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Context: The optimal duration of treatment of women with postmenopausal osteoporosis is uncertain.Objective: To compare the effects of discontinuing alendronate treatment after 5 years vs continuing for 10 years.Design and Setting: Randomized, double-blind trial conducted at 10 US clinical centers that participated in the Fracture Intervention Trial (FIT).Participants: One thousand ninety-nine postmenopausal women who had been randomized to alendronate in FIT, with a mean of 5 years of prior alendronate treatment.Intervention: Randomization to alendronate, 5 mg/d (n = 329) or 10 mg/d (n = 333), or placebo (n = 437) for 5 years (1998-2003).Main Outcome Measures: The primary outcome measure was total hip bone mineral density (BMD); secondary measures were BMD at other sites and biochemical markers of bone remodeling. An exploratory outcome measure was fracture incidence.Results: Compared with continuing alendronate, switching to placebo for 5 years resulted in declines in BMD at the total hip (-2.4%; 95% confidence interval [CI], -2.9% to -1.8%; P<.001) and spine (-3.7%; 95% CI, -4.5% to -3.0%; P<.001), but mean levels remained at or above pretreatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate: 55.6% (P<.001) for C-telopeptide of type 1 collagen, 59.5% (P < .001) for serum n = propeptide of type 1 collagen, and 28.1% (P<.001) for bone-specific alkaline phosphatase, but after 5 years without therapy, bone marker levels remained somewhat below pretreatment levels 10 years earlier. After 5 years, the cumulative risk of nonvertebral fractures (RR, 1.00; 95% CI, 0.76-1.32) was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. Among those who continued, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24-0.85) but no significant reduction in morphometric vertebral fractures (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60-1.22). A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities, with bone turnover (double labeling) seen in all specimens.Conclusions: Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years.Trial Registration: clinicaltrials.gov Identifier: NCT 00398931. [ABSTRACT FROM AUTHOR]

Context: As endogenous estradiol increases, risk of breast cancer increases. Raloxifene competes with endogenous estrogen for binding to estrogen receptors in breast tissue. A woman's estradiol level may alter the effects of raloxifene on breast cancer and other outcomes.Objective: To test the hypothesis that raloxifene reduces breast cancer risk more in women with relatively high estradiol levels than in women with very low estradiol levels.Design: Analysis of the Multiple Outcomes of Raloxifene Evaluation, a randomized, double-blind, placebo-controlled trial conducted from 1994 to 1999.Setting: One hundred eighty community settings and medical practices in 25 countries including the United States.Participants: A total of 7290 postmenopausal women aged 80 years or younger with osteoporosis who had baseline serum estradiol concentrations measured by a central laboratory using a sensitive assay. Women with a history of breast cancer or estrogen use were excluded.Intervention: Participants were randomly assigned to receive 60 mg/d or 120 mg/d of raloxifene (n = 4843) or matching placebo (n = 2447) for 4 years.Main Outcome Measure: New cases of histopathologically confirmed breast cancer in the treatment and placebo groups, stratified by estradiol levels.Results: In the placebo group, women with estradiol levels greater than 10 pmol/L (2.7 pg/mL) had a 6.8-fold higher rate of breast cancer (3.0% per 4 years; 95% confidence interval [CI], 1.8%-4.1%) than that of women with undetectable estradiol levels (0.6% per 4 years; 95% CI, 0%-1.1%; P =.005 for trend). Women with estradiol levels greater than 10 pmol/L in the raloxifene group had a rate of breast cancer that was 76% (95% CI, 53%-88%) lower than that of women with estradiol levels greater than 10 pmol/L in the placebo group (absolute rate reduction, 2.2% [95% CI, 1.0%-3.5%; number needed to treat = 45]). In contrast, women with undetectable estradiol levels had similar breast cancer risk whether or not they were treated with raloxifene (risk difference, -0.1%; 95% CI, -0.8% to 0.6%; P =.02 for the interaction). In this cohort, treating women with estradiol levels greater than 10 pmol/L with raloxifene for 4 years would have avoided 47% of breast cancer cases.Conclusions: Measurement of estradiol level by sensitive assay in postmenopausal women identifies those at high risk of breast cancer who may benefit most from raloxifene. If confirmed, this suggests that measuring estradiol and treating women with high estradiol levels could substantially reduce the rate of breast cancer among postmenopausal women. [ABSTRACT FROM AUTHOR]

Context: Raloxifene hydrochloride is a selective estrogen receptor modulator that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting.Objective: To determine whether women taking raloxifene have a lower risk of invasive breast cancer.Design and Setting: The Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter, randomized, double-blind trial, in which women taking raloxifene or placebo were followed up for a median of 40 months (SD, 3 years), from 1994 through 1998, at 180 clinical centers composed of community settings and medical practices in 25 countries, mainly in the United States and Europe.Participants: A total of 7705 postmenopausal women, younger than 81 (mean age, 66.5) years, with osteoporosis, defined by the presence of vertebral fractures or a femoral neck or spine T-score of at least 2.5 SDs below the mean for young healthy women. Almost all participants (96%) were white. Women who had a history of breast cancer or who were taking estrogen were excluded.Intervention: Raloxifene, 60 mg, 2 tablets daily; or raloxifene, 60 mg, 1 tablet daily and 1 placebo tablet; or 2 placebo tablets.Main Outcome Measures: New cases of breast cancer, confirmed by histopathology. Transvaginal ultrasonography was used to assess the endometrial effects of raloxifene in 1781 women. Deep vein thrombosis or pulmonary embolism were determined by chart review.Results: Thirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (relative risk [RR], 0.24; 95% confidence interval [CI], 0.13-0.44; P<.001). To prevent 1 case of breast cancer, 126 women would need to be treated. Raloxifene decreased the risk of estrogen receptor-positive breast cancer by 90% (RR, 0.10; 95% CI, 0.04-0.24), but not estrogen receptor-negative invasive breast cancer (RR, 0.88; 95% CI, 0.26-3.0). Raloxifene increased the risk of venous thromboembolic disease (RR, 3.1; 95% CI, 1.5-6.2), but did not increase the risk of endometrial cancer (RR, 0.8; 95% CI, 0.2-2.7).Conclusion: Among postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during 3 years of treatment with raloxifene. [ABSTRACT FROM AUTHOR]

Context: Mammography is recommended and is cost-effective for women aged 50 to 69 years, but the value of continuing screening mammography after age 69 years is not known. In particular, older women with low bone mineral density (BMD) have a lower risk of breast cancer and may benefit less from continued screening.Objective: To compare life expectancy and cost-effectiveness of screening mammography in elderly women based on 3 screening strategies.Design: Decision analysis and cost-effectiveness analysis using a Markov model.Patients: General population of women aged 65 years or older.Interventions: The analysis compared 3 strategies: (1) Undergoing biennial mammography from age 65 to 69 years; (2) undergoing biennial mammography from age 65 to 69 years, measurement of distal radial BMD at age 65 years, discontinuing screening at age 69 years in women in the lowest BMD quartile for age, and continuing biennial mammography to age 79 years in those in the top 3 quartiles of distal radius BMD; and (3) undergoing biennial mammography from age 65 to 79 years.Main Outcome Measures: Deaths due to breast cancer averted, life expectancy, and incremental cost-effectiveness ratios.Results: Compared with discontinuing mammography screening at age 69 years, measuring BMD at age 65 years in 10000 women and continuing mammography to age 79 years only in women with BMD in the top 3 quartiles would prevent 9.4 deaths and add, on average, 2.1 days to life expectancy at an incremental cost of $66773 per year of life saved. Continuing mammography to age 79 years in all 10000 elderly women would prevent 1.4 additional breast cancer deaths and add only 7.2 hours to life expectancy at an incremental cost of $117689 per year of life saved compared with only continuing mammography to age 79 years in women with BMD in the top 3 quartiles.Conclusions: This analysis suggests that continuing mammography screening after age 69 years results in a small gain in life expectancy and is moderately cost-effective in those with high BMD and more costly in those with low BMD. Women's preferences for a small gain in life expectancy and the potential harms of screening mammography should play an important role when elderly women are deciding about screening. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that bone mineral density (BMD) is associated with the risk of developing breast cancer in older women.Design: Prospective cohort study with mean (SD) follow-up of 3.2 (1.6) years.Setting: Four clinical centers, one each located in the following areas: Baltimore, Md; Minneapolis, Minn; Portland, Ore; and the Monongahela Valley in Pennsylvania.Participants: A total of 6854 nonblack women who were 65 years of age or older and enrolled in the Study of Osteoporotic Fractures.Measurements: Radius and calcaneus BMD by single photon absorptiometry at baseline; hip and spine BMD by dual-energy x-ray absorptiometry 2 years later.Main Outcome Measure: Breast cancer confirmed by medical record review.Results: A total of 97 women developed breast cancer. In the multivariate model, adjusting for age, the degree of obesity, and other important covariates, the risk of breast cancer was about 30% to 50% higher per 1 SD increase in BMD (relative risk, distal radius BMD=1.50; 95% confidence interval, 1.16-1.95). The age-adjusted incidence rate of breast cancer per 1000 person-years among women in the lowest quartile of distal radius BMD was 2.46, compared with 5.99 among women with the highest BMD. Women with BMD above the 25th percentile were at 2.0 to 2.5 times increased risk of breast cancer compared with women below the 25th percentile. Results were consistent across all BMD sites.Conclusions: Bone mineral density predicts the risk of breast cancer in older women. The magnitude of the association is similar to that observed between BMD and all fractures. Our findings suggest a link between 2 of the most common conditions affecting a woman's health. Identifying a common denominator for these conditions should substantially improve our understanding of their etiology and prevention. [ABSTRACT FROM AUTHOR]

Importance: While adults aged 80 years and older account for 70% of hip fractures in the US, performance of fracture risk assessment tools in this population is uncertain., Objective: To compare performance of the Fracture Risk Assessment Tool (FRAX), Garvan Fracture Risk Calculator, and femoral neck bone mineral density (FNBMD) alone in 5-year hip fracture prediction., Design, Setting and Participants: Prognostic analysis of 3 prospective cohort studies including participants attending an index examination (1997 to 2016) at age 80 years or older. Data were analyzed from March 2023 to April 2024., Main Outcomes and Measures: Participants contacted every 4 or 6 months after index examination to ascertain incident hip fractures and vital status. Predicted 5-year hip fracture probabilities calculated using FRAX and Garvan models incorporating FNBMD and FNBMD alone. Model discrimination assessed by area under receiver operating characteristic curve (AUC). Model calibration assessed by comparing observed vs predicted hip fracture probabilities within predicted risk quintiles., Results: A total of 8890 participants were included, with a mean (SD) age at index examination of 82.6 (2.7) years; 4906 participants (55.2%) were women, 866 (9.7%) were Black, 7836 (88.1%) were White, and 188 (2.1%) were other races and ethnicities. During 5-year follow-up, 321 women (6.5%) and 123 men (3.1%) experienced a hip fracture; 818 women (16.7%) and 921 men (23.1%) died before hip fracture. Among women, AUC was 0.69 (95% CI, 0.67-0.72) for FRAX, 0.69 (95% CI, 0.66-0.72) for Garvan, and 0.72 (95% CI, 0.69-0.75) for FNBMD alone (FNBMD superior to FRAX, P = .01; and Garvan, P = .01). Among men, AUC was 0.71 (95% CI, 0.66-0.75) for FRAX, 0.76 (95% CI, 0.72-0.81) for Garvan, and 0.77 (95% CI, 0.72-0.81) for FNBMD alone (P < .001 Garvan and FNBMD alone superior to FRAX). Among both sexes, Garvan greatly overestimated hip fracture risk among individuals in upper quintiles of predicted risk, while FRAX modestly underestimated risk among those in intermediate quintiles of predicted risk., Conclusions and Relevance: In this prognostic study of adults aged 80 years and older, FRAX and Garvan tools incorporating FNBMD compared with FNBMD alone did not improve 5-year hip fracture discrimination. FRAX modestly underpredicted observed hip fracture probability in intermediate-risk individuals. Garvan markedly overpredicted observed hip fracture probability in high-risk individuals. Until better prediction tools are available, clinicians should prioritize consideration of hip BMD, life expectancy, and patient preferences in decision-making regarding drug treatment initiation for hip fracture prevention in late-life adults.

Importance: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years., Observations: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up., Conclusions and Relevance: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.

Importance: The best approach to identify younger postmenopausal women for osteoporosis screening is uncertain. The Fracture Risk Assessment Tool (FRAX), which includes self-identified racial and ethnic information, and the Osteoporosis Self-assessment Tool (OST), which does not, are risk assessment tools recommended by US Preventive Services Task Force guidelines to identify candidates for bone mineral density (BMD) testing in this age group., Objective: To compare the ability of FRAX vs OST to discriminate between younger postmenopausal women who do and do not experience incident fracture during a 10-year follow-up in the 4 racial and ethnic groups specified by FRAX., Design, Setting, and Participants: This cohort study of Women's Health Initiative participants included 67 169 women (baseline age range, 50-64 years) with 10 years of follow-up for major osteoporotic fracture (MOF; including hip, clinical spine, forearm, and shoulder fracture) at 40 US clinical centers. Data were collected from October 1993 to December 2008 and analyzed between May 11, 2022, and February 23, 2023., Main Outcomes and Measures: Incident MOF and BMD (in a subset of 4607 women) were assessed. The area under the receiver operating characteristic curve (AUC) for FRAX (without BMD information) and OST was calculated within each racial and ethnic category., Results: Among the 67 169 participants, mean (SD) age at baseline was 57.8 (4.1) years. A total of 1486 (2.2%) self-identified as Asian, 5927 (8.8%) as Black, 2545 (3.8%) as Hispanic, and 57 211 (85.2%) as White. During follow-up, 5594 women experienced MOF. For discrimination of MOF, AUC values for FRAX were 0.65 (95% CI, 0.58-0.71) for Asian, 0.55 (95% CI, 0.52-0.59) for Black, 0.61 (95% CI, 0.56-0.65) for Hispanic, and 0.59 (95% CI, 0.58-0.59) for White women. The AUC values for OST were 0.62 (95% CI, 0.56-0.69) for Asian, 0.53 (95% CI, 0.50-0.57) for Black, 0.58 (95% CI, 0.54-0.62) for Hispanic, and 0.55 (95% CI, 0.54-0.56) for White women. For discrimination of femoral neck osteoporosis, AUC values were excellent for OST (range, 0.79 [95% CI, 0.65-0.93] to 0.85 [95% CI, 0.74-0.96]), higher for OST than FRAX (range, 0.72 [95% CI, 0.68-0.75] to 0.74 [95% CI, 0.60-0.88]), and similar in each of the 4 racial and ethnic groups., Conclusions and Relevance: These findings suggest that within each racial and ethnic category, the US FRAX and OST have suboptimal performance in discrimination of MOF in younger postmenopausal women. In contrast, for identifying osteoporosis, OST was excellent. The US version of FRAX should not be routinely used to make screening decisions in younger postmenopausal women. Future investigations should improve existing tools or create new approaches to osteoporosis risk assessment for this age group.

Importance: Whether prediabetes is associated with fracture is uncertain., Objective: To evaluate whether prediabetes before the menopause transition (MT) is associated with incident fracture during and after the MT., Design, Setting, and Participants: This cohort study used data collected between January 6, 1996, and February 28, 2018, in the Study of Women's Health Across the Nation cohort study, an ongoing, US-based, multicenter, longitudinal study of the MT in diverse ambulatory women. The study included 1690 midlife women in premenopause or early perimenopause at study inception (who have since transitioned to postmenopause) who did not have type 2 diabetes before the MT and who did not take bone-beneficial medications before the MT. Start of the MT was defined as the first visit in late perimenopause (or first postmenopausal visit if participants transitioned directly from premenopause or early perimenopause to postmenopause). Mean (SD) follow-up was 12 (6) years. Statistical analysis was conducted from January to May 2022., Exposure: Proportion of visits before the MT that women had prediabetes (fasting glucose, 100-125 mg/dL [to convert to millimoles per liter, multiply by 0.0555]), with values ranging from 0 (prediabetes at no visits) to 1 (prediabetes at all visits)., Main Outcomes and Measures: Time to first fracture after the start of the MT, with censoring at first diagnosis of type 2 diabetes, initiation of bone-beneficial medication, or last follow-up. Cox proportional hazards regression was used to examine the association (before and after adjustment for bone mineral density) of prediabetes before the MT with fracture during the MT and after menopause., Results: This analysis included 1690 women (mean [SD] age, 49.7 [3.1] years; 437 Black women [25.9%], 197 Chinese women [11.7%], 215 Japanese women [12.7%], and 841 White women [49.8%]; mean [SD] body mass index [BMI] at the start of the MT, 27.6 [6.6]). A total of 225 women (13.3%) had prediabetes at 1 or more study visits before the MT, and 1465 women (86.7%) did not have prediabetes before the MT. Of the 225 women with prediabetes, 25 (11.1%) sustained a fracture, while 111 of the 1465 women without prediabetes (7.6%) sustained a fracture. After adjustment for age, BMI, and cigarette use at the start of the MT; fracture before the MT; use of bone-detrimental medications; race and ethnicity; and study site, prediabetes before the MT was associated with more subsequent fractures (hazard ratio for fracture with prediabetes at all vs no pre-MT visits, 2.20 [95% CI, 1.11-4.37]; P = .02). This association was essentially unchanged after controlling for BMD at the start of the MT., Conclusions and Relevance: This cohort study of midlife women suggests that prediabetes was associated with risk of fracture. Future research should determine whether treating prediabetes reduces fracture risk.

Importance: The burden of fractures among postmenopausal women is high. Although nontraumatic fractures are strong risk factors for future fracture, current clinical guidelines do not address traumatic fractures., Objective: To determine how future fracture risk varies according to whether an initial fracture is traumatic or nontraumatic., Design, Setting, and Participants: We conducted a prospective observational study using data from the Women's Health Initiative Study (WHI) (enrollment, September 1994-December 1998; data analysis, September 2020 to March 2021), which enrolled postmenopausal women aged 50 to 79 years at baseline at 40 US clinical centers. The WHI Clinical Trials and WHI Bone Density Substudy, conducted at 3 of the clinical centers, asked participants to report the mechanism of incident fractures. Of 75 335 participants, information regarding incident fracture and covariates was available for 66 874 participants (88.8%), who comprised the analytic sample of this study. Mean (SD) follow-up was 8.1 (1.6) years., Interventions: None., Main Outcomes and Measures: Incident clinical fractures were self-reported at least annually and confirmed using medical records. Participants reported the mechanism of incident fracture as traumatic or nontraumatic., Results: Among the 66 874 participants in the analytic sample (mean [SD] age, 63.1 [7.0] years and 65.3 [7.2] years among women without and with clinical fracture, respectively), 7142 participants (10.7%) experienced incident fracture during the study follow-up period. The adjusted hazard ratio (aHR) of subsequent fracture after initial fracture was 1.49 (95% CI, 1.38-1.61). Among women whose initial fracture was traumatic, the association between initial fracture and subsequent fracture was significantly increased (aHR, 1.25; 95% CI, 1.06-1.48). Among women whose initial fracture was nontraumatic, the association between initial fracture and subsequent fracture was also increased (aHR, 1.52; 95% CI, 1.37-1.68). Confidence intervals for associations between initial fracture and subsequent fracture were overlapping for traumatic and nontraumatic initial fracture strata., Conclusions and Relevance: In this cohort study, among postmenopausal women older than 50 years, fracture was associated with a greater risk of subsequent fracture regardless of whether the fracture was traumatic or nontraumatic. These findings suggest that clinical osteoporosis assessment should include high-trauma as well as low-trauma fractures.

Importance: The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials., Objective: To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women's Health Initiative clinical trials., Design, Setting, and Participants: Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017., Interventions: In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years' median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years' median intervention duration., Main Outcomes and Measures: The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer., Results: Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93; P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P < .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95; P= .11)., Conclusions and Relevance: In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.

Importance: The role of endogenous progesterone in the development of breast cancer remains largely unexplored to date, primarily owing to assay sensitivity limitations and low progesterone concentrations in postmenopausal women. Recently identified progesterone metabolites may provide insights as experimental data suggest that 5α-dihydroprogesterone (5αP) concentrations reflect cancer-promoting properties and 3α-dihydroprogesterone (3αHP) concentrations reflect cancer-inhibiting properties., Objective: To evaluate the association between circulating progesterone and progesterone metabolite levels and breast cancer risk., Design, Setting, and Participants: Using a sensitive liquid chromatography-tandem mass spectrometry assay, prediagnostic serum levels of progesterone and progesterone metabolites were quantified in a case-cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (n = 15 595). Participation was limited to women not receiving exogenous hormone therapy at the time of blood sampling (1992-1993). Incident breast cancer cases (n = 405) were diagnosed during 12 follow-up years and a subcohort of 495 postmenopausal women were randomly selected within 10-year age and clinical center strata. Progesterone assays were completed in July 2017; subsequent data analyses were conducted between July 15, 2017, and December 20, 2018., Exposures: Circulating concentrations of pregnenolone, progesterone, and their major metabolites., Main Outcomes and Measures: Development of breast cancer, with hazard ratios (HRs) and 95% CIs was estimated using Cox proportional hazards regression adjusted for key confounders, including estradiol. Evaluation of hormone ratios and effect modification were planned a priori., Results: The present study included 405 incident breast cancer cases and a subcohort of 495 postmenopausal women; the mean (SD) age at the time of the blood draw was 67.2 (6.2) years. Progesterone concentrations were a mean (SD) of 4.6 (1.7) ng/dL. Women with higher circulating progesterone levels were at an increased risk for breast cancer per SD increase in progesterone levels (HR, 1.16; 95% CI, 1.00-1.35; P = .048). The association with progesterone was linear in a 5-knot spline and stronger for invasive breast cancers (n = 267) (HR, 1.24; 95% CI, 1.07-1.43; P = .004). Among women in the lowest quintile (Q1) of circulating estradiol (<6.30 pg/mL) elevated progesterone concentrations were associated with reduced breast cancer risk per SD increase in progesterone levels (HR, 0.38; 95% CI, 0.15-0.95; P = .04) and increased risk among women in higher quintiles of estradiol (Q2-Q5; ≥6.30 pg/mL) (HR, 1.18; 95% CI, 1.04-1.35; P = .01; P = .04 for interaction)., Conclusions and Relevance: In this case-cohort study of postmenopausal women, elevated circulating progesterone levels were associated with a 16% increase in the risk of breast cancer. Additional research should be undertaken to assess how postmenopausal breast cancer risk is associated with both endogenous progesterone and progesterone metabolites and their interactions with estradiol.

Importance: Examining trends in mortality following hip fracture and its associated factors is important for population health surveillance and for developing preventive interventions., Objective: To examine temporal trends in, and risk factors associated with, mortality following hip fracture over 18 years in Singapore., Design, Setting, and Participants: This retrospective, population-based cohort study included men and women aged 50 years and older admitted to Singapore hospitals for first hip fracture identified and followed up from 2000 to 2017. Demographic information, fracture type, and Charlson Comorbidity Index (CCI) score were retrieved from nationwide claims data, and mortality data were from the National Death Registry. Data were analyzed from August 2018 to December 2019., Main Outcomes and Measures: Adjusted hazard ratios (aHRs) and their 95% confidence intervals were estimated using Cox proportional hazards regression. Kaplan-Meier life table methods were used to calculate survival following the hip fracture on a cohort basis. The crude survival over time since fracture was compared by sex, age group, ethnicity, CCI, and fracture type. Standardized mortality ratios (SMRs) were calculated using all-cause mortality obtained from Singapore population life tables., Results: Among 36 082 first inpatient admissions for hip fractures (mean [SD] patient age, 78.2 [10.1] years; 24 902 [69.0%] female; 30 348 [84.1%] Chinese, 2863 [7.9%] Malay, 1778 [4.9%] Indian, and 1093 [3.0%] other ethnicity), elevated rates of mortality were observed for male sex (aHR, 1.46; 95% CI, 1.41-1.52), Malay ethnicity (aHR, 1.23; 95% CI, 1.15-1.30 vs Chinese ethnicity), older age (aHR, 5.20; 95% CI, 4.27-6.34 for age ≥85 years vs 50-54 years), high CCI score (aHR, 3.62; 95% CI, 3.42-3.84 for CCI ≥6 vs CCI of 0), trochanteric fractures (aHR, 1.11; 95% CI, 1.06-1.16 vs cervical fractures), and earlier cohorts (aHR, 0.59; 95% CI, 0.56-0.62 for 2012-2017 vs 2000-2005). Absolute mortality decreased significantly over time: by 21% in 2006 to 2011 and by 40% in 2012 to 2017, compared with 2000 to 2005. On long-term follow-up, differences in survival associated with sex and ethnicity tended to diminish, whereas differences associated with older age, higher CCI score, and trochanteric fractures increased. In the first year after fracture, reductions in SMR were observed comparing the periods 2013 to 2016 with 2003 to 2007 in women (SMR, 2.05; 95% CI, 1.91-2.20 vs SMR, 2.54; 95% CI, 2.39-2.70, respectively) but not among men (SMR, 3.28; 95% CI, 3.04-3.54 vs SMR, 3.42; 95% CI, 3.18-3.68, respectively)., Conclusions and Relevance: Malay ethnicity, older age, male sex, prefracture comorbidity, and trochanteric fractures were independently associated with increased risk of death, identifying population groups that could be targeted for intervention strategies. The improvement in relative mortality for women but not men suggests the need to develop interventions that improve mortality outcomes for men.

Importance: Physical activity is inversely associated with hip fracture risk in older women. However, the association of physical activity with fracture at other sites and the role of sedentary behavior remain unclear., Objective: To assess the associations of physical activity and sedentary behavior with fracture incidence among postmenopausal women., Design, Setting, and Participants: The Women's Health Initiative prospective cohort study enrolled 77 206 postmenopausal women aged 50 to 79 years between October 1993 and December 1998 at 40 US clinical centers. Participants were observed for outcomes through September 2015, with data analysis conducted from June 2017 to August 2019., Exposures: Self-reported physical activity and sedentary time., Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs for total and site-specific fracture incidence., Results: During a mean (SD) follow-up period of 14.0 (5.2) years among 77 206 women (mean [SD] age, 63.4 [7.3] years; 66 072 [85.6%] white), 25 516 (33.1%) reported a first incident fracture. Total physical activity was inversely associated with the multivariable-adjusted risk of hip fracture (>17.7 metabolic equivalent [MET] h/wk vs none: HR, 0.82; 95% CI, 0.72-0.95; P for trend < .001). Inverse associations with hip fracture were also observed for walking (>7.5 MET h/wk vs none: HR, 0.88; 95% CI, 0.78-0.98; P for trend = .01), mild activity (HR, 0.82; 95% CI, 0.73-0.93; P for trend = .003), moderate to vigorous activity (HR, 0.88; 95% CI, 0.81-0.96; P for trend = .002), and yard work (HR, 0.90; 95% CI, 0.82-0.99; P for trend = .04). Total activity was positively associated with knee fracture (>17.7 MET h/wk vs none: HR, 1.26; 95% CI, 1.05-1.50; P for trend = .08). Mild activity was associated with lower risks of clinical vertebral fracture (HR, 0.87; 95% CI, 0.78-0.96; P for trend = .006) and total fractures (HR, 0.91; 95% CI, 0.87-0.94; P for trend < .001). Moderate to vigorous activity was positively associated with wrist or forearm fracture (HR, 1.09; 95% CI, 1.03-1.15; P for trend = .004). After controlling for covariates and total physical activity, sedentary time was positively associated with total fracture risk (>9.5 h/d vs <6.5 h/d: HR, 1.04; 95% CI, 1.01-1.07; P for trend = .01). When analyzed jointly, higher total activity mitigated some of the total fracture risk associated with sedentary behavior. Analysis of time-varying exposures resulted in somewhat stronger associations for total physical activity, whereas those for sedentary time were materially unchanged., Conclusions and Relevance: In older ambulatory women, higher total physical activity was associated with lower total and hip fracture risk but higher knee fracture risk. Mild activity and walking were associated with lower hip fracture risk, a finding with important public health implications because these activities are common in older adults. The positive association between sedentary time and total fracture risk requires further investigation.

Importance: Previous studies have suggested an association between cataract surgery and decreased risk for all-cause mortality potentially through a mechanism of improved health status and functional independence, but the association between cataract surgery and cause-specific mortality has not been previously studied and is not well understood., Objective: To examine the association between cataract surgery and total and cause-specific mortality in older women with cataract., Design, Setting, and Participants: This prospective cohort study included nationwide data collected from the Women's Health Initiative (WHI) clinical trial and observational study linked with the Medicare claims database. Participants in the present study were 65 years or older with a diagnosis of cataract in the linked Medicare claims database. The WHI data were collected from January 1, 1993, through December 31, 2015. Data were analyzed for the present study from July 1, 2014, through September 1, 2017., Exposures: Cataract surgery as determined by Medicare claims codes., Main Outcomes and Measures: The outcomes of interest included all-cause mortality and mortality attributed to vascular, cancer, accidental, neurologic, pulmonary, and infectious causes. Mortality rates were compared by cataract surgery status using the log-rank test and Cox proportional hazards regression models adjusting for demographics, systemic and ocular comorbidities, smoking, alcohol use, body mass index, and physical activity., Results: A total of 74 044 women with cataract in the WHI included 41 735 who underwent cataract surgery. Mean (SD) age was 70.5 (4.6) years; the most common ethnicity was white (64 430 [87.0%]), followed by black (5293 [7.1%]) and Hispanic (1723 [2.3%]). The mortality rate was 2.56 per 100 person-years in both groups. In covariate-adjusted Cox models, cataract surgery was associated with lower all-cause mortality (adjusted hazards ratio [AHR], 0.40; 95% CI, 0.39-0.42) as well as lower mortality specific to vascular (AHR, 0.42; 95% CI, 0.39-0.46), cancer (AHR, 0.31; 95% CI, 0.29-0.34), accidental (AHR, 0.44; 95% CI, 0.33-0.58), neurologic (AHR, 0.43; 95% CI, 0.36-0.53), pulmonary (AHR, 0.63; 95% CI, 0.52-0.78), and infectious (AHR, 0.44; 95% CI, 0.36-0.54) diseases., Conclusions and Relevance: In older women with cataract in the WHI, cataract surgery is associated with lower risk for total and cause-specific mortality, although whether this association is explained by the intervention of cataract surgery is unclear. Further study of the interplay of cataract surgery, systemic disease, and disease-related mortality would be informative for improved patient care.

Importance: In one-third of older men with anemia, no recognized cause can be found., Objective: To determine if testosterone treatment of men 65 years or older with unequivocally low testosterone levels and unexplained anemia would increase their hemoglobin concentration., Design, Setting, and Participants: A double-blinded, placebo-controlled trial with treatment allocation by minimization using 788 men 65 years or older who have average testosterone levels of less than 275 ng/dL. Of 788 participants, 126 were anemic (hemoglobin ≤12.7 g/dL), 62 of whom had no known cause. The trial was conducted in 12 academic medical centers in the United States from June 2010 to June 2014., Interventions: Testosterone gel, the dose adjusted to maintain the testosterone levels normal for young men, or placebo gel for 12 months., Main Outcomes and Measures: The percent of men with unexplained anemia whose hemoglobin levels increased by 1.0 g/dL or more in response to testosterone compared with placebo. The statistical analysis was intent-to-treat by a logistic mixed effects model adjusted for balancing factors., Results: The men had a mean age of 74.8 years and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 30.7; 84.9% were white. Testosterone treatment resulted in a greater percentage of men with unexplained anemia whose month 12 hemoglobin levels had increased by 1.0 g/dL or more over baseline (54%) than did placebo (15%) (adjusted OR, 31.5; 95% CI, 3.7-277.8; P = .002) and a greater percentage of men who at month 12 were no longer anemic (58.3%) compared with placebo (22.2%) (adjusted OR, 17.0; 95% CI, 2.8-104.0; P = .002). Testosterone treatment also resulted in a greater percentage of men with anemia of known cause whose month 12 hemoglobin levels had increased by 1.0 g/dL or more (52%) than did placebo (19%) (adjusted OR, 8.2; 95% CI, 2.1-31.9; P = .003). Testosterone treatment resulted in a hemoglobin concentration of more than 17.5 g/dL in 6 men who had not been anemic at baseline., Conclusions and Relevance: Among older men with low testosterone levels, testosterone treatment significantly increased the hemoglobin levels of those with unexplained anemia as well as those with anemia from known causes. These increases may be of clinical value, as suggested by the magnitude of the changes and the correction of anemia in most men, but the overall health benefits remain to be established. Measurement of testosterone levels might be considered in men 65 years or older who have unexplained anemia and symptoms of low testosterone levels., Trial Registration: clinicaltrials.gov Identifier: NCT00799617.

Importance: As men age, they experience decreased serum testosterone concentrations, decreased bone mineral density (BMD), and increased risk of fracture., Objective: To determine whether testosterone treatment of older men with low testosterone increases volumetric BMD (vBMD) and estimated bone strength., Design, Setting, and Participants: Placebo-controlled, double-blind trial with treatment allocation by minimization at 9 US academic medical centers of men 65 years or older with 2 testosterone concentrations averaging less than 275 ng/L participating in the Testosterone Trials from December 2011 to June 2014. The analysis was a modified intent-to-treat comparison of treatment groups by multivariable linear regression adjusted for balancing factors as required by minimization., Interventions: Testosterone gel, adjusted to maintain the testosterone level within the normal range for young men, or placebo gel for 1 year., Main Outcomes and Measures: Spine and hip vBMD was determined by quantitative computed tomography at baseline and 12 months. Bone strength was estimated by finite element analysis of quantitative computed tomography data. Areal BMD was assessed by dual energy x-ray absorptiometry at baseline and 12 months., Results: There were 211 participants (mean [SD] age, 72.3 [5.9] years; 86% white; mean [SD] body mass index, 31.2 [3.4]). Testosterone treatment was associated with significantly greater increases than placebo in mean spine trabecular vBMD (7.5%; 95% CI, 4.8% to 10.3% vs 0.8%; 95% CI, -1.9% to 3.4%; treatment effect, 6.8%; 95% CI, 4.8%-8.7%; P < .001), spine peripheral vBMD, hip trabecular and peripheral vBMD, and mean estimated strength of spine trabecular bone (10.8%; 95% CI, 7.4% to 14.3% vs 2.4%; 95% CI, -1.0% to 5.7%; treatment effect, 8.5%; 95% CI, 6.0%-10.9%; P < .001), spine peripheral bone, and hip trabecular and peripheral bone. The estimated strength increases were greater in trabecular than peripheral bone and greater in the spine than hip. Testosterone treatment increased spine areal BMD but less than vBMD., Conclusions and Relevance: Testosterone treatment for 1 year of older men with low testosterone significantly increased vBMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip. A larger, longer trial could determine whether this treatment also reduces fracture risk., Trial Registration: clinicaltrials.gov Identifier: NCT00799617.

Importance: Most cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions., Objective: To determine if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI)., Design, Setting, and Participants: The Testosterone Trials (TTrials) were 7 trials to assess the efficacy of testosterone treatment in older men with low testosterone levels. The Cognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 US academic medical centers, 788 men who were 65 years or older with a serum testosterone level less than 275 ng/mL and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n = 394) or placebo (n = 394). A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance. Enrollment in the TTrials began June 24, 2010; the final participant completed treatment and assessment in June 2014., Interventions: Testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year., Main Outcomes and Measures: The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to -26), executive function (Trail-Making Test B minus A; range, -290 to 290), and spatial ability (Card Rotation Test; score range, -80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months., Results: Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247 were assigned to receive testosterone and 246 to receive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, -0.07 [95% CI, -0.92 to 0.79]; P = .88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (-0.28 [95% CI, -0.76 to 0.19]; P = .24), executive function (-5.51 [95% CI, -12.91 to 1.88]; P = .14), or spatial ability (-0.12 [95% CI, -1.89 to 1.65]; P = .89)., Conclusions and Relevance: Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions., Trial Registration: clinicaltrials.gov Identifier: NCT00799617.

Importance: Recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk., Objective: To test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume., Design, Setting, and Participants: Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014., Intervention: Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months., Main Outcomes and Measures: The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis)., Results: Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, -27 Agatston units; 95% CI, -80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group., Conclusions and Relevance: Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding., Trial Registration: clinicaltrials.gov Identifier: NCT00799617.

Importance: Considerable efforts have been undertaken to relate single nutrients to bone health. To this point, results are inconsistent. Suboptimal single nutrient intake does not occur in isolation but rather reflects a poor diet quality., Objective: To assess the association between adherence to a diet quality index constructed on the basis of dietary recommendations or existing healthy dietary patterns and fractures in postmenopausal women., Design, Setting, and Participants: Post hoc analysis was conducted of longitudinal data from 40 clinical centers throughout the United States included in the Women's Health Initiative (WHI) observational study. Participants in the prospective cohort included 93 676 women who were eligible for the WHI if they were aged 50 to 79 years. Recruitment was conducted from October 1, 1993, to December 31, 1998, with the study ending August 29, 2014. The WHI food frequency questionnaire was used to derive nutrient and food intake at baseline. Diet quality and adherence were assessed by scores on the alternate Mediterranean Diet (aMED), a 9-category measure of adherence to a Mediterranean dietary pattern; the Healthy Eating Index 2010 (HEI-2010), a 100-point measure of 12 food components; the 11-item Alternate Healthy Eating Index 2010 (AHEI-2010); or the 8-component Dietary Approaches to Stop Hypertension (DASH) diet score., Main Outcomes and Measures: Outcome measures included incident total and hip fractures. Hazard ratios (HRs) by quintiles of dietary index scores were estimated using Cox proportional hazards regression analyses., Results: Of the 93 676 participants, 90 014 were included in the analysis (mean [SD] age, 63.6 [7.4]) years. During a median follow-up time of 15.9 years, there were 2121 cases of hip fractures and 28 718 cases of total fractures. Women scoring in the highest quintile (Q5) of the aMED index had a lower risk for hip fractures (HR, 0.80; 95% CI, 0.66-0.97), with an absolute risk reduction of 0.29% and a number needed to treat of 342 (95% CI, 249-502). No association between the aMED score and total fractures was observed (Q5 HR, 1.01; 95% CI, 0.95-1.07). Higher HEI-2010 or DASH scores tended to be inversely related to hip fracture risk, but the results were nonsignificant (Q5 HR, 0.87; 95% CI, 0.75-1.02; and Q5 HR, 0.89; 95% CI, 0.75-1.06, respectively). The AHEI-2010 score was associated with neither hip nor total fractures., Conclusions and Relevance: Higher adherence to a Mediterranean diet is associated with a lower risk for hip fractures. These results support that a healthy dietary pattern may play a role in maintaining bone health in postmenopausal women.

Importance: Studies have shown that bisphosphonates may have antitumor and antimetastatic properties. Recently, observational studies have suggested a possible protective effect of bisphosphonates on breast cancer, but the effect of bisphosphonate use on risk of breast cancer has not been tested in randomized trials., Objective: To assess the relationship of postmenopausal breast cancer incidence and bisphosphonate use using data from 2 randomized (1:1), double-blind, placebo-controlled trials., Design, Setting, and Participants: The Fracture Intervention Trial (FIT) randomly assigned 6459 women aged 55 to 81 years to alendronate or placebo for a mean follow-up of 3.8 years. The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) randomly assigned 7765 women aged 65 to 89 years to annual intravenous zoledronic acid or placebo for a mean follow-up of 2.8 years. Data were collected at clinical centers in the United States (FIT and HORIZON-PFT) and in Asia and the Pacific, Europe, North America, and South America (HORIZON-PFT). Women, in either study, with recurrent breast cancer or who reported a history of breast cancer were excluded from analyses. In each trial, a blinded review was conducted of each cancer adverse event report to verify incident invasive breast cancer cases. The primary analysis compared events in the active vs placebo group using a log-rank test., Intervention: Alendronate vs placebo (FIT) or zoledronic acid vs placebo (HORIZON-PFT)., Main Outcomes and Measures: Hazard ratio for incident breast cancer in the bisphosphonate treatment group compared to the placebo group., Results: There was no significant difference in the rate of breast cancer in FIT: 1.5% (n = 46) in the placebo group and 1.8% (n = 57) in the alendronate group (hazard ratio [HR], 1.24 [95% CI, 0.84-1.83]). In HORIZON-PFT, there was also no significant difference: 0.8% (n = 29) in the placebo group and 0.9% (n = 33) in the zoledronic acid group (HR, 1.15 [95% CI, 0.70-1.89]). There was also no significant difference when the data from FIT and HORIZON-PFT were pooled (HR, 1.20 [95% CI, 0.89-1.63])., Conclusions and Relevance: These 2 randomized clinical trials do not support the findings from observational research. Contrary to the results from observational studies, we found that 3 to 4 years of bisphosphonate treatment did not decrease the risk of invasive postmenopausal breast cancer., Trial Registration: clinicaltrials.gov Identifier: NCT00049829 (HORIZON-PFT).

Importance: Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention., Objective: To report a comprehensive, integrated overview of findings from the 2 Women's Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up., Design, Setting, and Participants: A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers., Interventions: Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010., Main Outcomes and Measures: Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death., Results: During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials., Conclusions and Relevance: Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women., Trial Registration: clinicaltrials.gov Identifier: NCT00000611.

Context: Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D., Objective: To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes., Design, Setting, and Participants: Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies., Main Outcome Measure: Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up., Results: Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism., Conclusion: Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.

Context: Type 2 diabetes mellitus (DM) is associated with higher bone mineral density (BMD) and paradoxically with increased fracture risk. It is not known if low BMD, central to fracture prediction in older adults, identifies fracture risk in patients with DM., Objective: To determine if femoral neck BMD T score and the World Health Organization Fracture Risk Algorithm (FRAX) score are associated with hip and nonspine fracture risk in older adults with type 2 DM., Design, Setting, and Participants: Data from 3 prospective observational studies with adjudicated fracture outcomes (Study of Osteoporotic Fractures [December 1998-July 2008]; Osteoporotic Fractures in Men Study [March 2000-March 2009]; and Health, Aging, and Body Composition study [April 1997-June 2007]) were analyzed in older community-dwelling adults (9449 women and 7436 men) in the United States., Main Outcome Measure: Self-reported incident fractures, which were verified by radiology reports., Results: Of 770 women with DM, 84 experienced a hip fracture and 262 a nonspine fracture during a mean (SD) follow-up of 12.6 (5.3) years. Of 1199 men with DM, 32 experienced a hip fracture and 133 a nonspine fracture during a mean (SD) follow-up of 7.5 (2.0) years. Age-adjusted hazard ratios (HRs) for 1-unit decrease in femoral neck BMD T score in women with DM were 1.88 (95% confidence interval [CI], 1.43-2.48) for hip fracture and 1.52 (95% CI, 1.31-1.75) for nonspine fracture, and in men with DM were 5.71 (95% CI, 3.42-9.53) for hip fracture and 2.17 (95% CI, 1.75-2.69) for nonspine fracture. The FRAX score was also associated with fracture risk in participants with DM (HRs for 1-unit increase in FRAX hip fracture score, 1.05; 95% CI, 1.03-1.07, for women with DM and 1.16; 95% CI, 1.07-1.27, for men with DM; HRs for 1-unit increase in FRAX osteoporotic fracture score, 1.04; 95% CI, 1.02-1.05, for women with DM and 1.09; 95% CI, 1.04-1.14, for men with DM). However, for a given T score and age or for a given FRAX score, participants with DM had a higher fracture risk than those without DM. For a similar fracture risk, participants with DM had a higher T score than participants without DM. For hip fracture, the estimated mean difference in T score for women was 0.59 (95% CI, 0.31-0.87) and for men was 0.38 (95% CI, 0.09-0.66)., Conclusions: Among older adults with type 2 DM, femoral neck BMD T score and FRAX score were associated with hip and nonspine fracture risk; however, in these patients compared with participants without DM, the fracture risk was higher for a given T score and age or for a given FRAX score.

Context: Fetuin-A is a hepatic secretory protein that binds the insulin receptor and inhibits insulin action in vitro. In prior cross-sectional studies in humans, higher fetuin-A levels were associated with insulin resistance. However, the longitudinal association of fetuin-A with incident type 2 diabetes mellitus is unknown., Objective: To determine whether fetuin-A levels are associated with incident diabetes in older persons., Design, Setting, and Participants: Observational study among 3075 well-functioning persons aged 70 to 79 years. In this case-cohort study, we retrospectively measured fetuin-A levels in baseline serum among 406 randomly selected participants without prevalent diabetes, and all participants who developed incident diabetes mellitus during a 6-year follow-up (to August 31, 2005)., Main Outcome Measure: Incident diabetes mellitus., Results: Incident diabetes developed in 135 participants (10.1 cases/1000 person-years). Participants with fetuin-A levels within the highest tertile (> 0.97 g/L) had an increased risk of incident diabetes (13.3 cases/1000 person-years) compared with participants in the lowest tertile (< or = 0.76 g/L) (6.5 cases/1000 person-years) in models adjusted for age, sex, race, waist circumference, body weight, physical activity, blood pressure level, fasting glucose level, high-density lipoprotein cholesterol concentration, triglyceride concentration, and C-reactive protein level (adjusted hazard ratio, 2.41; 95% confidence interval, 1.28-4.53; P = .007). The association was not affected by adipocytokine levels but was moderately attenuated by adjustment for visceral adiposity (adjusted hazard ratio of highest vs lowest tertile 1.72; 95% confidence interval, 0.98-3.05; P = .06)., Conclusion: Among well-functioning older persons, serum fetuin-A is associated with incident diabetes, independent of other markers of insulin resistance.

Context: Vertebral fractures are the most common osteoporotic fracture. Women with low bone mineral density (BMD) and prevalent vertebral fractures have a greater risk of incident vertebral fractures over the short-term, but their absolute risk of vertebral fracture over the long-term is uncertain., Objective: To examine the absolute risk of incident vertebral fracture by BMD and prevalent vertebral fracture status over 15 years., Design, Setting, and Participants: A total of 9704 white women were recruited at 4 US clinical centers and enrolled in the Study of Osteoporotic Fractures, a longitudinal cohort study. Of these, 2680 attended a clinic visit an average of 14.9 years after baseline; mean age of 68.8 years at entry and 83.8 years at follow-up. Mean Outcome Measure Incident vertebral fractures identified from lateral spinal radiographs defined as a decrease of at least 20% and 4 mm at any vertebral level. Prevalent vertebral fractures were identified on the baseline radiographs using vertebral morphometry. Bone mineral density was measured at the total hip and lumbar spine using dual-energy x-ray absorptiometry., Results: Of the 2680 women, 487 (18.2%) had an incident vertebral fracture including 163 of the 394 (41.4%) with a prevalent vertebral fracture at baseline and 324 of the 2286 (14.2%) without a prevalent vertebral fracture at baseline (odds ratio, 4.21; 95% confidence interval, 3.33-5.34). Low BMD was associated with an increased risk of incident vertebral fracture (odds ratio per 1 SD decrease in total hip BMD, 1.78 [95% confidence interval, 1.58-2.00]). The absolute risk of vertebral fracture ranged from 56% among women with total hip BMD T score of -2.5 or less and a prevalent vertebral fracture to 9% in women with normal BMD and no prevalent vertebral fracture., Conclusions: Low BMD and prevalent vertebral fractures are independently related to new vertebral fractures over 15 years of follow-up. Women with a prevalent vertebral fracture have a substantially increased absolute risk of an incident fracture, especially if they have osteoporosis diagnosed by BMD.

Context: It is widely believed that fractures resulting from high trauma are not osteoporotic; however, this assumption has not been studied prospectively., Objective: To examine the association between bone mineral density (BMD) and high-trauma fracture and between high-trauma fracture and subsequent fracture in older women and men., Design, Setting, and Participants: Two prospective US cohort studies in community-dwelling adults 65 years or older from geographically diverse sites. The Study of Osteoporotic Fractures followed up 8022 women for 9.1 years (1988-2006). The Osteoporotic Fractures in Men Study followed up 5995 men for 5.1 years (2000-2007)., Main Outcome Measures: Hip and spine BMD were assessed by dual-energy x-ray absorptiometry. Incident nonspine fractures were confirmed by radiographic report. Fractures were classified, without knowledge of BMD, as high trauma (due to motor vehicle crashes and falls from greater than standing height) or as low trauma (due to falls from standing height and less severe trauma)., Results: Overall, 264 women and 94 men sustained an initial high-trauma fracture and 3211 women and 346 men sustained an initial low-trauma fracture. For women, each 1-SD reduction in total hip BMD was similarly associated with an increased risk of high-trauma fracture (multivariate relative hazard [RH], 1.45; 95% confidence interval [CI], 1.23-1.72) and low-trauma fracture (RH, 1.49; 95% CI, 1.42-1.57). Results were consistent in men (high-trauma fracture RH, 1.54; 95% CI, 1.20-1.96; low-trauma fracture RH, 1.69; 95% CI, 1.49-1.91). Risk of subsequent fracture was 34% (95% CI, 7%-67%) greater among women with an initial high-trauma fracture and 31% (95% CI, 20%-43%) greater among women with an initial low-trauma fracture, compared with women having no high- or low-trauma fracture, respectively. Risk of subsequent fracture was not modeled for men., Conclusions: Similar to low-trauma nonspine fractures, high-trauma nonspine fractures are associated with low BMD and increased risk of subsequent fracture in older adults. High-trauma nonspine fractures should be included as outcomes in osteoporosis trials and observational studies.

Context: Black women have a lower rate of fracture than white women, but whether bone mineral density (BMD) predicts fracture risk as well in black women as it does in white women is not established., Objective: To examine the association between BMD and incident nonspinal fractures in older black and white women., Design, Setting, and Participants: Prospective cohort study of baseline data collected from 1986 through 1990 (7334 white women aged 67-99 years) and from 1996 through 1998 (636 black women aged 65-94 years) at 4 US clinical centers in the Study of Osteoporotic Fractures; mean (SD) follow-up of 6.1 (1.5) years until October 1, 2004., Main Outcome Measures: Incident nonspinal fractures were confirmed by radiograpic report. Total hip and femoral neck BMD and bone mineral content were measured by dual energy x-ray absorptiometry., Results: A total of 58 black women had a combined total of 61 fractures and 1606 white women had a combined total of 1712 fractures. In age-adjusted proportional hazard models, a 1-SD decrease in femoral neck BMD was associated with a 37% increased risk of fracture in black women (relative risk [RR], 1.37; 95% confidence interval [CI], 1.08-1.74) and a 49% increase in fracture in white women (RR, 1.49; 95% CI, 1.40-1.58). Adjustment for body weight and other risk factors for fracture weakened the association between BMD and fracture, especially among black women (multivariable adjusted RR per 1-SD decrease in femoral neck BMD for black vs white women: RR, 1.20 [95% CI, 0.93-1.55] vs RR, 1.42 [95% CI, 1.32-1.52]). The absolute incidence of fracture across the pooled BMD distribution was 30% to 40% lower among black women at every BMD tertile. The lower risk of fracture among black compared with white women was independent of BMD and other risk factors (RR, 0.48; 95% CI, 0.36-0.64)., Conclusions: Decreased total hip and femoral neck BMD is associated with an increased risk of fracture in both older black and white women, but this relationship was largely explained by other risk factors in black women. Black women have a lower fracture risk than white women at every level of BMD. Race-specific normative databases may be appropriate for the densitometric definition of osteoporosis.

Context: In the Women's Health Initiative trial of estrogen-plus-progestin therapy, women assigned to active treatment had fewer fractures., Objective: To test the hypothesis that the relative risk reduction of estrogen plus progestin on fractures differs according to risk factors for fractures., Design, Setting, and Participants: Randomized controlled trial (September 1993-July 2002) in which 16 608 postmenopausal women aged 50 to 79 years with an intact uterus at baseline were recruited at 40 US clinical centers and followed up for an average of 5.6 years., Intervention: Women were randomly assigned to receive conjugated equine estrogen, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102)., Main Outcome Measures: All confirmed osteoporotic fracture events that occurred from enrollment to discontinuation of the trial (July 7, 2002); bone mineral density (BMD), measured in a subset of women (n = 1024) at baseline and years 1 and 3; and a global index, developed to summarize the balance of risks and benefits to test whether the risk-benefit profile differed across tertiles of fracture risk., Results: Seven hundred thirty-three women (8.6%) in the estrogen-plus-progestin group and 896 women (11.1%) in the placebo group experienced a fracture (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.69-0.83). The effect did not differ in women stratified by age, body mass index, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of hormone therapy, BMD, or summary fracture risk score. Total hip BMD increased 3.7% after 3 years of treatment with estrogen plus progestin compared with 0.14% in the placebo group (P<.001). The HR for the global index was similar across tertiles of the fracture risk scale (lowest fracture risk tertile, HR, 1.20; 95% CI, 0.93-1.58; middle tertile, HR, 1.23; 95% CI, 1.04-1.46; highest tertile, HR, 1.03; 95% CI, 0.88-1.24) (P for interaction =.54)., Conclusions: This study demonstrates that estrogen plus progestin increases BMD and reduces the risk of fracture in healthy postmenopausal women. The decreased risk of fracture attributed to estrogen plus progestin appeared to be present in all subgroups of women examined. When considering the effects of hormone therapy on other important disease outcomes in a global model, there was no net benefit, even in women considered to be at high risk of fracture.

Context: Physical activity has been related to reduced mortality, but it is not clear whether changes in physical activity affect mortality among older women., Objective: To examine the relationship of changes in physical activity and mortality among older women., Design, Setting, and Participants: Prospective cohort study conducted at 4 US research centers (Baltimore, Md; Portland, Ore; Minneapolis, Minn; and Monongahela Valley, Pa) among 9518 community-dwelling white women aged 65 years or older who were assessed at baseline (1986-1988), 7553 of whom were reassessed at a follow-up visit (1992-1994; median, 5.7 years later)., Main Outcome Measures: Walking and other physical activities at baseline and follow-up; vital status, with cause of death confirmed by death certificates/discharge summaries, tracked for up to 12.5 years after baseline (up to 6.7 years after the follow-up visit)., Results: Compared with continually sedentary women, those who increased physical activity levels between baseline and follow-up had lower mortality from all causes (hazard rate ratio [HRR], 0.52; 95% confidence interval [CI], 0.40-0.69), cardiovascular disease (HRR, 0.64; 95% CI, 0.42-0.97), and cancer (HRR, 0.49; 95% CI, 0.29-0.84), independent of age, smoking, body mass index, comorbid conditions, and baseline physical activity level. Associations between changes in physical activity and reduced mortality were similar in women with and without chronic diseases but tended to be weaker among women aged at least 75 years and among those with poor health status. Women who were physically active at both visits also had lower all-cause mortality (HRR, 0.68; 95% CI, 0.56-0.82) and cardiovascular mortality (HRR, 0.62; 95% CI, 0.44-0.88) than sedentary women., Conclusion: Increasing and maintaining physical activity levels could lengthen life for older women but appears to provide less benefit for women aged at least 75 years and those with poor health status.

Objective: To evaluate the relationship of the ankle/arm blood pressure index to short-term mortality in women 65 years of age or older., Design: Prospective cohort study with average follow-up of 4.3 years., Setting: Rural community near Pittsburgh, Pa., Participants: A total of 1492 white women 65 years of age or older, living in the community and ambulatory without the help of another person., Outcome Measures: All-cause and cause-specific mortality., Results: The ankle/arm index (the systolic pressure in the posterior tibial artery divided by that in the brachial artery) was measured in 1986 through 1988 and found to be 0.9 or less in 82 (5.5%) of the women, 67 of whom reported no symptoms of claudication. Comparing women with an index of 0.9 or less with those with an index greater than 0.9, the relative risk for all-cause mortality 4 years later (after adjustment for age, smoking, and other risk factors) was 3.1 (95% confidence interval [Cl], 1.7 to 5.5); for heart disease, 3.7 (95% Cl, 1.2 to 11.6); for cardiovascular diseases, 4.0 (95% Cl, 1.3 to 8.5); for cancer, 3.3 (95% Cl, 1.3 to 8.5); and for all other causes, 1.1 (95% Cl, 0.1 to 9.2). Similar levels of risk were found after excluding women with symptoms of claudication and/or a history of cardiovascular disease at baseline., Conclusions: Healthy, older women with an ankle/arm index of 0.9 or less are at high risk of death and therefore may be considered for aggressive therapy to modify cardiovascular risk factors.

To determine whether measurement of bone density predicts hip fracture in women, we prospectively studied 9703 nonblack women aged 65 years and older who had measurements of bone mineral density using single-photon absorptiometry in the calcaneus, distal radius, and proximal radius. During an average of 1.6 years of follow-up, 53 hip fractures occurred. The risk of hip fracture was inversely related to bone density at all three measurement sites. After adjusting for age, the relative risk of hip fracture was 1.66 for a decrease of 1 SD in the bone density at the calcaneus (95% confidence interval, 1.22 to 2.26), 1.55 (95% confidence interval, 1.13 to 2.11) at the distal radius, and 1.41 (95% confidence interval, 1.06 to 1.88) at the proximal radius. None of the three measurements was a significantly better predictor of hip fracture than the others. After adjusting for bone mineral density, the risk of hip fracture doubled for each 10-year increase in age (relative risk, 2.09; 95% confidence interval, 1.31 to 3.33). We conclude that decreased bone density in the appendicular skeleton is associated with an increased risk of hip fracture, but this accounts for only part of the age-related increase in risk of hip fracture among older women.

To examine the interactions between hormone levels and calcium with cortical bone, we have attempted to combine risk factors for the development of peak skeletal mass with factors that may be related to the maintenance of bone integrity after menopause. A total of 174 postmenopausal women participated in our study. There was little relationship found between androgen hormones and radial bone density. Estrone levels were independently related to radial bone density. Examination of the relationship of calcium intake to bone revealed a protective effect solely in women who reported high "lifetime" calcium intakes. Taking calcium and estrone together revealed an additive relationship between the two factors, in that women with high estrone and high calcium levels had significantly greater bone density than women with less calcium and/or estrone. The results suggest that a lifetime of adequate calcium intake coupled with adequate levels of serum estrogens could maximize bone density after menopause.