Bruce Ettinger

Hormone Therapy To Prevent Disease and Prolong Life in Postmenopausal Women

Abstract ▪Purpose:To critically review the risks and benefits of hormone therapy for asymptomatic postmenopausal women who are considering long-term hormone therapy to prevent disease or to prolong...

Estrogen Replacement Therapy and Fractures in Older Women

Estrogen replacement therapy is the cornerstone of preventive therapy for osteoporosis and fractures. Current users of estrogen have a statistically significant decreased risk for hip [1-10], wrist [1, 5, 6, 8, 11], and spine fractures [8, 11, 12]. A recent meta-analysis [13] suggested a 25% decrease in the risk for hip fracture in women who reported using estrogen. The International Consensus Development Conference on Osteoporosis [14] concluded that estrogen therapy is the only well-established preventive measure that could significantly decrease the number of osteoporotic fractures. Nevertheless, several important issues remain unresolved. Most research has examined the effect of estrogen on specific fractures associated with osteoporosis (hip, wrist, spine). The effect on all fractures has not been established. The decrease in fracture risk associated with estrogen use is greatest among current or recent users, and the decreased risk tends to diminish with time after stopping estrogen [1, 4, 9]. It is unknown whether previous use, even if initiated around menopause and continued for a substantial length of time, confers any benefit. Most studies [1-9, 12] have examined the relation between unopposed estrogen and fractures. One cohort study [10] with about 30% of participants reporting use of estrogen plus progestin showed similar protective effects on the risk for hip fracture. This study did not, however, compare the relative risks separately for unopposed estrogen and combination therapy (estrogen plus progestin). The effectiveness of estrogen in preventing fractures in elderly women is also uncertain. Estrogen has been shown to be effective in preserving bone mass in elderly women [15, 16], but recent data [17] from Framingham showed little protective effect of an average of 10 years of estrogen therapy on bone density among women 75 years of age and older. In other prospective [9, 10] and casecontrol studies [3], the protective effects of estrogen on fracture were greater in younger women and weaker [3, 9] or nonexistent [10] in older women. In the Study of Osteoporotic Fractures, our prospective study of 9704 women who were 65 years of age or older, we assessed estrogen use and bone mass at baseline and ascertained incident fractures every 4 months to examine the association between estrogen use and fracture in elderly women. Methods Participants From September 1986 through October 1988, women who were at least 65 years of age were recruited for the Study of Osteoporotic Fractures in Portland, Oregon; Minneapolis, Minnesota; Baltimore County, Maryland; and the Monongahela Valley near Pittsburgh, Pennsylvania. Age-eligible women were recruited from population-based lists of women (voter registration, drivers license, and Health Maintenance Organizations membership lists) [18]. The response to these mass mailings varied from 8% in Pittsburgh (voter registration lists) to 19% in Portland (Kaiser Health Plan membership lists). We excluded black women because of their lower incidence of fractures, women who were unable to walk without the assistance of another person, and women who had had bilateral hip replacements. Estrogen Use Detailed information on use of estrogen and progestin was collected at the baseline interview. Information on use of estrogen was missing in 136 women; these women were excluded from all analyses. Participants were asked to bring all medications to the clinic for verification of use, preparation, and dosage. In addition, pictures of tablets were presented to participants to assist them in the recollection of previously prescribed hormone preparations. Information was collected about oral and parenteral estrogens (skin patches, injections, vaginal creams, and suppositories) and oral progestins. Our analyses were confined to oral preparations. Data were also collected on age at initiation of use of hormone preparations and on whether a participant had used such preparations for the entire time period since initiation and, if not, when she had stopped. Initiation of estrogen use with respect to menopause was determined by comparing the age at last menstrual period with the age at initiation of estrogen. To estimate duration of use, women were asked to check all ages, from 40 to 100 years of age, at which they had used estrogen. Duration of use was calculated by adding the total number of years that a woman had used estrogen. Because we were interested in examining the effect of initiation of estrogen and the effect of duration of use with respect to menopause, we excluded from the initiation and duration analyses 889 women for whom age at menopause could not be determined and 231 women who had started estrogen therapy more than 5 years before menopause. Measurement of Bone Mass Bone mineral density (g/cm2) was measured using single-photon absorptiometry (OsteoAnalyzer, Siemens-Osteon, Wahiawa, Hawaii). Details of these methods have been reported elsewhere [18]. We scanned three sites, including the distal radius, the proximal radius, and the calcaneus. The distal radius is composed of about 60% cortical and 40% trabecular bone, the proximal radius is about 99% cortical bone [19], and the calcaneus is about 97% trabecular bone [20]. Other Measurements Reported health status, type of menopause, alcohol consumption, physical activity, and cigarette smoking were assessed by a questionnaire that was reviewed with the participant by a trained interviewer. Women were considered to have had surgical menopause if they reported bilateral oophorectomy at the age they stopped menstruating. The measure of alcohol consumption was drinks per week adjusted for atypical drinking, especially heavy drinking during the previous 30 days. Dietary calcium intake was assessed by a food frequency questionnaire and by interview using standardized food models to estimate portion sizes [21]. Total calcium intake included dietary and supplemental calcium. Women were asked if they walked for exercise and if they had fallen in the previous 12 months. A modified Paffenbarger questionnaire was used to assess sports and recreation for the previous year, expressed in kcal/wk [22]. History of osteoporosis was ascertained by asking women if a physician had ever told them whether or not they had osteoporosis or a spine fracture. Women were also asked whether they had ever taken the following medications: thiazide diuretics, thyroid hormones, sedatives, anxiolytics, and Tums or calcium supplements. Cognitive function was assessed using the Modified Mini-Mental Status examination [23]. During the clinic examination, body weight was measured (after removal of shoes and heavy outer clothing) using a balance beam scale. Height was measured (after removal of shoes) using a Harpenden stadiometer (Holtain Ltd., Dyved, United Kingdom). Height and weight were used to calculate the body mass index (kg/m2). Ascertainment of Incident Fractures Details of our method for identifying new fractures during follow-up have been published [24]. Briefly, we contacted participants every 4 months by postcard or telephone to ask whether they had sustained a fracture or fall. More than 99.5% of these follow-up contacts were completed. We interviewed participants about the way in which the fracture occurred. To confirm fractures, we obtained a copy of the radiographic report, which had to specifically mention the occurrence of an acute fracture. Hip fractures were also confirmed by radiologic review of copies of radiographs. We excluded fractures that occurred because of major trauma such as motor vehicle accidents. Most vertebral fractures do not come to medical attention; these fractures must be discovered by systematically obtaining radiographs from all participants and by comparing them with previous radiographs. Hence, self-reported vertebral fractures were not included. Duration of fracture follow-up was calculated as the time to first occurrence of a fracture. Follow-up for fractures ranged from 0.02 years to 6.5 years. All nonspinal fractures that occurred before 1 April 1993 were included. For women who died during the follow-up period, date of death was used as the end of follow-up when fracture follow-up was not appropriate. The category all nonspinal fractures included hip and wrist fractures. Fractures of the distal radius or ulna were considered wrist fractures. Hip fractures were defined as those of the proximal femur. Statistical Analysis Estrogen use was classified as never, previous, or current. Chi-square tests of homogeneity and analyses of variance and covariance were used to compare baseline characteristics by estrogen use. Proportional hazard regression models were used to assess the relation between estrogen use and fracture. Women who had never used any type of estrogen formed the reference group for all analyses. Separate models were done for current and previous users. To test the hypothesis that the protective effect of estrogen use may be underestimated if a history of osteoporosis is not taken into account, we stratified by history of osteoporosis or spine fracture (or both). We also stratified patients by estrogen regimen (unopposed estrogen compared with estrogen and progestin) and by age ( 75 years or >75 years). Stratification by estrogen regimen was confined to those with wrist and all nonspinal fractures because combination therapy was not used frequently in our cohort and because few participants in this group had hip fractures. The multivariate model included age, body mass index, total calcium intake (supplemental and dietary), physical activity (kcal/wk), surgical menopause (yes or no), history of smoking (yes or no), history of thyroid medication use, current use of thiazide diuretics, history of osteoporosis or spine fracture or both (yes or no), current use of sedatives or anxiolytics, alcohol consumption (drinks/wk), cognitive function (Mini-Mental Status examination 23), and falls in the previous year

The Association of Radiographically Detected Vertebral Fractures with Back Pain and Function: A Prospective Study

Radiographically detected vertebral fractures (hereafter referred to as vertebral fractures) are a hallmark of postmenopausal osteoporosis and an important end point in clinical trials of osteoporosis treatment. Women with vertebral fractures have low bone mass compared with women without these fractures and, independently of bone mass, have an increased risk for additional vertebral and other fractures [1-4]. Vertebral fractures are common: Five percent of 50-year-old white women and 25% of 80-year-old women have had at least one vertebral fracture [5]. Surprisingly, however, the manner in which vertebral fractures affect health remains uncertain. Cross-sectional studies in community-derived samples of older women have demonstrated only a modest association [6-8] or no association [9-11] between prevalent vertebral fractures and back pain or disability. Cross-sectional studies do not distinguish more recent fractures from older vertebral fractures and may fail to capture transient increases in pain or disability [12], a limitation that may underestimate the clinical effect of these fractures [13]. Back pain is common among elderly women [14], and frequent causes of back pain, such as degenerative disc disease, facet joint osteoarthritis, spinal stenosis, and scoliosis, may obscure the impact of vertebral fracture. Only about one third of new vertebral fractures come to medical attention [15, 16], suggesting that most vertebral fractures are asymptomatic. However, attitudes toward back pain in older women and access to health care may also play a role in determining whether vertebral fractures come to medical attention. We examined the effect of incident vertebral fractures on back pain and back-related functional limitations in a large community-based sample of elderly women who underwent serial spinal radiography and annual assessments of back pain and disability over the same period. Methods Participants Study patients were participants in the Study of Osteoporotic Fractures, a cohort recruited from population-based listings in four U.S. metropolitan areas. Details of the design of this study are published elsewhere [17]. Lateral spine radiographs were obtained for 9677 white women between the ages of 65 and 99 years (median age, 70 years) who underwent baseline examination between 1986 and 1988. Repeated spinal radiographs suitable for morphometry were obtained for 7223 women (75% of the original cohort) at a follow-up clinic visit held an average of 3.7 years (range, 1.3 to 5.1 years) later. All participants gave informed consent. Vertebral Morphometry Lateral radiographs of the thoracic and lumbar spine were obtained in accordance with current guidelines [18]. Quantitative vertebral morphometry was performed using six-point digitization as described elsewhere [3, 19] to calculate the anterior (Ha), mid- (Hm), and posterior (Hp) height for each vertebral body from T4 to L4. A system of triage of radiographs, described elsewhere [3, 20], was used to reduce the number of radiographs requiring morphometric measurements. Briefly, trained technicians separated sets of radiographs into normal, uncertain, or probably fractured groups on the basis of a limited semiquantitative grading scheme that categorized women by the most abnormal vertebral level [20]. Uncertain grades were further categorized by the study radiologist as normal or probably fractured. Morphometry was done on the radiograph pairs that were categorized as probably fractured (42%). In a random sample of 503 women whose radiographs were triaged and then digitized, triage missed no incident fractures according to the study definition. Definition of Vertebral Fracture A vertebra was classified as having a prevalent fracture on the baseline radiograph if any of the following ratios were more than 3 SDs (>4 SDs for severe fractures) below the normal mean for that vertebral level: (Ha/Hp), (Hm/Hp), or a combination of (H/H [] 1) and (Hai/Hai 1) [3, 21]. A new (incident) fracture was identified if any of the three vertebral heights (Ha, Hm, or Hp) on follow-up radiographs decreased by 20% or more and by at least 4 mm compared with the baseline height. Incident fractures identified by morphometry were reviewed by a radiologist to exclude imaging artifacts or such conditions as osteophytosis and Scheuermann disease; 7% of vertebrae meeting the morphometric criteria for incident fracture were reclassified as not fractured. Incident Clinical Fractures We used previously described methods [22] to assess the occurrence of clinical fractures of any bone during follow-up. Women were considered to have a clinical vertebral fracture if they reported a new diagnosis of spinal fracture and a clinical radiology report confirmed that a vertebral fracture was present. Measurements of Pain, Disability, and Limited Activity We evaluated outcome measures by using a previously described questionnaire [7, 23] that asked about back pain and back-related disability in the past 12 months and the number of days of limited activity due to back pain. The questionnaire was administered at baseline and at three annual follow-up contacts held before assessment of vertebral fractures. The third follow-up contact coincided with follow-up radiography. Back pain was assessed on scales of frequency (0, never or rarely; 1, some of the time; 2, most of the time; or 3, all of the time) and severity (0, no pain; 1, mild pain; 2, moderate pain; or 3, severe pain). The two pain questions had high internal consistency (Cronbach = 0.81) and were summed for a total score that could range from 0 to 6. We defined clinically significant back pain as pain that was experienced most or all of the time or pain that was moderate or severe. Women without significant back pain at baseline were considered to have increased back pain if clinically significant pain had developed between any follow-up contacts. For women with clinically significant back pain at baseline, increased back pain was defined as an increase in total pain score of at least two points. Both types of increase had a similar association with incident fractures and thus were combined for a single outcome. Back-related disability was assessed with questions about the degree of difficulty (0, no difficulty; 1, some difficulty; 2, much difficulty; or 3, unable to perform activity) in six activities of daily living that involved the back (bending down to pick up light-weight objects, lifting a 10-pound object from the floor, reaching for objects just above the head, putting on socks or stockings, getting in and out of an automobile, and standing for 2 hours). These measures were combined in a back-related disability score ranging from 0 to 18. As reported elsewhere [7], this scale has high internal consistency (Cronbach = 0.82) and is highly correlated (Spearman r = 0.73) with a more extensive instrument used to assess disability caused by low back pain [24]. We defined clinically significant disability as much difficulty or unable in one or more of the six activities. Women without significant disability at baseline were considered to have increased disability if clinically significant disability had developed between any follow-up contacts. For women with clinically significant disability at baseline, increased disability was defined as an increase in disability score of at least three points. Both types of increase had a similar association with incident fractures and thus were combined for a single outcome. We also asked participants if they had limited their activities because of back pain since the last contact; if the answer was yes, we asked for the number of days they had stayed in bed and the number of days on which activity was limited (not including days in bed) because of back pain. Questions were adapted from previous surveys [25, 26]. For all follow-up contacts, we summed the number of days of bed rest and, in a separate measure, the number of days of limited activity; we then divided these numbers by the total years of follow-up to estimate the average number of affected days per year. Other Measurements The baseline questionnaire assessed potential confounding factors that may be associated with the risk for incident vertebral fracture and with back pain or disability, including smoking (current or past smoker); inactivity, defined as walking less than one block daily (yes or no); a previous physician diagnosis of osteoporosis or spinal fracture (yes or no); current use of estrogen (yes or no); hip pain in the past 12 months (yes or no); and height at 25 years of age. At the baseline examination, we assessed height and weight and calculated body mass index (kg/m2). We assessed grip strength by using an isometric dynamometer (Jamar Hydraulic Hand Dynamometer, JA Preston, Jackson, Mississippi) at baseline and at the follow-up examination and calculated change in grip strength between the two measurements. A random sample of 16% of baseline spine radiographs was assessed for spinal disc degeneration by using previously published methods [27]. Statistical Analysis Unless otherwise indicated, analyses were done separately in groups stratified by the presence of one or more baseline prevalent vertebral fractures. Descriptive and bivariate associations were assessed by using the t-test for continuous variables and the chi-square test for dichotomous variables. The association between incident vertebral fractures and dichotomous outcomes (increased back pain and increased back disability) was analyzed with logistic regression techniques. We analyzed the association of incident vertebral fracture with days of bed rest and days of limited activity per year by using Poisson regression. The distribution of days of bed rest (mean SD, 0.44 5.15) and limited-activity days (16.3 53.7) indicate that considerable overdispersion is present. Poisson regression allowing for this overdispersion provides a good estimation and inferential scheme [2

Long-Term Estrogen Replacement Therapy Prevents Bone Loss and Fractures

Abstract Although several case-control studies have shown an inverse association between postmenopausal estrogen use and fractures, quantitation of fracture incidence has been lacking. To quantify ...

Endogenous Hormones and the Risk of Hip and Vertebral Fractures among Older Women

BACKGROUND AND METHODS In postmenopausal women, the serum concentrations of endogenous sex hormones and vitamin D might influence the risk of hip and vertebral fractures. In a study of a cohort of women 65 years of age or older, we compared the serum hormone concentrations at base line in 133 women who subsequently had hip fractures and 138 women who subsequently had vertebral fractures with those in randomly selected control women from the same cohort. Women who were taking estrogen were excluded. The results were adjusted for age and weight. RESULTS The women with undetectable serum estradiol concentrations (<5 pg per milliliter [18 pmol per liter]) had a relative risk of 2.5 for subsequent hip fracture (95 percent confidence interval, 1.4 to 4.6) and subsequent vertebral fracture (95 percent confidence interval, 1.4 to 4.2), as compared with the women with detectable serum estradiol concentrations. Serum concentrations of sex hormone-binding globulin that were 1.0 microg per deciliter (34.7 nmol per liter) or higher were associated with a relative risk of 2.0 for hip fracture (95 percent confidence interval, 1.1 to 3.9) and 2.3 for vertebral fracture (95 percent confidence interval, 1.2 to 4.4). Women with both undetectable serum estradiol concentrations and serum sex hormone-binding globulin concentrations of 1 microg per deciliter or more had a relative risk of 6.9 for hip fracture (95 percent confidence interval, 1.5 to 32.0) and 7.9 for vertebral fracture (95 percent confidence interval, 2.2 to 28.0). For those with low serum 1,25-dihydroxyvitamin D concentrations (< or =23 pg per milliliter [55 pmol per liter]), the risk of hip fracture increased by a factor of 2.1 (95 percent confidence interval, 1.2 to 3.5). CONCLUSIONS Postmenopausal women with undetectable serum estradiol concentrations and high serum concentrations of sex hormone-binding globulin have an increased risk of hip and vertebral fracture.

Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy.

Abstract We assessed serially the bone mineral loss in 37 premenopausal women for 24 months after oophorectomy and determined the dose-response for conjugated estrogen therapy in preventing this lo...

Postmenopausal bone loss is prevented by treatment with low-dosage estrogen with calcium.

Bone mass was measured prospectively in 73 women during the period immediately after menopause. By comparing the rates of loss at three skeletal sites, we assessed the protective effects of calcium supplements given alone or combined with low-dosage estrogen therapy. After 2 years of follow-up, spinal trabecular mineral content, measured by quantitative computed tomography, decreased by a mean of 9.0% (p = 0.002 compared with baseline) in untreated women and a mean of 10.5% (p = 0.0001) in women given calcium supplements alone. By contrast, women given conjugated estrogens, 0.3 mg/d, with calcium supplements showed an insignificant increase of 2.3%. Significant losses of a lesser magnitude were seen in the appendicular cortical skeleton of women not receiving therapy and in those receiving calcium alone, but no significant changes were observed in women receiving estrogen with calcium.

Differential Effects of Teriparatide on BMD After Treatment With Raloxifene or Alendronate

We investigated the effects of 18 months of treatment with teriparatide in patients previously treated with long‐term antiresorptive therapy using bone turnover markers and bone densitometry. Previous raloxifene treatment allowed for teriparatide‐induced early bone marker and BMD increases comparable with previously published results for treatment‐naïve patients. Conversely, previous alendronate treatment reduced the bone marker and BMD response.

Risk for fracture in women with low serum levels of thyroid-stimulating hormone

Osteoporosis and thyroid dysfunction are both common in older women; 8% to 13% of women older than 50 years of age have biochemical evidence of thyroid dysfunction (1, 2), and 30% are osteoporotic according to bone density criteria (3). Although osteoporotic fractures have long been associated with florid hyperthyroidism (4) and, more recently, with a history of hyperthyroidism in older women (5), the relationship between biochemical evidence of excess thyroid hormone and fracture risk is not known (6, 7). Indirect evidence suggests that excess thyroid hormone due to endogenous disease or exogenous overuse of thyroid hormone may be associated with detrimental effects on bone, even in asymptomatic persons. For example, several biochemical markers of bone turnover are elevated in women with excess thyroid hormone (8, 9). Findings from studies of the relationship between excess thyroid hormone and bone mass are conflicting (10-17). However, factors other than bone mass, such as neuromuscular function and bone quality, contribute to risk for fracture (5) and may be adversely affected by excess thyroid hormone. Results of previous small, retrospective studies of thyroid function and fractures have also been conflicting (18-21). To our knowledge, no large prospective studies have examined the relationship between excess thyroid hormone and subsequent fracture. In light of the conflicting information on bone mass and the paucity of studies with fracture as an end point, several experts have noted the need for longitudinal studies of thyroid function and fracture risk (22-26). To test the hypothesis that low levels of serum thyroid-stimulating hormone (TSH) increase the risk for hip, vertebral, and any nonspine fracture, we performed a prospective study of postmenopausal women enrolled in the Study of Osteoporotic Fractures. Methods Patients The Study of Osteoporotic Fractures is a prospective cohort study of risk factors for fracture among 9704 women (5). White women older than 65 years of age were recruited in 1986 to 1988 from population-based listings at four clinical centers (Portland, Oregon; Minneapolis, Minnesota; Pittsburgh, Pennsylvania; and Baltimore, Maryland). The institutional review boards of all four centers gave approval for this study involving human research subjects. Measurements Baseline Measurements Participants were interviewed and examined during the baseline visit. Detailed information about physician-diagnosed medical conditions and past medication use was collected, and trained interviewers confirmed current medication use by examination of pill bottles. Participants were asked specifically about self-rated health, previous physician diagnoses of hyperthyroidism or Graves disease, and previous use of thyroid hormone. In addition to standardized assessments of height and weight, bone mass of the calcaneus was determined by using single-photon absorptiometry (OsteoAnalyzer, Siemens-Osteon, Wahiawa, Hawaii) and lateral radiographs of the thoracic and lumbar spine were obtained (27, 28). Serum was collected from each participant and stored at 190 C. Approximately 2 years after the baseline visit, bone mineral density of the proximal femur was measured in 82% of the cohort by using dual-energy x-ray absorbtiometry (Hologic QDR 1000, Waltham, Massachusetts) (29). Levels of TSH were measured in archived sera obtained at baseline by using a highly sensitive, third-generation chemiluminescent assay (Endocrine Science, Calabasas, California). The normal range for this assay is 0.5 to 5.5 mU/L; the functional sensitivity (defined as the concentration at which the interassay coefficient of variation is 20%) is approximately 0.05 mIU/L (30). At TSH concentrations of 0.5 mIU/L, the intra-assay coefficient of variation is 4.7% and the interassay coefficient of variation is 6.3%. Thirty randomly selected specimens were blindly submitted for duplicate analysis; the correlation between these two TSH results was high (r = 0.95). Previous studies have shown that TSH levels are highly stable in frozen sera over prolonged periods (31, 32). Other studies have demonstrated that among ambulatory adults, TSH levels of 0.1 mIU/L or less are highly correlated with a diminished response to thyroid-releasing hormone stimulation (33) and are associated with an increased incidence of atrial fibrillation (34). Ascertainment of Incident Fractures After the baseline visit, women were contacted by mail every 4 months about the occurrence of fractures. Hip fractures were confirmed by review of the appropriate radiographs by a radiologist at the coordinating center; other nonspine fractures were confirmed by review of written radiology reports. Fractures resulting from excessive trauma (such as motor vehicle accidents) were excluded. Follow-up for fracture and vital status was more than 99% complete. Lateral spine radiographs were repeated in 7299 women (79% of surviving women) after a mean (SD) follow-up of 3.7 0.4 years, and 7238 pairs of radiographs were judged to be adequate for assessment of incident vertebral fractures. Women without follow-up radiographs were older and reported poorer health at baseline compared with those who had follow-up radiographs (35). Vertebral fractures were identified by using computer-assisted morphometric evaluation (36), and incident vertebral fractures were defined as a 20% or greater and 4 mm or greater reduction in anterior, mid-vertebral, or posterior vertebral height between the baseline and follow-up radiographs (37). The persons who assessed the radiographs had no knowledge of the participants medical history or TSH level. Selection of Case and Control Samples for Fracture Analyses Using an efficient case-cohort approach that maintains statistical power but avoids expensive biochemical measurements in the entire cohort (38-40), we randomly selected baseline serum samples from 148 women with hip fracture and 149 women with incident vertebral fracture after the baseline visit. We randomly selected 398 women from the original cohort, independent of fracture status, to be controls. This random sample, which we refer to as the subsample in this report, included 14 of the 148 women selected as incident hip fracture cases and 15 of the 149 women selected as incident vertebral fracture cases; these women were removed from the subsample and were analyzed as cases of hip and vertebral fracture, respectively. To create a fracture-free control group, we excluded women from the subsample with other nonspine fractures during follow-up (n = 80 for the hip fracture analyses and n = 58 for the vertebral fracture analyses). Ninety women in the subsample had missing or technically inadequate radiographs and could not be analyzed for vertebral fracture outcomes. The analyses of any nonspine fracture were performed in the randomly selected subsample by using standard prospective cohort methods. After 14 women with unconfirmed fracture, 5 women with fracture from extreme trauma, and 6 women with spine fractures were excluded, the analysis of nonspine fracture included 100 women with documented nonspine fracture occurring after study entry and 273 without fracture. Random selection was done by using a computerized random-number generator. Statistical Analysis Continuous variables were plotted, and distributions, means, and standard deviations were examined. Levels of TSH were categorized as low ( 0.1 mIU/L), borderline low (>0.1 but <0.5 mIU/L), normal (0.5 to 5.5 mIU/L), or high (>5.5 mIU/L). Associations with hip fracture were examined by using proportional hazards analyses (Epicure, Hirosoft International, Seattle, Washington) that took into account the case-cohort sampling design. The proportionality assumption was not violated. Results are reported as relative hazards with 95% CIs. Logistic regression was used to analyze incident vertebral fracture; these results are reported as odds ratios with 95% CIs. Cox proportional-hazards models were used to determine associations with nonspine fracture among the randomly selected subsample. Multivariate models were constructed to adjust for potential confounders. Potential confounders were selected on the basis of biologic plausibility (for example, use of thyroid hormone) or a strong univariate association (P 0.1) with TSH level (for example, age) or fracture (for example, estrogen use). We found no association (P>0.1) between TSH level and maternal history of fracture, height, neuromuscular function, or corticosteroid use, which are known to be associated with fracture in this cohort (5). The final multivariate models for each fracture type included TSH level, age, previous hyperthyroidism, self-rated health, and current use of thyroid hormone and estrogen. To determine whether the increased risk for fracture in women with low TSH levels was mediated by reduced bone mass or some other mechanism, we examined the effect of further adjusting the final multivariate models for calcaneal bone mass measured at the baseline visit. The effect of adjustment for bone mineral density at the femoral neck, measured approximately 2 years after the baseline visit, was similar to that observed for calcaneal bone mineral density. Role of the Funding Source The funding source had no role in the collection, analysis, interpretation, or publication of these data. Results During a maximum follow-up of 5.9 years, 332 women had a first hip fracture, 389 had an incident vertebral fracture detected on paired spinal radiographs, and 2520 had nonspine fractures. Women who had incident hip, vertebral, or any nonspine fractures were older and had lower bone mass than controls (Table 1). Women with hip fractures were more likely to report previous hyperthyroidism. Mean TSH levels were similar among women with and without fracture, but the proportion of women with a low TSH level ( 0.1 mIU/L) was significantly greater among those with hip or vertebral fracture. Overall, 11% of participants

The Effects of Tibolone in Older Postmenopausal Women

BACKGROUND Tibolone has estrogenic, progestogenic, and androgenic effects. Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain. METHODS In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of -2.5 or less at the hip or spine or a T score of -2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels. RESULTS During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P=0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups. CONCLUSIONS Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis. (ClinicalTrials.gov number, NCT00519857.)