Publications by authors named "Jane A Cauley"

644 Publications

After the initial fracture in postmenopausal women, where do subsequent fractures occur?

EClinicalMedicine 2021 May 5;35:100826. Epub 2021 May 5.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States.

Background: The locations of subsequent fractures after initial fracture in postmenopausal women are poorly characterized.

Methods: We conducted a prospective analysis of subsequent fractures after initial fracture in Women's Health Initiative (1993-2018) participants who provided follow-up (mean 15.4 years, SD 6.2 years) data ( = 157,282 participants; baseline age 50-79; 47,458 participants with incident fracture). Cox proportional hazards models were adjusted for age, race/ethnicity, body mass index, and other covariates.

Findings: The risk of each type of subsequent fracture was increased after each type of initial fracture. Incident lower arm/wrist fracture was associated with significantly elevated risks of subsequent fractures at the upper arm/shoulder, upper leg, knee, lower leg/ankle, hip/pelvis, and spine (adjusted hazard ratios [aHRs] ranging 2·63-5·68). The risk of hip fracture was increased after initial lower arm or wrist fracture (aHR 4·80, 95% CI 4·29-5·36), initial upper arm or shoulder fracture (aHR 5·06, 95% CI 4·39-5·82), initial upper leg fracture (aHR 5·11, 95% CI 3·91-6·67), initial knee fracture (aHR 5·03, 95% CI 4·20-6·03), initial lower leg/ankle fracture (aHR 4·10, 95% CI 3·58-4·68), and initial spine fracture (aHR 6·69, 95% CI 5·95-7·53). Associations were significant in all age groups, even women aged 50-59 years. Risks of subsequent fracture were more pronounced among non-Hispanic Black, Hispanic/Latina, and Asian/Pacific Islander than among non-Hispanic White women.

Interpretation: Increased risk of subsequent fracture is observed for all fracture types across all ages. Women who experience any of these fractures should be targeted for interventions to prevent subsequent fractures.

Funding: National Institutes of Health HHSN268201600018C,HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eclinm.2021.100826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176125PMC
May 2021

Associations of accelerometer-determined sedentary behavior and physical activity with physical performance outcomes by race/ethnicity in older women.

Prev Med Rep 2021 Sep 19;23:101408. Epub 2021 May 19.

Division of Research, Kaiser Permanente Northern California, Oakland, CA 94610, United States.

To determine the cross-sectional associations of accelerometer-measured time spent in physical activity intensity categories (sedentary, low and high light intensity, or moderate to vigorous intensity physical activity (MVPA) with physical performance outcomes [stair climb ascent, 40 foot walk test, and short physical performance battery (SPPB)] in older women and examine differences by race/ethnicity. Data were from 1,256 Study of Women's Health Across the Nation (SWAN) participants [aged 64.9 (2.7) years at Visit 15 (2015-16); 54.1% non-White]. Three sets of adjusted multivariable linear or logistic regression models were built to test the study objectives using the backward elimination approach to identify relevant covariates. In the full analytic sample, a 10 min increment in MVPA was related to faster performance on the stair climb [β = -0.023 (95% CI: -0.04, -0.005) seconds] and 40 foot walk test [β = -0.066 (95% CI: -0.133, -0.038) seconds], and a 9% lower odds [OR: 0.91; 95% CI: 0.87, 0.96; p = 0.004] of limitations based on the SPPB. Statistically significant differences by race/ethnicity were found for the stair climb ascent time as MVPA was associated with better performance for White, Chinese, and Japanese participants while high light intensity physical activity, but not MVPA, was deemed beneficial in Black women. Findings from the isotemporal substitution models were consistent. Findings further support the importance of MVPA on physical performance outcomes in older women. Further research is needed to examine the complex associations between physical (in)activity and physical performance outcomes by race/ethnicity to provide more targeted recommendations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pmedr.2021.101408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173313PMC
September 2021

Race/ethnic difference in trabecular bone score in midlife women: The Study of Women's Health Across the Nation (SWAN).

Arch Osteoporos 2021 06 8;16(1):91. Epub 2021 Jun 8.

Department of Medicine, Division of Geriatrics, UCLA, Los Angeles, CA, USA.

There was no difference in Trabecular Bone Score (TBS) comparing White and Black women after adjusting for body mass index (BMI) and diabetes status. Japanese women had lower TBS than White women. Our results diverge from established differences in fracture rates by race/ethnicity.

Introduction: The TBS was developed as an indirect measure of vertebral bone microarchitecture derived from texture analysis of lumbar spine DXA scans. There is little information on race/ethnic differences in TBS.

Methods: We compared TBS in 656 White, 492 Black, and 268 Japanese pre- and early perimenopausal women. We used a beta version of TBS that accounts for tissue thickness using DXA measured soft tissue thickness rather than BMI. The relation between BMI and tissue thickness corrected TBS differed by BMI; we used a three-segment linear spline to adjust for BMI.

Results: The women were, on average, 46.5 years of age; 50% were premenopausal. In BMI and diabetes adjusted models, there was no difference in TBS between White and Black women. TBS was modestly (2%) lower in the Japanese women compared to White women, p = 0.04. In a sensitivity analysis, restricting the analysis to those with BMI 24-31 kg/m, results were similar.

Conclusions: TBS was similar in Black and White women after accounting for tissue thickness and adjusting for BMI, diabetes, and other covariates. The Japanese women had modestly lower TBS. These results diverge from established race/ethnic differences in fracture rates and areal bone mineral density, underscoring the need for further studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11657-021-00951-4DOI Listing
June 2021

Risk of Subsequent Fractures in Postmenopausal Women After Nontraumatic vs Traumatic Fractures.

JAMA Intern Med 2021 Jun 7. Epub 2021 Jun 7.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamainternmed.2021.2617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185628PMC
June 2021

Body Weight, BMI, Percent Fat and Associations with Mortality and Incident Mobility Limitation in Older Men.

Geriatrics (Basel) 2021 May 18;6(2). Epub 2021 May 18.

Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN 55454, USA.

How different measures of adiposity are similarly or differentially related to mobility limitation and mortality is not clear. In total, 5849 community-dwelling men aged ≥65 years (mean age: 72 years) were followed mortality over 10 years and self-reported mobility limitations (any difficulty walking 2-3 blocks or with climbing 10 steps) at six contacts over 14 years. Baseline measures of adiposity included weight, BMI and percent fat by DXA. Appendicular lean mass (ALM, by DXA) was analyzed as ALM/ht2. Proportional hazards models estimated the risk of mortality, and repeated measures generalized estimating equations estimated the likelihood of mobility limitation. Over 10 years, 27.9% of men died; over 14 years, 48.0% of men reported at least one mobility limitation. We observed U-shaped relationships between weight, BMI, percent fat and ALM/ht2 with mortality. There was a clear log-linear relationship between weight, BMI and percent fat with incident mobility limitation, with higher values associated with a greater likelihood of mobility limitation. In contrast, there was a U-shaped relationship between ALM/ht2 and incident mobility limitation. These observational data suggest that no single measure of adiposity or body composition reflects both the lowest risk of mortality and the lowest likelihood for developing mobility limitation in older men.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/geriatrics6020053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162350PMC
May 2021

Nutritional epidemiology and the Women's Health Initiative: a review.

Am J Clin Nutr 2021 05;113(5):1083-1092

Lundquist Institute for Innovative Biomedical Research at Harbor-UCLA Medical Center, Torrance, CA, USA.

The dietary modification (DM) clinical trial, within the Women's Health Initiative (WHI), studied a low-fat dietary pattern intervention that included guidance to increase vegetables, fruit, and grains. This study was motivated in part from uncertainty about the reliability of observational studies examining the association between dietary fat and chronic disease risk by using self-reported dietary data. In addition to this large trial, which had breast and colorectal cancer as its primary outcomes, a substantial biomarker research effort was initiated midway in the WHI program to contribute to nutritional epidemiology research more broadly. Here we review and update findings from the DM trial and from the WHI nutritional biomarker studies and examine implications for future nutritional epidemiology research. The WHI included the randomized controlled DM trial (n = 48,835) and a prospective cohort observational (OS) study (n = 93,676), both among postmenopausal US women, aged 50-79 y when enrolled during 1993-1998. Also reviewed is a nutrition and physical activity assessment study in a subset of 450 OS participants (2007-2009) and a related controlled feeding study among 153 WHI participants (2010-2014). Long-term follow-up in the DM trial provides evidence for intervention-related reductions in breast cancer mortality, diabetes requiring insulin, and coronary artery disease in the subset of normotensive healthy women, without observed adverse effects or changes in all-cause mortality. Studies of intake biomarkers, and of biomarker-calibrated intake, suggest important associations of total energy intake and macronutrient dietary composition with the risk for major chronic diseases among postmenopausal women. Collectively these studies argue for a nutrition epidemiology research agenda that includes major efforts in nutritional biomarker development, and in the application of biomarkers combined with self-reported dietary data in disease association analyses. We expect such efforts to yield novel disease association findings and to inform disease prevention approaches for potential testing in dietary intervention trials. This trial was registered at clinicaltrials.gov as NCT00000611.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcn/nqab091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120331PMC
May 2021

Increase in C-Reactive Protein Predicts Increase in Rate of Bone Mineral Density Loss: The Study of Women's Health Across the Nation.

JBMR Plus 2021 Apr 16;5(4):e10480. Epub 2021 Mar 16.

Department of Medicine, Division of Geriatrics University of California, Los Angeles (UCLA) Los Angeles CA USA.

This longitudinal cohort study's aim was to detect whether larger increases in C-reactive protein (CRP) predict greater amounts of subsequent bone loss in women transitioning from premenopause to postmenopause. Participants were initially 42 to 52 years of age and premenopausal or early perimenopausal. The sample included 1431 women who were not using hormone therapy and whose CRP values were not consistent with acute inflammation. Individual fixed effects (IFE) models estimated the association of log CRP with subsequent bone mineral density (BMD) decline rate, adjusted for menopause transition (MT) stage (1: premenopausal or early perimenopausal; 2: late perimenopausal or early postmenopausal; or 3: late postmenopausal), body mass index, diabetes, smoking, alcohol, bone active medications, and anti-inflammatory medications. BMD decline at both the lumbar spine (LS) and femoral neck (FN) was faster for observations made in MT stage 2 than that during other stages (all  < .001). In adjusted IFE models, MT stage modified the relation between increase in CRP and BMD decline rate (interaction values <.05). Each within-woman doubling of CRP was associated with a 0.09% faster yearly decline in FN BMD in MT stages 1 ( = .006) and 3 ( = .03), and 0.10% faster decline in LS BMD in MT stage 3 only ( = .007). Within-woman increases in CRP in premenopause and early perimenopause and in late postmenopause predict faster BMD decline in the next ~2 years, but the magnitude of CRP's effect is small. © 2021 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbm4.10480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046126PMC
April 2021

Sarcopenia Definitions as Predictors of Fracture Risk Independent of FRAX , Falls, and BMD in the Osteoporotic Fractures in Men (MrOS) Study: A Meta-Analysis.

J Bone Miner Res 2021 Jul 8;36(7):1235-1244. Epub 2021 Apr 8.

Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield, UK.

Dual-energy X-ray absorptiometry (DXA)-derived appendicular lean mass/height (ALM/ht ) is the most commonly used estimate of muscle mass in the assessment of sarcopenia, but its predictive value for fracture is substantially attenuated by femoral neck (fn) bone mineral density (BMD). We investigated predictive value of 11 sarcopenia definitions for incident fracture, independent of fnBMD, fracture risk assessment tool (FRAX ) probability, and prior falls, using an extension of Poisson regression in US, Sweden, and Hong Kong Osteoporois Fractures in Men Study (MrOS) cohorts. Definitions tested were those of Baumgartner and Delmonico (ALM/ht only), Morley, the International Working Group on Sarcopenia, European Working Group on Sarcopenia in Older People (EWGSOP1 and 2), Asian Working Group on Sarcopenia, Foundation for the National Institutes of Health (FNIH) 1 and 2 (using ALM/body mass index [BMI], incorporating muscle strength and/or physical performance measures plus ALM/ht ), and Sarcopenia Definitions and Outcomes Consortium (gait speed and grip strength). Associations were adjusted for age and time since baseline and reported as hazard ratio (HR) for first incident fracture, here major osteoporotic fracture (MOF; clinical vertebral, hip, distal forearm, proximal humerus). Further analyses adjusted additionally for FRAX-MOF probability (n = 7531; calculated ± fnBMD), prior falls (y/n), or fnBMD T-score. Results were synthesized by meta-analysis. In 5660 men in USA, 2764 Sweden and 1987 Hong Kong (mean ages 73.5, 75.4, and 72.4 years, respectively), sarcopenia prevalence ranged from 0.5% to 35%. Sarcopenia status, by all definitions except those of FNIH, was associated with incident MOF (HR = 1.39 to 2.07). Associations were robust to adjustment for prior falls or FRAX probability (without fnBMD); adjustment for fnBMD T-score attenuated associations. EWGSOP2 severe sarcopenia (incorporating chair stand time, gait speed, and grip strength plus ALM) was most predictive, albeit at low prevalence, and appeared only modestly influenced by inclusion of fnBMD. In conclusion, the predictive value for fracture of sarcopenia definitions based on ALM is reduced by adjustment for fnBMD but strengthened by additional inclusion of physical performance measures. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.4293DOI Listing
July 2021

Endogenous Progestogens and Colorectal Cancer Risk among Postmenopausal Women.

Cancer Epidemiol Biomarkers Prev 2021 Jun 7;30(6):1100-1105. Epub 2021 Apr 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

Background: The role of progestogens in colorectal cancer development is poorly characterized. To address this, our group developed a highly sensitive assay to measure concentrations of seven markers of endogenous progestogen metabolism among postmenopausal women.

Methods: The markers were measured in baseline serum collected from postmenopausal women in a case-cohort study within the breast and bone follow-up to the fracture intervention trial (B∼FIT). We followed women not using exogenous hormones at baseline (1992-1993) for up to 12 years: 187 women with incident colorectal cancer diagnosed during follow-up and a subcohort of 495 women selected on strata of age and clinical center. We used adjusted Cox regression models with robust variance to estimate risk for colorectal cancer [hazard ratios (HR), 95% confidence intervals (CI)].

Results: High concentrations of pregnenolone and progesterone were not associated with colorectal cancer [quintile(Q)5 versus Q1: pregnenolone HR, 0.71, 95% CI, 0.40-1.25; progesterone HR, 1.25; 95% CI, 0.71-2.22]. A trend of increasing risk was suggested, but statistically imprecise across quintiles of 17-hydroxypregnenolone (Q2 to Q5 HRs, 0.75-1.44; , 0.06).

Conclusions: We used sensitive and reliable assays to measure multiple circulating markers of progestogen metabolism. Progestogens were generally unassociated with colorectal cancer risk in postmenopausal women.

Impact: Our findings are consistent with most prior research on circulating endogenous sex hormones, which taken together suggest that sex hormones may not be major drivers of colorectal carcinogenesis in postmenopausal women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-20-1568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172440PMC
June 2021

Association between 25-Hydroxyvitamin D and Metabolic Syndrome in Older Adults: The Health, Aging and Body Composition Study.

Int J Endocrinol 2021 13;2021:6671823. Epub 2021 Mar 13.

For the Health ABC Study, Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Objective: Low 25-hydroxyvitamin D (25[OH]D) levels and metabolic syndrome (MetS) are prevalent among older adults; however, longitudinal studies examining 25(OH)D status and MetS are lacking. We explore the association of 25(OH)D levels with prevalent and incident MetS in white and black older adults. . A total of 1620 white and 1016 black participants aged 70-79 years from the Health ABC cohort with measured 25(OH)D levels and data on MetS and covariates of interest were examined. The association between 25(OH)D levels and prevalent MetS at baseline and incident MetS at 6-year follow-up was examined in whites and blacks separately using logistic regression adjusting for demographics, lifestyle factors, and renal function.

Results: At baseline, 635 (39%) white and 363 (36%) black participants had prevalent MetS. In whites, low 25(OH)D levels were associated with prevalent MetS (adjusted OR (95% CI), 1.85 (1.47, 2.34)) and 1.96 (1.46, 2.63) for 25(OH)D of 20-<30 and <20 vs. ≥30 ng/ml, respectively). The association was attenuated after adjustment for BMI but remained significant. No association was found between 25(OH)D levels and prevalent MetS in blacks. Among those without MetS at baseline (765 whites, 427 blacks), 150 (20%) whites and 87 (20%) blacks had developed MetS at 6-year follow-up. However, 25(OH)D levels were not associated with incident MetS in whites or blacks.

Conclusion: In older adults, low 25(OH)D levels were associated with increased odds of prevalent MetS in whites but not in blacks. No association was observed between 25(OH)D levels and incident MetS in either whites or blacks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2021/6671823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981173PMC
March 2021

Urinary Phthalate Biomarkers and Bone Mineral Density in Postmenopausal Women.

J Clin Endocrinol Metab 2021 Jun;106(7):e2567-e2579

Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, USA.

Context: Phthalates are endocrine-disrupting chemicals that could disrupt normal physiologic function, triggering detrimental impacts on bone.

Objective: We evaluated associations between urinary phthalate biomarkers and BMD in postmenopausal women participating in the prospective Women's Health Initiative (WHI).

Methods: We included WHI participants enrolled in the BMD substudy and selected for a nested case-control study of phthalates and breast cancer (N = 1255). We measured 13 phthalate biomarkers and creatinine in 2 to 3 urine samples per participant collected over 3 years, when all participants were cancer free. Total hip and femoral neck BMD were measured at baseline and year 3, concurrent with urine collection, via dual-energy x-ray absorptiometry. We fit multivariable generalized estimating equation models and linear mixed-effects models to estimate cross-sectional and longitudinal associations, respectively, with stratification on postmenopausal hormone therapy (HT) use.

Results: In cross-sectional analyses, mono-3-carboxypropyl phthalate and the sum of di-isobutyl phthalate metabolites were inversely associated with total hip BMD among HT nonusers, but not among HT users. Longitudinal analyses showed greater declines in total hip BMD among HT nonusers and with highest concentrations of mono-3-carboxyoctyl phthalate (-1.80%; 95% CI, -2.81% to -0.78%) or monocarboxynonyl phthalate (-1.84%; 95% CI, -2.80% to -0.89%); similar associations were observed with femoral neck BMD. Among HT users, phthalate biomarkers were not associated with total hip or femoral neck BMD change.

Conclusion: Certain phthalate biomarkers are associated with greater percentage decreases in total hip and femoral neck BMD. These findings suggest that phthalate exposure may have clinically important effects on BMD, and potentially fracture risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgab189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266434PMC
June 2021

Associations between longitudinal trajectories of insomnia symptoms and sleep duration with objective physical function in postmenopausal women: the Study of Women's Health Across the Nation.

Sleep 2021 Mar 11. Epub 2021 Mar 11.

Division of Research, Kaiser Permanente Northern California.

Study Objectives: Examine the association between trajectories of self-reported insomnia symptoms and sleep duration over 13 years with objective physical function.

Methods: We utilized data from 1627 Study of Women's Health Across the Nation (SWAN) participants, aged 61.9±2.7 y at the end of the 13-y follow-up. Latent class growth models identified trajectories of insomnia symptoms (trouble falling asleep, frequent night-time awakenings, and/or early-morning awakening) and sleep duration over 13 y. Physical function tests were performed at the end of the 13-y period: 40-ft walk, 4-m walk, repeated chair stand, grip strength, and balance. Multivariable regression analyses examined each physical function measure according to the insomnia symptom or sleep duration trajectory group.

Results: Five insomnia symptom trajectories and two sleep duration trajectories were identified. Women with a consistently high likelihood of insomnia symptoms and women with a decreased likelihood of insomnia symptoms (i.e., improving) had slower gait speed (3.5% slower 40-ft walk [consistently high], 3.7% slower 4-m walk [improving]; each P≤.05) than those with a consistently low likelihood of insomnia symptoms. In contrast, women with a steep increase in the likelihood of insomnia symptoms over time and women with persistent insufficient sleep duration had lower odds of having a balance problem (odds ratio [OR]=0.36 and OR=0.61, respectively; each P<.02) compared to those with a consistently low likelihood of insomnia symptoms and those with persistent sufficient sleep duration, respectively.

Conclusion: These results suggest that women's sleep during midlife has important implications for maintaining physical function during the transition into older adulthood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/sleep/zsab059DOI Listing
March 2021

Effect of dietary protein intake on bone mineral density and fracture incidence in older adults in the Health, Aging, and Body Composition study.

J Gerontol A Biol Sci Med Sci 2021 Mar 3. Epub 2021 Mar 3.

Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC.

Background: Dietary recommendations may underestimate the protein older adults need for optimal bone health. This study sought to determine associations of protein intake with bone mineral density (BMD) and fracture among community-dwelling white and black older adults.

Methods: Protein as a percentage of total energy intake (TEI) was assessed with a food frequency questionnaire in 2,160 older adults (73.5±2.8 years; 51.5% women; 35.8% black) in the Health, Aging, and Body Composition prospective cohort. Hip, femoral neck, and whole body BMD was assessed by dual-energy x-ray absorptiometry at baseline and 4 years, and lumbar trabecular, cortical, and integral BMD was assessed by computed tomography at baseline and 5 years. Fragility fractures over 5 years were adjudicated from self-report data collected every 6 months. Associations with tertiles of protein intake were assessed using analysis of covariance for BMD and multivariate Cox regression for fracture, adjusting for confounders.

Results: Participants in the upper protein tertile (≥15% TEI) had 1.8-6.0% higher mean hip and lumbar spine BMD compared to the lower protein tertile (<13% TEI; p<0.05). Protein intake did not affect change in BMD at any site over the follow-up period. Participants in the upper protein tertile had a reduced risk of clinical vertebral fracture over five years of follow-up (Hazard Ratio: 0.36 [95% Confidence Intervals (CI), 0.14, 0.97] vs. lower protein tertile, p=0.04).

Conclusions: Older adults with higher protein intake (≥15% TEI) had higher BMD at the hip, whole body, and lumbar spine, and a lower risk of vertebral fracture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/glab068DOI Listing
March 2021

Bone age is not just for kids.

Elife 2021 Mar 2;10. Epub 2021 Mar 2.

Endocrine Research Unit, San Francisco Department of Veterans Affairs Medical Center, Department of Medicine, University of California, San Francisco, San Francisco, United States.

More informed discussions between physicians and older adults about the consequences of an initial osteoporotic fracture could encourage more patients to consider treatments that protect against future fracture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.66916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924936PMC
March 2021

Gut microbiome pattern reflects healthy ageing and predicts survival in humans.

Nat Metab 2021 02 18;3(2):274-286. Epub 2021 Feb 18.

Institute for Systems Biology, Seattle, WA, USA.

The gut microbiome has important effects on human health, yet its importance in human ageing remains unclear. In the present study, we demonstrate that, starting in mid-to-late adulthood, gut microbiomes become increasingly unique to individuals with age. We leverage three independent cohorts comprising over 9,000 individuals and find that compositional uniqueness is strongly associated with microbially produced amino acid derivatives circulating in the bloodstream. In older age (over ~80 years), healthy individuals show continued microbial drift towards a unique compositional state, whereas this drift is absent in less healthy individuals. The identified microbiome pattern of healthy ageing is characterized by a depletion of core genera found across most humans, primarily Bacteroides. Retaining a high Bacteroides dominance into older age, or having a low gut microbiome uniqueness measure, predicts decreased survival in a 4-year follow-up. Our analysis identifies increasing compositional uniqueness of the gut microbiome as a component of healthy ageing, which is characterized by distinct microbial metabolic outputs in the blood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42255-021-00348-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169080PMC
February 2021

Height Loss in Old Age and Fracture Risk Among Men in Late Life: A Prospective Cohort Study.

J Bone Miner Res 2021 Jun 19;36(6):1069-1076. Epub 2021 Mar 19.

Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.

To assess the association of height loss in old age with subsequent risk of hip and any clinical fracture in men late in life while accounting for the competing risk of mortality, we used data from 3491 community-dwelling men (mean age 79.2 years). Height loss between baseline and follow-up (mean 7.0 years between examinations) was categorized as <1 cm (referent group), ≥1 to <2 cm, ≥2 to <3 cm, and ≥3 cm. Men were contacted every 4 months after the follow-up examination to ask about fractures (confirmed by radiographic reports) and ascertain vital status (deaths verified by death certificates). Competing risk methods were used to estimate absolute probabilities of fracture outcomes by height loss category and calculate adjusted risks of fracture outcomes by height loss. During an average of 7.8 years, 158 (4.5%) men experienced a hip fracture and 1414 (40.5%) died before experiencing this event. The absolute 10-year probability of fracture events accounting for the competing risk of death increased with greater height loss. For example, the hip fracture probability was 2.7% (95% confidence interval [CI] 1.9-3.8%) among men with height loss <1 cm increasing to 11.6% (95% CI 8.0-16.0%) among men with height loss ≥3 cm. After adjustment for demographics, fall history, multimorbidity, baseline height, weight change, and femoral neck bone mineral density and considering competing mortality risk, men with height loss ≥3 cm versus <1 cm had a nearly twofold (subdistribution hazard ratio [HR] = 1.94, 95% CI 1.06-3.55) higher risk of hip fracture and a 1.4-fold (subdistribution HR = 1.42, 95% CI 1.05-1.91) increased risk of any clinical fracture. Height loss ≥3 cm in men during old age was associated with higher subsequent risk of clinical fractures, especially hip fractures, even after accounting for the competing risk of death and traditional skeletal and non-skeletal risk factors. © 2021 American Society for Bone and Mineral Research (ASBMR).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.4278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255268PMC
June 2021

Response to "Red Cell Distribution Width Is a Risk Factor for Hip Fracture in Elderly Men Without Anemia".

J Bone Miner Res 2021 Jun 28;36(6):1203. Epub 2021 Jan 28.

San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.4242DOI Listing
June 2021

Validation of Perceived Mental Fatigability Using the Pittsburgh Fatigability Scale.

J Am Geriatr Soc 2021 May 20;69(5):1343-1348. Epub 2021 Jan 20.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Objectives: Establish reliability, concurrent and convergent validity of the Pittsburgh Fatigability Scale (PFS) Mental subscale.

Design: Cross-sectional.

Setting: Older adults from two University of Pittsburgh registries, Baltimore Longitudinal Study of Aging (BLSA), and Long Life Family Study (LLFS).

Participants: PFS Mental subscale validation was conducted using three cohorts: (1) Development Sample (N = 664, 59.1% women, age 74.8 ± 6.4 years, PFS Mental scores 10.3 ± 9.1), (2) Validation Sample I-BLSA (N = 430, 51.9% women, age 74.5 ± 8.2 years, PFS Mental scores 9.4 ± 7.9), and (3) Validation Sample II-LLFS (N = 1,917, 54.5% women, age 72.2 ± 9.3 years, PFS Mental scores 7.5 ± 8.2).

Measurements: Development Sample, Validation Sample I-BLSA, and Validation Sample II-LLFS participants self-administered the 10-item Pittsburgh Fatigability Scale. Validation Sample II-LLFS completed cognition measures (Trail Making Tests A and B), depressive symptomatology (Center for Epidemiologic Studies-Depression Scale, CES-D), and global fatigue from two CES-D items.

Results: In the Development Sample and Validation Sample I-BLSA, confirmatory factor analysis showed all 10 items loaded on two factors: social and physical activities (fit indices: SRMSR = 0.064, RMSEA = 0.095, CFI = 0.91). PFS Mental scores had strong internal consistency (Cronbach's α = 0.85) and good test-retest reliability (ICC = 0.78). Validation Sample II-LLFS PFS Mental scores demonstrated moderate concurrent and construct validity using Pearson (r) or Spearman (ρ) correlations against measures of cognition (Trail Making Tests A (r = 0.14) and B (r = 0.17) time), depressive symptoms (r = 0.31), and global fatigue (ρ = 0.21). Additionally, the PFS Mental subscale had strong convergent validity, discriminating according to established clinical or cognitive testing cut points, with differences in PFS Mental scores ranging from 3.9 to 7.6 points (all P < .001). All analyses were adjusted for family relatedness, field center, age, sex, and education.

Conclusions: The validated PFS Mental subscale may be used in clinical and research settings as a sensitive, one-page self-administered tool of perceived mental fatigability in older adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgs.17017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127403PMC
May 2021

Higher Fatigue Prospectively Increases the Risk of Falls in Older Men.

Innov Aging 2021 27;5(1):igaa061. Epub 2020 Nov 27.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pennsylvania, US.

Background And Objectives: Fatigue is a common complaint and shares many risk factors with falls, yet the independent contribution of fatigue on fall risk is unclear. This study's primary aim was to assess the association between fatigue and prospective fall risk in 5642 men aged 64-100 enrolled in the Osteoporotic Fractures in Men Study (MrOS). The secondary aim was to examine the association between fatigue and recurrent fall risk.

Research Design And Methods: Fatigue was measured at baseline using the Medical Outcomes Study (short form) single-item question "During the past four weeks, how much of the time did you feel energetic?" Responses were then classified: higher fatigue = "none," "a little," or "some" of the time and lower fatigue = "a good bit," "most," or "all" of the time. We assessed falls using triannual questionnaires. Fall risk was examined prospectively over 3 years; recurrent falling was defined as at least 2 falls within the first year. Generalized estimating equations and multinomial logistic regression modeled prospective and recurrent fall risk as a function of baseline fatigue status, adjusted for demographics, medications, physical activity, and gait speed.

Results: Men with higher (26%) versus lower baseline fatigue were older (75.1 ± 6.2 vs 73.2 ± 5.7 years), 24% less active, and had worse physical function (gait speed = 1.09 ± 0.24 vs 1.24 ± 0.21 m/s), all < .0001. Within 1 year, 25.4% ( = 1409) had fallen at least once, of which 47.4% ( = 668) were recurrent fallers. Men with higher versus lower fatigue had 25% increased fall risk (relative risk = 1.25, 95% CI: 1.14-1.36) over 3 years follow-up, but had 50% increased odds of recurrent falling (odds ratio = 1.50, 95% CI: 1.22-1.85) within the first year.

Discussion And Implications: Fatigue is an important risk factor of falling independent of established risk factors. Reductions in fatigue (ie, increased energy) may lessen the burden of falls in older men and provide a novel avenue for fall risk intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/geroni/igaa061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788315PMC
November 2020

Jump power, leg press power, leg strength and grip strength differentially associated with physical performance: The Developmental Epidemiologic Cohort Study (DECOS).

Exp Gerontol 2021 03 24;145:111172. Epub 2020 Nov 24.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Background: Weight-bearing jump tests that measure lower-extremity muscle power may be more strongly related to physical performance measures vs. non-weight-bearing leg press power, leg press strength and grip strength. We investigated if multiple muscle function measures differentially related to standard physical performance measures.

Materials/methods: In the Developmental Epidemiologic Cohort Study (DECOS; N = 68; age 78.5 ± 5.5 years; 57% women; 7% minorities), muscle function measures included power in Watts/kg (functional, weight-bearing: jump; mechanical: Nottingham power rig; Keiser pneumatic leg press) and strength in kg/kg body weight (Keiser pneumatic leg press; hand-held dynamometry). Physical performance outcomes included 6 m usual gait speed (m/s), usual-paced 400 m walk time (seconds), and 5-repeated chair stands speed (stands/s).

Results: Women (N = 31; 79.8 ± 5.0 years) had lower muscle function and slower gait speed compared to men (N = 25; 78.7 ± 6.6 years), though similar 400 m walk time and chair stands speed. In partial Pearson correlations adjusted for age, sex, race and height, muscle function measures were moderately to strongly correlated with each other (all p < 0.05), though the individual correlations varied. In multiple regression analyses, each muscle function measure was statistically associated with all physical performance outcomes in models adjusted for age, sex, race, height, self-reported diabetes, self-reported peripheral vascular disease and self-reported pain in legs/feet (all p < 0.05). Jump power (β = 0.75) and grip strength (β = 0.71) had higher magnitudes of association with faster gait speed than lower-extremity power and strength measures (β range: 0.32 to 0.58). Jump power (β = 0.56) had a slightly lower magnitude of association with faster 400 m walk time vs. Keiser power (β = 0.61), and a higher magnitude of association vs. Nottingham power, Keiser strength and grip strength (β range: 0.41 to 0.47). Jump power (β = 0.38) had a lower magnitude of association with chair stands speed than any other power or strength measures (β range: 0.50 to 0.65).

Conclusions: Jump power/kg and grip strength/kg may be more strongly related to faster gait speed, a standard measure of physical function and vital sign related to disability and mortality in older adults, compared to leg press power/strength. However, jump power/kg had a similar magnitude of association with 400 m walk time as Keiser power/kg and a lower magnitude of association with faster chair stands speed than the other muscle function measures. Importantly, choice of muscle function measures should carefully reflect the study focus and methodologic considerations, including population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exger.2020.111172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855418PMC
March 2021

Clinically Important Differences for Mobility Measures Derived from the Testosterone Trials.

J Am Geriatr Soc 2021 Feb 18;69(2):517-523. Epub 2020 Nov 18.

Section of Geriatric Medicine, Yale School of Medicine, New Haven, Connecticut, USA.

Background/objectives: Accurate estimates of clinically important difference (CID) are required for interpreting the clinical importance of treatments to improve physical function, but CID estimates vary in different disease populations. We determined the CID for two common measures of walking ability in mobility-limited older men.

Design: Longitudinal, multisite placebo-controlled trial.

Setting/participants: Men enrolled in the Testosterone Trials who had self-reported mobility limitation and gait speed less than 1.2 m/second (n = 429). Testosterone- and placebo-allocated participants were combined for this study.

Results: Mean changes from baseline, adjusting for time-in-intervention and site, were 29.6, 13.2, 12.5, -2.4, and -32.6 m for 6MWD, and 15.4, 7.2, 2.1, -3.4, and -7.2 for PF10 in men who reported their mobility was "very/much better," "little better," "no change," "little worse," or "much worse," respectively. CID estimates using regression, ROC, and eCDF varied from 5.0-29.6 m for 6MWD, and 5.0-15.2 points for PF10.

Conclusion: CID estimates vary by the population studied and by the method and precision of measurement. Increases of 16 to 30 m for 6MWD and 5 to 15 points for PF10 over 12 months appear to be clinically meaningful in mobility-limited, older hypogonadal men. These CID estimates may be useful in the design of efficacy trials of therapies to improve physical function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgs.16942DOI Listing
February 2021

Relationships Between Level and Change in Sarcopenia and Other Body Composition Components and Adverse Health Outcomes: Findings from the Health, Aging, and Body Composition Study.

Calcif Tissue Int 2021 03 15;108(3):302-313. Epub 2020 Nov 15.

MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.

We investigated how baseline values and rates of decline in components of sarcopenia and other body composition parameters relate to adverse clinical outcomes using the Health, Aging, and Body Composition Study. 2689 participants aged 70-79 years were studied. Appendicular lean mass, whole body fat mass, and total hip BMD were ascertained using DXA; muscle strength by grip dynamometry; and muscle function by gait speed. Baseline values and 2-3 year conditional changes (independent of baseline) in each characteristic were examined as predictors of mortality, hospital admission, low trauma fracture, and recurrent falls in the subsequent 10-14 years using Cox regression (generalized estimating equations used for recurrent falls) with adjustment for sex, ethnicity, age, and potential confounders. Lower levels and greater declines in all parameters (excluding hip BMD level) were associated (p < 0.05) with increased rates of mortality; fully-adjusted hazard ratios per SD lower gait speed and grip strength were 1.27 (95% CI 1.19, 1.36) and 1.14 (1.07, 1.21), respectively. Risk factors of hospital admission included lower levels and greater declines in gait speed and grip strength, and greater declines in hip BMD. Lower levels and greater declines in fat mass and hip BMD were associated with low trauma fracture. Lower gait speed, higher fat mass, and both lower levels and greater declines in grip strength were related to recurrent falls. Lower baseline levels and greater declines in musculoskeletal parameters were related to adverse outcomes. Interventions to maximize peak levels in earlier life and reduce rates of age-related decline may reduce the burden of disease in this age group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00223-020-00775-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881954PMC
March 2021

Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Antiresorptive Drugs: Proportion of Treatment Effect Explained.

J Bone Miner Res 2021 Feb 2;36(2):236-243. Epub 2020 Oct 2.

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.

Few analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction seeking to estimate the proportion of treatment effect explained (PTE) by BTMs. Pooling such information would be useful to assess new ARs or novel dosing regimens. In the Foundation for the National Institutes of Health (FNIH) Bone Quality project, we analyzed individual-level data from up to 62,000 participants enrolled in 12 bisphosphonate (BP) and four selective estrogen receptor modulator (SERM) placebo-controlled fracture endpoint trials. Using BTM results for two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and pro-collagen I N-propeptide [PINP]) and one bone resorption marker (C-terminal telopeptide of type I collagen [CTX]) and incident fracture outcome data, we estimated the PTE using two different models. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 5 years of follow-up. For vertebral fracture, the results showed that changes in all three BTMs at 6 months explained a large proportion of the treatment effect of ARs (57 to >100%), but not for and non-vertebral or hip fracture. We conclude that short-term AR treatment-related changes in bone ALP, PINP, and CTX account for a large proportion of the treatment effect for vertebral fracture. Change in BTMs is a useful surrogate marker to study the anti-fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.4178DOI Listing
February 2021

Association Between Variation in Red Cell Size and Multiple Aging-Related Outcomes.

J Gerontol A Biol Sci Med Sci 2021 Jun;76(7):1288-1294

San Francisco Coordinating Center, California.

Background: We tested whether greater variation in red blood cell size, measured by red cell distribution width (RDW), may predict aging-related degenerative conditions and therefore, serve as a marker of biological aging.

Methods: Three thousand six hundred and thirty-five community-dwelling older men were enrolled in the prospective Osteoporotic Fractures in Men Study. RDW was categorized into 4 groups (≤13.0%, 13.1%-14.0%, 14.1%-15.0%, and ≥15.1%). Functional limitations, frailty, strength, physical performance, and cognitive function were measured at baseline and 7.4 years later. Falls were recorded in the year after baseline; hospitalizations were obtained for 2 years after baseline. Mortality was assessed during a mean of 8.3 years of follow-up.

Results: Participants with greater variability in red cell size were weaker, walked more slowly, and had a worse cognitive function. They were more likely to have functional limitations (35.2% in the highest RDW category vs 16.0% in the lowest, p < .001) and frailty (30.3% vs 11.3%, p < .001). Those with greater variability in red cell size were more likely to develop new functional limitations and to become frail. The risk of having 2 or more falls was also greater (highest 19.2% vs lowest 10.3%, p < .001). The risk of hospitalization was higher in those with the highest variability (odds ratio [95% confidence interval], 1.8 [1.3-2.5]) compared with the lowest. Variability in red cell size was related to total and cause-specific mortality.

Conclusion: Greater variability in red cell size is associated with diverse aging-related outcomes, suggesting that it may have potential value as a marker for biological aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/glaa217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202142PMC
June 2021

Premenopausal and early postmenopausal trabecular bone score (TBS) and fracture risk: Study of Women's Health Across the Nation (SWAN).

Bone 2020 11 27;140:115543. Epub 2020 Jul 27.

Department of Medicine, Division of Geriatrics, UCLA, Los Angeles, CA, 10945 Le Conte Ave, Suite 2339, Los Angeles, CA 90095, United States of America. Electronic address:

Background: Evidence that trabecular bone score (TBS), an index of bone microstructure, is a risk factor for future fracture comes mainly from studies of late postmenopausal women.

Objective: To discern whether premenopausal TBS or early postmenopausal TBS predict fracture.

Design: A 22-year, prospective analysis from the Study of Women's Health Across Nation.

Setting: Community-based cohort.

Participants: 272 Black, 174 Japanese, and 364 White women.

Main Outcome Measures: Incident fractures: 292 in premenopausal sample and 141 in early postmenopausal sample.

Results: Separate Cox proportional hazard regressions modeled time to incident fracture as a function of TBS measured during premenopause or early postmenopause. Models were initially adjusted for age, race/ethnicity, SWAN clinical site, body mass index, use of calcium, vitamin D, bone beneficial or bone adverse medication. Next, we added lumbar spine (LS) or femoral neck (FN) bone mineral density (BMD) and, finally, history of prior fracture, to the models. For each standard deviation decrement in premenopausal TBS, fracture hazard was elevated by 17% (relative hazard [RH] 1.17 [95% CI, 1.02-1.35]); after adjusting for LS or FN BMD, the relation between premenopausal TBS and fracture was no longer statistically significant. There was a similar-magnitude, marginally statistically significant, association between early postmenopausal TBS and fracture, unadjusted for BMD (RH 1.15 [0.95-1.39]).

Conclusions: Variation in premenopausal TBS is related to fracture risk, but this association is not independent of BMD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2020.115543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526344PMC
November 2020

Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials.

JAMA 2020 07;324(4):369-380

Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, Washington.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2020.9482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388026PMC
July 2020

Treatment-related changes in bone mineral density as a surrogate biomarker for fracture risk reduction: meta-regression analyses of individual patient data from multiple randomised controlled trials.

Lancet Diabetes Endocrinol 2020 08;8(8):672-682

Center for Advanced Orthopedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.

Background: The validation of bone mineral density (BMD) as a surrogate outcome for fracture would allow the size of future randomised controlled osteoporosis registration trials to be reduced. We aimed to determine the association between treatment-related changes in BMD, assessed by dual-energy x-ray absorptiometry, and fracture outcomes, including the proportion of treatment effect explained by BMD changes.

Methods: We did a pooled analysis of individual patient data from multiple randomised placebo-controlled clinical trials. We included data from multicentre, randomised, placebo-controlled, double-blind trials of osteoporosis medications that included women and men at increased osteoporotic fracture risk. Using individual patient data for each trial we calculated mean 24-month BMD percent change together with fracture reductions and did a meta-regression of the association between treatment-related differences in BMD changes (percentage difference, active minus placebo) and fracture risk reduction. We also used individual patient data to determine the proportion of anti-fracture treatment effect explained by BMD changes and the BMD change needed in future trials to ensure fracture reduction efficacy.

Findings: Individual patient data from 91 779 participants of 23 randomised, placebo-controlled trials were included. The trials had 1-9 years of follow-up and included 12 trials of bisphosphonate, one of odanacatib, two of hormone therapy (one of conjugated equine oestrogen and one of conjugated equine oestrogen plus medroxyprogesterone acetate), three of PTH receptor agonists, one of denosumab, and four of selective oestrogen receptor modulator trials. The meta-regression revealed significant associations between treatment-related changes in hip, femoral neck, and spine BMD and reductions in vertebral (r 0·73, p<0·0001; 0·59, p=0·0005; 0·61, p=0·0003), hip (0·41, p=0·014; 0·41, p=0·0074; 0·34, p=0·023) and non-vertebral fractures (0·53, p=0·0021; 0·65, p<0·0001; 0·51, p=0·0019). Minimum 24-month percentage changes in total hip BMD providing almost certain fracture reductions in future trials ranged from 1·42% to 3·18%, depending on fracture site. Hip BMD changes explained substantial proportions (44-67%) of treatment-related fracture risk reduction.

Interpretation: Treatment-related BMD changes are strongly associated with fracture reductions across randomised trials of osteoporosis therapies with differing mechanisms of action. These analyses support BMD as a surrogate outcome for fracture outcomes in future randomised trials of new osteoporosis therapies and provide an important demonstration of the value of public access to individual patient data from multiple trials.

Funding: Foundation for National Institutes of Health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-8587(20)30159-5DOI Listing
August 2020

Effect of Abaloparatide on Bone Mineral Density and Fracture Incidence in a Subset of Younger Postmenopausal Women with Osteoporosis at High Risk for Fracture.

Clin Ther 2020 06 6;42(6):1099-1107.e1. Epub 2020 Jun 6.

School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

Purpose: Current treatment guidelines recommend treatment for postmenopausal women with a T score <2.5 regardless of age. This subgroup analysis evaluated the efficacy and safety of abaloparatide in younger postmenopausal women considered to be at high risk for fracture.

Methods: Subgroup analysis of women in the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial who were <65 years old and met modified utilization management criteria (baseline T score ≤-2.5 [any site] and ≥1 prevalent vertebral and/or ≥1 prior clinical fracture within 5 years of randomization).

Findings: A total of 296 women (age range, 49-64 years) were included. Significant increases in bone mineral density from baseline were observed for abaloparatide versus placebo at all 3 sites at 6 months (p < 0.01 for total hip and femoral neck; p < 0.0001 for lumbar spine), 12 months (p < 0.0001 at all 3 sites), and 18 months (p < 0.0001 at all 3 sites). Fracture rates were numerically lower for abaloparatide versus placebo, consistent with the overall trial results, although the differences were not statistically significant. The number needed to treat to prevent 1 additional vertebral fracture after 18 months of treatment versus placebo was 18 for abaloparatide and 21 for teriparatide. The number needed to treat had nonsignificant trends toward lower values with abaloparatide versus teriparatide for nonvertebral fractures (23 vs 40) and clinical fractures (16 vs 73) and similar for major osteoporotic fractures (24 vs 27). The safety profile was consistent with the overall ACTIVE population.

Implications: Findings of this subgroup (post hoc) analysis are consistent with the overall ACTIVE population. Abaloparatide appears to be effective and well tolerated in this subgroup of younger postmenopausal women. ClinicalTrials.gov identifier: NCT01343004.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinthera.2020.04.012DOI Listing
June 2020