venous thromboembolism in a comparable manner as with estrogen therapy. Also, its lack of efficacy in reducing hot flushes or preventing vaginal dryness may limit its use in young symptomatic postmenopausal women. Also, its lack of reimbursement in women with no prior fragility fracture must be taken into account.     

Comparison of the effects of raloxifene and low-dose hormone replacement therapy on bone mineral density and bone turnover in the treatment of postmenopausal osteoporosis.

OBJECTIVE: The aim of the present study was to compare the effects of raloxifene and low-dose hormone replacement therapy (HRT) on bone mineral density (BMD) and bone turnover markers in the treatment of postmenopausal osteoporosis. METHODS: Forty-two postmenopausal osteoporotic women, who were randomized to receive raloxifene 60 mg or estradiol 1 mg/norethisterone acetate 0.5 mg daily for 1 year, were studied. All women received calcium 600 mg/day and vitamin D 400 IU/day. BMD and markers of bone turnover were measured at baseline and at 12 months. RESULTS: After 12 months of treatment, there were statistically significant increases in BMD in both groups at all sites (all p < 0.05). For the lumbar spine, the increase in BMD was 2.3% for raloxifene compared with 5.8% for low-dose HRT and corresponding values for total body BMD were 2.9% for raloxifene and 4.6% for low-dose HRT; the increases being significantly greater in the low-dose HRT group (p < 0.001 and p = 0.02, respectively). Although the increase in BMD at the hip was significant for both raloxifene (2.1%) and low-dose HRT (3.2%) compared with baseline, the difference between the two regimens did not reach statistical significance. The decrease in serum C-terminal telopeptide fragment of type I collagen and serum osteocalcin levels for the low-dose HRT group (-53% and -47%, respectively) was significantly greater than for the raloxifene group (-23% and -27%, respectively; both p < 0.01). CONCLUSIONS: In postmenopausal women with osteoporosis, low-dose HRT produced significantly greater increases in BMD of the lumbar spine and total body and greater decreases in bone turnover than raloxifene at 12 months.     

The role of the primary care physician in diagnosis and management of osteoporosis

It is estimated that 28,000,000 women in the United States have low bone mass (osteopenia) or osteoporosis. More than 1.5 million osteoporotic fractures occur annually. Because osteoporosis is asymptomatic until fracture occurs, early diagnosis requires both an awareness of risk and specific testing. The National Osteoporosis Foundation (NOF) has published guidelines for diagnosis and treatment, but these have important limitations. Bone mineral density (BMD) testing is the method of choice for diagnosis, and is more predictive of fracture risk than hypertension is of stroke or hypercholesterolemia is of myocardial infarction. Although the diagnosis of osteoporosis, as defined by the World Health Organization, is a T-score of < or =-2.5, the association between BMD and fracture risk is a continuous rather than threshold effect, and NOF guidelines suggest treating at higher T-scores, depending on risk factors. Important risk factors include age, current smoking, low body weight (<127 lbs.), maternal history of fracture, and personal history of fracture. Data from the National Osteoporosis Risk Assessment (NORA) study are presented, demonstrating the usefulness of peripheral BMD measurements in identifying postmenopausal women at risk of fracture. Several therapeutic options, including hormone replacement therapy, raloxifene, calcitonin, alendronate, and risendronate, are now available to the clinician. It can be argued that we currently have all necessary tools to eliminate osteoporosis and osteoporotic fracture.     

Fracture prevention in postmenopausal osteoporosis: a review of treatment options

Several treatment options are available to reduce the risk of fractures in postmenopausal women with or at risk for osteoporosis. A MEDLINE search was conducted to evaluate anti-fracture and adverse event data of osteoporosis therapies from trials in postmenopausal women. Among the anti-resorptive therapies, the bisphosphonates alendronate and risedronate have demonstrated consistent efficacy in reducing vertebral and nonvertebral fracture risk. Once-weekly alendronate and risedronate produced similar improvements in bone mineral density compared with their once-daily counterparts with similar tolerability. Daily injections of teriparatide resulted in statistically significant reductions in the risk of vertebral and nonvertebral fractures, and trials of ibandronate, raloxifene, and calcitonin nasal spray showed reductions in vertebral fracture risk. Hormone therapy has demonstrated clinical fracture risk reduction; however, safety outcomes from the Women's Health Initiative study have raised concerns regarding long-term use of these preparations. These data can guide clinical decision-making regarding the selection of an osteoporosis therapy. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to summarize adverse events data of osteoporosis therapies from trials in postmenopausal women, explain that only a few therapies have shown a consistent efficacy in reducing vertebral and nonvertebral fractures, and state that data from the Women's Health Initiative study have raised concerns regarding long-term use of estrogen-progestin therapy.     

Selektive Östrogenrezeptormodulatoren (SERM)

Background

Selective estrogen receptor modulators (SERMs) belong to a heterogeneous, nonsteroidal drug class that have estrogenic or anti-estrogenic properties, respectively.

Indications

Drug-specific indications are breast cancer treatment (tamoxifen), osteoporosis prevention and therapy (raloxifene, bazedoxifene), and infertility treatment (clomiphene). Furthermore, in some countries, tamoxifen and raloxifene are approved for breast cancer prevention in high-risk women. The newly approved combination of bazedoxifene and conjugated estrogens is an interesting possibility for the treatment of postmenopausal women suffering from vasomotor symptoms and presenting simultaneously an increased osteoporosis and breast cancer risk. A promising SERM is ospemifene which was approved by the U.S. Food and Drug Administration in 2013 for dyspareunia due to postmenopausal vaginal atrophy.

     

Postmenopausal osteoporosis.

Osteoporosis affects approximately 28 million Americans and costs about $14 billion a year. Low bone density is the most important risk factor for osteoporosis. The National Osteoporosis Foundation recommends bone density testing for all women over 65 and earlier (around the time of menopause) for women who have risk factors or who are considering therapy. Biochemical markers of bone remodeling, such as urine collagen cross links, may be useful to decide if treatment is needed and to determine the effectiveness of treatment. Once the diagnosis of osteoporosis is made, it is time to consider management options. A healthy life style is important for everyone: an adequate intake of calcium and vitamin D and regular weight-bearing exercise. Pharmacologic agents are indicated for all patients with fragility fractures and for many patients with low bone density. Estrogen is the agent of choice for both prevention and treatment of postmenopausal osteoporosis; however, once estrogen is stopped, bone mass levels drop fairly quickly. Long-term adherence to hormone replacement therapy is not good. Effective alternatives for prevention of bone loss in recently menopausal women include alendronate (a bisphosphonate) and raloxifene (a selective estrogen-receptor modulator). Effective alternatives for treatment of established osteoporosis include alendronate and nasal calcitonin. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader will be able to understand the clinical impact and sequlae of osteoporosis in women, how to identify the high risk patient and those patient that should be screened, the various tests that are available for screening and monitoring, and the various pharmacologic therapies for osteoporosis.     

Selective estrogen receptor modulators: a new category of compounds to extend postmenopausal women's health

Selective estrogen receptor modulators (SERMs) are a new category of therapeutic agents, which bind with high affinity to estrogen receptors and mimic the effect of estrogens in some tissues but act as estrogen antagonists in others. Tamoxifen, a triphenylethylene derivative, was the first clinically available SERM. It is a potent anti-estrogen in the breast, and its use in breast cancer patients has made it the most widely prescribed antineoplastic drug worldwide. It has estrogen-like activity on bone metabolism, as well as cholesterol reduction. However, its ability to produce proliferation, and polyp formation, and even carcinomas, in the endometrium is well known. A new SERM, raloxifene, a benzothiopene derivative, has a clinical profile similar to tamoxifen's. However, preclinical as well as clinical studies reveal that unlike tamoxifen it is a pure anti-estrogen in the uterus. It has recently been FDA approved for prevention of osteoporosis in postmenopausal women. This report reviews pertinent preclinical and currently available clinical studies about this new SERM and discusses clinical applicability.     

Comparison of the effects of raloxifene and low-dose hormone replacement therapy on bone mineral density and bone turnover in the treatment of postmenopausal osteoporosis

Objective. The aim of the present study was to compare the effects of raloxifene and low-dose hormone replacement therapy (HRT) on bone mineral density (BMD) and bone turnover markers in the treatment of postmenopausal osteoporosis.

Methods. Forty-two postmenopausal osteoporotic women, who were randomized to receive raloxifene 60 mg or estradiol 1 mg/norethisterone acetate 0.5 mg daily for 1 year, were studied. All women received calcium 600 mg/day and vitamin D 400 IU/day. BMD and markers of bone turnover were measured at baseline and at 12 months.

Results. After 12 months of treatment, there were statistically significant increases in BMD in both groups at all sites (all p < 0.05). For the lumbar spine, the increase in BMD was 2.3% for raloxifene compared with 5.8% for low-dose HRT and corresponding values for total body BMD were 2.9% for raloxifene and 4.6% for low-dose HRT; the increases being significantly greater in the low-dose HRT group (p < 0.001 and p = 0.02, respectively). Although the increase in BMD at the hip was significant for both raloxifene (2.1%) and low-dose HRT (3.2%) compared with baseline, the difference between the two regimens did not reach statistical significance. The decrease in serum C-terminal telopeptide fragment of type I collagen and serum osteocalcin levels for the low-dose HRT group (?53% and ?47%, respectively) was significantly greater than for the raloxifene group (?23% and ?27%, respectively; both p < 0.01).

Conclusions. In postmenopausal women with osteoporosis, low-dose HRT produced significantly greater increases in BMD of the lumbar spine and total body and greater decreases in bone turnover than raloxifene at 12 months.     

Clinical efficacy of raloxifene in postmenopausal women.

A new class of compounds known as selective estrogen receptor modulators (SERMs) may possess the optimal combination of characteristics desirable in a drug designed for use in postmenopausal women. Among this class of compounds, raloxifene is the most studied and is currently available for clinical use in some countries for the prevention of osteoporosis in post-menopausal women. Raloxifene is a non-steroidal benzotiophene derivative shown to prevent bone loss at axial and appendicular sites and reduce serum cholesterol, like estrogen, in oophorectomized rats and in postmenopausal women. In animal models, unlike estrogen, raloxifene does not stimulate breast or uterine tissues. These appealing attributes make raloxifene a potential treatment for osteoporosis and other menopause related risks in middle aged and elderly women. Multicenter studies have been performed in early postmenopausal women, randomly assigned to receive raloxifene 30, 60, or 150 mg/day or placebo. All subjects received a calcium supplement. Bone mineral density, which was measured twice a year over 24 months by dual X-ray absorptiometry, decreased significantly at all skeletal sites with placebo, and significantly increased with raloxifene at the spine, hip, and total body at the three doses. At 24 months, the mean increase with raloxifene 60 mg compared with placebo was 2.4% at the lumbar spine and at the total hip, and 2% at the total body. Markers of bone formation (serum osteocalcin and bone specific alkaline phosphatase) and of resorption (urinary CrossLaps) decreased significantly to the premenopausal range within 3-6 months of treatment with raloxifene. In addition, total serum and low-density lipoprotein cholesterol decreased significantly in all raloxifene therapy groups in a dose-related fashion. Serum HDL-cholesterol and triglycerides were not significantly changed by therapy. The most commonly observed side-effect was hot flushes, with patients taking raloxifene reporting a slightly higher rate of flushes (25%) than those on placebo (18%). This adverse event usually occurred within the first few months of therapy, was generally mild, and did not result in excess study dropout (raloxifene 1.5%, placebo 2.1%). Preliminary 2-year data indicated that raloxifene is not associated with an increased risk of breast cancer. In summary, the clinical efficacy and safety of raloxifene is very promising and this compound will offer a particularly attractive choice for postmenopausal women.     

激素补充治疗与中老年女性骨质疏松症

骨质疏松症是中老年妇女的常见病。雌激素有明确抑制骨吸收的作用。绝经后由于雌激素的缺乏,导致骨量的快速丢失,使中、老年女性患骨质疏松症的危险大大高于男性。绝经后激素治疗能有效阻止骨丢失,维持骨量,降低骨折危险。特别提倡在60岁以前或绝经10年内开始使用激素治疗。此期间启用激素治疗,除对骨骼的保护作用外,还可以明显缓解绝经症状及降低冠心病风险,获益最多,风险最小。选择绝经激素治疗,是基于生活质量、健康优先原则和个人危险因素而做的个人决策。     

Pathogenesis of osteoporosis

Five major risk factors for osteoporosis have been identified: age, initial bone density, the menopause, bioavailability of calcium, and sporadic factors. Age appears to be the major determinant of bone mass. During a lifetime, a woman will typically lose 50% of her trabecular bone and 35% of her cortical bone. Bone density is affected by the amount of bone developed during growth, as well as by the subsequent rate of loss. Strong evidence has shown that loss of ovarian function leads to an accelerated phase of bone loss. Bone turnover rates increase, but resorption occurs faster than formation. This acceleration slows with time, reaching the level of the underlying slower phase of bone loss approximately 10 years after the onset of menopause. The role of calcium intake in preventing osteoporosis remains a matter of debate. Other factors shown to affect the risk of osteoporosis include low weight, smoking, alcohol intake, and degree of physical activity. The fact that not all postmenopausal women develop osteoporosis suggests that other, as-yet-undetermined factors may play a role in this condition.     

Prädiktion und endokrine Prävention des Mammakarzinoms

A variety of parameters may be used to assess an individual woman’s risk of developing breast cancer, among them personal history in a standardized form, e.g. the Claus and Gail models, postmenopausal serum estradiol levels, bone mineral density, and mammographic breast density. The endocrine prevention of breast cancer using the antiestrogen tamoxifen and the selective estrogen receptor modulator (SERM) raloxifene has been assessed in a number of prospective randomized trials. Based on these trials, it is reasonable to recommend raloxifene to women with osteoporosis and an elevated risk of breast cancer. Tamoxifen as a breast cancer preventive agent should be limited to women who are at a significantly elevated risk according to standard models as well as to women affected by BRCA-2 mutations and those affected by either BRCA-1 or BRCA-2 mutations who have developed unilateral breast cancer. The results of ongoing clinical trials on the preventive potential of aromatase inhibitors will be available in the near future.     

Influence of estrogen replacement therapy on endogenous calcitonin production rates.

Calcitonin is now a well-accepted therapy for inhibition of bone loss, both in the first years of menopause and in established osteoporosis. However, its exact role in the pathogenesis of that disease as well as the interactions between calcitonin production and estrogen metabolism remain unsolved. In order to clarify the influence of estrogen replacement therapy (ERT) on calcitonin secretory capacity, we measured whole plasma immunoreactive calcitonin basal levels, metabolic clearance rates and production rates in a group of postmenopausal women, before and after a daily intake for 28 days of 0.625 mg/day of conjugated equine estrogens, and again 4 weeks after the withdrawal of that estrogen replacement therapy. No significant changes appeared in immunoreactive calcitonin or immunoreactive calcitonin metabolic clearance rate but the production rate significantly increased over the 28 days (mean +/- SEM, from 21.3 +/- 5.1 pg/ml to 25.2 +/- 5.9 pg/ml, p less than 0.05), and then decreased 4 weeks after therapy was withdrawn to the initial level (17.9 +/- 3.6 pg/ml). We concluded that estrogen replacement therapy significantly increases calcitonin secretory capacity. This confirms the interactions between calcitonin production and estrogen metabolism, and may provide an explanation concerning the mode of action of estrogen replacement therapy in prevention of postmenopausal bone loss.     

Genetic polymorphism of the calcitonin receptor gene and bone mineral density in Polish population of postmenopausal women

INTRODUCTION: In recent years the influence of genetic factors in the pathogenesis of osteopenia and osteoporosis was indicated. The investigations focused on the gene coding for calcitonin receptor. The goal of our analysis was to determine the genotype frequencies of AluI polymorphism of the calcitonin receptor gene (CTR) in the group of Polish postmenopausal women and its possible contribution to osteoporosis development. MATERIAL AND METHODS: 139 postmenopausal women with osteopenia (t-score value from -1.0 to -2.5) (mean age 58.5 +/- 5.9 years, mean age of menopause 49.8 +/- 3.9 years) have been investigated. AluI polymorphism of the CTR gene was determined using PCR/RFLP assay. We have analysed 3 subgroups: CC, CT, and TT. In each subgroup mean weight, height, body mass index (BMI), mean age of menopause and years since menopause (YSM) and parameters of bone turnover: bone mineral density (BMD), t-score, index: young adults (YA) and--age matched (AM) have been analysed. Additionally the group of 138 selected women (mean age 26.5 +/- 4.3 years) as general population has been analysed. RESULTS: In investigated group the frequency of all 3 genotypes was determined as follows: CC: CT : TT = 8.6 : 45.3 : 46.1. Analysing BMD in particular subgroups the higher value for the CT genotype (0.967 +/- 0.161 g/cm2) was found. Similarly t-score (-1.94), YA (80.6%) and AM (90.8%) index were higher in CT genotype carriers. CONCLUSION: Our results suggest possible connection of the AluI polymorphism of the CTR gene with osteopenia and osteoporosis development. To confirm this tendency further investigations in the large number population are necessary.     

Raloxifene: a selective modulator of estrogen receptors

It has been demonstrated that postmenopausal hypoestrogenia induces numerous complications including osteoporosis and increased risk of cardiovascular disease. Oral or transdermal administration of estrogens can reduce these risks, but induces adverse effects. Recently, raloxifene, a new molecule from the benzothiophene family, has been demonstrated to prevent postmenopausal bone loss. It does not induce endometrial stimulation, and recent studies show that it could reduce breast cancer incidence. Its mode of action, consisting of mixed agonist and antagonistic estrogenic actions on different organs and systems, allows to classify it into the selective estrogen receptor modulator (SERM) family. In this review article, we will describe the characteristics of the molecule, its mode of action and the potential indications of its clinical use.     

Primary hyperparathyroidism is common in postmenopausal women with forearm fracture and low bone mineral density

OBJECTIVE: The most common etiologies of osteoporosis in women are estrogen deficiency and, later on in life, the functional changes caused by aging. There are, however, numerous causes of secondary bone loss. Little is known about the prevalence of concomitant disease in women with distal forearm fracture, which is the most common of the classical osteoporotic fractures. METHOD: Postmenopausal healthy women between 45 and 65 years of age with a forearm fracture were invited to join a prospective randomized study evaluating the effect of physical training on bone mineral density. The main inclusion criteria were previous forearm fracture and BMD T-score in the interval -1 to -3.0. Of the 167 postmenopausal women with a forearm fracture, 23% had a normal BMD, 59% had osteopenia, and 18% had osteoporosis. RESULTS: Of the 119 patients meeting the BMD criteria for inclusion, one patient was found to have sprue, two were diagnosed with thyreotoxicos, and eight had primary hyperparathyroidism. The prevalence of primary hyperparathyroidism in this population was 6.7%, and thus three times higher than that previously observed in healthy Swedish postmenopausal women. CONCLUSION: The data suggest an increased prevalence of primary hyperparathyroidism in women with forearm fracture and low bone mass, and imply the importance of basic laboratory screening in this population.