Identifying postmenopausal women at high risk of fracture in populations: a comparison of three strategies

OBJECTIVES: To describe the prevalence of risk factors for women at high risk of fracture in a population-based sample of postmenopausal women who were not using hormone replacement therapy (HRT), to demonstrate how the estimated prevalence of women at high risk of future fracture is affected by the different criteria used for classification, and to characterize the populations identified and missed by each of the criteria. A key study objective was to compare the proportion of postmenopausal women at high risk of fracture in a managed care population using several different definitions of who is at high risk. DESIGN: The Osteoporosis Population-based Risk Assessment study, a randomized trial of three screening strategies. SETTING: Conducted at Group Health Cooperative in western Washington state. PARTICIPANTS: Women aged 60 to 79 who had not used HRT for at least 12 months were chosen at random. MEASUREMENTS: In one of the trial arms, 428 women had their bone mineral density (BMD) measured at the hip and spine (L1-L4) using dual energy x-ray absorptiometry. Minimum t scores and z scores at all sites were used for classification. Risk factors for fractures were assessed at the time of the BMD scan. RESULTS: Guidelines based on the Study of Osteoporotic Fractures classified 25.1% of the women as being at high risk of fracture, compared with 30.0% and 68.0% using World Health Organization (WHO) recommendations and National Osteoporosis Foundation guidelines, respectively. Classification based on low BMD alone (WHO) failed to include more than 50% of women who had already experienced a clinical fracture. CONCLUSIONS: Prevalence of women at high risk of fracture not using HRT varies notably depending on the criteria used for identification. The criteria used to identify women to target for primary and secondary prevention of osteoporotic fractures has major implications for population-based prevention strategies.     

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.     

Hormone replacement therapy

Hormone Replacement Therapy (HRT) is replacement of depleted endogenous estrogen for postmenopausal women. Usually progestin is used in combination to avoid endometrial proliferation. As for bone metabolism, estrogens exert bone protective effect through inhibition of bone absorption. HRT has been shown to improve bone mineral density and to lower the risk of osteoporotic bone fracture. However, the results of recent large scale clinical studies in the U.S. indicate that HRT not only raise the risk of breast cancer, but also increase the incidence of atherosclerotic cardiovascular diseases. According to these studies, the benefit of HRT does not outweigh its risk except the treatment of postmenopausal vasomotor symptoms. To resolve this problem, low dose HRT and SERM (selective estrogen receptor modulator) regimens are under investigation.     

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.     

Right or wrong of the hormone replacement therapy involving osteoporosis

Hormone Replacement Therapy (HRT) is replacement of depleted endogenous estrogen for postmenopausal women. Usually progestin is used in combination to avoid endometrial proliferation. As for bone metabolism, estrogens exert bone protective effect through inhibition of bone absorption. HRT has been shown to improve bone mineral density and to lower the risk of osteoporotic bone fracture. However, recent clinical studies proved that HRT not only raise the risk of breast cancer, but also increase the incidence of atherosclerotic cardiovascular diseases. Other than the treatment of postmenopausal vasomotor symptoms, the benefit of HRT is thought to be hard to outweigh its risk. To resolve this problem, low dose HRT and SERM (Selective Estrogen Receptor Modulator) regimens are under investigation. The evidences of androgen replacement for aged men are not accumulated enough to verify its effects and long term safety.     

Aromatase inhibitor-associated bone loss in breast cancer patients is distinct from postmenopausal osteoporosis

Women with breast cancer are increasingly being diagnosed and treated earlier in the disease process, resulting in significantly improved clinical outcomes. Aromatase inhibitor (AI) therapy has shown superior efficacy compared with tamoxifen in postmenopausal women and is quickly becoming the therapy of choice in this setting. However, adjuvant AI therapy depletes residual estrogen and is associated with rapid bone loss and increased fracture risk distinctly different from those observed in postmenopausal osteoporosis. Aromatase inhibitor-associated bone loss (AIBL) occurs at a rate at least 2-fold higher than bone loss seen in healthy, age-matched postmenopausal women, resulting in a significantly higher fracture incidence regardless of the AI administered. Thus, antiresorptive treatments designed to address postmenopausal osteoporosis may not be sufficient in this unique population. Furthermore, current guidelines for the management of bone health in women with breast cancer may not correctly identify patients who may benefit from therapy. Consequently, breast cancer patients receiving adjuvant AI therapy will require specialized management strategies to identify and treat patients at high risk for fracture. Recently, nitrogen-containing bisphosphonates have emerged as the treatment of choice for the prevention of AIBL and the reduction of fracture risk in this setting.     

Prospective 10-year study of the determinants of bone density and bone loss in normal postmenopausal women,including the effect of hormone replacement therapy

OBJECTIVE: To prospectively assess bone density and the factors determining the rate of bone loss over a 10-year period of postmenopausal life. DESIGN: Prospective, observational study. METHODS: One hundred and four normal White postmenopausal women, baseline mean age 59 years (range 47-71 years) completed the study (mean duration of follow-up 10.2 years, range 9.4-10.6 years). None had diseases or were taking medications affecting bone metabolism at entry to the study. Information was collected on medical, fracture and smoking history, alcohol use, dietary calcium intake and physical activity. Body composition and bone density were measured by dual-energy X-ray absorptiometry at baseline and at 10 years. Biochemical, haematological and hormonal analyses were performed. RESULTS: Twenty-four percent of the women started hormone replacement therapy (HRT) during the study period; most of these remained on therapy at follow-up. The mean duration of therapy was 6.6 years (range 2.8-10.4 years). The use of HRT was associated with significant gains in bone density (total body + 3.0%, trochanter + 4.2%, Ward's triangle + 4.4%, spine + 10.5%) and a significant reduction in vertebral fracture risk [standardized risk ratio compared with non-HRT users 0.42 (confidence interval 0.18-0.83)]. HRT use was not associated with greater weight gain than that occurring in other members of the cohort. The baseline and follow-up bone densities in the non-HRT users were highly correlated (0.82 < or = r < or = 0.91, P < or = 0.0001) and baseline bone density accounted for the majority of the variance in the 10-year results. Multivariate analyses showed that the independent correlates of rate of change of bone density were weight and fat mass (both baseline values and changes during follow-up), time after menopause, sex hormone concentrations, urinary calcium loss, PTH levels and haemoglobin concentration (which may reflect nutrition and health). CONCLUSIONS: Bone density is highly predictable over an extended period of time in normal postmenopausal women. Maintenance of body weight and good health reduce bone loss. HRT is effective for treating osteoporosis, with improvement in bone density and reduction in vertebral fractures. Good compliance with HRT long-term is achievable. These findings are relevant to deciding the frequency of bone density measurement, and in advising women regarding prevention and treatment of postmenopausal bone loss.     

Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis

Glucocorticoid-induced bone loss should be prevented, and if present, should be treated (Table 2). Supplementation with calcium and vitamin D at a dosage of 800 IU/day, or an activated form of vitamin D (e.g., alfacalcidiol at 1 microg/day or calcitriol at 0.5 microg/day), should be offered to all patients receiving glucocorticoids, to restore normal calcium balance. This combination has been shown to maintain bone mass in patients receiving long-term low-to-medium-dose glucocorticoid therapy who have normal levels of gonadal hormones. However, while supplementation with calcium and vitamin D alone generally will not prevent bone loss in patients in whom medium-to-high-dose glucocorticoid therapy is being initiated, supplementation with calcium and an activated form of vitamin D will prevent bone loss. There are no data available to support any conclusion about the antifracture efficacy of the combination of calcium supplementation plus an activated form of vitamin D. Antiresorptive agents are effective in the treatment of glucocorticoid-induced bone loss. All of these agents either prevent bone loss or modestly increase lumbar spine bone mass and maintain hip bone mass. While there are no randomized controlled trials of prevention of glucocorticoid-induced bone loss or radiographic vertebral fracture outcomes with HRT or testosterone, patients receiving long-term glucocorticoid therapy who are hypogonadal should be offered HRT. The bisphosphonates are effective for both the prevention and the treatment of glucocorticoid-induced bone loss. Large studies have demonstrated that bisphosphonates also reduce the incidence of radiographic vertebral fractures in postmenopausal women with glucocorticoid-induced osteoporosis. Treatment with a bisphosphonate is recommended to prevent bone loss in all men and postmenopausal women in whom long-term glucocorticoid treatment at > or =5 mg/day is being initiated, as well as in men and postmenopausal women receiving long-term glucocorticoids in whom the BMD T-score at either the lumbar spine or the hip is below normal. While there is little information on the prevention or treatment of bone loss in premenopausal women, these women, too, may lose bone mass if they are being treated with glucocorticoids, so prevention of bone loss with antiresorptive agents should be considered. If bisphosphonate therapy is being considered for a premenopausal woman, she must be counseled regarding use of appropriate contraception. The therapies to prevent or treat glucocorticoid-induced bone loss should be continued as long as the patient is receiving glucocorticoids. Data from large studies of anabolic agents (e.g., PTH) and further studies of combination therapy in patients receiving glucocorticoids are eagerly awaited so additional options will be available for the prevention of this serious complication of glucocorticoid treatment.     

Individualizing therapy to prevent long-term consequences of estrogen deficiency in postmenopausal women.

BACKGROUND: Alendronate sodium and raloxifene hydrochloride were recently approved for the prevention of postmenopausal osteoporosis, but data on their clinical efficacy are limited. We compared these drugs with hormone replacement therapy (HRT) to help women and physicians guide postmenopausal treatment decisions. OBJECTIVE: To help physicians understand how they can best help women choose the most beneficial therapy after menopause based on their individual risk profile. METHODS: We developed a decision analytic Markov model to compare the effects of alendronate therapy, raloxifene therapy, and HRT on risks of hip fracture, coronary heart disease (CHD), breast cancer, and life expectancy. Regression models linked individual risk factors to future disease risks and were modified by drug effects on bone density, lipid levels, and associated breast cancer effects. RESULTS: Hormone replacement therapy, alendronate therapy, and raloxifene therapy have similar predicted efficacies in preventing hip fractures (estimated relative risk, 0.57, 0.54, and 0.58, respectively). Hormone replacement therapy should be more than 10 times more effective than raloxifene therapy in preventing CHD, but raloxifene therapy may not induce breast cancer. Women at low risk for hip fracture, CHD, and breast cancer do not benefit significantly from any treatment. Among women at average risk, HRT was preferred unless raloxifene therapy could reduce the risk of breast cancer by at least 66%, compared with a 47% increase for HRT. Women at high risk for CHD benefit most from HRT; women at high risk for breast cancer but low risk for CHD benefit most from raloxifene therapy, but only if it lowers the risk of breast cancer. CONCLUSION: Because of significant differences in the impact of these drugs, treatment choice depends on an individual woman's risk for hip fracture, CHD, and breast cancer.     

Premenopausal bone health assessment

The World Health Organization criteria for classification of bone mineral density (BMD) cannot be applied to premenopausal women because the relationship between BMD and fracture risk is not the same as in postmenopausal women. Approximately 2.5% of premenopausal women have BMD that is more than 2.0 standard deviations below the mean BMD of an age-, gender-, and ethnicity-matched reference population. Most premenopausal women with low BMD have low peak bone mass and low 5-to 10-year probability of fracture. The management of these patients involves nonpharmacologic lifestyle measures and reassurances that fracture risk is low. A minority of premenopausal women with low BMD have significant elevation of fracture risk, usually a result of contributing diseases, conditions, or medications that may be identified and treated. Premenopausal women with fractures are at increased risk for postmenopausal osteoporosis and fractures later in life.     

Selective estrogen-receptor modulators

Tamoxifen is useful for adjuvant treatment of breast cancer and in some women for the prevention of breast cancer. The risk-benefit ratio in regard to the skeleton and perhaps other organ systems may very well be different for postmenopausal versus premenopausal women. In postmenopausal women, tamoxifen (20 mg/d) increased BMD in the spine and perhaps the hip; however, the effect on fracture risk is unclear. Therefore, for postmenopausal women with osteoporosis, consideration should be given to the addition of an agent that is shown to have efficacy against fractures (such as bisphosphonates), even while these women are on tamoxifen. For women at only modest or moderate risk, with bone density above the osteoporosis range (T score above -2.5) and no major fracture history, tamoxifen is probably adequate for 5 years of use. Potentially serious adverse effects include venous thromboembolism, uterine cancer, benign uterine disease, and cataracts. Raloxifene (60 mg/d) protects against vertebral fractures over 4 years in women with osteoporosis, produces small increases in bone mass of the spine, hip, and total body, and reduces bone turnover in postmenopausal women with or without osteoporosis. No significant effect has yet been demonstrated on nonvertebral fractures after 4 years of treatment. Raloxifene has the additional benefit of substantially reducing the risk of ER-positive invasive breast cancer and does not increase the risk of uterine disease. Raloxifene increases the risk of venous thromboembolic disease to the same degree as tamoxifen and estrogen. Therefore, SERMS and estrogens are generally contraindicated in women with a previous history of venous thromboembolism or those who are at significantly increased risk. Raloxifene is probably most useful in women who have osteoporosis (T score = -2.5) or who are at risk (T score less than -1.5 with clinical risk factors) in the middle menopausal period (age 55-65) or in the early menopausal period in women who have no significant hot flashes. At this stage in life, vertebral fractures are common, but hip fractures are not. Therefore, women who take raloxifene can expect a reduction in the likelihood of having a vertebral fracture, and possibly breast cancer. The lack of definitive efficacy against hip fracture is not a major deterrent to use of this agent in this age group because hip fracture risk is very low. Raloxifene might not be the treatment of choice for elderly women who are at particularly high risk of hip fracture.     

Effects of hormone replacement therapy on bone mineral density in postmenopausal women with primary hyperparathyroidism: four-year follow-up and comparison with healthy postmenopausal women

BACKGROUND: Long-term treatment of patients with asymptomatic primary hyperparathyroidism remains controversial, but the presence of osteoporosis is regarded as an indication for parathyroidectomy. Hormone replacement therapy (HRT) is a possible alternative therapy in osteopenic postmenopausal women with the disorder, and results of short-term studies suggest a beneficial effect on bone mass comparable to that achieved by parathyroidectomy. Longer-term data are required to further assess the efficacy of this treatment in chronic stable primary hyperparathyroidism. METHODS: We report the results of the extension from 2 to 4 years of a randomized, placebo-controlled trial of HRT in postmenopausal women with primary hyperparathyroidism. Of 23 postmenopausal women with primary hyperparathyroidism, 11 received active HRT with conjugated equine estrogen, 0.625 mg/d, and medroxyprogesterone acetate, 5 mg/d, and 12 received placebo. Bone mineral density was measured throughout the skeleton at 6-month intervals using dual-energy x-ray absorptiometry in these women and in 50 normocalcemic age-matched control subjects. None of the 23 patients withdrew during the extension period. RESULTS: Changes in bone mineral density were more positive in those taking HRT than placebo, with the between-group differences at 4 years being 4.6% in the total body, 7.5% in the lumbar spine, 7.4% in the femoral neck, 8.2% in the femoral trochanter, 6.8% in the legs, and 7.0% in the forearm (P<.01). At skeletal sites composed predominantly of cortical bone, there was a progressive divergence of the 2 groups. Biochemical markers of bone turnover remained lower throughout the study in women taking HRT. When rates of bone loss were compared between the placebo group and healthy women of comparable age, bone loss tended to be more marked throughout the skeleton in women with hyperparathyroidism, but only in the total body and its legs subregion was this difference significant. CONCLUSIONS: Hormone replacement therapy is efficacious in the long-term management of osteopenia in postmenopausal women with primary hyperparathyroidism and thus represents an important new therapeutic option for asymptomatic patients who do not have other indications for surgery. Bone loss seems to be accelerated in untreated primary hyperparathyroidism.     

Selective estrogen receptor modulators—A new age of estrogens in cardiovascular disease?

A large body of evidence suggests hormone replacement therapy (HRT) reduces cardiovascular risk in postmenopausal women. It is, however, associated with serious side effects, such as increased risk of breast and endometrial cancer. This has likely caused uneasiness among both women and health care providers. A new class of compounds, called selective estrogen receptor modulators (SERMs), have emerged. Through their interactions at the estrogen receptor level they have become a class of compounds distinct from estrogen. While they share similar effects with estrogen on such factors as lipid profile and bone density, they affect other tissues differently. Specifically, they do not induce endometrial hyperplasia and are therefore not associated with endometrial cancer. In vitro studies have also shown that they inhibit lipoprotein oxidation and vascular smooth muscle cell proliferation. The cumulative effects of these compounds may prove quite beneficial in reducing cardiovascular risk in postmenopausal women while avoiding serious side effects. This may, in turn, ease much of the anxiety surrounding the issue of HRT. Clinical trials are presently being conducted to evaluate the effectiveness of raloxifene, a SERM, on cardiovascular risk reduction in postmenopausal women.     

Cardiovascular Effects of Tibolone: A Selective Tissue Estrogenic Activity Regulator

Traditionally, it was accepted that long‐term hormone replacement therapy (HRT) has a cardiovascular beneficial effect in postmenopausal women with and without coronary artery disease (CAD). However, randomized trials in postmenopausal women have not shown any benefit in either primary or secondary prevention of cardiovascular events. Therefore, these findings have raised the question of whether traditional HRT (i.e., estrogen and progesterone) has a cardioprotective effect in women at risk for or with established CAD. Concerns about the use of conventional HRT have led to a search for alternatives. Tibolone is a synthetic compound with estrogenic, androgenic, and progestogenic properties that relieves climacteric symptoms and prevents postmenopausal bone loss. Tibolone possesses a tissue‐selective mechanism of action that differs from that of estrogen and/or progestogen. Unlike these compounds, tibolone's metabolites play a central role in its mode of action. Tibolone is widely used for HRT. However, its clinical impact on cardiovascular disease is still under study. The current review focuses on the effects of tibolone on the cardiovascular system and discusses clinical investigations with this compound in postmenopausal women.     

Clinical Application of Spine Trabecular Bone Score (TBS)

Trabecular bone score (TBS) is a software program recently approved by the US Food and Drug Administration for post-acquisition processing of lumbar spine dual-energy X-ray absorptiometry images that allows assessment of bone texture as a surrogate for bone microarchitecture. Low TBS values are associated with increased risk of major osteoporotic fracture risk in postmenopausal women and men aged 40 years and older independent of BMD. TBS data can be used to adjust FRAX probability of fracture. As such, TBS data can be useful in osteoporosis treatment initiation decisions. Following treatment initiation, TBS increases are smaller than seen with BMD; at present, there is insufficient evidence that TBS can be used to monitor treatment. TBS may be particularly helpful in fracture risk prediction for those with diabetes mellitus or receiving glucocorticoid therapy, but additional validation of existing observations is needed. In summary, TBS should not be used alone to guide treatment initiation, but can be used with FRAX to estimate fracture probability in postmenopausal women and older men, thereby facilitating treatment initiation decisions.     

An approach to identifying osteopenic women at increased short-term risk of fracture

BACKGROUND: Identification and management of women to reduce fractures is often limited to T scores less than -2.5, although many fractures occur with higher T scores. We developed a classification algorithm that identifies women with osteopenia (T scores of -2.5 to -1.0) who are at increased risk of fracture within 12 months of peripheral bone density testing. METHODS: A total of 57 421 postmenopausal white women with baseline peripheral T scores of -2.5 to -1.0 and 1-year information on new fractures were included. Thirty-two risk factors for fracture were entered into a classification and regression tree analysis to build an algorithm that best predicted future fracture events. RESULTS: A total of 1130 women had new fractures in 1 year. Previous fracture, T score at a peripheral site of -1.8 or less, self-rated poor health status, and poor mobility were identified as the most important determinants of short-term fracture. Fifty-five percent of the women were identified as being at increased fracture risk. Women with previous fracture, regardless of T score, had a risk of 4.1%, followed by 2.2% in women with T scores of -1.8 or less or with poor health status, and 1.9% for women with poor mobility. The algorithm correctly classified 74% of the women who experienced a fracture. CONCLUSIONS: This classification tool accurately identified postmenopausal women with peripheral T scores of -2.5 to -1.0 who are at increased risk of fracture within 12 months. It can be used in clinical practice to guide assessment and treatment decisions.     

Lessons learned from the WHI: HRT requires a cautious and individualized approach

The Women's Health Initiative (WHI) was a randomized, double-blinded, placebo-controlled study that evaluated the benefits and risks of hormone replacement therapy (HRT) for healthy postmenopausal women. The results indicated that HRT: 1) does not confer cardiovascular or cognitive protection; 2) increases breast cancer risk in women with a uterus; 3) increases stroke risk in women with hysterectomy; and 4) does not improve overall quality of life. HRT does, however, decrease fracture rates and vasomotor symptoms. Because the results were surprising in light of prior observational and animal research, the study generated enormous controversy as to how to use HRT. Our position is that long-term HRT is not appropriate for most postmenopausal women, but treatment should be individualized for each patient.     

Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: a randomized, controlled clinical trial.

Alendronate and estrogen are effective therapies for postmenopausal osteoporosis, but their efficacy and safety as combined therapy are unknown. The objective of this study was to evaluate the addition of alendronate to ongoing hormone replacement therapy (HRT) in the treatment of postmenopausal women with osteoporosis. A total of 428 postmenopausal women with osteoporosis, who had been receiving HRT for at least 1 yr, were randomized to receive either alendronate (10 mg/day) or placebo. HRT was continued in both groups. Changes in bone mineral density (BMD) and biochemical markers of bone turnover were assessed. Compared with HRT alone, at 12 months, alendronate plus HRT produced significantly greater increases in BMD of the lumbar spine (3.6% vs. 1.0%, P < 0.001) and hip trochanter (2.7% vs. 0.5%, P < 0.001); however, the between-group difference in BMD at the femoral neck was not significant (1.7% vs. 0.8%, P = 0.072). Biochemical markers of bone turnover (serum bone-specific alkaline phosphatase and urine N-telopeptide) decreased significantly at 6 and 12 months with alendronate plus HRT, and they remained within premenopausal levels. Addition of alendronate to ongoing HRT was generally well tolerated, with no significant between-group differences in upper gastrointestinal adverse events or fractures. This study demonstrated that, in postmenopausal women with low bone density despite ongoing treatment with estrogen, alendronate added to HRT significantly increased bone mass at both spine and hip trochanter and was generally well tolerated.     

Effects of hormone replacement therapy on coagulation and fibrinolysis in postmenopausal women

It has been speculated that hormone replacement therapy (HRT) containing relatively low dose of estrogen would be different from oral contraceptive pills in causing thromboembolism because activation of coagulation depends on the amount of estrogen. In contrast to this knowledge, activation of coagulation pathways has been detected in postmenopausal women treated with HRT in the observational and clinical studies. In this regard, recent studies have reported a 2 to approximately 4 fold risk of venous thromboembolism or pulmonary embolism in postmenopausal women receiving HRT than in non-users of estrogen. On the other hands, HRT has shown to enhance systemic fibrinolysis with decreased plasma plasminogen activator inhibitor-1 (PAI-1) levels. In addition, levels of D-dimer exhibited a significant inverse correlation with PAI-1 levels, suggesting enhanced fibrinolysis potential. However, small doses of estrogen/progestogen induce increases in fibrinolytic capacity via a marked reduction of PAI-1. In other words, HRT at conventional dosages may affect fibrinolytic activity to a greater extent than coagulation activity, whereas the converse trend holds at higher estrogen doses. The increase in fibrinolytic potential was independent of any effect on coagulation of CEE at conventional dosages. However, in contrast to healthy postmenopausal women, we recently reported that HRT did not significantly decrease PAI-1 antigen levels and rather, increased tissue factor activity and prothrombin fragment F(1+2) levels from baseline in hypertensive and/or overweight postmenopausal women. Activation of coagulation following HRT may not be balanced by activation of fibrinolysis in some postmenopausal women. Thrombogenic events are considered more likely in patients with certain heritable conditions, such as platelet antigen-2 (PIA-2) polymorphisms. Further, Factor V Leiden mutation increases the risk of primary and recurrent venous thromboembolic events by three to sixfold and the risk of myocardial infarction. Indeed, HRT may decrease or increase atherothrombosis risk depending on the presence of Factor V Leiden mutation. Thus, HRT should not be initiated in women with established coronary artery disease or the coexistence of other risk factors for hypercoagulability-malignancy, immobility, obesity, diabetes, advanced age, or inherited traits. However, HRT at conventional dosages improves fibrinolysis potential in healthy postmenopausal women.     

Influence of 17beta-oestradiol on blood pressure of postmenopausal women at high vascular risk.

OBJECTIVES: It remains an unsolved issue whether hormone replacement therapy (HRT) lowers blood pressure. This randomized trial examined the effect of 17beta-oestradiol combined cyclically with gestodene on blood pressure of postmenopausal women who were not on antihypertensive medication. All subjects had an increased risk for adverse vascular events as indicated by intima-media thickness of carotid arteries and standard risk factors. DESIGN AND SETTING: Two hundred and twenty-six postmenopausal women were randomized to oral treatment for 48 weeks with 1 mg of 17beta-oestradiol per day continuously, plus 0.025 mg gestodene on days 17-28 of each 4-week cycle (HRT 1), or plus gestodene in each third cycle only (HRT 2), or no HRT. According to predefined criteria, four subjects in HRT 1, 12 in HRT 2 and 13 in no HRT who were started on antihypertensive medication were excluded from the analysis. Thirty subjects ended participation prematurely for other reasons. Resting blood pressure was measured at baseline and after 12, 22 and 48 weeks. RESULTS: During treatment diastolic blood pressure changed significantly in both HRT groups compared to no HRT, by -3.7 +/- 9.8 mmHg, -3.0 +/- 8.8 mmHg and 1.0 +/- 9.9 mmHg at week 48 in groups HRT 2, HRT 1 and no HRT, respectively (P = 0.008 for HRT 2 versus no HRT, P = 0.027 for HRT 1 versus no HRT). The higher the diastolic blood pressure was at beginning the greater was the decrease. The decrease of systolic blood pressure was not significantly different between groups. CONCLUSIONS: For postmenopausal women with high cardiovascular risk but without antihypertensive medication, long-term treatment with 17beta-oestradiol combined with gestodene lowers diastolic blood pressure.