Management of Postmenopausal Osteoporosis

Postmenopausal osteoporosis is a very common disease, and approximately half of all women aged >50 years will experience an osteoporotic fracture during the remainder of their lifetime. The predominant cause of postmenopausal osteoporosis is the decline in estrogen levels, which causes an increase in bone turnover, and results in a loss of bone mass throughout the entire skeleton. Fragility fractures, either vertebral or nonvertebral, have a considerable adverse effect on quality of life in women with osteoporosis and place a significant burden on society in terms of healthcare costs.Management of postmenopausal osteoporosis includes alteration of modifiable risk factors (e.g. lifestyle and propensity to fall), ensuring adequate calcium and vitamin D intake, and pharmacological treatment to decrease fracture risk by slowing or preventing bone loss and preserving bone strength. Raloxifene (Evista®), a selective estrogen receptor modulator that partially mimics the effects of estrogen on bone and lipid metabolism and acts as an antiestrogen in the breast and endometrium, is indicated for the prevention and treatment of postmenopausal osteoporosis. Raloxifene increases bone mineral density at vertebral and nonvertebral sites, and decreases the risk of vertebral fracture to a similar extent to the bisphosphonates alendronate and risedronate. However, effects on nonvertebral fracture risk, including the risk of hip fracture, have not been observed.Raloxifene appears to reduce breast cancer risk (in women at average risk) and cardiovascular risk (in women at increased risk) without stimulating the endometrium, and does not cause vaginal bleeding or breast pain. However, the drug causes hot flashes in some women, and increases the risk of venous thromboembolic events by about the same amount as hormone replacement therapy (HRT).In economic models, raloxifene is cost effective compared with no treatment, HRT, calcitonin, or alendronate for the prevention or treatment of postmenopausal osteoporosis.In conclusion, raloxifene is a valuable and cost-effective therapy for preventing the progression of osteoporosis and for reducing vertebral fracture risk in osteoporotic postmenopausal women. The tendency for raloxifene to cause hot flashes, and its apparent lack of effect on hip fracture risk, may preclude its use in women with vasomotor symptoms and in patients at high risk for hip fracture. Results from large ongoing trials are needed to confirm the effects of raloxifene on breast cancer and cardiovascular disease. However, the effects of raloxifene on breast cancer and cardiovascular risk without stimulating the endometrium make the drug an attractive therapy for the prevention and treatment of postmenopausal osteoporosis.     

Selective estrogen-receptor modulators (SERM's) in postmenopausal women]

Selective oestrogen receptor modulators (SERMs) constitute a group of new drugs which mimic oestrogen in some organs and tissues but have an oestrogen antagonistic mode of action in other tissues. In postmenopausal women these compounds have a favourable effect on lipoprotein cholesterol levels in the blood and bone mineral density, thereby reducing fracture risk, especially in the vertebral column. In contrast to oestrogen therapy SERMs reduce the risk of mammary carcinoma. Currently tamoxifen and raloxifene are the best known SERMs. Tamoxifen increases endometrial hyperplasia and the risk of endometrial carcinoma. Raloxifene inhibits uterine tissue proliferation and does not appear to influence the endometrium directly. Raloxifene appears to be finding a place for itself in the treatment and prevention of osteoporosis in postmenopausal women. At this moment it is not yet possible to foresee what the impact of SERMs will be in the treatment and prevention of cardiovascular diseases and breast cancer.     

Hormone replacement therapy and breast cancer risk in a nationally representative cohort

BACKGROUND: The relative risk of breast cancer associated with the use of postmenopausal hormone replacement therapy (HRT) continues to be debated. We used a nationally representative cohort to study the issue. METHODS: This analysis utilized data from the NHANES I Epidemiologic Follow-up Study. Subjects were interviewed in 1971 through 1974 and four waves of follow-up interviews were conducted through 1992. Survival analysis of 5,761 postmenopausal women provided estimates of the relative risk of breast cancer in users of HRT when compared with non-users, controlling for potential confounders. RESULTS: There were 219 incident cases of breast cancer in 73,253 person-years of follow-up. The incidence rate was 326 per 100,000 person-years in women who had never used HRT and 255 per 100,000 in women who had ever used HRT. There was no statistically significant association between the HRT use and subsequent development of breast cancer: relative risk (RR) = 0.8, 95% confidence interval 0.6, 1.1. There was no trend in RR by length of HRT use: less than 3 years HRT use, RR = 0.9; 3 to 9 years , RR = 0.5; 10 or more years, RR = 0.8. CONCLUSIONS: This study, based on a nationally representative cohort followed for up to 22 years, failed to find an increased risk of breast cancer associated with the use of HRT. It provides further evidence that if there is an increased risk of breast cancer associated with HRT use, this risk is small.     

The Impact of Risk on Preference Values: Implications for Evaluations of Postmenopausal Osteoporosis Therapy

Objective: The objective was to assess the impact of different levels of risk of disease on a woman's preferences for health states. Women were provided with health scenarios incorporating different levels of lifetime risks for breast cancer, hip fracture, and coronary heart disease (CHD). In this way, we were able to determine the incremental effect of changes in risks of each disease on preference values.
Methods and Data: Preference values and utility scores were obtained for six health scenarios by both the feeling thermometer (FT) and standard gamble (SG) methods. Scenarios presented the different lifetime risks of CHD, breast cancer, and hip fracture associated with and not associated with long-term use of hormone replacement therapy (HRT) and raloxifene. Risks of breast cancer were based on perceived risks and population risks. The sample population consisted of 40 healthy female volunteers aged between 45 and 65 years randomly selected from the Ottawa-Carleton district.
Results: Based on their perceived risk of breast cancer, the women had higher value scores for the raloxifene risk profile than for both HRT ( p = .002) and no therapy ( p = .003), with similar results for analyses based on population risks and from utility scores. Regression analysis showed that the risk of breast cancer ( p <.001) was the only disease risk that was statistically significantly associated with women's preferences.
Conclusions: Women had significant preferences over the different risk profiles, primarily due to the incremental effect on changes in values for the risk of breast cancer. Therefore, studies evaluating therapies for osteoporosis should consider patient preferences for living with different risk profiles.     

Socioeconomic status and mortality in Swedish women: opposing trends for cardiovascular disease and cancer

We examined relations between socioeconomic status and cardiovascular disease, cancer, and diabetes mellitus in a 24-year prospective study of 1,462 Swedish women. Two socioeconomic indicators were used: the husband's occupational category for married women and a composite indicator combining women's educational level with household income for all women. The husband's occupational category was strongly associated with cardiovascular disease and cancer mortality in opposite directions, independent of age and other potential confounders. Women with husbands of lower occupational categories had an increased risk of cardiovascular disease mortality [relative risk (RR) = 1.60; 95% confidence interval (95% CI) = 1.09-2.33] while experiencing lower rates of all-site cancer mortality (RR = 0.69; 95% CI = 0.50-0.96). A similar relation was seen with the composite variable: women with low socioeconomic status had an increased risk of cardiovascular disease (RR = 1.37; 95% CI = 1.01-1.84) but a somewhat lower risk for cancer of all sites (RR = 0.86; 95% CI = 0.66-1.11). Finally, morbidity data (diabetes mellitus, stroke, and breast cancer) yielded results that were consistent with the mortality trends, and breast cancer appeared to account for a major part of the association between total cancer and high socioeconomic status. In summary, higher socioeconomic status was associated with decreased cardiovascular disease mortality and excess cancer mortality, in such a way that only a weak association was seen for all-cause mortality.     

Effect of body mass on the association between estrogen replacement therapy and mortality among elderly US women

In observational studies, estrogen replacement therapy is associated with decreased cardiovascular disease rates and increased breast cancer rates. Recent evidence suggests that the impact of estrogen use on disease outcomes may vary by body mass. In a prospective study of 290,827 postmenopausal US women with no history of cancer or cardiovascular disease at enrollment in 1982, the authors examined the association between postmenopausal estrogen use and all-cause, coronary heart disease, stroke, all-cancer, and breast cancer death rates and whether these associations differed by body mass. After 12 years of follow-up, results from Cox proportional hazards models showed that all-cause death rates were lower among baseline estrogen users than never users (rate ratio (RR) = 0.82, 95% confidence interval (CI): 0.78, 0.87). The lowest relative risk was found for coronary heart disease (RR = 0.66, 95% CI: 0.58, 0.77). The inverse association between estrogen use and coronary heart disease mortality was strongest for thin women (body mass index <22 kg/m2) (RR = 0.49, p for interaction = 0.02). Breast cancer mortality did not increase with estrogen use overall, and no increased risk was observed for thin or heavy women. In this population, the reduction in coronary heart disease mortality among estrogen users was greatest for thinner women. Additional studies are needed to confirm or refute these results.     

A prospective study of job strain and risk of breast cancer

BACKGROUND: There is conflicting evidence on whether stress is a risk factor for breast cancer. The present study examined prospectively the relationship between stress at work and risk of breast cancer. METHODS: Participants comprised 26 936 postmenopausal women in the Nurses' Health Study ages 46-72 who were in paid employment, and who had no previous history of cancer. Multivariate-adjusted regression analysis was used to examine the relationship between job strain (measured by the Karasek Job Content Questionnaire in 1992) and risk of incident invasive and in situ breast cancer. RESULTS: From 1992 through 1994, 219 women were diagnosed with breast cancer. No evidence was found for a relationship between job stress and risk of breast cancer. Compared with women in low strain jobs, the multivariate-adjusted relative risks of breast cancer were RR = 0.78 (95% CI : 0.52-1.16) for high-strain jobs; RR = 0.76 (95% CI : 0.49-1.17) for active jobs; and RR = 0.94 (95% CI : 0.67-1.34) for passive jobs. Although job strain was related to less breast cancer screening among women in highly demanding jobs, it was not associated with tumour size. CONCLUSIONS: Job stress was not related to an increase in the incidence of breast cancer in the present cohort of nurses.     

酒精摄入与女性乳腺癌发病风险的Meta分析

目的 探讨酒精摄入与女性乳腺癌发病风险的关联性。方法 通过Stata 12.0软件对国内外发表的有关酒精摄入与女性乳腺癌发病风险的队列研究和病例对照研究进行Meta分析。结果 共纳入16项病例对照研究和15项队列研究,包括50 519例患者和973 216例对照者。病例对照研究Meta分析提示,酒精暴露可明显增加女性个体发生乳腺癌的风险,合并OR值为1.18,95％置信区间为1.05～1.32;以绝经状态为亚组的Meta分析提示,酒精暴露可增加绝经后女性个体发生乳腺癌的风险,合并OR值为1.26,95％置信区间为1.08～1.46。队列研究Meta分析提示,有酒精暴露者女性乳腺癌的发生率是非饮酒者的1.1倍,合并RR值为1.10,95％置信区间为1.06～1.15;以绝经状态为亚组的Meta分析提示,有酒精暴露的绝经后女性乳腺癌的发生率是非饮酒者的1.1倍,合并RR值为1.14,95％置信区间为1.10～1.19。结论 酒精摄入可显著提高女性尤其绝经后乳腺癌的发病风险。     

Psychotropic medication use and risk of hormone-related cancers: the New York University Women's Health Study

BACKGROUND: The use of psychotropic medications may increase the risk of hormone-related cancers in females through increased gonadotropin secretion, but the data from epidemiologic studies are limited to evaluate the hypothesis. METHODS: The association between the use of psychotropic medications and cancer incidence was studied in a prospective cohort study that involves 15,270 women who participated in mammographic screening. The relative risks (RR) and 95 per cent confidence intervals (CIs) for cancer associated with the use of psychotropic medications were estimated by the Cox's proportional hazard model. RESULTS: During an average of 7.3 years of follow-up, 1,130 incident cases of cancer were identified, including 566 breast, 67 endometrial and 47 ovarian cancers. The use of any type of psychotropic medication at baseline was associated with increased risks of breast [relative risk (RR) = 1.39, 95 per cent CI 1.11-1.74], endometrial (RR=1.71; 95 per cent CI 0.93-3.14) and ovarian (RR= 1.48, 95 per cent CI 0.69-3.16) cancers, whereas no increase in risk was observed for other cancers (RR = 1.06). When the subjects were divided by menopausal status at baseline, premenopausal women tended to have higher risk of all hormone-related cancers (RR = 1.73, 95 per cent CI 1.27-2.35) than postmenopausal women (RR=1.23, 95 per cent CI 0.94-1.62). The magnitude of the RR associated with the use of these medications did not change by length of follow-up. Analysis by type of medication did not find that the association was limited to specific types. CONCLUSION: The observed association needs to be confirmed in further studies based on more detailed medication history.     

Lack of association between Hashimoto thyroiditis and breast cancer: a quantitative research synthesis

Several authors have suggested a positive association between Hashimoto thyroiditis (HT) and breast cancer (BrCa). Others have refuted these findings; hence, this subject remains controversial. We therefore reviewed the world literature on this subject accumulated over the last 50 years and performed a quantitative research synthesis, a meta-analysis variant. The incidence risk ratios and 95% confidence intervals (CI's) were calculated for each study and the combined relative risk (RR) was estimated. We found 37 relevant studies, of which only 13 were accessible to analysis. A significant association (RR=1.40; CI=1.29-1.53, P<0.022) was found for 6 of the 13 studies pertaining to 1,431 women. However, in the cumulative population of 14,226 women (from all 13 studies), we failed to demonstrate an association between the diagnoses of HT and BrCa (RR=1.07; CI=0.99-1.15; P=0.08). In conclusion, we believe that selection bias or institutional referral bias, in at least some of the "positive" studies, may have led to the spurious recognition of an association between HT and BrCa, especially as both of these conditions are highly prevalent in women between the 4th and 7th decade of life.     

A prospective cohort study of postmenopausal hormone use and risk of breast cancer in US women

The association between history of postmenopausal hormone use as of 1976 and breast cancer incidence during 1976-1980 was examined prospectively among 33,335 married, postmenopausal registered nurses aged 30-55 years at entry. Half the women reported postmenopausal hormone use, and one fourth had taken these drugs for over five years. During 1976-1980, 221 new cases of breast cancer were identified. The relative risk (RR) for those who had used postmenopausal hormones when compared with women who had never used them was 1.1 (95% confidence limits (CL) 0.8, 1.4); for current and past users, the relative risks were 1.0 (95% CL 0.7, 1.4) and 1.3 (95% CL 0.9, 1.8), respectively. These ratios were not substantially modified by whether or not a woman's ovaries had been removed or by other known breast cancer risk factors. No increase in breast cancer risk was apparent among women who had used postmenopausal hormones for less than five years (RR = 1.0, 95% CL 0.5, 1.6). An apparent effect among the subgroup of women who had used them for five to nine years (RR = 1.5, 95% CL 1.0, 2.2) was not present among the few women with longer-term use (RR = 0.9, 95% CL 0.4, 1.6). These findings are moderately reassuring, but since there are as yet few women in this cohort with long-term durations of use and, particularly, with long intervals since first use, continued follow-up of this and other cohorts will be required before firm conclusions can be drawn, especially among specific subgroups.     

Low risk of hip fracture among elderly breast cancer survivors

PURPOSE: Prior research has shown that women with either osteoporotic fracture or low bone density are at a decreased risk of breast cancer. Little prior work has evaluated whether women with breast cancer are at a decreased risk of osteoporotic fracture. METHODS: We used data from the National Cancer Institute's Surveillance Epidemiology and End Results (SEER)-Medicare program to study the risk of hip fracture among elderly female Medicare beneficiaries with and without histories of breast cancer. Using the SEER file, we identified elderly women survivors of stage 0, I, or II breast cancer (N=5980) diagnosed between the ages of 55 and 64 years; using the Medicare 5% file, we identified elderly women without histories of cancer (N=23,165) from SEER regions. Using Medicare claims from 1993 through 1998, we followed women for hospitalization for hip fracture or death until December 31, 1998. RESULTS: We found the rate ratio of hospitalization for hip fracture for breast cancer survivors relative to comparison patients was 0.63 (95% CI: 0.43-0.94) after adjusting for age, race, socioeconomic status, geographic location, cohort entry year, and medical comorbidity. CONCLUSIONS: We conclude that survivors of early stage post-menopausal breast cancer are at significantly lower risk of hip fracture than women who do not have histories of breast cancer.     

Lifetime alcohol consumption and postmenopausal breast cancer rate in Denmark: a prospective cohort study

Alcohol intake may be one of the few modifiable risk factors for breast cancer. In a prospective cohort of 29,875 women with 423 cases of breast cancer during 1993-2000, we examined the relationship between postmenopausal breast cancer incidence rate and alcohol consumption in different life periods. When alcohol intake during four age ranges, twenties, thirties, forties and fifties was evaluated, only the intake in the fifties increased the risk of breast cancer [rate ratio (RR)=1.12 (95% CI: 1.05-1.19)] per 10 g/d increase in alcohol intake. After adjustment for intake at study entry, this association was no longer present [RR=1.01 (95% CI: 0.91-1.13)]. The cumulative lifetime alcohol intake, adjusted for recent intake, showed no association with postmenopausal breast cancer risk. Recent alcohol intake, adjusted for the alcohol intake in the other life time periods, showed a significant association of RR=1.09 (95% CI: 1.00-1.18) per 10 g/d. There was no indication of a higher risk among women with early drinking start, nor did women who started to drink before their first birth have a higher risk than women who started to drink later in life. Our results suggest that baseline intake of alcohol is a more important determinant of postmenopausal breast cancer risk than earlier lifetime exposure.     

Active and passive smoking in breast cancer: prospective results from the Nurses' Health Study

BACKGROUND: The role of active and passive smoking in breast cancer remains controversial. METHODS: Using data collected in the prospective Nurses' Health Study, we examined the influence of active and passive smoking on the incidence of invasive breast cancer. The analysis was based on women responding to the 1982 questionnaire, which included questions on passive smoking exposure. Information on active smoking was collected in biennial questionnaires. A total of 78,206 women were followed prospectively from 1982 until June 1996. RESULTS: Of these women, 3,140 reported a diagnosis of invasive breast cancer during follow-up. Compared with never active smoking, relative risks (RR) of breast cancer were 1.04 (95% CI = 0.94-1.15) for current active smoking and 1.09 (95% CI = 1.00-1.18) for past active smoking. The RR for regular passive exposure at work and at home was 0.90 (95% CI = 0.67-1.22). For active smoking, a modest increase in risk was confined to women who began smoking before the age of 17 (RR = 1.19; 95% CI = 1.03-1.37). CONCLUSION: Results suggest that passive smoking is unrelated to breast cancer. However, results for active smoking are compatible with a small increase in risk when smoking is initiated at young ages.     

Is radiographic vertebral fracture a risk factor for mortality?

Clinical fractures predict increased mortality risk, but few studies report mortality based on prevalent radiographically defined vertebral fracture. This study examined whether radiographically defined vertebral fracture is a risk factor for mortality in older adults. The 1,580 participants in California (631 men, 949 women) were aged > or =50 years in 1992-1996. Lateral spine radiographs, and information about medical history and behaviors, were obtained. Overall, 55 (8.7%) men and 123 (13%) women had at least one prevalent fracture at baseline; of these, 48 women and 14 men had two or more. Over 7.6 years, 460 participants died, 27.6% without and 41.0% with prevalent fractures (p < 0.001). Prevalent vertebral fracture was not associated with all-cause mortality in both sexes combined (adjusted hazard ratio = 1.09, 95% confidence interval: 0.84, 1.42) or sex-specific analyses (women: adjusted hazard ratio = 1.15, 95% confidence interval: 0.83, 1.59; men: adjusted hazard ratio = 0.89, 95% confidence interval: 0.55, 1.46). However, women with two or more prevalent fractures had increased risk of all-cause mortality (adjusted hazard ratio = 1.56, 95% confidence interval: 1.01, 2.40; p = 0.04). Women with any prevalent vertebral fractures also had increased mortality risk from "other" causes (adjusted hazard ratio = 1.59, 95% confidence interval: 1.03, 2.45; p = 0.04) but not cardiovascular disease or cancer. A single radiographic vertebral fracture is not a risk for mortality in older women; larger, longer studies of men and those with two or more radiographic vertebral fractures are needed.     

Breast cancer incidence in women with abnormal cytology in nipple aspirates of breast fluid.

This is a prospective study of breast cancer risk in relation to nipple aspirate fluid cytology in 2,701 volunteer white women from the San Francisco Bay Area first enrolled between 1973 and 1980. The women were not pregnant or lactating and were free of breast cancer within 6 months of entry into the study. The breast cancer status of this cohort was determined between June 1988 and April 1991. Follow-up was complete for 87% (n = 2,343) of the cohort, representing 29,961 person-years and an average of 12.7 years of follow-up. The overall breast cancer incidence was 4.4% (104 of 2,343) and rose with fluid cytology findings as follows: no fluid obtained, 2.6% (9 of 352); unsatisfactory specimen, 4.8% (15 of 315); normal cytology, 4.3% (56 of 1,291); epithelial hyperplasia, 5.5% (18 of 327); and atypical hyperplasia, 10.3% (6 of 58). Relative risks for breast cancer and their 95% confidence intervals were estimated by Cox regression, adjusting for age and year of entry. Compared with the relative risk for women who yielded no fluid, relative risks were: unsatisfactory specimen, relative risk (RR) = 1.4 (95% confidence interval (CI) 0.6-3.3); normal cytology, RR = 1.8 (95% CI 0.9-3.6); epithelial hyperplasia, RR = 2.5 (95% CI 1.1-5.5); and atypical hyperplasia, RR = 4.9 (95% CI 1.7-13.9). These findings were strongest for and were mainly confined to women aged 25-54 years. Women with atypical hyperplasia and a first-degree family history of breast cancer were six times more likely to develop breast cancer than were women with atypical hyperplasia but without a family history of breast cancer (95% CI 1.0-30.2). These findings provide strong support for our hypothesis that hyperplasia and atypical hyperplasia diagnosed in nipple aspirates of breast fluid are associated with an increased risk of breast cancer.     

A prospective study of the development of breast cancer in 16,692 women with benign breast disease

The authors studied the relation between benign breast disease and subsequent breast cancer in 16,692 women with biopsy-diagnosed benign breast disease who had participated in the Breast Cancer Detection Demonstration Project throughout the United States. Women were classified into one of five benign breast disease categories: atypical hyperplasia, proliferative disease without atypia, nonproliferative disease, fibroadenoma, and other benign breast disease. A total of 485 incident cases of breast cancer were identified in the women from August 1973 to February 1986 after a median follow-up period of 8.3 years from the diagnosis of benign breast disease. Age-adjusted incidence rates were calculated for benign breast disease types stratified by family history and calcification status. Relative risk (RR) estimates of breast cancer for women in the five benign breast disease categories, compared with the screened women who did not develop recognizable breast disease (normal subjects), were computed using the proportional hazards model. Results indicated that risk was associated with the degree of epithelial atypia. Over all age groups, women with nonproliferative disease, proliferative disease without atypia, and atypical hyperplasia displayed progressively increasing risks of 1.5, 1.9, and 3.0, respectively, compared with normal subjects, with 95% confidence intervals (CI) exceeding unity. Particularly high risk was seen among women under age 46 years with atypical hyperplasia (RR = 5.7, 95% CI 3.0-10.6). Women with fibroadenoma as the only indication of their benign breast disease had a relative risk of 1.7, with a lower 95% confidence limit of 1.0. No increased risk was seen for women with other benign breast disease. Positive family history (RR = 1.8) and calcification (RR = 1.2) significantly increased a woman's risk proportionately over the risk associated with each benign breast disease subtype. The authors conclude that the risk of developing breast cancer varies by category of benign breast disease and is directly related to the degree of epithelial atypia.     

Maternal risk of breast cancer and birth characteristics of offspring by time since birth.

We examined the association between birth characteristics of offspring and the subsequent maternal risk of breast cancer in a population-based cohort of 998,499 women, 13 to 48 years of age at entry. There were 9,495 incident cases of breast cancer during 12.8 million person-years of follow-up among these women. Compared with mothers of singleton infants, mothers having a multiple birth had an increased risk of breast cancer in the first 5 years after a birth (relative risk (RR) = 1.8; 95% confidence interval (CI) = 1.1-2.8). The risk for mothers having a heavy-weighted child (>3.75 kg), as compared with a child of light weight (< or =3 kg), was also slightly increased (RR = 1.2; 95% CI = 0.9-1.5). This latter effect was primarily due to an increased incidence of tumors larger than 2 cm at diagnosis (RR = 1.4; 95% CI = 0.9-1.9). Our findings are compatible with the hypothesis that the hormonal level during pregnancy influences the risk of breast cancer in the early years after delivery.